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This study aimed to identify factors associated with a strong home blood pressure (BP)-lowering effect of esaxerenone and the incidence of elevated serum potassium levels in hypertensive patients treated with esaxerenone. A pooled analysis of five multicenter, prospective, open-label single-arm studies was conducted, including 479 patients in the full analysis set (FAS) and 492 patients in the safety analysis set. Multivariate linear regression analysis of morning home systolic BP (SBP) and diastolic BP (DBP) changes from baseline to Week 12 in the FAS (primary endpoint) showed that male sex (estimated change 4.37 mmHg), office pulse rate ≥100 beats/min (25.10 mmHg), and calcium channel blocker (CCB) use as a basal antihypertensive agent (4.53 mmHg) were significantly associated with a positive estimated change (weaker BP-lowering effect) in morning home SBP. CCB use (3.70 mmHg) was associated with a positive estimated change in morning home DBP. Urine albumin-to-creatinine ratio 30 to <300 mg/gCr (-4.13 mmHg) was significantly associated with a negative estimated change (stronger BP-lowering effect) in morning home SBP. Based on multivariate logistic regression analysis, elevated baseline serum potassium level (≥4.5 vs < 4.5 mEq/L, odds ratio 13.502) was significantly associated with a high incidence of serum potassium level ≥5.5 mEq/L after esaxerenone treatment. In conclusion, factors associated with a strong BP-lowering effect of esaxerenone were female sex and use of renin-angiotensin system inhibitors as a basal antihypertensive drug. Patients with baseline serum potassium levels ≥4.5 mEq/L had an increased risk of developing elevated serum potassium levels (≥5.5 mEq/L) after esaxerenone treatment.

DOI： 10.1038/s41440-024-01818-0

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BACKGROUND: Magnesium deficiency is associated with various health conditions, but its impact on the progression of chronic kidney disease (CKD) remains unclear. This study aimed to investigate the association between serum magnesium levels and prognosis of renal function in CKD patients. METHODS: This is an analysis of the Japan Chronic Kidney Disease Database Ex (J-CKD-DB-Ex), which is a multicenter prospective cohort including CKD patients enrolled from January 1, 2014 to December 31, 2020. We included adult outpatients with CKD stage G3 and G4 at the time of initial magnesium measurement. Patients were classified by magnesium levels as low (<1.7 mg/dl), normal (1.7-2.6 mg/dl), or high (>2.6 mg/dl). The primary outcomes were the composite of an eGFR < 15 ml/min/1.73 m2 or a ≥30% reduction in eGFR from the initial measurement, which was defined as CKD progression. We applied the Kaplan-Meier analysis and Cox regression hazard model to examine the association between magnesium levels and CKD progression. RESULTS: The analysis included 9868 outpatients during the follow-up period. The low magnesium group was significantly more likely to reach CKD progression. Cox regression, adjusting for covariates and using the normal magnesium group as the reference, showed that the hazard ratio for the low magnesium group was 1.20 (1.08-1.34). High magnesium was not significantly associated with poor renal outcomes compared with normal magnesium. CONCLUSION: Based on large real-world data, this study demonstrated that low magnesium levels are associated with poorer renal outcomes.

DOI： 10.1007/s10157-024-02486-7

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Cronkhite-Canada syndrome (CCS) is a non-hereditary disorder characterized by non-neoplastic hamartomatous gastrointestinal polyposis, hair loss, nail atrophy, hyperpigmentation, and diarrhea. While the relationship between CCS and nephritis remains unclear, seven cases of nephritis complicated by CCS have been reported to date, all of which were membranous nephropathy (MN). A 57-year-old man presented with taste disturbance, hair loss, nail plate atrophy, skin pigmentation, and frequent diarrhea. Endoscopic findings showed multiple polyposis of the stomach and large intestine. Given the above, he was diagnosed with CCS. The symptoms gradually improved with prednisolone treatment, although urinary protein and hypoproteinemia appeared during the tapering of prednisolone. He was diagnosed with MN using a renal biopsy, and immunofluorescence microscopy with IgG subclass staining showed predominantly diffuse granular capillary wall staining of IgG4. The cause of secondary MN was not found, including malignant tumors. Nephrotic-range proteinuria persisted despite treatment with prednisolone and cyclosporine. Additional treatment with mizoribine resulted in incomplete remission type 1 of nephrotic syndrome, suggesting that mizoribine may be a treatment option for patients with CCS with steroid-resistant MN. Considering a high prevalence of hypoproteinemia due to chronic diarrhea and protein-losing enteropathy in patients with CCS, proteinuria might be overlooked; thus, follow-up urinalysis would be recommended in patients with CCS.

DOI： 10.1007/s13730-024-00908-9

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AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors often cause a transient decrease in glomerular filtration rate (GFR) shortly after the initiation, referred to as the 'initial drop'. However, the clinical significance of this initial drop in real-world practice remains unclear. MATERIALS AND METHODS: Using the nationwide Japan Chronic Kidney Disease Database, we examined factors that affected the initial drop, in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We also evaluated the effects of the initial drop on a composite kidney outcome (a decline in GFR of ≥50% or progression to end-stage kidney disease). RESULTS: Data from 2053 patients with CKD and T2DM newly prescribed an SGLT2 inhibitor were analysed. The follow-up period after SGLT2 inhibitor administration was 1015 days (interquartile range: 532, 1678). Multivariate linear regression models revealed that the concomitant use of the renin-angiotensin system inhibitors and diuretics, urinary protein levels ≥2+, and changes in GFR before the initiation of the SGLT2 inhibitor were associated with a larger initial GFR decline (β = -0.609, p = .039; β = -2.298, p < .001; β = -0.936, p = .048; β = -0.079, p < .001, respectively). Patients in the quartile with the largest initial GFR decline experienced a higher incidence of the subsequent composite kidney outcome than those in the other quartiles (p < .001). CONCLUSIONS: The concomitant use of renin-angiotensin system inhibitors and diuretics, higher urine protein levels and pre-treatment GFR changes were associated with a larger initial GFR decline. Of these factors, the use of a diuretic had the largest effect. Furthermore, patients with CKD and T2DM experiencing an excessive initial GFR drop might be at a higher risk of adverse kidney outcomes.

DOI： 10.1111/dom.15611

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Diabetic nephropathy remains the leading cause of end-stage kidney disease in many countries, and additional therapeutic targets are needed to prevent its development and progression. Some angiogenic factors are involved in the pathogenesis of diabetic nephropathy. Vasohibin-2 (VASH2) is a novel proangiogenic factor, and our previous study showed that glomerular damage is inhibited in diabetic Vash2 homozygous knockout mice. Therefore, we established a VASH2-targeting peptide vaccine as a tool for anti-VASH2 therapy in diabetic nephropathy. In this study, the preventive effects of the VASH2-targeting peptide vaccine against glomerular injury were examined in a streptozotocin (STZ)-induced diabetic mouse model. The mice were subcutaneously injected with the vaccine at two doses 2 wk apart and then intraperitoneally injected with 50 mg/kg STZ for 5 consecutive days. Glomerular injury was evaluated 20 wk after the first vaccination. Treatment with the VASH2-targeting peptide vaccine successfully induced circulating anti-VASH2 antibody without inflammation in major organs. Although the vaccination did not affect blood glucose levels, it significantly prevented hyperglycemia-induced increases in urinary albumin excretion and glomerular volume. The vaccination did not affect increased VASH2 expression but significantly inhibited renal angiopoietin-2 (Angpt2) expression in the diabetic mice. Furthermore, it significantly prevented glomerular macrophage infiltration. The preventive effects of vaccination on glomerular injury were also confirmed in db/db mice. Taken together, the results of this study suggest that the VASH2-targeting peptide vaccine may prevent diabetic glomerular injury in mice by inhibiting Angpt2-mediated microinflammation.NEW & NOTEWORTHY This study demonstrated preventive effects of VASH2-targeting peptide vaccine therapy on albuminuria and glomerular microinflammation in STZ-induced diabetic mouse model by inhibiting renal Angpt2 expression. The vaccination was also effective in db/db mice. The results highlight the importance of VASH2 in the pathogenesis of early-stage diabetic nephropathy and the practicability of anti-VASH2 strategy as a vaccine therapy.

DOI： 10.1152/ajprenal.00341.2023

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BACKGROUND: EMPA-KIDNEY assessed the effects of empagliflozin 10 mg once daily vs. placebo in 6609 patients with chronic kidney disease (CKD) at risk of progression, including 612 participants from Japan. METHODS: Eligibility required an estimated glomerular filtration rate (eGFR) of ≥ 20 < 45; or ≥ 45 < 90 ml/min/1.73m2 with a urinary albumin-to-creatinine ratio (uACR) of ≥ 200 mg/g. The primary outcome was a composite of kidney disease progression (end-stage kidney disease, a sustained eGFR decline to < 10 ml/min/1.73m2 or ≥ 40% from randomization, or renal death) or cardiovascular death. In post-hoc analyses, we explored the effects of empagliflozin in participants from Japan vs. non-Japan regions, including additional models assessing whether differences in treatment effects between these regions could result from differences in baseline characteristics. RESULTS: Japanese participants had higher levels of albuminuria and eGFR than those from non-Japan regions. During a median of 2.0 year follow-up, a primary outcome occurred in 432 patients (13.1%) in the empagliflozin group and in 558 patients (16.9%) in the placebo group (hazard ratio [HR], 0.72, 95% confidence interval [95%CI] 0.64-0.82; P < 0.0001). Among the participants from non-Japan regions, there were 399 vs. 494 primary outcomes (0.75, 0.66-0.86), and 33 vs. 64 (0.49, 0.32-0.75; heterogeneity p = 0.06) in Japan. Results were similar when models explicitly considered treatment interactions with diabetes status, categories of eGFR/uACR, and recruitment in Japan (heterogeneity p = 0.08). Safety outcomes were broadly comparable between the two groups, and by Japanese status. CONCLUSIONS: Empagliflozin safely reduced the risk of "kidney disease progression or cardiovascular death" in patients with CKD, with consistent effects in participants from Japan.

DOI： 10.1007/s10157-024-02489-4

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INTRODUCTION: ACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1-7) causing vasodilatation by acting on the Mas receptor. In diabetic kidney disease (DKD), it is still unclear whether plasma or urine ACE2 levels predict renal outcomes or not. RESEARCH DESIGN AND METHODS: Among 777 participants with diabetes enrolled in the Urinary biomarker for Continuous And Rapid progression of diabetic nEphropathy study, the 296 patients followed up for 9 years were investigated. Plasma and urinary ACE2 levels were measured by the ELISA. The primary end point was a composite of a decrease of estimated glomerular filtration rate (eGFR) by at least 30% from baseline or initiation of hemodialysis or peritoneal dialysis. The secondary end points were a 30% increase or a 30% decrease in albumin-to-creatinine ratio from baseline to 1 year. RESULTS: The cumulative incidence of the renal composite outcome was significantly higher in group 1 with lowest tertile of plasma ACE2 (p=0.040). Group 2 with middle and highest tertile was associated with better renal outcomes in the crude Cox regression model adjusted by age and sex (HR 0.56, 95% CI 0.31 to 0.99, p=0.047). Plasma ACE2 levels demonstrated a significant association with 30% decrease in ACR (OR 1.46, 95% CI 1.044 to 2.035, p=0.027) after adjusting for age, sex, systolic blood pressure, hemoglobin A1c, and eGFR. CONCLUSIONS: Higher baseline plasma ACE2 levels in DKD were protective for development and progression of albuminuria and associated with fewer renal end points, suggesting plasma ACE2 may be used as a prognosis marker of DKD. TRIAL REGISTRATION NUMBER: UMIN000011525.

DOI： 10.1136/bmjdrc-2024-004237

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DOI： 10.1210/clinem/dgae359

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Understanding the association between compliance to the Chronic Kidney Disease (CKD) guidelines in real-world clinical settings and renal outcomes remains a critical gap in knowledge. A comprehensive analysis was conducted using data from a national, multicenter CKD registry. This study included 4,455 patients with an estimated glomerular filtration rate (eGFR) measurement on the index date and eight additional metrics recorded within six months. These metrics comprised serum electrolyte levels, low-density lipoprotein cholesterol, hemoglobin, and the use of renin-angiotensin system inhibitors. The primary outcome was a composite of renal events, defined by a decline in eGFR to < 15 mL/min/1.73 m2 or a reduction of ≥ 30% in eGFR, confirmed by follow-up tests. Over a median follow-up of 513 days, 838 renal events were observed. High serum potassium levels (> 5.4 mmol/L) were associated with increased event rates compared to lower levels. Similarly, low serum sodium-chloride levels (< 33) correlated with higher event rates. Usage of renin-angiotensin system inhibitors, low serum calcium (< 8.4 mg/dL), and high uric acid levels (> 7.0 mg/dL) were also linked to increased events. Conversely, higher hemoglobin levels (≥ 13 g/dL) were associated with lower event rates. Compliance to guidelines, categorized into quartiles based on the number of met metrics, revealed a significantly reduced risk of events in the highest compliance group (meeting 8 metrics) compared to the lowest (0-5 metrics). Compliance to CKD guidelines in clinical practice is significantly associated with improved renal outcomes, emphasizing the need for guideline-concordant care in the management of CKD.

DOI： 10.1038/s41598-024-62152-6

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AIMS/INTRODUCTION: Insulin resistance syndrome and lipoatrophic diabetes are rare conditions characterized by the development of treatment-refractory diabetes with severe insulin resistance. We recently conducted a 24 week, multicenter, single-arm trial (EMPIRE-01) that demonstrated a certain level of effectiveness and safety of empagliflozin for these conditions. To evaluate treatment safety over a longer period, we have now performed an additional 28 week trial (EMPIRE-02) that followed on from EMPIRE-01. MATERIALS AND METHODS: The primary and secondary outcomes were safety and efficacy evaluations, respectively. All eight subjects of the EMPIRE-01 trial participated in EMPIRE-02. RESULTS: Twenty adverse events (AEs) were recorded among five individuals during the combined 52 week treatment period of both trials. Whereas one case of chronic hepatitis B was moderate in severity, all other AEs were mild. There were thus no serious AEs or events necessitating discontinuation or suspension of treatment or a reduction in drug dose. Whereas ketoacidosis or marked increases in serum ketone body levels were not observed, the mean body mass of the subjects was decreased slightly after completion of EMPIRE-02. The improvement in mean values of glycemic parameters observed in EMPIRE-01 was not sustained in EMPIRE-02, mostly because of one individual whose parameters deteriorated markedly, likely as a result of nonadherence to diet therapy. The improvement in glycemic parameters was sustained during EMPIRE-02 after exclusion of this subject from analysis. CONCLUSIONS: Empagliflozin demonstrated a certain level of safety and efficacy for the treatment of insulin resistance syndrome and lipoatrophic diabetes over 52 weeks, confirming its potential as a therapeutic option.

DOI： 10.1111/jdi.14226

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The beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on kidney function are well-known; however, their molecular mechanisms are not fully understood. We focused on 78-kDa glucose-regulated protein (GRP78) and its interaction with SGLT2 and integrin-β1 beyond the chaperone property of GRP78. In streptozotocin (STZ)-induced diabetic mouse kidneys, GRP78, SGLT2, and integrin-β1 increased in the plasma membrane fraction, while they were suppressed by canagliflozin. The altered subcellular localization of GRP78/integrin-β1 in STZ mice promoted epithelial mesenchymal transition (EMT) and fibrosis, which were mitigated by canagliflozin. High-glucose conditions reduced intracellular GRP78, increased its secretion, and caused EMT-like changes in cultured HK2 cells, which were again inhibited by canagliflozin. Urinary GRP78 increased in STZ mice, and in vitro experiments with recombinant GRP78 suggested that inflammation spread to surrounding tubular cells and that canagliflozin reversed this effect. Under normal glucose culture, canagliflozin maintained sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA) activity, promoted ER robustness, reduced ER stress response impairment, and protected proximal tubular cells. In conclusion, canagliflozin restored subcellular localization of GRP78, SGLT2, and integrin-β1 and inhibited EMT and fibrosis in DKD. In nondiabetic chronic kidney disease, canagliflozin promoted ER robustness by maintaining SERCA activity and preventing ER stress response failure, and it contributed to tubular protection.

DOI： 10.2337/db23-0581

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AIM: To evaluate whether sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy is associated with a reduction of renal events compared with other glucose-lowering drugs (oGLDs) among Japanese people with type 2 diabetes (T2D) and grade 3 (G3) chronic kidney disease (CKD) in a real-world clinical practice setting. MATERIALS AND METHODS: People with T2D who were newly prescribed an SGLT2i or an oGLD from April 2014 to November 2021 (without prior use of index drugs for ≥ 1 year prior to index date) and G3 CKD (estimated glomerular filtration rate [eGFR] ≥ 30 to < 60 mL/min/1.73 m2) were selected from the Medical Data Vision database (MDV-DB) and the Real-World Data database (RWD-DB). SGLT2i and oGLD users were matched (1:1) using propensity score on patient background characteristics. The primary endpoint was a composite of the development of end-stage kidney disease or a sustained decline in eGFR of 50% or more. Hazard ratios (HRs) were estimated using the Cox proportional hazards model. RESULTS: Overall, 3190 (1595 per group) patients in the MDV-DB and 2572 (1286 per group) patients in the RWD-DB were included in the analyses. The composite outcome was significantly lower in the SGLT2i group than in the oGLD group in the MDV-DB (HR 0.49, 95% confidence interval [CI] 0.33 to 0.74, P < 0.001) and in the RWD-DB (HR 0.57, 95% CI 0.37 to 0.88, P = 0.011). CONCLUSIONS: Japanese people with T2D and G3 CKD initiating an SGLT2i had a lower risk of renal events than people initiating an oGLD.

DOI： 10.1111/dom.15461

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A 68-year-old woman was admitted to our hospital because of a rapid progression of renal dysfunction with positive myeloperoxidase antineutrophil cytoplasmic antibody and was diagnosed with rapidly progressive glomerulonephritis associated with microscopic polyangiitis (MPA). Severe right rectus sheath hematoma (RSH) bleeding from the inferior epigastric artery developed after starting hemodialysis, which required 4 transarterial embolizations due to recurrent bleeding. After additional treatment with methylprednisolone pulse therapy and rituximab, no rebleeding occurred. Although the giant hematoma reached the pelvis, it shrank spontaneously without any intervention. Nontraumatic RSH should therefore be considered when treating patients with multiple risk factors.

DOI： 10.2169/internalmedicine.3239-23

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DOI： 10.2169/internalmedicine.3050-23

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The global pandemic of coronavirus infection 2019 (COVID-19) was an unprecedented public health emergency. Several clinical studies reported that heart disease, lung disease, diabetes, hypertension, dyslipidemia, and obesity are critical risk factors for increased severity of and hospitalization for COVID-19. This is largely because patients with these underlying medical conditions can show poor immune responses to the COVID-19 vaccinations. Diabetes is one of the underlying conditions most highly associated with COVID-19 susceptibility and is considered a predictor of poor prognosis of COVID-19. We therefore investigated factors that influence the anti-SARS-CoV-2 spike IgG antibody titer after three doses of vaccination in patients with type 2 diabetes. We found that obesity was associated with low anti-SARS-CoV-2 spike IgG antibody titers following three-dose vaccination in type 2 diabetics. Obese patients with type 2 diabetes may have attenuated vaccine efficacy and require additional vaccination; continuous infection control should be considered in such patients.

DOI： 10.18926/AMO/66927

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DOI： 10.1093/ndt/gfae078

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BACKGROUND: Nail-patella syndrome (NPS) is a rare autosomal dominant disorder that is characterized by dysplasia of the nails, hypoplasia and/or dislocation of the patella and the presence of iliac horns. Using the CARE guidelines, we present the first reported case of NPS that was newly diagnosed at the onset of rheumatoid arthritis (RA). CASE PRESENTATION: A 74-year-old man was admitted to our hospital due to an 8-month history of arthralgia in bilateral wrists, elbows and fingers. He had a past history of glaucoma and left patella dislocation that had been operatively recentered at the age of 15 years. Laboratory data showed elevated levels of serum C-reactive protein and rheumatoid factor and an elevated titer of anti-SS-A antibodies, while estimated glomerular filtration rate (eGFR), titers of other antibodies and the results of a urinary test were normal. An X-ray showed deformity of bilateral radial heads and the right elbow, and magnetic resonance imaging (MRI) of his hands showed synovitis and erosion in the multiple swollen joints of the wrists and fingers. In addition to these typical features of RA, he had bilateral thumb nail dysplasia with mild hypoplasia of bilateral patellae and iliac horns as shown by the X-ray. He was diagnosed as having autosomal dominant disorder NPS co-existing with RA and he was treated with methotrexate in combination with an oral Janus kinase (JAK) inhibitor, leading to induction of remission. CONCLUSIONS: We have presented a rare case of NPS that was newly diagnosed at the onset of RA. Clinical and radiographic findings of NPS are highlighted in this case report for diagnosing NPS on the basis of typical manifestations.

DOI： 10.1186/s12891-024-07242-2

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INTRODUCTION: Insulin resistance syndrome and lipoatrophic diabetes are characterized by severe insulin resistance and are often refractory to treatment. Trials assessing the efficacy of antidiabetes drugs for these rare conditions have been limited, however. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which lower glycemia independently of insulin action, have shown efficacy for type 2 diabetes with insulin resistance. We here investigated the efficacy and safety of the SGLT2 inhibitor empagliflozin for treatment of insulin resistance syndrome and lipoatrophic diabetes. METHODS: The trial was conducted at five academic centers in Japan and included seven patients with insulin resistance syndrome and one patient with lipoatrophic diabetes. Participants received 10 mg of empagliflozin daily. If the hemoglobin A1c (HbA1c) level was ≥ 7.0% (52 mmol/mol) after 12 weeks, the dose was adjusted to 25 mg. The study duration was 24 weeks, and the primary outcome was the change in HbA1c level by the end of the treatment period. Safety evaluations were performed for all participants. RESULTS: By the end of the 24-week treatment period, the mean HbA1c level for all eight patients had decreased by 0.99 percentage points (10.8 mmol/mol) (95% confidence interval [CI], 0.59 to 1.38 percentage points, 6.6 to 14.9 mmol/mol) and the mean fasting plasma glucose concentration had declined by 63.9 mg/dL (3.55 mmol/L) (95% CI 25.5 to 102.3 mg/dL, 1.42 to 5.68 mmol/L). Continuous glucose monitoring revealed a reduction in mean glucose levels from 164.3 ± 76.1 to 137.6 ± 46.6 mg/dL (9.13 ± 4.23 to 7.65 ± 2.59 mmol/L) as well as an increase in the time in range (70-180 mg/dL) from 58.9 ± 36.1% to 70.8 ± 18.3%. Seventeen mild adverse events were recorded in five individuals throughout the study period. No severe events were reported. The mean body mass showed a slight decrease and the mean serum ketone body concentration showed a slight increase during treatment. CONCLUSION: Our results demonstrate that empagliflozin shows a certain level of efficacy and safety for treatment of insulin resistance syndrome and lipoatrophic diabetes. TRIAL REGISTRATION: jRCTs2051190029 and NCT04018365.

DOI： 10.1007/s13300-023-01526-x

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Fabry disease (FD) is an X-linked disorder resulting in a deficiency of α-galactosidase A (GLA) activity. The R112H mutation of GLA is relatively common in Japanese FD patients, characterized by a late-onset phenotype, almost normal to mild lyso-Gb3 elevation, and mild clinical symptoms, despite low GLA activity. This is due to the structural features of the R112H GLA protein. We herein report the case of a 42-year-old male patient with late-onset FD with a R112H mutation. The patient exhibited only renal involvement with no other organ damage and was successfully treated with galactosidase beta and subsequent migalastat for approximately 10 years. Especially, migalastat was clinically effective in normalizing plasma lyso-Gb3 levels and inhibiting the progression of renal damage associated with FD. Therefore, the use of migalastat in the FD patients with R112H mutation is highly recommended based on this case report.

DOI： 10.3389/fmed.2024.1383309

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BACKGROUND: Inhibition of glucose influx into proximal tubular cells (PTCs) by sodium-glucose co-transporter 2 (SGLT2) inhibitors revealed prominent therapeutic impacts on diabetic kidney disease (DKD). Collectrin (CLTRN) serves as a chaperone for the trafficking of neutral amino acid transporters in the apical membranes of proximal tubular cells. We investigated the beneficial effects of reduced influx of amino acids into proximal tubular cells in diabetes and obesity model of Cltrn-/y mice. METHODS: Cltrn+/y and Cltrn-/y mice at 5 weeks of age were assigned to standard diet- (STD) and streptozotocin and high fat diet-treated (STZ-HFD) groups. RESULTS: At 22-23 weeks of age, body weight and HbA1c levels significantly increased in STZ-HFD-Cltrn+/y compared to STD-Cltrn+/y; however, they were not altered in STZ-HFD-Cltrn-/y compared to STZ-HFD-Cltrn+/y. At 20 weeks of age, urinary albumin creatinine ratio (UACR) was significantly reduced in STZ-HFD-Cltrn-/y compared to STZ-HFD-Cltrn+/y. Under the treatments with STZ and HFD, the Cltrn gene deficiency caused significant increase in urinary concentration of amino acids such as Gln, His, Gly, Thr, Tyr, Val, Trp, Phe, Ile, Leu and Pro. In proximal tubular cells in STZ-HFD-Cltrn+/y, the enlarged lysosomes with diameter of 10 μm or more were associated with reduced autolysosomes, and the formation of giant lysosomes was prominently suppressed in STZ-HFD-Cltrn-/y. Phospho-mTOR and inactive form of phospho-TFEB were reduced in STZ-HFD-Cltrn-/y compared to STZ-HFD-Cltrn+/y. CONCLUSIONS: The reduction of amino acids influx into proximal tubular cells inactivated mTOR, activated TFEB, improved lysosome function, and ameliorated vacuolar formation of PTCs in STZ-HFD-Cltrn-/y mice.

DOI： 10.34067/KID.0000000000000333

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RATIONALE & OBJECTIVE: Assessment of kidney biopsies provides crucial information for diagnosis and disease activity, as well as prognostic value. Kidney-biopsy specimens occasionally contain veno-muscular complex (VMC), which consists of muscle tissues around the kidney venous system in the corticomedullary region. However, the role of VMC and the clinical significance of VMC variants are poorly understood. In the present study, we investigated kidney prognostic values of VMC variants. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Among 808 patients who underwent a kidney biopsy from 2011 to 2019, 246 patients whose kidney biopsy specimens contained VMC were enrolled. PREDICTORS: VMC variants; inflammatory-VMC (an infiltration of ≥80 inflammatory cells/mm2-VMC area) and VMC hypertrophy (hyper-VMC, a VMC average width ≥850 μm), and the interstitial fibrosis/tubular atrophy (IFTA) score. OUTCOMES: A decline in estimated glomerular filtration rate (eGFR) ≥40% from the baseline or commencement of kidney replacement therapy. ANALYTICAL APPROACH: Cox proportional hazards model. RESULTS: Among 246 patients with data on VMC, mean baseline eGFR was 56.0±25.6 ml/min per 1.73 m2; 80 had high inflammatory-VMC, and 62 had VMC hypertrophy. There were 51 kidney events over median follow-up of 2.5 years. We analyzed 2 VMC variants. Multivariable logistic regression analysis revealed that eGFR negatively correlated with the presence of both inflammatory-VMC and hyper-VMC. A Cox proportional hazards analysis revealed that inflammatory-VMC (but not hyper-VMC) was independently associated with the primary outcome after adjustments for known risk factors of progression, including proteinuria, eGFR, and the interstitial fibrosis/tubular atrophy (IFTA) score (hazard ratio, 1.97; 95% confidence interval, 1.00-3.91). LIMITATIONS: Single-center study and small sample size. CONCLUSIONS: Assessment of inflammatory-VMC provides additional kidney prognostic information to known indicators of kidney disease progression in patients who undergo kidney biopsy. PLAIN-LANGUAGE SUMMARY: Assessment of kidney biopsies provides crucial information for diagnosis, disease activity, and prognostic value. Kidney-biopsy specimens occasionally contain veno-muscular complex (VMC), which consists of muscle tissues around the kidney venous system. Currently, the role of VMC in kidney health and diseases and the clinical significance of VMC variants are poorly understood. In the present study, we have shown that an infiltration of ≥80 inflammatory cells/mm2-VMC area (inflammatory-VMC) is independently associated with kidney disease progression after adjustments for known risk factors of progression. Therefore, assessment of inflammatory-VMC provides additional kidney prognostic information to known indicators of kidney disease progression in patients who undergo kidney biopsy.

DOI： 10.1016/j.xkme.2023.100733

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Peritoneal fibrosis (PF) is a primary reason for discontinuing peritoneal dialysis, which involves characteristic changes of peritoneal mesothelial cells (PMCs). We previously reported preventive effects of implanting human epithelial-like PMCs (P-Epi) for mouse PF caused by mechanical peritoneum scrapings. In the present study, we analysed the preventive effects of culture supernatant of P-Epi in PF. Concentrated culture supernatant of P-Epi or human fibroblast-like PMCs (P-Fibro) or vehicles was injected into nude mice that had undergone mechanical scraping of the parietal and visceral peritoneum, and thickness and amount of adhesions were analysed. Although increased peritoneal adhesions and peritoneum thickening were observed in the vehicle-injected positive control group compared to the sham operation group, fewer number of adhesions and less thickness were observed in the mice treated with culture supernatant of P-Epi, but not P-Fibro, compared to the vehicle-injected positive controls. Immunofluorescent analysis revealed that the expression of extracellular matrix, type I collagen and fibronectin, was lower in the mice treated with culture supernatant of P-Epi than in the vehicle-injected positive controls. In addition, exosomes from P-Epi significantly reduced transforming growth factor-β (TGF-β)-induced expressions of type I collagen and fibronectin in 3T3 fibroblast cells. Collectively, culture supernatant of P-Epi has preventive effects on PF, thus cell therapy is not necessarily required. Further exploration of substances secreted by P-Epi and their protective mechanisms could lead to the development of therapeutic strategies to limit PF.

DOI： 10.1177/08968608231213577

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BACKGROUND: Abdominal aortic aneurysm (AAA) is an arterial disease characterized by dilatation of the aortic wall. It has been suggested that neutrophil counts and neutrophil elastase activity are associated with AAA. We investigated whether a neutrophil elastase (NE) inhibitor, sivelestat (Siv), had a protective effect against angiotensin II (AngII)-induced AAAs. METHODS: Male apolipoprotein E-deficient mice were assigned into 3 groups: Vehicle+saline, AngII+saline, and AngII+Siv. All mice were administered intraperitoneally with either Siv or vehicle twice daily after AngII infusion. RESULTS: In the 4-week AngII infusion study, plasma NE concentration (p=0.041) and its activity (p=0.011) were elevated by AngII. These increases were attenuated by Siv (concentration:p=0.010, activity:p=0.027). Further, plasma elastase activity was closely correlated with aortic width (R=0.6976, p<0.001). In the 1-week AngII infusion study, plasma and tissue elastase activity increased by AngII (plasma:p=0.034, tissue:p<0.001), but were reduced by Siv (plasma:p=0.014, tissue:p=0.024). AngII increased aortic width (p=0.011) but was attenuated by co-administration of Siv (p=0.022). Moreover, Siv decreased the incidence of AAAs (p=0.009). Elastin fragmentation induced by AngII was reduced by Siv. Many inflammatory cells that were either CD68 or Gr-1 positive were observed in the AngII+saline group, whereas few inflammatory cells were accumulated in the AngII+Siv group. MMP-2 and MMP-9 were enhanced by AngII, but were reduced by Siv. In vitro, MMP-2 activity was induced by human NE (medium:p<0.001, cells:p=0.001), which was attenuated by co-incubation of Siv in medium (p<0.001) and protein of human aortic smooth muscle cells (p=0.001). CONCLUSION: Siv attenuated AngII-induced AAA through the inhibition of NE.

DOI： 10.1093/ajh/hpad107

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We present a case of microhematuria, proteinuria and hypocomplementemia that developed in a 55-year-old female who was being treated with an infliximab biosimilar (IFX-BS) for rheumatoid arthritis (RA). Renal biopsy showed lupus nephritis (ISN/RPS classification class IV+V). Treatment with the IFX-BS was discontinued, and treatment with prednisolone, hydroxychloroquine and abatacept was started, resulting in clinical remission of lupus nephritis and RA. Although tumor necrosis factor-α (TNF-α) inhibitors are known to induce production of autoantibodies, symptoms are usually limited to skin involvement or arthritis, and renal complications are rare. Physicians should be aware of the risk of lupus nephritis and carefully monitor patients for the development of renal involvement during treatment with TNF-α inhibitors.

DOI： 10.1093/mrcr/rxad061

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AIM: Among patients with Immunoglobulin A (IgA) nephropathy, we aimed to identify trajectory patterns stratified by the magnitude of haematuria and proteinuria using repeated urine dipstick tests, and assess whether the trajectories were associated with kidney events. METHODS: Using a nationwide multicentre chronic kidney disease (CKD) registry, we analysed data from 889 patients with IgA nephropathy (mean age 49.3 years). The primary outcome was a sustained reduction in eGFR of 50% or more from the index date and thereafter. During follow-up (median 49.0 months), we identified four trajectories (low-stable, moderate-decreasing, moderate-stable, and high-stable) in both urine dipstick haematuria and proteinuria measurements, respectively. RESULTS: In haematuria trajectory analyses, compared to the low-stable group, the adjusted hazard ratios (HRs) (95% confidence interval [CI]) for kidney events were 2.59 (95% CI, 1.48-4.51) for the high-stable, 2.31 (95% CI, 1.19-4.50) for the moderate-stable, and 1.43 (95% CI, (0.72-2.82) for the moderate-decreasing groups, respectively. When each proteinuria trajectory group was subcategorized according to haematuria trajectories, the proteinuria group with high-stable and with modest-stable haematuria trajectories had approximately 2-times higher risk for eGFR reduction ≥50% compared to that with low-stable haematuria trajectory. CONCLUSION: Assessments of both haematuria and proteinuria trajectories using urine dipstick could identify high-risk IgA nephropathy patients.

DOI： 10.1111/nep.14250

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In diabetes, the impairment of insulin secretion and insulin resistance contribute to hypertriglyceridemia, as the enzymatic activity of lipoprotein lipase (LPL) depends on insulin action. The transport of LPL to endothelial cells and its enzymatic activity are maintained by the formation of lipolytic complex depending on the multiple positive (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 [GPIHBP1], apolipoprotein C-II [APOC2], APOA5, heparan sulfate proteoglycan [HSPG], lipase maturation factor 1 [LFM1] and sel-1 suppressor of lin-12-like [SEL1L]) and negative regulators (APOC1, APOC3, angiopoietin-like proteins [ANGPTL]3, ANGPTL4 and ANGPTL8). Among the regulators, GPIHBP1 is a crucial molecule for the translocation of LPL from parenchymal cells to the luminal surface of capillary endothelial cells, and maintenance of lipolytic activity; that is, hydrolyzation of triglyceride into free fatty acids and monoglyceride, and conversion from chylomicron to chylomicron remnant in the exogenous pathway and from very low-density lipoprotein to low-density lipoprotein in the endogenous pathway. The null mutation of GPIHBP1 causes severe hypertriglyceridemia and pancreatitis, and GPIGBP1 autoantibody syndrome also causes severe hypertriglyceridemia and recurrent episodes of acute pancreatitis. In patients with type 2 diabetes, the elevated serum triglyceride levels negatively correlate with circulating LPL levels, and positively with circulating APOC1, APOC3, ANGPTL3, ANGPTL4 and ANGPTL8 levels. In contrast, circulating GPIHBP1 levels are not altered in type 2 diabetes patients with higher serum triglyceride levels, whereas they are elevated in type 2 diabetes patients with diabetic retinopathy and nephropathy. The circulating regulators of lipolytic complex might be new biomarkers for lipid and glucose metabolism, and diabetic vascular complications.

