AIM:Elevated resting heart rate has been associated with increased risks of all-cause mortality and cardiovascular events. However, its association with the development of chronic kidney disease (CKD) among individuals with established CKD risk factors under clinical care remains uncertain. METHODS:We analysed 1210 participants with one or more CKD risk factors, an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2, and no proteinuria at baseline, enrolled in the Fukushima Cohort Study, to evaluate the association between baseline resting heart rate and new-onset CKD. Participants were classified into three groups according to baseline heart rate: < 70 (reference), 70-79 and ≥ 80 bpm. Associations were examined using Cox proportional hazards models adjusted for demographic, clinical and treatment covariates. RESULTS:During a mean follow-up of 4.3 years, 353 participants developed CKD. Compared with the reference group (< 70 bpm), the adjusted hazard ratios for CKD were 0.94 (95% confidence interval, 0.71-1.25) in the 70-79 bpm group and 1.35 (95% confidence interval, 1.04-1.74) in the ≥ 80 bpm group. Subgroup analysis showed that the association between resting heart rate and new-onset CKD was stronger among participants with diabetes than among those without. CONCLUSION:Among individuals with CKD risk factors but without CKD at baseline, a higher resting heart rate was associated with an increased risk of incident CKD.

INTRODUCTION:Adequate vascular access is essential for stable hemodialysis treatment. Several clinical factors have been reported to affect arteriovenous fistula (AVF) patency;however, data focusing on Japanese patients remain limited. This study aimed to evaluate one-year AVF patency rates and associated clinical factors in Japanese patients. METHODS:We retrospectively analyzed 580 patients who underwent AVF creation at a single center between July 2013 and December 2020. One-year AVF patency rates were estimated using the Kaplan-Meier method, and factors associated with AVF failure were examined using Cox proportional hazards regression. RESULTS:The overall one-year primary, assisted primary, and secondary AVF patency rates were 15.4%, 78.3%, and 79.1%, respectively. In multivariate analyses, older age (adjusted HR 1.02, 95% CI 1.00-1.04), reduced preoperative cardiac function (ejection fraction ≤50%;adjusted HR 1.98, 95% CI 1.20-3.26), and catheter use at dialysis initiation (adjusted HR 1.51, 95% CI 1.02-2.22) were associated with an increased risk of AVF failure. CONCLUSIONS:In Japanese patients undergoing hemodialysis, older age, reduced cardiac function, and catheter use at dialysis initiation were factors associated with one-year AVF failure. These findings highlight the importance of minimizing catheter use and assessing cardiovascular status when planning vascular access.

Variants in the inverted formin-2 (INF2) gene are a known cause of hereditary focal segmental glomerulosclerosis (FSGS) and Charcot–Marie–Tooth disease. We report a case of rapidly progressive FSGS associated with a rare INF2 variant. A 12-year-old boy developed proteinuria and was diagnosed with FSGS at age 14 following a renal biopsy. Steroid therapy and subsequent immunosuppressive treatments, including plasma exchange, were ineffective. At age 15, a heterozygous missense variant in exon 6 of the INF2 gene (c.763G>A, p.Asp255Asn) was identified. Despite conservative management, the patient progressed to end-stage kidney disease at age 17. Although exon 6 variants are rarely reported, the present case showed a relatively aggressive renal course.

OBJECTIVE:: Evidence on the prognostic value of estimated glomerular filtration rate (eGFR) slope in Asian individuals with hypertension is limited. We examined associations of eGFR slope with cardiovascular events, kidney events, and all-cause mortality in a Japanese cohort. METHODS:: We studied 1814 adults with hypertension from the Fukushima Cohort Study. eGFR slope over 1-2 years was classified as <3 (stable), 3-<7 (moderate decline), or ≥7 (rapid decline) ml/min/1.73 m 2 /year. The primary outcome was cardiovascular events; secondary outcomes were kidney events and all-cause death. Associations were evaluated using multivariable Cox models, restricted cubic splines, and time-dependent Cox models. Missing data and confounding were addressed using multiple imputation and inverse probability weighting. RESULTS:: Over a median follow-up of 5.5 years, 193 cardiovascular events, 77 kidney events, and 118 deaths occurred. Compared with the stable group, the rapid-decline group had higher risks of cardiovascular events [hazard ratio (HR) 1.63, 95% confidence interval (CI) 1.10-2.40], kidney events (HR 6.54, 95% CI 3.39-12.63), and all-cause death (HR 2.05, 95% CI 1.28-3.28). Spline analyses suggested U-shaped associations for cardiovascular events and mortality. Findings were consistent after imputation and weighting, and time-dependent analyses showed progressively increasing cardiovascular risk. CONCLUSION:: Short-term eGFR slope was strongly associated with cardiovascular, kidney, and mortality outcomes in Japanese individuals with hypertension, supporting its use for clinical risk stratification.

