Understanding the Korean Dialysis Cohort for Mineral, Vascular Calcification, and Fracture (ORCHESTRA) Study: Design, Method, and Baseline Characteristics.

INTRODUCTION: End-stage renal disease (ESRD) is a growing disease worldwide, including Korea. This is an important condition that affects patient outcome. To provide optimal management for mineral disturbance, vascular calcification, and bone disease in ESRD patients, the Korean dialysis cohort for mineral, vascular calcification, and fracture (ORCHESTRA) study was conducted by enrolling Korean dialysis patients. METHODS: Sixteen university-affiliated hospitals and one Veterans' Health Service Medical Center participated in this study. This prospective cohort study enrolled approximately 900 consecutive patients on dialysis between May 2019 and January 2021. Enrolled subjects were evaluated at baseline for demographic information, laboratory tests, radiologic imaging, and bone mineral densitometry (BMD) scans. After enrollment, regular assessments of the patients were performed, and their biospecimens were collected according to the study protocol. The primary outcomes were the occurrence of major adverse cardiovascular events, invasive treatment for peripheral artery disease, and osteoporotic fractures. The secondary outcomes were hospitalization for cerebrovascular disease or progression of abdominal aortic calcification. Participants will be assessed for up to 3 years to determine whether primary or secondary outcomes occur. RESULTS: Between May 2019 and January 2021, all participating centers recruited 900 consecutive dialysis patients, including 786 undergoing hemodialysis (HD) and 114 undergoing peritoneal dialysis (PD). The mean age of the subjects was 60.4 ± 12.3 years. Males accounted for 57.7% of the total population. The mean dialysis vintage was 6.1 ± 6.0 years. The HD group was significantly older, had a longer dialysis vintage, and more comorbidities. Overall, the severity of vascular calcification was higher and the level of BMD was lower in the HD group than in the PD group. CONCLUSION: This nationwide, multicenter, prospective cohort study focused on chronic kidney disease-mineral and bone disorder and aimed to provide clinical evidence to establish optimal treatment guidelines for Asian dialysis patients.

Relationship Between High-Density Lipoprotein Cholesterol and Mortality in Elderly Hemodialysis Patients: Data From the Korean Society of Geriatric Nephrology Retrospective Cohort.

OBJECTIVES: The association between high-density lipoprotein (HDL) cholesterol levels and mortality in elderly patients undergoing hemodialysis is not well established. Thus, this study investigated HDL levels and mortality in elderly Korean patients undergoing hemodialysis. METHODS: We recruited 1860 incident hemodialysis patients aged greater than 70 years from a retrospective cohort of the Korean Society of Geriatric Nephrology. The primary outcome measure was all-cause mortality. RESULTS: The mean age of the cohort was 77.8 years, and 1049 (56.4%) were men. When we grouped the patients into HDL cholesterol tertiles, the T1 group (HDL level <30 mg/dL in men and <33 mg/dL in women) had a higher proportion of patients with end-stage kidney disease due to diabetic nephropathy. During the median follow-up period of 3.1 years, 1109 (59.7%) deaths occurred. In a multivariable Cox regression model, the T1 group had a significantly higher risk of mortality (hazard ratio [HR], 1.28; 95% confidence interval, 1.10-1.50; P = .002) compared to the T3 group. A nonlinear analysis using a restrictive spline curve showed that low HDL cholesterol levels were associated with increased HR when HDL cholesterol levels were <40 mg/dL; however, there was no association between HDL cholesterol and mortality when HDL cholesterol levels were >40 mg/dL. Triglyceride/HDL ratio was not significantly associated with the risk of mortality (HR per 1 log increase, 1.08; 95% confidence interval, 0.99-1.18; P = .069). CONCLUSIONS: Low HDL cholesterol levels are associated with an increased risk of mortality in elderly patients undergoing hemodialysis. However, there was no significant relationship between HDL cholesterol levels and mortality when levels were below 40 mg/dL. Therefore, low HDL cholesterol levels may be a useful risk factor for predicting mortality in elderly patients undergoing hemodialysis.

Effect of low-density lipoprotein level and mortality in older incident statin-naïve hemodialysis patients.

