Discordance Between Cystatin C and Creatinine Provides Insights into Tubular Function and Clinical Outcomes in Sickle Cell Disease

Background: The degree of discordance in glomerular filtration rate estimation (eGFR) by cystatin C (eGFRcys) compared to creatinine (eGFRcreat) provides insights into both tubular secretion and adverse clinical outcomes in the general population. Whether these associations are valid in sickle cell disease (SCD) is unknown. SCD pathophysiology markedly increases proximal tubular secretion of creatinine and promotes chronic inflammation (which can elevate cystatin C [CysC] levels). We investigated the differences between eGFRcys and eGFRcreat in SCD compared to non-SCD and the association between eGFRdiscordance and common SCD outcomes. Methods: We performed a 2-center cross-sectional study of 1060 adult Black race patients over 5 years (2020-2025) across chronic kidney disease (CKD) stages 1-5, excluding dialysis. SCD was confirmed by hemoglobin electrophoresis. Outcomes of interest were eGFR difference (eGFRdiff [eGFRcys - eGFRcreat]) and eGFR ratio (eGFRratio [eGFRcys/eGFRcreat]). Outcomes were examined in SCD vs non-SCD (linear regression), across CKD stages (trend tests), and in common SCD outcomes (logistic regression): left ventricular hypertrophy (LVH), pulmonary hypertension (pHTN), heart failure (HF) and stroke. Demographics, vital signs, comorbidities and medications were included in multivariable analyses. Results: We identified 184 SCD and 876 non-SCD patients. The mean age was 58±17 years, 55% were female, the mean eGFRcys was 50±31 mL/min, and the mean eGFRcreat was 60±33 mL/min. The mean eGFRdiff was -9±17 and the mean eGFRratio was 0.85±0.27. Before and after adjusted analyses, eGFRdiff was larger (adjusted β -14.4, p<0.01) and eGFRratio was lower (adjusted β -0.16, p<0.01) in SCD compared to non-SCD. The trend test for CKD stages in SCD was significant for narrowing eGFRdiff (Z=3.2, p<0.01) and decreasing eGFRratio (Z= -2.1, p=0.04) from stages 1-5. Larger than median SCD eGFRdiff was associated with LVH (adjusted odds ratio [aOR] 2.49, p=0.03), pHTN (aOR 2.62, p<0.01), and HF (aOR 4.28, p<0.01) but not stroke (aOR 1.39; p=0.53). Lower than median SCD eGFRratio results were similar. Conclusion: eGFRdiff and eGFRratio in SCD are more discordant than in non-SCD and associated with adverse cardiac outcomes, but not with stroke. CysC may be of unique clinical utility in interrogating renal tubular function and cardiac events in SCD. Funding: Other NIH Support - Research reported in this abstract was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award Number UL1 TR003163 and under the CTSA KL2 Program award number 5KL2TR003981-04. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.