Comparative effects of sodium-glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors on kidney function decline in Japanese individuals with type 2 diabetes.

BACKGROUND: Limited direct comparative studies exist in terms of the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase-4 inhibitors (DPP4is) on the kidney outcomes in Japanese individuals with type 2 diabetes. METHODS: This retrospective cohort study included 561 Japanese adults with type 2 diabetes, who were newly prescribed either an SGLT2i or a DPP4i and had an eGFR ≥ 30 mL/min/1.73 m2. The cohort comprised 207 women and 354 men, with a mean (± standard deviation) age of 63 (± 12) years. The exposure and outcome were SGLT2i or DPP4i initiation and eGFR slope during the overall follow-up period, restricted to participants who were followed for ≥2 years. We adopted the on-treatment analysis. Analysis of covariance was used to compare the adjusted eGFR slope between the two groups, incorporating 10 variables at baseline. RESULTS: During the median follow-up period of 3.4 years, least square mean (95% CI) eGFR slopes were -1.91 (-2.15, -1.67) and -1.12 (-1.58, -0.67) mL/min/1.73 m2/year in individuals treated with a DPP4i (n = 460) and an SGLT2i (n = 101), respectively, demonstrating statistical significance (p = 0.002). The robustness of this finding was strengthened by sensitivity analyses. CONCLUSIONS: This study provides potential evidence of the superiority of SGLT2is over DPP4is in slowing kidney function decline in Japanese adults with type 2 diabetes and eGFR ≥ 30 mL/min/1.73 m2.

Association between 1-year changes in urinary albumin-to-creatinine ratio and kidney disease progression in Japanese individuals with diabetes: a historical cohort study.

BACKGROUND: The National Kidney Foundation recently proposed a ≥ 30% decrease in urinary albumin-to-creatinine ratio (UACR) over 0.5-2 years as a surrogate endpoint for chronic kidney disease (CKD) progression in individuals with baseline UACR > 30 mg/g. This historical cohort study aimed to determine the applicability of a decrease in UACR, within as little as 1 year, as a surrogate endpoint for Japanese individuals with type 2 diabetes mellitus (T2D). METHODS: A total of 5067 individuals with T2D were divided into three groups based on 1-year change in UACR: ≥ 30% decrease (UACR decreased group), < 30% decrease and < 30% increase (UACR unchanged group), or ≥ 30% increase (UACR increased group). The primary endpoint was a composite of a ≥ 30% decline in estimated glomerular filtration rate (eGFR) or the initiation of kidney replacement therapy, whichever occurred first. RESULTS: At baseline, the proportions of individuals with normoalbuminuria, microalbuminuria, and eGFR ≥ 60 mL/min/1.73 m2 were 68.1%, 22.1%, and 75.5%, respectively. During a median follow-up of 6.8 years, 926 individuals (18.3%) reached the composite endpoint. Adjusted hazard ratios (vs. the UACR unchanged group) for the UACR decreased and increased groups were 0.758 (95% confidence interval [CI], 0.636-0.905; P = 0.002) and 1.304 (95% CI, 1.108-1.536; P = 0.001), respectively. CONCLUSIONS: These findings support the use of 1-year changes in UACR as a surrogate endpoint for the progression of CKD and the implementation of a ≥ 30% decrease in UACR as a positive efficacy endpoint in Japanese individuals with T2D and early-stage kidney disease.

Comparison of the Effect of Bromfenac versus Betamethasone Ophthalmic Solutions in Patients with Diabetic Macular Edema.

