American Journal of Nephrology最新文献

Background Chronic kidney disease (CKD) is highly prevalent in very old adults and frequently coexists with frailty, multimorbidity and limited life expectancy. In this population, the risk-benefit balance of standard KDIGO‑style treatment targets for blood pressure, glycemic control, albuminuria, lipid management, anemia and CKD-mineral and bone disorder is fundamentally altered. The clinical trials underpinning these recommendations enrolled few very old patients and virtually no frail octogenarians or nonagenarians, so the evidence base is poorly aligned with the realities of advanced age. Methods and aims This narrative review examines CKD progression in frail very old adults, with particular attention to frailty, geriatric syndromes, and competing risks of end‑stage kidney disease (ESKD) and death. It then proposes a pragmatic framework to adapt KDIGO‑style targets by incorporating frailty assessment, life expectancy and patient goals of care into therapeutic decisions. Results: For each major treatment domain, the discussion moves from abstract targets to clinically meaningful, individualized ranges, emphasizing treatment simplification, systematic deprescribing, and preservation of physical and cognitive function as primary outcomes. Conclusions: The review identifies urgent research priorities, including trials that intentionally enroll frail older adults, evaluations of deprescribing strategies, and studies comparing conservative kidney management with dialysis in this highly vulnerable and rapidly growing patient group.

Introduction: Individuals with kidney dysfunction have greater risk of mortality, especially cardiovascular mortality, but current markers of kidney function, including estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR), may not adequately capture this risk. Proenkephalin (PENK) is an emerging biomarker reflecting kidney glomerular function. We evaluated the association of PENK with all-cause and cardiovascular mortality in The REasons for Geographic and Racial Disparities in Stroke (REGARDS) cohort study and whether associations varied by sex and race.

Methods: PENK was measured in 1,021 Black and White participants randomly sampled from REGARDS. We evaluated the association of PENK with all-cause and cardiovascular mortality in nested multivariable Cox-proportional hazard models adjusting for confounders including UACR and eGFR calculated using the 2021 CKD-EPI combined creatinine-cystatin C race-free equation. Effect modification by sex and race was tested.

Results: Mean age was 67 years, 50% were women, 50% were Black, mean eGFR was 82 ml/min/1.73m2 and median UACR was 7.7 mg/g. There were 471 deaths and 142 cardiovascular deaths over a median follow-up of 11.6 years. When adjusting for comorbidities and UACR, each doubling of PENK was associated with higher risk of death (HR 1.22, 95% CI 1.00 to 1.48, p=0.05) but this association was not significant after adjusting for eGFR (HR 0.85, 95% CI 0.65 to 1.10, p=0.85). There was a significant interaction by sex (p-interaction=0.004) with higher PENK levels associated with lower mortality in women. PENK was associated with cardiovascular mortality after adjusting for comorbidities and UACR (HR 1.70, 95% CI 1.20 to 2.42, p=0.004), but this was not significant when adjusting for eGFR (HR 1.36, 95% CI 0.84 to 2.21, p=0.20). There was no significant interaction by sex or race.

Conclusion: PENK does not provide additional risk stratification for all-cause and cardiovascular mortality beyond current biomarker measures of eGFR.

Introduction: Ischemia and hypoxia are central drivers of acute kidney injury (AKI) and hypoxia-inducible factor (HIF) is a key regulator of cellular oxygen homeostasis. Our previous study showed that HIF-1α is protective during the early stage of AKI; however, its role in the transition from AKI to chronic kidney disease (CKD) remains unclear. Cellular senescence has been implicated in CKD progression and can be accelerated by hypoxia. Nevertheless, whether HIF-1α signaling mediates cellular senescence and promotes the AKI-to-CKD transition is poorly understood.

Methods: Ischemia-reperfusion injury models of AKI with adaptive repair (AR) or maladaptive repair (MAR) were used to examine the dynamics of HIF-1α, cellular senescence and autophagy. In human renal proximal tubular epithelial cells (HK-2), a hypoxia/reoxygenation (H/R) injury model was used to evaluate the relationships among HIF-1α, autophagy and senescence. Finally, the association between HIF-1α levels and cellular senescence was assessed in renal biopsies from CKD patients.

