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Background An investigation into the causality of the effects of physical activity and specific sedentary activities on kidney function in the general population is warranted. Methods In this observational cohort study, first, the clinical associations of the prevalence of stages 3–5 chronic kidney disease (CKD) and the estimated glomerular filtration rate (eGFR) with physical activity, determined by self-report or objective wrist-band accelerometer results, and sedentary activities (watching television, using a computer and driving) were investigated in 329 758 UK Biobank participants. To assess causality, a two-sample Mendelian randomization (MR) analysis was performed to investigate the associations of a genetic predisposition to physical activity and a sedentary lifestyle with the risk of kidney function impairment in an independent CKDGen genome-wide association study (N = 567 460). The findings were replicated with the 321 024 UK White British Biobank participants in the allele-score-based one-sample MR. Results A higher degree of self-reported or accelerometer-determined moderate-to-vigorous physical activity was associated with a higher eGFR, while a longer time spent watching television was significantly associated with a lower eGFR and a higher prevalence of CKD. The two-sample MR demonstrated that the genetic predisposition to a higher degree of physical activity was associated with a lower risk of CKD and a higher eGFR, while the genetically predicted television watching duration was associated with a higher risk of CKD and a lower eGFR. The other sedentary behaviors yielded inconsistent results. The findings were similarly replicated in the one-sample MR. Conclusion Physical activity and television watching causally affect kidney function in the general population.

Background Horseshoe kidney (HSK) is a congenital disorder that is usually asymptomatic, but that increases the risks of kidney stones and infectious disease. However, renal outcomes such as end-stage renal disease (ESRD) in patients with HSK remain unclear.MethodsIn total, 146 patients with HSK (age of ≥20 years) from two tertiary hospitals were included in this study. Control individuals who underwent medical check-ups were selected by matching for age, sex, serum creatinine level, hypertension and diabetes. The hazard ratios (HRs) for the risks of ESRD and all-cause mortality were calculated after adjustment for multiple variables.ResultsThe proportions of HSK-related complications for obstruction, kidney stones, urinary tract infection and urogenital cancer were 26, 25, 19 and 4%, respectively. During the median follow-up period of 9 years (maximum 32 years), the incidence of ESRD was 2.6/10 000 person-years. The risk of ESRD in patients with HSK was higher than in control individuals [adjusted HR = 7.6; 95% confidence interval (CI) 1.14–50.47]. All-cause mortality did not differ between the two groups (adjusted HR = 0.6; 95% CI 0.08–4.29).ConclusionsPatients with HSK are at risk of ESRD, which may be attributable to the high prevalence of complications. Accordingly, these patients should be regarded as having chronic kidney disease and require regular monitoring of both kidney function and potential complications.

Background and Aims Linear decline of glomerular filtration rate (GFR) is associated with aggravating the patient outcomes. Serum creatinine, which is commonly used for estimating GFR, often fluctuates throughout the serial measurement. The clinical significance of creatinine fluctuation among the general population whose renal function is prior to chronic kidney disease (CKD) development had not been demonstrated yet. Thus, we investigated the study to evaluate the impact of creatinine variability on patient outcomes. Method A nationwide retrospective cohort study was performed usaing the database of Korean National Health Insurance System. Adult patients who received national health screening program and measured creatinine for ≥3 times between 2012 and 2016 were considered. Those who previously developed CKD were excluded. The variability of creatinine values were presented with variability independent of mean (VIM). The patients were classified into quartiles of the VIM and Q4 presented highest variability of creatinine. Then, the risks of myocardial infarction (MI), stroke and death were assessed according to the extent of variability. Results During the median follow up of 3.27 years, 3,509,899 participants were examined for association of creatinine variability and cardiovascular outcomes. Participants with higher creatinine variability were significantly associated with elevated risk of MI (hazard ratio (HR) (95% confidence interval (95% CI)) 1.11 (1.04-1.18), stroke (HR (95%CI) 1.06 (1.00-1.13)) and death (HR (95%CI) 1.15 (1.09-1.21)), compared to those with the lowest quartile of creatinine variability. Conclusion Increased creatinine variability exhibited association with elevated risk of MI, stroke and death. In general population, whose renal function is prior to CKD development, monitoring of creatinine variability needs to be considered as the parameter of predicting the adverse outcomes, in addition to the decline of GFR.

