INTRODUCTION: In sickle cell disease (SCD), ischemia-reperfusion and heme release from hemoglobin during hemolysis can activate the lectin pathway and the alternative pathway of complement, respectively. Increased C3 activation fragments and C5b-9 deposition have been observed in the kidneys of the Townes SCD mouse model. Uncontrolled complement activation is associated with glomerular injury in several kidney diseases, including atypical hemolytic uremic syndrome, C3 glomerulopathy, diabetic nephropathy, and glomerulonephritis. Complement activation markers are elevated in SCD and associated with persistent inflammation. Our previous global urine proteomics analysis showed an 8.4-fold increase in urinary CD59 levels (p=2.51×10-8) in SCD patients with hemoglobinuria. CD59, a membrane attack complex inhibitory protein, protects human cells from damage during complement activation. However, the relationship between C59 and chronic kidney disease (CKD) progression in SCD remains unclear. We hypothesize that urinary CD59 levels correlate with the progression of CKD and that CD59 detection could improve early identification and staging of SCD CKD. METHODS: We evaluated urine samples from the University of Illinois at Chicago cohort (UIC, n = 36) collected during clinic visits while patients were in a steady state. Urine samples were assayed for CD59, VCAM, and hemoglobin (Hgb) using ELISA (R&D Systems) and normalized to urinary creatinine (uCr). Hemoglobinuria was defined as uHgb/uCr > 0.8 ng/mg. Stages of CKD were determined using the criteria of the NKF. Pearson correlation and receiver operating characteristic (ROC) analysis were performed using GraphPad Prism 10. RESULTS: In SCD patients without renal disease, uCD59/uCr levels were similar to the levels obtained in the control non-SCD participants (447.24±208.49 ng/mg in control vs. 395.04±183.53 ng/mg in SCD, p=0.6612). Levels of uCD59/uCr increased by 3.2-fold in SCD patients with hemoglobinuria (p=4.597×10-6). UCD59/uCr levels strongly correlated with the marker of endothelial injury, uVCAM/uCr levels (r=0.5810, R2=0.3376, p=0.0005) and stages of CKD (r=0.6642, R2=0.4412, p 359.2 ng/mg. Differentiation of the late stage CKD (stages 3-4) from the early stage also demonstrated high sensitivity (80%, 95%CI 28.36-99.49%), specificity (78%, 95%CI 52.36-93.59%), OR=3.6, and AUC (0.8556±0.08611, p=0.0171) for uCD59/uCr>562.4 ng/mg. CONCLUSIONS: Elevated urinary CD59 levels correlate with hemoglobinuria, endothelial injury, and stages of CKD. Thus, the uCD59 levels may be used for the detection of early-stage CKD and differentiation of early and late stages of CKD. This work was supported by NIH grants 1R01HL125005, 5U54MD007597, and 1SC1HL150685. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Egharevba et al. (Fri,) studied this question.