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The clinical characteristics and treatment of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) after initiating chronic hemodialysis remain unknown. We retrospectively enrolled 11 adult patients with AAV receiving chronic hemodialysis in our hospital from 2000–2016. We collected data describing each patient's clinical findings and treatment before and after initiating hemodialysis. Patients with AAV with and without post-hemodialysis AAV relapse were compared statistically. The average observation period was 6.8 ± 4.1 years, and the interval between diagnosis and initiating chronic hemodialysis was 1.9 ± 2.6 years. Before initiating chronic hemodialysis, five patients (45%) experienced 12 AAV relapses, with diagnoses made serologically or symptomatically. After initiating chronic hemodialysis, four patients experienced nine relapses, with no significant difference between the number of relapses and the number of patients experiencing relapse (p = 0.067 and 0.083, respectively). For patients' entire clinical courses before initiating chronic hemodialysis, the average steroid dose was 11.6 ± 6.9 g/y. Comparing before and after initiating chronic hemodialysis, the steroid dose decreased significantly to 3.3 ± 1.4 g/y after initiating chronic hemodialysis (p = 0.0012). Two of 11 patients died of serious infections after initiating chronic hemodialysis. Our results showed that the number of relapses tended to be lower despite a significantly different lower amount of steroid after initiating hemodialysis compared with before initiating hemodialysis, and the burn-out phenomenon specific to uremic patients was inferred. We believe that early tapering of steroids should be considered to avoid death rather than focusing only on relapse.

Background/Aims: Aortic arch calcification (AoAC) is a fatal complication in dialysis. AoAC progression-related molecules in continuous ambulatory peritoneal dialysis (CAPD) remain unclear. Methods: AoAC was estimated using plain chest radiography scoring (AoACS) in 30 CAPD patients (age 49.3 ± 13.4 years). AoAC progression was defined as increased AoACS on follow-up chest X-ray at the end of the study (progressors). Fibroblast growth factor-23 and osteoprotegerin (OPG) were measured. Results: Median follow-up was 38.5 months. Progressors were older, had shorter PD vintage, higher body mass index, and higher serum OPG levels (255.6 ± 109.2 pg/mL) than nonprogressors (183.4 ± 68.2 pg/mL; p = 0.0400). Progressors also showed higher pulse pressure (62.4 ± 20.0 mm Hg) and pulse wave velocity (1,909.9 ± 310.6 cm/s) than nonprogressors (48.5 ± 13.6 mm Hg; p = 0.0030 and 1,390.1 ± 252.8 cm/s; p = 0.0005, respectively). Conclusion: AoAC progression was associated with increased aortic stiffness. OPG may be associated with AoAC progression in CAPD.

Carnitine deficiency is a common condition in hemodialysis patients. Therefore, abnormalities in fatty acid metabolism and organic acid metabolism are also common in dialysis patients. Tandem mass spectrometry is a standard technique in pediatric and neonatal medicine. However, it could be a new powerful tool in other fields for estimating the state of intracellular fatty acid metabolism.Tandem mass spectrometry has recently revealed the relationships between carnitine profile and dialysis patients' anemia, reduced physical function, and survival rate. Fatty acid and organic acid metabolism, which could previously only be evaluated qualitatively, can now be quantitatively assessed. Key Message: The applications of tandem mass spectrometry are expected to expand not only in the field of dialysis but also in clinical medicine in general.

To explore novel genetic loci for diabetic nephropathy, we performed genome-wide association studies (GWAS) for diabetic nephropathy in Japanese patients with type 2 diabetes. We analyzed the association of 5,768,242 single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes, 2,380 nephropathy cases and 5,234 controls. We further performed GWAS for diabetic nephropathy using independent Japanese patients with type 2 diabetes, 429 cases and 358 controls and the results of these two GWAS were combined with an inverse variance meta-analysis (stage-1), followed by a de novo genotyping for the candidate SNP loci (p < 1.0 x 10^) in an independent case-control study (Stage-2; 1,213 cases and 1,298 controls). After integrating stage-1 and stage-2 data, we identified one SNP locus, significantly associated with diabetic nephropathy; rs56094641 in FTO, P = 7.74 x 10^. We further examined the association of rs56094641 with diabetic nephropathy in independent Japanese patients with type 2 diabetes (902 cases and 1,221 controls), and found that the association of this locus with diabetic nephropathy remained significant after integrating all association data (P = 7.62 x 10^). We have identified FTO locus as a novel locus for conferring susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes., 論文

