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To investigate the association of body weight variability (BWV) with adverse cardiovascular (CV) outcomes in patient with pre-dialysis chronic kidney disease (CKD), a total of 1867 participants with pre-dialysis CKD from Korean Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) were analyzed. BWV was defined as the average absolute difference between successive values. The primary outcome was a composite of non-fatal CV events and all-cause mortality. Secondary outcomes were fatal and non-fatal CV events and all-cause mortality. High BWV was associated with increased risk of the composite outcome (adjusted hazard ratio (HR) 1.745, 95% confidence interval (CI) 1.065 to 2.847) as well as fatal and non-fatal CV events (adjusted HR 1.845, 95% CI 1.136 to 2.996) and all-cause mortality (adjusted HR 1.861, 95% CI 1.101 to 3.145). High BWV was associated with increased risk of fatal and non-fatal CV events, even in subjects without significant body weight gain or loss during follow-up periods (adjusted HR 2.755, 95% CI 1.114 to 6.813). In conclusion, high BWV is associated with adverse CV outcomes in patients with pre-dialysis CKD.

Maslinic acid (MA), also named crategolic acid, is a pentacyclic triterpene extracted from fruits and vegetables. Although various beneficial pharmacological effects of MA have been revealed, its effect on renal fibrosis remains unclear. This study was designed to clarify whether MA could attenuate renal fibrosis and determine the putative underlying molecular mechanisms. We demonstrated that MA-treated mice with unilateral ureteral obstruction (UUO) developed a histological injury of low severity and exhibited downregulated expression of fibrotic markers, including α-smooth muscle actin (α-SMA), vimentin, and fibronectin by 38, 44 and 40%, and upregulated expression of E-cadherin by 70% as compared with untreated UUO mice. Moreover, MA treatment restored the expression levels of α-SMA, connective tissue growth factor, and vimentin to 10, 7.8 and 38% of those induced by transforming growth factor (TGF)-β in NRK49F cells. MA decreased expression of Smad2/3 phosphorylation and Smad4 in UUO kidneys and TGF-β treated NRK49F cells ( p < 0.05, respectively). Notably, MA specifically interferes with MyD88, an adaptor protein, thereby mitigating Smad4 nuclear expression ( p < 0.01 compared to TGF-β treated group) and ameliorating renal fibrotic changes ( p < 0.01 for each fibrotic markers compared to TGF-β induced cells). In addition, in the UUO model and lipopolysaccharide-induced NRK49F cells, MA treatment decreased the expression of IL-1β, TGF-α and MCP-1, ICAM-1, associated with the suppression of NF-κB signaling. These findings suggest that MA is a potential agent that can reduce renal interstitial fibrosis, to some extent, via targeting TGF-β/Smad and MyD88 signaling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sun, Byon, Kim, Choi, Park, Joo, Kim, Jung, Bae, Ma and Kim.)

Apparent treatment-resistant hypertension (ATRH) is closely related to chronic kidney disease (CKD); however, the long-term outcomes and the effects of improvement in ATRH in patients with CKD are not well understood. We evaluated the relationship between the persistence of ATRH and the progression of CKD. This cohort study enrolled 1921 patients with CKD. ATRH was defined as blood pressure above 140/90 mmHg and intake of three different types of antihypertensive agents, including diuretics, or intake of four or more different types of antihypertensive agents, regardless of blood pressure. We defined ATRH subgroups according to the ATRH status at the index year and two years later. The prevalence of ATRH at baseline was 14.0%. The presence of ATRH at both time points was an independent risk factor for end-point renal outcome (HR, 1.41; 95% CI, 1.04-1.92; p = 0.027). On the other hand, the presence of ATRH at any one of the time points was not statistically significant. In conclusion, persistent ATRH is more important for the prognosis of renal disease than the initial ATRH status. Continuous follow-up and appropriate treatment are important to improve the renal outcomes.

Background: Minimal change disease (MCD) is one of the most common causes of nephrotic syndrome worldwide. Hyperuricemia increases the end-stage renal disease (ESRD) risk in glomerulonephritis. In this study, we aimed to determine the effect of high serum uric acid levels on the progression to ESRD in MCD., Methods: A total of 800 patients diagnosed with MCD by kidney biopsy were retrospectively analyzed. We determined the relationship of hyperuricemia with the progression to ESRD in MCD using the Cox proportional hazard model and Kaplan-Meier survival analysis. The primary outcome was defined as the initiation of dialysis or kidney transplantation., Results: A total of 42 patients (5.3%) progressed to ESRD during the follow-up period. In the restricted cubic spline curve, serum uric acid levels exhibited a positive correlation with ESRD progression in patients with MCD. In the fully adjusted model, the risk of MCD progression increased by 29% for every 1 mg/dL increase in the baseline serum uric acid level (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.09-1.54; p = 0.004). Falling into the high uric acid group (serum uric acid level > 7 mg/dL in men and > 6 mg/dL in women) was also a risk factor for progression of MCD to ESRD (HR, 3.40; 95% CI, 1.59-7.31; p < 0.001)., Conclusion: Our study shows that hyperuricemia is an independent risk factor for the progression to ESRD in patients with MCD.

Background: Hypertension is the most important modifiable risk factor for mortality and morbidity in chronic kidney disease and coronary artery syndrome. The effect of hypertension prior to percutaneous coronary intervention (PCI) on the development of end-stage renal disease (ESRD) is unknown., Methods: We used nationally representative data from the Korean National Health Insurance System-140,164 subjects were enrolled during 2010-2015; they were free of ESRD at enrolment, underwent PCI, and were followed up until 2017. Blood pressure (BP) was measured within at least 2 years prior to PCI. The primary outcome was the development of ESRD., Results: During a median follow-up of 5.4 years, 2,082 participants (1.5%) developed ESRD. The highest systolic BP group (>160 mmHg) showed a higher hazard ratio (3.69; 95% confidence interval, 2.61-5.23) than the reference group (110-119 mmHg). Similar results were observed in the highest diastolic BP group (>120 mmHg), which showed a higher hazard ratio than the reference group (70-79 mmHg). However, ESRD risk showed a J-shaped relationship with baseline systolic and diastolic BP at 113 and 74 mmHg in diabetes mellitus subgroup, respectively, after adjustment for potential confounders., Conclusion: Our study showed that a high systolic or diastolic BP prior to PCI was independently associated with an increased incidence of ESRD.

Background: Although anastomosing hemangiomas are very rare and benign vascular neoplasms, these tumors are more common among patients with end-stage kidney disease. Incidental finding of these tumors in the kidney or adrenal gland has been reported. Herein, we describe a case in which an anastomosing hemangioma was misdiagnosed as a renal cell carcinoma before kidney transplant., Case Presentation: A 35-year-old woman with lupus nephritis was admitted to our emergency department for suspected uremic symptoms of nausea and general weakness. She had received hemodialysis due to end-stage kidney disease, and a living-donor kidney transplantation from her father was planned. On pre-operative contrast-enhanced computed tomography and magnetic resonance imaging, a 1.7 cm renal cell carcinoma was observed in the right kidney. On staining after radical nephrectomy, irregularly shaped vascular spaces of various sizes were observed, with these spaces having an anastomosing pattern. As the findings of the anastomosing hemangioma are similar to those of a renal cell carcinoma on imaging, histology examination was necessary to confirm the diagnosis of anastomosing hemangioma and to prevent delay in listing for kidney transplantation. Good kidney function was achieved after transplantation, with no tumor recurrence., Conclusion: Our case underlines the importance for prompt surgical resection of an enhancing renal mass to confirm diagnosis in patients scheduled for kidney transplantation to avoid any delay., (© 2021. The Author(s).)