DOI： 10.1111/jdi.14056

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Kidney diseases are worldwide public health problems affecting millions of people. However, there are still limited therapeutic options against kidney diseases. Semaphorin 3A (SEMA3A) is a secreted and membrane-associated protein, which regulates diverse functions, including immune regulation, cell survival, migration and angiogenesis, thus involving in the several pathogeneses of diseases, including eyes and neurons, as well as kidneys. SEMA3A is expressed in podocytes and tubular cells in the normal adult kidney, and recent evidence has revealed that excess SEMA3A expression and the subsequent signaling pathway aggravate kidney injury in a variety of kidney diseases, including nephrotic syndrome, diabetic nephropathy, acute kidney injury, and chronic kidney disease. In addition, several reports have demonstrated that the inhibition of SEMA3A ameliorated kidney injury via a reduction in cell apoptosis, fibrosis and inflammation; thus, SEMA3A may be a potential therapeutic target for kidney diseases. In this review article, we summarized the current knowledge regarding the role of SEMA3A in kidney pathophysiology and their potential use in kidney diseases.

DOI： 10.3390/diagnostics13193038

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Acute kidney injury (AKI) is a clinical syndrome where a rapid decrease in kidney function and/or urine output is observed, which may result in the imbalance of water, electrolytes and acid base. It is associated with poor prognosis and prolonged hospitalization. Therefore, an early diagnosis and treatment to avoid the severe AKI stage are important. While several biomarkers, such as urinary L-FABP and NGAL, can be clinically useful, there is still no gold standard for the early detection of AKI and there are limited therapeutic options against AKI. miRNAs are non-coding and single-stranded RNAs that silence their target genes in the post-transcriptional process and are involved in a wide range of biological processes. Recent accumulated evidence has revealed that miRNAs may be potential biomarkers and therapeutic targets for AKI. In this review article, we summarize the current knowledge about miRNAs as promising biomarkers and potential therapeutic targets for AKI, as well as the challenges in their clinical use.

DOI： 10.3390/diagnostics13182893

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OBJECTIVES: There is a high prevalence of burnout among rheumatologists. Grit, which is defined as possessing perseverance and a passion to achieve long-term goals, is predictive of success in many professions; however, whether grit is associated with burnout remains unclear, especially among academic rheumatologists, who have multiple simultaneous responsibilities. Thus, the purpose of this study was to examine the associations between grit and self-reported burnout components-professional efficacy, exhaustion, and cynicism-in academic rheumatologists. METHODS: This cross-sectional study involved 51 rheumatologists from 5 university hospitals. The exposure was grit, measured using mean scores for the 8-item Short Grit Scale (range, 1-5 [5 = extremely high grit]). The outcome measures were mean scores for 3 burnout domains (exhaustion, professional efficacy, and cynicism; range, 1-6; measured using the 16-item Maslach Burnout Inventory-General Survey). General linear models were fitted with covariates (age, sex, job title [assistant professor or higher vs lower], marital status, and having children). RESULTS: Overall, 51 physicians (median age, 45 years; interquartile range, 36-57; 76% men) were included. Burnout positivity was found in 68.6% of participants (n = 35/51; 95% confidence interval [CI], 54.1, 80.9). Higher grit was associated with higher professional efficacy (per 1-point increase; 0.51 point; 95% CI, 0.18, 0.84) but not with exhaustion or cynicism. Being male and having children were associated with lower exhaustion (-0.69; 95% CI, -1.28, -0.10; p = 0.02; and -0.85; 95% CI, -1.46, -0.24; p = 0.006). Lower job title (fellow or part-time lecturer) was associated with higher cynicism (0.90; 95% CI, 0.04, 1.75; p = 0.04). CONCLUSIONS: Grit is associated with higher professional efficacy among academic rheumatologists. To prevent burnout among staff, supervisors who manage academic rheumatologists should assess their staff's individual grit.

DOI： 10.1097/RHU.0000000000001989

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OBJECTIVES: PARPs, which are members of the poly(ADP-ribose) polymerase superfamily, promote tumorigenesis and tumour-associated inflammation and are thus therapeutic targets for several cancers. The aim of the present study is to investigate the mechanistic insight into the roles PARPs for inflammation. METHODS: Primary murine macrophages were cultured in the presence or absence of the PARP5 inhibitor NVP-TNKS656 to examine the role of PARP5 for cytokine production. RESULTS: In contrast to the roles of other PARPs for induction of inflammation, we found in the present study that pharmacologic inhibition of PARP5 induces production of inflammatory cytokines in primary murine macrophages. We found that treatment with the PARP5 inhibitor NVP-TNKS656 in macrophages enhanced steady-state and LPS-mediated cytokine production through degradation of IκBα and subsequent nuclear translocation of NF-κB. We also found that pharmacologic inhibition of PARP5 stabilises the adaptor protein 3BP2, a substrate of PARP5, and that accelerated cytokine production induced by PARP5 inhibition was rescued in 3BP2-deleted macrophages. Additionally, we found that LPS increases the expression of 3BP2 and AXIN1, a negative regulator of β-catenin, through suppression of PARP5 transcripts in macrophages, leading to further activation of cytokine production and inhibition of β-catenin-mediated cell proliferation, respectively. Lastly, we found that PARP5 inhibition in macrophages promotes osteoclastogenesis through stabilisation of 3BP2 and AXIN1, leading to activation of SRC and suppression of β-catenin, respectively. CONCLUSIONS: Our results show that pharmacologic inhibition of PARP5 against cancers unexpectedly induces adverse autoinflammatory side effects through activation of innate immunity, unlike inhibition of other PARPs.

DOI： 10.55563/clinexprheumatol/qf55h8

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Sensitive biomarkers can enhance the diagnosis, prognosis, and surveillance of chronic kidney disease (CKD), such as diabetic kidney disease (DKD). Plasma growth differentiation factor 15 (GDF15) levels are a novel biomarker for mitochondria-associated diseases; however, it may not be a useful indicator for CKD as its levels increase with declining renal function. This study explores urinary GDF15's potential as a marker for CKD. The plasma and urinary GDF15 as well as 15 uremic toxins were measured in 103 patients with CKD. The relationship between the urinary GDF15-creatinine ratio and the uremic toxins and other clinical characteristics was investigated. Urinary GDF15-creatinine ratios were less related to renal function and uremic toxin levels compared to plasma GDF15. Additionally, the ratios were significantly higher in patients with CKD patients with diabetes (p = 0.0012) and reduced with statin treatment. In a different retrospective DKD cohort study (U-CARE, n = 342), multiple and logistic regression analyses revealed that the baseline urinary GDF15-creatinine ratios predicted a decline in estimated glomerular filtration rate (eGFR) over 2 years. Compared to the plasma GDF15 level, the urinary GDF15-creatinine ratio is less dependent on renal function and sensitively fluctuates with diabetes and statin treatment. It may serve as a good prognostic marker for renal function decline in patients with DKD similar to the urine albumin-creatinine ratio.

DOI： 10.1038/s41598-023-39657-7

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Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Sjögren's syndrome (SjS), and sarcoidosis are systemic diseases targeting multiple organs. While a careful differential diagnosis of these diseases is often required, their co-occurrence in the same patient has been previously reported. We herein report a 58-year-old Japanese man diagnosed with the co-occurrence of three systemic diseases (AAV, SjS, and sarcoidosis) in addition to monoclonal gammopathy of undetermined significance (MGUS), which emphasizes the importance of considering the possible co-occurrence of these diseases as well as their differentiation.

DOI： 10.2169/internalmedicine.0966-22

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A 34-year-old woman with pulmonary arterial hypertension (PAH) was admitted to the hospital. She had been diagnosed with PAH three years earlier and treated with triple vasodilator therapy. She was positive for anti-U1 ribonucleoprotein antibodies but did not show any other symptoms associated with autoimmune diseases. Corticosteroid and cyclophosphamide therapy was administered, suspecting the involvement of immunological pathophysiology. After 3 weeks, the mean pulmonary artery pressure decreased from 50 to 38 mmHg without any change in the vasodilators. Immunosuppressive therapy was effective in this patient with PAH with an anti-U1 ribonucleoprotein-antibody-positive response and might be an option for patients with these specific features.

DOI： 10.2169/internalmedicine.1407-22

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Solid pseudopapillary tumor (SPT) is a low-grade malignant tumor of the pancreas. SPT typically affects women and can occur in ectopic pancreatic region; however, it also occurs rarely in retroperitoneum. The tumor may be bulky at the time of diagnosis since there is no specific clinical manifestation. Here we present an older male case with retroperitoneal SPT. A 67-year-old man consulted for intermittent fever and lumbago. His basal hormonal profile screened out a functional tumor. Computed tomography (CT) showed a gigantic mass in his left adrenal region. A normal left adrenal gland was not identified, and the tumor's feeding artery was recognized as the left adrenal artery by the contrast-enhanced CT. Adrenal malignant tumor was suspected, and tumor resection was performed. The resected tumor size was 15 × 10 × 9 cm. Histologically, epithelial-like cells with round nuclei and a small amount of eosinophilic cytoplasm proliferated in papillary (around the blood vessels) or uniformly solid form. By immunostaining, tumor cells were vimentin, CD56, cytokeratin AE1/AE3, CD10, β-catenin in the nucleus, cyclin D1, and PgR positive. These findings led to the diagnosis of SPT. Although rare, SPT should be considered as a differential diagnosis in cases of a mass arising from the adrenal region.

DOI： 10.1210/jcemcr/luad090

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The mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, the role and nature of impaired ETC in kidney diseases remains poorly understood. Here, we generate diabetic mice with podocyte-specific overexpression of Ndufs4, an accessory subunit of mitochondrial complex I, as a model investigate the role of ETC integrity in diabetic kidney disease (DKD). We find that conditional male mice with genetic overexpression of Ndufs4 exhibit significant improvements in cristae morphology, mitochondrial dynamics, and albuminuria. By coupling proximity labeling with super-resolution imaging, we also identify the role of cristae shaping protein STOML2 in linking NDUFS4 with improved cristae morphology. Together, we provide the evidence on the central role of NDUFS4 as a regulator of cristae remodeling and mitochondrial function in kidney podocytes. We propose that targeting NDUFS4 represents a promising approach to slow the progression of DKD.

DOI： 10.21203/rs.3.rs-3070079/v1

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Brown adipose tissue (BAT) plays a critical role in metabolic homeostasis. BAT dysfunction is associated with the development of obesity through an imbalance between energy expenditure and energy intake. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is the master regulator of adipogenesis. However, the roles of PPARγ and thiazolidinediones (TZDs) in the regulation of BAT metabolism remain unclear. TZDs, which are selective PPARγ activators, improve systemic insulin resistance in animals and humans. In the present study, we generated brown adipocyte-specific PPARγ-deficient mice (BATγKO) to examine the in vivo roles of PPARγ and TZDs in BAT metabolism. In electron microscopic examinations, brown adipocyte-specific PPARγ deletion promoted severe whitening of brown fat and morphological alteration of mitochondria. Brown adipocyte-specific PPARγ deletion also reduced mRNA expression of BATselective genes. Although there was no difference in energy expenditure between control and BATγKO mice in calorimetry, norepinephrine-induced thermogenesis was impaired in BATγKO mice. Moreover, pioglitazone treatment improved diet-induced insulin resistance in the control mice but not in the BATγKO mice. These findings suggest that BAT PPARγ is necessary for the maintenance of brown adipocyte function and for the insulin-sensitizing action of TZDs.

DOI： 10.18926/AMO/65489

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Fabry disease is an X-linked lysosomal storage disorder caused by defective enzyme activity of α-galactosidase A and treated with enzyme replacement therapy (ERT) with recombinant α-galactosidase. ERT reduces left ventricular mass assessed by echocardiography or magnetic resonance imaging. However, electrocardiogram changes during ERT have not been fully elucidated. In the present case, ERT with agalsidase alfa for 4 years decreased QRS voltage and negative T depth along with a reduction of left ventricular mass and wall thickness and improvement of symptoms in a female patient with Fabry disease. Long-term observation of electrocardiogram changes might be useful for determining the efficacy of ERT in this case.

DOI： 10.1536/ihj.22-752

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The receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor that regulates inflammation, cell migration, and cell fate. Systemic lupus erythematosus (SLE) is a chronic multiorgan autoimmune disease. To understand the function of RAGE in SLE, we generated RAGE-deficient (Ager-/-) lupus-prone mice by backcrossing MRL/MpJ-Faslpr/J (MRL-lpr) mice with Ager-/- C57BL/6 mice. In 18-week-old Ager-/- MRL-lpr, the weights of the spleen and lymph nodes, as well as the frequency of CD3+CD4-CD8- cells, were significantly decreased. Ager-/- MRL-lpr mice had significantly reduced urine albumin/creatinine ratios and markedly improved renal pathological scores. Moreover, neutrophil infiltration and neutrophil extracellular trap formation in the glomerulus were significantly reduced in Ager-/- MRL-lpr. Our study is the first to reveal that RAGE can have a pathologic role in immune cells, particularly neutrophils and T cells, in inflammatory tissues and suggests that the inhibition of RAGE may be a potential therapeutic strategy for SLE.

DOI： 10.1016/j.clim.2023.109317

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OBJECTIVE: Fatigue is one of the most common complaints and is a potentially modifiable issue in systemic lupus erythematosus (SLE). Studies suggest that alcohol consumption has a protective effect against the development of SLE; however, an association between alcohol consumption and fatigue in patients with SLE has not been studied. Here, we assessed whether alcohol consumption was associated with fatigue using lupus patient-reported outcomes (LupusPRO). METHODS: This cross-sectional study, conducted between 2018 and 2019, included 534 patients (median age, 45 years; 87.3% female) from 10 institutions in Japan. The main exposure was alcohol consumption, which was defined as the frequency of drinking [<1 day/month (none group), ≤1 day/week (moderate group), and ≥2 days/week (frequent group)]. The outcome measure was the Pain Vitality domain score in LupusPRO. Multiple regression analysis was performed as the primary analysis after adjusting for confounding factors, such as age, sex, and damage. Subsequently, the same analysis was performed as a sensitivity analysis after multiple imputations (MIs) for missing data (n = 580). RESULTS: In total, 326 (61.0%) patients were categorized into the none group, 121 (22.7%) into the moderate group, and 87 (16.3%) into the frequent group. The frequent group was independently associated with less fatigue compared with none group [β = 5.98 (95% CI 0.19-11.76), p = 0.04], and the results did not substantially deviate after MI. CONCLUSIONS: Frequent drinking was associated with less fatigue, which highlights the need for further longitudinal studies focusing on drinking habits in patients with SLE.

DOI： 10.1177/09612033231159471

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INTRODUCTION: While chronic kidney disease (CKD) is one of the most important contributors to mortality from non-communicable diseases, the number of nephrologists is limited worldwide. Medical cooperation is a system of cooperation between primary care physicians and nephrological institutions, consisting of nephrologists and multidisciplinary care teams. Although it has been reported that multidisciplinary care teams contribute to the prevention of worsening renal functions and cardiovascular events, there are few studies on the effect of a medical cooperation system. METHODS: We aimed to evaluate the effect of medical cooperation on all-cause mortality and renal prognosis in patients with CKD. One hundred and sixty-eight patients who visited the one hundred and sixty-three clinics and seven general hospitals of Okayama city were recruited between December 2009 and September 2016, and one hundred twenty-three patients were classified into a medical cooperation group. The outcome was defined as the incidence of all-cause mortality, or renal composite outcome (end-stage renal disease or 50% eGFR decline). We evaluated the effects on renal composite outcome and pre-ESRD mortality while incorporating the competing risk for the alternate outcome into a Fine-Gray subdistribution hazard model. RESULTS: The medical cooperation group had more patients with glomerulonephritis (35.0% vs. 2.2%) and less nephrosclerosis (35.0% vs. 64.5%) than the primary care group. Throughout the follow-up period of 5.59 ± 2.78 years, 23 participants (13.7%) died, 41 participants (24.4%) reached 50% decline in eGFR, and 37 participants (22.0%) developed end-stage renal disease (ESRD). All-cause mortality was significantly reduced by medical cooperation (sHR 0.297, 95% CI 0.105-0.835, p = 0.021). However, there was a significant association between medical cooperation and CKD progression (sHR 3.069, 95% CI 1.225-7.687, p = 0.017). CONCLUSION: We evaluated mortality and ESRD using a CKD cohort with a long-term observation period and concluded that medical cooperation might be expected to influence the quality of medical care in the patients with CKD.

DOI： 10.3390/jpm13040582

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BACKGROUND: IgA nephropathy (IgAN) is a major cause of chronic glomerulonephritis worldwide. T cell dysregulation has been reported to contribute to the pathogenesis of IgAN. Methods We measured a broad range of Th1, Th2 and Th17 cytokines in the serum of IgAN patients. We searched for significant cytokines, which were associated with clinical parameters and histological scores in IgAN patients. RESULTS: Among 15 cytokines, the levels of soluble CD40L (sCD40L) and IL-31 were higher in IgAN patients and were significantly associated with a higher estimated glomerular filtration rate (eGFR), a lower urinary protein to creatinine ratio (UPCR), and milder tubulointerstitial lesions (i.e., the early phase of IgAN). Multivariate analysis revealed that serum sCD40L was an independent determinant of a lower UPCR after adjustment for age, eGFR, and mean blood pressure (MBP). CD40, a receptor of sCD40L, has been reported to be upregulated on mesangial cells in IgAN. The sCD40L/CD40 interaction may directly induce inflammation in mesangial areas and may therefore be involved in the development of IgAN. CONCLUSIONS: The present study demonstrated the significance of serum sCD40L and IL-31 in the early phase of IgAN. Serum sCD40L may be a marker of the beginning of inflammation in IgAN.

DOI： 10.3390/jcm12052023

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While hypothyroidism increases serum creatinine (Cr) levels, it is uncertain whether the elevation is mediated via a decline in the glomerular filtration rate (GFR) or the reflection of enhanced Cr production from the muscles or both. In the present study, we explored an association between urinary Cr excretion rate (CER) and hypothyroidism. A total of 553 patients with chronic kidney disease were enrolled in a cross-sectional study. Multiple linear regression analysis was performed to explore the association between hypothyroidism and urinary CER. The mean urinary CER was 1.01 ± 0.38 g/day and 121 patients (22%) had hypothyroidism. The multiple linear regression analysis revealed explanatory variables with urinary CER, including age, sex, body mass index, 24 h Cr clearance (24hrCcr), and albumin while hypothyroidism was not considered an independent explanatory variable. In addition, scatter plot analysis with regression fit line representing the association between estimated GFR calculated using s-Cr (eGFRcre) and 24hrCcr revealed that eGFRcre and 24hrCcr had strong correlations with each other in hypothyroid patients as well as euthyroid patients. Collectively, hypothyroidism was not considered an independent explanatory variable for urinary CER in the present study and eGFRcre is a useful marker to evaluate kidney function regardless of the presence of hypothyroidism.

DOI： 10.3390/diagnostics13040669

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AIMS/INTRODUCTION: Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes produce IL-18 upon being activated by various stimuli via the P2 receptors. Previously, we showed that serum and urine IL-18 levels are positively associated with albuminuria in patients with type 2 diabetes, indicating the involvement of inflammasome activation in the pathogenesis of diabetic kidney disease (DKD). In the present study, we investigated whether the administration of suramin, a nonselective antagonist of the P2 receptors, protects diabetic KK.Cg-Ay /TaJcl (KK-Ay) mice against DKD progression. MATERIALS AND METHODS: Suramin or saline was administered i.p. to KK-Ay and C57BL/6J mice once every 2 weeks for a period of 8 weeks. Mouse mesangial cells (MMCs) were stimulated with ATP in the presence or absence of suramin. RESULTS: Suramin treatment significantly suppressed the increase in the urinary albumin-to-creatinine ratio, glomerular hypertrophy, mesangial matrix expansion, and glomerular fibrosis in KK-Ay mice. Suramin also suppressed the upregulation of NLRP3 inflammasome-related genes and proteins in the renal cortex of KK-Ay mice. P2X4 and P2X7 receptors were significantly upregulated in the isolated glomeruli of KK-Ay mice and mainly distributed in the glomerular mesangial cells of KK-Ay mice. Although neither ATP nor suramin affected NLRP3 expression in MMCs, suramin inhibited ATP-induced NLRP3 complex formation and the downstream expression of caspase-1 and IL-18 in MMCs. CONCLUSIONS: These results suggest that the NLRP3 inflammasome is activated in a diabetic kidney and that inhibition of the NLRP3 inflammasome with suramin protects against the progression of early stage DKD.

DOI： 10.1111/jdi.13930

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Chronic kidney disease (CKD) is a syndrome characterized by a gradual loss of kidney function with decreased estimated glomerular filtration rate (eGFR), which may be accompanied by an increase in the urine albumin-to-creatinine ratio (UACR). Although trans-ethnic genome-wide association studies (GWASs) have been conducted for kidney-related traits, there have been few analyses in the Japanese population, especially for the UACR trait. In this study, we conducted a GWAS to identify loci related to multiple kidney-related traits in Japanese individuals. First, to detect loci associated with CKD, eGFR, and UACR, we performed separate GWASs with the following two datasets: 475 cases of CKD diagnosed at seven university hospitals and 3471 healthy subjects (dataset 1) and 3664 cases of CKD-suspected individuals with eGFR <60 ml/min/1.73 m2 or urinary protein ≥ 1+ and 5952 healthy subjects (dataset 2). Second, we performed a meta-analysis between these two datasets and detected the following associated loci: 10 loci for CKD, 9 loci for eGFR, and 22 loci for UACR. Among the loci detected, 22 have never been reported previously. Half of the significant loci for CKD were shared with those for eGFR, whereas most of the loci associated with UACR were different from those associated with CKD or eGFR. The GWAS of the Japanese population identified novel genetic components that were not previously detected. The results also suggest that the group primarily characterized by increased UACR possessed genetically different features from the group characterized by decreased eGFR.

DOI： 10.1038/s10038-022-01094-1

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Metformin has been a long-standing prescribed drug for treatment of type 2 diabetes (T2D) and its beneficial effects on virus infection, autoimmune diseases, aging and cancers are also recognized. Metformin modulates the differentiation and activation of various immune-mediated cells such as CD4+ and CD+8 T cells. The activation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) pathway may be involved in this process. Recent studies using Extracellular Flux Analyzer demonstrated that metformin alters the activities of glycolysis, oxidative phosphorylation (OXPHOS), lipid oxidation, and glutaminolysis, which tightly link to the modulation of cytokine production in CD4+ and CD+8 T cells in various disease states, such as virus infection, autoimmune diseases, aging and cancers.

DOI： 10.3390/ijms24010755

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INTRODUCTION: Treating diabetic nephropathy with low-density lipoprotein (LDL) apheresis reduces proteinuria and improves prognosis. However, its impact on patients' quality of life (QoL) is unclear. This study evaluated the effect of LDL apheresis on QoL in patients with diabetes, proteinuria, and hypercholesterolemia. METHODS: In this nationwide multicenter prospective study, we enrolled 40 patients with diabetes. Inclusion criteria were proteinuria (defined as an albumin/creatinine ratio ≥3 g/g), serum creatinine levels <2 mg/dL, and serum LDL ≥120 mg/dL despite drug treatment. LDL apheresis was performed 6-12 times within 12 weeks. The 36-item Short Form Health Survey (SF-36) was used to analyze QoL. RESULTS: The study enrolled 35 patients (27 men and 8 women; mean age 58.9 ± 11.9 years). A comparison of baseline SF-36 values with those at the end of the course of apheresis found an improvement in the mean physical component summary (37.9 ± 11.4 vs. 40.6 ± 10.5, p = 0.051) and a significant increase in the mean mental component summary (MCS) (49.4 ± 8.4 vs. 52.5 ± 10.9, p = 0.026). A multivariable linear regression analysis revealed a history of coronary heart disease negatively correlated with the MCS increase at the end of the course of apheresis (β coefficient -6.935, 95% confidence interval, 13.313 to-0.556, p = 0.034). CONCLUSION: Our results suggest that LDL apheresis may improve the mental and physical QoL in patients with diabetes, proteinuria, and hypercholesterolemia.

DOI： 10.1159/000527900

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DOI： 10.3389/fendo.2023.1251148

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Ubiquitin-mediated proteasomal degradation is a post-transcriptional protein modification that is comprised of various components including the 76-amino acid protein ubiquitin (Ub), Ub-activating enzyme (E1), Ub-conjugating enzyme (E2), ubiquitin ligase (E3), deubiquitinating enzyme (DUB) and proteasome. We and others have recently provided genetic evidence showing that E3-ubiquitin ligases are associated with bone metabolism, the immune system and inflammation through ubiquitylation and subsequent degradation of their substrates. Dysregulation of the E3-ubiquitin ligase RNF146-mediated degradation of the adaptor protein 3BP2 (SH3 domain-binding protein 2) causes cherubism, an autosomal dominant disorder associated with severe inflammatory craniofacial dysmorphia syndrome in children. In this review, on the basis of our discoveries in cherubism, we summarize new insights into the roles of E3-ubiquitin ligases in the development of human disorders caused by an abnormal osteoimmune system by highlighting recent genetic evidence obtained in both human and animal model studies.

DOI： 10.3389/fimmu.2023.1120710

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DOI： 10.1093/rap/rkad096

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DOI： 10.1111/dom.14114

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Introduction Clinical data of esaxerenone in hypertensive patients with diabetic kidney disease (DKD) are lacking. We evaluated the efficacy and safety of esaxerenone in patients with DKD and an inadequate response to blood pressure (BP)-lowering treatment. Methods In this multicenter, open-label, prospective study, patients were divided into urinary albumin-to-creatinine ratio subcohorts (UACR < 30, 30 to < 300, and 300 to < 1000 mg/gCr). Esaxerenone was initiated at 1.25 mg/day and followed by incremental dose escalation based on BP and serum potassium level monitoring. The treatment period was 12 weeks. The primary endpoint was change in morning home systolic BP/diastolic BP (SBP/DBP) from baseline to end of treatment (EOT). Secondary endpoints included achievement rate of target BP, change in UACR from baseline, and safety. Results In total, 113 patients were enrolled. Morning home SBP/DBP significantly decreased from baseline to EOT in the total population (- 11.6/- 5.2 mmHg, both p < 0.001) and in all UACR subcohorts (all p < 0.001). The target BP achievement rate was 38.5%. Significant reductions in bedtime home and office BPs were also shown in the total population and all UACR subcohorts. UACR significantly improved from baseline to EOT in the total (- 50.9%, p < 0.001) and all UACR subcohorts (all p < 0.001). Incidence of serum potassium elevation as drug-related treatment emergent adverse events was 2.7%. The change from baseline in estimated glomerular filtration rate (eGFR) was - 4.8 mL/min/1.73 m(2). Conclusion Esaxerenone demonstrated a BP-lowering effect and improved albuminuria. The effects were consistent regardless of the severity of albuminuria without clinically relevant serum potassium elevation and eGFR reduction.

DOI： 10.1007/s12325-022-02294-z

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Language：English   Publisher：OXFORD UNIV PRESS  

DOI： 10.1093/rheumatology/keac284

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ENDOCRINE SOC  

Pheochromocytomas and paragangliomas (PPGLs) are classified into 3 major categories with distinct driver genes: pseudohypoxia, kinase signaling, and Wnt-altered subtypes. PPGLs in the Wnt-altered subtype are sporadic and tend to be aggressive with metastasis, where somatic gene fusions affecting mastermind-like 3 (MAML3) and somatic mutations in cold shock domain containing E1 (CSDE1) cause overactivation of Wnt-beta-catenin signaling. However, the relation between Wnt-beta-catenin signaling and the biological behavior of PPGLs remains unexplored. In rat pheochromocytoma PC12 cells, Wnt3a treatment enhanced cell proliferation and suppressed mRNA expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine biosynthesis, and dopamine secretion. We identified the expression of sclerostin in PC12 cells, which is known as an osteocyte-derived negative regulator for Wnt signaling-driven bone formation. Inhibition of endogenous Wnt pathway by XAV939 or sclerostin resulted in attenuated cell proliferation and increased TH expression. Furthermore, Wnt3a pretreatment suppressed bone morphogenetic protein (BMP)-induced Smad1/5/9 phosphorylation whereas BMPs enhanced sclerostin expression in PC12 cells. In the Wnt-altered subtype, the increased Wnt-beta-catenin pathway may contribute the aggressive clinical behavior with reduced catecholamine production. Furthermore, upregulated expression of sclerostin by BMPs may explain the osteolytic metastatic lesions observed in metastatic PPGLs.

DOI： 10.1210/jendso/bvac121

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Real-time ultrasound-guided renal biopsy is generally applied to diagnose multiple kidney diseases. A practical simulation model is desired since it is an invasive technique with higher risks of complications such as bleeding. We developed a simple simulation tool for ultrasound-guided renal biopsy using boiled eggs. Boiled chicken eggs were embedded in the agar, and a biopsy simulation was performed using a real-time ultrasound-guided technique as the renal biopsy simulator by trainees and biopsy-proficient nephrologists, and the feedback from the participants was obtained. The ultrasonographic evaluation revealed a clear contrast between egg yolk and white, which clearly mimicked the kidney cortex and medulla region. In addition, we observed the needle entering the egg white under needle penetration, and we obtained the biopsy core consisting of egg white. As for the simulations, all the participants succeeded in obtaining the appropriate samples. A total of 92% of the trainees agreed that the simulation could reduce their fears of performing renal biopsies in patients. In addition, all the trainees and biopsy-proficient nephrologists recommend using the simulator for trainees before conducting renal biopsies on patients. The total cost of the simulator was low (<USD 1/simulator). Collectively, our simulation tool using boiled eggs may be a good candidate for practical simulation models of renal biopsy.

DOI： 10.1111/nep.14079

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PORTFOLIO  

Hypothyroidism is known to be correlated with kidney function and nephrotic range proteinuria. However, it is uncertain whether non-nephrotic proteinuria is associated with hypothyroidism. This study aimed to evaluate the association of proteinuria and hypothyroidism in chronic kidney disease (CKD) patients. We conducted a cross-sectional study composed of 421 CKD patients in a single hospital with measurements of 24-h urine protein excretion (UP) and thyroid function tests. Spearman correlation analysis revealed that 24-h Cr clearance (24hrCcr) was positively (r = 0.273, p < 0.001) and UP was negatively (r = - 0.207, p < 0.001) correlated with free triiodothyronine. Frequency distribution analysis stratified by CKD stage and UP for hypothyroidism revealed that the prevalence of hypothyroidism was higher among participants with higher CKD stage and nephrotic range proteinuria. Multivariate logistic regression analysis revealed that 24hrCcr and UP were significantly correlated with hypothyroidism (24hrCcr/10 mL/min decrease: odds ratio [OR], 1.29; 95% confidence interval [CI], 1.18-1.41; UP/1 g increase: OR, 1.10; 95% CI, 1.03-1.17). In addition, nephrotic range proteinuria, but not moderate UP (UP: 1.5-3.49 g/day), was significantly correlated with hypothyroidism compared to UP < 0.5 g/day. In summary, decreased kidney function and nephrotic range proteinuria, not non-nephrotic proteinuria, are independently associated with the hypothyroidism.

DOI： 10.1038/s41598-022-19226-0

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Cardiac fibrosis is characterized by the net accumulation of extracellular matrix in the myocardium and is an integral component of most pathological cardiac conditions. Cilostazol, a selective inhibitor of phosphodiesterase type III with anti-platelet, anti-mitogenic, and vasodilating properties, is widely used to treat the ischemic symptoms of peripheral vascular disease. Here, we investigated whether cilostazol has a protective effect against Angiotensin II (AngII)-induced cardiac fibrosis. Male apolipoprotein E-deficient mice were fed either a normal diet or a diet containing cilostazol (0.1% wt/wt). After 1 week of diet consumption, the mice were infused with saline or AngII (1000 ng kg(-1) min(-1)) for 28 days. AngII infusion increased heart/body weight ratio (p < 0.05), perivascular fibrosis (p < 0.05), and interstitial cardiac fibrosis (p < 0.0001), but were significantly attenuated by cilostazol treatment (p < 0.05, respectively). Cilostazol also reduced AngII-induced increases in fibrotic and inflammatory gene expression (p < 0.05, respectively). Furthermore, cilostazol attenuated both protein and mRNA abundance of osteopontin induced by AngII in vivo. In cultured human cardiac myocytes, cilostazol reduced mRNA expression of AngII-induced osteopontin in dose-dependent manner. This reduction was mimicked by forskolin treatment but was cancelled by co-treatment of H-89. Cilostazol attenuates AngII-induced cardiac fibrosis in mice through activation of the cAMP-PKA pathway.

DOI： 10.3390/ijms23169065

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Insights from epidemiological, clinical and basic research are illuminating the interplay between metabolic disorders, cardiovascular disease (CVD) and kidney dysfunction, termed cardio-renal-metabolic (CRM) disease. Broadly defined, CRM disease involves multidirectional interactions between metabolic diseases such as type 2 diabetes (T2D), various types of CVD and chronic kidney disease (CKD). T2D confers increased risk for heart failure, which-although well known-has only recently come into focus for treatment, and may differ by ethnicity, whereas atherosclerotic heart disease is a well-established complication of T2D. Many people with T2D also have CKD, with a higher risk in Asians than their Western counterparts. Furthermore, CVD increases the risk of CKD and vice versa, with heart failure, notably, present in approximately half of CKD patients. Molecular mechanisms involved in CRM disease include hyperglycaemia, insulin resistance, hyperactivity of the renin-angiotensin-aldosterone system, production of advanced glycation end-products, oxidative stress, lipotoxicity, endoplasmic reticulum stress, calcium-handling abnormalities, mitochondrial malfunction and deficient energy production, and chronic inflammation. Pathophysiological manifestations of these processes include diabetic cardiomyopathy, vascular endothelial dysfunction, cardiac and renal fibrosis, glomerular hyperfiltration, renal hypoperfusion and venous congestion, reduced exercise tolerance leading to metabolic dysfunction, and calcification of atherosclerotic plaque. Importantly, recognition of the interaction between CRM diseases would enable a more holistic approach to CRM care, rather than isolated treatment of individual conditions, which may improve patient outcomes. Finally, aspects of CRM diseases may differ between Western and East Asian countries such as Japan, a super-ageing country, with potential differences in epidemiology, complications and prognosis that represent an important avenue for future research.

