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Aims/Introduction We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD). Materials and Methods The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population. Results The IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P, The Diabetic Nephropathy Remission and Regression Team Trial in Japan was designed to clarify the beneficial effects of multifactorial intensified intervention by the team approach with medical staffs at each institution. There was an overall trend toward a lower risk on the development of kidney events in the intensive treatment group than in the conventional treatment group in this trial, but the benefit of intensive treatment could not be confirmed statistically. Lipid control by statin was associated with lower risk of kidney events in addition to strict control of blood glucose and blood pressure.

Aims Consensus‐derived guidelines recommend renal stenting for patients with atherosclerotic renal artery disease (ARAD) and heart failure (HF). The aim of this prospective multi‐centre observational study was to verify our hypothesis that changes in E/e′, an echocardiographic correlate of left ventricular (LV) filling pressure, following renal stenting may differ between ARAD patients with and without HF. Methods and results This study enrolled de novo ARAD patients undergoing renal stenting at 14 institutions. The primary endpoint was the difference in E/e′ change between ARAD patients with and without HF. Clinical and echocardiographic data were prospectively collected at baseline, the day following renal stenting, and 1 month and 6 months afterwards. ARAD patients with HF were defined as patients with New York Heart Association (NYHA) Class 2 and more, or a history of HF hospitalization. A total of 76 patients were included, and 39% were ARAD patients with HF. ARAD patients with HF had significantly lower estimated glomerular filtration rate (P = 0.028) and higher NYHA functional class (P

A 27-year-old man who developed heavy proteinuria with hematuria and acute kidney injury 2 weeks after a fever was referred to our hospital. Because he had low complements without autoantibodies, we clinically diagnosed him with infection-related glomerulonephritis. The proliferation of mesangial cells and endothelial cells with glomerular deposits of immunoglobulin A and complement 3 was found. Deposition of glomerular nephritis-associated plasmin receptor, a marker of infection-related glomerulonephritis, was also found. In addition, the distribution of nephritis-associated plasmin receptor deposition almost perfectly matched the plasmin activity-positive region. Over 3 months later, his symptoms were resolved, although moderate proteinuria and active urine sediment were persistent. He underwent a second renal biopsy, and the histological findings revealed that he had immunoglobulin A nephropathy. Therefore, we diagnosed him with infection-related glomerulonephritis superimposed on immunoglobulin A nephropathy at the first renal biopsy. The glomerular deposition of nephritis-associated plasmin receptor is a useful marker and may cause worsening urinalysis findings after bacterial infection in cases of chronic glomerulonephritis.

A 31-year-old woman with retinitis pigmentosa who had been diagnosed with renal failure due to nephrosclerosis related to hypertensive disorders of pregnancy was referred to our hospital to prepare for renal replacement therapy. Ultrasonography and MRI of the kidneys revealed multiple corticomedullary cysts. A renal biopsy showed that the tubules were tortuous and atrophic with segmented tubular basement membrane thickening. These findings indicated that she had Senior-Løken syndrome. A molecular genetic analysis was performed, and homozygous deletion of the gene encoding nephronophthisis-1 was found. Thus, the clinical diagnosis of Senior-Løken syndrome was genetically confirmed. Because her renal function was gradually worsening, she was scheduled to undergo living donor kidney transplantation. Senior-Løken syndrome, which is recognised as a very rare paediatric inherited disease characterised by nephronophthisis and eye problems, can cause adult-onset end-stage renal failure.

Background Pleuroperitoneal leak is an uncommon but significant complication of peritoneal dialysis. Although the exact pathogenesis of pleuroperitoneal communication remains unclear, the pressure gradient between the thorax and abdominal cavity has been thought to play a major role. Case presentation A 48-year-old man with diabetes mellitus and hypertension who had been treated with continuous ambulatory peritoneal dialysis (1.5 L dwells four times a day) for 3 months was admitted because of massive right-sided pleural effusion. He underwent video-assisted thoracoscopic surgery for blebs on the diaphragm. Six weeks after diaphragmatic repair, he resumed peritoneal dialysis (1.5 L dwells four times a day) with once-a-week hemodialysis. Thereafter, pleural effusion was not significant on a chest radiogram. Six months after surgery, his dwell volume increased from 1500 to 2000 ml, and significant right-sided pleural effusion also developed. Conclusion Pleuroperitoneal leak caused by blebs can recur even after surgical treatment, and reducing the dwell volume may be effective for patients with pleuroperitoneal communication.

The patient was a 75-year-old man who was admitted to our hospital because of fatigue, leg edema and heavy proteinuria. Due to his cloudy urine and elevated triglyceride level in his urine, he was diagnosed with chyluria. Tests for infectious disease were negative, and lymphoscintigraphy showed no blockage in the lymphatic system. He was therefore diagnosed with idiopathic chyluria. Hypothyroidism was also found and his cloudy urine and heavy proteinuria disappeared without dietary modifications after starting levothyroxine treatment for hypothyroidism. The patient is currently being followed up in an outpatient clinic and is doing well, with no recurrence of chyluria.

Background O-linked β- N -acetylglucosamine modification O-GlcNAcylation) is a post-translational modification of intracellular proteins, serving as a nutrient sensor. Growing evidence has demonstrated its physiological and pathological importance in various mammalian tissues. This study examined the physiological role of O-GlcNAcylation in podocyte function and development. Methods O-GlcNAc transferase (Ogt) is a critical enzyme for O-GlcNAcylation and resides on the X chromosome. To abrogate O-GlcNAcylation in podocytes, we generated congenital and tamoxifen (TM)-inducible podocyte-specific Ogt knockout mice (Podo-Ogt y/- and TM-Podo-Ogt y/- , respectively) and analyzed their renal phenotypes. Results Podo-Ogt y/- mice showed normal podocyte morphology at birth. However, they developed albuminuria at 8 weeks of age, increasing progressively until age 32 weeks. Glomerular sclerosis, proteinuria-related tubulointerstitial lesions and markedly altered podocyte foot processes, with decreased podocin expression, were observed histologically in 32-week-old Podo-Ogt y/- mice. Next, we induced adult-onset deletion of the Ogt gene in podocytes by TM injection in 8-week-old TM-Podo-Ogt y/- mice. In contrast to Podo-Ogt y/- mice, the induced TM-Podo-Ogt y/- mice did not develop albuminuria or podocyte damage, suggesting a need for O-GlcNAcylation to form mature foot processes after birth. To test this possibility, 3-week-old Podo-Ogt y/- mice were treated with Bis-T-23, which stimulates actin-dependent dynamin oligomerization, actin polymerization and subsequent foot process elongation in podocytes. Albuminuria and podocyte damage in 16-week-old Podo-Ogt y/- mice were prevented by Bis-T-23 treatment. Conclusions O-GlcNAcylation is necessary for maturation of podocyte foot processes, particularly after birth. Our study provided new insights into podocyte biology and O-GlcNAcylation.

