Renin-Angiotensin System Blockade Does Not Alter Long-Term Kidney Outcomes in Sickle Cell Disease

Background: Sickle disease (SCD) is associated with faster kidney function decline compared to normal hemoglobin phenotypes. The role of renin angiotensin system inhibitors (RASI) in modifying long-term kidney outcomes in SCD is not well described despite several studies showing antiproteinuric effects of RASI in SCD. This study aimed to describe long-term kidney outcomes in adult SCD patients on RASI. Methods: A single-center observational study of adult patients with SCD on RASI (exposure) and SCD not on RASI (reference) between 2010 and 2021 was performed. Inclusion criteria were patients with a baseline eGFR≥15 ml/min/1.73m2, ≥3 estimated glomerular filtration rate (eGFR) values, and ≥1 year between first and last eGFR values. The outcomes of interest were the difference in the mean change in eGFR per year (evaluated using linear mixed models), rapid eGFR decline (≥3 ml/min/1.73m2/year), incident stage 5 chronic kidney disease (CKD), and mortality (described using Cox proportional hazard models). Propensity score matching (1:3) adjusted for 16 baseline characteristics. Time-updated RASI use was utilized in all models. All other covariates (demographics, comorbidities, medications, labs) were baseline values. Results: In total 1,960 SCD patients (476 RASI, 1,484 reference) were identified. After matching, 442 reference patients were used. Matched cohort median follow-up was 4.6 (IQR 2.5-8.3) years with a median of 24 (IQR 10-60) eGFR values, a mean±SD age of 43±16 years, 59% female, and mean baseline eGFR±SD of 97±29 ml/min/1.73m2. All results were compared to the matched reference. The adjusted mean eGFR change in RASI users was +0.02 (95% confidence interval [CI] -1.06 to +1.08) ml/min/1.73m2/year. Rapid eGFR decline (hazard ratio [HR] 0.80; 95% CI 0.51-1.25), incident stage 5 CKD (HR, 0.28; 95% CI 0.06-1.21) and mortality (HR, 0.61; 95% CI 0.30-1.25) were not significantly different. Among RASI users only, the adjusted mean eGFR change pre- vs. during-RASI use was -0.13 (95% CI -0.30 to +0.03) ml/min/1.73m2/year. Conclusion: In the largest observational study to date of adult SCD RAS blockade, RASI use was not associated with adverse or improved long-term kidney outcomes compared to no RASI use. Therefore, if RASI are indicated in SCD, adverse long-term kidney outcomes should not be a concern. Conversely, RASI should not be started solely to slow kidney function decline in SCD. Funding: Other NIH Support - KL2