Candidate Surrogate End Points for ESRD after AKI

Abstract

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.

Keywords: acute renal failure; end stage kidney disease; glomerular filtration rate.

Figure 1.

Risk of ESRD increases with postdischarge decline in eGFR after major surgery. (Upper panels) Risk of ESRD associated with postdischarge change in eGFR after major surgery by postoperative AKI status. (Lower panels) Distribution of postdischarge change in eGFR after major surgery by postoperative AKI status. Both estimates are at (A) 30, (B) 60, (C) 90, (D) 180, and (E) 365 days postdischarge. Black diamonds refer to stable eGFRs among those without AKI (the reference). Red circles refer to eGFR declines of 30% among those with AKI. Red lines are at eGFR decline of 30%, and red percentages refer to the prevalence of eGFR decline ≥30% among those survivors with postoperative AKI. The y axis is depicted on the log scale. HR, hazard ratio.

Figure 2.

Receiver-operating characteristic (ROC) for ESRD according to eGFR declines at 30, 60, 90, and 180 days postmajor surgery overall and within the population with postoperative AKI.