Tumors producing IGF-2 (IGF-2oma) are a major cause of spontaneous hypoglycemia. The treatment mainstay is surgical resection. Many case reports note resolution of hypoglycemia after IGF-2oma resection; however, outcomes are variable according to tumor type. We report a case of resolving hypoglycemia, observed on continuous glucose monitoring, after resection of an IGF-2-producing solitary fibrous tumor of pleura and review the current literature.A 69-year-old woman presented with impaired consciousness because of hypoglycemia. An IGF-2oma was diagnosed as the cause for hypoglycemia because of decreased serum insulin and IGF-1, the presence of a pleural tumor, and a high-molecular-weight form of serum IGF-2 detected by Western immunoblot. Surgical resection was performed; pathological examination demonstrated a solitary fibrous tumor with low-grade malignancy. Continuous glucose monitoring showed reversal of hypoglycemia after tumor resection. Approximately 2 years after resection, the patient has no signs of tumor recurrence or hypoglycemia.An IGF-2-producing solitary fibrous tumor of pleura in this case caused hypoglycemia. From a search of the literature of 2004-2014, 32 cases of IGF-2oma with hypoglycemia that underwent radical surgery were identified; in 19 (59%) patients, hypoglycemia was reversed, and there was no subsequent recurrence. The remaining 13 (41%) patients experienced tumor recurrence or metastasis an average of 43 months after initial tumor resection. The tumor of the present case was a low-grade malignancy. Regular follow-up with biomarker monitoring of glucose metabolism and assessment of hypoglycemic symptomatology, in conjunction with imaging tests, is important for detecting possible tumor recurrence and metastasis.

Background The impact of serum lipid abnormalities on the progression of diabetic kidney disease (DKD) remains conflicting. Furthermore, gender differences in the association between dyslipidaemia and outcome of DKD are largely unknown. We therefore conducted this single-centre observational cohort study to clarify gender differences in the association between serum lipid profiles and the progression of DKD. Methods Seven hundred and twenty-three Japanese type 2 diabetes mellitus (T2DM) patients with normoalbuminuria or microalbuminuria, 280 women and 443 men, with a mean (± SD) age of 63 ± 11 years were studied. The endpoint was the progression to a more advanced stage of albuminuria. For statistical analyses, Cox proportional hazard model analyses were conducted. Results During the mean follow-up period of 4.3 years, 62 of 477 patients with normoalbuminuria and 69 of 246 patients with microalbuminuria reached the endpoint. A significant interaction between high-density lipoprotein (HDL) cholesterol and gender was detected (P(interaction) = 0.04); therefore, separate analyses were conducted for men and women. Overall, in men, the univariate Cox proportional hazard model revealed that higher triglycerides and lower HDL cholesterol levels were significantly associated with higher risk of reaching the endpoint. In the multivariate Cox proportional hazard model, only HDL cholesterol levels remained as an independent predictor of the endpoint (hazard ratio 0.391, P = 0.01). In women, no serum lipid parameters were associated with the endpoint. Conclusions Lower HDL cholesterol levels seem to be associated with the progression of DKD in men but not in women.

To identify genetic elements that might confer susceptibility to diabetic nephropathy, we performed a genome-wide analysis of gene-based single nucleotide polymorphisms (SNPs) in a large cohort of Japanese patients with diabetes. In case-control association studies, patients with type 2 diabetes were divided into two groups, one having retinopathy as well as overt nephropathy and the other (the control group) having diabetic retinopathy but with no signs of renal involvement. Genotyping of these patients at >55,000 SNP loci indicated a gene encoding solute carrier family 12 member 3 (SLC12A3) to be a good candidate for the susceptibility to diabetic nephropathy, in view of a significant association of one landmark SNP located in the 24th intron (χ2 = 15.4, P = 0.000087, odds ratio = 2.53 [95% CI 1.57–4.09]). Subsequent analysis of additional genetic variations in this gene identified several SNPs that were significantly associated with nephropathy, especially one in exon 23 (+78 G to A: Arg913Gln, χ2 = 18.5, P = 0.00002, odds ratio = 2.53 [95% CI 1.64–3.90]). The results implicated that substitution of Arg913 to Gln in the SLC12A3 gene might reduce the risk to develop diabetic nephropathy and suggested that the gene product might be a potential target for the prevention or treatment of this disease.

