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Background: Fabry disease is a rare X-linked genetic lysosomal disorder caused by mutations in the GLA gene encoding alpha-galac tosidase A. Despite some data showing that profibrotic and proinflammatory cytokines and oxidative stress could be involved in Fabry disease-related renal injury, the pathogenic link between metabolic derangement within cells and renal injury remains unclear. Methods: Renal fibrosis was triggered by unilateral ureteral obstruction (UUO) in mice with Fabry disease to investigate the pathogen ic mechanism leading to fibrosis in diseased kidneys. Results: Compared to kidneys of wild-type mice, lamellar inclusion bodies were recognized in proximal tubules of mice with Fabry dis ease. Sirius red and trichrome staining revealed significantly increased fibrosis in all UUO kidneys, though it was more prominent in obstructed Fabry kidneys. Renal messenger RNA levels of inflammatory cytokines and profibrotic factors were increased in all UUO kidneys compared to sham-operated kidneys but were not significantly different between UUO control and UUO Fabry mice. Protein levels of Nox2, Nox4, NQO1, catalase, SOD1, SOD2, and Nrf2 were not significantly different between UUO control and UUO Fabry kidneys, while the protein contents of LC3-II and LC3-I and expression of Beclin1 were significantly decreased in UUO kidneys of Fabry disease mouse models compared with wild-type mice. Notably, TUNEL-positive cells were elevated in obstructed kidneys of Fabry dis ease mice compared to wild-type control and UUO mice. Conclusion: These findings suggest that impaired autophagy and enhanced apoptosis are probable mechanisms involved in en hanced renal fibrosis under the stimulus of UUO in Fabry disease.

Background/Aims: Because weight control is important in treatment of type 2 diabetes, it is essential to understand the associations between weight change and the risk of microvascular complications among patients with type 2 diabetes. We examined whether weight changes early after new-onset diabetes have an impact on the clinical outcomes of diabetic nephropathy and retinopathy. Methods: Using the Korean National Health Insurance Service-National Health Screening Cohort database, 181,872 patients newly diagnosed with type 2 dia betes who were free of end-stage renal disease (ESRD) and proliferative diabetic retinopathy (PDR) during 2007 to 2012 were followed to the end of 2016. Weight change was defined as the difference in body weight from the time of diabetes di agnosis to 2 years later. Results: We identified 180 cases of ESRD and 780 cases of PDR followed up for a median of 5.5 years from the index year at 2 years after diagnosis. Those with 5% to 10% weight gain showed a significantly higher hazard ratio (HR) for ESRD, compared with those with ≤ 5% weight change after adjusting for several con founding factors, including the baseline estimated glomerular filtration rate (HR, 1.75; 95% confidence interval [CI], 1.14 to 2.70). Those with ≥ 10% weight loss showed the lowest HR for PDR (HR, 0.52; 95% CI, 0.33 to 0.83), whereas those with ≥ 10% weight gain showed the highest HR for PDR (HR, 3.20; 95% CI, 2.51 to 4.08). Conclusions: Weight gain after new-onset diabetes was associated with increased risk of ESRD and PDR whereas weight loss with decreased risk of PDR, but not ESRD.

Immunoglobulin M nephropathy (IgMN) is an idiopathic glomerulonephritis characterized by diffuse deposits of IgM in the glomerular mesangium. However, its renal prognosis remains unknown. We compared renal outcomes of IgMN patients with those of patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), or mesangial proliferative glomerulonephritis (MsPGN) from a prospective observational cohort, with 1791 patients undergoing native kidney biopsy in eight hospitals affiliated with The Catholic University of Korea between December 2014 and October 2020. IgMN had more mesangial proliferation and matrix expansion than MsPGN and more tubular atrophy and interstitial fibrosis than MCD. IgMN patients had decreased eGFR than MCD patients in the earlier follow-up. However, there was no significant difference in urine protein or eGFR among all patients at the last follow-up. When IgMN was divided into three subtypes, patients with FSGS-like IgMN tended to have lower eGFR than those with MCD-like or MsPGN-like IgMN but higher proteinuria than MsPGN-like IgMN without showing a significant difference. The presence of hypertension at the time of kidney biopsy predicted ≥20% decline of eGFR over two years in IgMN patients. Our data indicate that IgMN would have a clinical course and renal prognosis similar to MCD, FSGS, and MsPGN.

Objective Obesity and type 2 diabetes are becoming increasingly prevalent worldwide and are both associated with the increased incidence of kidney and bladder cancers. However, previous reports have provided conflicting results. We investigated the impact of body mass index (BMI) and diabetes on the incidence of both cancers in the general population. Methods Using nationally representative data from the Korean National Health Insurance System, 9,777,133 subjects without any malignancy who underwent health examinations in 2009 were followed to the end of 2017. Results After a median follow-up period of 8.32 years, 12,544 incidents of kidney cancer and 15,137 incidents of bladder cancer were identified. The hazard ratio (HR) for kidney cancer was the lowest in people with a BMI 2 (HR: 0.82, 95% confidence interval (CI): 0.72–0.94) and the highest in those with a BMI ≥30 kg/m2 (HR: 1.71, 95% CI: 1.57–1.87) compared to a reference BMI group (18.5–23 kg/m2). In subjects with diabetes, obesity was associated with increased risk of kidney cancer, although the HRs were lower than observed in those without diabetes. Otherwise, there was a reduction in risk of bladder cancer with obesity in men and the HR for bladder cancer was not affected by BMI increase in women. There was a strongly positive association between diabetes and bladder cancer in the total study population. Conclusions Obesity was a strong risk factors for kidney cancer, whereas the association between obesity and bladder cancer differed by gender. The subjects with diabetes had a higher risk for both cancers than those without diabetes.