DOI： 10.1111/dom.14829

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Background: The aim of the study was to define whether edaravone, a free-radical scavenger, influenced angiotensin II (AngII)-induced atherosclerosis and abdominal aortic aneurysms (AAAs) formation. Methods: Male apolipoprotein E-deficient mice (8-12 weeks old) were fed with a normal diet for 5 weeks. Either edaravone (10 mg/kg/day) or vehicle was injected intraperitoneally for 5 weeks. After 1 week of injections, mice were infused subcutaneously with either AngII (1000 ng/kg/min, n = 16-17 per group) or saline (n = 5 per group) by osmotic minipumps for 4 weeks. Results: AngII increased systolic blood pressure equivalently in mice administered with either edaravone or saline. Edaravone had no effect on plasma total cholesterol concentrations and body weights. AngII infusion significantly increased ex vivo maximal diameters of abdominal aortas and en face atherosclerosis but was significantly attenuated by edaravone administration. Edaravone also reduced the incidence of AngII-induced AAAs. In addition, edaravone diminished AngII-induced aortic MMP-2 activation. Quantitative RT-PCR revealed that edaravone ameliorated mRNA abundance of aortic MCP-1 and IL-1 beta. Immunostaining demonstrated that edaravone attenuated oxidative stress and macrophage accumulation in the aorta. Furthermore, edaravone administration suppressed thioglycolate-induced mice peritoneal macrophages (MPMs) accumulation and mRNA abundance of MCP-1 in MPMs in male apolipoprotein E-deficient mice. In vitro, edaravone reduced LPS-induced mRNA abundance of MCP-1 in MPMs. Conclusions: Edaravone attenuated AngII-induced AAAs and atherosclerosis in male apolipoprotein E-deficient mice via anti-oxidative action and anti-inflammatory effect.

DOI： 10.3390/biom12081117

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Systemic lupus erythematosus (SLE) is a potentially fatal systemic autoimmune disease, and its etiology involves both genetic and environmental factors such as sex hormone imbalance, genetic predisposition, epigenetic regulation, and immunological factors. Dysregulation of microRNA (miRNA) is suggested to be one of the epigenetic factors in SLE. miRNA is a 22-nucleotide single-stranded noncoding RNA that contributes to post-transcriptional modulation of gene expression. miRNA targeting therapy has been suggested to be useful for the treatment of cancers and other diseases. Gene knockout and miRNA targeting therapy have been demonstrated to improve SLE disease activity in mice. However, these approaches have not yet reached the level of clinical application. miRNA targeting therapy is limited by the fact that each miRNA has multiple targets. In addition, the expression of certain miRNAs may differ among cell tissues within a single SLE patient. This limitation can be overcome by targeted delivery and chemical modifications. In the future, further research into miRNA chemical modifications and delivery systems will help us develop novel therapeutic agents for SLE.

DOI： 10.18926/AMO/63887

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FUTURE MEDICINE LTD  

Background: It is important to identify additional prognostic factors for diabetic kidney disease. Materials & methods: Baseline levels of ten cytokines (APRIL/TNFSF13, BAFF/TNFSF13B, chitinase 3-like 1, LIGHT/TNFSF14, TWEAK/TNFSF12, gp130/sIL-6R beta, sCD163, sIL-6R alpha, sTNF-R1, sTNF-R2) were measured in two cohorts of diabetic patients. In one cohort (n = 777), 156 individuals were randomly sampled after stratification and their plasma samples were analyzed; in the other cohort (n = 69), serum samples were analyzed in all the individuals. The levels of cytokines between rapid (estimated glomerular filtration rate decline >5 ml/min/1.73 m(2)/year) and non-rapid decliners were compared. Results: Multivariate analysis demonstrated significantly high levels of LIGHT/TNFSF14, TWEAK/TNFSF12 and sTNF-R2 in rapid decliners. Conclusion: These three cytokines can be potential biomarkers for the progression of diabetic kidney disease.

DOI： 10.2217/bmm-2021-1104

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The combination of sarcopenia and obesity (sarcopenic obesity) is associated with the development of metabolic syndrome and cardiovascular events. The molecular pathways that develop sarcopenic obesity have studied intensively. Transmembrane protein 97 (TMEM97) is 176 amino acids conserved integral membrane protein with four transmembrane domains that is expressed in several types of cancer. Its physiological significance in adipose tissue and skeletal muscle has been unclear. We studied TMEM97-transgenic mice and mice lacking TMEM97, and our findings indicate that TMEM97 expression is regulated in adipose tissue and skeletal muscle from obesity. TMEM97 represses adipogenesis and promotes myogenesis in vitro. Fat-specific TMEM97 transgenic mice showed systemic insulin resistance. Mice overexpressing TMEM97 in skeletal muscle exhibited systemic insulin resistance. Mice lacking TMEM97 were protected against diet-induced obesity and insulin resistance. These phenotypes are associated with the effects of TMEM97 on inflammation genes in adipose tissue and skeletal muscle. Our findings indicates that there is a link between TMEM97 and chronic inflammation in obesity.

DOI： 10.18926/AMO/63717

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Language：English   Publisher：FRONTIERS MEDIA SA  

Kidney diseases are a major health problem worldwide. Despite advances in drug therapies, they are only capable of slowing the progression of kidney diseases. Accordingly, potential kidney regeneration strategies with stem cells have begun to be explored. There are two different directions for regenerative strategies, de novo whole kidney fabrication with stem cells, and stem cell therapy. De novo whole kidney strategies include: 1) decellularized scaffold technology, 2) 3D bioprinting based on engineering technology, 3) kidney organoid fabrication, 4) blastocyst complementation with chimeric technology, and 5) the organogenic niche method. Meanwhile, stem cell therapy strategies include 1) injection of stem cells, including mesenchymal stem cells, nephron progenitor cells, adult kidney stem cells and multi-lineage differentiating stress enduring cells, and 2) injection of protective factors secreted from these stem cells, including growth factors, chemokines, and extracellular vesicles containing microRNAs, mRNAs and proteins. Over the past few decades, there have been remarkable step-by-step developments in these strategies. Here, we review the current advances in the potential strategies for kidney regeneration using stem cells, along with their challenges for possible clinical use in the future.

DOI： 10.3389/fcell.2022.892356

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Podocytes are highly specialized epithelial cells in glomeruli, with a complex morphology composed of a cell body, primary processes, and foot processes, which maintain barrier function in glomerular filtration. The microtubule-based cytoskeleton is necessary for podocyte morphology. Microtubule structure and function can be affected by post-translational modification of tubulin, including detyrosination. Recent studies have shown that vasohibin-1 (VASH1), an antiangiogenic factor, has tubulin carboxypeptidase activity that causes detyrosination of α-tubulin. We aimed to examine the role of VASH1 in regulating α-tubulin detyrosination in podocytes and the potential involvement of VASH1 deficiency in renal morphology. In normal mouse kidneys, detyrosinated α-tubulin was mainly identified in glomeruli, especially in podocytes; meanwhile, in cultured immortalized podocytes, α-tubulin detyrosination was promoted with cell differentiation. Notably, α-tubulin detyrosination in glomeruli was diminished in Vash1 homozygous knockout (Vash1-/-) mice, and knockdown of VASH1 in cultured podocytes prevented α-tubulin detyrosination. Although VASH1 deficiency-induced downregulation of detyrosination caused no remarkable glomerular lesions, urinary albuminuria excretion and glomerular volume were significantly higher in Vash1-/- mice than in wild-type mice. Furthermore, decreased glomerular nephrin expression and narrower slit diaphragms width were observed in Vash1-/- mice. Taken together, we demonstrated that α-tubulin detyrosination in podocytes was mainly regulated by VASH1 and that VASH1 deficiency-mediated decreases in α-tubulin detyrosination led to minor alterations in podocyte morphology and predisposition to albuminuria. VASH1 expression and α-tubulin detyrosination may be novel targets for maintaining glomerular filtration barrier integrity.

DOI： 10.1016/j.bbrc.2022.02.047

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PORTFOLIO  

Accumulation of senescent cells in various tissues has been reported to have a pathological role in age-associated diseases. Elimination of senescent cells (senolysis) was recently reported to reversibly improve pathological aging phenotypes without increasing rates of cancer. We previously identified glycoprotein nonmetastatic melanoma protein B (GPNMB) as a seno-antigen specifically expressed by senescent human vascular endothelial cells and demonstrated that vaccination against Gpnmb eliminated Gpnmb-positive senescent cells, leading to an improvement of age-associated pathologies in mice. The aim of this study was to elucidate whether GPNMB plays a role in senescent cells. We examined the potential role of GPNMB in senescent cells by testing the effects of GPNMB depletion and overexpression in vitro and in vivo. Depletion of GPNMB from human vascular endothelial cells shortened their replicative lifespan and increased the expression of negative cell cycle regulators. Conversely, GPNMB overexpression protected these cells against stress-induced premature senescence. Depletion of Gpnmb led to impairment of vascular function and enhanced atherogenesis in mice, whereas overexpression attenuated dietary vascular dysfunction and atherogenesis. GPNMB was upregulated by lysosomal stress associated with cellular senescence and was a crucial protective factor in maintaining lysosomal integrity. GPNMB is a seno-antigen that acts as a survival factor in senescent cells, suggesting that targeting seno-antigens such as GPNMB may be a novel strategy for senolytic treatments.

DOI： 10.1038/s41598-022-10522-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI  

Patients with psoriasis are frequently complicated with metabolic syndrome; however, it is not fully understood how obesity and dyslipidemia contribute to the pathogenesis of psoriasis. To investigate the mechanisms by which obesity and dyslipidemia exacerbate psoriasis using murine models and neonatal human epidermal keratinocytes (NHEKs), we used wild-type and Apoe-deficient dyslipidemic mice, and administered a high-fat diet for 10 weeks to induce obesity. Imiquimod was applied to the ear for 5 days to induce psoriatic dermatitis. To examine the innate immune responses of NHEKs, we cultured and stimulated NHEKs using IL-17A, TNF-alpha, palmitic acid, and leptin. We found that obesity and dyslipidemia synergistically aggravated psoriatic dermatitis associated with increased gene expression of pro-inflammatory cytokines and chemokines. Treatment of NHEKs with palmitic acid and leptin amplified pro-inflammatory responses in combination with TNF-alpha and IL-17A. Additionally, pretreatment with palmitic acid and leptin enhanced IL-17A-mediated c-Jun N-terminal kinase phosphorylation. These results revealed that obesity and dyslipidemia synergistically exacerbate psoriatic skin inflammation, and that metabolic-disorder-associated inflammatory factors, palmitic acid, and leptin augment the activation of epidermal keratinocytes. Our results emphasize that management of concomitant metabolic disorders is essential for preventing disease exacerbation in patients with psoriasis.

DOI： 10.3390/ijms23084312

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

Dysregulation of Toll-like receptor (TLR) signaling contributes to the pathogenesis of autoimmune diseases. Here, we provide genetic evidence that tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, negatively regulates TLR2 signaling. We show that mice lacking tankyrase in myeloid cells developed severe systemic inflammation with high serum inflammatory cytokine levels. We provide mechanistic evidence that tankyrase deficiency resulted in tyrosine phosphorylation and activation of TLR2 and show that phosphorylation of tyrosine 647 within the TIR domain by SRC and SYK kinases was critical for TLR2 stabilization and signaling. Last, we show that the elevated cytokine production and inflammation observed in mice lacking tankyrase in myeloid cells were dependent on the adaptor protein 3BP2, which is required for SRC and SYK activation. These data demonstrate that tankyrase provides a checkpoint on the TLR-mediated innate immune response.

DOI： 10.1172/JCI140869

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Language：English   Publisher：WILEY  

DOI： 10.1111/nep.13966

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Background: Glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) plays a crucial role in lipolytic processing. Previous studies have shown that GPIHBP1 mutations cause severe hypertriglyceridemia and that serum GPIHBP1 levels are marginally higher in patients with coronary heart disease; however, the role of GPIHBP1 in type 2 diabetes mellitus (T2DM) remains unknown. Objective: We investigated the association between circulating GPIHBP1 levels and the prevalence of microvascular complications in T2DM. Methods: A total of 237 subjects with T2DM and 235 non-diabetic control subjects were enrolled in this study. Their serum GPIHBP1 levels were evaluated using ELISA assays. Results: Circulating GPIHBP1 levels were higher in patients with T2DM (952.7 pg/mL [761.31234.6], p < 0.0001) than in non-diabetic subjects (700.6 [570.8-829.6]), but did not differ in T2DM patients with or without hypertriglyceridemia. Serum GPIHBP1 levels were significantly higher in patients with T2DM with diabetic retinopathy (DR), diabetic nephropathy (DN), and microvascular complications than in those without these complications. Multivariable logistic regression and receiver operating characteristic (ROC) curve analyses revealed that the presence of microvascular complications, but not macrovascular complications, was independently associated with serum GPIHBP1 levels, which could Conclusions: Elevated GPIHBP1 levels are associated with microvascular complications in T2DM

DOI： 10.1016/j.jacl.2022.01.006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Introduction Several epidemiological studies have shown that silica exposure triggers the onset of systemic lupus erythematosus (SLE); however, the clinical characteristics of silica-associated SLE have not been well studied. Patient concerns A 67-year-old man with silicosis visited a primary hospital because of a fever and cough. His respiratory condition worsened, regardless of antibiotic medication, and he was referred to our hospital. Diagnosis The patient showed leukopenia, lymphopenia, serum creatinine elevation with proteinuria and hematuria, decreased serum C3 level, and was positive for anti-double stranded DNA antibody, anti-nuclear antibody, and direct Coombs test. He was diagnosed with SLE. Renal biopsy was performed, and the patient was diagnosed with lupus nephritis (class IV-G(A/C) + V defined by the International Society of Nephrology/Renal Pathology Society classification). Computed tomography revealed acute interstitial pneumonitis, bronchoalveolar lavage fluid showed elevation of the lymphocyte fraction, and he was diagnosed with lupus pneumonitis. Interventions Prednisolone (50 mg/day) with intravenous cyclophosphamide (500 mg/body) were initiated. Outcomes The patient showed a favorable response to these therapies. He was discharged from our hospital and received outpatient care with prednisolone slowly tapered off. He had cytomegalovirus and herpes zoster virus infections during treatment, which healed with antiviral therapy. Review: We searched for the literature on sSLE, and selected 11 case reports and 2 population-based studies. The prevalence of SLE manifestations in sSLE patients were comparative to that of general SLE, particularly that of elderly-onset SLE. Our renal biopsy report and previous reports indicate that lupus nephritis of sSLE patients show as various histological patterns as those of general SLE patients. Among the twenty sSLE patients reported in the case articles, three patients developed lupus pneumonitis and two of them died of it. Moreover, two patients died of bacterial pneumonia, one developed aspergillus abscesses, one got pulmonary tuberculosis, and one developed lung cancer. Conclusion Close attention is needed, particularly for respiratory system events and infectious diseases, when treating patients with silica-associated SLE using immunosuppressive therapies.

DOI： 10.1097/MD.0000000000028872

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Introduction: The pathogenic roles of aberrantly glycosylated IgA1 have been reported. However, it is unexplored whether the profiling of urinary glycans contributes to the diagnosis of IgAN. Methods: We conducted a retrospective study enrolling 493 patients who underwent renal biopsy at Okayama University Hospital between December 2010 and September 2017. We performed lectin microarray in urine samples and investigated whether c-statistics of the reference standard diagnosis model employing hematuria, proteinuria, and serum IgA were improved by adding the urinary glycan intensity. Results: Among 45 lectins, 3 lectins showed a significant improvement of the models: Amaranthus caudatus lectin (ACA) with the difference of c-statistics 0.038 (95% CI: 0.019-0.058, p < 0.001), Agaricus bisporus lectin (ABA) 0.035 (95% CI: 0.015-0.055, p < 0.001), and Maackia amurensis lectin (MAH) 0.035 (95% CI: 0.015-0.054, p < 0.001). In 3 lectins, each signal plus reference standard showed good reclassification (category-free NRI and relative IDI) and good model fitting associated with the improvement of AIC and BIC. Stratified by eGFR, the discriminatory ability of ACA plus reference standard was maintained, suggesting the robust renal function-independent diagnostic performance of ACA. By decision curve analysis, there was a 3.45% net benefit by adding urinary glycan intensity of ACA to the reference standard at the predefined threshold probability of 40%. Conclusions: The reduction of Gal(beta 1-3)GalNAc (T-antigen), Sia(alpha 2-3)Gal(beta 1-3)GalNAc (Sialyl T), and Sia(alpha 2-3)Gal(beta 1-3)Sia(alpha 2-6)GalNAc (disialyl-T) was suggested by binding specificities of 3 lectins. C1GALT1 and COSMC were responsible for the biosynthesis of these glycans, and they were known to be downregulated in IgAN. The urinary glycan analysis by ACA is a useful and robust noninvasive strategy for the diagnosis of IgAN.

DOI： 10.1159/000520998

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI  

Objective: The prevention of chronic kidney disease (CKD) progression is an important issue from health and financial perspectives. We conducted a single-year cross-sectional study to clarify the prevalence of CKD and its risk factors along with variations in these factors among five medical regions in Okayama Prefecture, Japan. Methods and Results: Data concerning the renal function and proteinuria as well as other CKD risk factors were obtained from the database of the Japanese National Health Insurance. The proportion of CKD patients at an increased risk of progression to end-stage renal disease (ESRD), classified as orange and red on the CKD heatmap, ranged from 6-9% and did not vary significantly by the regions. However, the causes of the increased severity differed between regions where renal dysfunction was predominant and regions where there were many patients with proteinuria. CKD risk factors, such as diabetes mellitus, hypertension, hyper low-density lipoprotein-cholesterolemia, obesity, smoking and lack of exercise, also differed among these regions, suggesting that different regions need tailored interventions that suit the characteristics of the region, such as an increased health checkup ratio, dietary guidance and promotion of exercise opportunities. Conclusions: Approximately 6-9% of people are at an increased risk of developing ESRD (orange or red on a CKD heatmap) among the population with National Health Insurance in Okayama Prefecture. The underlying health problems that cause CKD may differ among the regions. Thus, it is necessary to consider intervention methods for preventing CKD progression that are tailored to each region's health problems.

DOI： 10.3390/jpm12010097

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HINDAWI LTD  

Objective. We examined whether or not day-to-day variations in lipid profiles, especially triglyceride (TG) variability, were associated with the exacerbation of diabetic kidney disease. Methods. We conducted a retrospective and observational study. First, 527 patients with type 2 diabetes mellitus (DM) who had had their estimated glomerular filtration rate (eGFR) checked every 6 months since 2012 for over 5 years were registered. Variability in postprandial TG was determined using the standard deviation (SD), SD adjusted (Adj-SD) for the number of measurements, and maximum minus minimum difference (MMD) during the first three years of follow-up. The endpoint was a & GE;40% decline from baseline in the eGFR, initiation of dialysis or death. Next, 181 patients who had no micro- or macroalbuminuria in February 2013 were selected from among the 527 patients for an analysis. The endpoint was the incidence of microalbuminuria, initiation of dialysis, or death. Results. Among the 527 participants, 110 reached a & GE;40% decline from baseline in the eGFR or death. The renal survival was lower in the higher-SD, higher-Adj-SD, and higher-MMD groups than in the lower-SD, lower-Adj-SD, and lower-MMD groups, respectively (log-rank test p=0.0073, 0.0059, and 0.0195, respectively). A lower SD, lower Adj-SD, and lower MMD were significantly associated with the renal survival in the adjusted model (hazard ratio, 1.62, 1.66, 1.59; 95% confidence intervals, 1.05-2.53, 1.08-2.58, 1.04-2.47, respectively). Next, among 181 participants, 108 developed microalbuminuria or death. The nonincidence of microalbuminuria was lower in the higher-SD, higher-Adj-SD, and higher-MMD groups than in the lower-SD, lower-Adj-SD, and lower-MMD groups, respectively (log-rank test p=0.0241, 0.0352, and 0.0474, respectively). Conclusions. Postprandial TG variability is a novel risk factor for eGFR decline and the incidence of microalbuminuria in patients with type 2 DM.

DOI： 10.1155/2022/3157841

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FRONTIERS MEDIA SA  

MicroRNAs expressed in adipocytes are involved in transcriptional regulation of target mRNAs in obesity, but miRNAs critically involved in this process is not well characterized. Here, we identified upregulation of miR-221-3p and miR-222-3p in the white adipose tissues in C57BL/6 mice fed with high fat-high sucrose (HFHS) chow by RNA sequencing. Mir221 and Mir222 are paralogous genes and share the common seed sequence and Mir221/222AdipoKO mice fed with HFHS chow demonstrated resistance to the development of obesity compared with Mir221/222(flox/y). Ddit4 is a direct target of Mir221 and Mir222, and the upregulation of Ddit4 in Mir221/222AdipoKO was associated with the suppression of TSC2 (tuberous sclerosis complex 2)/mammalian target of rapamycin complex 1 (mTORC1)/S6K (ribosomal protein S6 kinase) pathway. The overexpression of miR-222-3p linked to enhanced adipogenesis, and it may be a potential candidate for miRNA-based therapy.

DOI： 10.3389/fendo.2021.750261

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BACKGROUND: Although vitamin D concentration is reportedly associated with the pathogenesis and pathology of systemic lupus erythematosus (SLE), benefits of vitamin D supplementation in SLE patients have not been elucidated, to our knowledge. We investigated the clinical impacts of vitamin D supplementation in SLE. METHODS: A cross-sectional analysis was performed using data from a lupus registry of nationwide institutions. We evaluated vitamin D supplementation status associated with disease-related Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) as a parameter of long-term disease activity control. RESULTS: Of the enrolled 870 patients (mean age: 45 years, mean disease duration: 153 months), 426 (49%) received vitamin D supplementation. Patients with vitamin D supplementation were younger (43.2 vs 47.5 years, P < 0.0001), received higher doses of prednisolone (7.6 vs 6.8 mg/day, P = 0.002), and showed higher estimated glomerular filtration rates (79.3 vs 75.3 mL/min/1.73m2, P = 0.02) than those without supplementation. Disease-related SDI (0.73 ± 1.12 vs 0.73 ± 1.10, P = 0.75), total SDI, and SLE Disease Activity Index (SLEDAI) did not significantly differ between patients receiving and not receiving vitamin D supplementation. Even after excluding 136 patients who were highly recommended vitamin D supplementation (with age ≥ 75 years, history of bone fracture or avascular necrosis, denosumab use, and end-stage renal failure), disease-related SDI, total SDI, and SLEDAI did not significantly differ between the two groups. CONCLUSIONS: Even with a possible Vitamin D deficiency and a high risk of bone fractures in SLE patients, only half of our cohort received its supplementation. The effect of vitamin D supplementation for disease activity control was not observed.

DOI： 10.1371/journal.pone.0270569

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TECH SCIENCE PRESS  

Mesenchymal stem cells (MSCs) have abilities to mediate tissue protection through mechanisms of antiapoptosis, anti-oxidative stress and anti-fibrosis as well as tissue regeneration through mechanisms of cell proliferation, differentiation and angiogenesis. These effects by MSCs are mediated by a variety of factors, including growth factors, cytokines and extracellular vesicles (EVs). Among these factors, EVs, containing proteins, mRNA and microRNAs (miRNA), may carry their contents into distant tissues with high stability. Therefore, the treatment with MSC-derived EVs may be promising as 'natural' drug delivery systems (DDS). Especially, the treatment of MSCderived EVs with the manipulation of specific miRNAs expression has been reported to be beneficial under a variety of diseases and tissue injuries. The overexpression of specific miRNAs in the EVs might be through pre-loading method using the gene editing system by plasmid vector or post-loading method to load miRNA mimics into EVs by electroporation or calcium chloride-mediated transfection. Despite current several challenges for clinical use, it should open the next era of regenerative medicine for a variety of diseases. In this article, we highlight the therapeutic potential of MSC-derived EVs as 'natural' DDS and current challenges.

DOI： 10.32604/biocell.2022.018594

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INTRODUCTION: While it is well known that thyroid function may affect kidney function, the transition of the chronic kidney disease (CKD) status before and after treatment for thyroid disorders, as well as the factors affecting this change, remains to be explored. In the present study, we focused on the change in kidney function and their affecting factors during the treatment for both hyperthyroidism and hypothyroidism. METHODS: Eighty-eight patients with hyperthyroidism and fifty-two patients with hypothyroidism were enrolled in a retrospective and longitudinal case series to analyze the changes in kidney function and their affecting factors after treatment for thyroid disorders. RESULTS: Along with the improvement of thyroid function after treatment, there was a significant decrease in estimated glomerular filtration rate (eGFR) in hyperthyroidism (an average ΔeGFR of -41.1 mL/min/1.73 m2) and an increase in eGFR in hypothyroidism (an average ΔeGFR of 7.1 mL/min/1.73 m2). The multiple linear regression analysis revealed that sex, eGFR, free thyroxine (FT4) and free triiodothyronine (FT3) could be considered independent explanatory variables for ΔeGFR in hyperthyroidism, while age, eGFR, and FT3 were detected as independent explanatory variables in hypothyroidism. In addition, the stratification by kidney function at two points, pre- and post-treatment for thyroid disorders, revealed that 4.5% of the participants with hyperthyroidism were pre-defined as non-CKD and post-defined as CKD, indicating the presence of "masked" CKD in hyperthyroidism. On the other hand, 13.5% of the participants with hypothyroidism presented pre-defined CKD and post-defined non-CKD, indicating the presence of "reversible" CKD status in hypothyroidism. CONCLUSIONS: We uncovered the population of masked CKD in hyperthyroidism and reversible CKD status in hypothyroidism, thereby re-emphasizing the importance of a follow-up to examine kidney function after treatment for hyperthyroidism and the routine evaluation of thyroid function in CKD patients as well as the appropriate hormone therapy if the patient has hypothyroidism.

DOI： 10.3389/fendo.2022.1048863

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DOI： 10.1136/ANNRHEUMDIS-2022-EULAR.1406

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DOI： 10.1016/J.HELIYON.2022.E11271

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DOI： 10.3390/MEDICINA58111529

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/S43587-021-00151-2

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Other Link： https://www.nature.com/articles/s43587-021-00151-2

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

Renal fibrosis is the common pathological pathway in progressive renal diseases. In the present study, we analyzed the roles of semaphorin 3 A (SEMA3A) on renal fibrosis and the effect of SEMA3A inhibitor (SEMA3A-I) using a unilateral ureteral obstruction (UUO) mouse model. Expression of SEMA3A in the proximal tubulus and neuropilin-1, a recepor of SEMA3A, in fibloblast and tubular cells were increased in UUO kidneys. The expression of myofibroblast marker tenascin-C and fibronection as well as renal fibrosis were increased in UUO kidneys, all of which were ameliorated by SEMA3A-I. In addition, the JNK signaling pathway, known as the target of SEMA3A signaling, was activated in proximal tubular cells and fibroblast cells after UUO surgery, and SEMA3A-I significantly attenuated the activation. In vitro, treatments with SEMA3A as well as transforming growth factor-beta 1 (TGF-beta 1) in human proximal tubular cells lost epithelial cell characteristics, and SEMA3A-1 significantly ameliorated this transformation. The JNK inhibitor SP600125 partially reversed SEMA3A and TGF-beta 1-induced cell transformation, indicating that JNK signaling is involved in SEMA3A-induced renal fibrosis. In addition, treatment with SEMA3A in fibroblast cells activated expression of tenascin-C, collagen type I, and fibronection, indicating that SEMA3A may accelerate renal fibrosis through the activation of fibroblast cells. Analysis of human data revealed the positive correlation between urinary SEMA3A and urinary N-acetyl-beta-D-glucosaminidase, indicating the association between SEMA3A and tubular injury. In conclusion, SEMA3A signaling is involved in renal fibrosis through the JNK signaling pathway and SEMA3A-I might be a therapeutic option for protecting from renal fibrosis.NEW & NOTEWORTHY Renal fibrosis is the common pathological pathway in the progression of renal diseases. This study, using a unilateral ureteral obstruction (UUO) mouse model, indicated increased semaphorin3A (SEMA3A) signaling in renal tubular cells as well as fibroblast cells under UUO surgery, and SEMA3A inhibitor ameliorated UUO-induced renal fibrosis through the regulation of JNK signaling. The study proposes the potential therapeutic option of SEMA3A inhibitor to treat renal fibrosis.

DOI： 10.1152/ajprenal.00234.2021

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Objectives To investigate the association between duration of consecutive presence of decoy cells on urine cytology and BK virus nephropathy after kidney transplantation. Methods In total, 121 kidney transplant recipients were retrospectively evaluated. The best duration of consecutive presence of decoy cells that could be used to predict BK virus nephropathy was analyzed using the area under the curve for each duration, and recipients were divided into two groups based on the best predictive performance. The effectiveness of SV40 immunostaining on urinary cytology was also analyzed. Results In total, 2534 urine specimens as well as SV40 immunostaining in 2241 urine specimens were analyzed. Six consecutive months of decoy cell positivity had the best predictive performance for BK virus nephropathy (area under the curve = 0.832). The incidence of BK virus nephropathy in recipients with positive decoy cells for 6 months or more consecutive months (5/44) was significantly higher than in those who had positive decoy cells for less than 6 months (0/77; P = 0.005). Decoy cell positivity had a sensitivity, specificity, positive predictive value, and negative predictive value for BK virus nephropathy of 100%, 66%, 11%, and 100% respectively. SV40 immunostaining provided slightly better specificity (68%) and positive predictive value (12%). Conclusions The detection of decoy cells at 6 months or more on urine cytology had high predictive value for BK virus nephropathy in kidney transplant recipients. SV40 immunostaining on urine cytology added minimal diagnostic accuracy.

DOI： 10.1111/iju.14679

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Introduction: Drug-induced acute interstitial nephritis (DI-AIN) is an important cause of acute kidney injury. In renal biopsy specimens, tubulitis with eosinophilic infiltration is suggestive of DI-AIN. Although corticosteroid therapy and discontinuation of the offending drug can improve renal dysfunction in most cases of DI-AIN, some patients experience AIN recurrence, leading to corticosteroid dependency. Corticosteroid-dependent eosinophilic interstitial nephritis presents a difficult dilemma in diagnosis and information regarding optimum management is limited. Patient concerns: A 25-year-old man, who received treatment with carbamazepine, zonisamide, valproate, and lacosamide for temporal lobe epilepsy, showed an increase in serum creatinine level from 0.98 to 1.29 mg/dL over a period of 6 months. Although he exhibited no symptoms, his serum creatinine level continued to increase to 1.74 mg/dL. Diagnosis: Renal biopsy revealed tubulitis and interstitial inflammatory infiltrates with eosinophils. Immunological and ophthalmological examinations showed no abnormal findings, and thus, his renal dysfunction was presumed to be caused by DI-AIN. Although oral prednisolone (PSL) administration (40 mg/d) and discontinuation of zonisamide immediately improved his renal function, AIN recurred 10 months later. The increase in PSL dose along with discontinuation of valproate and lacosamide improved renal function. However, 10 months later, recurrent AIN with eosinophilic infiltration was confirmed by further biopsy. The patient was therefore diagnosed with corticosteroid-dependent eosinophilic interstitial nephritis. Interventions: To prevent life-threatening epilepsy, carbamazepine could not be discontinued; hence, he was treated with an increased dose of PSL (60 mg/d) and 1500 mg/d of mycophenolate mofetil (MMF). Outcomes: MMF was well tolerated and PSL was successfully tapered to 5 mg/d; renal function stabilized over a 20-month period. Lessons: The presence of underdetermined autoimmune processes and difficulties in discontinuing the putative offending drug discontinuation are contributing factors to corticosteroid dependency in patients with eosinophilic interstitial nephritis. MMF may be beneficial in the management of corticosteroid-dependent eosinophilic interstitial nephritis by reducing the adverse effects related to high-dose and long-term corticosteroid use.

DOI： 10.1097/MD.0000000000028252

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Language：English   Publisher：WILEY  

DOI： 10.1111/jdi.13655

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER DIABETES ASSOC  

OBJECTIVE Randomized controlled trials have shown kidney-protective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors, and clinical practice databases have suggested that these effects translate to clinical practice. However, long-term efficacy, as well as whether the presence or absence of proteinuria and the rate of estimated glomerular filtration rates (eGFR) decline prior to SGLT2 inhibitor initiation modify treatment efficacy among type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) patients, is unknown. RESEARCH DESIGN AND METHODS Using the Japan Chronic Kidney Disease Database (J-CKD-DB), a nationwide multicenter CKD registry, we developed propensity scores for SGLT2 inhibitor initiation, with 1:1 matching with patients who were initiated on other glucose-lowering drugs. The primary outcome included rate of eGFR decline, and the secondary outcomes included a composite outcome of 50% eGFR decline or end-stage kidney disease. RESULTS At baseline, mean age at initiation of the SGLT2 inhibitor (n = 1,033) or other glucose-lowering drug (n = 1,033) was 64.4 years, mean eGFR was 68.1 mL/min per 1.73 m(2), and proteinuria was apparent in 578 (28.0%) of included patients. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs. other drugs 0.75 mL/min/1.73 m(2) per year [0.51 to 1.00]). During a mean follow-up of 24 months, 103 composite kidney outcomes occurred: 30 (14 events per 1,000 patient-years) among the SGLT2 inhibitors group and 73 (36 events per 1,000 patient-years) among the other drugs group (hazard ratio 0.40, 95% CI 0.26-0.61). The benefit provided by SGLT2 inhibitors was consistent irrespective of proteinuria and rate of eGFR decline before initiation of SGLT2 inhibitors (P-heterogeneity >= 0.35). CONCLUSIONS The benefits of SGLT2 inhibitors on kidney function as observed in clinical trials translate to patients treated in clinical practice with no evidence that the effects are modified by the underlying rate of kidney function decline or the presence of proteinuria.

DOI： 10.2337/dc21-1081

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Language：English   Publisher：FRONTIERS MEDIA SA  

DOI： 10.3389/fendo.2021.811189

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOC STUDY XENOBIOTICS  

We evaluated the impact of vonoprazan on blood concentrations of tacrolimus via a retrospective analysis of 52 renal transplant recipients who took tacrolimus and converted from rabeprazole to vonoprazan between August 2018 and September 2019. We compared tacrolimus trough levels upon conversion among groups that were classified based on cytochrome P450 (CYP) gene polymorphisms. CYP3A5 groups were heterozygous or homozygous for CYP3A5*1 and CYP3A5*3 alleles. CYP2C19 geno-types were classified as extensive (*1/*1), intermediate (* 1/*2 and *1/*3) or poor metabolizers (*2/*2, *2/ *3 and *3/*3). Tacrolimus trough levels increased only 0.3 ng/mL upon conversion in the CYP3A5*3/*3 group: 5.8 [3.4-7.2] vs 6.1 [3.8-7.9]; p = 0.06. No statistically significance changes in tacrolimus levels also occurred in the CYP3A5*1/*1 or CYP3A5*1/*3 groups. Subgroup analyses of CYP3A5*3/*3 demonstrated low changes for all three CYP2C19 subgroups: 5.2 [4.3-6.5] vs 6.2 [4.3-7.9]; p = 0.07, 6.1 [3.4-7.2] vs 6.7 [4.6-7.9]; p = 0.12 and 5.4 [3.6-6.5] vs 4.7 [3.8-6.3]; p = 1.00, respectively. Conversion to vonoprazan thus resulted in little increase of tacrolimus trough levels, even in the group predicted to be most susceptible (CYP3A5*3/*3 and 2C19*1/*1), thus supporting the safety of concomitant use of vonoprazan with tacrolimus. (C) 2021 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.dmpk.2021.100407

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Language：English   Publisher：FRONTIERS MEDIA SA  

Several large clinical trials have shown renal and cardioprotective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in diabetes patients, and the protective mechanisms need to be elucidated. There have been accumulating studies which report that SGLT2 inhibitors ameliorate autophagy deficiency of multiple organs. In overnutrition diseases, SGLT2 inhibitors affect the autophagy via various signaling pathways, including mammalian target of rapamycin (mTOR), sirtuin 1 (SIRT1), and hypoxia-inducible factor (HIF) pathways. Recently, it turned out that not only stagnation but also overactivation of autophagy causes cellular damages, indicating that therapeutic interventions which simply enhance or stagnate autophagy activity might be a "double-edged sword" in some situations. A small number of studies suggest that SGLT2 inhibitors not only activate but also suppress the autophagy flux depending on the situation, indicating that SGLT2 inhibitors can "regulate" autophagic activity and help achieve the appropriate autophagy flux in each organ. Considering the complicated control and bilateral characteristics of autophagy, the potential of SGLT2 inhibitors as the regulator of autophagic activity would be beneficial in the treatment of autophagy deficiency.