BACKGROUND:Platelet indices, including platelet distribution width (PDW) and mean platelet volume (MPV), reflect platelet activation and have been associated with kidney disease progression in various populations. However, whether these indices are associated with incident chronic kidney disease (CKD) in high-risk individuals remains unclear. METHODS:We retrospectively examined the associations of PDW and MPV with incident CKD using longitudinal data from 1,281 individuals without CKD but with one or more established CKD risk factors (hypertension, diabetes mellitus, dyslipidemia, or a history of cardiovascular disease) in the Fukushima Cohort Study. Participants were categorized into quartiles according to baseline PDW or MPV. The primary outcome was incident CKD. RESULTS:During a median follow-up of 5.2 years, 384 participants developed incident CKD. Higher quartiles of PDW and MPV were associated with increased cumulative incidence of CKD in Kaplan-Meier analyses. Compared with the second PDW quartile, the highest quartile was associated with a significantly higher risk of incident CKD (adjusted hazard ratio 1.51, 95% confidence interval 1.11-2.06). A similar association was observed for MPV. However, when PDW and MPV were simultaneously included in the multivariable model, only PDW remained significantly associated with incident CKD, whereas the association of MPV was no longer statistically significant. In addition, analyses treating these indices as continuous variables did not show statistically significant associations. CONCLUSION:PDW and MPV showed associations with incident CKD in high-risk individuals; however, these findings were not consistent across all analyses. Therefore, the results should be interpreted as hypothesis-generating and require further confirmation.

INTRODUCTION:The red blood cell distribution width/albumin ratio (RAR) has been reported to be a prognostic marker for adverse clinical outcomes. However, there is limited data on the relationship between RAR and renal function in patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate the effect of RAR on renal prognosis in patients with T2DM. RESEARCH DESIGN AND METHODS:This retrospective cohort study included 907 patients with T2DM enrolled in the Fukushima Cohort Study, divided into two groups (high and low RAR) according to their baseline RAR. The association between RAR and renal events was assessed using Kaplan-Meier curves and multivariate Cox regression analyses. Receiver operating characteristic (ROC) curve analyses, as well as the net reclassification index (NRI) and integrated discrimination improvement (IDI), examined the differences between RAR and red blood cell distribution width (RDW) alone. RESULTS:The high RAR group showed an increased risk of renal events in the Kaplan-Meier curve analysis. Compared with the low RAR group, the high RAR group showed an increased risk of renal events (adjusted hazard ratio [HR]: 3.40, 95% confidence interval: 1.76-6.57). RAR exhibited a significantly higher area under the curve (AUC), NRI, and IDI for renal events than RDW. CONCLUSION:We observed an association between high RAR and worse renal outcomes in patients with T2DM. RAR assessment may have potential utility as a predictive tool for renal prognosis.