Results: The AR group exhibited rapid and sufficient HIF-1α expression, accompanied by acute senescence, with HIF-1α levels returning to baseline upon the completion of repair. In contrast, the MAR group showed delayed and sustained HIF-1α activation, driving chronic senescence and progressive fibrosis. The activation of autophagy was closely associated with the expression of HIF-1α in the AR and MAR groups. In vitro, silencing HIF-1α expression attenuated autophagy activity, senescence and fibrosis in HK-2 cells under H/R. However, HIF-1α overexpression had the opposite effect. The autophagy activator rapamycin reversed the inhibitory effects of HIF-1α knockdown, whereas the autophagy inhibitor bafilomycin A1 diminished the pro-senescent and pro-fibrotic effects of HIF-1α overexpression. Analysis of CKD patient biopsies confirmed elevated HIF-1α expression, which correlated with reduced eGFR, increased fibrosis, and enhanced cellular senescence.

Conclusion: Adequate HIF-1α activation during early AKI is associated with acute senescence and renal repair, whereas sustained HIF-1α drives chronic senescence via persistent autophagy activation, and may contribute to the AKI-to-CKD transition.

Introduction: Enarodustat is an oral HIF-PHI for the treatment of chronic kidney disease anemia.

Methods: This phase 3, multicenter, randomized 24-week study assessed enarodustat's noninferiority to rHuEPO for treating hemodialysis-dependent CKD (HD-CKD) anemia. 100 ESAs-treated patients were randomized 1:1 to enarodustat or rHuEPO for a 24-week treatment with dose adjustment every 4 weeks to maintain hemoglobin (Hb) within target range 100-120 g/L. The primary efficacy endpoint was the between-group difference in mean Hb over weeks 20 to 24(evaluation period, (noninferiority margin: -10 g/L)). Safety was assessed by treatment-emergent adverse events (TEAEs).

Results: Of the 100 patients treated (enarodustat:50; rHuEPO:50), 93 completed the study. Demographic and baseline characteristics were comparable. During the evaluation period, the mean Hb level was 106.81 g/L in the enarodustat group and 99.68 g/L in the rHuEPO group. Enarodustat was noninferior to rHuEPO [least squares mean difference: 7.47 g/L (95% confidence interval: 4.17, 10.78); P< 0.001]. The mean Hb level in the enarodustat group remained within the target range throughout the treatment period, with a maintenance rate of 79.6% during weeks 20-24, versus 51.0% for rHuEPO. After switching from ESAs, the enarodustat group showed increased total iron-binding capacity (TIBC), transferrin, and serum iron, decreased hepcidin by week 4, and increased RET% by week 2. TEAEs incidences were comparable (enarodustat: 90.0%, rHuEPO: 90.0%) , with no additional safety concerns for enarodustat.

Conclusions: Enarodustat was noninferior to rHuEPO for the treatment of anemia in HD-CKD patients , with good safety and tolerability over 24 weeks.

Background: Vascular calcification is common in chronic kidney disease (CKD) and is associated with adverse cardiac outcomes. We investigated the relationship of T50, a measure of mineral stress that is associated with vascular calcification, with left ventricular (LV) echocardiographic abnormalities among patients with CKD in the Chronic Renal Insufficiency Cohort (CRIC).

Methods: Linear regression models were used to examine the cross-sectional associations of T50 with LV mass index, and multinomial logistic regression models were used to analyze the cross-sectional associations of T50 with echocardiographic evidence of LV concentric remodeling, LV concentric hypertrophy, and LV eccentric hypertrophy. Multivariable models adjusted for age, sex, race/ethnicity, clinical site, systolic blood pressure, body mass index, diabetes, smoking, history of cardiovascular disease, estimated glomerular filtration rate (eGFR), and 24-hour urinary protein.

Results: Among 2280 participants, mean age was 59 years and 47.0% were female; 28.5% showed evidence of LV concentric remodeling, 15.0% showed evidence of LV eccentric hypertrophy, and 36.3% showed evidence of LV concentric hypertrophy. In unadjusted model, each 1 standard deviation (1-SD) lower of T50 was associated with greater odds for eccentric hypertrophy and concentric hypertrophy. After sequential adjustment for demographics, clinical factors, and kidney function measures, these associations were lost for eccentric hypertrophy (OR per 1-SD lower: 1.09; 95% CI: 0.92 - 1.29) and concentric hypertrophy (OR per 1-SD lower: 1.05; 95% CI: 0.91 - 1.21). In the unadjusted model, each 1-SD lower of T50 was associated with increased LV mass index; this association was lost in the multivariable adjusted model (β = 0.33; 95% CI: -0.63 - 1.28). Similar findings were observed when T50 was examined in quartiles.

