Improvement in kidney function after 12 months of voxelotor in sickle cell disease patients

Abstract

Abstract Introduction: Sickle cell nephropathy (SCN) is characterized by glomerular and tubulointerstitial damage, as well as glomerular hyperfiltration in the early stages. This is followed by a progressive decline in the glomerular filtration rate (GFR), albuminuria, and impaired urine concentration abilities. Endothelial dysfunction associated with chronic hemolysis appears to be a key factor in the development of SCN. The HEMOPROVE study (NCT05199766) is an open-label, single-arm, single-dose, phase II study in SCD patients. Patients are treated with voxelotor (1500 mg daily) for 48 weeks. The primary endpoint was to evaluate the effect of voxelotor on reducing intravascular hemolysis parameters. One of the secondary endpoints was the impact of voxelotor on renal laboratory parameters, which were assessed at baseline and at months 6 and 12. Methods: Patients with SS or S-beta0 thalassemia had to be more than one month from a vaso-occlusive crisis and three months from a transfusion. Patients under hydroxyurea (HU) or angiotensin-converting enzyme inhibitors (ACEi) had to have received a stable dose for at least three months. Patients were secondarily excluded from the M6 and/or M12 analyses if they had received more than 3 RBC units during the study period. GFR was measured using iohexol urinary clearance, which is more suitable than plasma clearance in cases of glomerular hyperfiltration. For patients with irregular voiding, mGFR was determined using iohexol plasma clearance. The urine albumin-to-creatinine ratio (ACR) was determined from a 24-hour urine collection. Glomerular hyperfiltration was defined as an mGFR greater than 134 ml/min/1.73 m². Hypofiltration was defined as an mGFR <90 mL/min/1.73 m². An improvement in mGFR after 12 months of treatment for patients with pathological mGFR at baseline (hyperfiltration or hypofiltration) was defined as a reduction in mGFR for patients with hyperfiltration, provided it did not fall below 90 mL/min/1.73 m²; or an increase in mGFR for patients with hypofiltration. Plasma oxyhemoglobin (HbO₂) was measured by spectrophotometry (BET 18P3417). Data are presented as median [IQR]. Paired data comparisons were made using the Wilcoxon test. Correlation analysis was performed using the Spearman test. Results: Twenty-nine patients were enrolled in the study. Six patients discontinued prematurely: four due to transfusions, one due to voluntary withdrawal, and one due to poor venous access. In addition, one patient died from sepsis with multiorgan failure, and four others discontinued following the withdrawal of the Voxelotor by Pfizer. A total of 19 patients (10 females and 9 males; mean age: 42 years [range 36–48]) were evaluable at M0, M6, and M12. Fifty-three percent of patients were treated with hydroxyurea (HU) and 37% with angiotensin-converting enzyme inhibitors (ACEi). Hemoglobin levels increased from 7.2 g/dL [6.6; 7.7] to 9.0 g/dL [8.2; 10.1] at M12 (p < 0.05). Plasma HbO₂ decreased from 7 µM [4.6-13.9] to 4 µM [3.1-5.8] at M12 (p = 0.0003). In the six patients with glomerular hyperfiltration, mGFR decreased from 150 [140; 162] to 134 [131; 176] at M6 (p < 0.05) and to 120 ml/min/1.73 m² [112; 140] at M12 (p < 0.05). No patient in this group achieved an mGFR <90 ml/min/1.73 m² after 12 months of treatment. In the four patients with normofiltration, mGFR remained unchanged at 107 (95; 115), 108 (99; 121), and 108 (97; 125) ml/min/1.73 m² at M0, M6, and M12, respectively. In the seven patients with hypofiltration, the mGFR increased from 66 ml/min/1.73 m² (55–88) to 80 ml/min/1.73 m² (73–95) at M6 (p < 0.05) and to 84.9 ml/min/1.73 m² (61–108) at M12 (p = 0.07). Improvements in mGFR were correlated with decreased plasma HbO₂ after 12 months of treatment (r = -0.67; p < 0.05). In the ten patients with ACR >3 mg/mmol, the ACR decreased from 6.7 mg/mmol (3.2–27.8) at M0 to 2.2 [1.1; 17.16] at M6 (p=0.12) and to 5.0 mg/mmol (2.3–20.6) at M12 (not statistically significant). The median fasting urine osmolality was low at baseline (363 mOsm/kg [353; 378]) and remained unchanged. Conclusions: During 12 months of treatment with voxelotor, the mGFR decreased in patients with glomerular hyperfiltration and increased in patients with reduced mGFR. The improvement in the mGFR was correlated with a decrease in plasma HbO₂. ACR and the ability to concentrate urine did not change significantly during the follow-up period.