Background and Aims A recent study demonstrated female rats more rapidly excreted urine sodium and water under saline bolus infusion than male rats, and suggested sexual dimorphisms in renal transporters. However, the sexual differences in renal salt and water excretion was not yet investigated with human data. We purposed to clarify whether the sexual difference of natriuretic and diuretic ability exists, and it contributes to decreasing blood pressure (BP) in nondiabetic chronic kidney disease (CKD) patients. Method This is a secondary analysis of an open-label, randomized, controlled study determining the effect of intensive low-salt diet education on BP and albuminuria in nondiabetic CKD patients. A total of 235 patients had stopped all renin-angiotensin blocking agents or diuretics during a run-in period for eight weeks (0w). After the run-in period, they received olmesartan (40mg daily) for eight weeks (8w), and then maintained the same medicine with low-salt diet education for an additional eight weeks (16w). Results Mean age of premenopausal women (n=50), same-aged young men (n=76), postmenopausal women (n=68), and same-aged older men (n=41) was 40.7, 40.2, 59.0, and 69.9 years old, respectively. Their MDRD eGFR was 76.2, 71.6, 59.8, and 58.8 mL/min/1.73m2, respectively. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) was lower in premenopausal women (129/79 mmHg) than in young men (134/83 mmHg). Daily salt intake decreased in 16w in premenopausal women (1839 → 1288mg, p=0.008) and young men (2494 → 1552mg, p=0.001) compared with them in 0w, while there was no significant change in postmenopausal women (2443 → 2171mg, p=0.610) and older men (2870 → 2366mg, p=0.458). Except for the premenopausal women (136 (0w) → 133 (16w) mEq/day, p=0.749), urine sodium excretion for 24 hours significantly decreased in 16w compared with that in 0w or 8w (young men: 154 (8w) → 137 (16w)mEq/day p=0.042, postmenopausal women: 152 (0w) → 128m (16w)Eq/day p=0.016, older men: 181 (0w) → 145 (16w)mEq/day p=0.019). Also, urine volume was significantly larger in the premenopausal women than in young men in 8w and 16w (8w: 1009 vs. 980mL p=0.002, 16w: 1004 vs. 978mL, p=0.006), while it was not different between postmenopausal women and older men (8w: 1002 vs. 990 p=0.347, 16w: 1003 vs. 1001 p=0.895). The urine volume was positively correlated with BP in the premenopausal women, while it was negatively associated with BP in young men in 16w. Conclusion Although sodium intake was similarly decreased in premenopausal women and young men, urine sodium excretion did not fall, and urine volume increased in premenopausal women. This phenomenon disappeared in postmenopausal women. Augmented natriuretic and diuretic potency might contribute to lower BP in premenopausal women with nondiabetic CKD.

Background and Aims The association of lipid parameters with cardiovascular outcomes and the impact of kidney function on this association have not been thoroughly evaluated in chronic kidney disease (CKD) patients with diabetes. Method We reviewed the National Health Insurance Database of Korea, containing the data of 10,505,818 subjects who received routine check-ups in 2009. We analyzed the association of lipid profile parameters with major adverse cardiovascular events (MACEs) risk and all-cause mortality in a nationally representative cohort of 51,757 lipid-lowering medication-naïve patients who had CKD and diabetes. Results Advanced CKD patients with eGFR Conclusion The LDL-c level predicted the risk for MACEs and all-cause mortality in both early and advanced CKD patients with diabetes, although the patterns of the association differed from each other. However, the TG/HDL-c ratio categories could not predict the risk for either MACEs or all-cause mortality in advanced CKD patients with diabetes, except that the TG/HDL-c ratio predicted MACE risk in early CKD patients with diabetes.