DOI： 10.3389/fphar.2021.761842

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Objectives: To compare the donor outcomes of living donor kidney transplantation between standard donors (SDs) and marginal donors (MDs) including diabetic patients (MD + DM).Methods: MDs were defined according to Japanese guideline criteria: (a) age >70-years, (b) blood pressure <= 130/80 mmHg on hypertension medicine, (c) body mass index >25 to <= 32 kg/m(2), (d) 24-h creatinine clearance >= 70 to <80 ml/min/1.73 m(2), and (e) hemoglobin A1c > 6.2 or <= 6.5 with oral diabetic medicine. Fifty-three of 114 donors were MDs. We compared donor kidney functions until 60 months postoperatively.Results: No kidney function parameters were different between SDs and MDs. When comparing SD and MD + DM, MD + DM had a lower postoperative eGFR (48 vs. 41 (1 (month), p = .02), 49 vs. 40 (12, p < .01), 48 vs. 42 (24, p = .04), 47 vs. 38 (36, p = .01)) and the percentage of residual eGFR (SD vs. MD + DM: 63 vs. 57 (1 (month), p < .01), 63 vs. 57 (2, p < .01), 64 vs. 56 (12, p < .01), 63 vs. 57 (24, p < .01), 63 vs. 52 (36, p = .02)). However, when MD with a single risk factor of DM was compared to SD, the difference disappeared. Nine out of 12 (75%) MD + DM had >= 2 risk factors.Conclusions: Although long-term observation of donor kidney function is necessary, careful MD + DM selection had the potential to expand the donor pool.

DOI： 10.1002/iid3.470

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Immune checkpoint inhibitor-induced diabetes mellitus is a rare immune-related adverse event. This report illustrates clinical data and insulin secretory ability before and after the onset of immune checkpoint inhibitor-induced diabetes.

DOI： 10.1002/ccr3.4574

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Language：English   Publisher：NATURE PORTFOLIO  

DOI： 10.1038/s41598-021-98293-1

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ABSTRACT: Peripheral arterial disease (PAD) is one of major vascular diseases which frequently coexists with coronary arterial disease and cerebrovascular disease. The patients with PAD have a poor prognosis when it progresses. A new blood pressure testing device enables to simultaneously measure brachial blood pressure (BP), central BP, and several vascular parameters, with easy and non-invasive, in a short time. Here, we aimed to evaluate these arterial stiffness parameters in patients with PAD.In this study, 243 consecutive patients who were suspected of having PAD and referred to our hospital from September 2016 to June 2019, were registered. Several parameters, such as brachial BP, central BP, aortic pulse wave velocity (aPWV), total vascular resistance (TVR), augmentation index (AI) and augmentation pressure (AP), were determined by Mobil-O-Graph. Ankle-brachial pressure index (ABI) was used to define PAD (ABI ≤ 0.9 as PAD). The relationship between PAD and central BP, aPWV, TVR, AI, or AP were investigated.One hundred sixty-two patients (67%) were categorized as the PAD group and 81 patients (33%) as the non-PAD group. In the PAD group, the systolic brachial BP and central systolic BP were significantly higher than those in the non-PAD group (138 ± 24 mmHg vs 131 ± 19 mmHg, P < .05, 125 ± 22 mmHg vs 119 ± 18 mmHg, P < .05, respectively). TVR, AI, and AP were significantly higher in the PAD group (1785 ± 379 dyn s/cm5 vs 1661 ± 317 dyn s/cm5, P < .05, 26.2 ± 13.0% vs 22.2 ± 13.3%, P < .05, 13.5 ± 9.4 mmHg vs 10.7 ± 7.2 mmHg, P < .05, respectively). No significant differences in diastolic BP, central diastolic BP, and aPWV were found between the groups. Multivariate logistic regression analysis revealed that PAD was significantly associated with TVR, AI, and AP (P < .05, respectively).TVR/AP/AI were significantly higher in the PAD group than in the non-PAD group.

DOI： 10.1097/MD.0000000000026931

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Language：English   Publisher：WILEY  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER  

Case presentation.A 49-year-old Asian male, who had undergone hemodialysis for >16 years, complained of a fever, dysgeusia and dysosmia, and was diagnosed with COVID-19 pneumonia based on severe acute respiratory syndrome coronavirus 2 polymerase chain reaction (SARS-CoV-2 PCR) and computed tomography (CT). Treatment was started with oral favipiravir and ciclesonide inhalation. On the 10th day of treatment, the patient had a persistent high fever and a chest CT showed exacerbation of pneumonia, so dexamethasone was intravenously started. He was discharged after confirming two consecutive negative SARS-CoV-2 PCR tests. Three months after COVID-19 treatment, a SARS-CoV-2 PCR test was negative and he underwent a deceased donor kidney transplantation. Basiliximab induction with triple drug immunosuppression consisting of extended-release tacrolimus, mycophenolate mofetil and prednisolone, which is our regular immunosuppression protocol, was used. He was discharged on postoperative day 18 without the need for postoperative hemodialysis or any complications. The serum creatinine level was 1.72 mg/dL 95 days postoperatively and he had a favorable clinical course that was similar to deceased donor kidney recipients without a history of SARS-CoV-2 infection.Conclusion. We report the first case of a kidney transplantation after COVID-19 treatment in Japan and the fourth case globally. We would like to provide information about our successful case due to the anticipated increase in similar candidates in the near future.(c) 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jiac.2021.03.018

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PORTFOLIO  

It is well-known that hypertension exacerbates chronic kidney disease (CKD) progression, however, the optimal target blood pressure (BP) level in patients with CKD remains unclear. This study aimed to assess the optimal BP level for preventing CKD progression. The risk of renal outcome among different BP categories at baseline as well as 1 year after, were evaluated using individual CKD patient data aged between 40 and 74 years from FROM-J [Frontier of Renal Outcome Modifications in Japan] study. The renal outcome was defined as >= 40% reduction in estimated glomerular filtration rate to<60 mL/min/1.73 m(2), or a diagnosis of end stage renal disease. Regarding baseline BP, the group of systolic BP (SBP) 120-129 mmHg had the lowest risk of the renal outcome, which increased more than 60% in SBP<greater than or equal to>130 mmHg group. A significant increase in the renal outcome was found only in the group of diastolic BP >= 90 mmHg. The group of BP<130/80 mmHg had a benefit for lowering the risk regardless of the presence of proteinuria, and it significantly reduced the risk in patients with proteinuria. Achieving SBP level<130 mmHg after one year resulted in a 42% risk reduction in patients with SBP level >= 130 mmHg at baseline. Targeting SBP level<130 mmHg would be associated with the preferable renal outcome.Clinical Trial Registration-URL: https://www.umin.ac.jp/ctr/. Unique identifier: UMIN000001159 (16/05/2008).

DOI： 10.1038/s41598-021-94467-z

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DOI： 10.3389/fonc.2021.729192

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMC  

BackgroundEmpathy, which involves understanding another person's experiences and concerns, is an important component for developing physicians' overall competence. This longitudinal study was designed to test the hypothesis that medical students' empathy can be enhanced and sustained by Humanitude Care Methodology, which focuses on perception, emotion and speech.MethodsThis six-year longitudinal observational study examined 115 students who entered Okayama University Medical School in 2013. The study participants were exposed to two empathy-enhancing programs: (1) a communication skills training program (involving medical interviews) and (2) a Humanitude training program aimed at enhancing their empathy. They completed the Jefferson Scale of Empathy (JSE) seven times: when they entered medical school, before participation in the first program (medical interview), immediately after the first program, before the second program (Humanitude exercise), immediately after the second program, and in the 5th and 6th year (last year) of medical school. A total of 79 students (69% of the cohort) completed all seven test administrations of the JSE.ResultsThe mean JSE scores improved significantly after participation in the medical interview program (p<0.01) and the Humanitude training program (p=0.001). However, neither program showed a sustained effect.ConclusionsThe Humanitude training program as well as medical interview training program, had significant short-term positive effects for improving empathy among medical students. Additional reinforcements may be necessary for a long-term sustained effect.

DOI： 10.1186/s12909-021-02773-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Background. We investigated the association between ABO-incompatible (ABO-I) kidney transplantation and early graft function. Methods. We retrospectively analyzed 95 patients who underwent living donor kidney trans-plantation between May 2009 and July 2019. It included 61 ABO-compatible (ABO-C) and 34 ABO-I transplantations. We extracted data on immunologic profile, sex, age, cold ischemic time, type of immunosuppression, and graft function. Two definitions were used for slow graft func-tion (SGF) as follows: postoperative day (POD) 3 serum creatinine level >3 mg/dL and estimated glomerular filtration rate (eGFR) <20 mL/min/1.73 m(2). Logistic regression analysis was per -formed to analyze the effect of ABO-I on the incidence of SGF . Results. The characteristics between the ABO-C and ABO-I were not different. ABO-I received rituximab and plasma exchange. Patients also received tacrolimus and mycophenolate mofetil for 2 weeks and prednisolone for 1 week before transplantation as preconditioning. Of the 95 study patients, 19 (20%) and 21 (22%) were identified with SGF according to POD 3 serum creatinine level or eGFR, respectively. Multivariable analysis revealed that ABO-I signifi- cantly reduced the incidence of SGF (odds ratio, 0.15; 95% confidence interval, 0.03-0.7; P = .02), and cold ischemic time >150 min increased the incidence of SGF (odds ratio, 6.5; 95% confidence interval, 1.7-25; P = .006). Similar results were identified in POD 3 eGFR. Inferior graft function in patients with SGF was identified up to 6 months after transplantation. Conclusion. ABO-I reduces the incidence of SGF, which is associated with an inferior graft function up to 6 months.

DOI： 10.1016/j.transproceed.2021.03.043

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Background: Although various biomarkers predict cardiovascular event (CVE) in patients with diabetes, the relationship of urinary glycan profile with CVE in patients with diabetes remains unclear.Methods: Among 680 patients with type 2 diabetes, we examined the baseline urinary glycan signals binding to 45 lectins with different specificities. Primary outcome was defined as CVE including cardiovascular disease, stroke, and peripheral arterial disease.Results: During approximately a 5-year follow-up period, 62 patients reached the endpoint. Cox proportional hazards analysis revealed that urinary glycan signals binding to two lectins were significantly associated with the outcome after adjustment for known indicators of CVE and for false discovery rate, as well as increased model fitness. Hazard ratios for these lectins (+1 SD for the glycan index) were UDA (recognizing glycan: mixture of Man5 to Man9): 1.78 (95% CI: 1.24-2.55, P = 0.002) and Calsepa [High-Man (Man2-6)]: 1.56 (1.19-2.04, P = 0.001). Common glycan binding to these lectins was high-mannose type of N-glycans. Moreover, adding glycan index for UDA to a model including known confounders improved the outcome prediction [Difference of Harrel's C-index: 0.028 (95% CI: 0.001-0.055, P = 0.044), net reclassification improvement at 5-year risk increased by 0.368 (0.045-0.692, P = 0.026), and the Akaike information criterion and Bayesian information criterion decreased from 725.7 to 716.5, and 761.8 to 757.2, respectively].Conclusion: The urinary excretion of high-mannose glycan may be a valuable biomarker for improving prediction of CVE in patients with type 2 diabetes, and provides the rationale to explore the mechanism underlying abnormal N-glycosylation occurring in patients with diabetes at higher risk of CVE.

DOI： 10.3389/fcvm.2021.668059

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BACKGROUNDVasohibin-2 (VASH2) has been isolated as a homologue of vasohibin-1 (VASH1) that promotes angiogenesis counteracting with VASH1. Chronic angiotensin II (AngII) infusion promotes both ascending and abdominal aortic aneurysms (AAs) in mice. The present study aimed to investigate whether exogenous VASH2 influenced AngII-induced vascular pathology in apolipoprotein E-deficient (ApoE(-/-)) mice.METHODSMale, ApoE(-/-) mice (9-14 weeks old) were injected with Ad LacZ or Ad VASH2. After a week, saline or AngII (1,000 ng/kg/minute) was infused into the mice subcutaneously via mini-osmotic pumps for 3 weeks. Consequently, all these mice were divided into 4 groups: saline + LacZ (n = 5), saline + VASH2 (n = 5), AngII + LacZ (n = 18), and AngII + VASH2 (n = 17).RESULTSExogenous VASH2 had no significant effect on ex vivo maximal diameters of abdominal aortas (AngII + LacZ: 1.67 0.17 mm, AngII + VASH2: 1.52 +/- 0.16 mm, n.s.) or elastin fragmentation and accumulation of inflammatory cells. Conversely, exogenous VASH2 significantly increased intima areas of aortic arches (AngII + LacZ: 16.6 +/- 0.27 mm(2), AngII + VASH2: 18.6 +/- 0.64 mm(2), P = 0.006). VASH2 effect of AngII-induced ascending AAs was associated with increased cleaved caspase-3 abundance. AngII-induced atherosclerosis was not altered by VASH2.CONCLUSIONSThe present study demonstrated that augmented VASH2 expression had no effect of AngII-induced abdominal AAs or atherosclerosis, while increasing dilation in the ascending aorta.

DOI： 10.1093/ajh/hpaa181

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Orexin is expressed mainly in the hypothalamus and is known to activate the hypothalamic-pituitary-adrenal (HPA) axis that is involved in various stress responses and its resilience. However, the effects of orexin on the endocrine function of pituitary corticotrope cells remain unclear. In this study, we investigated the roles of orexin A in pro-opiomelanocortin (POMC) transcription using mouse corticotrope AtT20 cells, focusing on the bone morphogenetic protein (BMP) system expressed in the pituitary. Regarding the receptors for orexin, type 2 (OXR2) rather than type 1 (OX1R) receptor mRNA was predominantly expressed in AtT20 cells. It was found that orexin A treatment enhanced POMC expression, induced by corticotropin-releasing hormone (CRH) stimulation through upregulation of CRH receptor type-1 (CRHR1). Orexin A had no direct effect on the POMC transcription suppressed by BMP-4 treatment, whereas it suppressed Smad1/5/9 phosphorylation and Id-1 mRNA expression induced by BMP-4. It was further revealed that orexin A had no significant effect on the expression levels of type I and II BMP receptors but upregulated inhibitory Smad6/7 mRNA and protein levels in AtT20 cells. The results demonstrated that orexin A upregulated CRHR signaling and downregulated BMP-Smad signaling, leading to an enhancement of POMC transcription by corticotrope cells.

DOI： 10.3390/ijms22094553

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Bone is a highly dynamic organ that undergoes remodeling equally regulated by osteoblast-mediated bone formation and osteoclast-mediated bone resorption. To clarify the regulation of osteoblastogenesis, primary murine osteoblasts are required for an in vitro study. Primary osteoblasts are isolated from neonatal calvariae through digestion with collagenase. However, the number of cells collected from one pup is not sufficient for further in vitro experiments, leading to an increase in the use of euthanized pups. We hypothesized that the viscosity of digested calvariae and digestion solution supplemented with collagenase results in cell clumping and reduction of isolated cells from bones. We simply added Benzonase, a genetically engineered endonuclease that shears all forms of DNAs/RNAs, in order to reduce nucleic acid-mediated viscosity. We found that addition of Benzonase increased the number of collected osteoblasts by three fold compared to that without Benzonase through reduction of viscosity. Additionally, Benzonase has no effect on cellular identity and function. The new osteoblast isolation protocol with Benzonase minimizes the number of neonatal pups required for an in vitro study and expands the concept that isolation of other populations of cells including osteocytes that are difficult to be purified could be modified by Benzonase.

DOI： 10.1038/s41598-021-87716-8

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Several studies have reported the efficacy and safety of polyphenols in human health; however, the verification of their efficacy remains insufficient. The aim of this study was to examine whether fisetin, one of flavonoids prevalently present in fruits and vegetables, could suppress lipopolysaccharide- (LPS-) induced inflammatory responses in macrophages. LPS increased proinflammatory mRNA abundance (MCP 1, IL-1 beta, and iNOS) but were suppressed by fisetin. The increment of nitric oxide by LPS, an oxidative stress factor, was attenuated by fisetin. In addition, LPS-enhanced phosphorylation of mitogen-activated protein kinase (ERK and JNK) was reduced. Finally, fisetin attenuated the expression or activity of uPA, uPAR, MMP-2, and MMP-9, which are known as associated factors of macrophage recruitment or infiltration. In conclusion, fisetin is a promising therapeutic agent for macrophage-related inflammation diseases, like sepsis and atherosclerosis.

DOI： 10.1155/2021/5570885

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BACKGROUND: While survival of systemic lupus erythematosus (SLE) patients has improved substantially, problems remain in the management of their emotional health. Medium to high-dose glucocorticoid doses are known to worsen emotional health; the effect is unclear among patients receiving relatively low-dose glucocorticoids. This study aims to investigate the association between low glucocorticoid doses and emotional health in lupus low disease activity state (LLDAS). METHODS: This cross-sectional study drew on data from SLE patients in 10 Japanese institutions. The participants were adult patients with SLE duration of ≥ 1 year who met LLDAS criteria at the study visit from April 2018 through September 2019. The exposure was the daily glucocorticoid dose (mg oral prednisolone). The outcome was the emotional health score of the lupus patient-reported outcome scale (range: 0 to 100). Multiple linear regression analysis was performed with adjustment for confounders including disease-related damage, activity, and psychotropic drug use. RESULTS: Of 192 patients enrolled, 175 were included in the analysis. Their characteristics were as follows: female, 89.7%; median age, 47 years (interquartile range (IQR): 37.0, 61.0). Median glucocorticoid dose was 4.0 mg (IQR 2.0, 5.0), and median emotional health score 79.2 (IQR 58.3, 91.7). Multiple linear regression analysis showed daily glucocorticoid doses to be associated with worse emotional health (β coefficient = - 2.54 [95% confidence interval - 4.48 to - 0.60], P = 0.01). CONCLUSIONS: Daily glucocorticoid doses were inversely associated with emotional health among SLE patients in LLDAS. Further studies are needed to determine whether glucocorticoid tapering leads to clinically significant improvements in emotional health.

DOI： 10.1186/s13075-021-02466-2

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Proximal tubular cells (PTCs) are crucial for maintaining renal homeostasis, and tubular injuries contribute to progression of diabetic kidney disease (DKD). However, the roles of visceral adipose tissue-derived serine protease inhibitor (vaspin) in the development of DKD is not known. We found vaspin maintains PTCs through ameliorating ER stress, autophagy impairment, and lysosome dysfunction in DKD. Vaspin-/- obese mice showed enlarged and leaky lysosomes in PTCs associated with increased apoptosis, and these abnormalities were also observed in the patients with DKD. During internalization into PTCs, vaspin formed a complex with heat shock protein family A (Hsp70) member 1 like (HSPA1L) as well as 78kDa glucose-regulated protein (GRP78). Both vaspin-partners bind to clathrin heavy chain and involve in the endocytosis. Notably, albumin-overload enhanced extracellular release of HSPA1L and overexpression of HSPA1L dissolved organelle stresses, especially autophagy impairment. Thus, vapsin/HSPA1L-mediated pathways play critical roles in maintaining organellar function of PTCs in DKD.

DOI： 10.1038/s42003-021-01902-y

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In IgA nephropathy (IgAN), IgA1 molecules are characterized by galactose deficiency in O-glycans. Here, we investigated the association between urinary glycosylation profile measured by 45 lectins at baseline and renal prognosis in 142 patients with IgAN. The primary outcome was estimated glomerular filtration rate (eGFR) decline (>4 mL/min/1.73 m(2)/year), or eGFR >= 30% decline from baseline, or initiation of renal replacement therapies within 3 years. During follow-up (3.4 years, median), 26 patients reached the renal outcome (Group P), while 116 patients were with good renal outcome (Group G). Multivariate logistic regression analyses revealed that lectin binding signals of Erythrina cristagalli lectin (ECA) (odds ratio [OR] 2.84, 95% confidence interval [CI] 1.11-7.28) and Narcissus pseudonarcissus lectin (NPA) (OR 2.32, 95% CI 1.11-4.85) adjusted by age, sex, eGFR, and urinary protein were significantly associated with the outcome, and they recognize Gal(beta 1-4)GlcNAc and high-mannose including Man(alpha 1-6)Man, respectively. The addition of two lectin-binding glycan signals to the interstitial fibrosis/tubular atrophy score further improved the model fitness (Akaike's information criterion) and incremental predictive abilities (c-index, net reclassification improvement, and integrated discrimination improvement). Urinary N-glycan profiling by lectin array is useful in the prediction of IgAN prognosis, since ECA and NPA recognize the intermediate glycans during N-glycosylation of various glycoproteins.

DOI： 10.1038/s41598-020-77736-1

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RATIONALE: Bronchial involvement alone is a rare initial manifestation of granulomatosis with polyangiitis (GPA). Herein, we report a case of refractory GPA with obstructive pneumonia caused by bronchial involvement. PATIENT CONCERNS: A 65-year-old man complained of a 2-week cough and fever. DIAGNOSES: Considering the presence of opacities and multiple consolidations in both lungs due to obstruction or stenosis on the bronchus, which did not respond to antibiotics, and proteinase-3-antineutrophil cytoplasmic autoantibody positivity, he was diagnosed with GPA. Positron emission tomography- computed tomography scan revealed no abnormal findings in the upper respiratory tract. INTERVENTIONS: He was treated with prednisolone (PSL, 50 mg/d) and intravenous cyclophosphamide. OUTCOMES: His general and respiratory symptoms improved. However, 8 weeks after PSL treatment at 20 mg/d, he developed a relapse of vasculitis along with sinusitis and hypertrophic pachymeningitis. Hence, PSL treatment was resumed to 50 mg/d, and weekly administration of rituximab was initiated. Consequently, the symptoms gradually mitigated. LESSONS: GPA with bronchial involvement is often intractable and requires careful follow-up, which should include upper respiratory tract and hypertrophic pachymeningitis assessment.

DOI： 10.1097/MD.0000000000024028

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Background Patients with diabetes mellitus and severe proteinuria present with poor renal prognoses, despite improvements in diabetes and kidney disease therapies. In this study, we designed a low-density lipoprotein (LDL)-cholesterol apheresis treatment for patients with diabetic nephropathy (DN)/diabetic kidney disease and severe proteinuria. This was a multicenter prospective LICENSE study to confirm the impact of LDL apheresis on proteinuria that exhibited hyporesponsiveness to treatment. In addition, we sought to determine the efficacy and safety of LDL apheresis by comparing the outcomes to those of historical controls in patients with diabetes, refractory hypercholesterolemia, and severe proteinuria. Methods This was a prospective, multicenter study, including 40 patients with diabetes, severe proteinuria, and dyslipidemia. LDL apheresis was performed 6-12 times over a 12-week period. The primary endpoint was the proportion of patients with a decrease in proteinuria excretion of at least 30% in the 6 months after starting therapy. The secondary endpoints included serum creatinine levels and laboratory variables, which were evaluated 4, 6, 12, 18, and 24 months after therapy initiation. Results LDL apheresis was performed on 40 registered patients with diabetes. The proportion of cases in which proteinuria decreased by 30% or more after 6 months of LDL apheresis was 25%, which was similar to that of historical controls. The overall survival and end-stage kidney disease-free survival rates were significantly higher in the LICENSE group compared to those in historical controls. Conclusion Our results suggest that LDL apheresis may be effective and safe for patients with diabetes, proteinuria, and dyslipidemia.

DOI： 10.1007/s10157-020-01959-9

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Nephrotic syndrome represents the clinical situation characterized by presence of massive proteinuria and low serum protein caused by a variety of diseases, including minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS) and membranous glomerulonephropathy. Differentiating between diagnoses requires invasive renal biopsies in general. Even with the biopsy, we encounter difficulties to differentiate MCNS and FSGS in some cases. There is no other better option currently available for the diagnosis other than renal biopsy. MicroRNAs (miRNAs) are no-coding RNAs of approximately 20 nucleotides in length, which regulate target genes in the post-transcriptional processes and have essential roles in many diseases. MiRNAs in serum and urine have been shown as non-invasive biomarkers in multiple diseases, including renal diseases. In this article, we summarize the current knowledge of miRNAs as the promising biomarkers for nephrotic syndrome.

DOI： 10.3390/ijms22010088

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Introduction: For human, the resolution of images is important for diagnosis. Many clinical applications of artificial intelligence have been studied, however there are few reports on the difference in diagnosis between humans and artificial intelligence on the point of the renal pathological image resolution. Objectives: We examined whether the resolution of renal pathological images affects diagnosis of artificial intelligence and human. Patients and Methods: From 885 renal biopsy patients, we collected renal IgA immunofluorescent pathological images that resolution is 4, 16, 32, 64, 128, 256 and 512 pixels for each patient, and divided into training data set and validation data set, and created optimum deep learning models for each resolution. To compare with artificial intelligence nephrologist also tried to diagnose by using the same validation data set images. Results: We inputted IgA immunofluorescent pathological images into each optimum model. Human could not identify specific staining site with four pixels images, however, each resolution optimum model showed high accuracy, average over 80%. The each accuarcy was observed higher depending on the resolution. The area under the curve (AUC) showed higher diagnosis ratio depending on the resolution, too. Nephrologist performed high diagnosis sensitivity depending on resolution images as same as artificial intelligence. However, nephrologists’ diagnosis observed large variations in specificity depending on resolution. These results suggested that the resolution might affect specificity for human not artificial intelligence Conclusion: The resolution of images might be important for not AI but human on the point of specificity.

DOI： 10.34172/jnp.2021.26

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A 65-year-old woman with systemic sclerosis and systemic lupus erythematosus developed acute kidney injury (AKI), Coombs-positive autoimmune hemolytic anemia and autoimmune thrombocytopenia; therefore, she was diagnosed with Evans syndrome (ES). Intravascular hemolysis was suggested as the cause of AKI based on the presence of acute tubular injury and trace hemosiderin deposits on the renal biopsy. The renal function, hemolytic anemia and thrombocytopenia were restored by an increased dose of glucocorticoids, hemodialysis, and plasma exchange. Although ES with severe hemolytic anemia is very rare, it is important to detect possible renal dysfunction when encountering patients with severe hemolysis.

DOI： 10.2169/internalmedicine.5976-20

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Lecithin cholesterol acyltransferase (LCAT) is a lipid-modification enzyme that catalyzes the transfer of the acyl chain from the second position of lecithin to the hydroxyl group of cholesterol (FC) on plasma lipoproteins to form cholesteryl acylester and lysolecithin. Familial LCAT deficiency is an intractable autosomal recessive disorder caused by inherited dysfunction of the LCAT enzyme. The disease appears in two different phenotypes depending on the position of the gene mutation: familial LCAT deficiency (FLD, OMIM 245900) that lacks esterification activity on both HDL and ApoB-containing lipoproteins, and fish-eye disease (FED, OMIM 136120) that lacks activity only on HDL. Impaired metabolism of cholesterol and phospholipids due to LCAT dysfunction results in abnormal concentrations, composition and morphology of plasma lipoproteins and further causes ectopic lipid accumulation and/or abnormal lipid composition in certain tissues/cells, and serious dysfunction and complications in certain organs. Marked reduction of plasma HDL-cholesterol (HDL-C) and corneal opacity are common clinical manifestations of FLD and FED. FLD is also accompanied by anemia, proteinuria and progressive renal failure that eventually requires hemodialysis. Replacement therapy with the LCAT enzyme should prevent progression of serious complications, particularly renal dysfunction and corneal opacity. A clinical research project aiming at gene/cell therapy is currently underway.

DOI： 10.5551/jat.RV17051

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Dynamin 1 is a neuronal endocytic protein that participates in vesicle formation by scission of invaginated membranes. Dynamin 1 is also expressed in the kidney; however, its physiological significance to this organ remains unknown. Here, we show that dynamin 1 is crucial for microtubule organization and stabilization in glomerular podocytes. By immunofluorescence and immunoelectron microscopy, dynamin 1 was concentrated at microtubules at primary processes in rat podocytes. By immunofluorescence of differentiated mouse podocytes (MPCs), dynamin 1 was often colocalized with microtubule bundles, which radially arranged toward periphery of expanded podocyte. In dynamin 1-depleted MPCs by RNAi, alpha-tubulin showed a dispersed linear filament-like localization, and microtubule bundles were rarely observed. Furthermore, dynamin 1 depletion resulted in the formation of discontinuous, short acetylated alpha-tubulin fragments, and the decrease of microtubule-rich protrusions. Dynamins 1 and 2 double-knockout podocytes showed dispersed acetylated alpha-tubulin and rare protrusions. In vitro, dynamin 1 polymerized around microtubules and cross-linked them into bundles, and increased their resistance to the disassembly-inducing reagents Ca(2+)and podophyllotoxin. In addition, overexpression and depletion of dynamin 1 in MPCs increased and decreased the nocodazole resistance of microtubules, respectively. These results suggest that dynamin 1 supports the microtubule bundle formation and participates in the stabilization of microtubules.

DOI： 10.1096/fj.202001240RR

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Objectives To analyze the effect and impact of low-dose rituximab induction therapy on cytomegalovirus infection in living-donor renal transplantation. Methods A total of 92 recipients undergoing living-donor renal transplantation at Okayama University Hospital from May 2009 to August 2018 were evaluated retrospectively. Indications for preoperative rituximab (200 mg/body) were the following: (i) ABO major mismatch; (ii) ABO minor mismatch; (iii) donor-specific anti-human leukocyte antigen antibody-positive; and (iv) focal segmental glomerulosclerosis. We excluded four recipients who were followed <3 months, five who received >200 mg/body rituximab and seven who received prophylactic therapy for cytomegalovirus. Results There were 59 patients in the rituximab group and 17 in the non-rituximab group. Groups differed significantly in age (median age 53vs37 years, respectively;P = 0.04), but not in sex (male 64%vs65%,P = 1.00), focal segmental glomerulosclerosis (3%vs0%,P = 1.00) or percentage of cytomegalovirus-seronegative recipients of renal allografts from cytomegalovirus-seropositive donors (12%vs18%,P = 0.68). The estimated glomerular filtration rate did not differ significantly between groups until 24 months after transplantation. Cytomegalovirus clinical symptoms (10%vs24%,P = 0.22), including fever >= 38 degrees C (5%vs12%,P = 0.31) and gastrointestinal symptoms (5%vs12%,P = 0.31), and the 5-year survival rates of death-censored graft loss (90%vs83%,P = 0.43) did not differ significantly between groups. Conclusions Low-dose rituximab induction therapy is effective in immunological high-risk recipients without increasing cytomegalovirus infection in the absence of valganciclovir prophylaxis.

DOI： 10.1111/iju.14382

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DOI： 10.1093/rheumatology/keaa333

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Renal impairment is a major concern in patients taking high-dose methotrexate (MTX) for malignancy, but it has not been fully explored in rheumatoid arthritis (RA) patients taking low-dose MTX. This study aimed to elucidate the dose-dependent effects of MTX on the renal function of patients with RA. We retrospectively reviewed 502 consecutive RA patients who were prescribed MTX for ≥ 1 year at Okayama University Hospital between 2006 and 2018. The primary outcome was the change in estimated glomerular filtration rate (eGFR) over 1 year. The association between MTX dosage (< 8, 8-12, and ≥ 12 mg/week) and the change in eGFR was evaluated using multiple linear regression analysis with adjustment for possible confounding factors including age, sex, disease duration, body weight, comorbidity, baseline eGFR, concomitant treatment, and disease activity. Mean patient age was 63 years; 394 (78%) were female. Median disease duration was 77 months, while mean MTX dosage was 8.6 mg/week. The last 1-year change of eGFR (mean ± SD) in patients treated with MTX < 8 (n = 186), 8-12 (n = 219), ≥ 12 mg/week (n = 97) decreased by 0.2 ± 7.3, 0.6 ± 8.6, and 4.5 ± 7.9 mL/min/1.73 m2/year, respectively (p < 0.0001). After adjustment for the confounding factors, MTX ≥ 12 mg/week was still correlated with a decrease in 1-year eGFR (beta-coefficient: - 2.5; 95% confidence interval, - 4.3 to - 0.6; p = 0.0089) in contrast to MTX 8-12 mg/week. Careful monitoring of renal function is required in patients with MTX ≥ 12 mg/week over the course of RA treatment regardless of disease duration.

DOI： 10.1038/s41598-020-75655-9

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The aim of the present study was to examine whether inhibition of Interleukin (IL)-6 signaling by MR16-1, an IL-6 receptor antibody, attenuates aortitis, cardiac hypertrophy, and arthritis in IL-1 receptor antagonist deficient (IL-1RA KO) mice. Four weeks old mice were intraperitoneally administered with either MR16-1 or non-immune IgG at dosages that were adjusted over time for 5 weeks. These mice were stratified into four groups: MR16-1 treatment groups, KO/MR low group (first 2.0 mg, following 0.5 mg/week, n=14) and KO/MR high group (first 4.0 mg, following 2.0 mg/week, n=19) in IL-1RA KO mice, and IgG treatment groups, KO/IgG group (first 2.0 mg, following 1.0 mg/week, n=22) in IL-1RA KO mice, and wild/IgG group (first 2.0 mg, following 1.0 mg/week, n=17) in wild mice. Aortitis, cardiac hypertrophy and arthropathy were histologically analyzed. Sixty-eight percent of the KO/IgG group developed aortitis (53% developed severe aortitis). In contrast, only 21% of the KO/MR high group developed mild aortitis, without severe aortitis (P<0.01, vs KO/IgG group). Infiltration of inflammatory cells, such as neutrophils, T cells, and macrophages, was frequently observed around aortic sinus of the KO/IgG group. Left ventricle and cardiomyocyte hypertrophy were observed in IL-1RA KO mice. Administration of high dosage of MR16-1 significantly suppressed cardiomyocyte hypertrophy. MR16-1 attenuated the incidence and severity of arthritis in IL-1RA KO mice in a dose-dependent manner. In conclusion, blockade of IL-6 signaling may exert a beneficial effect to attenuate severe aortitis, left ventricle hypertrophy, and arthritis.

DOI： 10.1042/CS20201036

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DOI： 10.2169/internalmedicine.4934-20

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DOI： 10.1016/j.ekir.2020.06.010

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The metabolic changes and dysfunction in CD8+T cells may be involved in tumor progression and susceptibility to virus infection in type 2 diabetes (T2D). In C57BL/6JJcl mice fed with high fat-high sucrose chow (HFS), multifunctionality of CD8+splenic and tumor-infiltrating lymphocytes (TILs) was impaired and associated with enhanced tumor growth, which were inhibited by metformin. In CD8+splenic T cells from the HFS mice, glycolysis/basal respiration ratio was significantly reduced and reversed by metformin. In the patients with T2D (DM), multifunctionality of circulating CD8+PD-1+T cells stimulated with PMA/ionomycin as well as with HLA-A*24:02 CMV peptide was dampened, while metformin recovered multifunctionality. Both glycolysis and basal respiration were reduced in DM, and glycolysis was increased by metformin. The disturbance of the link between metabolism and immune function in CD8+PD-1+T cells in T2D was proved by recovery of antigen-specific and non-specific cytokine production via metformin-mediated increase in glycolytic activity.

