Kidney360最新文献

Background: Hyperuricemia is a common metabolic disorder and a risk factor for multiple diseases, including CKD. Hyperuricemic nephropathy (HN) affects many individuals with hyperuricemia, yet its molecular mechanisms are not fully understood, and effective treatments are lacking.

Methods: In vitro, human tubular epithelial cells (HK-2) were exposed to uric acid for 36 hours, followed by transfection with microRNA mimic or FIH-1 siRNA. In vivo, HN was induced in mice using potassium oxonate (PO) and adenine (Ad) for two weeks. miR-295 mimic or anti-miR-295 was administered via tail vein injection, and mice were sacrificed for analysis.

Results: We demonstrated a significant increase of miR-295 in renal tubular cells in HN mice. Hyperuricemia led to the activation of hypoxia inducible factor-1α (HIF-1α), and inhibition of HIF-1α by YC-1 (a HIF-1α inhibitor) prevented the increase of miR-295. ChIP assay further verified HIF-1α binding to the miR-295 gene promoter directly. Functionally, Inhibition of miR-295 led to increased cell death and tubulointerstitial fibrosis in HN mice, whereas supplementation of miR-295 mimic had kidney protective effects in this model. miR-295 suppressed the expression of factor inhibiting hypoxia-inducible factor-1 (FIH-1) in both in vitro and in vivo models of HN. Luciferase microRNA target reporter assay further verified FIH-1 as a direct target of miR-295.In addition, knockdown of FIH-1 inhibits tubular cell apoptosis and profibrotic cytokines production in HK2 cells during uric acid treatment.

Conclusions: This study reveals a HIF-1α/miR-295/FIH-1 positive feedback loop that regulates tubular damage and fibrosis in HN.

Background: Glomerular disease (GD) is a prominent cause of kidney disease in adolescents and young adults (AYA), yet there is limited information on how this population fares compared to children and older adults.

Methods: We analyzed data from CureGN, a prospective cohort of patients of all ages with biopsy-proven GD. Patients with Minimal Change Disease (MCD), Focal Segmental Glomerulosclerosis (FSGS) and IgA Nephropathy (IgAN) were included. Patients were stratified into pediatric (≤13), AYA (14-25), and adult (≥26) groups, and compared by demographic, clinical, and disease characteristics. Associations between age group and relapse rate, change in kidney function, and time to remission were assessed using multivariate negative binomial, linear mixed effects, and Cox proportional hazards models respectively, stratified by disease type.

Results: Our study included 1868 patients (562 pediatric, 397 AYA, and 909 adults). Median follow up time was 4.9 years. Adults with MCD had fewer relapses (IRR 0.61, CI 0.41-0.91, P=0.01) while there was no difference between pediatric participants with MCD (IRR 1.23, CI 0.85 - 1.79, P=0.28) compared to AYA. Adults with IgAN had fewer relapses than AYA (IRR 0.55, CI 0.33 - 0.94, P=0.03). AYA had faster decline in kidney function compared to pediatric participants with FSGS (1.7 ml/min/1.73m2 per year vs 0.3 ml/min/1.73m2 per year, P=0.008) and IgAN (1.5 ml/min/1.73m2 per year vs 0.1 ml/min/1.73m2 increase per year, P=0.002). Pediatric participants with MCD achieved first observed remission sooner compared to AYA (HR 2.18, CI 1.03 -4.63, P=0.04). Adults with IgAN were slower to achieve first observed remission compared to AYA (HR 0.58, CI 0.37 - 0.91, P=0.02).

Conclusions: AYA with GD exhibit distinct clinical patterns compared to the pediatric and adult age groups, underscoring the need to approach care and research along an age-related continuum rather than a binary framework.

Background: Little is known regarding whether renal function during pregnancy among healthy women is associated with pregnancy outcomes. Evidence based on the universal screening of maternal eGFR is lacking. We investigated the association of maternal eGFR during the second trimester with fetal birthweight.

Methods: This prospective birth cohort study includes 1,666 singleton pregnant women (median age 36 years, median BMI 20.0) who had universal screening of eGFR during the second trimester. Participants were categorized into the quartile of eGFR. The 1st quartile group was defined as low eGFR, the 4th quartile group as high eGFR, and the 2nd and 3rd quartile group as reference. The primary outcomes are low birthweight (LBW) and small for gestational age (SGA). Multivariable logistic regression models were used to investigate the association of maternal eGFR and pregnancy outcomes.