Background and aims There is a growing evidence demonstrating an association between dyslipidemia and progression of chronic kidney disease (CKD), but results on the effects of high-density lipoprotein cholesterol (HDL-C) on renal outcome have been conflicting. In this study, the relationship between HDL-C variability and the risk for progression to end-stage renal disease (ESRD) was investigated. Methods This study analyzed data of 4,283,318 subjects who were free of ESRD at the time of enrollment, received more than three medical examinations from 2009 to 2012, and were followed to the end of 2015, based on the Korean National Health Insurance Service database. HDL-C variability was measured using the standard deviation, coefficient of variation, average real variability and variability independent of the mean (VIM). Results A total of 2,095 new cases of ESRD were observed during a median follow up of 3.38 years. There was a graded association between higher HDL-C variability and incident ESRD. In the multivariable adjusted model, hazard ratio comparing the highest and lowest quartiles of VIM of HDL-C was 1.82 (95% confidence interval, 1.58–2.09). The results were consistent when the variability of HDL-C was modeled using standard deviation, coefficient of variation and average real variability and were independent of other confounding factors, including the presence of CKD. Conclusions HDL-C variability independently predicted an increased risk for developing ESRD. Our findings suggest that identification of HDL-C variability may help improve risk stratification for the prevention of ESRD.

Few studies have investigated the impact of a change in metabolic syndrome (MetS) components on clinical renal outcomes in the general population. Using nationally representative data from the Korean National Health Insurance System, 13,310,924 subjects who underwent two health examinations over 2 years and were free from end-stage renal disease (ESRD) from 2009 to 2012 were followed to the end of 2016. The subjects were divided into four groups according to the change in MetS components between the two visits over 2 years: no MetS (–/–), post-MetS (–/+), pre-MetS (+/–), and both MetS (+/+). After a median follow up of 5.11 years, 18,582 incident ESRD cases were identified. In the multivariate adjusted model, the hazard ratio (HR) and 95% confidence interval (CI) for the development of ESRD in the both-MetS (+/+) group compared with the no-MetS (–/–) group was 5.65 (95% CI, 5.42–5.89), which was independent of age, sex, and baseline estimated glomerular filtration rate. Additionally, the HR for the pre-MetS (+/–) group versus the no-MetS (–/–) group was 2.28 (2.15–2.42). In subgroup analysis according to renal function, the impact of a change in MetS on the incidence of ESRD was more pronounced in individuals with advanced renal dysfunction. Subjects with resolved MetS components had a decreased risk of ESRD, but not as low as those that never had MetS components. This provides evidence supporting the strategy of modulating MetS in the general population to prevent the development of ESRD.

Aims To investigate the effectiveness of sodium-glucose co-transporter-2 (SGLT2) inhibitors on the risk of progression to end-stage renal disease (ESRD) and all-cause mortality in a broad range of patients with type 2 diabetes (T2D) using a Korean nationwide cohort.Materials and Methods Using data from the Korean National Health Insurance Service database from January 2014 to December 2017, a total of 701 674 patients were identified with T2D. We divided these patients into new users of SGLT2 inhibitors and new users of other glucose-lowering drugs (oGLDs). Using propensity scores, patients in the two groups were matched 1:1. We assessed the risk of ESRD and all-cause death.Results There were 45 016 patients in each group, and baseline characteristics were well balanced between the groups. The patients' mean age was 58.1 +/- 10.6 years and mean estimated glomerular filtration rate (eGFR) was 89.2 +/- 27.4 mL/min/1.73m(2), and 8% of patients had proteinuria. We identified 167 incident ESRD cases and 1070 all-cause deaths during follow-up. Use of SGLT2 inhibitors versus oGLDs was associated with a lower risk of ESRD (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.34 to 0.65) and all-cause death (HR 0.82, 95% CI 0.73 to 0.93). In a subgroup analysis by eGFR, initiation of SGLT2 inhibitor treatment, compared with oGLD treatment, was associated with lower risk of progression to ESRD among patients with eGFR 60 to 90 mL/min/1.73m(2) and those with eGFR = 90 and 60 to 90 mL/min/1.73m(2).Conclusion In this large nationwide study of Korean patients with T2D, initiation of SGLT2 inhibitors versus oGLDs was associated with lower risk of ESRD and all-cause death.

Background and Aims Few studies have investigated the impact of a change in metabolic syndrome (MetS) components on clinical renal outcomes in the general population. Method Using nationally representative data from the Korean National Health Insurance System, 13,310,924 subjects who underwent two health examinations over 2 years and were free from end-stage renal disease (ESRD) from 2009 to 2012 were followed to the end of 2016. The subjects were divided into four groups according to the change in MetS components between the two visits over 2 years: no MetS (–/–), post-MetS (–/+), pre-MetS (+/–), and both MetS (+/+). Results After a median follow up of 5.11 years, 18,582 incident ESRD cases were identified. In the multivariate adjusted model, the hazard ratio (HR) and 95% confidence interval (CI) for the development of ESRD in the both-MetS (+/+) group compared with the no-MetS (–/–) group was 5.65 (95% CI, 5.42–5.89), which was independent of age, sex, and baseline estimated glomerular filtration rate. Additionally, the HR for the pre-MetS (+/-) group versus the no-MetS (–/–) group was 2.28 (2.15–2.42). In subgroup analysis according to renal function, the impact of a change in MetS on the incidence of ESRD was more pronounced in individuals with advanced renal dysfunction. Subjects with resolved MetS components had a decreased risk of ESRD, but not as low as those that never had MetS components. Conclusion This provides evidence supporting the strategy of modulating MetS in the general population to prevent the development of ESRD.

The objective of this study was to investigate the optimal blood pressure (BP) target to prevent development of cardiovascular diseases (CVDs) in Korean subjects with type 2 diabetes mellitus. Using the Korean National Health Insurance Service database, 2 262 725 subjects with type 2 diabetes mellitus who underwent regular health checks between 2009 and 2012 were included. Subjects with previous CVDs were excluded. Participants were grouped by 10-mm Hg intervals of observed systolic BP (SBP) by 5-mm Hg intervals of diastolic BP. There were 124 466 deaths (5.50%), 67 235 cases of stroke (2.97%), and 41 726 myocardial infarctions (1.84%) during a median follow-up of 6.5 years. Compared with SBP 110 to 119 mm Hg, there was no increased risk among subjects with SBP 120 to 129 mm Hg, but SBP ≥130 mm Hg was associated with a significant increase in the incidence of CVDs. SBP 130 to 139 mm Hg was associated with a significant increase in the incidence of stroke (hazard ratio, 1.15; 95% CI, 1.12–1.18) and myocardial infarctions (hazard ratio, 1.05; 95% CI, 1.02–1.09) compared with SBP 110 to 119 mm Hg. Subjects with diastolic BP 80 to 84 mm Hg had a higher risk of CVDs than subjects with diastolic BP 75 to 79 mm Hg. The overall relationship between BP and CVD risk was positive, with a greater strength observed for younger age groups. The optimal cutoff for Korean patients with type 2 diabetes mellitus associated with lower CVD risk may be 130 mm Hg for SBP or 80 mm Hg for diastolic BP.