BACKGROUND: This study aimed to analyze low-density lipoprotein cholesterol (LDL-C) levels and their relationship with mortality in order to identify the appropriate lipid profile for older Korean hemodialysis patients. METHODS: We enrolled a total of 2,732 incident hemodialysis patients aged > 70 years from a retrospective cohort of the Korean Society of Geriatric Nephrology from 2010 Jan to 2017 Dec, which included 17 academic hospitals in South Korea. Of these patients, 1,709 were statin-naïve, and 1,014 were analyzed after excluding those with missing LDL-C level data. We used multivariate Cox regression analysis to select risk factors from 20 clinical variables among the LDL-C groups. RESULTS: The mean age of the entire patient population was 78 years, with no significant differences in age between quartiles Q1 to Q4. However, the proportion of males decreased as the quartiles progressed towards Q4 (p < 0.001). The multivariate Cox regression analysis, which included all participants, showed that low LDL-C levels were associated with all-cause mortality. In the final model, compared to Q1, the hazard ratios (95% confidence interval) were 0.77 (0.620-0.972; p = 0.027), 0.85 (0.676-1.069; p = 0.166), and 0.65 (0.519-0.824; p < 0.001) for Q2, Q3, and Q4, respectively, after adjusting for covariates, such as conventional and age-specific risk factors. The final model demonstrated that all-cause mortality increased as LDL-C levels decreased, as confirmed by a restrictive cubic spline plot. CONCLUSIONS: In older hemodialysis patients who had not previously received dyslipidemia treatment, elevated LDL-C levels were not associated with increased all-cause mortality. Intriguingly, lower LDL-C levels appear to be associated with an unfavorable effect on all-cause mortality among high-risk hemodialysis patients.

Inhibition of Xanthine Oxidase Protects against Diabetic Kidney Disease through the Amelioration of Oxidative Stress via VEGF/VEGFR Axis and NOX-FoxO3a-eNOS Signaling Pathway.

Xanthine oxidase (XO) is an important source of reactive oxygen species. This study investigated whether XO inhibition exerts renoprotective effects by inhibiting vascular endothelial growth factor (VEGF) and NADPH oxidase (NOX) in diabetic kidney disease (DKD). Febuxostat (5 mg/kg) was administered to streptozotocin (STZ)-treated 8-week-old male C57BL/6 mice via intraperitoneal injection for 8 weeks. The cytoprotective effects, its mechanism of XO inhibition, and usage of high-glucose (HG)-treated cultured human glomerular endothelial cells (GECs) were also investigated. Serum cystatin C, urine albumin/creatinine ratio, and mesangial area expansion were significantly improved in febuxostat-treated DKD mice. Febuxostat reduced serum uric acid, kidney XO levels, and xanthine dehydrogenase levels. Febuxostat suppressed the expression of VEGF mRNA, VEGF receptor (VEGFR)1 and VEGFR3, NOX1, NOX2, and NOX4, and mRNA levels of their catalytic subunits. Febuxostat caused downregulation of Akt phosphorylation, followed by the enhancement of dephosphorylation of transcription factor forkhead box O3a (FoxO3a) and the activation of endothelial nitric oxide synthase (eNOS). In an in vitro study, the antioxidant effects of febuxostat were abolished by a blockade of VEGFR1 or VEGFR3 via NOX-FoxO3a-eNOS signaling in HG-treated cultured human GECs. XO inhibition attenuated DKD by ameliorating oxidative stress through the inhibition of the VEGF/VEGFR axis. This was associated with NOX-FoxO3a-eNOS signaling.

Association between physical activity and risk of renal function decline and mortality in community-dwelling older adults: a nationwide population-based cohort study.

