According to recent evidence, ferroptosis is a major cell death mechanism in the pathogenesis of kidney injury and fibrosis.Despite the renoprotective effects of classical ferroptosis inhibitors, therapeutic approaches targeting kidney ferroptosis remain limited. In this study, we assessed the renoprotective effects of melatonin and zileuton as a novel therapeutic strategy against ferroptosis-mediated kidney injury and fibrosis. First, we identified RSL3-induced ferroptosis in renal tubular epithelial HK-2 and HKC-8 cells. Lipid peroxidation and cell death induced by RSL3 were synergistically mitigated by the combination of melatonin and zileuton. Combination treatment significantly downregulated the expression of ferroptosis-associated proteins, 4-HNE and HO-1, and upregulated the expression of GPX4. The expression levels of p-AKT and p-mTOR also increased, in addition to that of NRF2 in renal tubular epithelial cells. When melatonin (20 mg/kg) and zileuton (20 mg/kg) were administered to a unilateral ureteral obstruction (UUO) mouse model, the combination significantly reduced tubular injury and fibrosis by decreasing the expression of profibrotic markers, such as α-SMA and fibronectin. More importantly, the combination ameliorated the increase in 4-HNE levels and decreased GPX4 expression in UUO mice. Overall, the combination of melatonin and zileuton was found to effectively ameliorate ferroptosis-related kidney injury by upregulating the AKT/mTOR/ NRF2 signaling pathway, suggesting a promising therapeutic strategy for protection against ferroptosis-mediated kidney injury and fibrosis.

Antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis requires prompt diagnosis and treatment, since renal function at the time of diagnosis is significantly associated with renal outcomes. Here, we report two pediatric patients with ANCA-positive glomerulonephritis initially presenting with hematuria, mild proteinuria, and normal renal function. The first patient with a high myeloperoxidase-ANCA titer (>134 IU/mL) was diagnosed with rapidly progressive glomerulonephritis based on renal biopsy and treated with immunosuppressive therapy after 10 months of follow-up. The second patient with a low myeloperoxidase-ANCA titer (11 IU/mL) maintained normal kidney function without medication. Two cases showed different clinical course according to ANCA titer.

Background: s: Recently, alternative surrogate endpoints such as a 30% or 40% decline in estimated glomerular filtration rate (eGFR) or eGFR slope over 2 to 3 years have been proposed for predicting renal outcomes. However, the impact of GFR estimation methods on the accuracy and effectiveness of surrogate markers is unknown. Methods: We retrospectively enrolled participants in health screening programs at three hospitals from 1995 to 2009. We defined two different participant groups as YR1 and YR3, which had available 1-year or 3-year eGFR values along with their baseline eGFR levels. We compared the effectiveness of eGFR percentage change or slope to estimate end-stage renal disease (ESRD) risk according to two estimating equations (modified Modification of Diet in Renal Disease equation [eGFRm] and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation [eGFRc]) for GFR. Results: In the YR1 and YR3 groups, 9,971 and 10,171 candidates were enrolled and ESRD incidence during follow-up was 0.26% and 0.19%, respectively. The eGFR percentage change was more effective than eGFR slope in estimating ESRD risk, regardless of the method of estimation. A 40% of decline in eGFR was better than 30%, and a 3-year baseline period was better than a 1-year period for prediction accuracy. Although some diagnostic indices from the CKD-EPI equation were better, we found no significant differences in the discriminative ability and hazard ratios for incident ESRD between eGFRc and eGFRm in either eGFR percentage change or eGFR slope. Conclusion There were no significant differences in the prediction accuracy of GFR percentage change or eGFR slope between eGFRc and eGFRm in the general population.

Background: s: Recently, alternative surrogate endpoints such as a 30% or 40% decline in estimated glomerular filtration rate (eGFR) or eGFR slope over 2 to 3 years have been proposed for predicting renal outcomes. However, the impact of GFR estimation methods on the accuracy and effectiveness of surrogate markers is unknown. Methods: We retrospectively enrolled participants in health screening programs at three hospitals from 1995 to 2009. We defined two different participant groups as YR1 and YR3, which had available 1-year or 3-year eGFR values along with their baseline eGFR levels. We compared the effectiveness of eGFR percentage change or slope to estimate end-stage renal disease (ESRD) risk according to two estimating equations (modified Modification of Diet in Renal Disease equation [eGFRm] and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation [eGFRc]) for GFR. Results: In the YR1 and YR3 groups, 9,971 and 10,171 candidates were enrolled and ESRD incidence during follow-up was 0.26% and 0.19%, respectively. The eGFR percentage change was more effective than eGFR slope in estimating ESRD risk, regardless of the method of estimation. A 40% of decline in eGFR was better than 30%, and a 3-year baseline period was better than a 1-year period for prediction accuracy. Although some diagnostic indices from the CKD-EPI equation were better, we found no significant differences in the discriminative ability and hazard ratios for incident ESRD between eGFRc and eGFRm in either eGFR percentage change or eGFR slope. Conclusion There were no significant differences in the prediction accuracy of GFR percentage change or eGFR slope between eGFRc and eGFRm in the general population.

