Kidney Function Decline in Sickle Cell Disease: Associations with Renin-Angiotensin System Inhibitors

Renin-angiotensin system inhibitor use was not associated with slowed GFR decline in sickle cell disease. This null association did not change after excluding low-dose renin-angiotensin system inhibitors or including an interaction term with sickle cell disease therapies. Our findings highlight the limitations of real-world data and underscore the urgent need for prospective trials and novel therapeutics.

Sickle cell disease (SCD) is associated with accelerated kidney function decline, with no proven effective therapies. We examined the associations between treatment with renin-angiotensin system inhibitors (RASi) and eGFR decline in SCD.

This two-center observational study used electronic health record data of adult, Black patients with SCD (by hemoglobin electrophoresis), and ≥1-year follow-up between 2010 and 2024. We compared incident RASi users (exposure) to no treatment (reference). We created 1:1 propensity score-matched cohorts, balancing on demographics, vital signs, comorbidities, medications, and laboratory values. The primary end point was the difference in the mean change in eGFR per year, analyzing only chronic slopes (≥90 days postindex date) using linear mixed models on the matched cohorts. Sensitivity analyses were performed excluding patients with missing albuminuria and excluding low-dose RASi. Effect modification by SCD-modifying therapies was also examined.

Matched cohorts identified were primary analysis (358 patients), excluding missing albuminuria data (262 patients), and excluding low-dose RASi (270 patients). All cohorts achieved optimal standardized mean differences <0.2. After multivariable adjustment, there was no significant difference in eGFR decline between RASi and the reference in the primary cohort (-0.15 ml/min per year; 95% confidence interval [CI], -1.67 to +1.36; P = 0.84), the sensitivity analysis cohort excluding missing albuminuria data (+0.89 ml/min per year; 95% CI, -0.86 to +2.63; P = 0.32), and the sensitivity analysis cohort excluding low-dose RASi (+0.78 ml/min per year; 95% CI, -1.12 to +2.67; P = 0.42). All P values for interaction terms between RASi and SCD-modifying therapies in all models were >0.05.

In this large, real-world cohort of patients with SCD, RASi use was not associated with slowed eGFR decline. These findings underscore the limitations of observational data and highlight the urgent need for prospective trials to identify effective GFR-preserving therapies for this high-risk population.