Febuxostat has currently played pivotal role in the treatment of hyperuricemia, but there is little comprehensive information for the determinants of individual difference in efficacy of febuxostat. Therefore, the present study, a retrospective investigation, was carried out to analyze the effects of patient characteristics on the efficacy of febuxostat. A total of 225 patients who were continuously prescribed the same dose of febuxostat for 8-12 weeks from the initial therapy were enrolled in the present study. The data, including patient information and laboratory data, were collected from electronic medical records. Serum urate lowering effects of febuxostat were evaluated by calculating the change in serum urate level at baseline and at 8-12 weeks after starting febuxostat. The multiple regression analysis showed the change in serum urate level was significantly lower in male patients and in those with a lower baseline serum urate level, higher previous dose of allopurinol, lower dose of febuxostat and lower body surface area-unadjusted estimated glomerular filtration rate. Concomitantly administered drugs did not show a significantly influence on the efficacy of febuxostat. In conclusion, it should be noted that the serum urate lowering efficacy of febuxostat may decrease in patients with a higher previous dose of allopurinol, renal impairment or male patients. The basic findings of the present study are believed to contribute to the proper use of febuxostat.

Anticoagulants have recently been recognised as a cause of acute kidney injury (AKI). We describe the case of a 75-year-old man with IgA vasculitis and atrial fibrillation treated with rivaroxaban, who presented with macroscopic haematuria and an acute decline in renal function. Two months before referral, he noted palpable purpuric lesions and was diagnosed with IgA vasculitis based on skin biopsy findings; the skin lesion disappeared following treatment with a steroid external preparation. Renal biopsy revealed glomerular haemorrhage and red blood cell casts. Although rivaroxaban was withdrawn, his kidney function worsened and he was started on haemodialysis. His renal function did not recover. To the best of our knowledge, this is the first case of direct oral anticoagulant (DOAC)-related AKI in systemic vasculitis. During DOAC therapy, close monitoring of a patient’s urinalysis results and their renal function may be required for patients with systemic vasculitis to avoid AKI.

Glucose-stimulated insulin secretion (GSIS) by pancreatic β cells is biphasic. However, the physiological significance of biphasic GSIS and its relationship to diabetes are not yet fully understood. This study demonstrated that impaired first-phase GSIS follows fasting, leading to increased blood glucose levels and brain glucose distribution in humans. Animal experiments to determine a possible network between the brain and β cells revealed that fasting-dependent hyperactivation of AMP-activated protein kinase in the hypothalamus inhibited first-phase GSIS by stimulating the α-adrenergic pancreatic nerve. Furthermore, abnormal excitability of this brain-β cell neural axis was involved in diabetes-related impairment of first-phase GSIS in diabetic animals. Finally, pancreatic denervation improved first-phase GSIS and glucose tolerance and ameliorated severe diabetes by preventing β cell loss in diabetic animals. These results indicate that impaired first-phase GSIS is critical for brain distribution of dietary glucose after fasting. Furthermore, β cells in individuals with diabetes mistakenly sense that they are under conditions that mimic prolonged fasting. The present study provides additional insight into both β cell physiology and the pathogenesis of β cell dysfunction in type 2 diabetes., Highlights • Fasting-induced hypothalamic AMPK activation inhibited first-phase GSIS by stimulating the α-adrenergic nerve. • The brain-pancreas neural axis was involved in β cell dysfunction and glucose intolerance in diabetes. • Pancreatic denervation improved first-phase GSIS, glucose tolerance and β cell survival in type 2 diabetic animals. Glucose-stimulated insulin secretion (GSIS) from pancreatic β cells is biphasic. Furthermore, first-phase GSIS is inhibited in type 2 diabetes. This study revealed that fasting reduced first-phase GSIS by signaling via the brain-pancreatic β cell neural axis, which is essential for maintaining glucose supply to the brain at re-feeding after fasting. Abnormal excitability of this neural axis was also associated with impaired first-phase GSIS in type 2 diabetes. Surgical pancreatic denervation improved diabetes in an animal study. The present data reveal that diabetic β cells exist under conditions that mimic starvation and provide a therapeutic potency of pancreatic denervation against diabetes., Graphical Abstract Image 2

We report a case involving a 43-year-old Japanese woman with steroid-resistant focal segmental glomerular sclerosis (FSGS) and severe renal dysfunction, which was ameliorated by low-density lipoprotein apheresis (LDL-A). She had been treated with steroid therapy, but had experienced anuria for over 10 weeks and required hemodialysis. She was then treated with LDL-A, which resulted in improved urinary protein excretion and renal function. Her renal function recovered after 97 days of hemodialysis therapy. This case suggests that LDL-A may represent an effective rescue treatment in patients with FSGS and long-term anuria.

Worldwide, the number of patients with diabetes is increasing. Adults with diabetes have a two- to threefold increased risk of heart attack and stroke, and diabetic nephropathy is a leading cause of end-stage renal failure. Salt sensitivity of blood pressure is reported to be elevated in patients with diabetes. Hyperinsulinemia, hyperglycemia, and an activated sympathetic nervous system play key roles in the genesis of salt-sensitive blood pressure in individuals who are obese and/or have type 2 diabetes. In this review, I summarize previous research performed to improve our understanding of the relationship between salt and hypertension in diabetic patients.