PURPOSE: To examine the effect of 0.1% bromfenac (BF) ophthalmic solution and 0.1% betamethasone (BM) ophthalmic solution on diabetic macular edema (DME). METHODS: This was a prospective trial. Nineteen patients (mean age of 66.6 ± 10.1 years) with DME and mean retinal thickness within a diameter of 1 mm from the fovea (central subfield thickness: CST) of 250-500 µm were randomized and instilled with BF or BM. CST, best-corrected visual acuity (BCVA), and intraocular pressure (IOP) were measured at 4, 8, and 12 weeks after administration. RESULTS: CST at baseline (p = .128) and that at 4, 8, and 12 weeks of administration was not significantly different between the BF (10 patients) and BM groups (9 patients). In patients with glycated hemoglobin (HbA1c) <8.0%, CST, compared with baseline, was significantly decreased in the BF group (seven patients) at 8 (p = .025) and 12 weeks (p = .043) of administration. When compared with the baseline, no significant changes in BCVA were observed at any point in time in either group. Baseline IOP was comparable between the groups. In the BM group, the values of change in IOP from baseline significantly increased at 8 (p = .025) and 12 weeks (p = .044) of administration, with no significant changes in IOP over the 12 weeks of administration in the BF group. CONCLUSIONS: BF did not affect IOP even after 12 weeks of administration, suggesting its effect in reducing CST in DME with good glycemic control. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN-CTR); UMIN000026201, February 18, 2017; Japan Registry of Clinical Trials; jRCTs031180308, March 15, 2019.

Analysis of inflammatory cytokines and estimated glomerular filtration rate decline in Japanese patients with diabetic kidney disease: a pilot study.

Background: It is important to identify additional prognostic factors for diabetic kidney disease. Materials & methods: Baseline levels of ten cytokines (APRIL/TNFSF13, BAFF/TNFSF13B, chitinase 3-like 1, LIGHT/TNFSF14, TWEAK/TNFSF12, gp130/sIL-6Rß, sCD163, sIL-6Rα, sTNF-R1, sTNF-R2) were measured in two cohorts of diabetic patients. In one cohort (n = 777), 156 individuals were randomly sampled after stratification and their plasma samples were analyzed; in the other cohort (n = 69), serum samples were analyzed in all the individuals. The levels of cytokines between rapid (estimated glomerular filtration rate decline >5 ml/min/1.73 m2/year) and non-rapid decliners were compared. Results: Multivariate analysis demonstrated significantly high levels of LIGHT/TNFSF14, TWEAK/TNFSF12 and sTNF-R2 in rapid decliners. Conclusion: These three cytokines can be potential biomarkers for the progression of diabetic kidney disease.

Cross-sectional and longitudinal associations between dipstick hematuria and chronic kidney disease in patients with type 2 diabetes.

AIMS: To examine the association of dipstick hematuria with kidney function and albuminuria in patients with type 2 diabetes (T2D). METHODS: A total of 7,945 patients with T2D were studied. In the cross-sectional study, patients were classified into 6 groups based on the stage of albuminuria and estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m2 at baseline. In the longitudinal study where patients were classified by the presence of hematuria, the primary composite endpoint was a 30% decrease in eGFR from baseline or the initiation of kidney replacement therapy. Other outcomes included eGFR slope and stage progression of albuminuria. RESULTS: Cross-sectionally, hematuria was more prevalent in patients with more advanced stages of albuminuria and with lower eGFR, independently of each other. In the longitudinal study, patients with hematuria experienced 50% increased incidence of the primary endpoint (p < 0.001). The eGFR slope was steeper in patients with hematuria than in those without hematuria (p < 0.001). On the other hand, hematuria was unlikely to be associated with the progression of albuminuria. CONCLUSIONS: In patients with T2D, dipstick hematuria was associated with prevalent albuminuria and reduced eGFR, as well as faster decline in kidney function but not higher risk of development or progression of albuminuria.

Effects of dietary protein intake on renal outcome and mortality in patients with advanced diabetic nephropathy.

