Background: Chronic kidney disease (CKD) constitutes a major complication in sickle cell disease (SCD). Traditional SCD nephropathy results from hyperfiltration injury and glomerulotubular damage secondary to vaso-occlusion (VOC) and hemolysis. However, patients with compound variants such as hemoglobin (Hb) SC and HbSβ+ may have a distinct risk profile when compared to patients with HbSS. The objective of this study is to determine independent predictors of CKD in patients with mild compound SCD variants.

Methods: This IRB approved retrospective study was conducted at the Georgia Comprehensive Sickle Cell Center at Grady Memorial Hospital in Atlanta, GA. The study population includes adult patients (≥18 years) with HbSC/HbSβ+ confirmed by electrophoresis who received care at our facility from 2015-2025. Demographic variables, comorbid conditions (hypertension [HTN], diabetes mellitus [DM], obesity, pulmonary hypertension [PH], retinopathy, avascular necrosis [AVN]) and steady state laboratory parameters were analyzed. CKD status was obtained and defined as persistent estimated glomerular filtration rate <90 mL/min/1.73m² or persistent urine albumin-to-creatinine ratio > 30 mg/g. We also assessed the impact of hydroxyurea (HU) therapy and hemolysis parameters including lactate dehydrogenase (LDH) with high levels defined as >250 U/L and absolute reticulocyte count (ARC) with high levels defined as >150×10³/μL and their association with CKD diagnosis. High healthcare utilization was defined as ≥ 4 SCD related emergency room visits or ≥ 2 hospitalizations in 12 months.

Univariate analysis was done using T-test and chi-square while multivariate analysis using linear regression models adjusted for confounding variables. Statistical significance set at p <0.05. Abbreviations used: IQR (interquartile range), OR (odds ratio), RR (relative risk), CI (confidence interval).

Results: Our cohort included 494 patients (HbSC 61.2% and HbSβ+ 38.8%) with median age of 37 years (IQR 29-50); 56.9% females and 43.1% males. Median Hb was 11.34 g/dL (IQR 10.3-11.9), median ARC 206×10³/μL (IQR 120-265), and median LDH 198.5 U/L (IQR 126.1-220.0). HU was used in 19.2% of patients at a median dose of 13.44 mg/kg/day (IQR 10.0-17.5).

Comorbidities included CKD in 23.9% (comparable rates in HbSC and HbSβ+), HTN in 23.9%, obesity in 8.3% and DM in 6.9%. Complications related to SCD included retinopathy in 40.7% of 322 patients with documented retina exam, PH in 9% of 290 patients with cardiac assessment and AVN in 41.7%.

The OR for CKD in patients with DM was 5.28 (95% CI: 2.57-10.83, p<0.0001), HTN 4.57 (95% CI: 2.91-7.19 p<0.0001), obesity 1.35 (p=0.40), AVN 0.95 (p=0.79), retinopathy 1.04 (p=0.86), PAH 0.95 (p=0.92). Regarding hemolytic markers, OR of CKD in patients with LDH >250 U/L was 1.89 (95% CI: 1.10-3.25, p<0.05) and OR with ARC >150×10³/μL was 1.36 (p=0.2). In patients on HU, RR of CKD was 0.91 (p=0.10). Patients with high healthcare utilizations had an OR for CKD of 1.95 (95% CI: 1.32-2.89, p=0.001).

No significant positive interaction was observed in patients with CKD who had concurrent diagnoses of HTN and DM, nor in those with AVN and retinopathy. The combination of elevated LDH/ARC with SCD-related complications showed numerically increased CKD rates, albeit not statistically significant. Multivariate analysis revealed that HTN and DM were independent predictors of CKD with adjusted OR of 2.28 (p<0.01) and 1.78 (p<0.05) respectively. High healthcare utilization had an adjusted OR of 1.45 (p=0.048) and high LDH 1.75 (p=0.06).

Conclusion: In our cohort with compound SCD variants, cardiovascular risk factors (DM and HTN) and high healthcare utilization were statistically significant independent predictors of elevated CKD prevalence, whereas other SCD-related complications and hemolytic markers did not show statistically significant correlations with CKD rates, even upon evaluation for synergistic interactions. HU therapy utilization trended towards non-statistically significant lower CKD rates. These findings suggest that HTN and DM may be the main drivers of CKD, followed by VOC incidence as depicted by high rates of CKD in high healthcare utilizers. This underscores the importance of early screening and interventions for these cardiovascular risk factors. Prospective studies are needed to evaluate early intervention strategies targeting HTN and DM and their impact on CKD diagnosis and progression in compound SCD variants.

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2025
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