Rapidly growing tumors often experience hypoxia and nutrient (e.g., glucose) deficiency because of poor vascularization. Tumor cells respond to the cytotoxic effects of such stresses by inducing molecular adaptations that promote clonal selection of a more malignant tumor-initiating cell phenotype, especially in the innermost tumor regions. Here, we report a regulatory mechanism involving fucosylation by which glucose restriction promotes cancer stemness to drive drug resistance and tumor recurrence. Using hepatocellular carcinoma (HCC) as a model, we showed that restricted glucose availability enhanced the PERK/eIF2α/ATF4 signaling axis to drive fucosyltransferase 1 (FUT1) transcription via direct binding of ATF4 to the FUT1 promoter. FUT1 overexpression is a poor prognostic indicator for HCC. FUT1 inhibition could mitigate tumor initiation, self-renewal, and drug resistance. Mechanistically, we demonstrated that CD147, ICAM-1, EGFR, and EPHA2 are glycoprotein targets of FUT1, in which such fucosylation would consequently converge on deregulated AKT/mTOR/4EBP1 signaling to drive cancer stemness. Treatment with an α-(1,2)-fucosylation inhibitor sensitized HCC tumors to sorafenib, a first-line molecularly targeted drug used for advanced HCC patients, and reduced the tumor-initiating subset. FUT1 overexpression and/or CD147, ICAM-1, EGFR, and EPHA2 fucosylation may be good prognostic markers and therapeutic targets for cancer patients.

Psoriasis, a chronic inflammatory dermatosis, has been associated with chronic kidney disease or end-stage renal disease. However, the association of the changes or amount of proteinuria with psoriasis development has not been evaluated. Using the Korean National Health Screening database, we assessed psoriasis development until 2018 in 6,576,851 Koreans who underwent health examinations in 2009 and 2011. Psoriasis was defined using the International Classification of Diseases, 10th revision (ICD-10) code L40. The risk of psoriasis was evaluated according to change in proteinuria (never [Neg (no proteinuria)/Neg], new [Neg/Pos (proteinuria present)], past [Pos/Neg] and persistent [Pos/Pos] proteinuria) and the proteinuria amount. During a median 7.23-year follow-up, 162,468 (2.47%) individuals developed psoriasis. After adjustments, the hazard ratio (HR) for psoriasis was higher in the persistent proteinuria group (1.32 [1.24-1.40]) than in the never proteinuria group. The past proteinuria group showed better renal outcome (1.03 [1.00-1.07]) than the new (1.05 [1.01-1.07]) and never proteinuria (reference, 1.00) groups did. The amount of random urine proteinuria was associated with increased HR for psoriasis. Subgroup analyses for age, sex, estimated glomerular filtration rate (eGFR), hypertension and diabetes showed that the persistent proteinuria group had a higher risk of psoriasis than the never proteinuria group, especially at eGFR < 60 mL/min/1.73 m 2 . Persistent proteinuria is associated with psoriasis risk, and the proteinuria amount significantly affects psoriasis development.

ACE inhibitors or angiotensin II receptor blockers (ACEi/ARBs) have been a cornerstone of the management in kidney disease, but their use is often limited by undesired systemic effects, such as symptomatic hypotension. To minimize the extra-renal effects of ACEi/ARBs, we formulated hydrophobically modified glycol chitosan (HGC) nanomicelles releasing olmesartan (HGC-Olm) that specifically accumulated in the kidney, and investigated whether kidney-specific delivery of olmesartan by HGC nanomicelles could ameliorate organ damage in Col4a3 -/- mouse, a murine model of progressive chronic kidney disease mimicking human Alport syndrome. Ex vivo tracing demonstrated that intravenously injected HGC-Olm nanomicelles were specifically delivered to the kidney, with sustained release of olmesartan for more than 48 h. Contrary to the conventional delivery of olmesartan via oral route, injection of HGC-Olm nanomicelles did not alter blood pressure in Col4a3 -/- mice. Immunohistochemistry revealed that HGC nanomicelles were diffusely distributed from the cortex and glomeruli to the outer medulla, sparing the inner medulla. Phenotypic analysis showed that the attenuation of kidney fibrosis in the kidney of Col4a3 -/- mice by HGC-Olm nanomicelles was comparable to that noted with conventionally delivered olmesartan. Therefore, our results suggest that HGC-Olm nanomicelles could be a safe and effective alternative drug delivery system for kidney diseases., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background/aims: This study aimed to investigate whether urinary angiotensinogen (UAGT) excretion was associated with elevated blood pressure in patients with chronic kidney disease (CKD) and to evaluate the relationship among blood pressure, intra-renal renin-angiotensin system (RAS) activity, and dietary sodium in patients with CKD., Methods: Participants from the Korean Cohort Study for Outcome in Patients with Chronic Kidney Disease (KNOW-CKD) were included. Of the total cohort of 2,238 individuals with CKD, we included 1,955 participants who underwent complete 24-hour urinary sodium (24-hour UNa) analysis. They were categorized into three groups according to three tertiles of their 24-hour UNa, reflecting daily salt intake. To measure intra-renal RAS activity, the UAGT excretion was assayed with an enzyme-linked immunosorbent assay., Results: Elevated 24-hour UNa levels, logarithm of UAGT-to-creatinine ratio (UAGT/Cr), increased waist-to-hip ratio, and decreased estimated glomerular filtration rate were the risk factors for increased systolic blood pressure. Systolic blood pressure showed a positive correlation with 24-hour UNa levels and logarithm of UAGT/Cr., Conclusion: UAGT and urinary sodium excretion are independent determinants of systolic blood pressure in patients with CKD. These findings suggest that increased systolic blood pressure in CKD patients is associated with both increased dietary sodium levels and intra-renal RAS activity. The risk of elevated systolic blood pressure in the 3rd tertile of both the UAGT/Cr and 24-hour UNa groups was about 2.3 times higher than that in the reference group.