IgA nephropathy (IgAN) is a globally well-known primary glomerular nephropathy. Hypertriglyceridemia (HTG) is one factor contributing to atherosclerosis and is a common complication of renal failure. HTG is a significant risk factor for decreased renal function in patients with IgAN. We evaluated the association of HTG with the histopathological features of IgAN patients. A total of 480 patients diagnosed with IgAN via kidney biopsy from eight university hospitals affiliated with the College of Medicine of the Catholic University of Korea were included in the final cohort. Pathological features were evaluated by eight expert pathologists with hospital consensus. HTG was defined as a serum triglyceride (TG) level of ≥150 mg/dL. In the study population analysis, the HTG group was older, with more males, higher body mass index (BMI), low-density lipoprotein cholesterol (LDL-C) and spot urine protein ratio, and lower estimated glomerular filtration rate (eGFR). In the lipid profile analysis, eGFR was negatively correlated with TGs/ high-density lipoprotein cholesterol (HDL) and triglyceride-glucose index (TyG). Proteinuria positively correlated with TGs/HDL, non-HDL/HDL, LDL/HDL, TyG, TGs and LDL. The percentages of global sclerosis (GS), segmental sclerosis (SS) and capsular adhesion (CA), and the scores for mesangial matrix expansion (MME) and mesangial cell proliferation (MCP), were more elevated in the HTG group compared to the normal TG group. Multivariable linear regression analysis showed that the percentages of global sclerosis, segmental sclerosis and capsular adhesion, as well as the scores for mesangial matrix expansion and mesangial cell proliferation, were positively associated with TG level. In binary logistic regression, the HTG group showed a higher risk for global sclerosis and segmental sclerosis. In conclusion, HTG is a significant risk factor for glomerulosclerosis in IgAN.

Objective— Recent data suggest that visit-to-visit variability of cholesterol is associated with cardiovascular events. We evaluated the role of lipid variability as a determinant of end-stage renal disease (ESRD). Approach and Results— Using nationally representative data from the Korean National Health Insurance System, 8 493 277 subjects who were free of ESRD and who underwent ≥3 health examinations during 2005 to 2010 were followed to the end of 2015. Total cholesterol (TC) variability was measured using the coefficient of variation, SD, and the variability independent of the mean. The primary outcome was the development of ESRD, defined as a combination of the relevant disease code and the initiation of renal replacement therapy. There were 11 247 cases of ESRD during a median follow-up of 6.1 years. There was a graded association between a higher TC variability and incident ESRD. In the multivariable adjusted model, the hazard ratios and 95% confidence intervals comparing the highest versus lowest quartiles of coefficient of variation of TC were 2.66 (95% confidence interval, 2.52–2.82). The results were consistent when the variability of TC was modeled using SD and variability independent of the mean and were independent of preexisting chronic kidney disease. Conclusions— Increasing TC variability was associated with an increasing incidence of ESRD.

Introduction In this study we evaluated the effect of electromyostimulation (EMS) on myosin heavy chain (MHC) isoform expression in denervated rat muscles to determine the optimal timing for EMS application. Methods EMS was initiated on post-injury day 1 for the group with denervation receiving immediate EMS (DIEMS) and on post-injury day 15 for the group with denervation receiving delayed EMS (DDEMS) in rat denervated muscles. Muscle wet weight and muscle fiber cross-sectional area (FCSA) were measured. MHC isoforms were analyzed in both protein homogenates and single muscle fibers. Results The expression levels of IIx and IIb isoforms of MHC were significantly lower and higher, respectively, in the gastrocnemius muscles of the DIEMS group, but not the DDEMS group. The DIEMS group also showed larger FCSA and a lower proportion of hybrid single fibers compared with the DDEMS group. Discussion These results indicate that immediate EMS is more effective than delayed EMS for aiding recovery of denervation-induced MHC changes. Muscle Nerve 56: E154-E161, 2017.

We investigated the relationship of changes in Metabolic syndrome (MetS) and its components with the risk of type 2 diabetes (T2D) in South Korea. Records of 10,806,716 adults aged ≥ 20 years without a history of T2D between 2009 and 2015 were retrieved from database of the South Korean National Health Insurance Service and analyzed. Changes in metabolic components were monitored over a two-year period with follow-up occurring at an average of 4.087 years. During the follow-up period, 848,859 individuals were diagnosed with T2D. The risk of diabetes was lowered with a decrease in the number of MetS components at baseline and the second visit (p for trend

Besides lowering glucose, empagliflozin, a selective sodium-glucose cotransporter-2 (SGLT2) inhibitor, have been known to provide cardiovascular and renal protection due to effects on diuresis and natriuresis. However, the natriuretic effect of SGLT2 inhibitors has been reported to be transient, and long-term data related to diuretic change are sparse. This study was performed to assess the renal effects of a 12-week treatment with empagliflozin (3 mg/kg) in diabetic OLETF rats by comparing it with other antihyperglycemic agents including lixisenatide (10 μg/kg), a glucagon-like peptide receptor-1 agonist, and voglibose (0.6 mg/kg), an α-glucosidase inhibitor. At 12 weeks of treatment, empagliflozin-treated diabetic rats produced still high urine volume and glycosuria, and showed significantly higher electrolyte-free water clearance than lixisenatide or voglibose-treated diabetic rats without significant change of serum sodium level and fractional excretion of sodium. In empagliflozin-treated rats, renal expression of Na+-Cl- cotransporter was unaltered, and expressions of Na+/H+ exchanger isoform 3, Na+-K+-2Cl- cotransporter, and epithelial Na+ channel were decreased compared with control diabetic rats. Empagliflozin increased an expression of aquaporin (AQP)7 but did not affect AQP3 and AQP1 protein expressions in diabetic kidneys. Despite the increased expression in vasopressin V2 receptor, protein and mRNA levels of AQP2 in empagliflozin-treated diabetic kidneys were significantly decreased compared to control diabetic kidneys. In addition, empagliflozin resulted in the increased phosphorylation of AQP2 at S261 through the increased cyclin-dependent kinases 1 and 5 and protein phosphatase 2B. These results suggest that empagliflozin may contribute in part to polyuria via its regulation of sodium channels and AQP2 in diabetic kidneys.

