Urinary Specific Gravity Decreases over Time in Adult Sickle Cell Patients

Introduction: Altered urinary concentration is one of the earliest and most common features of kidney disease in patients with sickle cell disease (SCD). This phenomenon is reversible in early age by transfusion but becomes fixed with time. Little data exist as to which additional clinical features are associated with impaired urinary concentration. Further, longitudinal changes in urinary concentration over time in adults have not been examined.

Methods: We conducted a retrospective study of adult sickle cell patients seen between January, 2004 and December, 2013 at a single center. Clinical and laboratory variables were abstracted from medical records. Specific gravity was assessed from random dipstick urinalysis results. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Patients had confirmed SCD, were at least 18 years old, and were evaluated during routine clinic visits. Mixed effects models were fit to evaluate the change in specific gravity over time. Clinical and laboratory variables, including measures of kidney function or disease, hemolysis markers and associated comorbidities, were evaluated for their association with baseline specific gravity and on specific gravity over time in age- and sex-adjusted analyses. We also compared those with severe phenotypes (SS/Sβ⁰) to those with mild phenotypes (SC/Sβ⁺). A multivariable model was constructed utilizing covariates identified in univariate analyses with a final model produced via backward elimination with age and sex adjustment retained. We included interaction terms between covariates and to evaluate the longitudinal association of these variables on change in specific gravity. We also employed similar approaches in analyses stratified for those with SS and Sβ⁰ disease from those with milder SC and Sβ⁺disease.

Results: Four hundred and forty-seven patients with SCD (SS = 280, SC = 102, Sβ⁰ = 22, Sβ⁺ = 33, SE = 2, SLepore = 2, SD = 2, SHPFH = 4) were followed over a median duration of 2.8 years (IQR: 0.99 - 6.3 years). Median age was 28.5 years (IQR: 20 - 40 years) and 238 were female (53%). Over time, specific gravity decreased (-0.00011 per year, SE 0.000030; p=0.0002). In stratified analysis, patients with SS/Sβ⁰ had a similar decrement (-0.00011, SE 0.000032; p=0.0005) while SC/Sb⁺ had a slightly lower decline (-0.00008, SE 0.000079; p=0.3) that was not statistically significant. Patients with SS/Sβ⁰ trended toward slightly higher baseline specific gravity (0.00079, SE 0.00035; p=0.03) compared to SC/Sb⁺ patients. At baseline, hemoglobin level (0.00017, SE 0.000079; p=0.03) and hemoglobinuria (0.00096, SE 0.00046; p=0.04) were associated with higher specific gravity. In multivariate modeling, only hemoglobinuria (0.0012; SE 0.00048; p=0.01) and SS/Sβ⁰ phenotypes (0.00096, SE 0. 00036; p=0.009) were associated with higher specific gravity. Over time, ferritin; (-0.00011, SE 0.000048; p=0.02) and priapism in men (-0.00029, SE 0.00010; p=0.006) were associated with annual decline in specific gravity. Use of angiotensin-converting-enzyme inhibitors/angiotensin receptor blockers (ACE-I/ARB) (0.00018, SE 0.000076; p=0.02) was associated with a rise in specific gravity. In multivariate analyses, only ferritin (-0.00012, SE 0.000048; p=0.01) was associated with annual decline in specific gravity When evaluated separately, SS/Sβ⁰ demonstrated nearly identical findings in multivariate analysis for ferritin (-0.00013, SE 0.000057; p=0.02).

Conclusion: Even in adult patients with SCD, specific gravity declines over time, and decline may be more prominent in those with SS/β⁰. Higher ferritin, a measure of iron overload, is associated with greater decline in specific gravity. Future prospective studies of kidney disease in SCD patients should include measures of specific gravity to better understand this phenomenon and its long-term consequences.