Background: Recently, we developed hydrophobically modified glycol chitosan (HGC) nanomicelles loaded with tacrolimus (TAC) (HGC-TAC) for the targeted renal delivery of TAC. Herein, we determined whether the administration of the HGC-TAC nanomicelles decreases kidney injury in a model of lupus nephritis. Lupus-prone female MRL/lpr mice were randomly assigned into three groups that received intravenous administration of either vehicle control, an equivalent dose of TAC, or HGC-TAC (0.5 mg/kg TAC) weekly for 8 weeks. Age-matched MRL/MpJ mice without Fas lpr mutation were also treated with HGC vehicle and used as healthy controls., Results: Weekly intravenous treatment with HGC-TAC significantly reduced genetically attributable lupus activity in lupus nephritis-positive mice. In addition, HGC-TAC treatment mitigated renal dysfunction, proteinuria, and histological injury, including glomerular proliferative lesions and tubulointerstitial infiltration. Furthermore, HGC-TAC treatment reduced renal inflammation and inflammatory gene expression and ameliorated increased apoptosis and glomerular fibrosis. Moreover, HGC-TAC administration regulated renal injury via the TGF-β1/MAPK/NF-κB signaling pathway. These renoprotective effects of HGC-TAC treatment were more potent in lupus mice compared to those of TAC treatment alone., Conclusion: Our study indicates that weekly treatment with the HGC-TAC nanomicelles reduces kidney injury resulting from lupus nephritis by preventing inflammation, fibrosis, and apoptosis. This advantage of a new therapeutic modality using kidney-targeted HGC-TAC nanocarriers may improve drug adherence and provide treatment efficacy in lupus nephritis mice.

Background Hypertension among young adults is common. However, the effect of isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), or systolic and diastolic hypertension (SDH) among young adults on chronic kidney disease (CKD) development is unknown. Methods and Results From a nationwide health screening database, we included 3 030 884 participants aged 20 to 39 years who were not taking antihypertensives at baseline examination in 2009 to 2010. Participants were categorized as having normal blood pressure (BP), elevated BP, stage 1 IDH, stage 1 ISH, stage 1 SDH, stage 2 IDH, stage 2 ISH, and stage 2 SDH. The primary outcome was incident CKD. A total of 5853 (0.19%) CKD events occurred. With normal BP as the reference, multivariable-adjusted hazard ratios (HRs) (95% CIs) for CKD were 1.14 (95% CI, 1.04-1.26), elevated BP; 1.19 (95% CI, 1.10-1.28), stage 1 IDH; 1.24 (95% CI, 1.08-1.42), stage 1 ISH; 1.39 (95% CI, 1.28-1.51), stage 1 SDH; 1.88 (95% CI, 1.63-2.16), stage 2 IDH; 1.84 (95% CI, 1.54-2.19), stage 2 ISH; 2.70 (95% CI, 2.44-2.98), stage 2 SDH. The HRs for CKD were attenuated in the patients who were antihypertensive and began medication within 1 year of medical checkup than in those without antihypertensives. Conclusions Among Korean young adults, those with elevated BP, stage 1 IDH, stage 1 ISH, stage 1 SDH, stage 2 IDH, stage 2 ISH, and stage 2 SDH were associated with a higher CKD risk than those with normal BP. The CKD risk in ISH and IDH groups was similar but lower than that in the SDH group. Antihypertensives attenuated the risk of CKD in young adults with hypertension.

Abstract: Data on the overall epidemiology and temporal trends of end-stage renal disease (ESRD) requiring hemodialysis in Korea are scarce. We aimed to estimate the prevalence and incidence of ESRD requiring hemodialysis in Korea between 2002 and 2017.Using the National Health Insurance Service database, we analyzed data from the entire Korean population between 2002 and 2017. Hemodialysis patients were identified using rare incurable disease codes (V001) or prescription of medical fee codes of hemodialysis (O7020 and O7021). We only included patients who had been maintained on hemodialysis for more than 90 days from the date of dialysis initiation, to exclude patients who required short-term dialysis for acute kidney injury, conversion to peritoneal dialysis, or kidney transplantation.During the 16-year follow-up, the number of hemodialysis patients in Korea has steadily increased from 11,215 in 2002 to 67,486 in 2017. The mean age of these patients has gradually increased from 55.57 ± 13.31 years in 2002 to 62.13 ± 13.23 years in 2017. In 2017, the crude prevalence rate of hemodialysis was 1303.4 per million population. Overall, the number of men tended to be somewhat higher than that of women, and the proportion of men increased slightly from 55.56% in 2002 to 58.45% in 2017. The proportion of diabetic patients increased rapidly from 23.84% to 47.84%, and the percentage of dyslipidemic patients rose from 18.9% to 86.7%. The number of incident hemodialysis patients increased significantly from 4406 in 2003 to 12,134 in 2014, and then decreased to 8090 in 2017. In the incident cases of hemodialysis, the observed increase in the proportion of male patients and in diabetes and dyslipidemia were similar to that of prevalent patients. The more recent era of hemodialysis initiation, the better 5-year survival rates were observed.The prevalence and incidence of hemodialysis in Korea gradually increased between 2002 and 2017. The proportion of men, and patients with diabetes and dyslipidemia requiring hemodialysis also increased continuously. The survival rate of hemodialysis patients was gradually improving. These findings may serve as a reference for future epidemiological studies on hemodialysis in Korea., Competing Interests: The authors have no conflict of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene (GLA). Male patients of FD develop early sign and symptoms in childhood or adolescence. However, "de novo somatic mosaicism" is rare and might be developed a relatively mild phenotype despite carrying a classic type. A 34-year-old male patient visited with foamy urine. Renal biopsy findings were consistent with FD. Leukocyte α-galactosidase activity was markedly reduced at 5.3 nmol/hr/mg (normal range, 25-126). Sequence analysis of the patient's GLA gene identified mosaicism for the mutation GLA[NM&#95;000169.2] c.820=/G>C. This mutation results in a substitution of the amino acid in position 274 from glycine to arginine. However, no family members showed FD-related symptoms, and the daughter of the patient was also tested for paternity and was identified as a real biological daughter, but DNA sequence analysis for FD showed no mutations. Based on these results, we diagnosed the patients as de novo mutation with somatic mosaicism. Next generation sequencing turned out that 58% of the readings had the mutated allele in buccal cells, 84% in blood, and 85% in urine, when 100% should be expected in a hemizygous affected male confirming the presence of somatic mosaicisms. The patient has been on treatment for enzyme replacement therapy (agalsidase-β, 1.0 mg/kg biweekly) for past 9 years and has maintained normal renal function (serum creatinine 1.0 mg/dL) with mild albuminuria (123 mg/g Cr). Therefore, this case suggests somatic mosaicism is one of important phenotype modifiers.

Autophagy is important for cells to break down and recycle cellular proteins, remove damaged organelles, and especially, for recovery from acute kidney injury (AKI). Despite research on the role and cellular mechanism of autophagy in AKI, the role of autophagy in the progression to chronic kidney disease (CKD) remains poorly understood. Here, using farnesoid X receptor (FXR) knockout (KO) mice, we determined whether FXR prevents the progression of AKI to CKD after renal ischemic-reperfusion (such as I/R) injury through the regulation of renal autophagy and apoptosis. FXR regulated genes that participate in renal autophagy under feeding and fasting conditions, such as hepatic autophagy, and the activation of FXR by agonists, such as GW4064 and INT-747, attenuated the increased autophagy and apoptosis of hypoxia-induced human renal proximal tubule epithelial (HK2) cells. The expression levels of autophagy-related and apoptosis-related proteins in FXR KO mice were increased compared with those in wild-type (WT) mice. We also showed that the increase in reactive oxidative species (ROS) in hypoxia-treated HK2 cells was attenuated by treatment with FXR agonist or by FXR overexpression, and that the level of ROS was elevated in FXR-deficient cells and mice. At 28 days after I/R injury, the autophagy levels were still elevated in FXR KO mice, and the expression levels of fibrosis-related proteins and ROS deposits were higher than those in WT mice. In conclusion, the regulation of renal autophagy and apoptosis by FXR may be a therapeutic target for the early stages of kidney damage, and the progression of AKI to CKD.