Aims The status of metabolic abnormalities including impaired fasting glucose (IFG) can change over time, yet little is known about how exposure duration to IFG is related to diabetes risk. Methods Using nationally representative data from the Korean National Health Insurance system, 2,513,127 people who were free of diabetes and who received four consecutive annual health examinations commencing in 2006 or 2007 were followed up at the end of 2016. IFG was defined as fasting blood glucose levels of 100–125 mg/dL. Participants were classified numerically according to the cumulative number of IFG diagnoses. Results Over 4 years, 53% of the population participants remained normoglycemic, while 3% had persistent IFG and 44% had intermittent IFG. The risk of type 2 diabetes mellitus (DM) increased gradually with increasing IFG exposure score. Subjects with an IFG exposure score of 2, 3, or 4 had a 3.75- to 9.77-fold increased hazard ratio (HR) for incident diabetes (IFG exposure score 0 reference; score 2, HR 3.75, 95% confidence interval [CI] 3.67–3.83; score 3, HR 6.21, 95% CI 6.08–6.36; score 4, HR 9.77, 95% CI 9.53–10.02). Conclusions Cumulative IFG exposure was associated with a higher risk of type 2 DM in a dose–response fashion.

Hyperuricemia is a significant risk factor for cardiovascular morbidity and chronic kidney disease progression. IgA nephropathy (IgAN) is a well-known primary glomerular nephropathy. Hyperuricemia is associated with a poor prognosis in IgAN patients. We evaluated the association of hyperuricemia with the histopathological severity of IgAN in male and female patients, 658 patients diagnosed with IgAN via kidney biopsy were initially included. Baseline patient data were collected by eight university hospitals affiliated with the College of Medicine of the Catholic University of Korea. Pathological features were independently evaluated by eight expert pathologists working in the hospitals, and the consensus was reached. Of the initial 658 patients, 517 were finally included (253 males and 264 females). Hyperuricemia was defined as a serum uric acid (UA) level &gt, 7.0 mg/dL for males and &gt, 5.6 mg/dL for females, 108 (42.7%) males and 95 (35.9%) females exhibited hyperuricemia. Compared to the patients with normal UA levels, the global glomerulosclerosis, segmental sclerosis, mesangial matrix expansion (MME), endocapillary proliferation (ECP), interstitial fibrosis (IF), and tubular atrophy (TA) scores were higher in hyperuricemic males and females. In multivariable linear regression, the serum UA level correlated significantly with the MME, ECP, IF, and TA scores of female IgAN patients only.

Several studies reported the effect of obesity on the progression of IgA nephropathy (IgAN). However, the impact of obesity on the clinicopathologic presentation of IgAN remains uncertain. This is a retrospective cross-sectional study from eight university hospitals in South Korea. Patients were categorized into three groups using the Asia-Pacific obesity classification based on body mass index (BMI). Clinical and histopathologic data at the time of renal biopsy were analyzed. Among 537 patients with IgAN, the obese group was more hypertensive and had lower estimated glomerular filtration rate and more proteinuria than other groups. The histologic scores for mesangial matrix expansion (MME), interstitial fibrosis, tubular atrophy, and mesangial C3 deposition differed significantly between the three groups. Among these histopathologic parameters, BMI was independently positively associated with MME score on multivariable linear regression analysis (p = 0.028). Using multivariable logistic regression analysis, the obese group was independently associated with higher MME scores compared to the normal weight/overweight group (p = 0.020). However, BMI was not independently associated with estimated glomerular filtration rate or proteinuria on multivariable analysis. Obesity was independently associated with severe MME in patients with IgAN. Obesity may play an important pathogenetic role in mesangial lesions seen in IgAN.

Objective It remains unclear which specific combinations of metabolic syndrome (MetS) components confer a higher risk of type 2 diabetes mellitus (T2DM). This study examined the relation of each and combinations of MetS components with the risk of T2DM. Methods We studied the records of 19,475,643 adults aged ≥ 20 years with no history of T2DM from the database of the Korean National Health Insurance Service covering 2009 to 2012. The hazard ratios (HRs) and confidence intervals (CIs) of T2DM were estimated using Cox proportional hazards models. Results During a median follow-up of 5.13 years, 1,906,963 individuals were diagnosed with T2DM. The multivariable-adjusted HRs for T2DM were 1.86 for MetS, 1.821 for elevated fasting plasma glucose (FPG), 1.484 for elevated triglycerides, 1.415 for reduced high-density lipoprotein (HDL) cholesterol, 1.413 for elevated blood pressure (BP), and 1.17 for abdominal obesity compared with those without. In the combinations of two components excluding elevated FPG, subjects with elevated triglycerides and reduced HDL cholesterol had the highest risk of T2DM (HR 1.71; 95% CI, 1.695–1.725). In three components, the highest risk combination was elevated FPG, elevated triglycerides, and reduced HDL cholesterol (HR 3.342; 95% CI, 3.308–3.376). Conclusions The combination of elevated triglycerides and reduced HDL cholesterol were more strongly associated with an increased risk of T2DM than other combinations except for elevated FPG.

Background Because weight control is a cornerstone of diabetes management, it is important to understand the relationship of weight change to risk of cardiovascular disease (CVD) among patients with type 2 diabetes mellitus (DM). We aimed to investigate whether changes in weight early after diagnosis influence the incidence of CVD and all-cause mortality in patients with type 2 DM. Methods Using nationally representative data from the Korean National Health Insurance System, 173,246 subjects with new-onset DM who underwent health examinations during 2007–2012 were included. Weight was measured at the time of diabetes diagnosis and 2 years later. Weight change over 2 years was divided into five categories of 5% weight change, from weight loss ≥ − 10% to weight gain ≥ 10%. Results There were 3113 deaths (1.8%), 2060 cases of stroke (1.2%), and 1767 myocardial infarctions (MIs) (1.0%) during a median follow-up of 5.5 years. Subjects with weight gain ≥ 10% had a significantly higher risk of stroke (hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.23–1.84), compared with the group with stable weight. There was no significant association between weight change after diagnosis of DM and incident MI. All-cause mortality showed a U-shaped curve according to weight change. The group with weight loss ≥ − 10% had the highest HR for all-cause mortality (HR 1.86; 95% CI 1.61–2.14) and the HR for weight gain ≥ 10% was 1.61 (95% CI 1.37–1.89). Conclusions Weight changes of more than 10% after diabetes diagnosis were associated with higher mortality and over 10% weight gain was associated with increased risk of stroke. Electronic supplementary material The online version of this article (10.1186/s12933-019-0838-9) contains supplementary material, which is available to authorized users.