Conclusion: Among the CRIC cohort, T50 was not associated with LV concentric remodeling, LV eccentric hypertrophy, or LV concentric hypertrophy after multivariable adjustment that included measures of kidney function.

Background: This phase III trial assessed desidustat's efficacy and safety compared with placebo for the treatment of anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD).

Methods: A multicenter, randomized, double-blind trial enrolled 152 NDD-CKD patients with anemia (101 desidustat, 51 placebo).

Primary endpoint: hemoglobin (Hb) change from baseline to weeks 7-9. Secondary endpoints included Hb response rate (≥100 g/L), time to target Hb, and target Hb maintenance (100-120 g/L). Safety evaluated treatment-emergent adverse events (TEAEs). Exploratory endpoints analyzed Hb dynamics (weeks 21-25) and serum hepcidin levels (baseline-week 53).

Results: After 9 weeks of treatment, desidustat increased hemoglobin level from 89.18 g/L to 105.66 g/L, whereas placebo decreased from 89.41 g/L to 88.51 g/L, with a mean difference of 17.52 g/L (95% CI: 14.35-20.68) in the FAS. And in the PPS, desidustat increased hemoglobin level from 88.86 g/L to 105.62 g/L, and placebo declined from 89.37 g/L to 87.57 g/L, with a mean difference of 18.39 g/L (95% CI: 15.39-21.39). Hb response rates were 85.15% vs. 23.53% (P<0.001). Median time to target Hb was 30 days with desidustat vs. 0 days with placebo (P<0.001). By week 9, desidustat maintained Hb within target range 51.68% of the time vs. 10.24% for placebo (P<0.001). TEAE incidence was comparable between groups. During weeks 21-25, Hb rose further (desidustat: +21.26 g/L; placebo: +26.63 g/L). Serum hepcidin decreased sharply in desidustat by week 9 (-67.43 ng/mL vs. -6.38 ng/mL; placebo), though placebo showed delayed reduction by week 25-levels equalized by week 53.

Conclusion: Desidustat significantly improved Hb levels and accelerated anemia correction in NDD-CKD patients versus placebo, with comparable safety.

Introduction: Acute kidney injury (AKI) is a common complication among hospitalized patients and is associated with substantial morbidity and mortality. Intravenous contrast media is frequently used in diagnostic imaging, but data on its safety in patients with established AKI remain limited. This study prospectively assessed renal and clinical outcomes following intravenous contrast administration in hospitalized patients with AKI Methods: In this prospective observational study, we included hospitalized adults diagnosed with AKI who underwent CT imaging with or without intravenous contrast between January 2023 and March 2024. The primary outcome was renal recovery within 7 days, defined as return of serum creatinine to baseline. Secondary outcomes included renal improvement within 72 hours, dialysis requirement after CT, length of stay, and in-hospital mortality.. Analyses were performed using inverse probability weighting(IPW), with propensity score matching (PSM) as a secondary robustness analysis.

Results: A total of 481 patients were analyzed; 282 received contrast and 188 did not. After IPW adjustment, renal recovery within 7 days occurred in 61.7% of the contrast group vs. 47.3% of the non-contrast group (OR 1.7, 95% CI 1.0-2.97, p = 0.05). Secondary outcomes were similar between groups. Results were consistent in a secondary PSM analysis. In the overall cohort, higher AKI stage and acute tubular injury were independently associated with lower recovery odds.

Conclusion: In hospitalized patients with AKI, intravenous contrast administration was not associated with worse renal or clinical outcomes, suggesting that contrast-enhanced CT may be acceptable in selected clinical settings.

Background: Tolvaptan slows disease progression of autosomal dominant polycystic kidney disease (ADPKD) in clinical trials, but real-world effectiveness remains uncertain. We evaluated the association between tolvaptan use and kidney function decline in a large tertiary-centre cohort.