Results: As compared to the reference group, the adjusted odds ratios (95% Confidence Intervals [CI]) for LBW and SGA in the low eGFR group were 2.25 (1.48-3.40) and 2.51 (1.63-3.87), respectively, and in the high eGFR group were 0.69 (0.40-1.19) and 0.55 (0.30-1.02), respectively. The adjusted odds ratios of eGFR per SD decrease (95% CI) for LBW and SGA were 1.92 (1.50-2.45) (p=0.013) and 2.07 (1.60-2.68) (p<.001). The prediction models were improved by adding eGFR to the models including covariates; for LBW (C statistics difference, +0.018; 95% CI, -0.004-0.040, net reclassification index (NRI), 0.377; 95% CI, 0.208-0.545, and integrated discrimination improvement (IDI), 0.0135; 95% CI, 0.005-0.022) and for SGA (C statistics difference, +0.041; 95% CI, 0.003-0.080, NRI, 0.408; 95% CI, 0.226-0.591, and IDI, 0.017; 95% CI, 0.009-0.025).

Conclusions: The lower maternal midterm eGFR is associated with LBW and SGA, while the higher eGFR is not. Evaluating midterm eGFR may help identify healthy women at risk of adverse birth outcomes.

Background: Dialysis may deplete the body of valuable solutes. We previously found that the diet-derived antioxidant ergothioneine was markedly depleted in hemodialysis (HD) patients. Standard peritoneal dialysis (PD) prescriptions provide lower clearances of small molecules than standard HD prescriptions. We therefore tested whether ergothioneine would be depleted in PD patients but to a lesser degree than in HD patients.

Methods: Blood levels of ergothioneine were compared in 16 PD patients, 16 HD patients, and 15 controls with normal kidney function. Levels were measured using liquid chromatography mass spectrometry in plasma and also in erythrocytes in which ergothioneine is normally highly concentrated. Ergothioneine clearances by PD and HD were also compared.

Results: Erythrocyte ergothioneine levels were much lower in both PD and HD patients than controls. The erythrocyte ergothioneine levels, however, were less depleted in PD patients than in HD patients. The erythrocyte levels in PD patients averaged 34% those of controls while levels in HD patients averaged only 10% those of controls. Plasma ergothioneine levels in dialysis patients were also lower than controls. The time-averaged clearance of ergothioneine was lower with PD than with HD, so that a standard PD regimen would remove less ergothioneine daily than a standard HD regimen at a given plasma level.

Conclusions: The antioxidant ergothioneine is depleted in PD patients but to a lesser extent than in HD patients. Benefits of ergothioneine repletion in dialysis patients remains to be assessed.

Background: Patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) develop progressive symptoms which impact quality of life. We distributed the Kidney Disease Symptom Survey (KDSS), an electronic patient-reported outcome measure (PROM), partially based on the Kidney Disease Quality of Life 36 (KDQoL-36) instrument, to patients with NDD-CKD. We aimed to evaluate the measurement properties of the KDSS when used in usual clinical care.

Methods: We conducted a retrospective analysis of electronic health record (EHR) data for patients with NDD-CKD who completed the KDSS as part of their routine nephrology care. We evaluated temporal stability of KDSS scores for individuals with stable kidney function, responsiveness of KDSS scores for individuals with worsening kidney function, and convergent construct validity of the KDSS with Medicare Annual Wellness Visit (AWV) assessments of patient-reported outcomes.

Results: Among 147 patients with stable NDD-CKD, there were strong correlations between sequential KDSS assessments of general health [Spearman's rank correlation (rho) 0.76], QoL (rho 0.63), physical symptoms (rho 0.74), and mental health (rho 0.71). For 35 individuals with worsening kidney function, the KDSS detecting a clinically important difference in physical symptom and mental health scores in ∼40% of respondents. There were moderate to strong correlations between KDSS and AWV assessments of general health (rho 0.64) and depressive symptoms (rho 0.50).

Conclusions: When used by diverse individuals with NDD-CKD, the KDSS had temporal stability for patients with stable kidney function, as well as moderate convergent construct validity for measuring general health and depressive symptoms. Responsiveness of the KDSS for physical symptoms and mental health was seen in only some individuals with kidney disease. Additional data demonstrating responsiveness to changes in kidney function, as well as interventions such as symptom management strategies, are needed to determine the clinical utility of the KDSS when used in usual care of patients with NDD-CKD.