Background In patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity. Methods We randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to

Glycated albumin (GA) is considered a more reliable marker than glycated hemoglobin (HbA1c) for monitoring glycemic control, particularly in diabetic hemodialysis patients. We investigated the associations of GA, HbA1c, and random serum glucose levels with survival, and evaluated possible targets for improving survival in diabetic hemodialysis patients. In this prospective, longitudinal, observational study, we enrolled 90 diabetic hemodialysis patients across six dialysis centers in Japan. The median duration of follow-up was 36.0 months (mean follow-up, 29.8 months; range, 3-36 months). There were 11 deaths during the observation period. GA was a significant predictor for mortality (hazard ratio, 1.143 per 1% increase in GA; 95% confidence interval, 1.011-1.292; P = 0.033), whereas HbA1c and random glucose levels were not predictors for mortality. Receiver operating characteristics curve analysis showed that the cutoff value of GA for predicting the risk of mortality was 25%. In the Kaplan-Meier analysis, the cumulative survival rate was significantly greater in patients with GA ≤ 25% than in patients with GA >25%. GA predicted the risk of all-cause and cardiovascular mortality in diabetic hemodialysis patients. Our results suggest that GA ≤ 25% is an appropriate target for improving survival in diabetic hemodialysis patients.

Aims/Introduction In Japan, liraglutide was recently approved for patients with type 2 diabetes. To our knowledge, there are no markers predicting successful switching from insulin therapy to liraglutide monotherapy in Japanese patients with type 2 diabetes and renal impairment. We therefore assessed clinical characteristics predicting successful switching. Materials and Methods We analyzed 21 patients with type 2 diabetes and estimated glomerular filtration rates

OBJECTIVE To improve prognosis, it is important to predict the incidence of renal failure and cardiovascular disease in type 2 diabetic patients before the progression to advanced nephropathy. We investigated the predictive effects of urinary liver-type fatty acid–binding protein (L-FABP), which is associated with renal tubulointerstitial damage, in renal and cardiovascular prognosis. RESEARCH DESIGN AND METHODS Japanese type 2 diabetic patients (n = 618) with serum creatinine ≤1.0 mg/dL and without overt proteinuria were enrolled between 1996 and 2000 and followed up until 2011. Baseline urinary L-FABP was measured with an enzyme-linked immunosorbent assay. The primary end points were renal and cardiovascular composites (hemodialysis, myocardial infarction, angina pectoris, stroke, cerebral hemorrhage, and peripheral vascular disease). The secondary renal outcomes were the incidence of a 50% decline in estimated glomerular filtration rate (eGFR), progression to an eGFR RESULTS During a 12-year median follow-up, 103 primary end points occurred. The incidence rate of the primary end point increased in a stepwise manner with increases in urinary L-FABP. In Cox proportional hazards analysis, the adjusted hazard ratio in patients with the highest tertile of urinary L-FBAP was 1.93 (95% CI 1.13–3.29). This relationship was observed even when analyzed separately in normoalbuminuria and microalbuminuria. Patients with the highest tertile of urinary L-FABP also demonstrated a higher incidence of the secondary renal outcomes. CONCLUSIONS Our results indicate that urinary L-FABP may be a predictive marker for renal and cardiovascular prognosis in type 2 diabetic patients without advanced nephropathy.

A recent genome-wide association study for diabetic nephropathy in European type 1 diabetes identified 3 candidate loci for diabetic nephropathy. In this study, we examined the association of the 3 single nucleotide polymorphism (SNP) loci with susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes. We genotyped 3 SNPs, rs7583877 in AFF3, rs12437854 in the RGMA-MCTP2 locus and rs7588550 in ERBB4, for 2,300 Japanese patients with type 2 diabetes [initial study, 1,055 nephropathy cases with overt proteinuria or with end-stage renal disease (ESRD) and 1,245 control patients with normoalbuminuria]. The association of these SNPs with diabetic nephropathy was examined by using a logistic regression analysis. We observed a significant association of rs7588550 in ERBB4 with diabetic nephropathy in the Japanese patients with type 2 diabetes, although the effect direction was not consistent with that in the European study [p = 0.0126, odds ratio (OR) = 0.79, 95 % confidence interval (CI): 0.65–0.95]. We further examined the association of rs7588550 with diabetic nephropathy in an independent Japanese cohort (596 nephropathy cases and 311 controls) and observed the same trend of the association with the initial study. We did not observe any association of the remaining 2 SNP loci with diabetic nephropathy in the present Japanese sample. The association of SNP loci derived from GWAS in European type 1 diabetes with diabetic nephropathy was not replicated in the Japanese patients with type 2 diabetes, although the ERBB4 locus may have some effect also in Japanese type 2 diabetes.

Autophagy meaning 'self-eating' in Greek, is a large-scale mechanism of intracellular degradation that seeks to maintain homeostasis in cells of all eukaryotes, from yeast to humans. Over the past several decades, autophagy research has actively proceeded both at home and abroad. As a result, studies have reported the physiological role of autophagy in different organs of mammals and of the role that impairment of its activation plays in the development of age-related diseases, abnormal glucose-lipid metabolism, and neurodegenerative disorders. Currently, new therapies targeting the regulation of activation of autophagy are anticipated, and research is continuing. In recent years, the role of autophagy in the kidneys has gradually been elucidated, and reports are indicating an association between autophagy and the development of various kidney diseases. This paper reviews the molecular mechanisms regulating autophagy and discusses new findings from autophagy research on the kidney and issues that have yet to be resolved.

Aim: Diabetic nephropathy is a serious complication in patients with type 2 diabetes. The aim of this study was to explore the factors associated with the progression of this complication in elderly patients with type 2 diabetes. Methods: This retrospective study of a subgroup of patients registered with the Japanese Elderly Diabetes Intervention Trial included 621 Japanese patients with type 2 diabetes mellitus (age ≥65 years, 346 with normoalbuminuria, 190 with microalbuminuria and 85 with overt proteinuria). Multivariate Cox proportional hazard regression model with a backward stepwise procedure was applied to select factors with significant effects on worsening of nephropathy stage and the doubling of serum creatinine. Results: During the follow up (median 52 months), 21% of patients progressed from normoalbuminuria and microalbuminuria to a worse nephropathy stage. Aging, female sex and high-density lipoprotein cholesterol were identified as independent and significant factors that worsen nephropathy stage. Also, 6.1% of patients showed doubling of serum creatinine during follow up. A positive history of cardiovascular disease, hyperuricemia and conventional therapy were identified as significant factors involved in the doubling of serum creatinine. The cumulative incidence of the doubling of serum creatinine was significantly lower in the intensive therapy group than the conventional therapy group (P = 0.016), although that of progression of nephropathy stage was similar in the two groups. Conclusions: We identified several factors associated with the progression of diabetic nephropathy in elderly patients with type 2 diabetes. The results suggest that multiple risk factor intervention seems important in preventing deterioration of renal dysfunction. Geriatr Gerontol Int 2012; 12 (Suppl. 1): 127–133.