Obesity has become a pandemic. It is one of the strongest risk-factors of new-onset chronic kidney disease (CKD). However, the effects of obesity and abdominal obesity on the risk of developing CKD in young adults has not been elucidated. From a nationwide health screening database, we included 3,030,884 young adults aged 20-39 years without CKD during a baseline examination in 2009-2010, who could follow up during 2013-2016. Patients were stratified into five levels based on their baseline body mass index (BMI) and six levels based on their waist circumference (WC; 5-cm increments). The primary outcome was the development of CKD. During the follow up, until 2016, 5853 (0.19%) participants developed CKD. Both BMI and WC showed a U-shaped relationship with CKD risk, identifying the cut-off values as a BMI of 21 and WC of 72 cm in young adults. The obesity group (odd ratio [OR] = 1.320, 95% confidence interval [CI]: 1.247-1.397) and abdominal obesity group (male WC ≥ 90, female WC ≥ 85) (OR = 1.208, 95%CI: 1.332-1.290) showed a higher CKD risk than the non-obesity or non-abdominal obesity groups after adjusting for covariates. In the CKD risk by obesity composite, the obesity displayed by the abdominal obesity group showed the highest CKD risk (OR = 1.502, 95%CI: 1.190-1.895), especially in those under 30 years old. During subgroup analysis, the diabetes mellitus (DM) group with obesity or abdominal obesity paradoxically showed a lower CKD risk compared with the non-obesity or non-abdominal obesity group. Obesity and abdominal obesity are associated with increased risk of developing CKD in young adults but a decreased risk in young adults with diabetes.

In the decades since the discovery of angiotensin-converting enzyme 2 (ACE2), its protective role in terms of antagonizing activation of the classical renin-angiotensin system (RAS) axis has been recognized in clinical and experimental studies on kidney and cardiovascular diseases. The effects of ACE inhibitor/angiotensin type 1 receptor blockers (ACEi/ARBs) on ACE2-angiotensin-(1-7) (Ang- (1-7))-Mas receptor (MasR) axis activation has encouraged the use of such blockers in patients with kidney and cardiovascular diseases, until the emergence of coronavirus disease 2019 (COVID-19). The previously unchallenged functions of the ACE2-Ang-(1-7)-MasR axis and ACEi/ARBs are being re-evaluated in the era of COVID-19; the hypothesis is that ACEi/ARBs may increase the risk of severe acute respiratory syndrome coronavirus 2 infection by upregulating the human ACE2 receptor expression level. In this review, we examine ACE2 molecular structure, function (as an enzyme of the RAS), and distribution. We explore the roles played by ACE2 in kidney, cardiovascular, and pulmonary diseases, highlighting studies that defined the benefits imparted when ACEi/ARBs activated the local ACE2- Ang-(1-7)-MasR axis. Finally, the question of whether ACEi/ARBs therapies should be stopped in COVID-19-infected patients will be reviewed by reference to the available evidence.

Tibetan sheep is one of primitive Chinese sheep breeds, which achieved the divergence about 2500 years ago in Qinghai plateau region. According to different geographic conditions, especially altitudes, Tibetan sheep evolved into different breeds. In this study, we performed whole genome resequencing of 5 representative Tibetan sheep breeds. Comparative genomic analysis showed that they can be divided into different clades with a close genetic relationship. However, some genes with common selective regions were enriched for hypoxic adaptability in different breeds living at higher altitude, including GHR, BMP15, and CPLANE1. Furthermore, breed-specific selective regions about physical characteristics, especially wool growth, were found in genes such as BSND, USP24, NCAPG, and LCORL. This study could contribute to our understanding about trait formation and offer a reference for breeding of Tibetan sheep.

Identification of individuals at risk of hypertension development based on socio-economic status have been inconclusive, due to variable definitions of low socio-economic status. We investigated whether educational status of individuals or their parents predicts prevalent hypertension in young adult population, by analyzing data of more than 37,000 non-institutionalized subjects from Korea National Health and Nutrition Examination Survey 2008 to 2017. Although low educational status of individual subjects was robustly associated with elevation of systolic blood pressure and increased prevalence of hypertension in general population, its impact on prevalent hypertension differed across age subgroups, and was remarkably attenuated in young adults. Parental educational status was significantly associated with prevalent hypertension in young adults, but not or only marginally in elderly population. Low parental educational status was also associated with high sodium intake in young adults, irrespective of subject's own educational status. These collectively indicate that parental educational status, rather than individual's own educational status, better and independently predicts prevalent hypertension in young adults, and that young adults with low parental educational status are prone to intake more sodium, possibly contributing to the increased risk of hypertension development. We expect that our findings could help define young individuals at risk of high sodium intake and hypertension.

Immunoglobin A (IgA) nephropathy causes chronic kidney disease worldwide. Therefore, identifying risk factors associated with the progression of IgA nephropathy is crucial. Anemia is a common complication of chronic kidney disease; however, few studies have investigated the effect of serum hemoglobin on the renal prognosis of IgA nephropathy. This study aimed to determine the effect of serum hemoglobin on the progression of IgA nephropathy. We retrospectively analyzed 4326 patients with biopsy-proven IgA nephropathy. We evaluated the effect of serum hemoglobin on IgA nephropathy progression using Kaplan-Meier survival analyses, the log-rank test, and the Cox proportional hazards model. The primary end-point was progression of IgA nephropathy, defined as dialysis initiation or kidney transplantation. Serum hemoglobin showed a nonlinear relationship with the progression of IgA nephropathy. The Cox proportional hazards model showed that the risk of progression of IgA nephropathy decreased 0.87 times for every 1.0 g/dL increase in serum hemoglobin. In subgroup analyses, reduced serum hemoglobin was an independent risk factor for IgA nephropathy progression only in women. There was no statistically significant interaction of serum hemoglobin between men and women ( P interaction = 0.177). Results of Sensitivity analysis were robust and consistent. Serum hemoglobin at diagnosis was an independent predictor for IgA nephropathy progression.

