American Journal of Kidney Diseases最新文献

Rationale & objective: The management and outcomes of kidney transplant recipients have evolved over the past three decades. This study of U.S patients whose first kidney allograft failed sought to understand long-term trends in subsequent waitlisting, re-transplantation, and all-cause mortality.

Study design: Retrospective cohort study.

Setting & participants: Patients recorded in the United States Renal Data System (USRDS) whose first kidney allograft failed between 1990 and 2019.

Exposure: The 5-year period in which the allograft failure occurred: 1990-1994, 1995-1999, 2000-2004, 2005-2009, 2010-2014, or 2015-2019.

Outcomes: 1) Waitlisting for re-transplantation, 2) re-transplantation, and 3) all-cause mortality following first allograft failure.

Analytical approach: Competing risk survival analyses using the approach described by Fine and Gray were used for the outcomes of waitlisting and re-transplantation. Cox proportional hazards models were used for the outcome of all-cause mortality.

Results: The absolute number of patients whose allograft failed and started dialysis increased from 3,197 in 1990 to 5,821 in 2019. Compared to 1990-1994, the rate of waitlisting for a second transplant increased with each subsequent 5-year period, peaking between 2005-2009 before decreasing again subsequently. The rate of re-transplantation following allograft failure decreased by 9%, 14%, 18%, 7%, and 11% in the sequential 5-year eras; and the mortality rate was 25% lower in 2015-2019 (HR=0.75, 95% CI, 0.72-0.77) compared to 1990-1994. Women had a reduced rate of waitlisting (HR 0.93, 95% CI 0.91-0.95) and lower rate of re-transplantation (HR 0.93, 95% CI 0.91, 0.95) compared to men. Compared to White patients, African-American and Hispanic patients had significantly lower rates of waitlisting, re-transplantation, and mortality.

Limitations: Retrospective data that lacks granular clinical information.

Conclusions: During the past three decades, among patients whose first kidney allograft failed and subsequently initiated dialysis, the rates of waitlisting for re-transplantation increased while the rates of re-transplantation and mortality decreased. Race-, ethnicity-, and sex-based disparities in waitlisting and re-transplantation were observed and warrant further investigation.

Rationale & objective: Current guidance recommends against the use of metformin in people with advanced kidney impairment despite a lack of supporting evidence. The aim of this observational study was to compare outcomes of patients with type 2 diabetes who continued versus stopped metformin after developing stage 4 chronic kidney disease (CKD) (eGFR <30 ml/min/1.73m²).

Study design: Nationwide observational cohort study.

Setting & participants: All adults with type 2 diabetes and incident stage 4 CKD in Scotland who were treated with metformin between January 2010 and April 2019.

Exposure: Stopping versus continuing metformin within six months following incident stage 4 CKD.

Outcomes: Primary outcome was all-cause mortality. Secondary outcomes included major adverse cardiovascular events (MACE).

Analytical approach: Target trial emulation with clone-censor-weight design and marginal structural models fit for sensitivity analyses.

Results: In a population of 371,742 Scottish residents with a diagnosis of type 2 diabetes before 30^th April 2019, 4,278 were identified as prevalent metformin users with incident CKD stage 4. Within six months of developing CKD stage IV, 1,713 (40.1%) individuals discontinued metformin. Compared with continuing metformin, stopping metformin was associated with a lower 3-year survival (63.7%, 95% CI 60.9 to 66.6 versus 70.5%, 95% CI 68.0 to 73.0; HR=1.26, 95% CI 1.10 to 1.44), while the incidence of MACE was similar between both strategies (HR=1.05, 95% CI 0.88 to 1.26). Marginal structural models confirmed the higher risk of all-cause mortality and similar risk of MACE in patients who stopped versus continued metformin (all-cause mortality: HR=1.34, 95% CI 1.08 to 1.67; MACE: HR=1.04, 95% CI 0.81 to 1.33).

Limitations: Residual confounding.

Conclusions: The continued use of metformin may be appropriate when eGFR falls below 30 ml/min/1.73m². Randomized controlled trials are needed to confirm these findings.

Rationale & objective: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) may offer an alternative erythropoiesis-stimulating agents (ESA) for the treatment of anemia in the setting of CKD. To investigate the efficacy and safety of conversion from long-acting erythropoiesis-stimulating agent (ESA) methoxy polyethylene glycol-epoetin beta (MPG-EPO) to the oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) vadadustat 3-times-weekly versus maintenance on MPG-EPO.

Study design: Phase 3b, open-label, noninferiority trial.

Setting & participants: Multicenter study in United States; 456 patients adults with anemia and dialysis-dependent chronic kidney disease.