Background and Aims Glomerular diseases, a set of debilitating and complex disease entities, are related to mortality and morbidity. To gain insight into pathophysiology and novel treatment targets of glomerular disease, various types of biospecimens linked to deep clinical phenotyping including clinical information, digital pathology, and well-defined outcomes are required. We provide the rationale and design of the KOrea Renal biobank NEtwoRk System TOward Next-generation analysis (KORNERSTONE). Method The KORNERSTONE, which has been initiated by Korea Centres for Disease Control and Prevention, is designed as a multi-centre, prospective cohort study and biobank for glomerular diseases. Clinical data, questionnaires will be collected at the time of kidney biopsy and subsequently every one year after kidney biopsy. All of the clinical data will be extracted from the electrical health record and automatically uploaded to the web-based database. High-quality digital pathologies are obtained and connected in the database. Various types of biospecimens are collected at baseline and during follow-up: serum, urine, buffy coat, stool, glomerular complementary DNA (cDNA), tubulointerstitial cDNA. All data and biospecimens are processed and stored in a standardised manner. The primary outcomes are mortality and end-stage renal disease. The secondary outcomes will be deterioration renal function, remission of proteinuria, cardiovascular events and quality of life. Disussion Ethical approval has been obtained from the institutional review board of each participating centre and ethics oversight committee. The KORNERSTONE is designed to deliver pioneer insights into glomerular diseases. The study design allows comprehensive, integrated and high-quality data collection on baseline laboratory findings, clinical outcomes including administrative data and digital pathologic images. This may provide various biospecimens and information to many researchers, establish the rationale for future more individualised treatment strategies for glomerular diseases. Conclusion In conclusion, we describe the objectives and clinical protocol for the KORNERSTONE. As the first large-scale glomerulonephropathy cohort study with the integration of clinical data, biospecimens and digital pathologic images in Korea, the KORNERSTONE will help to clarify the natural course, complication profiles, and novel treatment targets of the Asian population with glomerular disease.

Background and Aims A urine metabolomic biomarker from early immunoglobulin A nephropathy (IgAN) can be a useful tool for early detection or prognostic prediction of the disease. Method We profiled the urine metabolomes, using nuclear magnetic resonance (NMR) spectrometry, from 197 IgAN patients with eGFR ≥ 60 mL/min/1.73 m2, and the patients with same kidney function range but have diagnosis of membranous nephropathy (n=81) and minimal change disease (n=50) were included as the disease-control group. Additional 146 healthy controls who received routine health screenings and donated urine samples were included. We calculated the creatinine-adjusted urine concentrations of 27 urine metabolites. Urine metabolites specifically increased in urines from IgAN patients were identified, and their associations with the prognosis of the disease, determined with the outcome of eGFR 30% reduction from baseline, were investigated. Additional kidney biopsy samples from independent patients and controls were stained for molecules included in related biological process for experimental validation. Results Among the 15 metabolites higher in the urines from IgAN patients than those from the healthy controls, only glycine was the metabolite that the median level was significantly higher also than that of the disease-control group. We found that the higher levels of glycine, alanine, citrate, threonine, and valine were significantly associated with higher risks of 30% eGFR reduction in IgAN patients. Among the molecules related to metabolism of glycine, expressions of T and H proteins from glycine cleavage system were significantly reduced in the kidney biopsy slides from independent IgAN patients when compared to the controls. Conclusion Urine glycine may be a prognostic and pathophysiology-related biomarker of IgAN. A further study confirming the clinical usefulness and pathophysiologic significance of urine metabolites in IgAN patients is warranted.

