Papers - WADA Jun

Vesicular Glutamate Transporter 3 Is Involved in Glutamatergic Signalling in Podocytes

Naoko Nishii, Tomoko Kawai, Hiroki Yasuoka, Tadashi Abe, Nanami Tatsumi, Yuika Harada, Takaaki Miyaji, Shunai Li, Moemi Tsukano, Masami Watanabe, Daisuke Ogawa, Jun Wada, Kohji Takei, Hiroshi Yamada

International Journal of Molecular Sciences   2025.3

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DOI： 10.3390/ijms26062485

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Supplement-induced acute kidney injury reproduced in kidney organoids

Hiroyuki Nakanoh, Kenji Tsuji, Kazuhiko Fukushima, Soichiro Haraguchi, Shinji Kitamura, Jun Wada

American Journal of Nephrology   2025.2

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DOI： 10.1159/000544795

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Noncoding RNAs and diabetic kidney disease Reviewed

Jun Wada

Journal of Diabetes Investigation   2025.1

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DOI： 10.1111/jdi.14331

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The Gut–Kidney Axis in Chronic Kidney Diseases

Kenji Tsuji, Naruhiko Uchida, Hiroyuki Nakanoh, Kazuhiko Fukushima, Soichiro Haraguchi, Shinji Kitamura, Jun Wada

Diagnostics   2024.12

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DOI： 10.3390/diagnostics15010021

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Characteristics of diabetes mellitus patients with nonviral chronic liver disease who developed hepatocellular carcinoma. Reviewed International journal

Kyo Sasaki, Miwa Kawanaka, Yasuyuki Tomiyama, Akinobu Takaki, Motoyuki Otsuka, Fusao Ikeda, Naoko Yoshioka, Hideaki Kaneto, Jun Wada, Tetsuya Fukuda, Keisuke Hino, Sohji Nishina

Hepatology research : the official journal of the Japan Society of Hepatology   2024.10

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AIM: Type 2 diabetes mellitus (T2DM) is a well-known risk factor for hepatocellular carcinoma (HCC). However, HCC is often diagnosed at an advanced stage in patients with diabetes because of the lack of the best criteria for surveillance candidates. The aim of this study was to identify risk factors for HCC development in patients with diabetes with nonviral chronic liver disease. METHOD: Three hundred thirty T2DM patients with nonviral chronic liver disease who underwent surveillance for HCC by imaging techniques between 2009 and 2020 were enrolled in this multicenter cross-sectional retrospective study. The clinical and laboratory parameters of patients with and without HCC were compared. RESULTS: Age ≥65 years, alcohol intake, lack of hepatic steatosis, triglyceride level <111 mg/dL, Mac2 binding protein glycosylation isomer (M2BPGi) ≥0.9 cut-off index (COI), α-fetoprotein concentration ≥5 ng/mL, and des-γ-carboxy prothrombin concentration ≥26 mAU/mL were independently associated with HCC development. When stratified by age, only alcohol intake (odds ratio [OR] 114.19, p < 0.001) was associated with HCC development in patients aged <65 years, and medication for diabetes mellitus (OR 5.72, p = 0.001), lack of hepatic steatosis (OR 4.47, p = 0.002), lactate dehydrogenase ≥198 IU/L (OR 2.751, p = 0.031), M2BPGi ≥1.18 COI (OR 9.05, p < 0.001), and FIB-4 index ≥2.59 (OR 3.22, p = 0.017) were associated with HCC development in patients aged ≥65 years. CONCLUSIONS: In addition to age and advanced liver fibrosis, alcohol intake in younger T2DM patients and medication for DM and lack of hepatic steatosis in older T2DM patients should be considered for HCC surveillance by imaging.

DOI： 10.1111/hepr.14124

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A case of renal hypouricemia due to T217M mutation in SLC22A12 incidentally associated with IgA nephropathy. Reviewed International journal

Yoshimasa Sakurabu, Haruhito A Uchida, Toshihisa Tahara, Tomohiko Asakawa, Haruka Yamasaki, Katsuyoshi Katayama, Shugo Okamoto, Yasuhiro Onishi, Natsumi Matsuoka-Uchiyama, Keiko Tanaka, Hidemi Takeuchi, Kenji Tsuji, Ryoko Umebayashi, Yuki Ohashi, Kimiyoshi Ichida, Jun Wada

Clinical case reports   12 ( 9 )   e9368   2024.9

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A T217M heterozygous mutation in the SLC22A12 gene caused renal hypouricemia; this patient with IgA nephropathy had no findings other than IgA nephropathy on renal biopsy. Hypouricemia was susceptible to oxidative stress, but IgA nephropathy in the patient with hypouricemia could be treated with steroid pulse therapy without adverse events.

