Impact of Hyperfiltration during Early Childhood on the Natural History of Albuminuria in Pediatric Sickle Cell Anemia

Introduction: Pediatric patients with Sickle Cell Anemia (SCA) are at risk for developing albuminuria. Hyperfiltration precedes the development of albuminuria in patients with diabetes but the natural history of hyperfiltration on the progression to albuminuria has not been studied in children with SCA.

Methods: We have enrolled 185 participants with HbSS or SB0 thalassemia in a prospective pediatric cohort study evaluating progression to chronic kidney disease; the mean current age of participants in this cohort is 14 years. We have abstracted 817 urine microalbumin creatinine measurements and 891 estimations of GFR (eGFR) by Cystatin C. Abnormal urine albumin/creatinine is defined as >30mg/g. We defined persistent albuminuria as two abnormal spot urine microalbumin/creatinine measurements over three consecutive measurements and intermittent albuminuria as one abnormal urine measurement with two consecutive repeat measurement as normal. We performed descriptive and univariate statistics to characterize the natural history of the development of albuminuria. Next, as standard of care definitions of hyperfiltration (>140 ml/min/1.87) are not appropriate in SCA during early childhood (4-10 years of age), we a priori defined hyperfiltration as an eGFR ≥180 ml/min/1.87. We categorized patients with hyperfiltration during early childhood if the mean eGFR was >180 ml/min/1.87. We abstracted the mean white blood cell count (WBC), hemoglobin (Hb), and SCA therapy during early childhood and performed estimates of the odds ratio and used chi-squared test to compare the proportion of those who progressed to persistent albuminuria. Finally, we performed time to event analysis to obtain the estimated Kaplan-Meier curves for participants with and without hyperfiltration and used logrank test to compare their survival distributions.

Results: Among the 185 participants, 55 participants (30%) were identified with at least one episode of albuminuria and 130 patients (70%) have not yet developed an episode of albuminuria. Among the 55 participants identified with an albuminuria event, 36 participants (66%) are categorized as having persistent albuminuria while 19 patients (34%) demonstrated intermittent or only one episode of albuminuria. The mean age at the identification of a first albuminuria event was 11.0 years (range 2-18 years). Comparing patients that progressed to persistent vs intermittent albuminuria, we identified no significant differences for age at first episode of albuminuria (13.2 vs 11.9 years, p=0.3) or type of SCA modifying therapy at first episode of albuminuria (p=0.4).

We identified 90 participants with eGFR obtained between 4-10 years; 39 (43%) participants were categorized with hyperfiltration and 51 participants had a mean eGFR < 180 ml/min/1.87. Nine of the 39 (23%) participants categorized with hyperfiltration have progressed to develop persistent albuminuria as compared to 3 (6%) of the 51 without hyperfiltration progressed to persistent albuminuria; hyperfiltration was associated with a 4.8 higher odds of developing persistent proteinuria. (p=0.02). The mean eGFR during early childhood was also significantly higher among participants that progressed to albuminuria (186 vs 169 ml/min/1.87, p=0.04). We identified no significant impact of mean WBC (p=0.13), mean hemoglobin (p=0.07), or SCA therapy (p=0.22) in this subset of patients on progression to persistent albuminuria. As the current age of participants impacts identifying albuminuria outcomes, we performed a time to event analysis; participants identified with hyperfiltration during early childhood develop persistent albuminuria at an earlier age than participants without persistent albuminuria (logrank p=0.004). Finally, while persistent albuminuria was significantly associated with hyperfiltration during early childhood, we did not identify a difference in eGFR between patients with and without albuminuria during adolescence (Figure 1).

Conclusion: Although 30% of patients with SCA will develop an episode of albuminuria during childhood, only 19% of cohort participants developed persistent albuminuria. Early hyperfiltration is predictive for developing albuminuria and therapies should target reducing hyperfiltration in the first decade of life.

Figure 1

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Figure 1

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