GFR Decline as an Alternative End Point to Kidney Failure in Clinical Trials: A Meta-analysis of Treatment Effects From 37 Randomized Trials

Inker, Lesley A.; Heerspink, Hiddo J L; Mondal, Hasi; Schmid, Christopher H.; Tighiouart, Hocine; Noubary, Farzad; Coresh, Josef; Greene, Tom; Levey, Andrew S.

doi:10.1053/j.ajkd.2014.08.017

Cited by 122 publications

(127 citation statements)

References 59 publications

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“…Next, using the Cox proportional hazard model adjusted for the baseline characteristics, the aHRs for true endpoints and for surrogate endpoints in the olmesartan group were calculated, respectively. After this, the bootstrap method was used to calculate the aHR for true endpoints and surrogate endpoints in the Cox proportional hazard model adjusted for the baseline characteristics, and their ratios and 95% CI were obtained [36]:…”

Section: Discussionmentioning

confidence: 99%

“…To optimize the design and operation of clinical trials, the international working group meeting hosted by the National Kidney Foundation (NKF) and Food and Drug Administration (FDA) presented a series of papers reviewing the feasibility of using decrease in eGFR as surrogate endpoints of ESRD for clinical trials in 2014 [8][9][10][11]. The general conclusion of these papers supported 30-40% decrease in eGFR as a surrogate endpoint of ESRD [12].…”

Section: Introductionmentioning

confidence: 99%

“…However, the papers of the NKF-FDA Working Group had a limitation of predominantly using research data from Europe and North America [8][9][10][11]. For instance, in a major paper from the Working Group using the data from the CKD Prognosis Consortium, only 0.5% of study population for ESRD were Asians [8].…”

Section: Introductionmentioning

confidence: 99%

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Guidelines for clinical evaluation of chronic kidney disease

et al. 2018

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Guidelines for clinical evaluation of chronic kidney disease

et al. 2018

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“…11,12,[14][15][16][17][18] To approve a drug, the FDA requires that a development program show that a drug has an effect on a clinically meaningful end point or its reliable surrogate. 19 ESRD is a widely accepted, clinically meaningful end point; however, ESRD is simply too late an event for the majority of clinical trial participants-a rationale that applies to both clinical trials of AKI prevention and treatment and CKD progression.…”

Section: Discussionmentioning

confidence: 99%

“…Cox proportional hazards regression was used to determine the association of eGFR decline with subsequent ESRD and mortality, with time at risk beginning at the time of postdischarge eGFR assessment. Fully adjusted models included the following covariates: age, sex, race, body mass index (linear spline with a knot at 25 kg/m 2 ), hypertension, baseline eGFR (linear spline with knots at 60 and 90 ml/min per 1.73 m 2 ), diabetes, congestive heart failure, peripheral arterial disease, cerebrovascular disease, lung disease, liver disease, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, diuretic use, statin use, surgery type, laparoscopic procedure, and hospital day of surgical procedure (hospital days 0-4, 5-14, or [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Proteinuria was considered as a covariate, but it was missing in 90% of the study population and thus, not included in the primary analysis.…”

Section: Statistical Analysesmentioning

confidence: 99%

Candidate Surrogate End Points for ESRD after AKI

Grams

Sang²,

Coresh

et al. 2016

JASN

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AKI, a frequently transient condition, is not accepted by the US Food and Drug Association as an end point for drug registration trials. We assessed whether an intermediate-term change in eGFR after AKI has a sufficiently strong relationship with subsequent ESRD to serve as an alternative end point in trials of AKI prevention and/or treatment. Among 161,185 United States veterans undergoing major surgery between 2004 and 2011, we characterized in-hospital AKI by Kidney Disease Improving Global Outcomes creatinine criteria and decline in eGFR from prehospitalization to postdischarge time points and quantified associations of these values with ESRD and mortality over a median of 3.8 years. An eGFR decline of $30% at 30, 60, and 90 days after discharge occurred in 3.1%, 2.5%, and 2.6%, of survivors without AKI and 15.9%, 12.2%, and 11.7%, of survivors with AKI. For patients with in-hospital AKI compared with those with no AKI and stable eGFR, a 30% decline in eGFR at 30, 60, and 90 days after discharge demonstrated adjusted hazard ratios (95% confidence intervals) of ESRD of 5.60 (4.06 to 7.71), 6.42 (4.76 to 8.65), and 7.27 (5.14 to 10.27), with corresponding estimates for 40% decline in eGFR of 6.98 (5.21 to 9.35), 8.03 (6.11 to 10.56), and 10.95 (8.10 to 14.82). Risks for mortality were smaller but consistent in direction. A 30%-40% decline in eGFR after AKI could be a surrogate end point for ESRD in trials of AKI prevention and/or treatment, but additional trial evidence is needed.

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Decline in Estimated Glomerular Filtration Rate and Subsequent Risk of End-Stage Renal Disease and Mortality

Coresh

Turin

Matsushita

et al. 2014

JAMA

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Importance The established chronic kidney disease (CKD) progression endpoint, end-stage renal disease (ESRD) or doubling of serum creatinine (corresponding to a change in estimated glomerular filtration rate (eGFR) of −57% or greater) is a late event, limiting feasibility of nephrology clinical trials. Objective To characterize the association of decline in eGFR with subsequent progression to ESRD, with implications for using lesser declines in eGFR as potential alternative endpoints for CKD progression. Since most people with CKD die before reaching ESRD, we also investigated mortality risk. Data Sources Individual meta-analysis of up to 1.7 million participants with 12,344 ESRD events and 223,944 deaths from 35 cohorts. Study Selection Cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine over 1-3 years and outcome data. Data Extraction and Synthesis Transfer of individual participant data or standardized analysis of outputs for random effects meta-analysis took place between July 2012 and September 2013 with baseline eGFRs during 1975-2012. Main Outcomes and Measures ESRD (initiation of dialysis or transplantation) or all-cause mortality risk related to percent change in eGFR over 2 years adjusted for potential confounders and first eGFR. Results The adjusted hazard ratios (HR) of ESRD and mortality were exponentially higher with larger eGFR decline. Among participants with baseline eGFR <60 ml/min/1.73m2, the adjusted HRs for ESRD were 32.1 (95% CI 22.3-46.3) and 5.4 (4.5-6.4) for −57% and −30% eGFR changes, respectively. However, changes of −30% or greater were much more common than changes of −57% (6.9% (6.4-7.4%) vs. 0.79% (0.52-1.06%) in the whole consortium). This association was strong and consistent across length of baseline (1 or 3 years), baseline eGFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD for eGFR changes of −57%, −40%, −30% and 0% were 99% (95-100%), 83% (71-93%), 64% (52-77%), vs. 18% (15-22%) respectively at baseline eGFR of 35 ml/min/1.73m2. Corresponding mortality risks were 77% (71-82%), 60% (56-63%), 50% (47-52%), vs. 32% (31-33%), showing a similar but weaker pattern. Conclusions and Relevance Declines in eGFR smaller than doubling of serum creatinine occur more commonly and are strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in eGFR, such as 30% reduction over 2 years, as an alternative endpoint for CKD progression.

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GFR Decline as an Alternative End Point to Kidney Failure in Clinical Trials: A Meta-analysis of Treatment Effects From 37 Randomized Trials

Cited by 122 publications

References 59 publications

Guidelines for clinical evaluation of chronic kidney disease

Guidelines for clinical evaluation of chronic kidney disease

Candidate Surrogate End Points for ESRD after AKI

Decline in Estimated Glomerular Filtration Rate and Subsequent Risk of End-Stage Renal Disease and Mortality

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