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Impact of Loop Diuretics on Long-Term Kidney Outcome: A Post Hoc Analysis of the STOP-Angiotensin-Converting Enzyme
Sunil Bhandari1, Samir Mehta2, Natalie Ives2
1Department of Renal Medicine, Hull University Teaching Hospitals NHS Trust, Hull York Medical School, Kingston Upon Hull, United Kingdom.
Insights
Stopping renin-angiotensin system inhibitors (RASi) slowed kidney function decline in advanced CKD patients not on loop diuretics, but not in those on loop diuretics. Loop diuretic use was linked to high mortality.
Area of Science:
- Nephrology
- Pharmacology
- Clinical Trials
Background:
- The STOP-ACEi trial found no difference in kidney outcomes when stopping or continuing renin-angiotensin system inhibitors (RASi) in advanced chronic kidney disease (CKD).
- This post-hoc analysis examines the impact of concomitant loop diuretic use on RASi efficacy in advanced CKD patients.
Purpose of the Study:
- To investigate the interaction between loop diuretic use and the effect of stopping or continuing RASi on kidney outcomes in advanced CKD.
- To assess the impact of RASi withdrawal on estimated glomerular filtration rate (eGFR) and time-to-kidney failure events in patients with and without loop diuretics.
Main Methods:
- A post-hoc analysis of the STOP-ACEi trial involving patients with advanced CKD (eGFR < 30 ml/min/1.73m²).
- Patients were randomized to stop or continue RASi, stratified by loop diuretic use.
- Kidney outcomes, including eGFR slope and time-to-end-stage kidney disease (ESKD) or kidney replacement therapy (KRT), were analyzed using mixed-effects models and Cox regression.
Main Results:
- In patients not receiving loop diuretics, stopping RASi was associated with a steeper eGFR decline over 3 years compared to continuing RASi.
- In patients receiving loop diuretics, no significant difference in eGFR decline was observed between stopping and continuing RASi.
- The interaction between loop diuretic use and the effect of RASi on 3-year eGFR was statistically significant (p=0.01).
- Patients on loop diuretics had a high rate of ESKD/KRT (55%) and mortality (17%).
Conclusions:
- Loop diuretic use modifies the effect of RASi withdrawal on kidney function decline in advanced CKD.
- Stopping RASi may accelerate kidney function decline in advanced CKD patients not using loop diuretics.
- High mortality and ESKD/KRT rates in loop diuretic users highlight the need for further research and optimized management strategies.
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.
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