OBJECTIVE This study examined the association between baseline BMI, percentage weight change, and the risk of dementia in patients newly diagnosed with type 2 diabetes. RESEARCH DESIGN AND METHODS Using the South Korean National Health Insurance Service-National Health Screening Cohort database, we identified 167,876 subjects aged ≥40 years diagnosed with new-onset type 2 diabetes between 2007 and 2012. Their weight changes were monitored for ∼2 years after diagnosis, with follow-up assessments occurring for an average of 3.5 years. The hazard ratios (HRs) and Bonferroni-adjusted 95% CIs of all-cause dementia, Alzheimer disease (AD), and vascular dementia were estimated using multivariable Cox proportional hazards regression models. RESULTS We identified 2,563 incident dementia cases during follow-up. Baseline BMI among patients with new-onset type 2 diabetes was inversely associated with the risk of all-cause dementia and AD, independent of confounding variables (P for trend 10% (1.34 [95% CI 1.11–1.63] and 1.38 [1.08–1.76], respectively). Additionally, weight loss >10% was associated with an increased risk of AD (HR 1.26 [95% CI 1.01–1.59]). CONCLUSIONS A lower baseline BMI was associated with increased risks of all-cause dementia and AD in patients with new-onset type 2 diabetes. Weight loss or weight gain after the diagnosis of diabetes was associated with an increased risk of all-cause dementia. Weight loss was associated with an increased risk of AD.

Background/Aims: β2-Microglobulin (β2-M) is a surrogate marker of middle-molecule uremic toxins and is associated with mortality in chronic hemodialysis patients. However, the impact of serum β2-M levels on mortality in peritoneal dialysis (PD) patients is uncertain. The purpose of this study was to examine the association of serum β2-M levels with all-cause mortality in PD patients. Methods: A total of 771 PD patients were selected from the Clinical Research Center registry for end-stage renal disease cohort in Korea. Patients were categorized into 3 groups by tertiles of serum β2-M levels. The primary outcome was all-cause mortality. Results: The median value of serum β2-M was 23.6 mg/l (interquartile range 14.8-33.4 mg/l), and the median follow-up period was 39 months. The Kaplan-Meier analysis showed that the all-cause mortality rate was significantly different according to tertiles of serum β2-M in PD patients (p = 0.03, log-rank). Multivariate Cox proportional analysis showed that the hazards ratio for all-cause mortality was 1.02 (95% CI 1.01-1.04, p = 0.006) per 1 mg/l increase in β2-M after adjustment for multiple confounding factors that relate to malnutrition and inflammation marker. However, serum β2-M was not associated with all-cause mortality after adjustment for residual renal clearance. Conclusions: These results are supportive of the potential role of the serum β2-M level as a predictor of mortality in PD patients.

Background: Impaired vitamin D metabolism may contribute to the development and progression of chronic kidney disease. The purpose of this study was to determine associations of circulating vitamin D with the degree of proteinuria and estimated glomerular filtration rate (eGFR) in patients with biopsy-proven glomerular diseases. Methods: Clinical and biochemical data including blood samples for 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) levels were collected from patients at the time of kidney biopsy. Results: Serum 25(OH)D levels were not different according to eGFR. However, renal function was significantly decreased with lower serum 1,25(OH)2D levels (P < 0.001). The proportions of nephrotic-range proteinuria and renal dysfunction (eGFR ≤ 60 mL/min/1.73 m2) progressively increased with declining 1,25(OH)2D but not 25(OH)D. Multivariable linear regression analysis showed that 25(OH)D was significantly correlated with serum albumin and total cholesterol (β = 0.224, P = 0.006; β = -0.263, P = 0.001) and 1,25(OH)2D was significantly correlated with eGFR, serum albumin and phosphorus (β = 0.202, P = 0.005; β = 0.304, P < 0.001; β = -0.161, P = 0.024). In adjusted multivariable linear regression, eGFR and 24hr proteinuria were independently correlated only with 1,25(OH)2D (β = 0.154, P = 0.018; β = -0.171, P = 0.012), but not 25(OH)D. The lower level of 1,25(OH)2D was associated with the frequent use of immunosuppressive agents (P < 0.001). Conclusion: It is noteworthy in these results that circulating 1,25(OH)2D may be superior to 25(OH)D as a marker of severity of glomerular diseases.

The objective of this study was to evaluate the associations of blood lead and cadmium levels with estimated glomerular filtration rate (eGFR) and proteinuria in Korean adults. This was a cross-sectional study based on the Korea Nation Health and Nutrition Examination Survey (KNHANES) to analyze the association of blood lead and cadmium levels with renal dysfunction and urine protein excretion. We defined renal dysfunction as eGFR

Shoulder pain is a common problem in the elderly, which can frequently lead to disabilities. Adhesive capsulitis, rotator cuff disease, and osteoarthritis are main causes of shoulder pain in the elderly. Because the use of the upper extremity is especially pertinent to maintain independence in the elderly, proper management of shoulder pain is crucial to preserve or restore functional independence by reducing the degree of pain as much as possible. Successful treatment of shoulder pain in the elderly depends on not only an accurate diagnosis of etiologies and appropriate treatments according to clinical characteristics, but also understanding that the mechanisms of developing those diseases were closely related to the degenerative changes with age.