BACKGROUND: Physical activity (PA) is an important risk factor associated with health outcomes. However, the relationship between PA and kidney function decline in older adults remains unclear. We examined the influence of PA on kidney function decline and mortality in community-dwelling older adults. METHODS: Adults aged ≥ 65 years with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 who had available health checkup data from 2009 to 2010 were included. The cohort was followed annually through December 2015 for anthropometric, sociodemographic, and medical information including outcomes and biennially for laboratory information from the health checkup. We divided these patients into three groups according to self-reported PA (Inactive group: no leisure-time PA, Active group: vigorous activity for at least 80 min/week or a sum of moderate-intensity activity and walking for at least 300 min/week, Low-active group: level of PA between the definitions of the other two groups). Associations between the intensity of PA and death, cardiovascular death, and ≥ 50% eGFR decline were investigated. RESULTS: Among 102,353 subjects, 32,984 (32.23%), 54,267 (53.02%), and 15,102 (14.75%) were classified into the inactive, low-active, and active groups, respectively. The active group was younger, contained a higher proportion of men, and had higher frequencies of hypertension, diabetes mellitus, drinking, and smoking than the other groups. The active group had significantly lower incidence rates of mortality, cardiovascular mortality, and kidney function decline than the other groups (all p < 0.001). The active group also showed lower all-cause (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.70-0.82) and cardiovascular mortality (HR, 0.64; 95% CI, 0.53-0.78) and protection against ≥ 50% eGFR decline (HR, 0.81; 95% CI, 0.68-0.97) compared with the inactive group in the fully adjusted Cox proportional hazards regression model. CONCLUSIONS: High PA was an independent modifiable lifestyle factor for reducing mortality and protecting against declines in kidney function in older adults.

The Role of Sirtuins in Kidney Diseases.

Sirtuins (SIRTs) are class III histone deacetylases (HDACs) that play important roles in aging and a wide range of cellular functions. Sirtuins are crucial to numerous biological processes, including proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammals have seven different sirtuins, SIRT1-7, and the diverse biological functions of each sirtuin are due to differences in subcellular localization, expression profiles, and cellular substrates. In this review, we summarize research advances into the role of sirtuins in the pathogenesis of various kidney diseases including acute kidney injury, diabetic kidney disease, renal fibrosis, and kidney aging along with the possible underlying molecular mechanisms. The available evidence indicates that sirtuins have great potential as novel therapeutic targets for the prevention and treatment of kidney diseases.

Cilastatin Preconditioning Attenuates Renal Ischemia-Reperfusion Injury via Hypoxia Inducible Factor-1α Activation.

Cilastatin is a specific inhibitor of renal dehydrodipeptidase-1. We investigated whether cilastatin preconditioning attenuates renal ischemia-reperfusion (IR) injury via hypoxia inducible factor-1α (HIF-1α) activation. Human proximal tubular cell line (HK-2) was exposed to ischemia, and male C57BL/6 mice were subjected to bilateral kidney ischemia and reperfusion. The effects of cilastatin preconditioning were investigated both in vitro and in vivo. In HK-2 cells, cilastatin upregulated HIF-1α expression in a time- and dose-dependent manner. Cilastatin enhanced HIF-1α translation via the phosphorylation of Akt and mTOR was followed by the upregulation of erythropoietin (EPO) and vascular endothelial growth factor (VEGF). Cilastatin did not affect the expressions of PHD and VHL. However, HIF-1α ubiquitination was significantly decreased after cilastatin treatment. Cilastatin prevented the IR-induced cell death. These cilastatin effects were reversed by co-treatment of HIF-1α inhibitor or HIF-1α small interfering RNA. Similarly, HIF-1α expression and its upstream and downstream signaling were significantly enhanced in cilastatin-treated kidney. In mouse kidney with IR injury, cilastatin treatment decreased HIF-1α ubiquitination independent of PHD and VHL expression. Serum creatinine level and tubular necrosis, and apoptosis were reduced in cilastatin-treated kidney with IR injury, and co-treatment of cilastatin with an HIF-1α inhibitor reversed these effects. Thus, cilastatin preconditioning attenuated renal IR injury via HIF-1α activation.

Vascular calcification and left ventricular hypertrophy in hemodialysis patients: interrelationship and clinical impacts.

Background: We examined the relationship and combined effect of vascular calcification (VC) and left ventricular hypertrophy (LVH) on deaths and cardiovascular events (CVEs) in hemodialysis (HD) patients. Methods: Maintenance HD patients (n=341) were included. Echocardiography data and plain chest radiographs were used to assess LVH and aortic arch VC. Results: VC was found in 100 patients (29.3%). LVH was more prevalent in patients with VC compared with those without VC (70% vs. 50.2%, P=0.001). VC was independently associated with a 2.42-fold increased risk of LVH (95% CI, 1.26-4.65). In multivariate analysis, compared with patients with neither VC nor LVH, the coexistence of VC and LVH was independently associated with CVE (HR, 2.01; 95% CI, 1.09-3.72), whereas VC or LVH alone was not. Patients with both VC and LVH had the highest risk for a composite event of deaths or CVE (HR, 1.88; 95% CI, 1.15-3.06). Significant synergistic interaction was observed between VC and LVH (P for interaction=0.039). Conclusions: VC was independently associated with LVH. The coexistence of VC and LVH was associated with higher risk of deaths and CVEs than either factor alone. VC and LVH showed a synergistic interaction for the risk of deaths and CVEs.