BACKGROUND: The difficulty of adhering to a low-protein diet is a serious limitation of randomized controlled trials aimed at validating the efficacy of this therapy. In this observational study of patients with diabetic nephropathy, we examined the association of dietary protein intake (DPI) with renal outcome and mortality, taking into account the nutritional status. METHODS: We conducted a single-center historical cohort study of 449 adult Japanese patients with type 2 diabetes and the urinary albumin-to-creatinine ratio of ≥ 300 mg/g or estimated glomerular filtration rate of < 30 mL/min/1.73 m2. DPI was estimated with a formula using nitrogen levels in spot urine and body mass index. Malnutrition was defined as the Geriatric Nutritional Risk Index of ≤ 98. The primary and secondary endpoints were renal replacement therapy (RRT) initiation and mortality before RRT initiation, respectively. The Fine and Gray subdistribution hazard model was used to determine the relative effects of DPI on the respective endpoint. RESULTS: Decreased DPI was associated with lower incidence of RRT with an adjusted hazard ratio of 0.81 (95% confidence interval: 0.72-0.92, p < 0.001). The interaction between DPI and nutritional status with respect to mortality was significant (p interaction = 0.047). Decreased DPI was a risk factor for mortality in patients with malnutrition (p = 0.009) but not in those without malnutrition (p = 0.559). CONCLUSIONS: In patients with type 2 diabetic nephropathy, lower DPI was associated with lower incidence of RRT initiation, suggesting beneficial effects of a low-protein diet on kidneys. Conversely, lower DPI might lead to increased mortality in patients with malnutrition.

Transplantation of adipose-derived mesenchymal stem cell sheets directly into the kidney suppresses the progression of renal injury in a diabetic nephropathy rat model.

AIMS/INTRODUCTION: Adipose-derived mesenchymal stem cell (ASC) transplantation is a promising therapy for diabetic nephropathy (DN). However, intravascular administration of ASCs is associated with low engraftment in target organs. Therefore, we considered applying the cell sheet technology to ASCs. In this study, ASC sheets were directly transplanted into the kidneys of a DN rat model, and therapeutic consequences were analyzed. MATERIALS AND METHODS: Adipose-derived mesenchymal stem cells were isolated from adipose tissues of 7-week-old enhanced green fluorescent protein rats, and ASC sheets were prepared using a temperature-responsive culture dish. A DN rat model was established from 5-week-old Spontaneously Diabetic Torii fatty rats. Seven-week-old DN rats (n = 21) were assigned to one of the following groups: sham-operated (n = 6); ASC suspension (6.0 × 106  cells/mL) administered intravenously (n = 7); six ASC sheets transplanted directly into the kidney (n = 8). The therapeutic effect of the cell sheets was determined based on urinary biomarker expression and histological analyses. RESULTS: The ASC sheets survived under the kidney capsule of the DN rat model for 14 days after transplantation. Furthermore, albuminuria and urinary tumor necrosis factor-α levels were significantly lower in the ASC sheets transplanted directly into the kidney group than in the sham-operated and ASC suspension administered intravenously groups (P < 0.05). Histologically, the ASC sheets transplanted directly into the kidney group presented mild atrophy of the proximal tubule and maintained the renal tubular structure. CONCLUSIONS: Transplantation of ASC sheets directly into the kidney improved transplantation efficiency and suppressed renal injury progression. Therefore, the ASC sheet technology might be a promising novel treatment for DN.

Temporal trends in the prevalence of albuminuria and reduced eGFR in Japanese patients with type 2 diabetes.

Changes over time have been shown in renal manifestations in individuals with diabetes in the United States; however, whether the trends are shared across ethnicities is unknown. We conducted this single-center serial cross-sectional study to determine temporal changes in albuminuria and reduced kidney function in Japanese patients with type 2 diabetes. This study included adult Japanese patients with type 2 diabetes who first visited our institute between 2004 and 2013. Temporal changes during the 10 years in the frequency of albuminuria ( ≥ 30 mg/g creatinine) and reduced eGFR ( < 60 mL/min/1.73 m2) were analyzed using the univariate and multivariate logistic regression analyses and Granger causality test. 5331 Japanese patients with type 2 diabetes, 1892 women and 3439 men, with the mean age of 56 ± 13 years, were studied. There was no change in the prevalence of albuminuria in the univariate analysis; however, a significantly decreasing trend was observed after adjustment for several covariates. On the other hand, patients with reduced eGFR significantly increased over time, although the statistical significance disappeared after adjustment for the covariates, including levels of serum uric acid and hemoglobin and use of renin-angiotensin inhibitors. The Granger causality test showed that time series for use of RAS inhibitors and BMI had a causative role in time series for reduced eGFR. In conclusion, prevalence of albuminuria decreased and that of reduced eGFR remained stable after adjustment for clinical characteristics in Japanese patients with type 2 diabetes during the last decade.