Background: Immunoglobulin A nephropathy is the most prevalent primary glomerular disease worldwide; however, its heterogenous clinical course complicates prognostic prediction. Podometrics, a quantitative assessment of podocytes based on the recently proposed "podocyte depletion hypothesis," has been suggested as a potential predictor of renal outcomes in various glomerular diseases. Nevertheless, its correlation with the Oxford classification or the pre-biopsy estimated glomerular filtration rate slope remains unclear. This study aimed to investigate the association between podometrics and MEST-C scores and identify podometric parameters associated with the pre-biopsy estimated glomerular filtration rate slope.

Methods: Kidney biopsy specimens from 101 patients diagnosed with immunoglobulin A nephropathy at our institution between 2019 and 2022 were evaluated using the Oxford classification and podometrics. Patients were categorized into "decline" and "non-decline" groups based on their pre-biopsy estimated glomerular filtration rate slope. Urinary mRNA levels of podocyte markers (NPHS1 and NPHS2) were measured in 94 patients. Independent factors associated with the "decline" group were identified via multivariate nominal logistic regression analysis.

Results: Patients with stage S1 or T1/2 exhibited significantly lower podocyte densities and numbers compared with those with stage S0 or T0, respectively. Elevated urinary podocyte marker levels were associated with E1 and C1/C2 lesions. The "decline" group exhibited significantly lower podocyte density and number and larger mean podocyte volume compared with the "non-decline" group. In the multivariate analysis, a lower podocyte number was the only independent factor associated with the "decline" group.

Conclusions: The podocyte number at the time of kidney biopsy was associated with the pre-biopsy estimated glomerular filtration rate decline slope in patients with immunoglobulin A nephropathy. Furthermore, elevated urinary podocyte mRNA levels suggested the presence of E and C lesions. Podometrics may serve as a potentially less invasive marker for monitoring disease activity and guiding treatment strategies.

Background: Kidney disease contributes to both cognitive and physical decline; whether kidney health biomarkers relate to declining cognitive and physical performance separately and/or together is unknown.

Methods: Among 1,902 participants (26% Black; 53% female) in the Health, Aging and Body Composition Study with intact baseline gait speed (≥0.8 m/s) and cognition (modified Mini-Mental State [3MS] score≥90), we assessed baseline kidney-related biomarkers (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [UACR], serum 25-hydroxyvitamin D, plasma intact parathyroid hormone [iPTH], plasma alpha-klotho, serum intact fibroblast growth factor 23 [FGF23], and vitamin D metabolites) with joint trajectories of cognitive and physical performance. Grouped-based trajectory analysis of 3MS and 20-meter usual gait speed up to 10 years yielded three groups: Group 1 (n=660), superior longitudinal cognitive-physical performance; Group 2 (n=744), high sustained cognition and initially lower, declining gait; and Group 3 (n=498), lower initial cognitive-physical performance, both steeply declining. Three sequential multinomial regression models were built with covariate adjustment.

Results: In Model 1 (M1; kidney function), higher eGFR (per 10 ml/min/1.73m2) was associated with lower odds of being in Group 3 versus Group 1 (odds ratio[OR]=0.84, 95%confidence interval[CI]: 0.75-0.94, p=0.003) after covariate adjustment. Additionally, each doubling of UACR related to higher odds of being in Group 2 (OR=1.13, 95%CI: 1.04-1.23, p=0.006) and Group 3 (OR=1.23, 95%CI: 1.12-1.36, p<0.001) versus Group 1. Log2 25-hydroxyvitamin D and log2 iPTH, added in Model 2 (M2; clinical biomarkers), were not significantly associated with cognitive-physical trajectory (p=0.63, M2 versus M1). However, Model 3 (M3; research biomarkers adding alpha-klotho and FGF23) showed higher log-2 alpha-klotho associated with lower odds of being in Group 3 versus 1 (OR=0.70, 95%CI: 0.52-0.94, p=0.019).

Conclusions: Kidney health biomarkers are potential factors in dual maintenance/decline in cognitive-physical function. Improving kidney health may contribute to preserved function in older adults.