Background: A healthy microbiome helps maintain the gut barrier and mucosal immune tolerance. Previously, we demonstrated that acute kidney injury (AKI) provoked dysbiosis, gut inflammation, and increased permeability. Here, we investigated the renoprotective effects of the probiotic Bifidobacterium bifidum BGN4 and the underlying mechanisms thereof. Methods: C57BL/6 mice were subjected to bilateral renal ischemia-reperfusion injury (IRI) or sham operation. In the probiotic-treated group, BGN4 was administered by gavage once daily, starting 2 weeks before injury. Results: Administration of BGN4 significantly increased gut microbiome diversity and prevented expansion of the Enterobacteriaceae and Bacteroidetes that were the hallmarks of AKI-induced dysbiosis. Further, BGN4 administration also significantly reduced other IRI-induced changes in the colon microenvironment, including effects on permeability, apoptosis of colon epithelial cells, and neutrophil and proinflammatory macrophage infiltration. Mononuclear cells co-cultured with BGN4 expressed significantly increased proportions of CD103+/CD11c+ and CD4+ CD25+ Treg cells, suggesting a direct immunomodulatory effect. BGN4 induced Treg expansion in colon, mesenteric lymph nodes (MNL), and kidney. BGN4 also reduced CX3CR1intermediateLy6Chigh monocyte infiltration and interleukin (IL)-17A suppression in the small intestine, which may have attenuated AKI severity, kidney IL-6 messenger RNA expression, and AKI-induced liver injury. Conclusion Prior supplementation with BGN4 significantly attenuated the severity of IRI and secondary liver injury. This renoprotective effect was associated with increased Foxp3 and reduced IL-17A expression in the colon, MNL, and kidney, suggesting that BGN4-induced immunomodulation might contribute to its renoprotective effects. Probiotics may therefore be a promising strategy to reduce AKI severity and/or remote organ injury.

Background: Copeptin is secreted in equimolar amounts as arginine vasopressin, main hormone regulating body fluid homeostasis. A recent study reported a copeptin-based classification of osmoregulatory defects in syndromes of inappropriate antidiuresis that may aid in prediction of therapeutic success. We investigated usefulness of copeptin for differentiating etiologies of hyponatremia and predicting efficacy and safety of hypertonic saline treatment in hyponatremic patients. Methods: We performed a multicenter, prospective cohort study of 100 inpatients with symptomatic hyponatremia (corrected serum sodium [sNa] ≤ 125 mmol/L) treated with hypertonic saline. Copeptin levels were measured at baseline and 24 hours after treatment initiation, and patients were classified as being below or above median of copeptin at baseline or at 24 hours, respectively. Correlations between target, under correction, and overcorrection rates of sNa within 24 hours/24–48 hours and copeptin levels at baseline/24 hours were analyzed. Results: Mean sNa and median copeptin levels were 117.9 and 16.9 pmol/L, respectively. Ratio of copeptin-to-urine sodium allowed for an improved differentiation among some (insufficient effective circulatory volume), but not all hyponatremia etiologic subgroups. Patients with below-median copeptin levels at baseline achieved a higher target correction rate in 6/24 hours (odds ratio [OR], 2.97; p = 0.02/OR, 6.21; p = 0.006). Patients with below-median copeptin levels 24 hours after treatment showed a higher overcorrection rate in next 24 hours (OR, 18.00, p = 0.02). Conclusion There is a limited diagnostic utility of copeptin for differential diagnosis of hyponatremia. However, copeptin might be useful for predicting responses to hypertonic saline treatment in hyponatremic patients.