Intervention: Participants were randomized 1:1:1 either to vadadustat (starting dose: 600 mg thrice weekly), vadadustat (starting dose: 900 mg thrice weekly), or MPG-EPO, for up to 52 treatment weeks and 4 safety follow-up weeks after the end of treatment or early termination.

Outcomes: Primary and secondary efficacy endpoints were the mean change in hemoglobin from baseline during primary (weeks 20-26) and secondary (weeks 46-52) evaluation periods, respectively. Noninferiority was specified as a lower bound of the 95% CI above -0.75 g/dL for the difference in mean change in hemoglobin from baseline. Other efficacy endpoints were the proportion of participants with hemoglobin levels within the target range and the proportions of participants requiring ESA or red blood cell transfusion rescue for anemia during the evaluation periods. Transfusion rates were low and occurred at similar rates across treatment groups (2.7% and 4.0% in the combined vadadustat and MPG-EPO groups, respectively). Primary safety endpoints were any treatment-emergent and serious adverse events (AEs).

Results: After combining the vadadustat groups (600 mg and 900 mg thrice weekly, n=304), vadadustat was noninferior to MPG-EPO (n=152) for both primary (least squares mean treatment difference, -0.33; 95% CI, -0.53 to -0.13) and secondary efficacy endpoints (-0.33; -0.56 to -0.09). Mean hemoglobin concentrations were stable for all groups, except for an initial slight decline in the vadadustat 600 mg group, which stabilized by week 12. ESA rescue for anemia was more frequent in the MPG-EPO group (primary evaluation period, 27.7%; secondary evaluation period, 16.2%) than in the combined vadadustat (14.2%; 7.3%) groups. The incidences of any treatment-emergent and serious treatment-emergent AEs were similar across treatment groups.

Limitations: Potential errors in attribution of AEs as drug related.

Conclusions: Three-times-weekly vadadustat was noninferior to MPG-EPO on their effect on hemoglobin levels without detectable differences in AEs.

Focal Segmental Glomerulosclerosis (FSGS) is a characteristic histopathological lesion that is indicative of underlying glomerular dysfunction. It is not a single disease entity but rather a heterogeneous disorder that is an important cause of nephrotic syndrome and kidney failure in children and adults. The aim of this Kidney Health Initiative project was to evaluate potential endpoints for clinical trials in FSGS. This paper focuses on the data supporting proteinuria as a surrogate endpoint. Available data support the use of complete remission of proteinuria in patients with heavy proteinuria as a surrogate endpoint for progression to kidney failure. While substantial treatment effects on proteinuria that are short of a complete remission may also predict the effect of a treatment on progression to kidney failure, further work is needed to determine how such an endpoint should be defined. Fortunately, efforts are underway to bring together patient-level data from randomized controlled trials, observational studies, and registries to address this issue.

Rationale & objective: Optimal blood pressure (BP) targets in advanced CKD are controversial. More intensive BP lowering in the setting of advanced CKD is thought to be associated with risk of acute kidney injury, hyperkalemia, and ESKD. We aimed to conduct a pilot trial of intensive BP control to determine if lower SBP targets can be safely achieved for patients with CKD through titration of BP medications using in-home measured BP.

Study design: Non-blinded randomized controlled trial.

Settings & participants: 108 patients with advanced CKD (eGFR ≤30 mL/min/1.73 m²) and hypertension.

Interventions: Participants were randomized either to a target home SBP goal of <120 mmHg (N=66) or a less intensive SBP goal (N=42). Antihypertensive medications were titrated to achieve the target home SBP range in the first 4 months of the study and maintained until the end of the study. Home BP was measured using a wireless Bluetooth-enabled monitor that transmitted readings to providers in real-time.

Outcomes: The primary efficacy outcome was the difference in achieved clinic SBP between the two study arms from months 4-12. Safety outcomes included hyperkalemia, a composite outcome of falls or syncope, and onset of need for dialysis or kidney transplantation.

Results: The mean clinic SBP at month 12 was 124.7 mmHg in the intensive SBP group vs. 138.2 mmHg in the less intensive SBP group. Averaged over months 4-12, the achieved mean clinic SBP in the intensive SBP arm was 11.7 mmHg (95% CI 7.5 to 16 mmHg, p<0.001) lower than the mean SBP achieved in the less intensive SBP arm. Primary safety outcomes were not statistically significantly different between the two arms (all p>0.05).

Limitations: Small sample size which may limit our ability to detect clinically significant differences in rates of adverse outcomes; single-center design.

Conclusions: A clinic SBP goal of <120 mmHg is feasible to achieve with the help of real-time home BP monitoring and appears to be safe in this study population with advanced CKD. Larger trials to determine optimal BP targets in advanced CKD and the risks and benefits associated with more intensive BP control are warranted.