Unique Inflammatory Changes in Exocrine and Endocrine Pancreas in Enterovirus-Induced Fulminant Type 1 Diabetes.

CONTEXT: There are scant reports on the pathological changes of the exocrine and endocrine pancreas in fulminant type 1 diabetes mellitus (FT1DM). OBJECTIVE: To clarify the distinct pathological changes in the exocrine as well as the endocrine pancreas shortly after onset of diabetes in FT1DM. DESIGN: The exocrine and endocrine pancreases of 3 patients with FT1DM and 17 nondiabetic controls were immunohistochemically examined for islet and exocrine tissue inflammation, infiltrating mononuclear cell (MNC) CD subtype, enterovirus capsid protein 1 (VP1) localization, and CXC chemokine ligand 10 (CXCL10) and CXC chemokine receptor 3 (CXCR3) expressions. RESULTS: The median frequency of insulitis in the 3 FT1DM pancreases was 60%. In the nondiabetic control pancreases, no insulitis was observed. In the islets of FT1DM, the numbers of CD45+, CD3+, CD8+, CD68+, and CD11c+ MNCs were significantly higher than those of the control group. In the exocrine pancreas of FT1DM, the numbers of CD3+ T cells, CD8+ T cells, CD68+ macrophages, and CD11c+ dendritic cells were significantly higher than those of the control group. Infiltrating CD8+ T cells, CD68+ macrophages, and CD11c+ dendritic cells were observed around exocrine acinar cells in FT1DM. There was a close association between VP1 and CXCL10 expression in pancreatic exocrine ductal cells and acinar cells as well as islet cells in FT1DM. CXCL10+ exocrine cells were surrounded by CXCR3+ T cells. CONCLUSION: The pathological findings suggested that suppression of the activated CXCL10-CXCR3 axis in the exocrine as well as the endocrine pancreas is a novel therapeutic target in FT1DM and possibly in enterovirus-associated acute-onset type 1 diabetes.

Effects of statins on the kidneys in patients with type 2 diabetes.

BACKGROUND: Effects of statins on kidneys in diabetic patients remain unclear. METHODS: This was an observational, historical cohort study of type 2 diabetic patients with estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. We studied 412 patients newly prescribed statins, and 946 controls without a prescription history of statins (including the follow-up period). Outcomes were annual change in eGFR, ≥30 % decrease in eGFR from baseline, and progression of albuminuria, analyzed using a propensity score matching. RESULTS: A total of 168 pairs were matched for propensity score. Annual eGFR change (mL/min/1.73 m2/year) in the statin group was greater than in controls (-2.24 vs. -1.56, p = 0.024). The hazard ratio of the statin group (vs. controls) for ≥30 % decrease in eGFR and progression of albuminuria was 1.74 (p = 0.082) and 0.85 (p = 0.624), respectively. When the statin group was classified by differences in statin solubility, eGFR change and hazard ratio for ≥30 % decrease in eGFR in the lipophilic statin group were greater than in controls (-2.64 vs. -1.71, p = 0.031 and 2.15, p = 0.049); however, the outcomes in the hydrophilic statin group were not different (-2.35 vs. -1.71, p = 0.106 and 1.08, p = 0.827). The hazard ratio of lipophilic and hydrophilic statin group (vs. controls) for progression of albuminuria was 1.31 (p = 0.552) and 0.69 (p = 0.367). In the analyses using the unmatched cohort, similar results were obtained. CONCLUSIONS: Statins have no beneficial effects on kidneys in diabetic patients. In fact, lipophilic statins might have potential harmful effects on kidney function.