Resveratrol Ameliorates Contrast Induced Nephropathy Through the Activation of SIRT1-PGC-1α-Foxo1 Signaling in Mice.

BACKGROUND/AIMS: SIRT1 activation promotes the resistance of renal tubular cells to oxidative stress, and resveratrol is known as a SIRT1 activator. METHODS: Resveratrol was injected intraperitoneally with iohexol for 24 hours. NRK-52E cells were pretreated with resveratrol for 24 hours and then exposed to iohexol for 3 hours. Renal function was measured by serum creatinine and cell survival was assessed by MTT assay. We investigated whether resveratrol attenuates oxidative stress and apoptosis in contrast-induced nephropathy (CIN). RESULTS: Serum creatinine and tubular injury increased significantly after iohexol treatment, and resveratrol co-treatment attenuated the renal injury. Cell survival decreased after iohexol exposure and resveratrol reduced cell death induced by iohexol. Resveratrol was accompanied with the activation of SIRT1 and PGC-1α and dephosphorylation of FoxO1 in mice with CIN. SIRT1 and PGC-1α expression were decreased by iohexol, and increased significantly in resveratrol-pretreated cells. These processes resulted in reduction of oxidative stress and apoptosis both in vivo and in vitro experiments. Resveratrol decreased inflammatory cell infiltration induced by iohexol in mice with CIN. SIRT1 inhibition using siRNA in tubular cells accentuated the decrease of cell viability by iohexol. CONCLUSION: Resveratrol attenuated CIN by modulating renal oxidative stress and apoptosis through activation of SIRT1-PGC-1α-FoxO1 signaling.

Serum 1,25-dihydroxyvitamin D Better Reflects Renal Parameters Than 25-hydoxyvitamin D in Patients with Glomerular Diseases.

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 (ß = 0.224, P = 0.006; ß = -0.263, P = 0.001) and 1,25(OH)2D was significantly correlated with eGFR, serum albumin and phosphorus (ß = 0.202, P = 0.005; ß = 0.304, P < 0.001; ß = -0.161, P = 0.024). In adjusted multivariable linear regression, eGFR and 24hr proteinuria were independently correlated only with 1,25(OH)2D (ß = 0.154, P = 0.018; ß = -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.

Transitional cell carcinoma involving graft kidney in a kidney transplant recipient: a case report.

BACKGROUND: Kidney transplantation (KT) is the treatment option for patients with end stage renal disease (ESRD) to prolong survival and improve quality of life. Although the use of potent immunosuppressive agents increases graft survival in kidney transplantation recipients (KTRs), it may lead to the development of malignancy, including transitional cell carcinoma (TCC). TCC developing in the pelvis of graft kidney is very rare in KTRs. CASE PRESENTATION: A 40-year-old male visited hospital with complaints of nausea, vomiting and gross hematuria. Eleven years ago, he was diagnosed ESRD of unknown origin, and received a living related KT from his father 1 year later. Radiologic findings showed a huge polypoid mass in the pelvis of graft kidney with pelvo-calyceal dilation and a 3.3 cm-sized nodule in aortocaval chain and a 2.5 cm-sized nodule in right iliac chain as TCC stage IV. Sonography-guided percutaneous needle biopsy of pelvis mass in the graft kidney revealed a low grade urothelial cell carcinoma. Radical graft nephroureterectomy was performed and histopathological diagnosis confirmed as a low grade urothelial carcinoma of graft pelvis and ureter lumen, which invaded to perirenal fat and renal parenchyma with lymphovascular presence (T3Nx). The patient started with adjuvant concurrent chemo-radiation therapy and returned to regular hemodialysis. CONCLUSIONS: We report a rare case of TCC in the pelvis of graft kidney with already advanced disease at diagnosis in a young KTR. For the early diagnosis of TCC in KTRs, exposure history to Chinese herb or analgesics should be investigated before KT and high risk population in KTRs should be tightly performed regular postoperative surveillance for TCC and considered of less calcineurin inhibitor-based immunosuppressant protocol.

