Impact of Loop Diuretics on Long-Term Kidney Outcome: A Post Hoc Analysis of the STOP-Angiotensin-Converting Enzyme Inhibitor Trial.

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.