Background: Fabry disease is a rare X-linked lysosomal storage disorder caused by alpha-galactosidase A deficiency. With the advancement of molecular diagnostic tools, more disease-causing mutations in a-galactosidase A (GLA) have been identified in Fabry disease. We found a novel mutation in a Korean family with predominant renal manifestations of the disease. Case presentation: A 24-year-old man who wanted to donate a kidney to his 28-year-old brother with end-stage renal disease of unknown cause was evaluated. The 24-year-old man underwent percutaneous renal biopsy because of an accidentally found proteinuria. Electron microscopy of his renal biopsy showed numerous electron-dense multilamellar inclusions in the epithelial cytoplasm, typical for Fabry disease. Clinical and laboratory evaluation including the assessment of GLA enzyme activity and direct DNA sequencing in four members of the family were performed. Renal biopsy findings in the two affected male patients were described. Re-evaluation of a renal biopsy specimen of his 28-year-old brother obtained when he was diagnosed with renal failure revealed a very focal area of suspicious multilamellated structures in the Bowman's space. DNA sequencing on the young man, his brother, and his mother revealed a novel GLA gene mutation, c.263A > G (p.Tyr88Cys). The three all showed decreased alpha-galactosidase A activity. Conclusion: A novel GLA mutation, c.263A > G (p.Tyr88Cys), was found in a Korean family with predominant renal manifestations of Fabry disease.

Background: Anemia and iron deficiency are universal problems in patients with chronic kidney disease (CKD). However, decisive indicator to guide the further gastrointestinal (GI) workup has not been determined. Methods: We included 104 anemic patients with nondialysis-dependent CKD stages 3-5 (38 patients at stage 3, 26 patients at stage 4, and 40 patients at stage 5). Hemoglobin, serum ferritin, transferrin saturation (TSAT), mean corpuscular volume (MCV), and corrected reticulocyte count data were assessed to evaluate diagnostic utility for bleeding-related GI lesions, which were identified by esophagogastroduodenoscopy and colonoscopy. Results: Bleeding-related GI lesions were found in 55 (52.9%) patients, and patients with stage 5 CKD had a higher prevalence of gastric lesions than patients with CKD stage 3 or 4 (all p < 0.05). The areas under the receiver operating characteristic curves used to predict bleeding-related lesions were 0.69 for TSAT (p = 0.002) and 0.61 for serum ferritin (p = 0.085). The sensitivity and specificity of a cutoff value for TSAT < 20% were 0.59 and 0.74, respectively. Hemoglobin, MCV, and corrected reticulocyte levels had no significant diagnostic utility. On multivariable logistic regression, the chance of GI lesions increased by 6% for each 1% reduction in TSAT and increased 4.1-fold for patients with CKD stage 5 (all p < 0.05). Conclusions: TSAT is a useful indicator for determining the GI workup in anemic patients with nondialysis-dependent CKD stages 3-5. Stage 5 CKD is independently associated with bleeding-related lesions and TSAT should be used cautiously in these patients.

Malnutrition is a major issue in patients with chronic kidney disease (CKD), adversely affecting morbidity, mortality, functional activity and patients’ quality of life. Our knowledge of the pathogenic mechanisms of malnutrition in patients with CKD, including endstage renal disease, has been improved. This has led to the development of clinical practice guidelines for nutritional care in CKD which provide a framework for the nutritional issues facing patients and physiccians. Extensive research in the field of nutrition in patients with CKD has resulted in the formation of general guidelines, although some uncertainties still exist on some of the best therapeutic or preventive options in uremic malnutrition. It is important to search actively for malnutrition since early diagnosis and treatment can improve the prognosis for CKD patients and reduce the monetary costs connected with treatment.

A cross-sectional postal survey. To describe defecation stimulation methods and their outcomes, and to investigate the impact of bowel dysfunction on the quality of life (QoL) in community-dwelling persons with spinal cord injury in South Korea. Community-based, Korea. A cross-sectional postal survey was conducted. Questionnaires were sent to 459 chronic spinal cord injury (SCI) patients who were registered as members of the Korean Spinal Cord Injury Association. Defecation stimulation methods and their outcomes, the impact of bowel dysfunction on the QoL were investigated. A total of 388 subjects (44.5±10.8 year of age; men, 76.0%; duration of time since the onset of SCI, 14.2±9.5 years) responded. Bowel-related general, social and home QoL deterioration was found in >60%. Suppositories (Supp) were most frequently used, followed by digital rectal stimulation (DRS). The mini enema (ME), which is exclusively used in Korea, was utilized in 18.8%. A defecation time of 30 min was more frequently reported in patients who stimulated defecation with Supp than in those who used DRS. The use of MEs and warm-water irrigations were newly identified in Korea. Bowel care-related factors that greatly deteriorate the QoL were fecal incontinence, time in one defecation >60 min, perianal skin problem, flatus incontinence and hemorrhoids. Alleviating these factors might help to improve the QoL. In particular, stimulation methods to reduce time for defecation might be recommended to persons with chronic SCI.

Background Gamma-glutamyltransferase (GGT) is a biomarker of liver injury. GGT has also been reported to be a marker of oxidative stress and a predictor of mortality in the general population. Hemodialysis (HD) patients suffer from oxidative stress. The aim of our study was to investigate the relationship between serum GGT levels and clinical outcomes in HD patients. Methods A total of 1,634 HD patients were enrolled from the Clinical Research Center registry for end-stage renal disease, a prospective cohort in Korea. Patients were categorized into three groups by tertiles of serum GGT levels. The primary outcome was all-cause, cardiovascular, or infection-related mortality and hospitalization. Results During the median follow-up period of 30 months, the highest tertile of serum GGT levels had a significantly higher risk for all-cause mortality (hazard ratio (HR) 2.39, 95% confidence interval (CI), 1.55–3.69, P

Background Anthocyanins are major constituents of food colours and have been reported to possess anti-diabetic activities for potential medicinal use. The precise role of anthocyanins in diabetic nephropathy is poorly understood. We investigated whether anthocyanin-rich Seoritae extract (SE) can potentially prevent oxidative stress and lipotoxicity, which are the main causes of renal damage in diabetic nephropathy, via activation of AMP-activated protein kinase (AMPK) and the consequent effects on its target molecules. Methods Four groups of male C57BLKS/J db/m and db/db mice were used. Diabetic and non-diabetic mice were orally administered 10 mg/kg body weight SE daily for 12 weeks, starting at 8 weeks of age. Results db/db mice treated with anthocyanins showed decreased albuminuria. Anthocyanins ameliorated intra-renal lipid concentrations in db/db mice with improvement of glomerular matrix expansion and inflammation, which was related to increased phosphorylation of AMPK and activation of peroxisome proliferator-activated receptor (PPAR) α and PPARγ, and inhibited the activity of acetyl-CoA carboxylase and sterol regulatory element-binding protein 1. Anthocyanins reversed diabetes-induced increases in renal apoptosis and oxidative stress. In cultured human glomerular endothelial cells, anthocyanins prevented high glucose-induced oxidative stress and apoptosis through activation of AMPK in the same manner. Conclusions The results revealed that anthocyanins ameliorated diabetic nephropathy in db/db mice via phosphorylation of AMPK, the major energy-sensing enzyme, and the consequent effects on its target molecules, which appeared to prevent lipotoxicity-related apoptosis and oxidative stress in the kidney. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0563-4) contains supplementary material, which is available to authorized users.