Raoultella planticola peritonitis in a patient on continuous ambulatory peritoneal dialysis.

A 65-year-old man on continuous ambulatory peritoneal dialysis was admitted with peritonitis. Empirical antibiotic therapy was initiated, and Raoultella planticola was identified in the peritoneal fluid culture. We treated the patient with intraperitoneally administered ciprofloxacin and ceftazidime according to the antibiotic susceptibility. His condition improved, and he was well treated with a 2-week antibiotic course.

Diagnostic utility of immunochemical fecal occult blood tests to detect lower gastrointestinal lesions in patients with chronic kidney disease.

PURPOSE: The immunochemical fecal occult blood test (iFOBT) is a useful method to screen for lower gastrointestinal (GI) bleeding-related lesions. However, few studies have investigated the diagnostic utility of iFOBT in chronic kidney disease (CKD). METHODS: We included 691 patients with nondialysis-dependent CKD stages 2-5 or those receiving dialysis. Bleeding-related lower GI lesions were identified by colonoscopy, and the diagnostic utility of iFOBT was evaluated. RESULTS: Bleeding-related lower GI lesions were found in 9.2% of 491 patients with CKD stage 2, 17.8% of 107 patients with CKD stage 3/4, and 25.8% of 93 patients with CKD stage 5/dialysis (p < 0.001). Compared with CKD stage 2, CKD stage 5/dialysis was independently associated with a 2.80-fold risk for bleeding-related lesions (p = 0.019). The iFOBT was positive in 92 (13.3%) patients and the area under the receiver operating curve (AUC) for a bleeding-related lesion was 0.64 (p < 0.001). The sensitivity of iFOBT increased as the CKD stage worsened (20.0 vs 52.6 vs 58.3%; p = 0.002). However, the specificity to detect bleeding-related lesions decreased with the severity of CKD stage (94.6 vs. 78.4 vs. 76.8%; p < 0.001). The AUC of iFOBT to detect adenoma or carcinoma was 0.54 (p = 0.046), and a similar pattern of sensitivity and specificity was observed between different CKD stages. CONCLUSIONS: The prevalence of bleeding-related lower GI lesions and the sensitivity of iFOBT to detect these GI lesions increased in advanced CKD. However, iFOBT should be used cautiously in these patients because its specificity decreased.

Diameter of parathyroid glands measured by computed tomography as a predictive indicator for response to cinacalcet in dialysis patients with secondary hyperparathyroidism.

BACKGROUND/AIMS: Cinacalcet is one of the important treatments of secondary hyperparathyroidism (SHPT). We evaluated the role of computed tomography (CT) for parathyroid glands (PTGs) to determine the response to cinacalcet therapy in dialysis patients. METHODS: In study 1, we compared the predictive cutoff values of the largest volume or diameter of PTGs on ultrasonography or CT for achievement of target intact parathyroid hormone (iPTH) level according to K/DOQI guideline after cinacalcet treatment in a single dialysis center. In study 2, the role of the cutoff diameter of PTGs on CT in predicting responsive to cinacalcet therapy was reevaluated in dialysis patients with SHPT in multiple centers. RESULTS: In study 1, among the total population of 26 patients, the number of patients with baseline iPTH over 600 pg/mL was 16 (61%). In study 2, it was 45 (54%), among 82 patients. In study 1, the number of PTGs equal to or larger than the cutoff value (≥ 11.2 mm) on CT, not ultrasonography, was significantly higher in non-responders than in responders (p=0.038). In study 2, the proportion of patients with PTGs ≥ 11.2 mm on CT was significantly higher in non-responders than responders (p=0.003). Multivariate analysis showed that pretreatment iPTH (odds ratio [OR] 1.498, p=0.003) and the existence of enlarged PTGs on CT (OR 8.940, p=0.015) were significant clinical factors affecting the response to cinacalcet. CONCLUSIONS: The diameter of PTGs on CT could predict the response to cinacalcet in dialysis patients with SHPT.