DOI： 10.1038/s41598-020-71946-3

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DOI： 10.1177/0961203320935988

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DOI： 10.1097/RHU.0000000000001505

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Adult kidney stem cells are known to have important roles in renal regeneration after acute kidney injury. Although trophic factors from tissue stem cells have been reported to promote the regeneration of other organs, there is limited number of evidence of this phenomenon in the kidneys. Here, we explored the effects of secreted factors from kidney stem cells. We intraperitoneally administered culture supernatant obtained from adult rat kidney stem/progenitor cells into rat kidney ischemia/reperfusion injury models, and the treatment significantly ameliorated renal tubulointerstitial injury, suppressed tubular cell apoptosis, diminished inflammation and promoted the proliferation of both residual renal cells and immature cells. In vitro, treatment with culture supernatant from kidney stem cells significantly promoted cell proliferation and suppressed cisplatin-induced cell apoptosis in both normal rat kidney cells and kidney stem cells. In addition, treatment with culture supernatant increased the expression of nestin in normal rat kidney cells, suggesting the dedifferentiation of tubular cells into stem-like cells. Analysis of the culture supernatant revealed that it contained a variety of growth factors. Taken together, the results suggest that these factors together lead to renal regeneration. In conclusion, adult kidney stem cells contribute to renal regeneration indirectly through the secretion of regenerative factors.

DOI： 10.1016/j.scr.2020.101865

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Artificial Intelligence (AI) imaging diagnosis is developing, making enormous steps forward in medical fields. Regarding diabetic nephropathy (DN), medical doctors diagnose them with clinical course, clinical laboratory data and renal pathology, mainly evaluate with light microscopy images rather than immunofluorescent images because there are no characteristic findings in immunofluorescent images for DN diagnosis. Here, we examined the possibility of whether AI could diagnose DN from immunofluorescent images. We collected renal immunofluorescent images from 885 renal biopsy patients in our hospital, and we created a dataset that contains six types of immunofluorescent images of IgG, IgA, IgM, C3, C1q and Fibrinogen for each patient. Using the dataset, 39 programs worked without errors (Area under the curve (AUC): 0.93). Five programs diagnosed DN completely with immunofluorescent images (AUC: 1.00). By analyzing with Local interpretable model-agnostic explanations (Lime), the AI focused on the peripheral lesion of DN glomeruli. On the other hand, the nephrologist diagnostic ratio (AUC: 0.75833) was slightly inferior to AI diagnosis. These findings suggest that DN could be diagnosed only by immunofluorescent images by deep learning. AI could diagnose DN and identify classified unknown parts with the immunofluorescent images that nephrologists usually do not use for DN diagnosis.

DOI： 10.3390/diagnostics10070466

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The world faces the serious problem of aging. In this study, we aimed to investigate the effect of chlorogenic acid (CGA) on vascular senescence. C57/BL6 female mice that were 14 ± 3 months old were infused with either Angiotensin II (AngII) or saline subcutaneously for two weeks. These mice were administered CGA of 20 or 40 mg/kg/day, or saline via oral gavage. AngII infusion developed vascular senescence, which was confirmed by senescence associated-β-galactosidase (SA-β-gal) staining. CGA administration attenuated vascular senescence in a dose-dependent manner, in association with the increase of Sirtuin 1 (Sirt1) and endothelial nitric oxide synthase (eNOS), and with the decrease of p-Akt, PAI-1, p53, and p21. In an in vitro study, with or without pre-treatment of CGA, Human Umbilical Vein Endothelial Cells (HUVECs) were stimulated with H2O2 for an hour, then cultured in the absence or presence of 0.5-5.0 μM CGA for the indicated time. Endothelial cell senescence was induced by H2O2, which was attenuated by CGA treatment. Pre-treatment of CGA increased Nrf2 in HUVECs. After H2O2 treatment, translocation of Nrf2 into the nucleus and the subsequent increase of Heme Oxygenase-1 (HO-1) were observed earlier in CGA-treated cells. Furthermore, the HO-1 inhibitor canceled the beneficial effect of CGA on vascular senescence in mice. In conclusion, CGA exerts a beneficial effect on vascular senescence, which is at least partly dependent on the Nuclear factor erythroid 2-factor 2 (Nrf2)/HO-1 pathway.

DOI： 10.3390/ijms21124527

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Podocyte injury is an independent risk factor for the progression of renal diseases. Semaphorin3A (SEMA3A), expressed in podocytes and tubular cells in the mammalian adult kidneys, has been reported to regulate diverse biological functions and be associated with renal diseases. Here, we investigated pathological roles of SEMA3A signaling on podocyte injury using a doxorubicin (Dox)-induced mouse model and examined the therapeutic effect of SEMA3A-inhibitor (SEMA3A-I). We demonstrated that Dox caused massive albuminuria and podocyte apoptosis as well as an increase of SEMA3A expression in podocytes, all of which were ameliorated with SEMA3A-I treatment. In addition, c-Jun N-terminal kinase (JNK), known as a downstream of SEMA3A signaling, was activated in Dox-injected mouse podocytes while SEMA3A-I treatment partially blocked the activation. In vitro, SEMA3A-I protected against Dox-induced podocyte apoptosis and recombinant SEMA3A caused podocyte apoptosis with activation of JNK signaling. JNK inhibitor, SP600125, attenuated SEMA3A-induced podocyte apoptosis, indicating that the JNK pathway would be involved in SEMA3A-induced podocyte apoptosis. Furthermore, the analysis of human data revealed a positive correlation between levels of urinary SEMA3A and protein, suggesting that SEMA3A is associated with podocyte injury. In conclusion, SEMA3A has essential roles in podocyte injury and it would be the therapeutic target for protecting from podocyte injury.

DOI： 10.3390/ijms21114099

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BACKGROUND: The aim of the present study was to evaluate the association between the histology of active and chronic lesions and urinary protein and serum creatinine (SCr) levels, as common clinical endpoints in clinical trials for lupus nephritis (LN). METHODS: In total, 119 patients diagnosed with LN class III, IV, and V, as defined by the International Society of Nephrology/Renal Pathology Society, between 1990 and 2015, were enrolled in the present study. Multiple regression analysis was performed to explore semi-quantitative histological variables associated with urinary protein and SCr levels. RESULTS: The mean age of the enrolled patients was 45 years, and 79% were female. The mean SCr and mean urinary protein levels at the time of renal biopsy were 0.87 mg/dl and 3.00 g/gCr, respectively. Class IV (71%) was the most common type of LN followed by class III (17%), and class V (13%). Multicollinearity was confirmed between monocellular infiltration (variance inflation factor [VIF] = 10.22) and interstitial fibrosis (VIF = 10.29), and between karyorrhexis (VIF = 4.14) and fibrinoid necrosis (VIF = 4.29). Fibrinoid necrosis and monocellular infiltration were subsequently excluded, and multiple regression analysis revealed that only the urinary protein level was correlated with wire loop lesions (β-coefficient [β]: 1.09 and confidence interval [CI]: 0.35 to 1.83), and that the SCr level was correlated with glomerular sclerosis (β: 1.08 and CI: 0.43 to 1.74). CONCLUSION: As urinary protein and SCr levels were not quantitatively associated with active lesions, they may not accurately reflect the response to remission induction therapy in patients with LN.

DOI： 10.1186/s12882-020-01868-9

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Acute kidney injury (AKI) has been increasingly recognized as a risk factor for transition to chronic kidney disease. Recent evidence suggests that endothelial damage in peritubular capillaries can accelerate the progression of renal injury. Vasohibin-2 (VASH2) is a novel proangiogenic factor that promotes tumor angiogenesis. However, the pathophysiological roles of VASH2 in kidney diseases remain unknown. In the present study, we examined the effects of VASH2 deficiency on the progression of ischemia-reperfusion (I/R) injury-induced AKI. I/R injury was induced by bilaterally clamping renal pedicles for 25 min in male wild-type (WT) andVash2homozygous knockout mice. Twenty-four hours later, I/R injury-induced renal dysfunction and tubular damage were more severe in VASH2-deficient mice than in WT mice, with more prominent neutrophil infiltration and peritubular capillary loss. After induction of I/R injury, VASH2 expression was markedly increased in injured renal tubules. These results suggest that VASH2 expression in renal tubular epithelial cells might be essential for alleviating I/R injury-induced AKI, probably through protecting peritubular capillaries and preventing inflammatory infiltration.

DOI： 10.3390/ijms21124545

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The world faces the serious problem of aging. In this study, we aimed to investigate the effect of chlorogenic acid (CGA) on vascular senescence. C57/BL6 female mice that were 14 +/- 3 months old were infused with either Angiotensin II (AngII) or saline subcutaneously for two weeks. These mice were administered CGA of 20 or 40 mg/kg/day, or saline via oral gavage. AngII infusion developed vascular senescence, which was confirmed by senescence associated-beta-galactosidase (SA-beta-gal) staining. CGA administration attenuated vascular senescence in a dose-dependent manner, in association with the increase of Sirtuin 1 (Sirt1) and endothelial nitric oxide synthase (eNOS), and with the decrease of p-Akt, PAI-1, p53, and p21. In an in vitro study, with or without pre-treatment of CGA, Human Umbilical Vein Endothelial Cells (HUVECs) were stimulated with H(2)O(2)for an hour, then cultured in the absence or presence of 0.5-5.0 mu M CGA for the indicated time. Endothelial cell senescence was induced by H2O2, which was attenuated by CGA treatment. Pre-treatment of CGA increased Nrf2 in HUVECs. After H(2)O(2)treatment, translocation of Nrf2 into the nucleus and the subsequent increase of Heme Oxygenase-1 (HO-1) were observed earlier in CGA-treated cells. Furthermore, the HO-1 inhibitor canceled the beneficial effect of CGA on vascular senescence in mice. In conclusion, CGA exerts a beneficial effect on vascular senescence, which is at least partly dependent on the Nuclear factor erythroid 2-factor 2 (Nrf2)/HO-1 pathway.

DOI： 10.3390/ijms21124527

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Chronic damage accumulation affects not only mortality but also quality of life in patients with systemic lupus erythematosus (SLE). Risk factors for chronic damage were explored in SLE through different onset eras. Two hundred forty-five patients at Okayama University Hospital and Showa University Hospital were divided into three groups based on the onset era: a past-onset group (onset before 1995; n=83), middle-onset group (1996-2009; n=88), and recent-onset group (after 2010; n=74). The mean Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score as an index of chronic damage was 1.93, 1.24, and 0.53 in the past-, middle-, and recent-onset groups, respectively. In the past-onset group, the total SDI score was significantly associated with glucocorticoid monotherapy by linear regression analysis (beta-coefficient [beta]=0.63; 95% confidence interval [CI], 0.21-1.05) and C-reactive protein levels (beta=0.67; 95% CI, 0.27-1.07). In the middle-onset group, the total SDI score was significantly associated with the SLE Disease Activity Index at registration (beta=0.09; 95% CI, 0.03-0.12). Reducing the accumulation of chronic damage in SLE patients might be possible with the concomitant use of immunosuppressants and tight control of disease activity.

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Background Statin-associated necrotizing myopathy (SANM) is a rare autoimmune disorder caused by administration of statins. SANM is characterized by weakness due to necrosis and regeneration of myofibers. Here we report the first case of SANM with acute respiratory failure treated with noninvasive pressure support ventilation in addition to immunosuppressants. Case presentation A 59-year-old woman who had been treated with 2.5 mg/day of rosuvastatin calcium for 5 years stopped taking the drug 4 months before admission to our hospital due to elevation of creatine kinase (CK). Withdrawal of rosuvastatin for 1 month did not decrease the level of CK, and she was admitted to our hospital due to the development of muscle weakness of her neck and bilateral upper extremities. Anti-3-hydroxy-3-methylglutaryl coenzyme A reductase antibodies were positive. Magnetic resonance imaging showed myositis, and muscle biopsy from the right biceps brachii muscle showed muscle fiber necrosis and regeneration without inflammatory cell infiltration, suggesting SANM. After the diagnosis, she received methylprednisolone pulse therapy (mPSL, 1 g/day x 3 days, twice) and subsequent oral prednisolone therapy (PSL, 30 mg/day for 1 month, 25 mg/day for 1 month and 22.5 mg/day for 1 month), leading to improvement of her muscle weakness. One month after the PSL tapering to 20 mg/day, her muscle weakness deteriorated with oxygen desaturation (SpO2: 93% at room air) due to hypoventilation caused by weakness of respiratory muscles. BIPAP was used for the management of acute respiratory failure in combination with IVIG (20 g/day x 5 days) followed by mPSL pulse therapy (1 g/day x 3 days), oral PSL (30 mg/day x 3 weeks, then tapered to 25 mg/day) and tacrolimus (3 mg/day). Twenty-seven days after the start of BIPAP, she was weaned from BIPAP with improvement of muscle weakness, hypoxemia and hypercapnia. After she achieved remission with improvement of muscle weakness and reduction of serum CK level to a normal level, the dose of oral prednisolone was gradually tapered to 12.5 mg/day without relapse for 3 months. Conclusions Our report provides new insights into the role of immunosuppressants and biphasic positive airway pressure for induction of remission in patients with SANM.

DOI： 10.1186/s12890-020-01195-7

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Podocyte injury is an independent risk factor for the progression of renal diseases. Semaphorin3A (SEMA3A), expressed in podocytes and tubular cells in the mammalian adult kidneys, has been reported to regulate diverse biological functions and be associated with renal diseases. Here, we investigated pathological roles of SEMA3A signaling on podocyte injury using a doxorubicin (Dox)-induced mouse model and examined the therapeutic effect of SEMA3A-inhibitor (SEMA3A-I). We demonstrated that Dox caused massive albuminuria and podocyte apoptosis as well as an increase of SEMA3A expression in podocytes, all of which were ameliorated with SEMA3A-I treatment. In addition, c-Jun N-terminal kinase (JNK), known as a downstream of SEMA3A signaling, was activated in Dox-injected mouse podocytes while SEMA3A-I treatment partially blocked the activation. In vitro, SEMA3A-I protected against Dox-induced podocyte apoptosis and recombinant SEMA3A caused podocyte apoptosis with activation of JNK signaling. JNK inhibitor, SP600125, attenuated SEMA3A-induced podocyte apoptosis, indicating that the JNK pathway would be involved in SEMA3A-induced podocyte apoptosis. Furthermore, the analysis of human data revealed a positive correlation between levels of urinary SEMA3A and protein, suggesting that SEMA3A is associated with podocyte injury. In conclusion, SEMA3A has essential roles in podocyte injury and it would be the therapeutic target for protecting from podocyte injury.

DOI： 10.3390/ijms21114099

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Obesity is supposed to cause renal injury via autophagy deficiency. Recently, sodium glucose co-transporter 2 inhibitors (SGLT2i) were reported to protect renal injury. However, the mechanisms of SGLT2i for renal protection are unclear. Here, we investigated the effect of SGLT2i for autophagy in renal proximal tubular cells (PTCs) on obesity mice. We fed C57BL/6J mice with a normal diet (ND) or high-fat and -sugar diet (HFSD) for nine weeks, then administered SGLT2i, empagliflozin, or control compound for one week. Each group contained N = 5. The urinary N-acetyl-beta-d-glucosaminidase level in the HFSD group significantly increased compared to ND group. The tubular damage was suppressed in the SGLT2i-HFSD group. In electron microscopic analysis, multi lamellar bodies that increased in autophagy deficiency were increased in PTCs in the HFSD group but significantly suppressed in the SGLT2i group. The autophagosomes of damaged mitochondria in PTCs in the HFSD group frequently appeared in the SGLT2i group. p62 accumulations in PTCs were significantly increased in HFSD group but significantly suppressed by SGLT2i. In addition, the mammalian target of rapamycin was activated in the HFSD group but significantly suppressed in SGLT2i group. These data suggest that SGLT2i has renal protective effects against obesity via improving autophagy flux impairment in PTCs on a HFSD.

DOI： 10.3390/ijms21114054

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Language：English   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Rationale & Objective: The efficacy and safety of icodextrin versus glucose-only peritoneal dialysis (PD) regimens is unclear. The aim of this study was to compare once-daily long-dwell icodextrin versus glucose among patients with kidney failure undergoing PD.Study Design: Systematic review of randomized controlled trials (RCTs), enriched with unpublished data from investigator-initiated and industry-sponsored studies.Setting & Study Populations: Individuals with kidney failure receiving regular PD treatment enrolled in clinical trials of dialysate composition.Selection Criteria for Studies: Medline, Embase, CENTRAL, Ichushi Web, 10 Chinese databases, clinical trials registries, conference proceedings, and citation lists from inception to November 2018. Further data were obtained from principal investigators and industry clinical study reports.Data Extraction: 2 independent reviewers selected studies and extracted data using a prespecified extraction instrument.Analytic Approach: Qualitative synthesis of demographics, measurement scales, and outcomes. Quantitative synthesis with Mantel-Haenszel risk ratios (RRs), Peto odds ratios (ORs), or (standardized) mean differences (MDs). Risk of bias of included studies at the outcome level was assessed using the Cochrane risk-of-bias tool for RCTs.Results: 19 RCTs that enrolled 1,693 participants were meta-analyzed. Ultrafiltration was improved with icodextrin (medium-term MD, 208.92 [95% CI, 99.69-318.14] mL/24 h; high certainty of evidence), reflected also by fewer episodes of fluid overload (RR, 0.43 [95% CI, 0.24-0.78]; high certainty). Icodextrin-containing PD probably decreased mortality risk compared to glucose-only PD (Peto OR, 0.49 [95% CI, 0.24-1.00]; moderate certainty). Despite evidence of lower peritoneal glucose absorption with icodextrin-containing PD (medium-term MD, -40.84 [95% CI, -48.09 to -33.59] g/long dwell; high certainty), this did not directly translate to changes in fasting plasma glucose (-0.50 [95% CI, -1.19 to 0.18] mmol/L; low certainty) and hemoglobin A(1c) levels (-0.14% [95% CI, -0.34% to 0.05%]; high certainty). Safety outcomes and residual kidney function were similar in both groups; health-related quality-of-life and pain scores were inconclusive.Limitations: Trial quality was variable. The followup period was heterogeneous, with a paucity of assessments over the long term. Mortality results are based on just 32 events and were not corroborated using time-to-event analysis of individual patient data.Conclusions: Icodextrin for once-daily long-dwell PD has clinical benefit for some patients, including those not meeting ultrafiltration targets and at risk for fluid overload. Future research into patient-centered outcomes and cost-effectiveness associated with icodextrin is needed.

DOI： 10.1053/j.ajkd.2019.10.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Introduction: Immune checkpoint inhibitors including nivolumab, an antibody against programmed death-1, have been increasingly introduced in various cancer treatment regimens, and are reported to be associated with immune-related adverse events. Nivolumab-induced renal injury is generally caused by acute interstitial nephritis and is managed by drug discontinuation and steroid therapy. Although this agent can infrequently induce glomerulonephritis, the pathogenesis and therapeutic strategy remain undetermined. Patient concerns: A 78-year-old man was diagnosed with advanced gastric cancer with portal thrombosis. First- and second-line chemotherapies were ineffective; thus, nivolumab monotherapy was initiated. Although it effectively prevented tumor growth, proteinuria and microhematuria appeared 2 months later. Despite drug discontinuation, serum creatinine progressively increased from 0.72 to 1.45 mg/dL. Renal biopsy revealed mesangial IgA and C3 deposition in immunofluorescence analysis and mesangial proliferation with crescent formation in light microscopy. Diagnosis: The patient was diagnosed with IgA nephropathy. Based on the temporal relationship between the nivolumab therapy and abnormal urinalysis, IgA nephropathy was considered to have been induced by nivolumab. Interventions: A moderate dose (0.6 mg/kg/day) of prednisolone was orally administrated, with tapering biweekly. Outcomes: Steroid therapy stabilized his serum creatinine levels and markedly reduced proteinuria. However, bacterial pneumonia substantially impaired his performance status; thus, nivolumab could not be restarted despite tumor regrowth. Lessons: IgA nephropathy should be recognized as an uncommon renal adverse event during nivolumab therapy. After drug discontinuation, nivolumab-induced IgA nephropathy is likely to respond to moderate doses of steroid therapy with early tapering. However, more evidence is needed to determine whether nivolumab can be safely restarted during or after steroid therapy.

DOI： 10.1097/MD.0000000000020464

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Language：English   Publisher：NATURE RESEARCH  

The kidney is permeated by a highly complex vascular system with glomerular and peritubular capillary networks that are essential for maintaining the normal functions of glomerular and tubular epithelial cells. The integrity of the renal vascular network depends on a balance of proangiogenic and antiangiogenic factors, and disruption of this balance has been identified in various kidney diseases. Decreased levels of the predominant proangiogenic factor, vascular endothelial growth factor A (VEGFA), can result in glomerular microangiopathy and contribute to the onset of preeclampsia, whereas upregulation of VEGFA has roles in diabetic kidney disease (DKD) and polycystic kidney disease (PKD). Other factors that regulate angiogenesis, such as angiopoietin 1 and vasohibin 1, have been shown to be protective in animal models of DKD and renal fibrosis. The renal lymphatic system is important for fluid homeostasis in the kidney, as well as the transport of immune cells and antigens. Experimental studies suggest that the lymphangiogenic factor VEGFC might have protective effects in PKD, DKD and renal fibrosis. Understanding the physiological and pathological roles of factors that regulate angiogenesis and lymphangiogenesis in the kidney has led to the development of novel therapeutic strategies for kidney diseases.In this Review, the authors discuss current understanding of the expression and dysregulation of factors that regulate angiogenesis and lymphangiogenesis in the kidney, as well as potential therapeutic strategies to target these factors during various kidney diseases.

DOI： 10.1038/s41581-020-0260-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Aims/introduction The predictive low glucose management (PLGM) system was introduced in March 2018 in Japan. Although there are some reports demonstrating the benefit of PLGM in preventing hypoglycemia, no data are currently available in Japanese patients with type 1 diabetes mellitus (T1DM). The aim of the present study is to evaluate the effect of PLGM with sensor-augmented pump therapy in the prevention of hypoglycemia in Japanese patients. Materials and methods We included 16 patients with T1DM who used the MiniMed(R)640G system after switching from the MiniMed(R)620G system. We retrospectively analysed the data of the continuous glucose monitoring system in 1 month after switching to MiniMed(R)640G. Results The area under the curve (AUC) of hypoglycemia of < 70 mg/dL was lowered from 0.42 +/- 0.43 mg/dL day to 0.18 +/- 0.18 mg/dL day (P = 0.012). Correspondingly, the duration of severe hypoglycemia (< 54 mg/dL) was reduced significantly from 15.3 +/- 21.7 min/day to 4.8 +/- 6.9 min/day (P = 0.019). The duration of hypoglycemia was reduced, but the reduction was not significant. Regarding the AUC for hyperglycemia > 180 mg/dL and the duration of hyperglycemia did not change. With the PLGM function, 79.3% of the predicted hypoglycemic events were avoided. Conclusions The hypoglycemia avoidance rate was comparable to those in previous reports. In addition, we demonstrated that PLGM can markedly suppress severe hypoglycemia without deteriorating glycemic control in Japanese T1DM patients. It is necessary to further investigate the effective use of the PLGM feature such as establishing a lower limit and the timing of resumption.

DOI： 10.1007/s13340-019-00408-7

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Background The advent of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of patients with advanced malignancies. On the other hand, these drugs might cause immune-related adverse events (irAEs) including endocrinopathies and nephropathies. Thyroid dysfunction is one of the most common irAEs. For ICIs-induced nephropathies, most cases are due to tubulointerstitial nephritis, which might require steroid treatment. Here, we report a patient with non-small cell lung cancer treated with ICI who developed increased serum creatinine (s-Cr) levels due to ICIs-induced hypothyroidism. Case presentation A 57-year-old Asian man with refractory non-small cell lung cancer under ICIs therapy (pembrolizumab, an anti-programmed cell death-1 monoclonal antibody) developed increased s-Cr levels 5 months after the pembrolizumab initiation. His laboratory data, renal biopsy, and Gallium-67 scintigraphy findings denied pembrolizumab-induced tubulointerstitial nephritis. His renal function was correlated with thyroid function. Despite the increase of s-Cr levels, serum cystatin C levels were normal, which could be explained by the hypothyroidism. Levothyroxine treatment improved renal function as well as thyroid function. Then pembrolizumab was resumed, and both his thyroid and renal function remained normal level. Ultimately, we concluded that the increased s-Cr levels were caused by pembrolizumab-induced hypothyroidism. Conclusion All clinicians involved in ICI treatment need to recognize the possible increase in s-Cr levels caused by ICIs-induced hypothyroidism, and we propose monitoring serum cystatin C levels to differentiate ICIs-induced hypothyroidism from tubulointerstitial nephritis before invasive renal biopsies or steroid treatment, which are recommended by the prescribing information for pembrolizumab, are performed.

DOI： 10.1186/s12882-020-01775-z

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DOI： 10.1016/j.jns.2019.116460

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Immunoglobulin A (IgA) vasculitis (IgAV) is a small vessel vasculitis presenting cutaneous purpura, arthralgias and/or arthritis, acute enteritis and glomerulonephritis caused by deposition of the IgA1-mediated immune complex. Eosinophilic granulomatosis with polyangiitis (EGPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) characterised by eosinophil-rich and granulomatous inflammation in small to medium-sized vessels. Both IgAV and EGPA are classified as autoimmune systemic vasculitis, but the pathogenesis of immune complex-mediated IgAV and that of pauci-immune EGPA are different. Here we report a rare case of simultaneous development of IgAV and EGPA presenting palpable purpura and numbness in a patient with a history of asthma. Histological examination revealed leukocytoclastic vasculitis with deposition of IgA, IgM and C3 in the upper dermis and necrotising vasculitis with eosinophilic infiltration and granulomatous formation in the lower dermis and subcutaneous fat, indicating the existence of IgAV and EGPA. Our case provides evidence of concurrent development of two different types of vasculitis, which may affect disease-associated complications, therapeutic strategy and prognosis.

DOI： 10.1080/24725625.2019.1673528

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Autophagy is a cellular mechanism involved in the bulk degradation of proteins and turnover of organelle. Several studies have shown the significance of autophagy of the renal tubular epithelium in rodent models of tubulointerstitial disorder. However, the role of autophagy in the regulation of human glomerular diseases is largely unknown. The current study aimed to demonstrate morphological evidence of autophagy and its association with the ultrastructural changes of podocytes and clinical data in patients with idiopathic nephrotic syndrome, a disease in which patients exhibit podocyte injury. The study population included 95 patients, including patients with glomerular disease (minimal change nephrotic syndrome [MCNS], n = 41; idiopathic membranous nephropathy [IMN], n = 37) and 17 control subjects who underwent percutaneous renal biopsy. The number of autophagic vacuoles and the grade of foot process effacement (FPE) in podocytes were examined by electron microscopy (EM). The relationships among the expression of autophagic vacuoles, the grade of FPE, and the clinical data were determined. Autophagic vacuoles were mainly detected in podocytes by EM. The microtubule-associated protein 1 light chain 3 (LC3)-positive area was co-localized with the Wilms tumor 1 (WT1)-positive area on immunofluorescence microscopy, which suggested that autophagy occurred in the podocytes of patients with MCNS. The number of autophagic vacuoles in the podocytes was significantly correlated with the podocyte FPE score (r = -0.443, p = 0.004), the amount of proteinuria (r = 0.334, p = 0.033), and the level of serum albumin (r = -0.317, p = 0.043) in patients with MCNS. The FPE score was a significant determinant for autophagy after adjusting for the age in a multiple regression analysis in MCNS patients (p = 0.0456). However, such correlations were not observed in patients with IMN or in control subjects. In conclusion, the results indicated that the autophagy of podocytes is associated with FPE and severe proteinuria in patients with MCNS. The mechanisms underlying the activation of autophagy in association with FPE in podocytes should be further investigated in order to elucidate the pathophysiology of MCNS.

DOI： 10.1371/journal.pone.0228337

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ PUBLISHING GROUP  

Objective Glomerular filtration rate (GFR) decreases without or prior to the development of albuminuria in many patients with diabetes. Therefore, albuminuria and/or a low GFR in patients with diabetes is referred to as diabetic kidney disease (DKD). A certain proportion of patients with diabetes show a rapid progressive decline in renal function in a unidirectional manner and are termed early decliners. This study aimed to elucidate the prevalence of DKD and early decliners and clarify their risk factors.Research design and methods This combination cross-sectional and cohort study included 2385 patients with diabetes from 15 hospitals. We defined DKD as a urinary albumin to creatinine ratio (ACR) >= 30 mg/gCr and/or estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2). We classified patients into four groups based on the presence or absence of albuminuria and a decrease in eGFR to reveal the risk factors for DKD. We also performed a trajectory analysis and specified the prevalence and risk factors of early decliners with sequential eGFR data of 1955 patients in five facilities.Results Of our cohort, 52% had DKD. Above all, 12% with a low eGFR but no albuminuria had no traditional risk factors, such as elevated glycated hemoglobin, elevated blood pressure, or diabetic retinopathy in contrast to patients with albuminuria but normal eGFR. Additionally, 14% of our patients were early decliners. Older age, higher basal eGFR, higher ACR, and higher systolic blood pressure were significantly associated with early decliners.Conclusions The prevalence of DKD in this cohort was larger than ever reported. By testing eGFR yearly and identifying risk factors in the early phase of diabetes, we can identify patients at high risk of developing end-stage renal disease.

DOI： 10.1136/bmjdrc-2019-000902

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Autophagy is a cellular mechanism involved in the bulk degradation of proteins and turnover of organelle. Several studies have shown the significance of autophagy of the renal tubular epithelium in rodent models of tubulointerstitial disorder. However, the role of autophagy in the regulation of human glomerular diseases is largely unknown. The current study aimed to demonstrate morphological evidence of autophagy and its association with the ultrastructural changes of podocytes and clinical data in patients with idiopathic nephrotic syndrome, a disease in which patients exhibit podocyte injury. The study population included 95 patients, including patients with glomerular disease (minimal change nephrotic syndrome [MCNS], n = 41; idiopathic membranous nephropathy [IMN], n = 37) and 17 control subjects who underwent percutaneous renal biopsy. The number of autophagic vacuoles and the grade of foot process effacement (FPE) in podocytes were examined by electron microscopy (EM). The relationships among the expression of autophagic vacuoles, the grade of FPE, and the clinical data were determined. Autophagic vacuoles were mainly detected in podocytes by EM. The microtubule-associated protein 1 light chain 3 (LC3)-positive area was co-localized with the Wilms tumor 1 (WT1)-positive area on immunofluorescence microscopy, which suggested that autophagy occurred in the podocytes of patients with MCNS. The number of autophagic vacuoles in the podocytes was significantly correlated with the podocyte FPE score (r = -0.443, p = 0.004), the amount of proteinuria (r = 0.334, p = 0.033), and the level of serum albumin (r = -0.317, p = 0.043) in patients with MCNS. The FPE score was a significant determinant for autophagy after adjusting for the age in a multiple regression analysis in MCNS patients (p = 0.0456). However, such correlations were not observed in patients with IMN or in control subjects. In conclusion, the results indicated that the autophagy of podocytes is associated with FPE and severe proteinuria in patients with MCNS. The mechanisms underlying the activation of autophagy in association with FPE in podocytes should be further investigated in order to elucidate the pathophysiology of MCNS.

DOI： 10.1371/journal.pone.0228337

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Objective: The micro RNAs (miRNAs) and their target mRNAs are differentially expressed in various immune-mediated cells. Here, we investigated the role of Mir223 and sphingosine-1-phosphate receptor 1 (S1pr1) in the pathogenesis of systemic lupus erythematosus. Methods: We analyzed miRNA and mRNA profiling data of CD4+ splenic T cells derived from MRL/MpJ-Faslpr /J mice. We performed 3' untranslated region (UTR) luciferase reporter gene assay using human umbilical vein endothelial cells (HUVECs). We generated the B6-Mir223 -/- Faslpr/lpr mice and the lupus phenotypes were analyzed. Results: In CD4+ splenic T cells, we identified upregulation of miR-223-3p and downregulation of the possible target, S1pr1 by RNA sequencing of MRL/MpJ-Faslpr /J mice. The transfection with miR-223-3p mimic significantly suppressed a luciferase activity in HUVEC treated with a Lentivirus vector containing 3' UTR of S1pr1. The mRNA levels of S1pr1 were significantly decreased after miR-223-3p overexpression. In B6-Mir223 -/- Faslpr/lpr mice, the proportion of CD3+ T cells, CD3+CD4-CD8- cells, B cells, plasma cells, and S1PR1+CD4+ T cells in the spleen was significantly increased compared with that in B6-Mir223 +/+ Faslpr/lpr mice by flow cytometry. B6-Mir223 -/- Faslpr/lpr mice demonstrated the elevation of glomerular and renal vascular scores associated with enhanced intraglomerular infiltration of S1PR1+CD4+ T cells. Conclusion: Unexpectedly, the deletion of Mir223 exacerbated the lupus phenotypes associated with increased population of S1PR1+CD4+ T in spleen and the enhanced infiltration of S1PR1+CD4+ T cells in inflamed kidney tissues, suggesting compensatory role of Mir223 in the pathogenesis of lupus nephritis.

DOI： 10.3389/fimmu.2020.616141

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DOI： 10.1177/0961203319898766

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

We investigated the feasibility of robotic renal autotransplantation (RAT) in a porcine model to reduce invasiveness of RAT. Five pigs underwent robotic RAT using the da Vinci (R) robotic system. A robotic left nephrectomy was performed in all cases. Robotic RAT was performed on the left side in all but one case. Four ports were used. In 3 cases, the kidney was taken out through the GelPort (R) and irrigated on ice with Ringer's solution. In 2 cases, a complete intracorporeal robotic RAT was performed. An end-to-side anastomosis was performed between the renal vein and the external iliac vein and between the renal artery and the external iliac artery. Ureteroneocystostomy was also performed in 2 cases. All cases were performed robotically without open conversion. The median (IQR) console time was 3.1 (0.7) h, and the operative time was 3.8 (1.1) h. The estimated blood loss was 30 (0) ml. The warm ischemia time was 4.0 (0.2) min, and the cold ischemia time was 97 (17) min. Intracorporeal transarterial hypothermic renal perfusion was feasible in the 2 complete intracorporeal robotic RAT cases by using a perfusion catheter through a laparoscopic port. Robotic RAT has the potential to be a new minimally invasive substitute for conventional open surgery.

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Language：English   Publisher：OXFORD UNIV PRESS  

DOI： 10.1093/rap/rkz050

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DOI： 10.3390/ijms21030756

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DOI： 10.1136/ANNRHEUMDIS-2020-EULAR.1202

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Abdominal aortic aneurysms (AAAs) usually expand asymptomatically until the occurrence of a life-threatening event such as aortic rupture, which is closely associated with high mortality. AAA and aortic dissection are ranked among the top 10 causes of death in Japan. The major risk factors for AAA are age over 65 years, male gender, family history, and smoking. Thus, for prevention, smoking cessation is the most important lifestyle-intervention. For treatment, since AAA generally affects elderly people, less invasive treatment is preferable. However, the only established treatment for AAA is open repair and endovascular repair. This review describes potential medical treatments to slow aneurysm growth or prevent AAA rupture.

DOI： 10.18926/AMO/57710

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A 57-year-old man was diagnosed with IgA nephropathy. Hematuria and proteinuria were improved by tonsillectomy plus methylprednisolone pulse therapy. Lymphadenopathy, hypocomplementemia and pancytopenia were observed six years later, and urinalysis abnormalities recurred. A biopsy revealed mesangial proliferative glomerulonephritis with C3-dominant deposition. Human immunodeficiency virus (HIV) antibody demonstrated positive conversion. He was diagnosed with HIV-associated immune complex kidney disease (HIVICK). The hematuria, proteinuria and hypocomplementemia were improved by reducing the HIV viral load through antiretroviral therapy. When C3-dominant deposition is observed on a renal biopsy, HIVICK must be differentiated.

