Renin-angiotensin system inhibitors initiation and mortality in non-proteinuric chronic kidney disease: a target trial emulation

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Background Treatment options for nonproteinuric chronic kidney disease (CKD) are limited. While renin-angiotensin system inhibitors (RASIs) are cornerstone therapies for proteinuric CKD, evidence supporting the clinical benefit of RASIs initiation in nonproteinuric CKD is lacking. Methods We emulated sequential target trials using a retrospective cohort from the China Renal Data System (CRDS). Adults with nonproteinuric CKD (urine albumin-to-creatinine ratio <30 mg/g) were included to assess the intention-to-treat effect of initiating RASIs on all-cause and cardiovascular mortality. The primary estimate was the three-year risk difference. A composite kidney outcome (>25% eGFR decline with stage deterioration or kidney replacement therapy) was also explored. Results A total of 17 382 eligible person-trials (10 101 unique persons) were included. The three-year cumulative incidence of all-cause mortality was 14.88% (95% confidence interval [CI], 13.65% to 16.51%) and 18.26% (95% CI, 17.67% to 19.42%) in the RASIs initiation group and the control group, respectively, corresponding to a risk difference of − 3.39% (95% CI, −4.71% to − 2.07%). A significant association favoring RASIs initiation was also observed in terms of cardiovascular mortality, with a three-year risk difference of -1.46% (95%CI, -2.57% to -0.52%). Estimates from the subgroup and the sensitivity analyses were consistent with the primary analysis. A similar trend of association was observed for composite kidney outcomes, though the three-year cumulative risk difference between groups did not reach statistical significance (risk difference, −0.88%; 95% CI, −2.42% to 1.40%). Conclusions Initiation of RASIs may be associated with lower risks of all-cause and cardiovascular mortality in patients with nonproteinuric CKD.