Assessment of tubular reabsorption of phosphate as a surrogate marker for phosphate regulation in chronic kidney disease.

BACKGROUND/AIMS: Fibroblast growth factor 23 (FGF23) and soluble α-Klotho are emerging potential biomarkers of phosphorus and vitamin D metabolism which change in concentration in early chronic kidney disease (CKD) in order to maintain normal phosphorus levels. Tubular reabsorption of phosphate (TRP) has been commonly used to assess renal tubular phosphate transport. The aim of this study was to evaluate the usefulness of TRP as a surrogate marker of parameters of CKD-mineral bone disease (CKD-MBD) in CKD. METHODS: A cross-sectional study was performed in 93 stable patients with predialysis CKD stage 1-5. In all patients, TRP, estimated glomerular filtration rate (eGFR), calcium, phosphate, intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, serum FGF23 and urine soluble α-Klotho levels were measured. RESULTS: As renal function declined, TRP significantly decreased (P < 0.001; r = 0.763) and both iPTH and serum FGF23 increased (P < 0.001; r = -0.598, P < 0.001; r = -0.453, respectively). The prevalence of hyperphosphatemia, secondary hyperparathyroidism, FGF23 excess and abnormal TRP increased progressively with declining eGFR. Although TRP level changed later than FGF23, abnormal levels of both TRP and FGF23 were observed earlier than changes in iPTH and serum phosphate. Decreased TRP was found to be independently associated with decreased eGFR and increased iPTH but was not associated with urine soluble α-Klotho or serum FGF23 level in multiple linear regression analysis. CONCLUSION: TRP is a simple, useful and cost-saving surrogate marker of the assessment of altered mineral metabolism in CKD patients and can be used as an alternative to serum FGF23, especially for mild to moderate renal insufficiency.

Delayed treatment with oleanolic acid attenuates tubulointerstitial fibrosis in chronic cyclosporine nephropathy through Nrf2/HO-1 signaling.

BACKGROUND: Nuclear factor erythroid-2-related factor-2 (Nrf2) is known to protect against tissue injury by orchestrating antioxidant and detoxification responses to oxidative stress. This study investigated whether upregulation of Nrf2-dependent signaling by oleanolic acid (OA), which is known to activate Nrf2, could attenuate renal inflammation and fibrosis in cyclosporine (CsA)-induced kidney injury. METHODS: Male ICR mice were divided into four treatment groups: Vehicle (VH, n = 6), VH + OA (n = 6), CsA (n = 8), and CsA + OA (n = 8). For the OA-treated groups, OA (25 mg/kg/day) was administered by intraperitoneal injection for the final week of the 4-week experimental period. Renal function, morphologies and signaling were evaluated at the end of the study. RESULTS: Treatment with CsA resulted in decreased kidney function and urine osmolality and increased urine volume and urinary albumin levels. The CsA-induced changes were improved by OA treatment. Specifically, administration of OA decreased tubulointerstitial fibrosis and inflammation scores that were increased in CsA-treated mice. Furthermore, OA treatment decreased urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-epi-prostaglandin F2α (8-iso-PGF2α) levels. The beneficial effects of OA were attributed to an increased ratio of nuclear/total Nrf2 and subsequently enhanced expression of heme oxygenase (HO)-1, as well as a stable level of Kelch-like ECH-associated protein 1 (Keap1) expression, indicating that OA enhanced nuclear translocation of Nrf2. Increased apoptotic cell death and a high ratio of B cell leukaemia/lymphoma 2 (Bcl-2)-associated X protein (Bax) to Bcl-2 in CsA-treated mice were also significantly ameliorated by OA treatment. CONCLUSION: Our results suggest that OA activates Nrf2/HO-1 signaling in chronic CsA nephropathy, which may have beneficial effects on inflammation and oxidative stress.

Xanthine oxidoreductase inhibition ameliorates high glucose-induced glomerular endothelial injury by activating AMPK through the purine salvage pathway.