There is little evidence regarding the target blood pressure level in patients with type 2 diabetes mellitus without overt proteinuria.We followed 608 Japanese patients with type 2 diabetes without apparent cardiovascular disease and overt proteinuria who underwent cerebral magnetic resonance imaging for a mean of 7.5 years. The patients were categorized according to their mean systolic blood pressure during the follow-up period (strict:130 mm Hg, moderate: ≥130 and140 mm Hg, poor: ≥ 140 mm Hg). The risks for the primary composite outcome of death or end-stage renal disease were not different among the three groups. The renal risk of the doubling of serum creatinine for the poor group was significantly higher than those in other groups. In addition, among the patients without silent cerebral infarction (SCI), the renal risk was significantly lower in the strict group than in the moderate group. Further, in both the SCI and non-SCI groups, strict blood pressure control slowed the progression of albuminuria.In nonproteinuric diabetic patients without SCI, strict blood pressure control was associated with improved renal outcomes. There may be different effects of intensive blood pressure control on the renoprotection of diabetic patients according to their complications.

Aims/Introduction: Activation of the renin-angiotensin system (RAS) in the kidney plays an important role in renal function. The aim of this study was to investigate whether plasma and urinary angiotensinogen levels were associated with renal and cardiovascular prognosis in type 2 diabetic patients. Materials and Methods: We measured plasma and urinary angiotensinogen levels in the observational follow-up cohort of 234 Japanese type 2 diabetic patients (144 with normoalbuminuria, 90 with albuminuria) enrolled between 1998 and 1999 and followed them up until the end of 2008. The associations of these markers with the annual decline in the estimated glomerular filtration rate (eGFR) and incidence of renal and cardiovascular composite endpoints (chronic hemodialysis, myocardial infarction, angina pectoris, stroke and cerebral hemorrhage) were evaluated. Results: At baseline, urinary angiotensinogen levels correlated with urinary albumin-creatinine ratio, urinary β2-microglobulin and inversely with eGFR. In contrast, plasma angiotensinogen levels correlated neither with these renal factors nor with urinary angiotensinogen levels. In the follow-up study (median duration: 9 years), urinary angiotensinogen, but not plasma angiotensinogen, correlated inversely with the annual change in eGFR (r = −0.51, P

Anti-diabetic agent-related hypoglycemia is a serious complication in type 2 diabetic patients on hemodialysis. Therefore, we assessed the efficacy and tolerability of 24 weeks of monotherapy with vildagliptin, a dipeptidyl peptidase four inhibitor, which is a new class of antidiabetic agent. This open-label, single-arm clinical trial was performed on 26 patients on hemodialysis. The primary assessments were changes in postprandial glucose level and glycated albumin (GA). During the study, three patients dropped out, and data from 23 patients were analyzed. Significant reductions were seen in postprandial glucose (−2.60 ± 3.80 mmol/L, P

Aims/Introduction: Although increases in urinary protein excretion generally precede a decline in the glomerular filtration rate, non-proteinuric renal impairment is common in patients with diabetes. In the present study, we examined the relationship between indices of arterial stiffness and renal function in type 2 diabetic patients without proteinuria. Methods: Blood sampling, 24-h urine collection, brachial–ankle pulse wave velocity, and 24-h ambulatory blood pressure monitoring were performed in type 2 diabetic patients without overt proteinuria. The ambulatory arterial stiffness index was calculated as (1 – the regression slope of diastolic/systolic ambulatory blood pressure). Estimated glomerular filtration rate (eGFR)was calculated using the simplified prediction equation proposed by the Japanese Society of Nephrology. Results: Of 213 non-proteinuric patients with type 2 diabetes, 60 (28.2%) had a reduced eGFR (

Background Sirtuin is a member of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, and has been reported to play a pivotal role in energy expenditure, mitochondrial function and pathogenesis of metabolic diseases, including aging kidneys. In this study, we focused on the genes encoding sirtuin families, and examined the association between single nucleotide polymorphisms (SNPs) within genes encoding sirtuin families and diabetic nephropathy. Methods We examined 52 SNPs within the SIRT genes (11 in SIRT1, 7 in SIRT2, 14 in SIRT3, 7 in SIRT4, 9 in SIRT5, and 4 in SIRT6) in 3 independent Japanese populations with type 2 diabetes (study 1: 747 cases (overt proteinuria), 557 controls; study 2: 455 cases (overt proteinuria) and 965 controls; study 3: 300 cases (end-stage renal disease) and 218 controls). The associations between these SNPs were analyzed by the Cochran–Armitage trend test, and results of the 3 studies were combined with a meta-analysis. We further examined an independent cohort (195 proteinuria cases and 264 controls) for validation of the original association. Results We identified 4 SNPs in SIRT1 that were nominally associated with diabetic nephropathy (P

The importance of sleep disturbance and depression in patients with type 2 diabetes is unclear. Our objective was to evaluate their effects on the quality of life (QOL) of patients with type 2 diabetes. For the study, 270 patients were recruited from the Shiga Prospective Observational Follow-up Study for Diabetic Complications. Depressive symptoms, sleep disturbance, and QOL were assessed by use of the Zung Self-Rating Depression Scale (SDS), the Pittsburgh Sleep Quality Index (PSQI), and SF-8, respectively, after evaluation of their metabolic control and complications. Furthermore, 141 patients were recruited to repeat the same study after 6–12 (mean 7.3) months. Significant correlations were found among sleep disturbance, depression, and QOL in patients with type 2 diabetes. Patients undergoing insulin therapy had significantly higher SDS scores, meaning more depressive symptoms, than those not undergoing insulin therapy. Patients with painful neuropathy had higher PSQI and SDS scores and lower physical component of the QOL score than patients without painful neuropathy. In the follow-up observation it was found that the presence of neuropathy and elevated HbA1c level were predictors of increasing PSQI score and SDS score, respectively. It was found that the presence of painful neuropathy was a risk factor for sleep disturbance for type 2 diabetic patients. Sleep disturbance and depressive symptoms correlated significantly with the QOL scores of patients with type 2 diabetes, suggesting the importance of these indices for better management of diabetic patients.