Background: Inherited cystic kidney disease is a spectrum of disorders in which clusters of renal cysts develop as the result of genetic mutation. The exact methods and pipelines for defining genetic mutations of inherited cystic kidney disease are not clear at this point. This 3-year, prospective, multicenter, cohort study was designed to set up a cohort of Korean patients with inherited cystic kidney disease, establish a customized genetic analysis pipeline for each disease subtype, and identify modifying genes associated with the severity of the disease phenotype., Methods/design: From May 2020 to May 2022, we aim to recruit 800 patients and their family members to identify pathogenic mutations. Patients with more than 3 renal cysts in both kidneys are eligible to be enrolled. Cases of simple renal cysts and acquired cystic kidney disease that involve cyst formation as the result of renal failure will be excluded from this study. Demographic, laboratory, and imaging data as well as family pedigree will be collected at baseline. Renal function and changes in total kidney volume will be monitored during the follow-up period. Genetic identification of each case of inherited cystic kidney disease will be performed using a targeted gene panel of cystogenesis-related genes, whole exome sequencing (WES) and/or family segregation studies. Genotype-phenotype correlation analysis will be performed to elucidate the genetic effect on the severity of the disease phenotype., Discussion: This is the first nationwide cohort study on patients with inherited cystic kidney disease in Korea. We will build a multicenter cohort to describe the clinical characteristics of Korean patients with inherited cystic kidney disease, elucidate the genotype of each disease, and demonstrate the genetic effects on the severity of the disease phenotype., Trial Registration: This cohort study was retrospectively registered at the Clinical Research Information Service ( KCT0005580 ) operated by the Korean Center for Disease Control and Prevention on November 5th, 2020.

Background/aims: Despite recent improvements in the quality of life of patients with systemic lupus erythematosus (SLE), osteoporosis, and osteoporotic fractures are one of the major complications of SLE. Furthermore, limited data are available on the incidence and predictor of osteoporotic fractures in Korean patients with SLE. Herein, we aimed to assess the incidence and risk factors for osteoporotic fractures in Korean SLE patients compared to those without SLE., Methods: SLE patients aged ≥ 40 years (n = 10,434; mean age, 51.3 ± 9.1 years; women, 89.7%) were selected from the Korean National Health Insurance Service database, spanning a period from 2008 to 2014. Age- and sex-matched controls (n = 52,170) were randomly sampled in a 5:1 ratio from non-SLE individuals. The primary outcome was the first occurrence of osteoporotic fracture., Results: The incidence of osteoporotic fractures was significantly higher in the SLE patients (19.085 per 1,000 person-years) than in matched controls (6.530 per 1,000 person-years). According to the multivariable Cox proportional analysis, patients with SLE exhibited a higher osteoporotic fracture rate than the control group (hazards ratio, 2.964; 95% confidence interval, 2.754 to 3.188), even after adjustment for confounding variables. In the subgroup analysis, male SLE patients or SLE patients aged 40 to 65 years were associated with a higher osteoporotic fracture rate than women SLE patients or SLE patients aged ≥ 65 years, respectively., Conclusion: We found a 2.964-fold increased risk of osteoporotic fracture in SLE patients compared to age- and sex-matched non-SLE controls. Male or middle-aged SLE patients had a relatively higher fracture risk among patients with SLE.

The self-assembly of a stimuli-responsive amphiphilic polymer has been of great interest in the area of targeted drug delivery applications. In this article, a new amphiphilic polyurethane with a hydrophobic backbone consisting of a redox-responsive self-immolative unit and hydrophilic pendant triethylene glycol, which is periodically grafted on the backbone by a tertiary amine group, has been designed and synthesized. This amphiphilic polymer self-assembles into a micellar nanostructure (investigated by dynamic light scattering and transmission electron microscopy) in an aqueous medium and shows guest encapsulation property. Furthermore, the pH-responsive nature leads to the formation of a positively charged nanoassembly at a tumor-relevant pH (∼6.5-6.8), which is probed by zeta potential measurements. As the backbone was constructed with self-immolative, redox-responsive functionality, degradation of the polymer was observed in the presence of a reducing agent, glutathione (GSH), which results in disassembly of the self-assembled structure followed by guest release as probed by UV-vis spectroscopy. The triggered degradation and pH-specific charge generation (from neutral to positive), we believe, will have implications in the design of biodegradable polymers as supramoleular scaffolds for biomedical applications.

We report the case of a patient with nephrotic syndrome and toxic epidermal necrolysis (TEN) caused by statin use. The associated hyperlipidemia was controlled using proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitors. This is a unique case of treating hyperlipidemia with PCSK9 inhibitor in patient with nephrotic syndrome with TEN. A 54-year-old woman was admitted owing to generalized edema. She had massive proteinuria and was diagnosed with minimal change disease through kidney biopsy. Statins were used for treatment of hyperlipidemia associated with nephrotic syndrome; however, she developed a skin rash, which progressed to TEN. After discontinuation of statins, her skin symptoms improved; however, hyperlipidemia persisted. Because statins could not be administered, we injected evolocumab, a PCSK9 inhibitor, every 2 weeks. Since then, hyperlipidemia has been well controlled without any side effects. Thus, PCSK9 inhibitors may be a good alternative to control hyperlipidemia in patients with statin intolerance or serious side effects.

Data regarding health behavior-related factors and systolic or diastolic blood pressure to evaluate the association between blood pressure and kidney cancer are lacking. Using nationally representative data from the Korean National Health Insurance System, 9 746 445 participants without kidney cancer between January 1, 2006 and December 31, 2009 were followed up until December 31, 2017 to obtain data regarding cancer incidence. Participants were categorized, according to blood pressure, as normal (<120/80 mm Hg), elevated (120-129/<80 mm Hg), and hypertensive (≥130/80 mm Hg) with or without antihypertensive medication, according to the 2017 American College of Cardiology and American Heart Association blood pressure guidelines. Kidney cancer was noted in 11 083 participants during the 8-year follow-up. Participants with hypertension were at higher risk for kidney cancer than those without hypertension. Participants with hypertension using medication had a higher cancer risk than those not using medication and those with elevated blood pressure. The risk of kidney cancer significantly increased with higher systolic or diastolic blood pressure, in a dose-dependent manner, even after adjusting for antihypertensive medication use. Therefore, hypertension and high systolic or diastolic blood pressure, compared with normal blood pressure, were associated with an increased risk of kidney cancer.

Prolongation of the QT interval by antiarrhythmic drugs is the primary cause of torsade de pointes. Although there are previous reports of drug-induced torsade de pointes in patients undergoing hemodialysis, torsade de pointes caused by a sudden decrease of potassium levels in patients initiating hemodialysis has not been well described. A 70-year-old woman with recurrent bilateral gluteal abscesses visited the hospital for antibiotic treatment. Twenty-eight days after admission, atrial fibrillation with rapid ventricular rhythm was newly detected and was controlled with intravenous amiodarone treatment. After developing pulmonary edema that did not improve with diuretic treatment, she underwent emergency hemodialysis. During hemodialysis, serum potassium and magnesium levels decreased to 3.1 and 1.7 mg/dL, respectively. The electrocardiogram showed torsade de pointes. Amiodarone treatment was stopped, and magnesium sulfate was infused. A higher concentration of potassium dialysate was used in continuous renal replacement therapy. Torsade de pointes episodes halted, and QT interval prolongation normalized. We describe a case with a rare complication of torsade de pointes upon initiating hemodialysis in a patient with QT prolongation. When initiating hemodialysis, serum potassium levels as well as electrocardiograms should be monitored in patients with a prolonged QT interval.