DOI： 10.1002/ccr3.9368

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Guidelines for clinical evaluation of chronic kidney disease in early stages : AMED research on regulatory science of pharmaceuticals and medical devices. Reviewed

Yuka Sugawara, Eiichiro Kanda, Takayuki Hamano, Seiji Itano, Hirokazu Okada, Koji Tomori, Yusuke Watanabe, Wataru Asakura, Yoshitaka Isaka, Kunitoshi Iseki, Tomoko Usui, Yusuke Suzuki, Mototsugu Tanaka, Rimei Nishimura, Kei Fukami, Kunihiro Matsushita, Jun Wada, Hirotaka Watada, Kohjiro Ueki, Naoki Kashihara, Masaomi Nangaku

Clinical and experimental nephrology   28 ( 9 )   847 - 865   2024.9

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BACKGROUND: For the development of pharmaceutical products in kidney field, appropriate surrogate endpoints which can predict long-term prognosis are needed as an alternative to hard endpoints, such as end-stage kidney disease. Though international workshop has proposed estimated glomerular filtration rate (GFR) slope reduction of 0.5-1.0 mL/min/1.73 m /year and 30% decrease in albuminuria/proteinuria as surrogate endpoints in early and advanced chronic kidney disease (CKD), it was not clear whether these are applicable to Japanese patients. METHODS: We analyzed J-CKD-DB and CKD-JAC, Japanese databases/cohorts of CKD patients, and J-DREAMS, a Japanese database of patients with diabetes mellitus to investigate the applicability of eGFR slope and albuminuria/proteinuria to the Japanese population. Systematic review on those endpoints was also conducted including the results of clinical trials published after the above proposal. RESULTS: Our analysis showed an association between eGFR slope and the risk of end-stage kidney disease. A 30% decrease in albuminuria/proteinuria over 2 years corresponded to a 20% decrease in the risk of end-stage kidney disease patients with baseline UACR ≥ 30 mg/gCre or UPCR ≥ 0.15 g/gCre in the analysis of CKD-JAC, though this analysis was not performed on the other database/cohort. Those results suggested similar trends to those of the systematic review. CONCLUSION: The results suggested that eGFR slope and decreased albuminuria/proteinuria may be used as a surrogate endpoint in clinical trials for early CKD (including diabetic kidney disease) in Japanese population, though its validity and cutoff values must be carefully considered based on the latest evidence and other factors.

DOI： 10.1007/s10157-024-02514-6

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Factors influencing the efficacy and safety of esaxerenone in hypertensive patients: a pooled analysis of five clinical studies on different comorbidities. Reviewed International journal

Kazuomi Kario, Tomohiro Katsuya, Jun Wada, Hirohiko Motoki, Koichiro Kuwahara, Kenichi Tsujita, Takashi Taguchi, Ayumi Tanabe, Tatsuo Shimosawa

Hypertension research : official journal of the Japanese Society of Hypertension   2024.8

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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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Association of serum magnesium levels with renal prognosis in patients with chronic kidney disease. Reviewed

Seiji Kishi, Takaya Nakashima, Tadahiro Goto, Hajime Nagasu, Craig R Brooks, Hirokazu Okada, Kouichi Tamura, Toshiaki Nakano, Ichiei Narita, Shoichi Maruyama, Yuichiro Yano, Takashi Yokoo, Takashi Wada, Jun Wada, Masaomi Nangaku, Naoki Kashihara

Clinical and experimental nephrology   28 ( 8 )   784 - 792   2024.8

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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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A case of membranous nephropathy complicated by Cronkhite-Canada syndrome successfully treated with mizoribine. Reviewed

Hiroyuki Nakanoh, Kenji Tsuji, Shiho Morimoto, Kazuhiko Fukushima, Masaya Iwamuro, Haruhito A Uchida, Jun Wada

CEN case reports   2024.7

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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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Factors affecting the sodium-glucose cotransporter 2 inhibitors-related initial decline in glomerular filtration rate and its possible effect on kidney outcome in chronic kidney disease with type 2 diabetes: The Japan Chronic Kidney Disease Database. Reviewed International journal

Tomohiko Kanaoka, Hiromichi Wakui, Yuichiro Yano, Hajime Nagasu, Hiroshi Kanegae, Masaomi Nangaku, Yosuke Hirakawa, Naoki Nakagawa, Jun Wada, Kazuhiko Tsuruya, Toshiaki Nakano, Shoichi Maruyama, Takashi Wada, Masaaki Konishi, Takanori Nagahiro, Kunihiro Yamagata, Ichiei Narita, Motoko Yanagita, Yoshio Terada, Shinichi Araki, Masanori Emoto, Hirokazu Okada, Yoshitaka Isaka, Yusuke Suzuki, Takashi Yokoo, Hiromi Kataoka, Eiichiro Kanda, Naoki Kashihara, Kouichi Tamura

Diabetes, obesity & metabolism   26 ( 7 )   2905 - 2914   2024.7

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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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Preventive effects of vasohibin-2-targeting peptide vaccine for diabetic nephropathy. Reviewed International journal