OBJECTIVE Cross-sectional studies have reported increased levels of urinary type IV collagen in diabetic patients with progression of diabetic nephropathy. The aim of this study was to determine the role of urinary type IV collagen in predicting development and progression of early diabetic nephropathy and deterioration of renal function in a longitudinal study. RESEARCH DESIGN AND METHODS Japanese patients with type 2 diabetes (n = 254, 185 with normoalbuminuria and 69 with microalbuminuria) were enrolled in an observational follow-up study. The associations of urinary type IV collagen with progression of nephropathy and annual decline in estimated glomerular filtration rate (eGFR) were evaluated. RESULTS At baseline, urinary type IV collagen levels were higher in patients with microalbuminuria than in those with normoalbuminuria and correlated with urinary β2-microglobulin (β = 0.57, P < 0.001), diastolic blood pressure (β = 0.15, P < 0.01), eGFR (β = 0.15, P < 0.01), and urinary albumin excretion rate (β = 0.13, P = 0.01) as determined by multivariate regression analysis. In the follow-up study (median duration 8 years), urinary type IV collagen level at baseline was not associated with progression to a higher stage of diabetic nephropathy. However, the level of urinary type IV collagen inversely correlated with the annual decline in eGFR (γ = −0.34, P < 0.001). Multivariate regression analysis identified urinary type IV collagen, eGFR at baseline, and hypertension as factors associated with the annual decline in eGFR. CONCLUSIONS Our results indicate that high urinary excretion of type IV collagen is associated with deterioration of renal function in type 2 diabetic patients without overt proteinuria.

Aims/Introduction: Platelet-derived microparticles (PDMP) are released from the platelets either after activation or in response to physical stimulation in vivo. The present study examined the association between blood pressure and PDMP, and the effects of high-dose angiotensin receptor blockers (ARB) on PDMP in patients with type 2 diabetes. Materials and Methods: The study subjects consisted of 28 type 2 diabetes patients with blood pressure ≥130/80 mmHg who were treated with valsartan (80 mg daily). The patients were randomly assigned to take either 80 mg of telmisartan (Tel group) or 160 mg of valsartan (Val group) and then were followed up for 24 weeks. Thereafter, the patients were switched to combination therapy (5 mg of amlodipine with 40 mg of telmisartan [Tel group] or 80 mg of valsartan [Val group]) for 12 weeks. Results: Although the ambulatory blood pressure did not change, the PDMP levels were significantly decreased from baseline to week 24 (high dose ARB). In contrast, combination therapy reduced both blood pressure and PDMP levels compared with the baseline. Although the PDMP level was significantly correlated with the morning BP elevation at baseline and week 36 (combination therapy), this same relationship was not found at week 24. There were no significant differences in the blood pressure and PDMP levels between the two groups. Conclusions: Patients with morning hypertension might be at risk for cardiovascular diseases. High-dose renin-angiotensin system inhibition and blood pressure control are both considered to reduce cardiovascular events in patients with type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00048.x, 2010)

OBJECTIVE Genetic factors are believed to contribute to the development and progression of diabetic nephropathy. Recently, a genome-wide association study for diabetic nephropathy revealed four novel candidate loci in European American subjects with type 1 diabetes. In this study, we determined the association of the four loci with diabetic nephropathy in Japanese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS We genotyped 11 singlenucleotide polymorphisms (SNPs) in four distinct loci (rs39059 and rs39075 in the CPVL/CHN2, rs1888747 and rs10868025 in FRMD3, rs739401 and rs451041 in CARS, and rs1041466, rs1411766, rs6492208, rs7989848, and rs9521445 in a chromosome 13q locus) in four independent Japanese populations. RESULTS Six SNPs were nominally associated with diabetic nephropathy in one of the four Japanese populations (P < 0.05; rs451041 in study 1; rs39059 and rs1888747 in study 3; rs1411766 in studies 1 and 4; and rs7989848 and rs9521445 in study 4); however, no significant association was observed for any SNP after correction for multiple testing errors in the individual populations. Nevertheless, a meta-analysis performed for the data obtained from all four populations revealed that one SNP (rs1411766) in chromosome 13q was significantly associated with diabetic nephropathy in the Japanese populations (nominal P = 0.004, corrected P = 0.04, odds ratio 1.26 [95% CI = 1.07–1.47]). CONCLUSIONS Our results suggest that the rs1411766 locus may be commonly involved in conferring susceptibility to diabetic nephropathy among subjects with type 1 or type 2 diabetes across different ethnic groups.

OBJECTIVE Albuminuria in type 2 diabetic patients is a risk factor for cardiovascular disease. We investigated the correlation between albuminuria and spontaneous microaggregation of platelets (SMAP) formed under shear stress. RESEARCH DESIGN AND METHODS The study subjects were 401 type 2 diabetic individuals (252 with normoalbuminuria and 149 with albuminuria) who were examined for SMAP under conditions of shear stress only (no agonist stimulation) and the reversibility of platelet microaggregation after stimulation with 1 μmol/l ADP, measured by a laser light-cattering method. Active glycoprotein IIb/IIIa (GPIIb/IIIa) and P-selectin expression levels on platelets as an index of platelet activation were measured by whole-blood flow cytometry. RESULTS SMAP formation was noted in 53% of diabetic patients. All patients with SMAP showed an irreversible pattern of platelet microaggregates by a low dose of ADP. SMAP was observed in 75% of diabetic subjects with albuminuria and in 39% of those with normoalbuminuria. Multivariate logistic regression analysis identified urinary albumin excretion rate and brachial-ankle pulse-wave velocity as independent factors associated with SMAP. The degree of SMAP correlated with active GPIIb/IIIa (γ = 0.59, P < 0.001) and P-selectin (γ = 0.55, P < 0.001) expression levels. These early-activated platelet profiles were significantly inhibited in albuminuric patients with aspirin intake, although the effect was incomplete. CONCLUSIONS Our study demonstrated an independent association between albuminuria and early changes in activated platelet profiles of type 2 diabetic patients. Further follow-up and intervention studies are needed to establish whether the inhibition of SMAP affects the course of cardiovascular disease in type 2 diabetic patients.