The relationship between depressive symptoms and diabetic complications in elderly patients with diabetes: Analysis using the Diabetes Study from the Center of Tokyo Women's Medical University (DIACET).

AIMS: To investigate the association between likelihood or severity of depression and symptoms associated with diabetic complications in elderly Japanese patients with diabetes. METHODS: This single-center cross-sectional study included 4283 patients with diabetes, 65 years and older (mean age was 73 ± 6 years, 38.7% were women, 3.9% had type 1 diabetes). Participants completed a self-administered questionnaire including items on subjective symptoms associated with diabetic microangiopathy, frequency of clinical visits due to vascular diseases (heart diseases, stroke, or gangrene), hospitalization, and the Patient Health Questionnaire-9 (PHQ-9), a simple but reliable measure of depression. The associations between severity of depression and diabetic complications were examined using logistic regression analysis. RESULTS: According to the PHQ-9 scores, patients were classified into the following 3 categories: 0-4 points (n=2975); 5-9 points (n=842); and 10 or more points (n=466). Higher PHQ-9 scores were associated with increased odds ratios for retinopathy, symptoms related to peripheral polyneuropathy and autonomic neuropathy, and end-stage renal disease requiring dialysis after adjustment for age, gender, smoking status, and HbA1c (all p<0.05). CONCLUSIONS: Significant relationships were found between depression severity and chronic diabetic complications among elderly Japanese patients with diabetes.

A prospective observational study of early intervention with erythropoietin therapy and renal survival in non-dialysis chronic kidney disease patients with anemia: JET-STREAM Study.

BACKGROUND: There is limited data showing that early treatment for anemia could prolong renal survival in non-dialysis chronic kidney disease (CKD) patients. We therefore investigated the relationship between hemoglobin (Hb) levels at initiation of epoetin beta therapy and renal outcome in non-dialysis CKD patients with anemia. METHODS: In this prospective, multi-center, observational study, non-dialysis CKD patients with anemia who were naïve to erythropoiesis-stimulating agents (ESAs) were divided into three groups based on their Hb levels at initiation of epoetin beta therapy (Group I: 10 ≤ Hb < 11 g/dL, Group II: 9 ≤ Hb < 10 g/dL, and Group III: Hb < 9 g/dL). The primary endpoint was time to first occurrence of any renal event. For the primary analysis, an inverse probability weighted Cox regression model was used to adjust time-dependent selection bias in the artificially censored data. RESULTS: A total of 1113 patients were eligible for primary endpoint analysis. Risk of renal events was significantly higher in Group III compared with Group I (HR, 2.52; 95 % CI, 1.98-3.21; P < 0.0001); although not significant, the risk was also higher in Group II compared with Group I (HR, 1.48; 95 % CI, 0.91-2.40; P = 0.11). CONCLUSION: Initiation of ESA therapy when Hb levels decreased below 11 g/dL but not below 10 g/dL could be more effective at reducing the risk of renal events in non-dialysis CKD patients with anemia compared with initiation of ESA therapy at below 9 g/dL or even 10 g/dL.

Recurrence of diabetic kidney disease in a type 1 diabetic patient after kidney transplantation.

Post-transplant hyperglycaemia of diabetic patients may cause recurrent diabetic kidney disease (DKD) in kidney allografts. We report a patient with slowly progressive DKD with calcineurin inhibitor toxicity (CNI) toxicity after the kidney transplantation. A 28-year-old female with type 1 diabetes mellitus underwent successful kidney transplantation from her mother in April 2003, and the kidney graft survived for more than 10 years. She was treated with combined immunosuppressive therapy consisting of cyclosporine and mycophenolate mofetil. After transplantation, she continued to take insulin injection four times per day, but her glycosylated haemoglobin (HbA1c) was above 10%. Protocol allograft kidney biopsies performed 5 and 10 years after transplantation revealed the recurrence of slowly progressive diabetic kidney disease. In addition, arteriolar hyalinosis partly associated with calcineurin inhibitor toxicity (CNI) was detected with progression. Post-transplant hyperglycaemia causes recurrent diabetic kidney disease (DKD) in kidney allografts, but its progression is usually slow. For long-term management, it is important to prevent the progression of the calcineurin inhibitor arteriolopathy, as well as maintain favourable glycaemic control.