The first clinical manifestation of diabetic kidney disease is usually the development of microalbuminuria. However, recent studies have focused on diabetic patients with reduced glomerular filtration rate (GFR) without albuminuria. To evaluate the association of albuminuria and GFR with renal outcomes, we performed an observational study.A total of 3231 type 2 diabetic patients were included in this study between 2003 and 2005. There were 1249 women and the mean age was 59 ± 12 years. The renal endpoints were defined as the initiation of renal replacement therapy (RRT) or 50% reduction from the baseline of estimated GFR (eGFR).At baseline, 669 (20.7%) patients had eGFR60 mL/min per 1.73 m(2) and 1134 (35.1%) had albuminuria. During the mean follow-up period of 5.9 ± 1.6 years, 107 patients initiated RRT. A 50% reduction of eGFR from the baseline value was found in 279 patients. None of the normoalbuminuric subjects with or without reduced eGFR required RRT during the observational period (P 0.01). Compared to normoalbuminuria patients with eGFR ≥60 mL/min per 1.73 m(2) at baseline, the group of normoalbuminuria patients with reduced eGFR had a 2.5-fold risk of developing the renal endpoints, (95% confidence interval (CI): 1.0-6.3, P = 0.053). Patients with microalbuminuria with eGFR ≥60 mL/min per 1.73 m(2) at baseline had a 5.0-fold risk of developing the evaluated renal endpoints (95% CI: 2.8-8.8, P 0.001).Albuminuria was a significant predictor for the evaluated renal endpoints, but the impact of eGFR is likely to be less than that of albuminuria.

Patients with peripheral artery disease (PAD), defined as having low ankle-brachial pressure index (ABI), have increased risk for incident stroke compared with those without PAD. We aimed to reveal whether ABI abnormality, especially high ABI is associated with prevalent silent cerebral infarction (SCI) in type 2 diabetic patients.We studied 538 Japanese type 2 diabetic patients, 227 women and 311 men, with a mean [±SD] age of 64±11 years. All patients underwent cranial magnetic resonance imaging (MRI). Values of ABI were classified as low (0.9), normal (0.9≤ and1.3), and high (1.3≤). Logistic regression model was used to calculate odds ratio and 95% confidence interval (95% CI) for prevalent SCI.The mean ABI among the overall 538 patients was 1.09±0.16. Low and high ABI values were found in 52 (9.7%) and 33 (6.1%) patients, respectively. SCI was detected in 297 (55.2%) patients. The prevalence in patients with low, normal, and high ABI values were 88.5%, 49.7%, and 78.8 (p0.001), respectively. In the multivariate logistic regression analysis, both patients with high and low ABI were significantly increased risk of prevalent SCI (odds ratio 4.53, 95% CI 1.67-12.34, p=0.003 and odds ratio 3.50, 95% CI 1.50-10.29, p=0.005), independently of other traditional cardiovascular risk factors, than those with normal ABI.Both high and low ABI may be strongly associated with prevalent SCI in Japanese patients with type 2 diabetes.

OBJECTIVE To clarify the association of serum leptin levels with progression of diabetic kidney disease in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS This was an observational cohort study of 668 patients with T2D. Patients were classified into three groups by sex-specific tertile of leptin levels. Outcome measurements were the rate of change in estimated glomerular filtration rate (eGFR) and progression to a more advanced stage of albuminuria. RESULTS Patients with low or high leptin levels had a steeper eGFR decline (−2.07 and −2.14 mL/min/1.73 m2/year) than those with midrange leptin levels (−0.82 mL/min/1.73 m2/year; P < 0.01), whereas patients with low leptin levels had an elevated risk of progression of albuminuria as compared with those with high leptin levels (hazard ratio 3.125 [95% CI 1.302–7.499]). CONCLUSIONS Both low and high serum leptin levels were risk factors for kidney function decline. Meanwhile, lower serum leptin levels were associated with progression of albuminuria.

OBJECTIVE To investigate the association between aortic stiffness and incident albuminuria and the decline in estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We investigated 461 Japanese type 2 diabetic patients, comprising 199 women and 262 men, with a mean age of 59 ± 11 years. Patients were divided into two groups according to the median value of carotid-femoral pulse wave velocity (cf-PWV), which was used to evaluate aortic stiffness. The end point was defined as the transition from normo- to microalbuminuria or micro- to macroalbuminuria. The Cox proportional hazard model was used to calculate the hazard ratio (HR) and 95% CI. The correlation between cf-PWV and rate of change in eGFR was also determined by linear regression analysis. RESULTS The baseline mean (± SD) cf-PWV was 9.6 ± 2.4 m/s. During a median follow-up period of 5.9 years (range 0.3–8.6), progression of albuminuria was observed in 85 patients. The 5-year cumulative incidence of the end point in patients with cf-PWV below and above the median was 8.5 and 19.4%, respectively (P = 0.002, log-rank test). cf-PWV was significantly associated with incident albuminuria (HR 1.23, 95% CI 1.13–1.33, P < 0.001) by multivariate Cox regression analysis. A significant association between cf-PWV and annual change in eGFR was also suggested by multiple linear regression analysis (standardized estimate −0.095, P = 0.031). CONCLUSIONS Aortic stiffness is associated with incident albuminuria and the rate of decline in glomerular filtration rate in type 2 diabetic patients.

