Improvement in Kidney Function after 6 Months of Voxelotor in Sickle Cell Disease Patients

Introduction: Sickle cell nephropathy (SCN), involves both glomerular and tubulo-interstitial damages with glomerular hyperfiltration in the early stages followed by glomerular filtration rate (GFR) decrease, albuminuria, impaired urine concentration and acidification abilities. Endothelial dysfunction associated with chronic hemolysis seems 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 treated with Voxelotor 1500 mg daily for 48 weeks. The primary endpoint of this study is to evaluate the effect of Voxelotor on reducing intravascular hemolysis parameters after 48 weeks of treatment. An interim analysis of the HEMOPROVE trial was performed to evaluate the effect of 6 months of Voxelotor on kidney functions, such as measured glomerular filtration rate (mGFR), albuminuria, and urine concentration ability in SCD patients and its determinants. Final 48-week results may provide additional insight.

Method

SS or S–beta0 Thal patients were included if they were more than one month from a vaso-occlusive crisis, 3 months from a transfusion. A stable dose for at least 3 months was required for patients treated with hydroxyurea (HU) or angiotensin-converting enzyme inhibitors. GFR was measured using iohexol urinary clearance (six consecutive 30-min clearance periods after a 5 mL bolus of iohexol at 300 mg/mL and an equilibration for 90 min (distribution time of iohexol in the extracellular compartment)), which is more suitable than plasma clearance in patients with glomerular hyperfiltration. In case of incomplete or irregular voiding, mGFR was determined with plasma clearance of iohexol, and comparisons of mGFR values were made using iohexol plasma clearances for both measurements. Albumin / creatinine ratio was determined from 24h urine collection (ACR; mg/mmol). Urine concentration ability was the urinary osmolarity calculated on fasting morning urine. Glomerular hyperfiltration was defined as mGFR > 134 ml/min/1.73m² in patients under 40 years, and with the following equation in patients over 40 years: 154 – 0.73 x age (4). Chronic kidney disease was defined as mGFR < 90 ml/min/1.73m² (5). Data are presented as median [IQR]. [IQR]. Paired data comparisons were made with Wilcoxon and McNemar test for quantitative and categorical data, respectively. Correlation analysis was performed with Spearman test.

Results: 20 patients were included (90% SS), 10 women and 10 men, with a median age of 41 years [36 - 49]. Sixty percent of patients were treated with HU and 30% with ACE inhibitor. Hemoglobin (Hb) level increased from 7.3g/dL [6.7 - 7.7] to 8.8g/dL [8.4 - 9.6] (p<0.05), and LDH decreased from 602 U/I [526 - 647] to 476 U/I [339 -574] between baseline and M6 (p<0.05). Iohexol clearance was not performed in one patient due to poor venous access. Measured GFR decreased from 165.5 [150.1 - 170.3] to 134.5 [128.4 - 158.3] (p < 0.05) in patients with glomerular hyperfiltration (n=7), remained unchanged for six patients with normal GFR (112.7 [109.1 - 119.5] to 110.5 [101.8 - 125.3]) and improved for six patients with low GFR (62.3 [54.9 - 66.0] to 76.6 [73.0 - 80.5], p < 0.05). Baseline ACR was 3.0 mg/mmol [1.2 - 7.3], and decreased to 2.0 mg/mmol [0.9 - 4.2] at M6 (p < 0.05). At baseline, ten patients had an ACR ≥ 3 mg/mmol (microalbuminuria), including two patients with an ACR ≥ 30 mg/mmol (macroalbuminuria), at M6 only five patients had an ACR ≥ 3 mg/mmol, including one patient with ACR ≥ 30 mg/mmol (p = 0.07). ACR was missing for one patient at baseline, due to urine collection failure. Variations in ACR were correlated with variation in LDH (r = 0.56, p = 0.015). Fasting urine osmolarity was low at baseline and remained unchanged at M6, respectively 362 mOsm/Kg [353 - 377] and 352 mOsm/Kg [337 - 376].

Conclusions: After six months of treatment with Voxelotor, ACR decreased and mGFR decreased in patients with glomerular hyperfiltration and improved in patients with low GFR, without significant changes for those displaying a normal mGFR. These results were probably related to hemolysis improvement. There were no changes in the urine concentration ability.