Natural History of Albuminuria in Pediatric Sickle Cell Anemia

Understanding the natural history of albuminuria in children is critical so that pediatric patients with sickle cell anemia (SCA) can be identified and treated prior to progressive organ damage and early mortality from end-stage kidney disease. The ASH guidelines suggest treatment of albuminuria in SCA to prevent progression to end-stage kidney disease. However, 5-15% non-SCD pediatric patients can have intermittent orthostatic proteinuria, which is not associated with developing persistent chronic kidney disease. Therefore, we explored differences between intermittent and persistent episodes of albuminuria in SCA to ensure accurate identification and treatment of a potentially higher risk group of children at risk for kidney disease. Our goals were to determine the age to begin screening for albuminuria and if we could identify an albumin creatinine ratio (ACR) level predictive of persistent albuminuria.

Methods: We identified patients with HbSS/SB0 thalassemia who had albumin/creatinine ratios (ACR) obtained during standard of care clinic visits. We abstracted data on sex and age at every visit associated with an ACR measurement over 11 years. We categorized patients as persistent albuminuria according to national guidelines of two of three consecutive ACR measurements ≥30mg/g. We categorized patients as intermittent if only one of three consecutive ACR measurements ≥30mg/g; patients were categorized as never if all ACR measurements were <30.mg/g Finally, we identified the age and values for the first abnormal ACR and most current ACR measurement. We conducted statistical analyses using JMP Pro16 (Cary, NC)

Results: Among 352 pediatric patients with 1713 ACR levels measured, we categorized 58 (17%) patients as having persistent albuminuria, 50 (14%) with intermittent albuminuria, and 244 (69%) with not yet having developed albuminuria. The current mean age of participants who have not yet developed albuminuria (13.2±4.8 yrs) was significantly younger than patients with persistent albuminuria (17.2±3.4yrs, p<0.0001) and intermittent albuminuria (15.4±3.4 yrs, p=0.005). We did not identify a difference in the mean age at the first episode of albuminuria between persistent (13.4 ±3.9) and intermittent (13.0±4.6) albuminuria (p=0.6). No participants with persistent albuminuria had an abnormal ACR before age 5 years while 8% of participants had an abnormal level <5 yrs of age. Importantly, we identified 25% of patients with persistent albuminuria had their first abnormal ACR before 10 years (current NIH recommendations suggest starting to screen ACR at 10 years). Next, we identified that the highest ACR was predictive of persistent albuminuria (p<0.0001). We identified that a max ACR of ≥97.6 mg/g had an AUC of 0.88 for persistent albuminuria. For clinical purposes, we evaluated differences between ACR of ≥100mg/g. Among 43 participants with an ACR ≥ 100mg/g, 40 (43%) have developed persistent albuminuria; only 18 (27%) of 65 participants with max ACR < 100mg/g have developed persistent albuminuria. Participants with ACR ≥100mg/g have a 35 (95% CI: 10-127) times higher odds of developing persistent albuminuria. Among the 58 participants with persistent albuminuria, 40 (70%) currently have an abnormal ACR; 17 (34%) of 50 with intermittent albuminuria have a current abnormal ACR. Patients with persistent albuminuria have 4.3 (1.9-9.7) times higher odds of currently having albuminuria. Also, patients with a max ACR of ≥100mg/g and more likely to have current albuminuria as compared to patients with a max ACR<100mg/g (70.0% vs 41.5%, p=0.004). We identified no differences in sex among outcomes of albuminuria when age was included in the model. (p=0.08)

Conclusion: Our data suggests that pediatric patients with SCA should be screened for albuminuria before 10 years of age which is the current recommendation in NIH SCA guidelines; no patients developed persistent albuminuria starting before age 5. Second, using a cut-off ACR of 100mg/g is highly predictive of identifying patients with persistent albuminuria and patients with ACR ≥ 100mg/g should be considered as a high-risk group.

Ilonze:Global Blood Therapeutics: Consultancy. Lebensburger:BPL: Consultancy; Novartis: Consultancy; Forma Therapeutics: Consultancy; Agios Pharmaceuticals: Consultancy.