DOI： 10.2169/internalmedicine.2439-18

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OBJECTIVE: Although several autoantibodies have been identified for polymyositis/dermatomyositis (PM/DM) diagnosis, the clinical impact of these antibodies is yet to be elucidated. METHODS: Patients with PM/DM at Okayama University Hospital from 2012 to 2016 were historically enrolled, and antibody profiles were analyzed using line immunoassay. Hierarchical cluster analysis was performed based on serological analysis of anti-aminoacyl-tRNA synthetase (ARS) antibodies, including anti-Jo-1, PL-7, PL-12, EJ, OJ, and SS-A/Ro-52 antibodies. Clinical symptoms and relapse proportions were compared among these clusters. RESULTS: Sixty-one patients were enrolled in this study: 28 were diagnosed with PM, and 33 were diagnosed with DM. The following 3 clusters were determined: 1 (n = 10), anti-Jo-1 and anti-SS-A/Ro-52 antibodies double positive (10/10, 100%); 2 (n = 24), anti-SS-A/Ro-52 antibody positive (20/24, 83%), anti-Jo-1 antibody negative (24/24, 100%), and anti-ARS antibodies (excluding anti-Jo-1 antibody) positive (15/24, 63%); and 3 (n = 27), anti-Jo-1 and anti-SS-A/Ro52 antibodies double negative (26/27, 96%). The proportion of patients who relapsed was significantly lower in cluster 3 than it was in clusters 1 and 2 (risk ratio, 0.37; 95% confidence interval, 0.17-0.83; p = 0.026 and risk ratio, 0.42; 95% confidence interval, 0.20-0.89; P = 0.019, respectively). There was no difference in the proportion of relapsed patients between clusters 1 and 2. CONCLUSIONS: Our cluster analysis shows that anti-SS-A/Ro52 or any anti-ARS antibodies or both might be relevant to clinical outcomes.

DOI： 10.1097/RHU.0000000000000836

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AIM: Deteriorated health-related quality of life (HRQOL) is associated with increased risk for death in both chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients; however, the impact of HRQOL on CKD progression is not well investigated. METHODS: We aimed to evaluate the association between HRQOL and CKD progression in Japanese patients with CKD. One hundred and three outpatients who visited the department of nephrology at our hospital (mean estimated glomerular filtration rate (eGFR); 32.1 ± 11.2 mL/min per 1.73 m2 ) between April 2007 and March 2012 were enrolled in this study. The primary outcome was 30% decline of eGFR or ESRD. We assessed HRQOL of all participants at baseline, including the physical component summary (PCS), the mental component summary (MCS) and the role/social component summary (RCS), using SF-36. Based on the baseline score of PCS, MCS and RCS, we divided all subjects into two groups by median. RESULTS: We studied 66 men (64.1%) and 37 women aged 61.7 ± 10.0 years old. During approximately 2.5 years of follow-up period, 59 patients (57.3%) reached 30% eGFR decline or ESRD. Cox regression analyses demonstrated that lower MCS score was significantly associated with CKD progression (hazard ratio (HR) = 1.83, 95% CI = 1.04-3.21, P = 0.035), but that lower PCS score and RCS score were not (HR = 0.70, 95% CI = 0.39-1.25, P = 0.223; HR = 0.95, 95% CI = 0.54-1.67, P = 0.854, respectively). CONCLUSION: We found that impaired mental health was associated with CKD progression. The evaluation of the mental health should be performed in the patients with CKD.

DOI： 10.1111/nep.13515

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Acute kidney injury (AKI) is frequently encountered in clinical practice, particularly secondarily to cardiovascular surgery and administration of nephrotoxic agents, and is increasingly recognized for initiating a transition to chronic kidney disease. Clarifying the pathogenesis of AKI could facilitate the development of novel preventive strategies, because the occurrence of hospital-acquired AKI is often anticipated. Vasohibin-1 (VASH1) was initially identified as an antiangiogenic factor derived from endothelial cells. VASH1 expression in endothelial cells has subsequently been reported to enhance cellular stress tolerance. Considering the importance of maintaining peritubular capillaries in preventing the progression of AKI, the present study aimed to examine whether VASH1 deletion is involved in the pathogenesis of cisplatin-induced AKI. For this, we injected male C57BL/6J wild-type (WT) and VASH1 heterozygous knockout (VASH1+/-) mice intraperitoneally with either 20 mg/kg cisplatin or vehicle solution. Seventy-two hours after cisplatin injection, increased serum creatinine concentrations and renal tubular injury accompanied by apoptosis and oxidative stress were more prominent in VASH1+/- mice than in WT mice. Cisplatin-induced peritubular capillary loss was also accelerated by VASH1 deficiency. Moreover, the increased expression of ICAM-1 in the peritubular capillaries of cisplatin-treated VASH1+/- mice was associated with a more marked infiltration of macrophages into the kidney. Taken together, VASH1 expression could have protective effects on cisplatin-induced AKI probably by maintaining the number and function of peritubular capillaries.

DOI： 10.1152/ajprenal.00045.2019

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DOI： 10.1097/RHU.0000000000000694

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Eight years prior to her present admission, a 61-year-old Japanese woman was diagnosed with autoimmune hepatitis, slowly progressive insulin-dependent diabetes mellitus, and chronic thyroiditis; she had been treated with oral prednisolone (PSL). After she suddenly discontinued PSL, she newly developed systemic lupus erythematosus. A combination therapy of oral PSL and intravenous cyclophosphamide resulted in remission. She was finally diagnosed with autoimmune polyglandular syndrome (APS) type 3 (3A ,3B, 3D), complicated with four different autoimmune diseases. Since patients with type 3 APS may present many manifestations over a long period of time, they should be carefully monitored.

DOI： 10.18926/AMO/56940

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Recent large clinical trials failed to show clear benefits of percutaneous transluminal renal angioplasty (PTRA) as compared with medical therapy on patients with renal artery stenosis. It was also reported that proteinuria is an adverse prognostic factor after PTRA, and PTRA is less effective in patients with overt proteinuria. From the renoprotective point of view, to reduce proteinuria after PTRA is an important therapeutic goal in patients with renal artery stenosis with overt proteinuria. We hereby describe two patients successfully treated by combination therapy with PTRA and administration of angiotensin-converting enzyme (ACE) inhibitor for bilateral renal artery disease with overt proteinuria.

DOI： 10.2169/internalmedicine.2076-18

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BACKGROUND: Bacterial peritonitis is a serious complication of patients undergoing peritoneal dialysis (PD). Although the identification of causative organisms and use of appropriate antibiotics are essential for treatment, rare and fastidious bacteria are sometimes difficult to detect by conventional biochemical assays. Capnocytophaga canimorsus is a fastidious and slow-growing bacterium that forms a part of the normal oral flora of dogs and cats and is extremely rare as a peritonitis-causing organism. This report demonstrates the usefulness of a mass spectrometry-based technique in identifying such a rare organism in PD-related peritonitis and discusses the diagnosis and treatment of C. canimorsus peritonitis. CASE PRESENTATION: A 49-year-old woman with type 2 diabetes mellitus underwent PD for two years. Repeated exit-site infections led to subcutaneous pathway diversion two months ago. She was hospitalized with fever and abdominal pain as well as cloudy dialysis effluent. Laboratory data revealed increased serum C-reactive protein level and white blood cell (WBC) count in the effluent. Her exit site had no sign of infection, leading to the diagnosis of PD-related peritonitis. Initial therapy with intraperitoneal ceftazidime immediately ameliorated her symptoms, and the WBC count in the effluent normalized in five days. Culture test results of the dialysis effluent on admission were negative with no information regarding the infection route. However, mass spectrometry (MALDI Biotyper, Bruker Daltonics) successfully obtained the specific spectral pattern for C. canimorsus. She had four cats in her house and was advised not to allow the cats in the room where the bag exchange took place. CONCLUSIONS: C. canimorsus is a rare cause of peritonitis in PD patients and is usually susceptible to intraperitoneal third-generation cephalosporins. This mass spectrometry-based bacterial identification method could provide more opportunities to identify uncommon causes and promote appropriate antibiotics therapy in PD-related peritonitis.

DOI： 10.1186/s12882-019-1415-x

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DOI： 10.1097/RHU.0000000000000723

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Nephron-sparing treatment should be offered whenever possible to avoid dialysis in allograph cases. Cryoablation is a new treatment option for treating small-sized renal cell cancer (RCCs). We report a case of RCC arising in a kidney allograft treated by cryoablation. To our knowledge, this is the first case in Asia of RCC in a renal allograft treated using cryoablation. Contrast-enhanced CT-guided percutaneous renal needle biopsy and cryoablation were used to identify the RCC, which could not be identified by other techniques. The postoperative course was uneventful. Contrast-enhanced CT also showed no recurrence or metastases at the 6-month follow-up.

DOI： 10.18926/AMO/56871

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Sodium-glucose cotransporter 2 (SGLT2) inhibitors are drugs for diabetes and might prevent heart failure. In this study, we investigated the effects of tofogliflozin, an SGLT2 inhibitor, on cardiac hypertrophy and metabolism in hypertensive rats fed a high-fat diet. Dahl salt-sensitive (DS) rats, hypertensive model rats, and Dahl salt-resistant (DR) rats, non-hypertensive model rats, were fed a high-salt and high-fat diet containing tofogliflozin (0.005%) for 9 weeks to examine the effects of this drug on cardiac hypertrophy and metabolism. Tofogliflozin tended to suppress a rise of the systolic blood pressure, relative to the control, throughout the treatment period in both DR and DS rats, and significantly suppress a rise of the systolic blood pressure, relative to the control, at the 9th week in DS rats. Tofogliflozin reduced cardiac hypertrophy (heart weight/body weight) not only in DS rats but also in DR rats. Histological analysis showed that tofogliflozin significantly decreased cardiomyocyte hypertrophy and perivascular fibrosis in both DS and DR rats. Tofogliflozin significantly decreased the expression levels of genes related to cardiac hypertrophy (encoding for natriuretic peptides A and B and interleukin-6), and to cardiac fibrosis (encoding for transforming growth factor-β1 and collagen type IV), in DS rats. Recent studies have shown that hypertrophied and failing hearts shift to oxidizing ketone bodies as a significant fuel source. We also performed metabolome analysis for ventricular myocardial tissue. Tofogliflozin reduced 3-hydroxybutyrate, a ketone body, and significantly decreased the expression levels of β-hydroxybutyrate dehydrogenase 1 and 3-oxoacid CoA-transferase, which are related to ketone oxidization. In conclusion, tofogliflozin ameliorated cardiac hypertrophy and fibrosis along with reduction of ketone usage in myocardial tissue.

DOI： 10.1536/ihj.18-392

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Purpose: The purpose of present study was to evaluate the clinical efficacy of irbesartan on the anti-inflammatory and anti-oxidative stress effect in patients with hypertension compared to other ARBs. Further, we assessed the effect of the ARBs on kidney function and urinary albumin excretion. Methods: Eighty-five outpatients with hypertension who took an ARB except irbesartan more than 3 months were assigned into two groups, one continued the same ARB and the other switched the ARB to irbesartan for 6 months. Results: Although blood pressures were equally controlled (continue group: 148 ± 2/79 ± 2 mmHg to 131 ± 2/74 ± 2 mmHg; switch group: 152 ± 2/81 ± 2 mmHg to 132 ± 2/74 ± 2 mmHg; p < 0.001 each), the inflammatory markers (hsCRP, PTX3, MCP-1) and oxidative stress marker (MDA-LDL) did not change after 6 months in both groups. Urinary albumin excretion was significantly reduced only in the switch group without renal function deterioration (switch group 292.4 ± 857.9 mg/gCr to 250.6 ± 906.5 mg/gCr, p = 0.012). Conclusion: These results provide knowledge of the characteristics of irbesartan, suggesting appropriate choice of ARBs in the treatment for hypertension should be considered.

DOI： 10.1080/1354750X.2018.1548033

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Communications  

Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.

DOI： 10.1038/s41467-019-09735-4

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DOI： 10.2169/internalmedicine.1249-18

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Background: Chronic angiotensin II (AngII) infusion promotes ascending aortic dilation in C57BL/6J mice. Meanwhile, vasohibin-2 (VASH2) is an angiogenesis promoter in neovascularization under various pathologic conditions. The aim of this study was to investigate whether exogenous VASH2 influences chronic AngII-induced ascending aortic dilation. Methods and Results: Eight-ten-week-old male C57BL/6J mice were injected with adenovirus (Ad) expressing either VASH2 or LacZ. One week after the injection, mice were infused with either AngII or saline s.c. for 3 weeks. Mice were divided into 4 groups: AngII+VASH2, AngII+LacZ, saline+VASH2, and saline+LacZ. Overexpression of VASH2 significantly increased AngII-induced intimal areas as well as the external diameter of the ascending aorta. In addition, VASH2 overexpression promoted ascending aortic medial elastin fragmentation in AngII-infused mice, which was associated with increased matrix metalloproteinase activity and medial smooth muscle cell (SMC) apoptosis. On western blot analysis, accumulation of apoptotic signaling proteins, p21 and p53 was increased in the AngII+VASH2 group. Furthermore, transfection of human aortic SMC with Ad VASH2 increased p21 and p53 protein abundance upon AngII stimulation. Positive TUNEL staining was also detected in the same group of the human aortic SMC. Conclusions: Exogenous VASH2 exacerbates AngII-induced ascending aortic dilation in vivo, which is associated with increased medial apoptosis and elastin fragmentation.

DOI： 10.1253/circrep.CR-19-0008

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This study aimed to clarify the relationship between repeated measurements of casual (spot) and 24-h urinary sodium-to-potassium (Na/K) ratios in patients with chronic kidney disease (CKD). A total of 61 inpatients with CKD, 31 in stage 1-3 (eGFR [estimated glomerular filtration rate] ≥ 30 ml/min/1.73 m2) and 30 in stage 4-5 (eGFR < 30 ml/min/1.73 m2), aged 20-85 consuming a low-sodium diet (NaCl [sodium chloride] 6 g/day) were recruited. Urinary Na, K, and Na/K ratios were measured in both casual urine samples and 2-day, 24 h urine samples, and then analyzed by correlation and Bland-Altman analyses. Mean 24-h urine Na/K ratio was higher in participants in stage 4-5 (5.1) than in participants in stage 1-3 (4.1) CKD. Casual urine Na/K ratio was strongly correlated with 2-day, 24-h urine Na/K ratio by sampling 4 casual urine specimens every morning and evening in participants in stage 1-3 (r = 0.69-0.78), but not in stage 4-5 (r = 0.12-0.19). The bias for mean Na/K ratio between 2-day, 24-h urine, and the 4 casual urine sampling ranged from -0.86 to 0.16 in participants in stage 1-3, and the quality of agreement for the mean of this casual urine sampling was similar to that of sampling 8 casual urine samples for estimating 2-day, 24-h values. Methods using repeated casual urine Na/K ratios may provide a reasonable estimation of 24-h urine Na/K ratio in normotensive and hypertensive as well as individuals with stage 1-3, but not stage 4-5 CKD.

DOI： 10.1038/s41371-018-0127-1

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The impact of orexins on anterior pituitary function has yet to be clarified. We studied the effects of orexin A and its interaction with the bone morphogenetic protein (BMP) system on the regulatory role of prolactin synthesis using rat lactotrope GH3 cells expressing BMP-4. Orexin type 1 receptor (OX1R), but not type 2 receptor (OX2R), was predominantly expressed in GH3 cells. Orexin A suppressed forskolin-induced, but not basal, prolactin mRNA expression without reducing cAMP levels. Of note, orexin A suppressed BMP-4-induced prolactin mRNA and cAMP synthesis. Impairment of the effects of orexin by chemical inhibitors suggested involvement of the P38 pathway in the OX1R activity that suppresses BMP-4-induced PRL expression. Given that inhibition of BMP-receptor signaling reduced prolactin mRNA levels, endogenous BMP action is likely to be linked to the activation of prolactin synthesis by GH3 cells. Orexin A was revealed to suppress Smad1/5/9 phosphorylation and Id-1 transcription induced by BMP-4, which was restored in the presence of orexin-receptor antagonists, suggesting that the inhibitory effect of orexin A occurred via OX1R. Orexin A also reduced ALK-3 expression but increased inhibitory Smad6/7 expression, while BMP-4 treatment downregulated OX1R expression. These results indicated that orexin A plays an inhibitory role in prolactin production through suppression of endogenous BMP activity in GH3 cells, suggesting that a new functional role of the interaction between orexin and BMP-4 is modulation of prolactin levels in lactotrope cells.

DOI： 10.1016/j.peptides.2019.01.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Nature  

Global DNA hypomethylation in CD4+ cells in systemic lupus erythematosus (SLE) was suggested to play a key role in the pathogenesis. To identify new methylation-sensitive genes, we integrated genome-wide DNA methylation and mRNA profiling data in CD4+ cells of MRL/lpr (MRL) and C57BL6/J (B6) mice. We identified Cathepsin E (Ctse), in which 13 methyl-CpGs within 583 bp region of intron 1 were hypomethylated, and Ctse mRNA upregulated in MRL compared with B6 mice. One of methyl-CpGs, mCGCG was 93.3 ± 2.05% methylated in B6 mice, while 80.0 ± 6.2% methylated and mutated to CGGG in MRL mice. Kaiso is known to bind to mCGCG and we hypothesized that it represses expression of Ctse in B6 mice. The binding of Kaiso to mCGCG site in B6 mice was reduced in MRL mice revealed by ChIP-PCR. EL4 cells treated with 5-azaC and/or Trichostatin A showed the suppression of binding of Kaiso to mCGCG motif by ChIP-PCR and the overexpression of Ctse was demonstrated by qPCR. Ctse gene silencing by siRNA in EL4 cells resulted in reduction of IL-10 secretion. The hypomethylation of mCGCG motif, reduced recruitment of Kaiso, and increased expression of Ctse and Il-10 in CD4+ cells may be involved in the pathogenesis of SLE.

DOI： 10.1038/s41598-019-38809-y

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BACKGROUND & AIMS: Evidence of the advantages of enhanced recovery after surgery (ERAS) protocols following pancreaticoduodenectomy (PD) is limited. The aim of this study was to examine the efficiency of ERAS protocols in patients following PD. METHODS: Between June 2014 and October 2016, patients undergoing PD were randomly assigned to receive ERAS protocols or standard care. The primary endpoint was the postoperative length of stay. Secondary endpoints included postoperative complications, postoperative quality-of-life (QoR-40J), readmission, and medical cost. RESULTS: Of 80 eligible patients, 74 were analyzed in intention-to-treat principles: 37 in the control group and 37 in the ERAS group. The mean length of stay in the ERAS group was significantly shorter than that in the control group (20.1 ± 5.4 vs 26.9 ± 13.5 days, P < 0.001). The ERAS group had a significantly lower percentage of postoperative complications (32.4% vs 56.8%, P = 0.034) and readmissions (0% vs 8.1%, P = 0.038). Quality-of-life was also significantly better in the ERAS group (184 ± 12.4 vs 177 ± 14.5, P = 0.022). The total medical cost was lower in the ERAS group, but not significantly ($25,445 ± 5065 vs $28,384 ± 9999, P = 0.085). CONCLUSIONS: The optimization of ERAS protocols in patients undergoing PD is safe and accelerates perioperative recovery and quality-of-life, thereby reducing the length of stay. Morbidity was significantly decreased in the ERAS group without compromising surgical outcome. REGISTRATION NUMBER: UMIN000014068.

DOI： 10.1016/j.clnu.2018.01.002

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AIMS: Cytomegalovirus (CMV) infection under immunosuppression sometimes causes death. This study aimed to elucidate risk factors for CMV infection in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: Patients with AAV who underwent remission induction treatment at Okayama University Hospital between 2006 and 2016 were retrospectively analyzed. The primary outcome was the development of CMV infection within 3 months. RESULTS: Of the 111 patients, 13 (11.7%) patients developed CMV infection. Patients with CMV infection were older (p = 0.030) and had a higher body mass index (p = 0.029) in comparison to those without CMV infection. A higher proportion had a severe form (p = 0.001) and granulomatosis with polyangiitis (GPA) (p = 0.001), as well as a higher Birmingham Vasculitis Activity Score (p = 0.018) and C-reactive protein (p = 0.018) levels at baseline. Using logistic regression analysis, severe form and GPA were independent risk factors (odds ratio [OR] = 9.68, 95% confidence interval [CI] = 1.92-60.23, and OR = 7.46, 95% CI = 1.46-47.60, respectively). In addition, patients with CMV infection were more likely than those without infection to be glucocorticoid-related diabetes mellitus (p = 0.025). CONCLUSION: Our study highlights disease severity and subgroups of AAV as risk factors for CMV infection.

DOI： 10.1371/journal.pone.0218705

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Background: From 2011, Okayama municipal government started the health checkup follow-up project to find those who were unaware of suffering chronic kidney disease and to prevent from aggravation of CKD stage. In this study, we aimed to evaluate the effect of 2 years' CKD-follow-up project regarding renal function and CKD risks. Patients and methods: Those who received a health checkup by the national health insurance in Okayama city in 2011 were recruited. The patients with lifestyle-related diseases or metabolic syndrome were excluded. Subjects who had an estimated glomerular filtration rate<50 mL/min/1.73 m2 or urinary protein positive by dipstick test were defined as compromised renal function group. They were recommended to visit a medical institution. Non-compromised renal function participants with two or more risks for CKD (hyperglycemia, higher blood pressure, dyslipidemia, hyperuricemia) were recommended to receive a health guidance (risk group). The change of renal function and CKD risks between 2011 and 2013 in each group was examined. Results: A total of 28,309 people received a health checkup in 2011. In compromised renal function group, 39.5% (96/243) of the subjects improved their CKD stages in 2013 regardless of the visit of medical institutions or the frequency of receiving health checkup. In risk group, 63.4% (260/410) of the subjects decreased their CKD risks in 2013 independent of the reception of health guidance. Conclusion: In both compromised renal function group and risk group, more than half of subjects kept their kidney function (217/243) and decreased the number of CKD risks (260/410) in 2 years' follow-up. Receiving a health checkup itself and notification of one's own health condition could exert a protective effect on kidney function.

DOI： 10.2147/IJNRD.S198781

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Background: This study aimed to identify the clinical subgroups of polymyalgia rheumatica (PMR) using cluster analysis and compare the outcomes among the identified subgroups. Methods: We enrolled patients with PMR who were diagnosed at Okayama University Hospital, Japan between 2006 and 2017, met the 2012 European League Against Rheumatism/American College of Rheumatology provisional classification criteria for PMR, and were treated with glucocorticoids. Hierarchical cluster analysis using variables selected by principal component analysis was performed to identify the clusters. Subsequently, the outcomes among the identified clusters were compared in the study. The primary outcome was treatment response at 1 month after commencement of treatment. The secondary outcome was refractory clinical course, which was defined as the requirement of additional treatments or relapse during a 2-year observational period. Results: A total of 61 consecutive patients with PMR were enrolled in the study. Their mean age was 71 years, and 67% were female. Hierarchical cluster analysis revealed three distinct subgroups: cluster 1 (n = 14) was characterized by patients with thrombocytosis (all patients showed a platelet count of >45 × 10⁴/µl), cluster 2 (n = 38), by patients without peripheral arthritis, and cluster 3 (n = 9), by patients with peripheral arthritis. The patients in cluster 1 achieved treatment response less frequently than those in cluster 2 (14% versus 47%, p = 0.030). Refractory cases were more frequent in cluster 1 than in cluster 2; however, no significant difference was noted (71% versus 42%, p = 0.06). Conclusions: Thrombocytosis could predict the clinical course in patients with PMR.

DOI： 10.1177/1759720X19864822

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Background: Alterations in DNA methylation may be involved in disease progression in patients with chronic kidney disease (CKD). Recent studies have suggested that 5-methyl-2'-deoxycytidine (5MedC) may be a marker of hypermethylation of DNA. Currently, there is no information available regarding the urine levels of 5MedC and its association with the progression of CKD. Method: We examined the urine levels of 5MedC in spot urine samples from 308 patients with CKD (median age: 56 years, male: 53.2%, and glomerulonephritis: 51.0%) using a competitive enzyme-linked immunosorbent assay and investigated the relationships among urine 5MedC, urine albumin, urine α1-microglobulin (α1MG), and the laboratory parameters associated with CKD. The patients were followed for three years to evaluate renal endpoints in a prospective manner. Results: The urine 5MedC level was significantly increased in the later stages of CKD compared to the early to middle stages of CKD. In multiple logistic regression models, urine 5MedC was significantly associated with the prediction of later CKD stages. Urine 5MedC (median value, 65.9 μmol/gCr) was significantly able to predict a 30% decline in the estimated GFR or a development of end-stage renal disease when combined with macroalbuminuria or an increased level of urine α1MG (median value, 5.7 mg/gCr). Conclusion: The present data demonstrate that the urine 5MedC level is associated with a reduced renal function and can serve as a novel and potent biomarker for predicting the renal outcome in CKD patients. Further studies will be necessary to elucidate the role of urine DNA methylation in the progression of CKD.

DOI： 10.1155/2019/5432453

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DOI： 10.2169/INTERNALMEDICINE.1463-18

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DOI： 10.1136/ANNRHEUMDIS-2019-EULAR.3420

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DOI： 10.1136/ANNRHEUMDIS-2019-EULAR.3422

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INTRODUCTION: Acquired partial lipoatrophy has been reported after bone marrow transplantation during childhood; however, no adult cases have previously been reported. We herein report two adult cases of acquired partial lipoatrophy after transplantation. CASE PRESENTATION: A 28-year-old Japanese woman developed diabetic ketoacidosis and received insulin therapy after bone marrow transplantation. She manifested partial lipoatrophy of the extremities, prominent insulin resistance, hyperglycemia, hypertriglyceridemia, and fatty liver. A 40-year-old Japanese woman underwent liver transplantation from a living donor for alcoholic liver disease after abstinence from alcohol. She newly developed non-alcoholic steatohepatitis and diabetes. Non-alcoholic steatohepatitis progressed to liver failure, and a second liver transplantation from a brain-dead donor was performed at 42 years of age. She demonstrated loss of subdermal fat of the upper and lower extremities, prominent insulin resistance, hyperglycemia, and hypertriglyceridemia. In both cases, the injection of recombinant methionyl human leptin reversed all of the metabolic abnormalities. CONCLUSIONS: Acquired partial lipoatrophy after transplantation is a manifestation of chronic graft-versus-host disease in adults. This entity is associated with diabetes with prominent insulin resistance and severe hypertriglycemia and can be successfully treated with metreleptin for the long term.

DOI： 10.1186/s13256-018-1901-y

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RATIONALE: Familial Mediterranean fever (FMF) is a genetic autoinflammatory disorder characterized by serositis and recurrent fever. Previous reports identified patients with antineutrophil cytoplasmic antibody (ANCA)-positive FMF, but vasculitis symptoms were not reported. PATIENT CONCERNS: We report the case of a 44-year-old man with numbness. He had a history of 3 episodes of pleurisy and was being treated with propylthiouracil for hyperthyroidism. Because he was ANCA-positive, we suspected drug-induced ANCA-associated vasculitis and propylthiouracil was discontinued. However, his numbness was not ameliorated, and he again developed high fever with pleurisy. DIAGNOSIS: Diagnosis of FMF was finally made, and genetic analysis revealed compound heterozygous mutations in exon 2 of the familial Mediterranean fever gene (L110P/E148Q). INTERVENTIONS: The patient was treated with 0.5 mg/day of colchicine. OUTCOMES: His numbness improved, and fever has not recurred. LESSONS: Appearance of ANCA and development of vasculitis should be considered in a clinical course of FMF with hyperthyroidism.

DOI： 10.1097/MD.0000000000013805

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AIM: Since 1998, the leading cause of chronic hemodialysis in Japan has been diabetic nephropathy. Diabetes mellitus is known to be a risk factor for frailty, but it still remains unknown whether diabetic nephropathy is associated with frailty in chronic dialysis patients. The authors carried out the present study to reveal the association between frailty and diabetic nephropathy in chronic hemodialysis patients. METHODS: A total of 355 patients who were on hemodialysis were recruited. Participants were divided into two groups of either patients who suffered diabetic nephropathy with end-stage renal disease (DN group, n = 150) or not (Non-DN group, n = 205). The authors investigated the difference of the prevalence of frailty between the two groups. Furthermore, the authors examined the risk factors for frailty. RESULTS: The prevalence of frailty in the DN group was significantly higher than that in the Non-DN group (28.0% vs 16.5%, P = 0.0161). To evaluate the association between frailty and its risk factors, we compared frail patients (n = 71) and non-frail patients (n = 262). After adjusting their interrelationships by using multivariate logistic regression analysis, diabetic nephropathy was determined as a significant risk factor for frailty. CONCLUSIONS: The authors found the close association between frailty and diabetic nephropathy in chronic hemodialysis patients. Geriatr Gerontol Int 2018; 18: 1597-1602.

DOI： 10.1111/ggi.13534

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DOI： 10.1177/0961203318804892

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BACKGROUND: Numerous patients develop diabetes in response to glucocorticoid therapy. This study explored the efficacy, safety, and preventive potential of the dipeptidyl peptidase-4 inhibitor, linagliptin (TRADJENTA®), in the development of glucocorticoid-induced diabetes mellitus. METHODS: From December 2014 to November 2015, we recruited non-diabetic Japanese patients scheduled for treatment with daily prednisolone ≥20 mg. Enrolled patients had at least one of following risk factors for glucocorticoid-induced diabetes mellitus: estimated glomerular filtration rate ≤ 60 mL/minute/1.73 m2; age ≥ 65 years; hemoglobin A1c > 6.0%. A daily dose of 5 mg of linagliptin was administered simultaneously with glucocorticoid therapy. The primary outcome was the development of glucocorticoid-induced diabetes mellitus. Additional orally administered hypoglycemic medications and/or insulin injection therapy was initiated according to the blood glucose level. RESULTS: Four of five patients developed glucocorticoid-induced diabetes mellitus within 1 week of glucocorticoid treatment. For 12 weeks, two of the four patients with glucocorticoid-induced diabetes mellitus required orally administered medications, but no patients required insulin. Blood glucose levels before breakfast and lunch tended to decrease with time; the median glucose levels before breakfast were 93 and 79.5 mg/dL at 1 and 3 weeks, respectively. Two patients experienced mild hypoglycemia around 2 weeks. Glucose levels after lunch remained high throughout all 4 weeks despite decreasing the glucocorticoid dosage. CONCLUSIONS: Linagliptin may be insufficient to prevent the development of glucocorticoid-induced diabetes mellitus but has the potential to reduce the requirement for insulin injection therapy. Treatment of glucocorticoid-induced diabetes mellitus was continued for at least 1 month and fasting hypoglycemia in early morning should be monitored after 2 weeks. TRIAL REGISTRATION: This trial was registered 02 November 2014 with UMIN Clinical Trials Registry (no. 000015588 ).

DOI： 10.1186/s13256-018-1817-6

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AIM: Trefoil factor 3 (TFF3) is a small peptide that is involved in mucosal protection. TFF3 is widely expressed in multiple tissues including kidney tissue. Previous studies have reported that the levels of urinary TFF3 are significantly increased in patients with chronic kidney disease. The aim of this study is to detect the TFF3 mRNA in kidney and elucidate the relationship between renal TFF3 mRNA and tubulointerstitial fibrosis in IgA nephropathy (IgAN). METHODS: We investigated the renal mRNA expression of TFF3 by real-time PCR analysis in biopsy specimens from patients with IgAN, other glomerulonephritis (OGN) and minor glomerular abnormalities (MGA). We also determined the renal localization of TFF3 and the levels of urinary TFF3 by immunostaining and ELISA, respectively. RESULTS: The renal TFF3 mRNA expression was significantly associated with the urinary TFF3 secretion and the tubulointerstitial fibrosis score in the IgAN group alone. Immunostaining of the renal specimen of IgAN patients revealed that TFF3 is located in the renal tubular epithelial cells. The locations were almost the same as those that showed uromodulin positivity; specifically, the thick ascending limb (TAL) of the loop of Henle and the early portion of the distal tubule. The urinary TFF3 levels were positively correlated with the levels of urinary biomarkers of tubulointerstitial injury in such patients. CONCLUSION: Renal TFF3 mRNA is associated with renal tubulointerstitial fibrosis in IgAN patients. The TFF3 located in the renal tubular epithelial cells may play a role in the progression of tubulointerstitial fibrosis in IgAN patients.

DOI： 10.1111/nep.13444

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Objective We aimed to investigate the relationships among chronic kidney disease (CKD), symptomatic ischaemic stroke, and carotid atherosclerosis. Methods We enrolled 455 patients who underwent carotid ultrasonography in our hospital, including 311 patients with symptomatic ischaemic stroke and 144 patients without symptomatic ischaemic stroke. Carotid intima-media thickness (IMT), the rate of internal carotid artery stenosis, and maximal plaque size were evaluated. Results The mean age of the patients was 68.5 ± 11.0 years and the mean estimated glomerular filtration rate (eGFR) was 68.8 ± 18.2 mL/min/1.73 m2. After adjustment for cardiovascular risk factors, the mean IMT was significantly higher in patients with CKD than in those without CKD. The IMT and eGFR were negatively correlated in patients with stroke (r = -0.169). Multiple logistic regression analyses showed that mean IMT, plaque size, and internal carotid artery stenosis were significant determinants of symptomatic ischaemic stroke after adjustment of multivariate risk factors. Furthermore, the eGFR was a negative determinant of symptomatic ischaemic stroke after adjusting for classical risk factors (odds ratio [95% confidence interval] = 0.868 [0.769-0.979]). Conclusion CKD might be associated with the carotid atherosclerosis and symptomatic ischaemic stroke.

DOI： 10.1177/0300060518781619

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Objectives The clinical condition of frailty is a common problem in the elderly population. However, the relationship between peripheral artery disease and frailty in hemodialysis patients remains unknown. The aim of this study was to identify the relationships between peripheral artery disease and frailty in Japanese chronic hemodialysis patients. Methods A total of 362 chronic hemodialysis patients who regularly visited six institutions were enrolled. To evaluate frailty, the modified Fried's frailty phenotype adjusted for Japanese were used. Peripheral artery disease was defined as ankle-brachial index <0.9. Results Of 362 patients, 62 patients (17.1%) were categorized as peripheral artery disease group and 300 patients (82.9%) as Non-peripheral artery disease group. The prevalence of frailty in the peripheral artery disease group was significantly higher than in the Non-peripheral artery disease group (34% vs. 18%, P = 0.0103). Non-shunt side grip strength was significantly stronger in the Non-peripheral artery disease group (23.6 kg vs. 17.0 kg, P < 0.0001). Thigh circumferences were also significantly larger in the Non-peripheral artery disease group (41.7 cm vs. 39.7 cm, P = 0.0054). A multivariate logistic regression analysis demonstrated that the factors independently associated with peripheral artery disease were as follows: frailty (odds ratio = 2.06, 95% confidence interval 1.09-3.89) and myocardial infarction (odds ratio = 3.74, 95% confidence interval 2.05-6.83). Conclusions It is concluded that peripheral artery disease is closely associated with frailty in hemodialysis patients.

