Use of multiple urinary biomarkers for the early detection of chronic kidney disease in sickle cell anemia

Abstract

Sickle cell anemia (SCA) affects ~100 000 people in the United States, primarily African Americans.1 The life expectancy for individuals with SCA is lower than that of African Americans without SCA (54 years vs 76 years, respectively).1 Around the third decade of their lives, patients develop long-term complications, which result in a lower quality, adjusted life expectancy.1 Chronic kidney disease (CKD) is one of the most common complications, affecting ~28% to 68% of patients and is associated with ~16% to 18% early mortality.2,3 The mechanism of CKD is multifactorial and includes hemolysis, inflammation, and iron overload leading to glomerular, tubular, and endothelial injury. Identification of the early stages of CKD in SCA can lead to the initiation of early treatment. High glomerular filtration rates (GFRs) and reduced urine concentrating ability are common in SCA and significantly impact CKD detection. Thus, novel biomarkers of early-stage CKD are highly desired. Recently, positive correlations between kidney injury molecule 1 (KIM-1) and N-acetyl-b-D-glucosaminidase (NAG) with persistent albuminuria was demonstrated in a longitudinal study of 303 patients with SCA.4,5 We identified urinary biomarkers of CKD, which reflect basic pathophysiological mechanisms of SCA, including iron homeostasis (ceruloplasmin [CP])6 and inflammation (orosomucoid [ORM]).7 However, the accuracy of each biomarker was not enough to be used individually. In this study, we tested the hypothesis that the combination of biomarkers for basic pathological mechanisms of SCA improves the accuracy of early detection of CKD. We re-evaluated results for 45 patients with SCA from the University of Illinois Chicago. The protocol was approved by the institutional review board, and individuals provided written informed consent. General and renal function characteristics of patients are shown in Table 1. An estimated GFR (eGFR) was calculated using the creatinine (Cr)–based equation without race adjustment.8 CKD was defined in accordance with the National Kidney Foundation Kidney Disease Outcomes Quality Initiatives guidelines: stage 0 (without CKD if eGFR >90 mL/min per 1.73 m2 and albuminuria <30 mg/g Cr) and stage 1 (eGFR >90 mL/min per 1.73 m2 and albuminuria ≥30 mg/g Cr). Random urine samples were collected during a clinic visit when patients were in a steady state. Urine levels of CP,6 hemoglobin (Hb),4 and ORM7 were measured using an enzyme-linked immunosorbent assay and normalization of urinary Cr levels.