It is unclear whether albuminuria and reduced glomerular filtration rate (GFR) independently increase the risk of incident stroke and coronary artery disease (CAD) in Japanese patients with diabetes. We investigated the independent effects of albuminuria and estimated GFR (eGFR) on the first occurrence of stroke and CAD in patients with type 2 diabetes mellitus (T2DM). We studied 1002 T2DM patients with eGFR (ml min−1 per 1.73 m2) ⩾15 and had no previous cardiovascular disease (CVD) history. GFR was estimated using the modified three-variable equation for the Japanese. Patients were divided into four eGFR categories: ⩾90, 60–89, 30–59 and 15–29. The end point was an incident stroke and CAD events. The Cox proportional hazard model was used to calculate hazard ratio and 95% confidence interval. During a mean follow-up period of 5.2±2.1 years, 72 episodes of stroke and 90 of CAD were observed. Multivariate Cox analysis revealed no significant association between the eGFR category and incident stroke. The stroke hazard ratio (95% confidence interval) in reference to patients with an eGFR ⩾90 was 0.78 (0.40–1.56) for patients with an eGFR of 60–89, 1.47 (0.70–3.10) for patients with an eGFR of 30–59 and 1.14 (0.39–3.35) for patients with an eGFR of 15–29. Reduced eGFR was a significant risk factor for CAD, with hazard ratios (95% confidence interval) for patients with an eGFRs of 60–89, 30–59 and 15–29 at 1.81 (1.01–3.57), 2.03 (1.04–4.40) and 3.01 (1.13–8.02), respectively. Reduced eGFR is independently associated with incident CAD but not stroke in Japanese patients with T2DM.

Chronic kidney disease (CKD) is an important risk factor for cardiovascular disease in patients with diabetes. The relationship between renal manifestations of CKD (albuminuria and decreased glomerular filtration rate) and silent cerebral infarction (SCI) has attracted attention; however, most studies examined the effects of components of CKD on prevalence of SCI. We sought to assess the relationship between SCI and the development and progression of nephropathy in type 2 diabetic patients. We studied 366 type 2 diabetic patients with normoalbuminuria (urinary albumin-to-creatinine ratio [ACR]30 mg g(-1), N=246) or microalbuminuria (ACR=30-299 mg g(-1), N=120). SCI was defined by cranial MRI. The primary end point was progression from normo- to microalbuminuria or from micro- to macroalbuminuria. The cumulative incidence of the primary end point was estimated using the Kaplan-Meier method. Risk estimates for reaching the end point were calculated using Cox proportional hazard model analyses. During a median follow-up period of 3.9 years, 23 normoalbuminuric and 24 microalbuminuric patients reached the primary end point. Patients with SCI (N=171) had a greater incidence of reaching the end point than those without SCI (N=195, P=0.020 by the log-rank test), with a hazard ratio of 2.02 (95% confidence interval=1.09-3.72, P=0.025) in the multivariate Cox regression model. Although the common pathogenesis of SCI and albuminuria in diabetic patients is still unclear, SCI may be a predictor of progression of nephropathy in type 2 diabetic patients.

Background. Nitric oxide (NO) is thought to play an important role in the pathogenesis of diabetic nephropathy. We conducted a prospective, observational cohort study to explore the relationship between plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, and the development and progression of nephropathy in patients with type 2 diabetes. Methods. This was a hospital-based observational cohort study in Japanese type 2 diabetic patients with normoalbuminuria [urinary albumin-to-creatinine ratio (ACR)

Diabetic nephropathy is a serious complication of diabetes and the leading cause of end-stage renal disease. Studies indicate both environmental and genetic factors contribute to the development and progression of diabetic nephropathy. In particular, epidemiological evidence shows a familial clustering of nephropathy in siblings with diabetes, supporting an important role of genetic susceptibility in the pathogenesis of diabetic nephropathy. A common approach in genetic research is assessment of candidate gene polymorphisms using case-control analysis; a number of studies have evaluated predictable candidate genes for diabetic nephropathy. In contrast, only a few studies have used a whole genome approach, such as scanning of micro-satellite markers, in the assessment of genetic susceptibility to diabetic nephropathy. A whole genome linkage analysis using families of Pima Indians showed susceptibility loci for diabetic nephropathy on chromosome 3, 7, and 20. Another linkage analysis using discordant sib-pairs of Caucasian families with type 1 diabetes identified a critical area on chromosome 3q. However, these results have been inconclusive and further investigation is required. Recently, a genome-wide, case-control analysis identifying susceptibility genes for diabetic nephropathy was performed. As a result, a single nucleotide polymorphism in exon 23 of the solute carrier family 12 (sodium-chloride cotransporter) member 3 gene was found to be strongly associated with diabetic nephropathy. Although further assessment of this polymorphism is needed, this strategy offers great promise in the identification of genetic factors predisposing patients to diabetic nephropathy. Identification of genetic susceptibility markers may offer new hope in the diagnosis and treatment of diabetic nephropathy.