Yuri Nakashima, Katsuyuki Tanabe, Tomoyo Mifune, Takato Nakadoi, Hiroki Hayashi, Hironori Nakagami, Yasufumi Sato, Jun Wada

American journal of physiology. Renal physiology   326 ( 6 )   F1054-F1065   2024.6

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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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Effects of empagliflozin in patients with chronic kidney disease from Japan: exploratory analyses from EMPA-KIDNEY. Reviewed

Masaomi Nangaku, William G Herrington, Shinya Goto, Shoichi Maruyama, Naoki Kashihara, Kohjiro Ueki, Jun Wada, Hirotaka Watada, Eitaro Nakashima, Ryonfa Lee, Dan Massey, Kaitlin J Mayne, Aiko Tomita, Richard Haynes, Sibylle J Hauske, Takashi Kadowaki

Clinical and experimental nephrology   28 ( 6 )   588 - 595   2024.6

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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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Plasma angiotensin-converting enzyme 2 (ACE2) is a marker for renal outcome of diabetic kidney disease (DKD) (U-CARE study 3). Reviewed International journal

Asami Ueno, Yasuhiro Onishi, Koki Mise, Satoshi Yamaguchi, Ayaka Kanno, Ichiro Nojima, Chigusa Higuchi, Haruhito A Uchida, Kenichi Shikata, Satoshi Miyamoto, Atsuko Nakatsuka, Jun Eguchi, Kazuyuki Hida, Akihiro Katayama, Mayu Watanabe, Tatsuaki Nakato, Atsuhito Tone, Sanae Teshigawara, Takashi Matsuoka, Shinji Kamei, Kazutoshi Murakami, Ikki Shimizu, Katsuhito Miyashita, Shinichiro Ando, Tomokazu Nunoue, Jun Wada

BMJ open diabetes research & care   12 ( 3 )   2024.5

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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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All three in one: it's a cohort, proteomics, and Mendelian randomization biomarker study. Reviewed International journal

Jun Wada

The Journal of clinical endocrinology and metabolism   2024.5

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DOI： 10.1210/clinem/dgae359

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Evaluating the associations between compliance with CKD guideline component metrics and renal outcomes. Reviewed International journal

Zannatun Nyma, Kaori Kitaoka, Yuichiro Yano, Hiroshi Kanegae, Nomin Bayaraa, Seiji Kishi, Hajime Nagasu, Toshiaki Nakano, Jun Wada, Shoichi Maruyama, Naoki Nakagawa, Kouichi Tamura, Takashi Yokoo, Motoko Yanagita, Ichiei Narita, Kunihiro Yamagata, Takashi Wada, Kazuhiko Tsuruya, Naoki Nakashima, Yoshitaka Isaka, Masaomi Nangaku, Naoki Kashihara, Hirokazu Okada

Scientific reports   14 ( 1 )   11481 - 11481   2024.5

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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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A multicenter, open‐label, single‐arm trial of the long‐term safety of empagliflozin treatment for refractory diabetes mellitus with insulin resistance (EMPIRE‐02) Reviewed

Yushi Hirota, Yasumasa Kakei, Junta Imai, Hideki Katagiri, Ken Ebihara, Jun Wada, Junichi Suzuki, Tatsuhiko Urakami, Takashi Omori, Wataru Ogawa

Journal of Diabetes Investigation   15 ( 9 )   1211 - 1219   2024.5

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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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GRP78 Contributes to the Beneficial Effects of SGLT2 Inhibitor on Proximal Tubular Cells in DKD Reviewed International journal

Atsuko Nakatsuka, Satoshi Yamaguchi, Jun Wada

Diabetes   73 ( 5 )   763 - 779   2024.5

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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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Renal outcomes with sodium‐glucose cotransporter 2 inhibitors in Japanese people with grade 3 chronic kidney disease and type 2 diabetes: Analysis of medical administrative databases Reviewed International journal

Hiroaki Iijima, Maki Gouda, Hideaki Hida, Kazumi Mori‐Anai, Akiko Takahashi, Ryoichi Minai, Hideki Ninomiya, Yoshiyuki Saito, Atsushi Miyawaki, Jun Wada

Diabetes, Obesity and Metabolism   26 ( 5 )   1615 - 1623   2024.5

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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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Successful treatment for life threatening recurrent non-traumatic rectus sheath hematoma in a case with microscopic polyangiitis with rapidly progressive glomerulonephritis. Reviewed

Hiroyuki Nakanoh, Hidemi Takeuchi, Morimoto Shiho, Yuya Terajima, Shugo Okamoto, Yasuhiro Onishi, Keiko Tanaka, Takayuki Katsuyama, Kenji Tsuji, Yoshinori Matsumoto, Katsuyuki Tanabe, Hiroshi Morinaga, Mayu Uka, Koji Tomita, Haruhito A Uchida, Takao Hiraki, Jun Wada

Internal medicine (Tokyo, Japan)   2024.4

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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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