Background/aims: The aim of this study was to evaluate the trend of incidence and prevalence of systemic lupus erythematosus (SLE) in South Korea from 2005 to 2015., Methods: From 2005 to 2015, individuals with SLE were identified from the National Health Insurance database, which records information on almost all Koreans. SLE was defined according to the International Classification of Diseases, 10th revision (ICD-10), code M32. The incidence was calculated per 100,000 person-years. The prevalence was calculated per 100,000 people and stratified by year, age group, sex, region, and income., Results: The annual prevalence of SLE increased slightly from 21.25/100,000 people in 2005 to 35.45/100,000 people in 2015. In contrast, the annual incidence of SLE decreased slightly from 5.42/100,000 person-years in 2005 to 3.6/100,000 person-years in 2015. The prevalence and incidence of SLE were 10- and 6-fold higher in women than in men, respectively. The peak age of prevalence and incidence was 30 to 39 years in 2005; in 2015, the peak age of prevalence was 30 to 49 years and of incidence was 20 to 49 years. Regional variation was observed in both incidence and prevalence of SLE. Jeju province showed the highest prevalence of SLE (44.54/100,000 person-years), and Gwangju province showed the highest incidence of SLE (6.98/100,000 person-years) in 2015. The income status did not affect the prevalence or incidence of SLE except in patients without income who received medical aid., Conclusion: The incidence of SLE has declined, but the prevalence has increased in Korea in recent years. Peak age of SLE trend to right shift in Korea.

In this study based on a large nationally representative sample of Korean adults, we investigated the potential associations of the body mass index (BMI) and waist circumference (WC) with mortality in patients undergoing hemodialysis. We obtained the data of 18,699 participants >20 years of age who were followed up with for 4 years and for whom BMI and WC information were available, using a nationally representative dataset from the Korean National Health Insurance System. Patients were stratified into five levels by their baseline BMI and into six levels by their WC (5-cm increments). A total of 4975 deaths occurred during a median follow-up period of 48.2 months. Participants with a higher BMI had a lower mortality rate than those with a lower BMI. In a fully adjusted Cox regression analysis, being overweight and obese was associated with a significantly lower relative risk of all-cause mortality relative to the reference group. Conversely, the mortality rate was higher among participants with a high WC than among those with a low WC. Participants with the highest WC had a higher risk of mortality, while those with the lowest WC level had a significantly lower risk of mortality. In conclusion, all-cause mortality was positively associated with WC, a measure of abdominal obesity, and inversely associated with BMI, a measure of body volume, in patients undergoing hemodialysis.

Domestic yaks are the most important livestock species on the Qinghai-Tibetan Plateau. Adult female yaks normally breed in warm season and enter anestrous in cold season. Currently, how the ovarian activity is regulated at the molecular level remains to be determined. This study was conducted to investigate follicular development and gene expression patterns of yak ovarian tissues in the warm and cold seasons. Dynamics of follicular development was evaluated based on histological analyses and global gene expression was examined by using RNA-sequencing (RNA-seq) technology. Firstly, we found that follicle development of yak cows in cold season was different from that in warm season. Interestingly, ovaries collected from yaks in cold season contained a significant higher number of antral follicles and some of these follicles showed signs of polycystic structure, indicating abnormal granulosa cell function. RNA-seq analyses of ovarian tissues from non-pregnant adult yaks in cold and warm season revealed that a list of 320 transcripts were differentially expressed, specifically, 79 were up-regulated and 241 were down-regulated in the ovaries from yaks during the cold season. Further analysis demonstrated that transcripts associated with estrogen secretion and metabolism signaling pathway were altered, including FST, CYP1A1, PIK3R1 and PIK3R2. This study showed histological features of follicle development and revealed candidate genes that may have important roles in regulating ovarian activities in the yak seasonal reproduction., Competing Interests: Declaration of competing interest None of the authors have any conflict of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

High serum adiponectin is noted in several conditions of chronic kidney disease (CKD) and is a predictor for end stage renal disease. However, the relationship between adiponectin level and renal disease progression is not well established. This study aimed to determine the relationship between serum adiponectin levels and CKD progression. This prospective longitudinal study included 2238 patients from the Korean Cohort Study for Outcomes in Patients with Chronic Kidney Disease. Patients were divided into quartiles according to their serum adiponectin level. Composite renal outcome was defined as one or more of the following: initiation of dialysis or transplantation, a two-fold increase in baseline serum creatinine levels, or a 50% decline in the estimated glomerular filtration rate (eGFR) during the follow-up period. A cox proportional hazard ratio model was applied to analyze the relationship between composite renal outcome and serum adiponectin levels. Serum adiponectin level was inversely associated with eGFR (p < 0.001) and positively correlated with urine albumin-creatinine ratio. The highest quartile of serum adiponectin was associated with an increased risk of adverse renal outomes (HR, 1.39; 95%CI, 1.05-1.84; p=0.021). On time-dependent receiver operating characteristic curve analysis, predictive ability of adiponectin for renal outcomes disappeared after adjusting for eGFR. Therefore, serum adiponectin may be a biomarker of renal dysfunction rather than a true risk factor in CKD progression.

Lupus nephritis (LN) is a major complication of systemic lupus erythematosus. Early intervention in lupus nephritis improves prognosis. There is an association between hyperuricemia and lupus nephritis; nevertheless, the sex-specific role of uric acid in lupus nephritis remains unclear. We retrospectively analyzed 578 patients diagnosed with LN by renal biopsy. We determine the relationship of serum uric acid to progression of LN using Kaplan-Meier survival analyses and Cox proportional hazards models. The primary end point was LN progression defined as the initiation of dialysis or kidney transplantation. Men had higher mean serum uric acid levels than did women. Every 1 mg/dL increase in baseline uric acid level increased the risk of LN progression by 15.1%. The serum uric acid level was an independent risk factor for LN progression in women (hazard ratio [HR], 1.158; confidence interval [CI], 1.018-1.317; p = 0.028) but not in men (HR, 1.499; CI, 0.964-2.331; p = 0.072). Sensitivity analysis involving serum uric acid terciles generated consistent and robust results. Serum uric acid level was an independent risk factor for LN progression in women but not in men.

Angiotensin-[1-7] (Ang-[1-7]) antagonize the actions of the renin-angiotensin-system via the Mas receptor and thereby exert renoprotective effects. Murine recombinant angiotensin-converting enzyme (ACE)2 was reported to show renoprotective effects in an experimental Alport syndrome model; however, the protective effect of direct administration of Ang-[1-7] is unknown. Here, we used Col4a3 -/- mice as a model of Alport syndrome, which were treated with saline or Ang- [1-7]; saline-treated wild-type mice were used as a control group. The mice were continuously infused with saline or Ang-[1-7] (25 μg/kg/h) using osmotic mini-pumps. Col4a3 -/- mice showed increased α-smooth muscle actin (SMA), collagen, and fibronectin expression levels, which were attenuated by Ang-[1-7] treatment. Moreover, Ang-[1-7] alleviated activation of transforming growth factor-β/Smad signaling, and attenuated the protein expression of ED-1 and heme oxygenase-1, indicating reduction of renal inflammation. Ang-[1-7] treatment further reduced the expression levels of inflammatory cytokines and adhesion molecules and attenuated apoptosis in human kidney cells. Finally, Ang-[1-7] downregulated TNF-α converting enzyme and upregulated ACE2 expression. Thus, treatment with Ang-[1-7] altered the ACE2-Ang-[1-7]-Mas receptor axis in the kidneys of Col4a3 -/- mice to attenuate the nephropathy progression of Alport syndrome.