A new Classification of Diabetic Nephropathy 2014: a report from Joint Committee on Diabetic Nephropathy.

The Joint Committee on Diabetic Nephropathy has revised its Classification of Diabetic Nephropathy (Classification of Diabetic Nephropathy 2014) in line with the widespread use of key concepts, such as the estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD). In revising the Classification, the Committee carefully evaluated, as relevant to current revision, the report of a study conducted by the Research Group of Diabetic Nephropathy, Ministry of Health, Labor and Welfare of Japan. Major revisions to the Classification are summarized as follows: (i) eGFR is substituted for GFR in the Classification; (ii) the subdivisions A and B in stage 3 (overt nephropathy) have been reintegrated; (iii) stage 4 (kidney failure) has been redefined as a GFR <30 mL/min/1.73 m(2), regardless of the extent of albuminuria; and (iv) stress has been placed on the differential diagnosis of diabetic nephropathy versus non-diabetic kidney disease as being crucial in all stages of diabetic nephropathy.

Obesity as an effect modifier of the association between leptin and diabetic kidney disease.

AIMS/INTRODUCTION: Obesity has been shown to be a modifier of the association between leptin levels and cardiovascular events. We examined whether obesity modifies the association between serum leptin levels and the progression of diabetic kidney disease. MATERIALS AND METHODS: This was an observational longitudinal study on patients with type 2 diabetes. We enrolled 410 and 348 patients in the eGFR and ACR cohorts, respectively. Patients were classified into three groups by sex-specific tertile of leptin levels. Obesity was defined as body mass index ≥25 kg/m(2). Outcomes were the rate of change in estimated glomerular filtration rate (eGFR) and progression to a more advanced stage of albuminuria. RESULTS: In the eGFR cohort, the mean eGFR change during the median follow-up period of 4.7 years was -1.4 mL/min/1.73 m(2)/year. An interaction between leptin levels (low, medium or high) and obesity (present or absent) on the change in eGFR was detected (P interaction = 0.003). In the lean group, adjusted eGFR decline in patients with low leptin was steeper than that in patients with medium leptin (2.1 and 0.8 mL/min/1.73 m(2)/year, P = 0.023). In the obese group, patients with high leptin had a steeper adjusted eGFR decline than those with medium leptin (1.7 and 0.6 mL/min/1.73 m(2)/year, P = 0.044). In the ACR cohort, 29 patients showed progression of albuminuria during the median follow-up period of 3.9 years. There was no interaction between leptin levels and obesity on the outcome (P interaction = 0.094). CONCLUSIONS: Obesity might modify the effects of leptin on kidney function decline in patients with type 2 diabetes.

Replication study for the association of 3 SNP loci identified in a genome-wide association study for diabetic nephropathy in European type 1 diabetes with diabetic nephropathy in Japanese patients with type 2 diabetes.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects.

