Angiotensin-Converting Enzyme Inhibitor Nephrotoxicity in Neonates with Cardiac Disease

Abstract

Angiotensin-converting enzyme inhibitors (ACEi) are commonly used for pediatric cardiology patients. However, studies examining their safety for neonates with cardiac disease are scarce. The current study aimed to test the hypothesis that ACEi-mediated nephrotoxicity occurs in neonates and may be underappreciated in this population. A retrospective review of 243 neonates with cardiac disease between 2007 and 2010 was performed. Demographic data, weight, length, captopril and enalapril dosing, serum [K⁺], serum creatinine, and concomitant medications during ACEi therapy were recorded and analyzed. Body surface area (BSA), creatinine clearance (CrCl), and change in [K⁺] were calculated. The age range of neonates at ACEi initiation was 15.9-18.1 days. The inclusion criteria was met by 206 neonates: 168 term (82%) and 38 preterm (18%) newborns. Of these neonates, 42% were female, and all the patients had a BSA smaller than 0.33 m² (a group known to have relative renal insufficiency). The mean dose of enalapril was 0.08 ± 0.007 mg/kg for the preterm neonates and 0.08 ± 0.003 mg/kg for the term neonates. The mean dose of captopril was 0.07 ± 0.009 mg/kg for the preterm neonates and 0.13 ± 0.019 mg/kg for the term neonates. A significant decrease in CrCl occurred for both the preterm (p < 0.01) and term (p < 0.001) neonates while they were receiving ACEi. However, the two groups did not differ significantly (p = 0.183). Nearly 42% of all the patients showed renal risk, with approximately 30% demonstrating renal failure by modified pRIFLE (pediatric risk, injury, failure, loss, and end-stage renal disease) criteria. Despite the lack of significantly different CrCl, the premature neonates were more likely to experience ACEi-related renal failure by pRIFLE (55%) than their term counterparts (23%; p < 0.001). Despite its common use for term neonates with cardiac disease, ACEi should be used cautiously and only when indications are clear. These results also raise the question whether ACEi should be used at all for preterm neonates.

Renal Consequences of Therapeutic Interventions in Premature Neonates

“…They found that treatment with the ACE inhibitors enalapril and captopril significantly lowered creatinine clearance and caused renal failure in 55% of premature neonates [47]. These findings are supported by case reports examining premature infants with heart disease treated with these drugs [48].…”

“…Lindle et al [47] conducted a retrospective review of 243 neonates with cardiac disease; 38 of these neonates were born prematurely. They found that treatment with the ACE inhibitors enalapril and captopril significantly lowered creatinine clearance and caused renal failure in 55% of premature neonates [47].…”

Epidemiology of acute kidney injury in children worldwide, including developing countries

“…Cohort studies have reported AKI due to nephrotoxic medications [20,69,[81][82][83][84], cardiac surgery/bypass [19,85], and sepsis [56,86], or AKI after admission to an ICU [7,20,[87][88][89].…”

Enalapril Associated with Furosemide Induced Acute Kidney Injury in an Infant with Heart Failure. A Case Report, a Revision of the Literature and a Pharmacovigilance Database Analysis

“…Thus, it is affected by ACE inhibitors' use that may account for the high risk of renal dysfunction development in infants [19,20]. Renal failure usually occurs within few days after starting the ACE-inhibitor or after increasing its dose and usually resolves uneventfully after dose reduction or cessation of the drug [21]. …”