In hemodialysis (HD) patients the glycated hemoglobin (Hb(A1c)) level may underestimate glycemic control. The aim of this study is to estimate accurate glycemic control in type 2 diabetic patients on HD. Type 2 diabetes patients (N = 87) who had been receiving maintenance HD for at least one year were enrolled. Hb(A1c) and the percentage of glycated albumin relative to total the serum albumin (%GA) were measured in blood samples and the factors that affected the %GA/Hb(A1c) ratio were examined. There were significant and positive correlations between the plasma glucose and either the Hb(A1c) levels (r = 0.539, P or = 30%, although a significant correlation was found between those parameters in the Ht or = 30%, with Ht or = 100 IU/kg/week were 3.41, 3.56 and 4.13, respectively. In HD patients, accurate glycemic control may be estimated as: Hb(A1c) x 1.14 if Ht > or = 30%; Hb(A1c) x 1.19 if Ht < 30% and treated with low dosages of EPO; and Hb(A1c) x 1.38 if Ht < 30% and treated with high dosages of EPO.

The improvement of salt-sensitive hypertension is a therapeutic target for various vascular diseases. Glucagon-like peptide 1 (GLP-1), an incretin peptide, has been reported to have natriuretic effect as well as blood glucose lowering effect, although its exact mechanism and clinical usefulness remain unclear. Here, we examined anti-hypertensive effect of exendin-4, a GLP-1 analog, in salt-sensitive obese db/db mice and angiotensin II (angII)-infused C57BLK6/J mice. The treatment of exendin-4 for 12 weeks inhibited the development of hypertension in db/db mice. In db/db mice, the urinary sodium excretion was delayed and blood pressure was elevated in response to a high-salt load, whereas these were attenuated by exendin-4. In db/db mice, intra-renal angII concentration was increased. Furthermore, exendin-4 prevented angII-induced hypertension in non-diabetic mice and inhibited angII-induced phosphorylation of ERK1/2 in cultured renal cells. Considered together, our results indicate that exendin-4 has anti-hypertensive effects through the attenuation of angII-induced high-salt sensitivity.

Strategies to prevent contrast-induced nephropathy (CIN) are suboptimal. Erythropoietin was recently found to be cytoprotective in a variety of nonhematopoietic cells, so it was hypothesized that the nonhematopoietic erythropoietin derivative asialoerythropoietin would prevent CIN. Nephropathy was induced in rats by injection of the radiocontrast medium Ioversol in addition to inhibition of prostaglandin and nitric oxide synthesis. Administration of a single dose of asialoerythropoietin before the induction of nephropathy significantly attenuated the resulting renal dysfunction and histologic renal tubular injury. Contrast-induced apoptosis of renal tubular cells was inhibited by asialoerythropoietin both in vivo and in vitro, and this effect was blocked by a Janus kinase 2 (JAK2) inhibitor in vitro. Furthermore, phospho-JAK2/signal transducer and activator of transcription 5 (STAT5) and heat-shock protein 70 increased after injection of asialoerythropoietin, suggesting that the effects of asialoerythropoietin may be mediated by the activation of the JAK2/STAT5 pathway. Overall, these findings suggest that asialoerythropoietin may have potential as a new therapeutic approach to prevent CIN given its ability to preserve renal function and directly protect renal tissue.

Diabetic nephropathy is a leading cause of end-stage renal disease, which is increasing in incidence worldwide, despite intensive treatment approaches such as glycemic and blood pressure control in patients with diabetes mellitus. New therapeutic strategies are needed to prevent the onset of diabetic nephropathy. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostases. These agents might prevent the progression of diabetic nephropathy, since PPAR agonists improve dyslipidemia and insulin resistance. Furthermore, data from murine models suggest that PPAR agonists also have independent renoprotective effects by suppressing inflammation, oxidative stress, lipotoxicity, and activation of the renin-angiotensin system. This review summarizes data from clinical and experimental studies regarding the relationship between PPARs and diabetic nephropathy. The therapeutic potential of PPAR agonists in the treatment of diabetic nephropathy is also discussed.

The early identification of type 2 diabetic patients at risk of developing microalbuminuria-an independent risk factor for renal and cardiovascular diseases-is important to improve the patients' outcomes. We investigated whether serum levels of IL-18, a proinflammatory cytokine, were a predictor of early renal dysfunction.A total of 249 Japanese type 2 diabetic patients without overt proteinuria were enrolled in an observational follow-up study (median follow-up 7 years), and their stage of diabetic nephropathy was classified and their estimated glomerular filtration rate (eGFR) was calculated annually.At baseline, serum levels of IL-18 were higher in subjects with microalbuminuria (n = 76) than in those with normoalbuminuria (n = 173). Elevated serum levels of IL-18 were associated with the progression of nephropathy to a higher stage in normoalbuminuric subjects (118 [interquartile range 91-159] ng/l vs 155 [interquartile range 121-205] ng/l, p = 0.003), but not in microalbuminuric subjects (154 [interquartile range 113-200] ng/l vs 160 [interquartile range 101-190] ng/l, p = 0.50). The adjusted risk for developing microalbuminuria was 3.6 (95% CI 1.2-10.4) in normoalbuminuric subjects with serum IL-18 levels above the median (/=134.6 ng/l), and was significantly enhanced in those urinary AERs at the upper end of the normal range (7.5 mug/min/= AER20 microg/min). Furthermore, the annual rate of decline in eGFR, when examined in the study population as a whole, was significantly greater in subjects with serum IL-18 levels above the median than in other subjects.The results of our observational follow-up study indicate that elevated serum levels of IL-18 may be a predictor of future renal dysfunction in type 2 diabetic patients with normoalbuminuria.

