Effects of Hydroxyurea and Renin-Angiotensin Blockade on Kidney Function in Sickle Cell Disease

Kidney disease is a common complication that leads to increased morbidity and early mortality in patients with sickle cell disease (SCD). Vaso-occlusion, hyperfiltration, hypertension, and cell-free hemoglobin/heme-mediated toxicity may contribute to the pathophysiology of kidney disease. Treatments for SCD-related kidney disease have been adopted from therapies used to treat other SCD-related complications (hydroxyurea [HU]) or diabetic nephropathy (angiotensin converting enzyme [ACE]-inhibitors or angiotensin receptor blockers [ARBs]), although their effects on kidney function are not clear.

We evaluated the effects of HU and ACE-inhibitors or ARBs on kidney function in a longitudinal cohort of 439 SCD patients enrolled into a prospective registry between 2011 and 2019. Patients were considered for the analysis if they had 6 months of kidney function values pre-therapy and remained on therapy for 6 months or longer. Changes in the estimated glomerular filtration rate (eGFR) and urine albumin concentration were compared prior to and after starting therapy using a mixed effects model.

The effects of HU on kidney function were evaluated in 49 SCD patients. The mean age was 38 years (standard deviation [SD] 11 years), 43% were male, and 80% were Hb SS/Sβ⁰-thalassemia genotype. The eGFR improved from an average decline of -3.3 mL/min/1.73m² in the 6 months prior to starting HU to an increase of +9.5 mL/min/1.73m² during HU therapy (P = 0.0002) (Table). The average change in albuminuria also improved from an increase of +1.2 mg/g creatinine pre-HU therapy to a decline of -1.2 mg/g creatinine during HU therapy, although the difference was not statistically significant (P = 0.17). In 47 SCD patients started on ACE-inhibitors or ARBs, the mean age was 45 years (SD 11 years), 43% were male, and 87% were Hb SS/Sβ⁰-thalassemia genotype. During ACE-inhibitor or ARB therapy, there was no observed difference in the change in eGFR pre- versus during therapy (P = 0.9) (Table). Albuminuria improved from an average change of -1.0 mg/g creatinine pre-therapy to -1.6 mg/g creatinine during therapy (P = 0.009).

Because clinical data are limited, current American Society of Hematology guidelines have conditional recommendations with low levels of certainty for the use of HU and ACE-inhibitors or ARBs to treat sickle cell nephropathy. In a longitudinal cohort of SCD patients, we demonstrate that during 6 months of therapy, there may be a benefit of HU in improving eGFR and of ACE-inhibitors or ARBs in reducing albuminuria. Larger and longer follow up studies of HU, ACE-inhibitors and ARBs as well as new targeted therapies to treat sickle cell nephropathy are urgently needed.