Platelet distribution width (PDW), which represents the heterogeneity of platelet size, can predict a poor prognosis in various populations. However, the PDW-to-serum albumin ratio (PAR) has not been evaluated in any disease population, and whether the PAR could be a prognostic marker in hypertension remains unknown. The relationship between the PAR and adverse outcomes was examined retrospectively using longitudinal data of 1,578 patients with hypertension from the Fukushima Cohort Study. Participants were categorized into tertiles by baseline PAR. The primary endpoint of the present study was a kidney event, defined as a combination of a 50% decline in eGFR from baseline and end-stage kidney disease requiring kidney replacement therapy. During the median follow-up period of 5.4 years, 146 patients had kidney events. The higher PAR group (tertile 3) showed an increased incidence of kidney events on Kaplan-Meier curve analysis. Compared with the lowest PAR tertile, the highest PAR tertile (tertile 3) showed a significantly higher risk of kidney events (adjusted hazard ratio 3.74, 95% confidence interval (CI) 1.65-8.48). Similar relationships were observed for risks of all-cause death and cardiovascular events. The predictive value of the PAR for kidney events was superior to that of PDW alone. The areas under the curves for PDW and the PAR were 0.61 (95% CI 0.56-0.66) and 0.77 (95% CI 0.74-0.81), respectively (P < 0.001). The PAR could be a useful predictive marker of adverse outcomes in this population.

Background: It is necessary to update the evidence of each phosphate-lowering agent on dialysis patients. Methods: From the CENTRAL, MEDLINE, EMBASE, and ClinicalTrial.gov databases, randomized controlled trials (RCTs) using oral phosphate-lowering agents on adult patients requiring maintenance dialysis were extracted. The treatment period was required for eight or more weeks, and the risk of bias was assessed according to the Cochrane Collaboration method. The outcomes were all-cause mortality, cardiovascular mortality, gastrointestinal (GI) events, fracture, coronary artery calcium score (CACS), serum calcium, phosphate, intact parathyroid hormone (iPTH), and bicarbonate levels. A network meta-analyses using multivariate random-effects models were performed for assessing the comparative effectiveness. The ranking of the phosphate-lowering agents was assessed using a surface under the cumulative ranking curve (SUCRA). Results: A total of 70 RCTs involving 15,551 participants were included. Eleven phosphate-lowering agents including calcium-based agents, sevelamer, bixalomer, lanthanum, sucroferric oxyhydroxide, ferric citrate, tenapanor, magnesium, nicotinamide, aluminum, and sucralfate were assessed. Sevelamer was significantly associated with lower all-cause mortality compared with calcium-based agents [risk ratio (95% Confidence Interval {CI}): 0.59 (0.37–0.94)], and sucroferric oxyhydroxide and tenapanor were estimated to rank high in terms of lowering all-cause mortality based on the SUCRA. The risk of GI events was the highest with nicotinamide, followed by sucroferric oxyhydroxide. Compared with calcium-based agents, CACS were significantly lower among those on lanthanum and sucroferric oxyhydroxide [standardized mean difference (95% CI): −0.26 (−0.52 to −0.01) and −0.50 (−0.95 to −0.06), respectively]. Serum calcium levels were higher and serum iPTH levels were lower in patients treated with calcium-based agents. Except for sevelamer, serum bicarbonate levels for all other agents were higher compared with placebo. Conclusions: Compared with calcium-based agents, sevelamer was associated with lower all-cause mortality, and sucroferric oxyhydroxide and lanthanum were associated with slower progression of CACS. Potential benefits and harms should be considered when selecting phosphate-lowering agents (PROSPERO: CRD42022328388).