Endothelial dysfunction is an early marker of atherosclerosis. Pioglitazone is commonly used in the treatment of type 2 diabetes and has vascular protective effects beyond its hypoglycemic ones. We investigated the vascular effects of short-term, low-dosage pioglitazone in patients with type 2 diabetes. The study included 15 subjects with type 2 diabetes with normoalbuminuria (age, 60.7 +/- 11.9 years; body mass index [BMI], 23.9 +/- 3.3 kg/m2). The patients received pioglitazone at 15 mg daily for 4 weeks. BMI, systolic and diastolic blood pressure, laboratory parameters (fasting plasma glucose, insulin, lipid profile, high-sensitive C-reactive protein [hsCRP], and adiponectin) were assessed at baseline and after treatment. The forearm blood flow (FBF) was measured during reactive hyperemia by strain-gauge plethysmography. Short-term, low-dosage pioglitazone did not improve glycemic control or insulin sensitivity. However, the peak FBF and flow debt repayment (FDR) were markedly improved. There was no correlation of the improvement of peak FBF and FDR with the observed changes of metabolic parameters. However, the increment of adiponectin and decrement of hsCRP were well correlated with the improvement of peak FBF. These results indicate that short-term low-dosage pioglitazone may improve vascular function via increasing adiponectin expression and decreasing low-grade inflammation in type 2 diabetic patients.

Recent studies have shown that metabolic syndrome is associated with an increased risk for chronic kidney disease. We recently found that the prevalence of sodium-sensitive hypertension in patients with metabolic syndrome was significantly higher than that in patients with essential hypertension but without metabolic syndrome. We therefore assessed the effects of benidipine, a long-acting calcium channel blocker, on the sodium sensitivity of blood pressure and renal hemodymamics in 5 patients with metabolic syndrome. Glomerular hemodynamics were assessed using pressure-natriuresis curves, which were constructed by plotting the urinary excretion of sodium as a function of the mean arterial pressure, which was calculated as the mean of 48 values based on 24-h monitoring, during the intake of low (3 g NaCl daily) and relatively high (10 g NaCl daily) sodium diets. Under the relatively high sodium diet condition, benidipine significantly lowered systolic and diastolic blood pressure. The pressure-natriuresis curve was steeper after the administration of benidipine. Benidipine lowered glomerular capillary hydraulic pressure (P(GC)) levels (from 54.4+/-7.5 to 47.0+/-7.0 mmHg, p=0.0152) and reduced both the resistance of the afferent arterioles (from 10,338+/-2,618 to 9,026+/-2,627 dyn.s/cm5, p=0.047) and the resistance of the efferent arterioles (from 4,649+/-2,039 to 2,419+/-2,081 dyn.s/cm(5), p=0.003). The urinary albumin excretion rate also decreased after the administration of benidipine. These findings indicated that benidipine may be effective for reducing the risk of developing chronic kidney disease in patients with metabolic syndrome.

The aim of the present study was to determine the influence of severe renal dysfunction (estimated glomerular filtration rate 2, including hemodialysis) on the pharmacokinetics and therapeutic effects of febuxostat using a population pharmacokinetic analysis. This study recruited patients with hyperuricemia who were initially treated with allopurinol, but were switched to febuxostat, and it consists of 2 sub-studies: a pharmacokinetic study (26 patients) and retrospective efficacy evaluation study (51 patients). The demographic and clinical data of patients were collected from electronic medical records. Plasma febuxostat concentrations were obtained at each hospital visit. Population pharmacokinetic modeling was performed with NONMEM version 7.2. A total of 128 plasma febuxostat concentrations from 26 patients were used in the population pharmacokinetic analysis. The data were best described by a 1-compartment model with first order absorption. Covariate analysis revealed that renal function did not influence the pharmacokinetics of febuxostat, whereas actual body weight significantly influenced apparent clearance and apparent volume of distribution. The retrospective efficacy analysis showed the favorable therapeutic response of febuxostat switched from allopurinol in patients with moderate to severe renal impairment. No serious adverse event associated with febuxostat was observed irrespective of renal function. The population pharmacokinetic analysis and therapeutic analysis of febuxostat revealed that severe renal dysfunction had no influence on the pharmacokinetic parameters of febuxostat. These results suggest that febuxostat is tolerated well by patients with severe renal impairment.

We investigated the association of urinary potassium and sodium excretion with the incidence of renal failure and cardiovascular disease in patients with type 2 diabetes.A total of 623 Japanese type 2 diabetic patients with eGFR≥60 ml/min per 1.73 m(2) were enrolled in this observational follow-up study between 1996 and 2003 and followed-up until 2013. At baseline, a 24-hour urine sample was collected to estimate urinary potassium and sodium excretion. The primary end point was renal and cardiovascular events (RRT, myocardial infarction, angina pectoris, stroke, and peripheral vascular disease). The secondary renal end points were the incidence of a 50% decline in eGFR, progression to CKD stage 4 (eGFR30 ml/min per 1.73 m(2)), and the annual decline rate in eGFR.During the 11-year median follow-up period, 134 primary end points occurred. Higher urinary potassium excretion was associated with lower risk of the primary end point, whereas urinary sodium excretion was not. The adjusted hazard ratios for the primary end point in Cox proportional hazards analysis were 0.56 (95% confidence interval [95% CI], 0.33 to 0.95) in the third quartile of urinary potassium excretion (2.33-2.90 g/d) and 0.33 (95% CI, 0.18 to 0.62) in the fourth quartile (2.90 g/d) compared with the lowest quartile (1.72 g/d). Similar associations were observed for the secondary renal end points. The annual decline rate in eGFR in the fourth quartile of urinary potassium excretion (-1.3 ml/min per 1.73 m(2)/y; 95% CI, -1.5 to -1.0) was significantly slower than those in the first quartile (-2.2; 95% CI, -2.4 to -1.8).Higher urinary potassium excretion was associated with the slower decline of renal function and the lower incidence of cardiovascular complications in type 2 diabetic patients with normal renal function. Interventional trials are necessary to determine whether increasing dietary potassium is beneficial.