Background and Aims Glomerular hyperfiltration is associated with all-cause mortality. Herein, we evaluated the association between glomerular hyperfiltration and the development of malignant disease, the most common cause of death, in an Asian population. Method We retrospectively reviewed the National Health Insurance Service database of Korea for people who received national health screenings from 2012 to 2013. Glomerular hyperfiltration was defined as the 95th percentile and greater after adjusting for age and sex. We performed a multivariate Cox regression analysis using glomerular hyperfiltration at the first health screening as the exposure variable and cancer development as the outcome variable to evaluate the impact of glomerular hyperfiltration on the development of malignant disease. Results A total of 1,953,123 examinations who followed-up for 4.9 years were included in this study. Among the 8 different site-specific malignant disease categories, digestive organs and female genital organs showed a significant associations between glomerular hyperfiltration and malignancy. The population with glomerular hyperfiltration showed an increased risk for stomach cancer (adjusted hazard ratio [aHR], 1.27), colorectal cancer (aHR, 1.23), and liver or intrahepatic malignancy (aHR, 1.40). In addition, the risk for uterine and ovarian cancer was significantly increased in the population with glomerular hyperfiltration (aHR, 1.36). Conclusion Glomerular hyperfiltration was associated with an increased risk for the development of malignant diseases in specific organs, such as the stomach, colorectum, uterus, and ovary. Glomerular hyperfiltration needs to be considered a significant sign of the need to evaluate the possibility of hidden adverse health conditions, including malignancies.

Background and Aims Cardiovascular disease is major cause of mortality among chronic kidney disease (CKD) patients, and it is fundamental to focus on reducing the potential risk factors. Regular physical activity is known to reduce the risk of cardiovascular disease in general population. However, whether the change of physical activity habits is beneficial for pre-dialysis CKD patients had not been examined thoroughly. Method We performed a nationwide population based cohort study using the database of Korean National Health Insurance System. Among adult patients who received national health screening program ≥2 times between 2012 and 2016, CKD patients were identified using the serum creatinine and dipstick albuminuria measurements. Those who previously underwent dialysis or diagnosed cardiovascular disease were excluded. The frequency and the intensity of the physical activity were obtained at least twice, from self-reported questionnaire during the health examination. The study groups were divided according to the status of physical activity habit alteration; active, quit exercise, start exercise, and inactive group. Then, the development of myocardial infarction (MI), stroke or death was assessed using the multivariate Cox regression analysis. Results During the median follow up of 3.18 years, 549,187 CKD patients were examined for adverse outcomes. Compared to those who remained inactive, the active group patients who consistently continued physical activity exhibited lower risk of MI (hazard ratio (HR); 0.76, 95% confidence interval (95% CI); 0.69-0.85), stroke (HR (95%CI) 0.69 (0.62-0.78)), and death (HR (95%CI) 0.62 (0.57-0.67)). Moreover, those who newly started physical activity also showed lower risk of adverse outcomes, compared to the inactive group (HR (95%CI) 0.83 (0.76-0.89)). Conclusion Continuation of physical activity in pre-dialysis CKD patients is beneficial to reduce the risk of cardiovascular disease development. Therefore, clinicians should encourage even mild intensity of physical activity to CKD patients.

