The Impact of Erythropoietin on Short- and Long-Term Kidney-Related Outcomes in Neonates of Extremely Low Gestational Age. Results of a Multicenter, Double-Blind, Placebo-Controlled Randomized Clinical Trial

Abstract

Objective: To evaluate whether extremely low gestational age neonates (ELGANs) randomized to erythropoietin have better or worse kidney-related outcomes during hospitalization and at 22-26 months of corrected gestational age (cGA) compared with those randomized to placebo.

Study design: We performed an ancillary study to a multicenter double-blind, placebo-controlled randomized clinical trial of erythropoietin in ELGANs.

Results: The prevalence of severe (stage 2 or 3) acute kidney injury (AKI) was 18.2%. We did not find a statistically significant difference between those randomized to erythropoietin vs placebo for in-hospital primary (severe AKI) or secondary outcomes (any AKI and serum creatinine/cystatin C values at days 0, 7, 9, and 14). At 22-26 months of cGA, 16% of the cohort had an estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m², 35.8% had urine albumin/creatinine ratio >30 mg/g, 23% had a systolic blood pressure (SBP) >95th percentile for age, and 40% had a diastolic blood pressure (DBP) >95th percentile for age. SBP >90th percentile occurred less often among recipients of erythropoietin (P < .04). This association remained even after controlling for gestational age, site, and sibship (aOR 0.6; 95% CI 0.39-0.92). We did not find statistically significant differences between treatment groups in eGFR, albumin/creatinine ratio, rates of SBP >95th percentile, or DBP >90th or >95th percentiles at the 2 year follow-up visit.

Conclusions: ELGANs have high rates of in-hospital AKI and kidney-related problems at 22-26 months of cGA. Recombinant erythropoietin may protect ELGANs against long-term elevated SBP but does not appear to protect from AKI, low eGFR, albuminuria, or elevated DBP at 22-26 months of cGA.

Keywords: acute kidney injury; acute renal failure; chronic kidney disease; hypertension; proteinuria.

Figure 1 (online only):

941 subjects were enrolled in the PENUT study. Of the 941, 18 were excluded from this study as 4 died prior to study drug, 1 was enrolled incorrectly and 13 died on days 0,1, 2 and we could not assign any kidney related outcomes. Therefore, the final sample of participants for short-term outcomes in REPaIReD were the 923 who received study drug and were alive on day 3. Of the 923, 454 received placebo and 469 received rhEpo. At the 24 month follow-up, 780 infants were evaluated (397 in placebo and 383 in rhEpo) groups. The number who had blood/urine collected at the 24 month visit are described in the figure and in text.

Figure 2a and 2b:

Mean creatinine levels over a rolling 7-day and 3-day window by treatment arm over time.

Figure 3a and 3b (online only):

Core Laboratory SCr and cystatin C (median and IQR) measurements on postnatal days 0, 7, 9, 14 by treatment arm.