Methods: This retrospective cohort study evaluated adults with ADPKD attending a specialist polycystic kidney disease clinic. Patients with <1 year of follow up or <3 estimated glomerular filtration (eGFR) measurements were excluded. eGFR slopes were estimated using piecewise linear mixed-effects models separating acute (<60 days) and chronic (60 days) phases, with the chronic slope defined as the primary outcome. Multivariable mixed-effects models and propensity score overlap weighting were used to adjust for baseline differences in covariates. Complete case analysis was performed as the primary analysis; multiple imputation was used as a sensitivity analysis. Patients receiving <6 months of tolvaptan were excluded from the primary slope analyses but retained for intention-to-treat comparisons.

Results: Of 327 patients, 119 initiated tolvaptan and 208 did not; mean duration of study follow up was 61.4 months. Tolvaptan-treated patients had a lower baseline eGFR and trended towards a faster pre-study eGFR decline. After full adjustment, tolvaptan was associated with a modest slowing in the chronic eGFR slope of +0.45 mL/min/1.73 m²/year; however, confidence intervals were wide (95% CI -0.37 to +1.18) and therefore compatible with clinically meaningful benefit or no effect. Findings were directionally consistent across complete-case, overlap-weighted, and multiple-imputation analyses with similarly imprecise confidence intervals. 61 patients (52.1%) discontinued therapy within 12 months of initiation, primarily due to aquaretic side effects. In subgroup analyses, tolvaptan patients treated for 1 year and tolvaptan responders treated for 2 years showed greater magnitudes of benefit with chronic slopes of +0.58 and +0.78 mL/min/1.73 m²/year respectively, when compared to untreated matched cohorts.

Conclusions: Tolvaptan was not associated with a statistically significant slowing of kidney function decline. Point estimates suggest a modest potential benefit which is attenuated when compared to controlled trials. Treatment discontinuation substantially limited treatment exposure. Further real-world evidence is required to clarify tolvaptan's true effectiveness outside controlled trial settings.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have demonstrated renoprotective effects in chronic kidney disease (CKD), but their therapeutic potential in membranous nephropathy (MN) remains unclear. In this study, analysis of the GEO database revealed that CAV1 expression is significantly upregulated in MN, suggesting a potential role in disease progression. A rat MN model was induced with cationic bovine serum albumin (C-BSA) and treated with canagliflozin (10 mg/kg). Renal function and histopathological changes were assessed. In vitro, MPC-5 podocytes were injured with complement C5a and treated with canagliflozin or CAV1 overexpression to explore mechanisms related to mitochondrial fission and apoptosis. Canagliflozin treatment markedly reduced proteinuria, increased serum albumin, and improved renal histology, including attenuation of mesangial hyperplasia, basement membrane thickening, and subepithelial electron-dense deposits. It also restored the expression of podocyte markers nephrin and podocin, inhibited the CAV1/PKA/DRP1 signaling pathway, preserved mitochondrial membrane potential, reduced pro-apoptotic markers Bax and cleaved caspase-3, and upregulated the anti-apoptotic protein Bcl-2. These findings suggest that canagliflozin alleviates podocyte injury and renal damage in MN by suppressing mitochondrial fission and apoptosis through inhibition of the CAV1/PKA/DRP1 signaling axis.

Background: The role of immune deposits and complement activation in APOL1 mediated focal segmental glomerulosclerosis (FSGS) remains unclear. Using the CureGN cohort, we examined the associations between APOL1 renal risk variants (RRVs), glomerular immune deposits, and urinary complement activation.

Methods: We analyzed glomerular IgG, IgM and C3 deposition, kidney biopsy findings, urinary membrane attack complex (sC5b9) levels and clinical data in FSGS patients, regardless of race. Study participants patients were categorized as high-risk (two RRVs) or low risk (zero to one RRV).

Results: Of 175 participants, 148 (84%) had genetic testing, among whom 31 were high-risk and 117 were low-risk participants. High-risk participants had a higher prevalence of collapsing FSGS (45% vs 11%, p<0.001) and mesangial IgG deposition (intensity>0) (32% vs 3%, p<0.001). Incident participants enrolled within 6 months of biopsy showed a trend toward higher urinary sC5b9 to protein ratio in high-risk participants [0.15 (0.08-0.31) vs 0.03 (0-0.20) μg/g, p=0.09]. IgG staining correlated with urinary sC5b9 levels (r=0.34, p=0.008), suggesting a link between IgG deposition and urinary membrane attack complex excretion.

Conclusions: APOL1 high-risk FSGS is associated with mesangial IgG deposition and increased urinary membrane attack complex levels, implicating immune-mediated mechanisms in FSGS pathogenesis.