Key PointsSevelamer was associated with lower all-cause mortality compared with calcium-based agents.Sucroferric oxyhydroxide and tenapanor were estimated to rank high in lowering all-cause mortality compared with other phosphate-lowering agents.Sucroferric oxyhydroxide and lanthanum were associated with slower progression of coronary artery calcium score compared with calcium-based agents.BackgroundIt is necessary to update the evidence of each phosphate-lowering agent on dialysis patients.MethodsFrom the CENTRAL, MEDLINE, Embase, and ClinicalTrial.gov databases, randomized controlled trials using oral phosphate-lowering agents on adult patients requiring maintenance dialysis were extracted. The treatment period was required for 8 or more weeks, and the risk of bias was assessed according to the Cochrane Collaboration method. The outcomes were all-cause mortality, cardiovascular mortality, gastrointestinal events, fracture, coronary artery calcium score (CACS), serum calcium, phosphate, intact parathyroid hormone, and bicarbonate levels. A network meta-analyses using multivariate random-effects models were performed for assessing the comparative effectiveness. The ranking of the phosphate-lowering agents was assessed using a surface under the cumulative ranking curve.ResultsA total of 70 randomized controlled trials involving 15,551 participants were included. Eleven phosphate-lowering agents including calcium-based agents, sevelamer, bixalomer, lanthanum, sucroferric oxyhydroxide, ferric citrate, tenapanor, magnesium, nicotinamide, aluminum, and sucralfate were assessed. Sevelamer was significantly associated with lower all-cause mortality compared with calcium-based agents (risk ratio [95% confidence interval]: 0.59 [0.37 to 0.94]), and sucroferric oxyhydroxide and tenapanor were estimated to rank high in lowering all-cause mortality on the basis of the surface under the cumulative ranking curve. The risk of gastrointestinal events was the highest with nicotinamide, followed by sucroferric oxyhydroxide. Compared with calcium-based agents, CACS was significantly lower among those on lanthanum and sucroferric oxyhydroxide (standardized mean difference [95% confidence interval]: -0.26 [-0.52 to -0.01] and -0.50 [-0.95 to-0.06], respectively). Serum calcium levels were higher, and serum intact parathyroid hormone levels were lower in patients treated with calcium-based agents. Except for sevelamer, serum bicarbonate levels for all other agents were higher compared with placebo.ConclusionsCompared with calcium-based agents, sevelamer was associated with lower all-cause mortality, and sucroferric oxyhydroxide and lanthanum were associated with slower progression of CACS. Potential benefits and harms should be considered when selecting phosphate-lowering agents (International prospective register of systematic reviews: CRD42022328388).

BACKGROUND AND AIMS:Malnutrition is associated with adverse outcomes across various populations, but its role in the development of chronic kidney disease (CKD) remains unclear. Our study evaluated relationship between nutritional status and CKD development in patients with CKD risk factors. METHODS:A total of 1,046 adults with one or more CKD risk factors, an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2, and no proteinuria were examined to investigate the association between nutritional status and new-onset CKD using longitudinal data from the Fukushima Cohort Study. Nutritional status was assessed using the Prognostic Nutritional Index (PNI), the Geriatric Nutritional Risk Index (GNRI), and Controlling Nutritional Status (CONUT) score. Cox proportional hazards modeling was used to evaluate the association between nutritional status and CKD development. The predictive performance of each nutritional index was assessed using receiver operating characteristic curves. RESULTS:During follow-up (median, 5.2 years), 325 participants developed CKD. Compared to the highest tertile, participants in the lowest tertile of the PNI showed a significantly increased risk of developing CKD (adjusted hazard ratio, 1.65; 95 % confidence interval, 1.21-2.24). Similar associations were observed for GNRI and CONUT scores in relation to CKD risk. Although the PNI showed a slightly higher AUC than the GNRI and CONUT score, the differences were small and not statistically significant. CONCLUSION:In this retrospective cohort study, poor nutritional status was associated with increased risk of CKD development in a high-risk population. Nutritional assessment using indices such as the PNI, GNRI, or CONUT score may help identify individuals at elevated risk for CKD, highlighting the potential role of nutritional interventions in CKD prevention. As all three indices showed comparable associations with CKD risk, each may be useful for risk stratification in clinical practice.

Background Dupilumab, a human monoclonal immunoglobulin G (IgG) antibody that targets the IL-4 and IL-13 receptors, is used to treat various allergic diseases. Several cases of dupilumab-associated autoimmune diseases have been reported in recent years, however, there have been no reports of anti-glomerular basement membrane (GBM) nephritis .Case presentation A 54-year-old woman had been receiving treatment for eosinophilic granulomatosis with polyangiitis (EGPA) since the age of 31. At the age of 51, due to worsening asthma symptoms and eosinophilic sinusitis, treatment with dupilumab was initiated. She was later admitted to the hospital with fever and rapidly progressive kidney dysfunction. Glucocorticoid therapy was started because the possibility of recurrence of EGPA was considered. However, her kidney dysfunction progressed without response, and she was transferred to our hospital. Laboratory tests on admission showed positive anti-GBM antibodies, and a kidney biopsy showed crescentic glomerulonephritis with linear IgG deposition along the GBM without findings suggesting the recurrence of EGPA, including eosinophilic infiltration, granuloma formation, or necrotizing vasculitis. Based on her laboratory data and kidney pathological findings, anti-GBM nephritis was diagnosed. Plasma exchange was performed a total of seven times. Although the anti-GBM antibody titer was decreased after the plasma exchanges, kidney function did not improve well. After additional treatment with intravenous cyclophosphamide, her kidney function improved, and she was discharged home. Conclusion Anti-GBM nephritis associated with EGPA is extremely rare, and dupilumab may have contributed to its development. In patients receiving dupilumab who develop rapidly progressive kidney dysfunction, the possibility of anti-GBM nephritis should be considered, and prompt diagnosis and therapeutic intervention are essential.

