Albuminuria has been associated with poor prognosis of individuals with Sickle Cell Anemia (SCA). However, albuminuria is often intermittent in these individuals, and its progression over time needs to be better understood. We aimed to investigate the progression of albuminuria and its risk factors in a large prospective cohort of children and adolescents with SCA.

We recruited steady-state pediatric patients with SCA at ‘Fundação Hemominas'outpatient clinic, Minas Gerais, Brazil. Random-spot urine samples were collected during routine visits. Albuminuria was defined by urinary Albumin/Creatinine Ratio (ACR) ≥30 mg/g. Participants were prospectively categorized by the presence or absence of albuminuria at baseline and at the follow-up urine test. Participants with albuminuria at baseline and at the follow-up urine test were considered to have Persistent Albuminuria (PA). Those without albuminuria at baseline or at the follow-up urine tests were classified as no albuminuria. Participants with no albuminuria at baseline who developed albuminuria at the follow-up test were considered progressors. Those with albuminuria at baseline but absent at follow-up were considered remitters. Baseline steady-state laboratory data were obtained from medical records. Baseline kidney injury biomarkers in urine were measured using multilplex xMAP®assays.

From 572 participants included in the cohort, a total of 414 participants (72.4%) provided two samples and were included in the longitudinal analysis. Mean age at baseline was 10.6±4.6 years, and 220 (53.1%) were males. Three hundred-one (72.7%) participants were receiving intensification therapy (HU, chronic blood transfusion, or both). There was no association between intensification therapies and PA. The median follow-up was 2.2 (6m–6y) years, providing 1,055.6 patient-years. Out of 414 participants, 292 (70.5%) did not have albuminuria, 36 (8.7%) were progressors, 24 (5.8%) remitters, and 62 (15%) had PA. Sixteen (25.8%) of participants with PA developed an abnormal ACR prior to 10-years of age. An ACR measurement ≥ 100 mg/g at the baseline was associated with 69-times (95% CI 25.1‒190.6; p < 0.001) higher odds of presenting PA. In multivariate analysis, besides an ACR measurement ≥ 100 mg/g at the baseline, PA was associated with high levels of indirect bilirubin (HR = 1.3, 95% CI 1.1–1.5; p = 0.014) and Tissue Inhibitor of Metalloproteinase 1 (TIMP-1) (HR = 1.006, 95% CI 1.002–1.009; p = 0.001).

This study provides important clinical and pathophysiological findings associated with PA in SCA. First, our data reinforce the need to screen for ACR prior to 10-years of age; despite the current clinical guidelines suggesting that screening for albuminuria in SCA should begin by 10-years. Second, an ACR ≥100 mg/g is a surrogate marker of PA. This threshold may allow early identification of individuals at the highest risk for chronic kidney disease, enabling therapeutic interventions to prevent renal function decline. Third, our data suggest that HU and chronic transfusions do not reduce the occurrence of PA, although this study is limited by its observational design. Finally, the association of PA with indirect bilirubin and TIMP-1 shed light on the potential therapeutic benefits of targeting these pathways.

This study showed a high prevalence of PA in children and adolescents with SCA. High levels of indirect bilirubin and of TIMP-1, and an ACR ≥100 mg/g at baseline were associated with an increased risk of PA.