Histone deacetylases have been a target of therapy for organ fibrosis. Here, we report the protective effect of CG200745 (CG), a novel histone deacetylase inhibitor, on tubulointerstitial fibrosis in Col4a3 -/- mice, a murine model of Alport syndrome. Morphological analyses revealed CG treatment markedly alleviated kidney fibrosis in Col4a3 -/- mice at the age of 7 weeks. CG prevented the activation of transforming growth factor β (TGFβ) and its downstream SMAD signaling in the kidney of Col4a3 -/- mice. As critical upstream regulators of TGFβ signaling, immunoblotting of whole kidney lysate of Col4a3 -/- mice reveled that intra-renal renin-angiotensin system (RAS) was activated with concurrent upregulation of inflammation and apoptosis, which were effectively suppressed by CG treatment. CG suppressed both activation of RAS and up-regulation of TGFβ signals in angiotensin II-stimulated HK-2 cells, a human kidney proximal tubular epithelial cell line. CG inhibited activation of TGFβ-driven signals and fibrosis in NRK-49F cells, a rat kidney fibroblast cell line, under angiotensin II-rich conditions. Collectively, CG was found to be effective both in proximal tubular epithelial cells by inhibiting local RAS and TGFβ signaling activation, as well as in fibroblasts by blocking their transition to myofibroblasts, attenuating renal fibrosis in a murine model of Alport syndrome.

The impact of obesity on health-related quality of life (HRQoL) in chronic kidney disease (CKD) population has not been elucidated, despite the impairment of HRQoL in the obese among general population. We hypothesized that the impact of obesity on HRQoL might be confounded by impaired renal function in CKD population, and that CKD would attenuate the impact of obesity on HRQoL. To compare the impact of obesity on HRQoL according to kidney function, 17,001 subjects from Korea National Health and Nutrition Examination Survey (2008-2011) were categorized by estimated glomerular filtration rate (eGFR), as follows: group 1, eGFR ≥ 90 mL/min/1.73 m 2 ; group 2, eGFR of 60-89 mL/min/1.73 m 2 ; group 3, eGFR < 60 mL/min/1.73 m 2 . The association between obesity parameters (body mass index, waist circumference and, truncal fat mass) and HRQoL parameters (EQ-5D index and EQ-VAS) were cross-sectionally analyzed. Despite robust correlations between obesity parameters and low EQ-5D index or EQ-VAS in general population, no significant association was observed in group 3 population. Impact of obesity on HRQoL in CKD population was only limitedly observed in the mobility domain of EQ-5D, as mobility limitation was associated with increased body mass index or waist circumference regardless of kidney function. Therefore, the impact of obesity on HRQoL seems significantly attenuated in CKD population, suggesting that the risk of obesity should not be over-estimated in patients with CKD, especially with respect to HRQoL.

Chronic underhydration and malnutrition can be associated with irreversible renal damage. This study investigated the association of meal frequency and breakfast skipping with chronic kidney disease (CKD) in South Korea. Participants (4370 participants from the Korean National Health and Nutrition Examination Survey VI 2013-2014) were divided into two groups based on meal frequency: ≥ 15 or < 15 meals/week. They were further divided into four groups based on the frequency of breakfast, lunch, and dinner consumed in the previous year. The data were analyzed with complex samples logistic regression. We found that 9.6% of the participants ( n = 412) had CKD, which was associated with gender, body mass index, serum fasting glucose, daily calorie intake, hypertension, diabetes, and cerebrovascular accident. Participants consuming <15 meals/week had a higher risk of CKD than those who consumed ≥15 meals/week (adjusted odds ratio [OR] 1.531, 95% confidence interval [CI] 1.209-1.938). Participants who rarely had breakfast showed a higher risk of CKD than those who had breakfast 5-7 times/week (adjusted OR 1.572, 95% CI 1.108-2.231). Our findings suggest that <15 meals/week or skipping breakfast is associated with a higher risk of CKD in the general South Korean population, especially for men or persons aged 42-64 years.

Hyperuricemia is a potential risk factor for immunoglobulin A nephropathy (IgAN) progression but its sex-specific effects on IgAN progression remain unclear. This study aimed to determine the effect of serum uric acid on IgAN progression and whether its effect varied according to sex. A total of 4339 patients who diagnosed with IgAN by renal biopsy were retrospectively analyzed. We assessed the association of serum uric acid on IgAN progression using Kaplan-Meier survival analyses and Cox proportional hazards models. The study's primary end point was IgAN progression that was defined as a 50% decline in the estimated glomerular filtration rate or the initiation of dialysis. On average, the serum uric acid levels were higher in the men than in the women. In the fully adjusted Cox proportional hazards model that considered all subjects, the risk of IgAN progression increased by about 25.6% for every 1 mg/dL increase in the baseline uric acid level. The serum uric acid level was an independent risk factor for IgAN progression in both sexes but its effect was more pronounced in the women (hazard ratio [HR], 1.383; confidence interval [CI],1.263 to 1.514; p < 0.001) than in the men (HR, 1.181; CI, 1.097 to 1.272; p < 0.001) ( p interaction < 0.001). A sensitivity analysis involving serum uric acid quartiles generated consistent and robust results. In conclusion, the serum uric acid level was an independent risk factor for IgAN progression and its effect was more pronounced among the women compared with that among the men., Competing Interests: The authors declare no competing interests.

We analyzed data from the Korean National Health Insurance Service (NHIS) to investigate whether smoking increases the risk of end-stage kidney disease (ESKD). This retrospective nationwide population-based cohort study included the data of 23,232,091 participants who underwent at least one health examination between 2009 and 2012. Smoking status was recorded at baseline. The incidence of ESKD was identified via ICD-10 codes and special medical aid codes from the Korean National Health Insurance Service database till December 2016. A Cox proportional-hazards model with multivariable adjustment was used to evaluate the association between smoking and ESKD incidence. Overall, 24.6% of participants were current smokers; 13.5% and 61.9%, were ex- and non-smokers, respectively. Overall, 45,143 cases of ESKD developed during the follow-up period. Current smokers (hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.35-1.43) and ex-smokers (HR, 1.09; 95% CI, 1.06-1.12) demonstrated a significant increase in the adjusted risk of ESKD compared to non-smokers. The risk of ESKD was directly proportional to the smoking duration, number of cigarettes smoked daily, and pack-years. In conclusion, smoking is associated with a greater risk of ESKD in the general Korean population; the risk increases with an increase in the smoking duration, number of cigarettes smoked daily, and pack-years.

The impact of health-related quality of life (HRQOL) on outcomes remains unclear in chronic kidney disease (CKD) patients despite its importance in socioeconomic aspects and individual health. We aim to identify the relationship between HRQOL and progression of CKD in pre-dialysis patients. A total 1622 patients with CKD were analyzed in the KoreaN cohort Study for Outcomes in patients With Chronic Kidney Disease, a prospective cohort study. CKD progression was defined as one or more of the following: initiation of dialysis or transplantation, a two-fold increase in baseline serum creatinine levels, or a 50% decline in the estimated glomerular filtration rate during the follow-up period. The group with CKD progression had lower scores of HRQOL than the group without CKD progression. A fully adjusted Cox proportional hazard ratio model showed that each low baseline physical and mental component summary score was associated with a higher risk of CKD progression. In Kaplan-Meier survival analysis using propensity score matched data, only low physical component summary scores showed statistical significance with CKD progression. Our study highlights low physical component summary score for an important prognostic factor of CKD progression. Risk-modification interventions for high-risk patients may provide benefits to individuals.