Acetyl coenzyme A carboxylase B gene (ACACB) single nucleotide polymorphism (SNP) rs2268388 is reproducibly associated with type 2 diabetes (T2DM)-associated nephropathy (DN). ACACB knock-out mice are also protected from obesity. This study assessed relationships between rs2268388, body mass index (BMI) and gene expression in multiple populations, with and without T2DM. Among subjects without T2DM, rs2268388 DN risk allele (T) associated with higher BMI in Pima Indian children (n = 2021; p-additive = 0.029) and African Americans (AAs) (n = 177; p-additive = 0.05), with a trend in European Americans (EAs) (n = 512; p-additive = 0.09), but not Germans (n = 858; p-additive = 0.765). Association with BMI was seen in a meta-analysis including all non-T2DM subjects (n = 3568; p-additive = 0.02). Among subjects with T2DM, rs2268388 was not associated with BMI in Japanese (n = 2912) or EAs (n = 1149); however, the T allele associated with higher BMI in the subset with BMI≥30 kg/m(2) (n = 568 EAs; p-additive = 0.049, n = 196 Japanese; p-additive = 0.049). Association with BMI was strengthened in a T2DM meta-analysis that included an additional 756 AAs (p-additive = 0.080) and 48 Hong Kong Chinese (p-additive = 0.81) with BMI≥30 kg/m(2) (n = 1575; p-additive = 0.0033). The effect of rs2268388 on gene expression revealed that the T risk allele associated with higher ACACB messenger levels in adipose tissue (41 EAs and 20 AAs with BMI>30 kg/m(2); p-additive = 0.018) and ACACB protein levels in the liver tissue (mixed model p-additive = 0.03, in 25 EA bariatric surgery patients with BMI>30 kg/m(2) for 75 exams). The T allele also associated with higher hepatic triglyceride levels. These data support a role for ACACB in obesity and potential roles for altered lipid metabolism in susceptibility to DN.

2008 Japanese Society for Dialysis Therapy: guidelines for renal anemia in chronic kidney disease.

The Japanese Society for Dialysis Therapy (JSDT) guideline committee, chaired by Dr Y. Tsubakihara, presents the Japanese guidelines entitled "Guidelines for Renal Anemia in Chronic Kidney Disease." These guidelines replace the "2004 JSDT Guidelines for Renal Anemia in Chronic Hemodialysis Patients," and contain new, additional guidelines for peritoneal dialysis (PD), non-dialysis (ND), and pediatric chronic kidney disease (CKD) patients. Chapter 1 presents reference values for diagnosing anemia that are based on the most recent epidemiological data from the general Japanese population. In both men and women, hemoglobin (Hb) levels decrease along with an increase in age and the level for diagnosing anemia has been set at <13.5 g/dL in males and <11.5 g/dL in females. However, the guidelines explicitly state that the target Hb level in erythropoiesis stimulating agent (ESA) therapy is different to the anemia reference level. In addition, in defining renal anemia, the guidelines emphasize that the reduced production of erythropoietin (EPO) that is associated with renal disorders is the primary cause of renal anemia, and that renal anemia refers to a condition in which there is no increased production of EPO and serum EPO levels remain within the reference range for healthy individuals without anemia, irrespective of the glomerular filtration rate (GFR). In other words, renal anemia is clearly identified as an "endocrine disease." It is believed that defining renal anemia in this way will be extremely beneficial for ND patients exhibiting renal anemia despite having a high GFR. We have also emphasized that renal anemia may be treated not only with ESA therapy but also with appropriate iron supplementation and the improvement of anemia associated with chronic disease, which is associated with inflammation, and inadequate dialysis, another major cause of renal anemia. In Chapter 2, which discusses the target Hb levels in ESA therapy, the guidelines establish different target levels for hemodialysis (HD) patients than for PD and ND patients, for two reasons: (i) In Japanese HD patients, Hb levels following hemodialysis rise considerably above their previous levels because of ultrafiltration-induced hemoconcentration; and (ii) as noted in the 2004 guidelines, although 10 to 11 g/dL was optimal for long-term prognosis if the Hb level prior to the hemodialysis session in an HD patient had been established at the target level, it has been reported that, based on data accumulated on Japanese PD and ND patients, in patients without serious cardiovascular disease, higher levels have a cardiac or renal function protective effect, without any safety issues. Accordingly, the guidelines establish a target Hb level in PD and ND patients of 11 g/dL or more, and recommend 13 g/dL as the criterion for dose reduction/withdrawal. However, with the results of, for example, the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) study in mind, the guidelines establish an upper limit of 12 g/dL for patients with serious cardiovascular disease or patients for whom the attending physician determines high Hb levels would not be appropriate. Chapter 3 discusses the criteria for iron supplementation. The guidelines establish reference levels for iron supplementation in Japan that are lower than those established in the Western guidelines. This is because of concerns about long-term toxicity if the results of short-term studies conducted by Western manufacturers, in which an ESA cost-savings effect has been positioned as a primary endpoint, are too readily accepted. In other words, if the serum ferritin is <100 ng/mL and the transferrin saturation rate (TSAT) is <20%, then the criteria for iron supplementation will be met; if only one of these criteria is met, then iron supplementation should be considered unnecessary. Although there is a dearth of supporting evidence for these criteria, there are patients that have been surviving on hemodialysis in Japan for more than 40 years, and since there are approximately 20 000 patients who have been receiving hemodialysis for more than 20 years, which is a situation that is different from that in many other countries. As there are concerns about adverse reactions due to the overuse of iron preparations as well, we therefore adopted the expert opinion that evidence obtained from studies in which an ESA cost-savings effect had been positioned as the primary endpoint should not be accepted unquestioningly. In Chapter 4, which discusses ESA dosing regimens, and Chapter 5, which discusses poor response to ESAs, we gave priority to the usual doses that are listed in the package inserts of the ESAs that can be used in Japan. However, if the maximum dose of darbepoetin alfa that can currently be used in HD and PD patients were to be used, then the majority of poor responders would be rescued. Blood transfusions are discussed in Chapter 6. Blood transfusions are attributed to the difficulty of managing renal anemia not only in HD patients, but also in end-stage ND patients who respond poorly to ESAs. It is believed that the number of patients requiring transfusions could be reduced further if there were novel long-acting ESAs that could be used for ND patients. Chapter 7 discusses adverse reactions to ESA therapy. Of particular concern is the emergence and exacerbation of hypertension associated with rapid hematopoiesis due to ESA therapy. The treatment of renal anemia in pediatric CKD patients is discussed in Chapter 8; it is fundamentally the same as that in adults.