DOI： 10.1177/1708538118756690

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OBJECTIVE: Because quantifying glycans with complex structures is technically challenging, little is known about the association of glycosylation profiles with the renal prognosis in diabetic kidney disease (DKD). RESEARCH DESIGN AND METHODS: In 675 patients with type 2 diabetes, we assessed the baseline urinary glycan signals binding to 45 lectins with different specificities. The end point was a decrease of estimated glomerular filtration rate (eGFR) by ≥30% from baseline or dialysis for end-stage renal disease. RESULTS: During a median follow-up of 4.0 years, 63 patients reached the end point. Cox proportional hazards analysis revealed that urinary levels of glycans binding to six lectins were significantly associated with the outcome after adjustment for known indicators of DKD, although these urinary glycans, except that for DBA, were highly correlated with baseline albuminuria and eGFR. Hazard ratios for these lectins were (+1 SD for the glycan index) as follows: SNA (recognizing glycan Siaα2-6Gal/GalNAc), 1.42 (95% CI 1.14-1.76); RCA120 (Galβ4GlcNAc), 1.28 (1.01-1.64); DBA (GalNAcα3GalNAc), 0.80 (0.64-0.997); ABA (Galβ3GalNAc), 1.29 (1.02-1.64); Jacalin (Galβ3GalNAc), 1.30 (1.02-1.67); and ACA (Galβ3GalNAc), 1.32 (1.04-1.67). Adding these glycan indexes to a model containing known indicators of progression improved prediction of the outcome (net reclassification improvement increased by 0.51 [0.22-0.80], relative integrated discrimination improvement increased by 0.18 [0.01-0.35], and the Akaike information criterion decreased from 296 to 287). CONCLUSIONS: The urinary glycan profile identified in this study may be useful for predicting renal prognosis in patients with type 2 diabetes. Additional investigation of glycosylation changes and urinary glycan excretion in DKD is needed.

DOI： 10.2337/dc18-0030

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We present a case of a woman with systemic lupus erythematosus (SLE) who had refractory episodes of neuromyelitis optica spectrum disorder (NMOSD) and was successfully treated with rituximab. She was positive for anti-aquaporin-4 (AQP4) antibody and had typical cranial and longitudinally extended spinal lesions but no optic nerve involvement. There is no established treatment for NMOSD/SLE overlap cases. Our experience suggests that rituximab may be effective for patients with combined SLE and anti-AQP4 antibody-positive NMOSD.

DOI： 10.1177/0961203318760994

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OBJECTIVE: In systemic lupus erythematosus (SLE), an autoimmune disease associated with multiple organ involvement, the development of lupus nephritis determines prognosis, and arthritis impairs quality of life. Galectin 9 (Gal-9, Lgals9) is a β-galactoside-binding lectin that has been used for clinical application in autoimmune diseases, since recombinant Gal-9, as a ligand for T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), induces apoptosis of activated CD4+TIM-3+ Th1 cells. This study was undertaken to investigate whether deficiency of Lgals9 has beneficial or deleterious effects on lupus in a murine model. METHODS: Gal-9+/+ and Gal-9-/- female BALB/c mice were injected with pristane, and the severity of arthritis, proteinuria, and levels of autoantibody production were assessed at several time points immediately following injection. At 7 months after pristane injection, renal pathologic features, the severity of joint inflammation, and formation of lipogranulomas were evaluated. Subsets of inflammatory cells in the spleen and peritoneal lavage were characterized, and expression levels of cytokines from peritoneal macrophages were analyzed. RESULTS: Lgals9 deficiency protected against the development of immune complex glomerulonephritis, arthritis, and peritoneal lipogranuloma formation in BALB/c mice in this murine model of pristane-induced lupus. The populations of T cell subsets and B cells in the spleen and peritoneum were not altered by Lgals9 deficiency in pristane-injected BALB/c mice. Furthermore, Lgals9 deficiency protected against pristane-induced lupus without altering the Toll-like receptor 7-type I interferon pathway. CONCLUSION: Gal-9 is required for the induction and development of lupus nephritis and arthritis in this murine model of SLE. The results of the current investigation provide a potential new strategy in which antagonism of Gal-9 may be beneficial for the treatment of nephritis and arthritis in patients with SLE through targeting of activated macrophages.

DOI： 10.1002/art.40467

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Aim: We developed a novel estimation method for hemoglobin A1c (HbA1c) in type 2 diabetes (T2D) patients with end-stage renal disease (ESRD). This method is based on the glycated albumin (GA) level. Methods: Of the 788 Japanese patients with T2D included in this study, 545 had normal renal function (NRF group) and 243 had ESRD. Oral glucose tolerance tests (OGTTs) were performed in 80 subjects. The variables GA, body mass index (BMI), hemoglobin (Hb), and estimated glomerular filtration rate (eGFR) were significantly associated with the GA-to-HbA1c ratio and were used to determine the estimated HbA1c (eHbA1c). One method of estimating HbA1c involved dividing GA by the GA-to-HbA1c ratio predicted from the estimated regression equation; the estimated HbA1c obtained in this manner was denoted eHbA1c-1. Results: eHbA1c-1 (%) = GA × [4.688 - 18.833 × GA-1 - 0.015 × BMI - 0.037 × Hb (- 0.002 × eGFR for patients without ESRD)]-1; adjusted R 2 = 0.676 for actual HbA1c. The sensitivity of eHbA1c-1 was better than that of GA for diabetes diagnosis using the 75-g OGTT. There were no differences in the slope of eHbA1c-1 versus GA and the variance of eHbA1c-1 between the ESRD and NRF groups. eHbA1c-1 was not associated with Hb, erythropoiesis-stimulating agent use, or ESRD concomitance. Conclusions: eHbA1c-1 may be a useful parameter for estimating HbA1c in T2D patients with ESRD.

DOI： 10.1007/s13340-018-0342-6

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Chronic kidney disease (CKD) is a major global health problem. Unless intensive intervention is initiated, some patients can rapidly progress to end-stage kidney disease. However, it is often difficult to predict renal outcomes using conventional laboratory tests in individuals with CKD. Therefore, many researchers have been searching for novel biomarkers to predict the progression of CKD. Angiogenesis is involved in physiological and pathological processes in the kidney and is regulated by the balance between a proangiogenic factor, vascular endothelial growth factor (VEGF)-A, and various endogenous antiangiogenic factors. In recent reports using genetically engineered mice, the roles of these antiangiogenic factors in the pathogenesis of kidney disease have become increasingly clear. In addition, recent clinical studies have demonstrated associations between circulating levels of antiangiogenic factors and renal dysfunction in CKD patients. In this review, we summarize recent advances in the study of representative endogenous antiangiogenic factors, including soluble fms-related tyrosine kinase 1, soluble endoglin, pigment epithelium-derived factor, VEGF-A165b, endostatin, and vasohibin-1, in associations with kidney diseases and discuss their predictive potentials as biomarkers of progression of CKD.

DOI： 10.3390/ijms19071859

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

Background: Diabetic nephropathy is a leading cause of end-stage kidney disease in the world. Although various types of treatment for diabetes, hypertension and dyslipidemia have improved prognosis and quality of life in patients with diabetic nephropathy, there still exist some diabetic patients with severe proteinuria showing poor prognosis. This clinical trial, LICENSE, aims to confirm the impact of LDL apheresis on proteinuria exhibiting hyporesponsiveness to treatment. Methods: This ongoing trial is a multicenter, prospective study of diabetic patients with severe proteinuria. The objective is to examine the impact of LDL apheresis on proteinuria in patients with diabetic nephropathy. The other subject is to investigate safety of LDL apheresis in these patients. Results: The subjects consist of diabetic patients with serum creatinine (Cr) levels below 2 mg/dL who present severe proteinuria above 3 g/g Cr or 3 g/day and LDL cholesterol above 120 mg/dL. The target number of registered patients will be 35 patients. Urinary protein excretion and renal function will be observed for 24 weeks after the treatment of LDL apheresis. Conclusion: This study will determine the effectiveness and safety of LDL apheresis for diabetic nephropathy patients with severe proteinuria and dyslipidemia.

DOI： 10.1007/s10157-017-1488-4

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Renal involvement is occasionally observed in Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT). It has been reported that galactose-deficient IgA is a closely linked to IgA nephropathy (IgAN), suggesting that patients with XLT/WAS associated with reduced galactosylation on serum IgA are susceptible to IgAN. It is necessary to pay more attention to patients with IgAN due to the potential complication with XLT/WAS. We here present a patient of XLT complicated with mild IgAN who underwent tonsillectomy combined with steroid pulse therapy to achieve complete clinical remission.

DOI： 10.18926/AMO/56077

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Acute kidney injury (AKI) has been associated with not only higher in-hospital mortality but also the subsequent development of chronic kidney disease (CKD). Recent evidence has suggested the involvement of mitochondrial dysfunction and impaired dynamics in the pathogenesis of AKI. Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that acts as a transcription factor to regulate the transcription of genes required for mitochondrial biogenesis and oxidative phosphorylation. In the present study, we examined the effects of ERRα deficiency on the progression of AKI induced by cisplatin. Male C57BL/6 J wild-type and ERRα-/- mice received a single intraperitoneal injection of 20 mg/kg cisplatin. Seventy-two hours after the injection, kidney function and morphology were evaluated. ERRα expression was observed in renal tubules, and cisplatin inhibited its translocation into nuclei. ERRα deficiency exacerbated cisplatin-induced renal dysfunction and tubular injury, as well as oxidative stress and apoptosis. ERRα-/- mice kidneys revealed lower mitochondrial DNA content and swollen mitochondria with reduced cristae. In addition, these mice had lower expression of the mitochondrial fusion protein mitofusin-2. The cisplatin-induced decrease in mitochondrial DNA and altered mitochondrial structure were more severe in ERRα-/- mice. In cultured mouse proximal tubular epithelial cells, the ERRα inverse agonist XCT-790 significantly inhibited mitofusin-2 expression and induced mitochondrial fragmentation. Taken together, our findings suggest the involvement of ERRα in the progression of cisplatin-induced AKI probably through impaired mitochondrial dynamics.

DOI： 10.1016/j.bbrc.2018.03.080

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The effects of incretins on ovarian steroidogenesis have not been clarified. In this study, we investigated the effects of incretins, including GIP and GLP-1, on ovarian steroidogenesis using rat primary granulosa cells. Treatment with incretins significantly suppressed progesterone synthesis in the presence of FSH, and the effect of GIP was more potent than that of GLP-1. In contrast, incretins had no significant effect on estrogen synthesis by rat granulosa cells. In accordance with the effects of incretins on steroidogenesis, GIP and GLP-1 suppressed the expression of progesterogenic factors and enzymes, including StAR, P450scc, 3βHSD, but not P450arom, and cellular cAMP synthesis induced by FSH. In addition, incretins moderately increased FSHR mRNA expression in granulosa cells. Of note, treatment with GIP, but not treatment with GLP-1, augmented Smad1/5/8 phosphorylation and transcription of the BMP target gene Id-1 induced by BMP-6 stimulation, suggesting that GIP upregulates BMP receptor signaling that can inhibit FSH-induced progesterone synthesis in rat granulosa cells. On the other hand, BMP-6 treatment suppressed the expression of GIP receptor but not that of GLP-1 receptor. Expression of the BMP type-I receptor ALK-3 was upregulated by treatment with GIP and GLP-1 and that of ALK-6 was also increased by GIP, while inhibitory Smad6 expression was impaired by GIP and GLP-1 in rat granulosa cells. Collectively, the results indicate that incretins, particularly GIP, impair FSH-induced progesterone production, at least in part, by upregulating BMP signaling in rat granulosa cells. The modulatory effects of incretins on endogenous BMP activity may be applicable to treatment of dysregulated steroidogenesis such as polycystic ovary syndrome.

DOI： 10.1016/j.jsbmb.2017.11.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Lippincott Williams and Wilkins  

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a permanent dilation of the abdominal aorta associated with rupture, which frequently results in fatal consequences. AAA tissue is commonly characterized by localized structural deterioration accompanied with inflammation and profound accumulation of leukocytes, although the specific function of these cells is unknown. Cilostazol, a phosphodiesterase III inhibitor, is commonly used for patients with peripheral vascular disease or stroke because of its anti-platelet aggregation effect and anti-inflammatory effect, which is vasoprotective effect. In this study, we evaluated the effects of cilostazol on angiotensin II-induced AAA formation. APPROACH AND RESULTS: Male apolipoprotein E-deficient mice were fed either normal diet or a diet containing cilostazol (0.1% wt/wt). After 1 week of diet consumption, mice were infused with angiotensin II (1000 ng/kg per minute) for 4 weeks. Angiotensin II infusion increased maximal diameters of abdominal aortas, whereas cilostazol administration significantly attenuated dilatation of abdominal aortas, thereby, reducing AAA incidence. Cilostazol also reduced macrophage accumulation, matrix metalloproteinases activation, and inflammatory gene expression in the aortic media. In cultured vascular endothelial cells, cilostazol reduced expression of inflammatory cytokines and adhesive molecules through activation of the cAMP-PKA (protein kinase A) pathway. CONCLUSIONS: Cilostazol attenuated angiotensin II-induced AAA formation by its anti-inflammatory effect through phosphodiesterase III inhibition in the aortic wall. Cilostazol may be a promising new therapeutic option for AAAs.

DOI： 10.1161/ATVBAHA.117.309707

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The population undergoing dialysis is aging worldwide, particularly in Japan. The clinical condition of frailty is the most problematic expression in the elderly population. Potential pathophysiological factors of frailty present in patients with CKD and are accentuated in patients with ESRD. The aim of this study was to identify the prevalence and predictors of frailty in Japanese HD patients. This study was a multicenter, cross-sectional and observational investigation conducted at 6 institutions. To evaluate frailty, the modified Fried's frailty phenotype adjusted for Japanese as the self-reported questionnaire was used. Of the 542 patients visiting each institution, 388 were enrolled in this study. In total, 26.0% of participants were categorized as not-frailty, 52.6% as pre-frailty and 21.4% as frailty. The prevalence of frailty increased steadily with age and was more prevalent in females than in males and the subjects with frailty received polypharmacy. A multivariate logistic regression analysis revealed that the factors independently associated with frailty were the following: female gender (odds ratio [OR] = 3.661, 95% confidence interval [CI] 1.398-9.588), age (OR = 1.065, 95% CI 1.014-1.119), age ≥ 75 years old (OR = 4.892, 95% CI 1.715-13.955), body mass index (BMI) < 18.5 (OR = 0.110, 95% CI 0.0293-0.416), number of medications being taken (OR = 1.351, 95% CI 1.163-1.570), diabetes mellitus (DM) (OR = 2.765, 95% CI 1.081-7.071) and MNA-SF ≤ 11 (OR = 7.405, 95% CI 2.732-20.072). Frailty was associated with the accumulation of risk factors. The prevalence of frailty in Japanese patients with HD was relatively lower than that previously reported in Western developed countries; however, it was extremely high compared to the general population regardless of age. Our findings suggest that frailty might be associated with an increase in the prevalence of adverse health outcomes in patients with HD.

DOI： 10.14336/AD.2017.0429

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BACKGROUND: A number of studies have suggested a bidirectional relationship of periodontitis with rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM). However, the genetic factors that underlie these relationships have not been elucidated. METHODS: We conducted a multicenter case-control study that included 185 patients with RA and chronic periodontitis (CP), 149 patients with T2DM and CP, 251 patients with CP, and 130 systemically and periodontally healthy controls from a cohort of Japanese adults to assess the shared genetic risk factors for RA and CP as well as for T2DM and CP. A total of 17 candidate single nucleotide polymorphisms (SNPs) associated with RA, T2DM, and CP were genotyped. RESULTS: Multiple logistic regression analyses revealed that the KCNQ1 rs2237892 was significantly associated with comorbidity of RA and CP (P = 0.005) after adjustment for age, sex, and smoking status. The carriers of the T allele among patients with RA and CP showed significantly higher disease activity scores including 28 joints using C-reactive protein values than the non-carriers (P = 0.02), although the age, female percentage, and smoking status were comparable. Other SNPs were not associated with comorbidity of RA and CP, T2DM and CP, or susceptibility to CP. CONCLUSION: The results of the present pilot study suggest for the first time that the KCNQ1 rs2237892 may constitute a shared genetic risk factor for RA and CP, but not for T2DM and CP in Japanese adults.

DOI： 10.1002/JPER.17-0412

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Double-stranded RNA (dsRNA) sensors including TLR3, MDA5 and RIG-I are expressed in epidermal keratinocytes and play an important immunological role by enhancing various innate and adaptive immune responses. Although the role of elevated extracellular calcium concentration in keratinocyte differentiation is well understood, the effect of high calcium on dsRNA sensors is not well studied. We investigated alterations in dsRNA sensor expression and antiviral activity induced by a high extracellular concentration of calcium in epidermal keratinocytes. Normal human epidermal keratinocytes (NHEKs) were stimulated with high calcium and/or synthetic dsRNA, poly (I:C). TLR3, IFIH1 (MDA5) and DDX58 (RIG-I) expression were measured via qPCR, and IFN-β and human beta-defensin 2 (HBD2) levels were measured using ELISA. TLR3 localization was evaluated with immunocytofluorescence. Antiviral activity was quantified with virus plaque assays using herpes simplex virus type 1 (HSV-1). High calcium significantly upregulated mRNA expression of TLR3, IFIH1 and DDX58 in NHEKs. In addition, high calcium significantly enhanced poly (I:C)-induced anti-HSV-1 activity in NHEKs. The antiviral molecule HBD2 but not IFN-β induction by poly (I:C) was enhanced by high calcium. Our findings indicate that high levels of extracellular calcium enhance the expression of dsRNA sensors and augment antiviral activity in epidermal keratinocytes.

DOI： 10.1111/exd.13456

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OBJECTIVE: The objective of this study is to elucidate predictors of relapse in patients with polymyositis and dermatomyositis (PM/DM). METHODS: Fifty PM/DM patients who achieved disease stabilization at Okayama University Hospital in 2004-2014 were enrolled retrospectively. Candidate predictors such as demographic factors, clinical symptoms, laboratory data, and treatment status were compared. RESULTS: The mean age of enrolled patients was 58 years; 34 were female. The patient groupings were as follows: 21 with PM, 27 with DM, and two with clinically amyopathic DM. During a mean observation period of 685 d, 5 patients (10%) died and 20 (40%) relapsed. The relapsed patients displayed baseline muscle weakness less frequently (85% versus 100%, p = .03) and anti-SS-A/Ro antibody more frequently (65% versus 27%, p = .007). Anti-SS-A/Ro-positive patients exhibited a higher relapse rate than anti-SS-A/Ro-negative patients (log-rank test, p = .03). Anti-SS-A/Ro-positive patients also exhibited higher anti-Jo-1 antibody positivity and lower levels of serum complement. After adjusting anti-Jo-1 antibody positivity, age, sex, CK <500 IU/L, and lung involvement, anti-SS-A/Ro positivity was still an independent risk factor for higher relapse-rate (odds ratio, 5.5; 95% confidence interval, 1.4-25.1). CONCLUSIONS: Anti-SS-A/Ro antibody positivity may be a useful biomarker for prediction of relapse.

DOI： 10.1080/14397595.2017.1317377

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DOI： 10.1038/hr.2017.88

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Public Library of Science  

Cystatin C is a cysteine protease inhibitor that is produced by nearly all human cells. The serum level of cystatin C is a stronger predictor of the renal outcome and the risk of cardiovascular events than the creatinine level. The resistive index (RI) on renal Doppler ultrasonography is a good indicator of vascular resistance as well as the renal outcomes in patients with chronic kidney disease (CKD). However, it is unclear whether serum cystatin C is associated with signs of vascular dysfunction, such as the renal RI. We measured the serum cystatin C levels in 101 CKD patients and investigated the relationships between cystatin C and markers of vascular dysfunction, including the renal RI, ankle-brachial pulse wave velocity (baPWV), intima-media thickness (IMT), and cardiac function. The renal RI was significantly correlated with the serum cystatin C level (p < 0.0001, r = 0.6920). The serum cystatin C level was found to be a significant determinant of the renal RI (p < 0.0001), but not the baPWV, in a multivariate regression analysis. The multivariate odds ratio of the serum cystatin C level for a renal RI of more than 0.66 was statistically significant (2.92, p = 0.0106). The area under the receiver-operating characteristic curve comparing the sensitivity and specificity of cystatin C for predicting an RI of more than 0.66 was 0.882 (cutoff value: 2.04 mg/L). In conclusion, the serum cystatin C level is an independent biomarker associated with the renal RI in patients with CKD.

DOI： 10.1371/journal.pone.0193695

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Angiogenesis has been implicated in glomerular alterations in the early stage of diabetic nephropathy. We previously reported the renoprotective effects of vasohibin-1 (VASH1), which is a novel angiogenesis inhibitor derived from endothelial cells, on diabetic nephropathy progression. Vasohibin-2 (VASH2) was originally identified as a VASH1 homolog and possesses pro-angiogenic activity in contrast to VASH1. In addition, VASH2 was recently shown to promote epithelial-to-mesenchymal transition via enhanced transforming growth factor (TGF)-β signaling in cancer cells. Herein, we investigated the pathogenic roles of VASH2 in diabetic nephropathy using VAHS2-deficient mice. The type 1 diabetes model was induced by intraperitoneal injections of streptozotocin in VASH2 homozygous knockout (VASH2LacZ/LacZ) or wild-type mice. These mice were euthanized 16 weeks after inducing hyperglycemia. Increased urine albumin excretion and creatinine clearance observed in diabetic wild-type mice were significantly prevented in diabetic VASH2-deficient mice. Accordingly, diabetes-induced increase in glomerular volume and reduction in glomerular slit-diaphragm density were significantly improved in VASH2 knockout mice. Increased glomerular endothelial area was also suppressed in VASH2-deficient mice, in association with inhibition of enhanced vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2), but not VEGF level. Furthermore, glomerular accumulation of mesangial matrix, including type IV collagen, and increased expression of TGF-β were improved in diabetic VASH2 knockout mice compared with diabetic wild-type mice. Based on the immunofluorescence findings, endogenous VASH2 localization in glomeruli was consistent with mesangial cells. Human mesangial cells (HMCs) were cultured under high glucose condition in in vitro experiments. Transfection of VASH2 small interfering RNA (siRNA) into the HMCs resulted in the suppression of type IV collagen production induced by high glucose compared with control siRNA. These results indicate that VASH2 may be involved in diabetes-induced glomerular alterations, particularly impaired filtration barrier and mesangial expansion. Therefore, VASH2 is likely to represent a promising therapeutic target for diabetic nephropathy.

DOI： 10.1371/journal.pone.0195779

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Introduction: Trefoil factor family (TFF) peptides are increased in serum and urine in patients with chronic kidney disease (CKD). However, whether the levels of TFF predict the progression of CKD remains to be elucidated. Methods: We determined the TFF levels using peptide-specific ELISA in spot urine samples and performed a prospective cohort study. The association between the levels of urine TFFs and other urine biomarkers as well as the renal prognosis was analyzed in 216 CKD patients (mean age: 53.7 years, 47.7% female, 56.9% with chronic glomerulonephritis, and mean eGFR: 58.5 ml/min/1.73 m2). Results: The urine TFF1 and TFF3 levels significantly increased with the progression of CKD stages, but not the urine TFF2 levels. The TFF1 and TFF3 peptide levels predicted the progression of CKD ≥ stage 3b by ROC analysis (AUC 0.750 and 0.879, resp.); however, TFF3 alone predicted CKD progression in a multivariate logistic regression analysis (odds ratio 3.854, 95% confidence interval 1.316-11.55). The Kaplan-Meier survival curves demonstrated that patients with a higher TFF1 and TFF3 alone, or in combination with macroalbuminuria, had a significantly worse renal prognosis. Conclusion: The data suggested that urine TFF peptides are associated with renal progression and the outcomes in patients with CKD.

DOI： 10.1155/2018/3024698

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© 2018 Excerpta Medica Inc. All rights reserved. Background : Because of westernization of lifestyle in recent years, the number of patients with lifestyle diseases, including obesity, metabolic syndrome, hypertension, dyslipidemia and diabetes mellitus, are increasing steadily. Recently, it has been noted that non-alcoholic fatty liver disease (NAFLD) alone can cause liver cirrhosis or liver cancer. Angiotensin type II receptor blocker (ARB) is widely used in clinical practice as an antihypertensive agent. In addition to the antihypertensive effect by inhibiting the renin-angiotensin system, ARB has been demonstrated to protect the multiple organs damage, including brain, heart and kidney. In recent years, many reports suggest that the renin-angiotensin system is involved in the development of liver fïbrosis. Objectives : We examined the protective effect of olmesartan on hepatic insufficiency and hepatic fibrosis marker in hypertensive patients with NAFLD. Methods : Olmesartan was administered to eleven hypertensive patients with NAFLD for 12 weeks. Results : Both office systolic blood pressure and diastolic blood pressure decreased from 141±3/82±2 mmHg to 130±7/76±4 mmHg (p = 0.035). AST decreased significantly from 48.8±4.5 IU/L to 42.2±4.6 IU/L (p=0.011), AST from 7l.7±7.8 IU/L to 59.8±8.5IU/L (p = 0.046), y-GTP from 102.3±21.6 IU/L to 90±20.3 IU/L (p = 0.049). Finally, regarding TGF β1, a significant change was observed from 14898±3101 pg/mL to 10738±2405pg/mL (p = 0.017). Conclusions: Olmesartan ameliorates hepatic insufficiency in hypertensive patients with NAFLD. Olmesartan may not only have a class effect of ARB but also have a drug effect, especially on NAFLD.

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DOI： 10.4049/jimmunol.1800810

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DOI： 10.1080/24725625.2017.1368436

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DOI： 10.1155/2018/8693137

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DOI： 10.1136/ANNRHEUMDIS-2018-EULAR.1895

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DOI： 10.1002/ART.40563

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Language：English   Publisher：WILEY  

DOI： 10.1111/nep.12973

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Aim
The purpose of this study was to investigate the effects of non-surgical periodontal treatment on hemoglobinA1c (HbA1c) levels, oxidative stress balance and quality of life (QOL) in patients with type 2 diabetes mellitus (T2DM) compared to no periodontal treatment (simple oral hygiene instructions only).
Methods
The design was a 6-month, single-masked, single center, randomized clinical trial. Patients had both T2DM and chronic periodontitis. Forty participants were enrolled between April 2014 and March 2016 at the Nephrology, Diabetology and Endocrinology Department of Okayama University Hospital. The periodontal treatment group (n = 20) received non-surgical periodontal therapy, including scaling and root planing plus oral hygiene instructions, and consecutive supportive periodontal therapy at 3 and 6 months. The control group (n = 17) received only oral hygiene instructions without treatment during the experimental period. The primary study outcome was the change in HbA1c levels from baseline to 3 months. Secondary outcomes included changes in oxidative stress balance (Oxidative-INDEX), the Diabetes Therapy-Related QOL and clinical periodontal parameters from baseline to 3 months and baseline to 6 months.
Results
Changes in HbA1c in the periodontal treatment group were not significantly different with those in the control group at 3 and 6 months. Systemic oxidative stress balance and QOL significantly improved in the periodontal treatment group compared to the control group at 3 months. In the subgroup analysis (moderately poor control of diabetes), the decrease in HbA1c levels in the periodontal treatment group was greater than that in the control group at 3 months but not significant.
Conclusions
In T2DM patients, non-surgical periodontal treatment improved systemic oxidative stress balance and QOL, but did not decrease HbA1c levels at 3 months follow-up.

DOI： 10.1371/journal.pone.0188171

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Several angiogenesis-related factors are known to play important roles in the pathogenesis of kidney disease. Vasohibin-2 (VASH-2) was recently reported as a novel proangiogenic factor. Although VASH-2 was demonstrated to accelerate tumor angiogenesis, its roles in non-tumor processes including renal disease have not been well elucidated yet. Here, we performed a retrospective study including an immunohistochemical analysis of human kidney biopsy specimens from 82 Japanese patients with a variety of kidney diseases, and we evaluated the correlations between the immunoreactivity of VASH-2 and the patients' clinicopathological parameters. VASH-2 immunoreactivity was detected in varying degrees in renal tubules as well as in peritubular capillaries and vasa recta. The cortical and medullary tubule VASH-2(+) scores were correlated with the presence of hypertension, and the medullary tubule VASH-2(+) score was significantly correlated with the blood glucose (p=0.029, r=0.35) and hemoglobin A1c levels (p=0.0066, r=0.39). Moreover, decreased VASH-2(+) scores in the vasa recta were associated with reduced renal function (p=0.0003). These results suggest that VASH-2 could play an important role in the pathogenesis of renal diseases, and that VASH-2 is closely associated with hypertension and impaired glucose tolerance.

DOI： 10.18926/AMO/55434

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

We herein present a case of a 38-year-old man who had bamboo spine and severe sacroiliitis and who was diagnosed with ankylosing spondylitis (AS). Infliximab (IFX) markedly improved the axial symptom but was discontinued due to the side effect of peripheral neuropathy. Switching from IFX to etanercept worsened the side effect. Rituximab (RTX) administration elicited a good response without side effects. RTX might be a suitable option for AS therapy when TNF inhibitors are difficult to use.

DOI： 10.18926/AMO/55444

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

We evaluated the efficacy of a neutralizing anti-high mobility group box 1 (HMGB1) monoclonal antibody in MRL/lpr lupus-prone mice. The anti-HMGB1 monoclonal antibody (5 mg/kg weight) or class-matched control immunoglobulin G2a (IgG2a) was administered intravenously twice a week for 4-15 weeks. Urine albumin was monitored, and histological evaluation of the kidneys was conducted at 16 weeks. Lymphadenopathies were evaluated by 1-(2'-deoxy-2'-[F-18]fluoro-beta-D-arabinofuranosyl) cytosine ([F-18] FAC) positron emission tomography/computed tomography (PET/CT) at 12 weeks. Following 4-week treatment, [F-18]FAC-PET/CT showed similar accumulation in cervical and axillary lymph nodes at 12 weeks of age. However, anti-HMGB1 monoclonal antibody sufficiently inhibited the increase in albuminuria compared to an isotype control following 15-week treatment. Complement deposition was also improved; however, there were no significant differences in IgG deposition and renal pathological scores between the two groups. Anti-double-stranded DNA (dsDNA) antibody titers and cytokine and chemokine levels were also unaltered. Although there were no significant differences in glomerular macrophage infiltration, neutrophil infiltration was significantly decreased by the anti-HMGB1 monoclonal antibody. Antagonizing HMGB1 treatment suppressed HMGB1 translocation from nuclei in the kidney and suppressed neutrophil extracellular traps. The anti-HMGB1 monoclonal antibody demonstrated therapeutic potential against albuminuria in lupus nephritis by inhibiting neutrophil recruitment and neutrophil extracellular traps.

DOI： 10.1016/j.omtm.2017.05.006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

DOI： 10.1007/s13340-017-0321-3

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The effects of melatonin on prolactin production and its regulatory mechanism remain uncertain. We investigated the regulatory role of melatonin in prolactin production using rat pituitary lactotrope GH3 cells by focusing on the bone morphogenetic protein (BMP) system. Melatonin receptor activation, induced by melatonin and its receptor agonist ramelteon, significantly suppressed basal and forskolin-induced prolactin secretion and prolactin mRNA expression in GH3 cells. The melatonin MT2 receptor was predominantly expressed in GH3 cells, and the inhibitory effects of melatonin on prolactin production were reversed by treatment with the receptor antagonist luzindole, suggesting functional involvement of MT2 action in the suppression of prolactin release. Melatonin receptor activation also suppressed BMP-4-induced prolactin expression by inhibiting phosphorylation of Smad and transcription of the BMP-target gene Id-1, while BMP-4 treatment upregulated MT2 expression. Melatonin receptor activation suppressed basal, BMP-4-induced and forskolin-induced cAMP synthesis; however, BtcAMP-induced prolactin mRNA expression was not affected by melatonin or ramelteon, suggesting that MT2 activation leads to inhibition of prolactin production through the suppression of Smad signaling and cAMP synthesis. Experiments using intracellular signal inhibitors revealed that the ERK pathway is, at least in part, involved in prolactin induction by GH3 cells. Thus, a new regulatory role of melatonin involving BMP-4 in prolactin secretion was uncovered in lactotrope GH3 cells.

DOI： 10.1016/j.peptides.2017.06.001

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Aims
Glomerular insudative lesions are a pathological hallmark of diabetic nephropathy (DN). However, paratubular basement membrane insudative lesions (PTBMIL) have not attracted much attention, and the association between such lesions and the renal prognosis remains unclear.
Methods
Among 142 patients with biopsy-proven DN and type 2 diabetes encountered from 1998 to 2011, 136 patients were enrolled in this study. Patients were classified into 3 groups (Group 1: mild, Group 2: moderate, Group 3: severe) according to the extent of cortical and medullary PTBMIL. The endpoint was a decline of the estimated glomerular filtration rate (eGFR) by &gt;= 40% from baseline or commencement of dialysis for end-stage renal disease. The Cox proportional hazard model was employed to calculate hazard ratios (HRs) and 95% confidence interval (CIs) for the death-censored endpoint.
Results
During a median follow-up period of 1.8 years (IQR: 0.9-3.5), the endpoint occurred in 104 patients. Baseline mean eGFR was 43.9 +/- 22.8 ml/min/1.73 m(2), and 125 patients (92%) had overt proteinuria. After adjusting for known indicators of DN progression, the HR for the endpoint was 2.32 (95% CI: 1.20-4.51) in PTBMIL Group 2 and 3.12 (1.48-6.58) in PTBMIL Group 3 versus PTBMIL Group 1. Furthermore, adding the PTBMIL Group to a multivariate model including known promoters of DN progression improved prediction of the endpoint (cindex increased by 0.02 [95% CI: 0.00-0.04]).
Conclusions
PTBMIL may be useful for predicting the renal prognosis of patients with biopsy-proven DN, but further investigation of these lesions in various stages of DN is needed.

DOI： 10.1371/journal.pone.0183190

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Systemic lupus erythematosus (SLE) damages multiple organs by producing various autoantibodies. In this study, we report that decreased microRNA (miR)-200a-3p causes IL-2 hypoproduction through zinc finger E-box binding homeobox (ZEB) 1 and C-terminal binding protein 2 (CtBP2) in a lupus-prone mouse. First, we performed RNA sequencing to identify candidate microRNAs and mRNAs involved in the pathogenesis of SLE. We found that miR-200a-3p was significantly downregulated, whereas its putative targets, ZEB2 and CtBP2, were upregulated in CD4(+) T cells from MRL/lpr-Tnfrsf6 (lpr) mice compared with C57BL/6J mice. ZEB1 and ZEB2 comprise the ZEB family and suppress various genes, including IL-2 by recruiting CtBP2. IL-2 plays a critical role in immune tolerance, and insufficient IL-2 production upon stimulation has been recognized in SLE pathogenesis. Therefore, we hypothesized that decreased miR-200a-3p causes IL-2 deficit through the ZEB1-CtBP2 and/or ZEB2-CtBP2 complex in SLE CD4(+) T cells. Overexpression of miR-200a-3p induced IL-2 production by downregulating ZEB1, ZEB2, and CtBP2 in EL4 cell lines. We further revealed that miR-200a-3p promotes IL-2 expression by reducing the binding of suppressive ZEB1-CtBP2 and ZEB2-CtBP2 complexes on negative regulatory element A in the IL-2 promoter in EL4 cells. Interestingly, the ZEB1-CtBP2 complex on negative regulatory element Awas significantly upregulated after PMA/ionomycin stimulation in lupus CD4(+) T cells. Our studies have revealed a new epigenetic pathway in the control of IL-2 production in SLE whereby low levels of miR-200a-3p accumulate the binding of the ZEB1-CtBP2 complex to the IL-2 promoter and suppress IL-2 production.