Background: Although percutaneous renal biopsy remains an essential tool in the diagnosis and treatment of renal diseases, in recent times the traditional procedure of nephrologists has been performed by non-nephrologists rather than nephrologists at many institutions. The present study assessed the safety and adequacy of tissue yield during percutaneous renal biopsy according to practitioners and techniques based on ultrasound. Methods: This study included 658 native renal biopsies performed from 2005 to 2010 at a single centre. The biopsies were performed by nephrologists or expert ultrasound radiologists using the ultrasound-marked blind or real-time ultrasound-guided techniques. Results: A total of 271 ultrasound-marked blind biopsies were performed by nephrologists, 170 real-time ultrasound guided biopsies were performed by nephrologists, and 217 real time ultrasound guided biopsies were performed by radiologists during the study period. No differences in post-biopsy complications such as haematoma, need for transfusion and intervention, gross haematuria, pain, or infection were observed among groups. Glomerular numbers of renal specimens from biopsies performed by nephrologists without reference to any technique were higher than those obtained from real-time ultrasound-guided biopsies performed by expert ultrasound radiologists. Conclusions: Percutaneous renal biopsy performed by nephrologists was not inferior to that performed by expert ultrasound radiologists as related to specimen yield and post-biopsy complications.

Background Renal interstitial fibrosis is a common final pathological process in the progression of kidney disease. This is primarily due to oxidative stress, which contributes to renal inflammation and fibrosis. Nuclear factor-erythroid-2-related factor 2 (Nrf2) is known to coordinate induction of genes that encode antioxidant enzymes. We investigated the effects of oleanolic acid, a known Nrf2 activator, on oxidative stress-induced renal inflammation and fibrosis. Methods One day before unilateral ureteral obstruction (UUO) performed in C57BL/6 mice, oleanolic acid treatment was initiated and was continued until 3 and 7 days after UUO. Renal inflammation and fibrosis, markers of oxidative stress, and changes in Nrf2 expression were subsequently evaluated. Results In the obstructed kidneys of UUO mice, oleanolic acid significantly attenuated UUO-induced collagen deposition and fibrosis on day 7. Additionally, significantly less inflammatory cell infiltration, a lower ratio of Bax to Bcl-2 expression, and fewer apoptotic cells on TUNEL staining were observed in the obstructed kidneys of oleanolic acid-treated mice. Oleanolic acid increased the expression of nuclear Nrf2, heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1 and heat shock protein 70, and decreased lipid peroxidation in the obstructed kidney of UUO mice. There were no changes in the expression of total Nrf2 and Kelch-like ECH-associated protein 1, indicating that oleanolic acid enhanced nuclear translocation of Nrf2. Conclusions These results suggest that oleanolic acid may exert beneficial effects on renal fibrosis by increasing nuclear translocation of Nrf2 and subsequently reducing renal oxidative stress.

The differential diagnosis of hypercalcaemia in patients with end-stage renal disease undergoing dialysis should be considered for causes related or unrelated to renal failure itself or therapies for renal failure. In particular, peritoneal dialysis may hinder awareness of a clinical problem due to its own peculiarities and effects on homeostasis of the body, thus creating misconceptions in interpreting laboratory data and diagnosing a disease. We describe here a case of systemic sarcoidosis which was delayed due to failure to recognise underestimated hypercalcaemia in a patient undergoing peritoneal dialysis. Clinicians need to remain aware of the change of minerals that may arise from peritoneal dialysis and should perform an extensive investigation for the cause of hypercalcaemia.

Objective: In this study, we investigated the predictive capacity of the brachial–ankle aortic pulse wave velocity (baPWV), a marker of arterial stiffness, for the decline in renal function and for cardiovascular events in the early stages of chronic kidney disease (CKD). Method: Two hundred forty-one patients who underwent a comprehensive check-up were included and were divided into two groups according to their estimated glomerular filtration rates (eGFR): patients with CKD categories G2, G3a and G3b (30 ≤ eGFR < 90 ml/min/1.73m 2 , eGFR < 90 group; n=117) and those with eGFR ≥ 90 ml/min/1.73 m 2 (eGFR ≥ 90 group; n=124). The change in renal function, the eGFR change, was determined by the slope of eGFR against time. We analysed whether baPWV was associated with eGFR change or predicted cardiovascular events. Results: baPWV was independently associated with eGFR change in a multivariate analysis of the total patients (β=–0.011, p=0.011) and remained significantly associated with eGFR change in a subgroup analysis of the eGFR < 90 group (β=–0.015, p=0.035). baPWV was independently associated with cardiovascular events (odds ratio=1.002, p=0.048) in the eGFR < 90 group, but not in the eGFR ≥ 90 group. The receiver operative characteristic curve analysis showed that 1,568 cm/sec was the cut-off value of baPWV for predicting CV events in the eGFR < 90 group (area under curve=0.691, p=0.03) Conclusions: In patients with early stages of CKD, baPWV was independently associated with the decline in renal function and short-term cardiovascular events.

