Pharmacovigilance of nephrotoxic drugs in neonates: the Pottel method for renal signal detection in ELBW neonates

Abstract Background Extreme low birth weight (ELBW) neonates (birth weight ≤ 1000 grams) are at high-risk to develop drug-induced acute kidney injury (AKI). However, we lack a pragmatic detection tool to capture their time-dependent (patho)physiologic serum creatinine (Scr) patterns. Pottel et al. suggested rescaling Scr by dividing Scr with the mean Scr-value of the age and sex specific reference population. We therefore explored if this Pottel method can detect drug-related nephrotoxic signals in ELBW neonates. Methods A previously used dataset on Scr changes in ELBW neonates exposed to ibuprofen, amikacin or vancomycin was updated to calculate Pottel scores for every available Scr value in the first 28 postnatal days. We hereby used already published postnatal age specific 50th centile values in an ELBW population. Linear mixed models were subsequently applied, analyzing Pottel scores as response variable and continuous time (day), drug exposure, and interaction thereof in the explanatory model. Results 3231 Scr observations in 201 ELBW neonates were collected. A statistically significant rise of Pottel scores was observed with ibuprofen treatment starting from postnatal day 4. In addition, a cumulative effect of treatment with mean Pottel scores on day 0 of 1.020 and on day 3 during treatment of 1.106 (95% CI 1.068–1.145, p < 0.001) was observed, when corrected for effect of antibiotics. Antibiotic administrations showed a small but statistical significant difference up to postnatal day 5. Conclusions As rescaled Scr biomarker, the Pottel method showed a clear signal in ibuprofen-exposed ELBW neonates, suggesting its applicability as pragmatic bedside tool to assess nephrotoxicity.