Background: The significance of ambulatory blood pressure (ABP) in Korean patients with chronic kidney disease (CKD) in relation to renal outcome or death remains unclear. We investigated the role of ABP in predicting end-stage renal disease or death in patients with CKD. Methods: We enrolled 387 patients with hypertension and CKD who underwent ABP monitoring and were followed for 1 year. Data on clinical parameters and outcomes from August 2014 to May 2018 were retrospectively collected. The composite endpoint was end-stage renal disease or death. Patients were grouped according to the mean ABP. Results: There were 66 endpoint events, 52 end-stage renal disease cases, and 15 mortalities. Among all patients, one developed end-stage renal disease and died. Mean ABP in the systolic and diastolic phases were risk factors for the development of composite outcome with hazard ratios of 1.03 (95% confidence interval [CI], 1.01-1.04; P < 0.001) and 1.04 (95% CI, 1.02-1.07; P = 0.001) for every 1 mmHg increase in BP, respectively. Patients with mean ABP between 125/75 and 130/80 mmHg had a 2.56-fold higher risk for the development of composite outcome (95% CI, 0.72-9.12; P = 0.147) as compared to those with mean ABP ≤ 125/75 mmHg. Patients with mean ABP ≥ 130/80 mmHg had a 4.79-fold higher risk (95% CI, 1.68-13.70; P = 0.003) compared to those with mean ABP ≤ 125/75 mmHg. Office blood pressure (OBP) was not a risk factor for the composite outcome when adjusted for covariates. Conclusion In contrast to OBP, ABP was a significant risk factor for end-stage renal disease or death in CKD patients.

Background: Serum uric acid (SUA) is recognized as a risk factor for chronic kidney disease (CKD) and mortality. However, there is controversy as to whether a high or low level of SUA is related to the risk of CKD progression or death, and whether it differs between males and females. Methods: We included 143,762 adults who underwent voluntary health screening between 1995 and 2009 in Korea. For each sex, we divided participants into sex-specific quintiles according to SUA levels and compared end-stage renal disease (ESRD) incidence and mortality between the groups with low and high SUA levels and those with middle SUA levels. Sex-specific Cox proportional hazard analyses were performed for ESRD and all-cause mortality. Results: Among the 143,762 participants, 0.2% (n = 272) developed ESRD. The hazard ratio (HR) of ESRD was higher in the highest (adjusted HR, 2.13; 95% confidence interval [CI], 1.18–3.84) and lowest (adjusted HR, 1.90; 95% CI, 1.02–3.51) SUA quintiles than in the middle SUA quintile in males and the highest SUA quintile in females (adjusted HR, 2.31; 95% CI, 1.10–4.84). Four-point three percent (n = 6,215) of participants died during a mean follow-up period of 157 months. The hazard ratio (HR) of all-cause mortality was higher in the highest SUA quintile than in the middle SUA quintile in males (adjusted HR, 1.15; 95% CI, 1.03–1.28) and females (adjusted HR, 1.17; 95% CI, 1.01–1.35). Conclusion Elevated levels of SUA are associated with increased risk for ESRD and all-cause mortality in both sexes. Low levels of SUA might be related to ESRD and death only in males, showing U-shaped associations. Our findings suggest sex-specific associations between SUA levels and ESRD development and mortality.

Purpose: This study evaluated the accuracy of the 24-hour diet recall method for estimating energy intakes in elderly women using the doubly labeled water (DLW) method. Methods: The subjects were 23 elderly women with a mean age of 70.3 ± 3.3 years and body mass index (BMI) of 23.9 ± 2.8 kg/m 2 . The total energy expenditure (TEEDLW ) was determined by using the DLW and used to validate the 24-hour diet recall method. The total energy intake (TEI) was calculated from the 24-hour diet recall method for three days. Results: TEI (1,489.6 ± 211.1 kcal/day) was significantly lower than TEEDLW (2,023.5 ± 234.9 kcal/day) and was largely under-reported by −533.9 ± 228.0 kcal/day (−25.9%). The accurate prediction rate of elderly women in this study was 8.7%. The Bland-Altman plot, which was used to evaluate the TEI and the TEEDLW , showed that the agreement between them was negatively skewed, ranging from −980.8 kcal/day to −86.9 kcal/day. Conclusion This study showed that the energy intake of elderly women was underreported.Strategies to increase the accuracy of the 24-hour diet recall methods in the elderly women should be studied through analysis of factors that affect underreporting rate. Further studies will be needed to assess the validity of the 24-hour diet recall method in other population groups.