DOI： 10.4049/jimmunol.1601705

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Aims: Nodular lesions are one of the most characteristic pathological changes of advanced diabetic nephropathy (DN). Previous studies have demonstrated that the pattern of both routine and collagen staining of nodular lesions changes during their development. However, the association between such changes of staining and the renal prognosis remains unclear.
Methods: Among 252 patients with biopsy-proven DN, 67 met the selection criteria and were enrolled to investigate this relationship. In all patients, nodular lesions were stained with periodic acid Schiff, periodic acid methenamine silver, and Masson trichrome stains, and immunostaining was done for type I, III, IV, V, and VI collagen. The endpoint was commencement of dialysis due to end-stage renal disease.
Results: At least one mesangiolytic nodular lesion (MNL) that showed faint staining for PAS and PAM was found in 61% of the patients. MNLs were negative for type IV collagen staining, unlike the strong positivity of non-MNLs, while type V and VI collagen staining were strongly positive in all nodular lesions. Cox proportional hazards regression analysis revealed that the hazard ratio (HR) for the endpoint was significantly higher in patients with at least one MNL than in patients with no MNLs after adjustment for known promoters of renal progression (HR: 2.94; 95% confidence interval: 1.24-7.07).
Conclusions: MNLs may reflect characteristic differences of collagen production and could be a useful prognostic indicator in patients with nodular lesions. Further investigation of the mechanism underlying these differences of collagen production could contribute to finding new therapeutic targets for DN. (C) 2017 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

DOI： 10.1016/j.diabres.2017.03.006

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Aims
To evaluate the incidence of GC-DM among patients with immunoglobulin A nephropathy (IgAN) and to confirm the risk factors for the development of GC-DM.
Methods
The medical records of patients with IgAN newly treated with the protocol of tonsillectomy combined with steroid pulse therapy were reviewed. The primary outcome was the development of GC-DM within the hospitalization period and during one year of follow-up.
Results
During hospitalization, 19 of the 95 patients developed GC-DM (20.0%), and the patients with GC-DM were significantly older and had a higher rate of family history of diabetes and higher HbA1c levels. The prevalence of hypertension was higher and the eGFR was numerically lower in patients with GC-DM than in those without. Older age (&gt;= 45 years) and a family history of diabetes emerged as independent risk factors for the development of GC-DM (odds ratio [OR], 6.3 and 95% confidence interval [CI], 1.6-27.6; OR, 4.4 and 95% CI, 1.216.6, respectively). No patients were newly diagnosed with GC-DM during 1-year observation period at out-patient clinic.
Conclusions
Among the patients with IgAN, 20% developed GC-DM during the hospitalization period, confirming the family history of diabetes is clinically necessary before starting GC therapy.

DOI： 10.1371/journal.pone.0178018

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background Olmesartan and azilsartan, angiotensin II receptor blockers (ARBs), are expected to decrease blood pressure more than the other ARBs. We conducted randomized-controlled trials to compare the practical efficacy of olmesartan with azilsartan.
Methods Eighty-four patients treated with the conventional ARBs for more than 3 months were assigned randomly to receive either 20 mg of olmesartan (olmesartan medoxomil, OL group) or 20 mg of azilsartan (azilsartan, not azilsartan medoxomil, AZ group) once daily for 16 weeks. The practical efficacy on blood pressure was compared between the OL and AZ groups.
Results Office blood pressure of both groups decreased significantly (OL group: 152/86-141/79 mmHg, P&lt;0.05, AZ group: 149/83-135/75 mmHg; P&lt;0.05). Diastolic home blood pressure in the AZ group decreased significantly (79 +/- 9-74 +/- 7 mmHg; P&lt;0.05), but not in the OL group (79 +/- 11-75 +/- 10 mmHg; P = 0.068). However, there were no significant differences between the groups. The dosage of olmesartan and azilsartan increased significantly and slightly for 16 weeks (OL group: 20.3-23.1 mg; P&lt;0.05, AZ group: 20.5-23.2 mg; P&lt;0.05), without a significant difference between groups. Furthermore, there were no significant differences in renal function, lipid profiles, brain natriuretic peptide, soluble fms-like tyrosine kinase-1, and urinary L-type fatty acid-binding protein between the two groups.
Conclusion Both olmesartan and azilsartan equally reduced blood pressures. Both olmesartan and azilsartan showed a renoprotective effect and were well tolerated without any major adverse events. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

DOI： 10.1097/MBP.0000000000000229

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Melatonin is functionally involved in the control of circadian rhythm and hormonal secretion. In the present study, we investigated the roles of melatonin in the interaction of catecholamine synthesis with adrenocortical steroids by focusing on bone morphogenetic protein (BMP)-4 expressed in the adrenal medulla using rat pheochromocytoma PC12 cells. Melatonin treatment significantly reduced the mRNA expression of catecholamine synthases, including the rate-limiting enzyme tyrosine hydroxylase (Th), 3,4-dihydroxyphenylalanine decarboxylase and dopamine-beta-hydroxylase expressed in PC12 cells. In accordance with changes in the expression levels of enzymes, dopamine production and CAMP synthesis determined in the culture medium and cell lysate were also suppressed by melatonin. The MT1 receptor, but not the MT2 receptor, was expressed in PC12 cells, and luzindole treatment reversed the inhibitory effect of melatonin on Th expression, suggesting that MT1 is a functional receptor for the control of catecholamine synthesis. Interestingly, melatonin enhanced the inhibitory effect of BMP-4 on Th mRNA expression in PC12 cells. Melatonin treatment accelerated BMP-4-induced phosphorylation of SMAD1/5/8 and transcription of the BMP target gene Id1. Of note, melatonin significantly upregulated Alk2 and Bmpr2 mRNA levels but suppressed inhibitory Smac16/7 expression, leading to the enhancement of SMAD1/5/8 signaling in PC12 cells, while BMP-4 did not affect Mt1 expression. Regarding the interaction with adrenocortical steroids, melatonin preferentially enhanced glucocorticoid-induced Th mRNA through upregulation of the glucocorticoid receptor and downregulation of Bmp4 expression, whereas melatonin repressed Th mRNA expression induced by aldosterone or androgen without affecting expression levels of the receptors for mineralocorticoid and androgen. Collectively, the results indicate that melatonin plays a modulatory role in catecholamine synthesis by cooperating with BMP-4 and glucocorticoid in the adrenal medulla. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jsbmb.2016.06.002

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Language：English   Publisher：WILEY  

DOI： 10.1111/jdi.12553

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

The molecular pathogenesis of non-alcoholic steatohepatitis (NASH) is not well defined. The objective of the present study was to identify disease progression-related cytokines and investigate the molecular pathogenesis of such changes in NASH.
A study population of 20 non-alcoholic fatty liver (NAFL) and 59 NASH patients diagnosed by liver biopsy and 15 healthy volunteers was recruited. The serum pro- and anti-inflammatory cytokines were measured by a multiple enzyme-linked immunosorbent assay. The hepatic mRNA expressions of cytokines were measured by real-time PCR. A monocyte cell line was stimulated with Toll-like receptor (TLR) ligand under a high glucose and insulin condition, and cellular cytokine mRNA expression was quantified.
One group of cytokines was higher in NAFL and NASH than in controls, while another group was higher in NASH than in NAFL and controls. The NASH-specific second group included interleukin (IL)-15 and interferon-gamma-inducible protein (IP)-10. In particular, IP-10 was higher in NAFL than in controls and higher in NASH than in NAFL and controls. The sensitivity to diagnose NASH was 90%, with specificity of 50%. Insulin resistance reflecting a high glucose and insulin condition resulted in higher IP-10 mRNA expression in the monocyte cell line only with concomitant TLR-2 stimulation.
IP-10 is a sensitive marker of the need for liver biopsy. Insulin resistance with bacteria-related TLR-2 stimulation might induce IP-10 production from monocytes. Insulin resistance and intestinal barrier function should be intensively controlled to prevent progression from NAFL to NASH.

DOI： 10.1007/s12072-016-9773-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

We herein describe two cases of refractory antineutrophil cytoplasmic antibody-associated vasculitis (AAV) complicated with diabetes insipidus (DI) possibly related to hypertrophic pachymeningitis (HP). One patient had microscopic polyangiitis and HP, which were refractory to cyclophosphamide, azathioprine, rituximab, mycophenolate mofetil (MMF), and mizoribine. Remission was finally achieved with the use of etanercept, but DI occurred 5 years later. The other patient had granulomatosis with polyangiitis, which that was refractory to cyclophosphamide, methotrexate, MMF, and rituximab. DI subsequently developed, but was successfully treated with etanercept. Dura mater hypertrophy was macroscopically observed in the latter case.

DOI： 10.2169/internalmedicine.8683-16

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Semaphorin3A is a secreted protein known to be involved in organogenesis, immune responses and cancer. In the kidney, semaphorin3A is expressed in the glomerular podocytes, distal tubules and collecting tubules, and believed to play a role in the regulation of the kidney development and function. We examined the serum and urinary semaphorin3A levels in 72 patients with renal disease and 5 healthy volunteers. The patients had been diagnosed with thin basement membrane disease (n=4), minimal change nephrotic syndrome (MCNS; n=22), IgA nephritis (n=21), membranous nephropathy (n=16) and focal segmental glomerular sclerosis (n=9). The level of urinary semaphorin3A in MCNS patients tended to be relatively high among all disease groups. We also investigated the urinary semaphorin3A level in 7 patients with MCNS from disease onset to remission during the drug therapy. MCNS patients in pre-remission states had higher urinary semaphorin3A levels than those in post-remission states receiving immunosuppressive therapies. These results suggested that the urinary semaphorin3A level correlates with the MCNS activity. Semaphorin3A has the potential as a biomarker for MCNS to clarify the reactivity for therapy and may be useful in examining other glomerular diseases with proteinuria as well.

DOI： 10.2147/IJNRD.S132980

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Leptospirosis is frequently associated with acute kidney injury. Some survivors are known to progress to chronic kidney disease due to sustained tubulointerstitial inflammation. We present a case of severe leptospirosis with acute renal failure. Although antibiotic therapy resolved the infection, moderate renal dysfunction remained. A renal biopsy demonstrated marked inflammatory infiltration in the tubules and interstitium. Many of the inflammatory cells were CD68-positive monocytes/macrophages, predominantly M1 phenotype. An intermediate dose of oral corticosteroids normalized the patient's serum creatinine levels. We suggest that corticosteroid therapy may be a therapeutic option for some patients with sustained tubulointerstitial nephritis who survive severe leptospirosis.

DOI： 10.2169/internalmedicine.56.8084

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Polyarteritis nodosa (PAN), characterized by arteritis of medium-sized blood vessels, is usually treated with a combination of glucocorticoids and immunosuppressants; however, some cases are refractory to these treatments. We herein report the case of a man with PAN that was refractory to various immunosuppressive treatments, including cyclophosphamide, methotrexate, and rituximab. After infliximab (IFX) treatment was initiated, his symptoms improved dramatically and remission was maintained. IFX is considered to be an effective alternative treatment for PAN which proves to be refractory to several immunosuppressive treatments.

DOI： 10.2169/internalmedicine.56.8235

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We herein report a patient with breast cancer who developed dermatomyositis (DM) immediately after mastectomy. She had a history of severe drug eruption during neoadjuvant chemotherapy six months previously. Within a month after the operation, myalgia and rash, including Gottron's papules, developed, and skeletal-muscle enzymes elevated, so she was diagnosed with probable DM according to the Bohan and Peter criteria. In many neoplastic DM cases, the course of the disease parallels the course of the malignancy. Possible mechanisms were suggested to explain the development of DM in the present case and offer new insight into autoimmune diseases.

DOI： 10.2169/internalmedicine.9194-17

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Objectives: To determine prognostic factors of methotrexate-associated lymphoproliferative disorder (MTX-LPD) and evaluate the efficacy and safety of biological therapy in rheumatoid arthritis (RA) complicated with MTX-LPD.
Methods: Thirty RA patients who developed MTX-LPD were investigated in this study. We compared the clinical and laboratory parameters of patients who achieved regression of LPD by MTX withdrawal with those who required chemotherapy and evaluated the clinical course of RA after LPD development.
Results: Twenty-three patients (76.7%) achieved regression of LPD by MTX withdrawal. Chemotherapyfree patients had a tendency of shorter RA duration (13.1 vs. 22.0 years, p = 0.108) and higher doses of MTX at LPD diagnosis (8.0 vs. 5.3 mg/w, p = 0.067) than patients who required chemotherapy. A significantly higher positive rate of peripheral blood Epstein-Barr virus (EBV)-DNA was observed in the chemotherapy-free group (9/9 vs. 0/3, p = 0.0002). Of 15 patients that received biological agents after LPD development, 14 patients (93.3%) demonstrated an improved disease activity of RA and persistent remission of LPD, whereas only one patient experienced relapse of LPD during tocilizumab therapy.
Conclusions: Peripheral blood EBV-DNA positivity is a potential prognostic marker of better outcome in MTX-LPD. Biological agents could be an option for the treatment of RA patients with MTX-LPD.

DOI： 10.1080/14397595.2016.1259714

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Language：English   Publisher：HINDAWI LTD  

Angiogenesis has been shown to be a potential therapeutic target for early stages of diabetic nephropathy in a number of animal experiments. Vascular endothelial growth factor (VEGF) is the main mediator for abnormal angiogenesis in diabetic glomeruli. Although beneficial effects of anti-VEGF antibodies have previously been demonstrated in diabetic animal experiments, recent basic and clinical evidence has revealed that the blockade of VEGF signaling resulted in proteinuria and renal thrombotic microangiopathy, suggesting the importance of maintaining normal levels of VEGF in the kidneys. Therefore, antiangiogenic therapy for diabetic nephropathy should eliminate excessive glomerular angiogenic response without accelerating endothelial injury. Some endogenous antiangiogenic factors such as endostatin and tumstatin inhibit overactivation of endothelial cells but do not specifically block VEGF signaling. In addition, the novel endothelium-derived antiangiogenic factor vasohibin-1 enhances stress tolerance and survival of the endothelial cells, while inhibiting excess angiogenesis. These factors have been demonstrated to suppress albuminuria and glomerular alterations in a diabetic mouse model. Thus, antiangiogenic therapy with promising candidates will possibly improve renal prognosis in patients with early stages of diabetic nephropathy.

DOI： 10.1155/2017/5724069

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Background/Aims: Bleeding is the most common complication after renal biopsy. Although numerous predictors of bleeding have been reported, it remains unclear whether arterial stiffness affects bleeding complications. Method: We performed an observational study of the renal biopsies performed in our division over an approximately 6-year period (May 2010 to May 2016). The clinical and laboratory factors were analyzed to reveal the risk factors associated with bleeding, with a focus on anemia (defined as a &gt;= 10% decrease in hemoglobin [Hb] after biopsy). The brachial-ankle pulse wave velocity (baPWV) was measured to evaluate arterial stiffness. Results: This study included 462 patients (male, n=244; female, n=218). Anemia (defined above) was observed in 54 patients (11.7%). The risk of anemia was higher in women, older patients, and patients with lower serum albumin, lower eGFR and lower diastolic blood pressure after biopsy. We then performed a further analysis of 187 patients whose baPWV data were available. Multivariate analysis revealed that a higher baPWV was an independent risk factor for anemia. ROC analysis for predicting anemia found that a baPWV value of 1839 cm/s had the best performance (AUC 0.689). Conclusion: An increased baPWV may be a more valuable predictor of bleeding than any of the other reported risk factors. (C) 2017 The Author(s) Published by S. Karger AG, Basel

DOI： 10.1159/000477453

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective To assess the safety of azathioprine (AZA) in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV).
Methods We retrospectively enrolled 67 consecutive AAV patients who had initiated AZA treatment from January 2006 to August 2014 at Okayama University Hospital. We evaluated the development of severe adverse events (AEs), AZA discontinuation due to total AEs (severe AEs included) within 1 year, and AZA-associated risk factors.
Results The patients' median age was 70 years old. Forty-nine women and 18 men participated at the initiation of the study. Fifty-eight (87%) patients experienced AEs, and 36 experienced severe AEs (21 hepatic and 11 cytopenic severe AEs). Thirty-one (46%) patients discontinued treatment because of AEs. Abnormal hepatic laboratory test results at the treatment initiation were more frequent in patients with hepatic severe AEs and were associated with treatment discontinuation. The leukocyte and neutrophil counts at the treatment initiation were lower in the patients who discontinued treatment because of cytopenic AEs than in those who continued treatment. Only two patients experienced flare-ups during treatment.
Conclusion The AE-associated AZA discontinuation rate in Japanese AAV patients was relatively high. AZA use warrants caution in patients with abnormal hepatic laboratory test results or low leukocyte or neutrophil counts.

DOI： 10.2169/internalmedicine.56.8287

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A 77-year-old man with high-grade fever, progressive renal dysfunction, high serum level of C-reactive protein and positive serum myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) was diagnosed with microscopic polyangiitis with rapidly progressive glomerulonephritis, and remission induction treatment with glucocorticoids and intravenous cyclophosphamide was initiated. Although his general condition improved in a short time, intracerebral hemorrhage occurred 12 days after the initiation of treatment and emergent hematoma evacuation was performed. However, he passed away on day 14. Surprisingly, even though no clinical findings for any organs except for renal involvement was detected before his death, autopsy revealed necrotizing vasculitis affecting various systemic organs including kidney, pancreas, liver, myocardium in ventricle, adipose tissue of the left adrenal gland, small intestine, gallbladder, bronchus, prostate, testis and spleen. It is difficult to detect widespread vasculitis without clinical symptoms and signs in patients with ANCA-associated vasculitis. A whole body assessment tool is necessary to detect unexpected vital organ damage, including cerebral vessels.

DOI： 10.1007/s13730-016-0219-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Background and Aims
Chronic kidney disease (CKD) and diabetes mellitus (DM) are considered as risk factors for cardiovascular diseases. The purpose of this study was to clarify the relationship of CKD and DM with the presence of abdominal aortic aneurysm (AAA).
Methods
We enrolled 261 patients with AAA (AAA+) and age-and-sex matched 261 patients without AAA (AAA-) at two hospitals between 2008 and 2014, and examined the association between the risk factors and the presence of AAA. Furthermore, in order to investigate the prevalence of AAA in each group, we enrolled 1126 patients with CKD and 400 patients with DM.
Results
The presence of CKD in patients with AAA+ was significantly higher than that in patients with AAA-(AAA+; 65%, AAA-; 52%, P = 0.004). The presence of DM in patients with AAA+ was significantly lower than that in patients with AAA-(AAA+; 17%, AAA-; 35%, P &lt; 0.001). A multivariate logistic regression analysis demonstrated that hypertension, ischemic heart disease and CKD were independent determinants, whereas, DM was a negatively independent determinant, for the presence of AAA. The prevalence of AAA in patients with CKD 65 years old and above was 5.1%, whereas, that in patients with DM 65 years old and above was only 0.6%.
Conclusion
CKD is a positively associated with the presence of AAA. In contrast, DM is a negatively associated with the presence of AAA in Japanese population.

DOI： 10.1371/journal.pone.0164015

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: A link between IgA nephropathy and Crohn's disease has recently been reported. Other researchers hypothesize that intestine-derived IgA complexes deposit in glomerular mesangial cells, eliciting IgA nephropathy. Intestinal mucosal plasma cells mainly secrete IgA(2). Nevertheless, IgA(1) deposition is strongly implicated as being the primary cause of IgA nephropathy.
Case presentation: A 46-year-old Japanese man developed IgA nephropathy 29 years ago, following tonsillectomy. As a result, a normal urinalysis was obtained. The patient previously suffered Crohn's disease followed by urinary occult blood and proteinuria six years ago. Exacerbation of IgA nephropathy was highly suspected. Therefore a renal biopsy was performed. A diagnosis of exacerbation of IgA nephropathy with mesangial cell proliferation and fibrotic cellular crescent was based upon the pathological findings. The patient exhibited a positive clinical course and eventually achieved a remission with immunosuppressive therapy including prednisolone treatment. Immunostaining for the detection of IgA subtypes was performed on both of his kidney and excised ileum. The results revealed IgA(1) and IgA(2) deposition by submucosal cells in intestine. Furthermore, IgA(1) deposition of mesangial areas in the patient's kidney, indicated an association of IgA(1) with the exacerbation of IgA nephropathy.
Conclusion: This case represents the possibility that the intestine-derived IgA(1) can be the origin of galactose-deficient IgA which is known to cause IgA nephropathy exacerbation.

DOI： 10.1186/s12882-016-0344-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

A cardioprotective response that alters ventricular contractility or promotes cardiomyocyte enlargement occurs with increased workload in conditions such as hypertension. When that response is excessive, pathological cardiac remodelling occurs, which can progress to heart failure, a leading cause of death worldwide. Mechanisms underlying this response are not fully understood. Here, we report that expression of angiopoietin-like protein 2 (ANGPTL2) increases in pathologically-remodeled hearts of mice and humans, while decreased cardiac ANGPTL2 expression occurs in physiological cardiac remodelling induced by endurance training in mice. Mice overexpressing ANGPTL2 in heart show cardiac dysfunction caused by both inactivation of AKT and sarco(endo) plasmic reticulum Ca2+-ATPase (SERCA) 2a signalling and decreased myocardial energy metabolism. Conversely, Angptl2 knockout mice exhibit increased left ventricular contractility and upregulated AKT-SERCA2a signalling and energy metabolism. Finally, ANGPTL2-knockdown in mice subjected to pressure overload ameliorates cardiac dysfunction. Overall, these studies suggest that therapeutic ANGPTL2 suppression could antagonize development of heart failure.

DOI： 10.1038/ncomms13016

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-Blackwell Publishing Ltd  

It is unclear whether the improvement in diabetic nephropathy by sodium glucose cotransporter 2 (SGLT2) inhibitors is caused by a direct effect on SGLT2 or by the improvement in hyperglycemia. Here, we investigated the effect of dapagliflozin on early-stage diabetic nephropathy using a mouse model of type 1 diabetes and murine proximal tubular epithelial cells. Eight-week-old Akita mice were treated with dapagliflozin or insulin for 12 weeks. Body weight, urinary albumin excretion, blood pressure, as well as levels of blood glucose and hemoglobin A1c were measured. Expansion of the mesangial matrix, interstitial fibrosis, and macrophage infiltration in kidneys were evaluated by histology. Oxidative stress and apoptosis were evaluated in kidneys and cultured proximal tubular epithelial cells. Compared with nontreated mice, dapagliflozin and insulin decreased blood glucose and hemoglobin A1c levels equally. Urine volume and water intake increased significantly in the dapagliflozin-treated group compared with those in the insulin-treated group, but there were no differences in body weight or blood pressure between the two groups. Macrophage infiltration and fibrosis in renal interstitium improved significantly in the dapagliflozin group compared with the insulin group. Oxidative stress was attenuated by dapagliflozin, and suppression occurred in a dose-dependent manner. RNAi knockdown of SGLT2 resulted in reduced oxidative stress. Dapagliflozin ameliorates diabetic nephropathy by suppressing hyperglycemia-induced oxidative stress in a manner independent of hyperglycemia improvement in Akita mice. Our findings suggest that dapagliflozin may be a novel therapeutic approach for the treatment of diabetic nephropathy.

DOI： 10.1002/prp2.239

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

A study to evaluate the effect of metformin on the immune system was commenced in July 2014. Metformin is one of the most commonly prescribed drugs for type 2 diabetes, and previous studies have reported that metformin has an anti-tumor effect. The aim of this study is to evaluate the efficacy of metformin on the immune system in human cancer patients in vivo. The primary outcome parameter will be the rate change in the population of CD8(+) T cells, which produce multiple cytokines.

DOI： 10.18926/AMO/54514

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Although graft survival following renal transplantation (RTx) has improved, outcomes following highrisk RTx are variable. Preexisting antibodies, including donor-specific antibodies (DSA), play an important role in graft dysfunction and survival. We have designed a study to investigate the safety and efficacy of anti-CD20 monoclonal antibodies (rituximab) in high-risk RTx recipients. Major eligibility criteria include: 1) major and minor ABO blood group mismatch, 2) positive DSA. Thirty-five patients will receive 200 mg/body of rituximab. The primary endpoint is the incidence of B cell depletion. This study will clarify whether rituximab is efficacious in improving graft survival in high-risk RTx recipients.

DOI： 10.18926/AMO/54507

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Language：English   Publisher：OKAYAMA UNIV MED SCHOOL  

The mitochondria are involved in active and dynamic processes, such as mitochondrial biogenesis, fission, fusion and mitophagy to maintain mitochondrial and cellular functions. In obesity and type 2 diabetes, impaired oxidation, reduced mitochondrial contents, lowered rates of oxidative phosphorylation and excessive reactive oxygen species (ROS) production have been reported. Mitochondrial biogenesis is regulated by various transcription factors such as peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha), peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs), and nuclear respiratory factors (NRFs). Mitochondrial fusion is promoted by mitofusin 1 (MFN1), mitofusin 2 (MFN2) and optic atrophy 1 (OPA1), while fission is governed by the recruitment of dynamin-related protein 1 (DRP1) by adaptor proteins such as mitochondrial fission factor (MFF), mitochondrial dynamics proteins of 49 and 51 kDa (MiD49 and MiD51), and fission 1 (FIS1). Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and PARKIN promote DRP1-dependent mitochondrial fission, and the outer mitochondrial adaptor MiD51 is required in DRP1 recruitment and PARKIN-dependent mitophagy. This review describes the molecular mechanism of mitochondrial dynamics, its abnormality in diabetes and obesity, and pharmaceuticals targeting mitochondrial biogenesis, fission, fusion and mitophagy.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER DIABETES ASSOC  

Coxsackie virus and adenovirus receptor-like membrane protein (CLMP) was identified as the tight junction-associated transmembrane protein of epithelial cells with homophilic binding activities. CLMP is also recognized as adipocyte adhesion molecule (ACAM), and it is upregulated in mature adipocytes in rodents and humans with obesity. Here, we present that aP2 promoter-driven ACAM transgenic mice are protected from obesity and diabetes with the prominent reduction of adipose tissue mass and smaller size of adipocytes. ACAM is abundantly expressed on plasma membrane of mature adipocytes and associated with formation of phalloidin-positive polymerized form of cortical actin (F-actin). By electron microscopy, the structure of zonula adherens with an intercellular space of approximate to 10-20 nm was observed with strict parallelism of the adjoining cell membranes over distances of 1-20 m, where ACAM and -actin are abundantly expressed. The formation of zonula adherens may increase the mechanical strength, inhibit the adipocyte hypertrophy, and improve the insulin sensitivity.

DOI： 10.2337/db15-1304

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ Publishing Group  

We report a case of a 20-year-old man presenting with acute painful blue fingers. All physical findings, including an Allen test, were normal, and systematic symptoms frequently seen in collagen diseases were absent. Although we performed a wide variety of investigations including medical imaging, no specific abnormal findings were observed. Skin biopsy pathology was an important reference. The patient's symptoms gradually improved and were completely resolved without specific treatment. Based on the clinical presentation and course, we gave a diagnosis of Achenbach's syndrome, developed in a young male. Achenbach's syndrome is rare, but still may be encountered in clinical practice. The symptoms can be startling to the patient, eliciting fear of something terrible when, in fact, the syndrome is relatively benign and has a good prognosis. Recognising this disease quickly after presentation helps to eliminate the anxiety of the patient, as well as reducing excessively invasive investigations. We present a case report to enlighten Achenbach's syndrome.

DOI： 10.1136/bcr-2016-214491

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Although obesity is undoubtedly major risk for non-alcoholic steatohepatitis (NASH), the presence of lean NASH patients with normal body mass index has been recognized. Here, we report that the insufficiency of phosphatidylethanolamine N-methyltransferase (PEMT) is a risk for the lean NASH. The Pemt-/-mice fed high fat-high sucrose (HFHS) diet were protected from diet-induced obesity and diabetes, while they demonstrated prominent steatohepatitis and developed multiple liver tumors. Pemt exerted inhibitory effects on p53-driven transcription by forming the complex with clathrin heavy chain and p53, and Pemt-/-mice fed HFHS diet demonstrated prominent apoptosis of hepatocytes. Furthermore, hypermethylation and suppressed mRNA expression of F-box protein 31 and hepatocyte nuclear factor 4 alpha resulted in the prominent activation of cyclin D1. PEMT mRNA expression in liver tissues of NASH patients was significantly lower than those with simple steatosis and we postulated the distinct clinical entity of lean NASH with insufficiency of PEMT activities.

DOI： 10.1038/srep21721

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS LTD  

Objective We have assessed the effectiveness of tacrolimus for minor flares in systemic lupus erythematosus (SLE) patients.
Methods The medical records of 313 patients were retrospectively reviewed over a period of seven years, from 2006 to 2013. We enrolled patients with minor flare treated with add-on tacrolimus, without glucocorticoid (GC) intensification (tacrolimus group). Minor flare was defined as a 1-point increase in a total score between 3 and 11 in the SLE Disease Activity Index (SLEDAI). We enrolled as controls patients who were administered increased doses of GC for minor flare (GC group). All patients were followed for one year. The primary outcome measure was the proportion of responders.
Results There were 14 eligible patients in the tacrolimus group and 20 eligible patients in the GC group. The mean SLEDAI at flare tended to be higher in the tacrolimus group than in the GC group (7.5 vs. 6.2, p=0.085). A mean dose of 1.6mg tacrolimus/day was administered for flare, while the mean GC dose was 13.7mg/day in the GC group. The proportion of responders was 86% (12/14) in the tacrolimus group and 75% (15/20) in the GC group (p=0.67). The mean dose of GC at 12 months was higher in the GC group than in the tacrolimus group (9.7mg/day vs. 7.1mg/day, p&lt;0.05). Only one patient discontinued tacrolimus because of fatigue after three months.
Conclusion Adding tacrolimus without increasing the GC dose may provide an effective treatment option for minor flares in patients with SLE.

DOI： 10.1177/0961203315600538

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Language：English   Publisher：NATURE PUBLISHING GROUP  

The innate immune system includes several classes of pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). These receptors detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the extracellular and intracellular space. Intracellular NLRs constitute inflammasomes, which activate and release caspase-1, IL-1 beta, and IL-18 thereby initiating an inflammatory response. Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the development and progression of diabetes mellitus and diabetic nephropathy. TLR2,TLR4, and the NLRP3 inflammasome can induce the production of various proinflammatory cytokines and are critically involved in inflammatory responses in pancreatic islets, and in adipose, liver and kidney tissues. This Review describes how innate immune system-driven inflammatory processes can lead to apoptosis, tissue fibrosis, and organ dysfunction resulting in insulin resistance, impaired insulin secretion, and renal failure. We propose that careful targeting of TLR2, TLR4, and NLRP3 signalling pathways could be beneficial for the treatment of diabetes mellitus and diabetic nephropathy.

DOI： 10.1038/nrneph.2015.175

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HINDAWI PUBLISHING CORP  

Poor maternal glycemic control increases maternal and fetal risk for adverse outcomes, and strict management of gestational diabetes mellitus (GDM) is recommended to prevent neonatal and maternal complications. However, risk factors for the requirement of antenatal insulin treatment (AIT) are not well-investigated in the pregnant women with GDM. We enrolled 37 pregnant women with GDM and investigated the risk for AIT by comparing the patients with AIT (AIT group; n = 10) and without insulin therapy (Diet group; n = 27). The 1-h and 2-h plasma glucose levels and the number of abnormal values in 75 g OGTT were significantly higher in AIT group compared with Diet group. By logistic regression analysis, plasma glucose level at 1-h was significant predictor for AIT and the odds ratios were 1.115 (1.004-1.239) using forward selection method and 1.192 (1.006-1.413) using backward elimination method. There were no significant differences in obstetrical outcomes and neonatal complications. 1-h plasma glucose levels in 75 g OGTT are useful parameters in predicting the requirement for AIT in GDM. Both maternal and neonatal complications are comparable in GDM patients with and without insulin therapy.

DOI： 10.1155/2016/9648798

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Idiopathic intracranial hypertension (IIH) is a syndrome of increased intracranial pressure and presents as an intractable headache, vomiting, and ophthalmologic manifestations. We herein report the case of a young girl who presented with bilateral abducens nerve palsy due to IIH as the onset of systemic lupus erythematosus (SLE). The patient was successfully treated with corticosteroid therapy. Our case lacked the typical symptoms of IIH, such as headache or nausea; therefore, it is necessary to carefully determine the cause of bilateral abducens nerve palsies. The development of IIH in SLE patients is a rare occurrence, but this manifestation should not be overlooked.

DOI： 10.2169/internalmedicine.55.5990

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN ATHEROSCLEROSIS SOC  

Aim: Visceral fat accumulation contributes to the development of metabolic syndrome. As visceral fat accumulation increases, adiponectin levels decrease; therefore, adiponectin provides a link between visceral fat accumulation and metabolic disorders. Genome-wide association studies (GWASs) have identified genetic variations in the cadherin 13 (CDH13) gene that are associated with adiponectin levels. Methods: We investigated whether single nucleotide polymorphisms (SNPs) in CDH13 was associated with adiponectin levels and metabolic syndrome traits independent of the visceral fat area (VFA), as measured using computed tomography (CT) in 945 Japanese individuals. Results: We found that three CDH13 SNPs reported by recent GWASs (i.e., rs3865188, rs4783244, and rs12051272) were significantly associated with higher adiponectin levels (P &lt; 1 x 10(-14)), even after adjustment for VFA. However, these adiponectin-inducing alleles of CDH13 SNPs were significantly associated with traits consistent with deteriorating metabolic symptoms, such as higher fasting insulin, homeostasis model assessment-insulin resistance (HOMA-IR) scores, and triglycerides and lower highdensity lipoprotein (HDL)-cho

DOI： 10.5551/jat.31567

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Background Several studies have demonstrated that spironolactone has an anti-albuminuric property in diabetic nephropathy. As an adverse event, spironolactone often induces the elevation of creatinine levels with hypotension and hyperkalemia. Therefore, we aimed to evaluate the efficacy and safety of spironolactone in Japanese patients with type 2 diabetes treated with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.
Methods Fifty-two Japanese patients with diabetic nephropathy and albuminuria (100 mg/gCr-2000 mg/gCr) treated with renin-angiotensin system (RAS) blockade were enrolled in a prospective, randomized, open-label study. The patients were subjected to add-on treatment with spironolactone 25 mg once daily and compared with matched controls for 8 weeks. The primary outcome was a reduction in the rate of albuminuria at 8 weeks compared with the baseline value. This study was registered with UMIN Clinical Trials Registry (000008016).
Results Albuminuria was reduced by 33 % (95 % confidence interval: 22-54; P = 0.0002) at 8 weeks with spironolactone. In the spironolactone group, blood pressure tended to lower and the estimated glomerular filtration rate (eGFR) was significantly decreased compared to those in the control group. When adjusted by systolic blood pressure and eGFR, spironolactone treatment still showed a significant effect on albuminuria reduction in a linear mixed model (coefficient +/- A standard error; 514.4 +/- A 137.6 mg/gCr, P &lt; 0.0005). No patient was excluded from the study because of hyperkalemia.
Conclusions Spironolactone reduced albuminuria along with conventional RAS inhibitors in patients with diabetic nephropathy. Our study suggests that spironolactone exerts anti-albuminuric effects independent of systemic hemodynamic alterations.

DOI： 10.1007/s10157-015-1106-2

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