Background: Obstructive sleep apnea (OSA) is known to be associated with metabolic dysregulation and incident cardiovascular diseases. However, its association with end-stage renal disease (ESRD) has not been clarified. This study aimed to evaluate longitudinally whether OSA is an independent risk factor for ESRD., Methods: This retrospective nationwide population-based cohort study included data on 67,359 patients with OSA and 336,795 age-, sex- and years of the enrollment-matched controls without OSA obtained from the Korean National Health Insurance Service database from 2009 to 2014. The study population was followed up from baseline to the date of ESRD diagnosis or until 2016. A Cox proportional-hazards model with multivariable adjustment was used to evaluate the association between OSA and incident ESRD., Results: A significantly higher incident ESRD risk (adjusted hazard ratio: 1.29, 95% confidence interval 1.02-1.62) was observed for patients older than 40 years with OSA than for matched controls, when adjusted for age, sex, income status, smoking, alcohol consumption, body mass index, diabetes, hypertension, dyslipidemia, estimated glomerular filtration rate, and proteinuria. The OSA group remained predictive of higher risk of ESRD incidence in subgroups of age ≥ 65 years, female sex, hypertension, dyslipidemia, proteinuria, and chronic kidney disease., Conclusion: OSA was associated with a higher risk of incident ESRD. Understanding the association between OSA and ESRD might provide further insights to establish national health care policy.

Receptor tyrosine kinases (RTKs) play important roles in the pathogenic processes of kidney fibrosis. However, the pathophysiological roles of recepteur d'origine nantais (RON), one of the receptor tyrosine kinases, have not yet been defined. We investigated whether the activation or sequence-specific small interfering RNA (siRNA) suppression of RON could regulate epithelial mesenchymal transition (EMT) and the expression of pro-fibrotic markers, and its underlying molecular mechanisms. Stable cell lines and transient transfection for RON and the transfected cells of siRNA for RON were developed to investigate the molecular mechanisms in human kidney proximal tubular epithelial (HK-2) and interstitial fibroblasts (NRK49F) cells. RON overexpression induced EMT and increased expression of fibrosis-related proteins such as N-cadherin, vimentin, transforming growth factor-β (TGFβ), αSMA, and fibronectin in HK-2 and NRK49F cells. RON overexpression increased various RTKs and the phosphorylation of Src (Y416) and Smad, while inhibition of RON by siRNA attenuated the expression of EMT- and fibrosis-related proteins and decreased RTKs such as insulin-like growth factor receptor (IGFR), fibroblast growth factor receptor 1 (FGFR1), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), as well as the phosphorylation of Src and Smad pathways. siRNA silencing of Src also attenuated the expression of IGFR, FGFR1, VEGFR, and PDGFR. Inhibition of RON can exert an anti-fibrotic effect by the inhibition of EMT and other RTKs through control of Src and Smad pathways in HK-2 and NRK49F cells.

Objectives: Cardiac involvement is present in more than half of the patients with systemic lupus erythematosus (SLE). However, large-scale studies on the prevalence of atrial fibrillation (AF) in this disease do not exist. We aimed to investigate the incidence and clinical significance of AF in SLE., Methods: Patients with SLE (n=21,143; mean age, 41.8±13.13 years; female, 90.38%) without previous AF were selected from the Korean National Health Insurance Service National Sample Cohort database between 2008 and 2014. Age-and sex-matched controls (n=105,715) were randomly sampled in a 5:1 ratio from the population of individuals without SLE from the same database. Both cohorts were followed-up for incidental AF and death until 2015., Results: AF was newly detected in 481 (2.27%) patients with SLE and 619 (0.59%) controls (incidence: 3.692 and 0.941 per 1000 person-years, respectively). After multivariate adjustment, SLE was found to be a risk factor for developing AF [hazard ratio (HR), 2.84; 95% confidence interval (CI), 2.50-3.23]. On subgroup analysis, younger (age <40) patients showed a higher incidence of AF. SLE patients with incidental AF had a higher mortality rate compared with patients without SLE with AF (HR, 2.35; 95% CI 1.73-3.20) and those with SLE without AF (HR, 3.53; 95% CI 2.84-4.39) after adjustment., Conclusions: SLE was an independent risk factor for AF development, especially in younger patients without previous AF, stressing the importance of cardiac assessment in this population. Development of AF in patients with SLE was associated with increased mortality.

The prevalence rates of hypertension and chronic kidney disease (CKD) are increasing with the aging of the population. Hypertension and CKD are closely related, and hypertension with accompanying CKD is difficult to control. This difficulty controlling blood pressure (BP) can be explained by changes in diurnal variation in BP, such as non-dipping and reverse dipping patterns, increased pulse pressure, and BP variability in CKD patients resulting in a high frequency of nocturnal hypertension or masked hypertension. CKD patients with uncontrolled or nocturnal hypertension are at increased risk for cardiovascular disease, progression of CKD, and all-cause death. Recent studies have shown that intensive reduction of systolic BP below 120 mmHg is seems to favor in CKD patients regardless of the presence or absence of diabetes. As BP control is difficult in patients with CKD, appropriate measurement of BP is important. Automated BP monitoring could reduce the so-called "white coat effect" (spike in BP) that may be triggered by measurement in a clinical setting. Moreover, out-of-office BP monitoring at home or ambulatory BP monitoring for 24 hours may provide critical information regarding diurnal BP variability and nocturnal BP in patients with CKD.

TGF-β/Smad signaling is a major pathway in progressive fibrotic processes, and further studies on the molecular mechanisms of TGF-β/Smad signaling are still needed for their therapeutic targeting. Recently, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) was shown to improve renal fibrosis, making it an attractive target for chronic kidney diseases (CKDs). Here, we show the mechanism by which PGC-1α regulates the TGF-β/Smad signaling pathway using HK-2 cell lines stably overexpressing empty vector (mock cells) or human PGC1α (PGC1α cells). Stable PGC-1α overexpression negatively regulated the expression of TGF-β-induced epithelial-mesenchymal transition (EMT) markers (fibronectin, E-cadherin, vimentin, and α-SMA) and EMT-related transcription factors (Snail and Slug) compared to mock cells, inhibiting fibrotic progression. Interestingly, among molecules upstream of Smad2/3 activation, the gene expression of only TGFβRI, but not TGFβRII, was downregulated in PGC-1α cells. In addition, the downregulation of TGFβRI by PGC-1α was associated with the upregulation of let-7b/c , miRNA for which the 3' untranslated region (UTR) of TGFβRI contains a binding site. In conclusion, PGC-1α suppresses TGF-β/Smad signaling activation via targeting TGFβRI downregulation by let-7b/c upregulation.