INTRODUCTION:Dyslipidemia is a major risk factor for cardiovascular disease in type 2 diabetes mellitus (T2DM), but its association with kidney disease progression remains incompletely defined. Although low high-density lipoprotein cholesterol (HDL-C) has been linked to diabetic nephropathy, evidence regarding hard kidney outcomes is limited. We examined the associations between HDL-C and kidney events in patients with T2DM, in comparison with other lipid parameters. RESEARCH DESIGN AND METHODS:A total of 1,033 patients with T2DM from the Fukushima Cohort Study were included. Participants were followed for kidney events, defined as a ≥50% decrease in estimated glomerular filtration rate (eGFR) or onset of kidney failure requiring kidney replacement therapy, and all-cause mortality over a median follow-up period of 5.3 years. Lipid parameters HDL-C, triglycerides (TG), low-density lipoprotein cholesterol, non-HDL-C, and TG/HDL-C ratio were categorized into quartiles and evaluated using Cox proportional hazards models, adjusted for age, sex, smoking history, history of cardiovascular disease, body mass index, systolic blood pressure, eGFR, hemoglobin A1c, and proteinuria. RESULTS:The median patient age was 66 years, 56% were men, and the median eGFR was 68.6 mL/min/1.73 m2. After multivariable adjustment, patients in the lowest HDL-C quartile (<42 mg/dL) had significantly higher risks of kidney events (adjusted HR 2.61, 95% CI 1.32 to 5.14) and all-cause mortality (adjusted HR 2.27, 95% CI 1.16 to 4.42) than the reference group (HDL-C 49-58 mg/dL). A U-shaped association was observed between HDL-C and all-cause mortality. Subgroup and sensitivity analyses were consistent. No significant associations were observed for other lipid parameters with either kidney events or mortality. CONCLUSIONS:Low HDL-C levels were independently associated with kidney events and all-cause mortality in patients with T2DM. Future studies are warranted to clarify whether interventions targeting HDL-C can improve kidney disease progression in this high-risk population. TRIAL REGISTRATION NUMBER:UMIN000040848.

ABSTRACT Introduction Mean platelet volume (MPV), which reflects platelet size and activity, is known to be elevated in patients with type 2 diabetes mellitus. Although increased MPV has been linked to poor glycemic control and diabetic vascular complications, evidence regarding its association with hard kidney outcomes remains limited. We aimed to investigate the relationship between MPV and kidney events in patients with type 2 diabetes mellitus. Materials and Methods We retrospectively analyzed longitudinal data from 1,076 Japanese patients with type 2 diabetes mellitus enrolled in the Fukushima Cohort Study. Participants were categorized into quartiles based on baseline MPV levels. The primary endpoint was kidney events, defined as a ≥50% decline in estimated glomerular filtration rate (eGFR) from baseline or progression to end‐stage kidney disease requiring kidney replacement therapy. The secondary endpoint was new‐onset cardiovascular events. Results During a median follow‐up of 5.3 years, 97 patients experienced kidney events. The second quartile (Q2) had the lowest incidence of kidney events. Compared with Q2 as the reference, patients in the highest quartile (Q4) had a significantly increased risk of kidney events (adjusted hazard ratio 2.05, 95% confidence interval 1.13–3.72). Higher MPV levels were also significantly associated with an increased risk of cardiovascular events. Conclusion Elevated MPV was independently associated with both kidney and cardiovascular events in Japanese patients with type 2 diabetes mellitus. MPV may serve as a simple and useful biomarker for predicting kidney disease progression in this high‐risk population.

