Association between Acute Declines in Estimated Glomerular Filtration Rate during Renin-Angiotensin System Inhibition and Risk of Adverse Outcomes

Key Points Renin-angiotensin system inhibition was favorable for risk of kidney failure (compared with 0% decline with use of placebo or other agents) up to declines in eGFR of 13% over a 3-month period. Relation between eGFR decline after renin-angiotensin system inhibitor initiation and risk of outcomes was stronger in the first 2 years of follow-up and waned over time. Background Declines in GFR occur commonly when renin-angiotensin system (RAS) inhibitors are started. Our objective was to determine the relation between declines in eGFR during trials of RAS inhibition and kidney outcomes. Methods We included participants with CKD (eGFR <60 ml/min per 1.73 m 2 ) from 17 trials of RAS inhibition. The exposure was subacute declines in eGFR expressed as % change between randomization and month 3, and in the subset of trials with data available, we also examined % change in eGFR between randomization and month 1. The primary outcome was kidney failure with replacement therapy. Cox proportional hazards models were used to examine the association between subacute declines in eGFR and risk of kidney failure. We used spline models to identify the threshold of change in eGFR below which RAS inhibition was favorable (conservatively comparing a given decline in eGFR with RAS inhibition to no decline in the comparator). Results A total of 11,800 individuals with mean eGFR 43 (SD 11) ml/min per 1.73 m 2 and median urine albumin-to-creatinine ratio of 362 mg/g (interquartile range, 50–1367) were included, and 1162 (10%) developed kidney failure. The threshold of decline in eGFR that favored the use of RAS inhibitors for kidney failure was estimated to be up to 13% (95% confidence interval, 8% to 17%) over a 3-month interval and up to 21% (95% confidence interval, 15% to 27%) over a 1-month interval after starting RAS inhibitors. Conclusions In patients treated with RAS inhibitors, ≤13% decline in eGFR over a 3-month period or ≤21% decline over a 1-month period was associated with lower risk of kidney failure compared with no decline in those assigned to placebo or other agents.