Xanthine oxidoreductase (XOR) contributes to reactive oxygen species production. We investigated the cytoprotective mechanisms of XOR inhibition against high glucose (HG)-induced glomerular endothelial injury, which involves activation of the AMP-activated protein kinase (AMPK). Human glomerular endothelial cells (GECs) exposed to HG were subjected to febuxostat treatment for 48 h and the expressions of AMPK and its associated signaling pathways were evaluated. HG-treated GECs were increased xanthine oxidase/xanthine dehydrogenase levels and decreased intracellular AMP/ATP ratio, and these effects were reversed by febuxostat treatment. Febuxostat enhanced the phosphorylation of AMPK, the activation of peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC)-1α and PPAR-α and suppressed the phosphorylation of forkhead box O (FoxO)3a in HG-treated GECs. Febuxostat also decreased nicotinamide adenine dinucleotide phosphate oxidase (Nox)1, Nox2, and Nox4 expressions; enhanced superoxide dismutase activity; and decreased malondialdehyde levels in HG-treated GECs. The knockdown of AMPK inhibited PGC-1α-FoxO3a signaling and negated the antioxidant effects of febuxostat in HG-treated GECs. Despite febuxostat administration, the knockdown of hypoxanthine phosphoribosyl transferase 1 (HPRT1) also inhibited AMPK-PGC-1α-FoxO3a in HG-treated GECs. XOR inhibition alleviates oxidative stress by activating AMPK-PGC-1α-FoxO3a signaling through the HPRT1-dependent purine salvage pathway in GECs exposed to HG conditions.

Organelle communication maintains mitochondrial and endosomal homeostasis during podocyte lipotoxicity.

Organelle stress exacerbates podocyte injury, contributing to perturbed lipid metabolism. Simultaneous organelle stresses occur in kidney tissues; therefore, a thorough analysis of organelle communication is crucial for understanding the progression of kidney diseases. Although organelles closely interact with one another at membrane contact sites, limited studies have explored their involvement in kidney homeostasis. The endoplasmic reticulum (ER) protein, PDZ domain-containing 8 (PDZD8), is implicated in multiple organelle tethering processes and cellular lipid homeostasis. In this study, we aimed to elucidate the role of organelle communication in podocyte injury using podocyte-specific Pdzd8-knockout mice. Our findings demonstrated that Pdzd8 deletion exacerbated podocyte injury in an accelerated obesity-related kidney disease model. Proteomic analysis of isolated glomeruli revealed that Pdzd8 deletion exacerbated mitochondrial and endosomal dysfunction during podocyte lipotoxicity. Additionally, electron microscopy revealed the accumulation of "fatty abnormal endosomes" in Pdzd8-deficient podocytes during obesity-related kidney diseases. Lipidomic analysis indicated that glucosylceramide accumulated in Pdzd8-deficient podocytes, owing to accelerated production and decelerated degradation. Thus, the organelle-tethering factor, PDZD8, plays a crucial role in maintaining mitochondrial and endosomal homeostasis during podocyte lipotoxicity. Collectively, our findings highlight the importance of organelle communication at the three-way junction among the ER, mitochondria, and endosomes in preserving podocyte homeostasis.

Mortality in patients receiving renal replacement therapy in South Korea.

Background: This study analyzed data from the end-stage renal disease patient registry collected by the Korean Society of Nephrology to explore trends in mortality among dialysis patients from 2001 to 2022. Methods: Mortality was analyzed in two ways: firstly, using the annual mortality rate; and secondly, by assessing survivability after a certain period of time since the initiation of dialysis. Additionally, we categorized the causes of death by disease group annually to observe how the proportions changed. Results: Since 2001, annual mortality for dialysis patients generally declined, except for a rise in 2020 and 2021 among hemodialysis patients. Overall mortality rates for all dialysis patients dropped from 74.2/1,000 person-years in 2001 to 42.3/1,000 person-years in 2022, with a more pronounced decrease in peritoneal dialysis. While survival probability over the 5 years following initiation of dialysis has shown a steady increase, short-term mortality from 2018 to 2020 affected by coronavirus disease 2019 (COVID-19) has shown a yearly increase by age group, with a greater effect in those aged 75 years and older. The leading causes of death for all dialysis patients have changed little, in the order of heart disease, infection, and vascular problems. Conclusion: While annual mortality and survival probability after dialysis initiation have generally improved in dialysis patients, there has been a temporary deterioration during the COVID-19 pandemic, most pronounced in the elderly.