Caffeine and kidney function at two years in former extremely low gestational age neonates

Pediatr Res 95, 257–266 (2024). doi: 10.1038/s41390-023-02792-y.

Harer, M.W., Griffin, R., Askenazi, D.J. et al.

Reviewed by: Matthew Gillen

Purpose

To determine the effect of caffeine exposure on kidney function at 22-26 months corrected gestational age in extremely low gestational age neonates (ELGANs).

Methods

Study Design

This was a retrospective secondary analysis of the PENUT trial, a prospective randomized clinical trial of recombinant human Erythropoietin (rhEpo) in ELGANs.

Patient characteristics

Patients included in the PENUT trial were between 24 0/7 and 27 6/7 weeks gestation at birth and less than 24 hours of age at the time of trial enrollment. Enrollment occurred between 1/2013 and 9/2016 across 19 NICUs in the United States. Exclusion criteria were major life-threatening anomalies, hematologic crises, hematocrit >65%, hydrops fetalis, and known congenital infection. Patients were stratified based on BPD status – defined as the use of supplemental oxygen at 36 weeks PMA – for analyses.

Exposure and primary outcomes

The exposure of interest was the duration of caffeine administration defined by the postmenstrual age (PMA) at which caffeine was discontinued.

The primary outcomes were three kidney metrics: low eGFR (<90 ml/min/1.73 m2), albuminuria (albumin creatinine ratio >30mg albumin/g creatinine), and high blood pressure (>95th percentile for age and sex based on 2017 AAP guidelines).

Results

Of the 941 patients enrolled, 598 patients had a 22-26 month follow up visit with at least one kidney metric measured. The overall mean PMA for caffeine discontinuation was 34.9 ± 2.7 weeks. The PMA at caffeine discontinuation varied with both gestational age at birth and site of enrollment, and caffeine discontinuation occurred at a later PMA in patients with BPD compared to those without BPD.

There were no significant differences in primary outcomes when patients were stratified based on PMA of caffeine discontinuation. However, when stratified by BPD status, for each additional week of caffeine, the BPD group had 15% increased odds of high blood pressure while the no BPD group had 22% decreased odds of low eGFR.

Discussion and Implications

In this retrospective secondary analysis of the PENUT trial, the authors investigated the effect caffeine exposure on kidney function at 22-26 months corrected age. The timing of caffeine discontinuation based on PMA did not affect kidney outcomes. Given the long-term pulmonary and neurological benefits of caffeine in preterm infants, it is surprising that caffeine does not have similar effects on kidney health. Interestingly, when patients were stratified based on BPD status, there were mixed effects on kidney outcomes. Patients with BPD who were on caffeine longer had increased odds of elevated blood pressure, and patients without BPD who were on caffeine longer had decreased odds of low eGFR. It would be very interesting to see how finer granularity – particularly with the definition of BPD (e.g., Jensen criteria for BPD; BPD phenotypes) – would affect the results of this study. As the authors point out, this study demonstrates that there is more to learn about the relationship between caffeine and long-term kidney health in preterm infants.