Abstract
KEY POINTS: Renin-angiotensin system inhibitors have less effect on decline in eGFR and no greater effect on delaying ESKD/KRT in patients receiving loop diuretics compared with those who do. Although loop diuretic use was not associated with higher rates of ESKD/KRT, it might be associated with a higher mortality. The decline in eGFR was slower in those taking loop diuretics. BACKGROUND: In the STOP-Angiotensin-Converting Enzyme Inhibitor trial, patients with advanced CKD were randomized to continue or stop renin-angiotensin system inhibitors (RASi) and showed no difference in kidney outcomes. This post hoc analysis investigates interactions with loop diuretic use. METHODS: Patients with eGFR <30 ml/min per 1.73 m 2 and progressive CKD were randomized to stop or continue RASi. Primary outcome was eGFR over 3 years using repeated-measures, mixed-effects linear regression, random-slope models. Cox models were used to calculate hazard ratios for time-to-event outcomes, including ESKD and KRT. RESULTS: At baseline, eGFR, arterial pressure, and proteinuria were similar for 133 patients taking loop diuretics and 278 who were not. Those receiving loop diuretics at randomization, least-squares mean (±SE) eGFR at 3 years was 12.3 (±1.1) for those stopping compared with 10.1 (±1.2) for those continuing RASi, trend favoring stopping RASi (+2.2; 95% confidence interval [CI], -0.9 to 5.4), but eGFR slope over 3 years was similar (-7.2 versus -7.7 ml/min per 1.73 m 2 ). Those not receiving loop diuretics, eGFR at 3-years was 8.8 (±0.8) and 11.6 (±0.8; discontinue and continue RASi groups), a difference favoring continuing RASi (-2.8; 95% CI, -4.9 to -0.8), and a steeper eGFR slope for those discontinuing RASi (-9.9 versus -7.6 ml/min per 1.73 m 2 ). The interaction between loop diuretic use and the effect of RASi on eGFR at 3 years and the three-way interaction between diuretic subgroup, effect of RASi, and time were both statistically significant ( P = 0.01 and P = 0.04, respectively). Of patients taking loop diuretics, 73 (55%) developed ESKD/KRT and 23 (17%) died. Of patients not taking loop diuretics, 170 (61%) developed ESKD/KRT and 19 (7%) died. CONCLUSIONS: Withdrawal of RASi was associated with a steeper decline in eGFR over 3 years in those not receiving loop diuretics, but this was not observed in those who were taking loop diuretics. Patients receiving loop diuretics had a high mortality. These data support the need for randomized trials investigating the efficacy and safety of loop diuretics in patients with advanced CKD.