A single nucleotide polymorphism within the acetyl-coenzyme A carboxylase beta gene is associated with proteinuria in patients with type 2 diabetes.

It has been suggested that genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy. A large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes identified the gene encoding acetyl-coenzyme A carboxylase beta (ACACB) as a candidate for a susceptibility to diabetic nephropathy; the landmark SNP was found in the intron 18 of ACACB (rs2268388: intron 18 +4139 C > T, p = 1.4x10(-6), odds ratio = 1.61, 95% confidence interval [CI]: 1.33-1.96). The association of this SNP with diabetic nephropathy was examined in 9 independent studies (4 from Japan including the original study, one Singaporean, one Korean, and two European) with type 2 diabetes. One case-control study involving European patients with type 1 diabetes was included. The frequency of the T allele for SNP rs2268388 was consistently higher among patients with type 2 diabetes and proteinuria. A meta-analysis revealed that rs2268388 was significantly associated with proteinuria in Japanese patients with type 2 diabetes (p = 5.35 x 10(-8), odds ratio = 1.61, 95% Cl: 1.35-1.91). Rs2268388 was also associated with type 2 diabetes-associated end-stage renal disease (ESRD) in European Americans (p = 6 x 10(-4), odds ratio = 1.61, 95% Cl: 1.22-2.13). Significant association was not detected between this SNP and nephropathy in those with type 1 diabetes. A subsequent in vitro functional analysis revealed that a 29-bp DNA fragment, including rs2268388, had significant enhancer activity in cultured human renal proximal tubular epithelial cells. Fragments corresponding to the disease susceptibility allele (T) had higher enhancer activity than those of the major allele. These results suggest that ACACB is a strong candidate for conferring susceptibility for proteinuria in patients with type 2 diabetes.