A novel robotic mirror therapy system was recently developed to provide proprioceptive stimulus to the hemiplegic arm during a mirror therapy. Validation of the robotic mirror therapy system was performed to confirm its synchronicity prior to the clinical study. The mean error angle range between the intact arm and the robot was 1.97 to 4.59 degrees. A 56-year-old male who had right middle cerebral artery infarction 11 months ago received the robotic mirror therapy for ten 30-minute sessions during 2 weeks. Clinical evaluation and functional magnetic resonance imaging (fMRI) studies were performed before and after the intervention. At the follow-up evaluation, the thumb finding test score improved from 2 to 1 for eye level and from 3 to 1 for overhead level. The Albert's test score on the left side improved from 6 to 11. Improvements were sustained at 2-month follow-up. The fMRI during the passive motion revealed a considerable increase in brain activity at the lower part of the right superior parietal lobule, suggesting the possibility of proprioception enhancement. The robotic mirror therapy system may serve as a useful treatment method for patients with supratentorial stroke to facilitate recovery of proprioceptive deficit and hemineglect., Graphical Abstract

Nafcillin is an antibiotic used for infections due to penicillin-resistant Staphylococcus aureus. In general, the adverse reactions to nafcillin have not been frequent and serious. We report here a new type of adverse reaction to nafcillin in a patient with end-stage renal disease in whom nafcillin caused the unexpected complication of bullous drug eruption and subseqent neutropenia. Three weeks after the start of intravenous nafcillin for the treatment of peritoneal dialysis peritonitis, the patient developed blisters on his right ankle. These became progressive and widespread, with bullae affecting most of the body surface. In addition, neutropenia developed three days after the appearance of bullous skin lesions. Spontaneous recovery of skin lesions and neutropenia was observed after the withdrawal of naficillin. When treating patients with chronic renal failure, physicians should be aware of these rare but potentially severe adverse reactions.

A 32-year-old woman was referred to our hospital with the sudden onset of low back and cervical pain during a hemodialysis session at a local hospital. She had been on hemodialysis because of progressive renal failure due to lupus nephritis. There were no external signs of trauma on physical examination. A few hours after admission …

목적: 신부전은 다발성 골수종에서 종종 발생하며 나쁜 예후를 보인다. 아시아의 다발성 골수종의 발생빈도와 특징은 서양과는 다른 것으로 알려져 있다. 이 연구의 목적은 다발성 골수종 환자들에서 신부전 발생의 위험인자 및 치료 후 신기능 회복 인자를 찾고자 하였다. 방법: 2005년부터 2008년까지 처음 다발성 골수종을 진단 받은 환자를 대상으로 하여 신부전의 발생과 관련된 인자를 조사하였고, 12주간의 치료 후에 신부전의 회복과 관련된 인자를 찾았다. 결과: 진단 당시 221명의 환자 중 86명(39%)에서 신부전이 발생하였다. 이변량 로지스틱 회기 분석에서 낮은 헤모글로빈(OR = 0.813, p = 0.02), 높은 베타-2 마이크로글로불린(OR = 1.006, p < 0.01), ACEi (OR = 2.783, p = 0.04) 사용이 신부전 발생의 독립적인 위험인자로 나타났다. 12주간의 치료 후, 86명 중에서 25 (29%)명의 신기능이 회복되었다. 항암치료에 반응을 보인 경우(OR = 6.044, p < 0.01)와 높은 eGFR (OR = 1.084, p < 0.01)이 회복과 연관된 인자로 나타 났다. 결론: 헤모글로빈 수치, 베타-2 마이크로글로불린, ACEi의 사용이 한국 다발성 골수종 환자에 있어 신부전 발생의 독립적인 위험인자이며 항암 치료에 반응여부와 진단 시의 eGFR이 신기능 회복의 예측인자이다.

Hematologic malignancies and lymphoproliferative disorders have been reported after using tumor necrosis factor-α inhibitor in patients suffering from spondyloarthropathy. Previously reported cases were treated by using infliximab and etanercept. Usually, it takes approximately several months for leukemia or lymphoproliferative disorders to occur after the application of those agents. However, we report a case of acute myeloid leukemia that developed after short term usage of adalimumab in a patient suffering from psoriatic arthritis.

Background The purpose of this study was to evaluate the association between blood manganese levels and the prevalence of chronic diseases in the Korean population. Methods This was a cross-sectional study based on the Korean National Health and Nutrition Examination Survey (KNAHNES). The study included 3996 participants 20 years of age or older whose blood manganese levels had been measured. The participants were also evaluated for the presence of five chronic diseases: diabetes, renal dysfunction, hypertension, ischemic heart disease, and stroke. Results Blood manganese levels were significantly lower in the diabetes group compared with the non-diabetes group (1.26 ± 0.02 vs. 1.35 ± 0.01 μg/dL; p = 0.001) and the renal dysfunction group compared with those with normal renal function (1.28 ± 0.03 vs. 1.35 ± 0.01 μg/dL; p = 0.04). There was no significant association between blood manganese levels and the presence of ischemic heart disease or stroke. A multivariate logistic regression analysis adjusted for age, sex, and body mass index was performed; the odds ratio was 0.652 (95% CI: 0.46–0.92) for diabetes and 0.589 (95% CI: 0.39–0.88) for renal dysfunction when comparing the higher quartiles (Q2-4) with the lowest quartile (Q1) of blood manganese level. The prevalence of diabetes was 7.6% in Q1 and 5.3% in Q2-4 (p = 0.02). Similarly, the prevalence of renal dysfunction was 6.8% in Q1, compared with 4.6% in Q2-4 (p = 0.02). Conclusion The prevalence of diabetes and renal dysfunction increased in participants with low blood manganese levels, suggesting that blood manganese may play a role in glucose homeostasis and renal function.

The patient was a 24-year-old man with a history of Down syndrome who presented himself with a 9-year history of intermittent gross painless hematuria with anemia. There were no external signs of trauma on physical examination except a pale appearance. Laboratory investigations revealed the hemoglobin and hematocrit levels were 6.2 g/dL and 22.5%, respectively. Although his family witnessed another episode of gross hematuria few weeks before admission, urinalysis on admission showed no evidence of hematuria. An initial abdominal ultrasonography showed normal size and echogenicity of both kidneys without definite focal lesion. However, computed tomography of the abdomen revealed entrapment of a retroaortic left renal vein between the aorta and the vertebral column (Fig. 1), indicating posterior nutcracker syndrome. After consultation, it was decided that he should undergo conservative follow-up. Figure 1 Abdominal CT of the patient. (A) The arrowhead indicates dilated left renal vein at the renal hilum. (B) The arrowhead indicates the passing of the left renal vein between the aorta and the vertebral body. The retroaortic left renal vein, also known as posterior nutcracker syndrome, is a rare congenital phenomenon. Because patients with Down syndrome usually have a decreased risk for vascular anomalies because of increased vascular endothelial growth factor inhibitors from an extra copy of chromosome 21, posterior nutcracker syndrome comorbid with Down syndrome is especially a rare diagnosis.