BackgroundSignal transducer and activator of transcription 3 (STAT3) is a latent transcription factor critical for T-cell function. Although inhibition of the Janus kinase 2 (JAK2)/STAT3 pathway has been reported to be protective against ischemia-reperfusion injury (IRI), the role of T cell–associated STAT3 in the pathogenesis of renal IRI has not been specifically defined.MethodsWe induced renal IRI in both mice with T cell–specific STAT3 knockout (Lck-Cre;STAT3flox/flox) and wild-type controls (C57BL/6) and assessed renal damage and inflammation at 48 h after IRI. Human proximal tubular epithelial cells grown under hypoxia were treated with a JAK2 inhibitor, caffeic acid 3,4-dihydroxy-phenylethyl ester, to determine the effect of JAK2/STAT3 inhibition on renal epithelia. Independently, we disrupted Cln 3-requiring 9 (Ctr9) to inhibit T helper 17 (Th17) activation via RNA interference and determined if Ctr9 inhibition aggravates renal injury through upregulated Th17 activation.ResultsThe Lck-Cre;STAT3flox/flox mice exhibited significantly reduced kidney damage compared with controls. This protective effect was associated with reduced intrarenal Th17 infiltration and proinflammatory cytokines. Human proximal tubular epithelial cells under hypoxia exhibited significant upregulation of interleukin 17 receptors, and pharmacologic inhibition of JAK2 significantly ameliorated this change. RNA interference with Ctr9 in splenocytes enhanced differentiation into Th17 cells. In vivo knockdown of Ctr9 in mice with renal IRI further aggravated Th17-associated inflammation and kidney injury.ConclusionsSTAT3 in T cells contributes to renal IRI through Th17 activation. Inhibition of Ctr9 further enhances Th17 activation and aggravates kidney injury, further supporting the role of Th17 cells in renal IRI.

Background Recent studies regarding immunoglobulin A nephropathy (IgAN) suggest no relationship between pregnancy and disease progression, although complicated pregnancies and impaired renal function are closely related. Methods This study used a propensity-score-matched cohort analysis. Among biopsy-confirmed IgAN women in three hospitals in Korea, those who experienced pregnancy after their diagnosis were included in the study group. Renal outcome was the composite of serum creatinine doubling, estimated glomerular filtration rate (eGFR) halving and events of end-stage renal disease. Pregnancies with preterm birth, low birth weight and pre-eclampsia were defined as complicated. Results Overall, 59 IgAN women who became pregnant after their diagnosis, and the same number of IgAN women who did not experience pregnancy were included in the control group. Although pregnancy itself did not worsen renal outcomes [adjusted hazard ratio (HR): 1.51; 95% confidence interval (CI) 0.57-4.01; P = 0.41], mothers with complicated pregnancies experienced worse renal prognosis, even after adjustment for baseline and pre-gestational characteristics (adjusted HR: 5.07; 95% CI 1.81-14.22; P = 0.002). Moreover, this relationship was only significant in mothers with decreased renal function (eGFR

The causes of accelerated atherosclerosis in end-stage renal disease (ESRD) patients are unknown, although recent studies have suggested that Chlamydia pneumoniae (Cp) infection and inflammation might be contributing factors. We aimed to evaluate the association of carotid atherosclerosis progression with Cp infection and inflammation in patients undergoing peritoneal dialysis (PD).This is a prospective observational study. A total of 52 non-diabetic prevalent PD patients were included. The intima-media thickness of a common carotid artery (CCA-IMT) was measured at baseline and after 36 months by B-mode ultrasonography. Serum antibodies to Cp and inflammatory markers were obtained at the time of initial measurement of the CCA-IMT.CCA-IMT progressors (deltaCCA-IMTor = 0.015 mm/year) had a higher prevalence of seropositivity for Cp IgA antibody, a higher level of Cp IgA antibodies indices, log IL-(interleukin-)6, and intercellular adhesion molecule-1 (ICAM-1) compared to the non-progressors (deltaCCA-IMT0.015 mm/year). On multivariate analysis, Cp IgA index and log IL-6 were independent risk a factors for CCA-IMT progression. Also, Cp IgA index had independent positive correlation with the magnitude of annual deltaCCA-IMT. Cp IgA antibody seropositive patients showed significantly higher mean annual deltaCCA-IMT than seronegative patients. Moreover, patients with both positive Cp IgA antibodies and elevated IL-6 above the median level showed higher deltaCCA-IMT than those with either factor alone.Our data showed that Cp and inflammation were significant risk factors of CCA-IMT change in PD patients. This study strengthens evidence that Cp is involved in the pathogenesis of atherosclerosis and also suggests that the effect of Cp infection under high inflammatory status might be a risk factor for progression of atherosclerosis.