Objective To assess whether an association between sodium-sensitive hypertension and metabolic syndrome exists; and whether, in patients with metabolic syndrome, the nocturnal fall of blood pressure decreases and salt restriction affects the circadian blood pressure rhythm. Methods Japanese patients with essential hypertension, who were treated without any antihypertensive agent, were maintained on a high-sodium diet and a low-sodium diet for 1 week each. On the last day of each diet, the 24-h blood pressures were measured. A diagnosis of metabolic syndrome was made according to the International Diabetes Foundation definition Results Among the 56 patients with essential hypertension, 15 patients were complicated with metabolic syndrome while 41 patients were not. The nocturnal blood pressure fall was significant in patients without metabolic syndrome, while it was not so in patients with metabolic syndrome. Only in patients with metabolic syndrome was the nocturnal blood pressure fall enhanced by sodium restriction. The prevalence of sodium-sensitive hypertension in patients with metabolic syndrome was significantly higher than in those without metabolic syndrome (70.6 versus 36.0%, respectively; P = 0.017). A multiple logistic regression analysis revealed central obesity to be an independent risk factor for sodium-sensitive hypertension (odds ratio, 1.41; 95% confidence interval, 1.04-1.91). Conclusions In patients with essential hypertension, an inter-relationship exists among metabolic syndrome, enhanced sodium sensitivity of the blood pressure and non-dipping. The elevated risk of cardiovascular diseases in patients with metabolic syndrome may be related to sodium-sensitive hypertension and non-dipping.

症例1は保存期腎不全で通院中の68歳の男性. 2005年2月, 左膝の疼痛, 腫脹のため, スリンダクの内服を開始した. スリンダク開始10日後より, 食欲低下, 全身倦怠感が出現. 全身倦怠感が強く, 腹痛, 嘔吐を伴ったため当科紹介. 腎不全の進行, アシドーシス, 高カリウム血症を認め, 直ちに血液透析を施行した. 血液透析中より腹痛が増強, 透析後の腹部CTにてfree airを認めたため, 緊急開腹手術を行い, 回腸末端より120cm口側に穿孔を伴った小腸潰瘍を認めた.症例2は72歳の男性. 2004年10月, 急性心筋梗塞を契機に血液透析に導入され, 近医で維持血液透析を行っていた. 2005年1月末より両下肢の安静時疼痛のため, ロキソプロフェンを内服していた. ロキソプロフェン開始5日後, 突然腹痛が出現し持続し, 近医でイレウスと診断され, 当院に緊急受診した. 腹部全体の圧痛, 筋性防御, Blumberg徴候, 炎症反応の上昇より, 消化管穿孔を疑い腹部CT施行. 肝前面に少量のfree airを認めた. 保存的治療に反応しないため, 翌日開腹術施行. トライツ靱帯より40cm肛門側の空腸に, 径8mmの穿孔を認めた.近年, 非ステロイド性抗炎症薬の使用者に小腸潰瘍が多発することが明らかにされてきた. 腎不全患者は, さまざまな合併症による疼痛を訴えることが多いが, 安易な非ステロイド性抗炎症薬の使用を慎むとともに, 非ステロイド性抗炎症薬の投与中に貧血低アルブミン血症, 腹痛などを生じた場合, 小腸の潰瘍や穿孔も考慮する必要がある.

症例は58歳, 糖尿病による慢性腎不全の女性. 2003年12月, 左被殻出血の脳室穿破にて入院. 開頭術後に維持血液透析となった. 第8病日より経管栄養を行っていたが, 第100病日頃より徐々に貧血が進行. 貧血はエリスロポエチン製剤に反応せず, 顆粒球減少症も伴ったため, 赤血球輸血および顆粒球コロニー刺激因子製剤投与を頻回に必要とした. 鉄, ビタミンB12, 葉酸の欠乏はなく, 自己抗体, 腫瘍マーカー, 血清免疫電気泳動, 胸腹部CT検査にても異常所見は得られなかった. 薬剤の影響も考え, 脳出血後に開始したすべての薬剤を中止したが, 中止1か月後でも貧血・顆粒球減少症は改善しなかった. 第160病日, 骨髄穿刺にて顆粒球系の空泡化変性を認め, 同日の血液検査にて, 銅およびセルロプラスミンの異常低値が判明した. 銅欠乏による貧血・顆粒球減少症と診断. 経静脈的な硫酸銅製剤投与 (1.25mg/日) にて, 速やかに貧血改善と顆粒球増加を認めた. 食事摂取が可能になった後は, 銅投与を中止しても貧血・顆粒球減少症は生じなかった. 経静脈栄養や経管栄養を施行している血液透析患者における貧血や顆粒球減少症の鑑別診断として, 銅欠乏を考慮に入れる必要がある.

We report a case of a 41-year-old Japanese man who presented with rapidly progressive glomerulonephritis, chronic sinusitis, and positive cytoplasmic-antineutrophil cytoplasmic antibody (c-ANCA). Renal biopsy showed crescentic glomerulonephritis, and he was diagnosed as having Wegener's granulomatosis. During the clinical course, he suffered from pulmonary bleeding, and combination therapy of steroid, immunosuppressant, and double filtration plasmapheresis (DFPP) was started. He rapidly entered remission after assistance through DFPP, suggesting the potential efficacy of DFPP for Wegener's granulomatosis, especially with pulmonary bleeding.

Bucillamine, a disease-modifying antirheumatic drug widely prescribed in Japan, is reported to be a cause of proteinuria. However, to date, the clinical course of the nephropathy associated with the use of bucillamine has not been described in detail.We analyzed renal biopsy findings from 10 patients with rheumatoid arthritis and concomitant bucillamine-induced nephropathy. Each patient was followed up until proteinuria had resolved.Proteinuria appeared 2-11 months after the initiation of the treatment with bucillamine. Nine patients, who stopped bucillamine treatment immediately (within 3 months) after the onset of proteinuria, were diagnosed as having stage I membranous nephropathy. Only one patient, who used bucillamine for 9.5 months after the onset of proteinuria, was diagnosed as having stage II membranous nephropathy. In all patients with stage I membranous nephropathy, the proteinuria disappeared within 7 months after they stopped bucillamine treatment. On the other hand, in the patient with stage II membranous nephropathy, the proteinuria persisted for 14 months after the use of bucillamine was stopped. In all the patients, the proteinuria resolved completely without deterioration of renal function. None of the patients has experienced recurrence of proteinuria.In patients with proteinuria induced by treatment with bucillamine, membranous nephropathy is the most common disorder. Immediate withdrawal of bucillamine results in prompt and complete resolution of proteinuria without deterioration of renal function.Bucillamine, a disease-modifying antirheumatic drug widely prescribed in Japan, is reported to be a cause of proteinuria. However, to date, the clinical course of the nephropathy associated with the use of bucillamine has not been described in detail.