Predicting the transition of kidney function in chronic kidney disease is difficult as specific symptoms are lacking and often overlooked, and progress occurs due to complicating factors. In this study, we applied time-series cluster analysis and a light gradient boosting machine to predict the trajectories of kidney function in non-dialysis dependent chronic kidney disease patients with baseline estimated glomerular filtration rate (GFR) ≥ 45 mL/min/1.73 m2. Based on 5-year changes in estimated GFR, participants were stratified into groups with similar trajectories by cluster analysis. Next, we applied the light gradient boosting machine algorithm and Shapley addictive explanation to develop a prediction model for clusters and identify important parameters for prediction. Data from 780 participants were available for analysis. Participants were classified into five classes (Class 1: n = 78, mean [± standard deviation] estimated GFR 100 ± 19.3 mL/min/1.73 m2; Class 2: n = 176, 76.0 ± 9.3 mL/min/1.73 m2; Class 3: n = 191, 59.8 ± 5.9 mL/min/1.73 m2; Class 4: n = 261, 52.7 ± 4.6 mL/min/1.73 m2; and Class 5: n = 74, 53.5 ± 12.0 mL/min/1.73 m2). Declines in estimated GFR were 8.9% in Class 1, 12.2% in Class 2, 4.9% in Class 3, 12.0% in Class 4, and 45.1% in Class 5 during the 5-year period. The accuracy of prediction was 0.675, and the top three most important Shapley addictive explanation values were 1.61 for baseline estimated GFR, 0.12 for hemoglobin, and 0.11 for body mass index. The estimated GFR transition of patients with preserved chronic kidney disease mostly depended on baseline estimated GFR, and the borderline for estimated GFR trajectory was nearly 50 mL/min/1.73 m2.

A higher heart rate is recognized as an independent risk factor for all-cause mortality and cardiovascular events in the general population. However, the association between elevated heart rate and clinical adverse outcomes in patients with non-dialysis-dependent chronic kidney disease (CKD) has not been sufficiently investigated. A total of 1353 participants enrolled in the Fukushima CKD Cohort Study were examined to investigate associations between resting heart rate and clinical adverse outcomes using Cox proportional hazards analysis. The primary outcome of the present study was all-cause mortality, with cardiovascular events as the secondary outcome. Participants were stratified into four groups based on resting heart rate levels at baseline (heart rate < 70/min, >= 70 and < 80/min, >= 80 and < 90/min, and >= 90/min). During the median observation period of 4.9 years, 123 participants died, and 163 cardiovascular events occurred. Compared with the reference level heart rate < 70/min group, the adjusted hazard ratios (HRs) for all-cause mortality were 1.74 (1.05-2.89) and 2.61 (1.59-4.29) for the heart rate >= 80 and < 90/min group and heart rate >= 90/min group, respectively. A significantly higher risk of cardiovascular events was observed in the heart rate >= 80/min and < 90/min group (adjusted HR 1.70, 1.10-2.62), but not in the heart rate >= 90/min group (adjusted HR 1.45, 0.90-2.34). In patients with non-dialysis-dependent CKD, a higher resting heart rate was associated with increased all-cause mortality.

IntroductionFatigue is reportedly associated with a poor prognosis in dialysis patients. The aim of the present study was to investigate whether fatigue on dialysis days or non-dialysis days is associated with mortality in patients on chronic hemodialysis.MethodsThis was a prospective study of 134 hemodialysis patients. The level of fatigue was evaluated using a visual analog scale (VAS). The association between high fatigue evaluated by the highest quartile of the VAS value and all-cause death was investigated.ResultsThe fatigue scale score was significantly higher on dialysis than on non-dialysis days. During the follow-up period (median 6.8 years), 42 patients died. Patients with high post-dialysis fatigue in the higher quartiles died more frequently compared to those with in the lower quartiles (p = 0.012). Multivariate Cox regression analysis showed that high post-dialysis fatigue was an independent predictor of all-cause death (adjusted hazard ratio 2.12, 95% confidence interval 1.10-4.07).ConclusionHigher post-dialysis fatigue is related to increased mortality.