The reported incidence of AKI in the NICU varies widely depending on the included population and AKI definition used [13-16]. Studies focusing in very low birth weight (VLBW) or extremely low birth weight (ELBW) infant population reported an AKI incidence of 13–56% [4, 5, 14, 17, 18] in their NICU stay. To the best of our knowledge, this is the first study analysing the AKI epidemiology of NSAID exposed premature infants using the KDIGO neonatal AKI definition. In our cohort, we found that 23% of premature infants <34 weeks GA developed AKI after NSAID exposure, and infants being treated for symptomatic PDA developed higher AKI rates than those who received the medication for IVH prophylaxis purposes (34% vs. 6%, p=0.005). Majority of infants were identified to have AKI with UO criteria compared to SCr criteria. All infants who had oliguria recovered by 36 hours after initiation of therapy, in line with a study focusing on the transient nature of renal impairment in neonates receiving indomethacin [19].
However, data from our symptomatic treatment cohort suggests that the transient oliguria may still be associated with clinically relevant fluid overload with a high maximal percentage of weight gain (median 11.1%, IQR 6.2-17.6%) observed from baseline. This is especially relevant with a recent analysis of 1007 premature infants from the landmark AWAKEN study showing that a positive peak fluid balance during the first postnatal week and the degree of positive fluid balance by day 7 of life were both independently associated for the need for mechanical ventilation at postnatal day 7[20].
In a recent study focusing on early-onset neonatal AKI (postnatal days 2–7, defined as an increase in serum creatinine >26.5 µmol/L (0.3 mg/dL) or UO <1 mL/kg/hour), the reported incidence was 21% [21]. Another study focusing on the cumulative incidence of AKI during the first two postnatal weeks in a prospective cohort study on 113 VLBW infants reported an incidence of 25%, though there was no mention of details of timing of administration of NSAID [22]. Reported risk factors associated with neonatal AKI include antenatal vascular damage such as maternal treatment of NSAID, lower GA and birth weight, lower Apgar score, small-for-gestational-age cases, necrotising enterocolitis, shock/dehydration, perinatal asphyxia, and administration of nephrotoxic medications. These factors are essentially concentrated in the most premature and severely ill infants [5, 23-25]. Understanding the aetiology of neonatal AKI is important, as these infants have been reported to have a significantly longer duration of mechanical ventilation and a higher mortality rate and/or chronic lung disease, even after adjusting for neonatal and maternal factors along with medication exposures [1, 4, 15, 18, 21, 26]. Cohort studies revealed that survivors of neonatal AKI may have an increased risk of developing hypertension, persistence of altered concentrating ability, focal segmental glomerulosclerosis, and renal dysfunction/insufficiency at five years of age or beyond [27-32].
Multiple autopsy studies in premature infants reported findings suggestive of early cessation of nephrogenesis, and increased glomerular volume, which is suggestive of hyperfiltration [7, 33]. The newborn kidney is particularly vulnerable to maldevelopment and dysfunction in an ex utero environment due to various stresses, mostly caused by decreased renal perfusion [23]. In a few studies, nephrotoxic injury is usually associated with the use of NSAID to close a PDA, especially with concomitant use of aminoglycosides [8, 34, 35]. However, the attributable risk of AKI associated with these 2 nephrotoxic agents is not clear. Commonly used medications to close PDA such as indomethacin or ibuprofen, inhibit the prostaglandin synthesis, and dramatically decrease renal blood flow and glomerular filtration rate, leading to oliguria [36]. A recent Cochrane review has suggested that, of these two medications, ibuprofen carries a lower risk of transient renal insufficiency, despite the fact that it has a similar effectiveness as indomethacin in closing a PDA [37].
After birth, the neonatal blood flow increases rapidly due to increased renal perfusion pressure and decreased renal vascular resistance due to neurohumoral changes, particularly in angiotensin II [38]. In premature infants, the glomerular filtration rate is even lower and increases more slowly than in term infants [39]. Our finding of a higher incidence of AKI among infants who were prescribed NSAIDs at a later stage of life (“symptomatic treatment”), who were born at a more advanced GA and with heavier birth weights [Table 2], seems to contradict what is known about renal physiology and the general characteristics of preterm infants at highest risk. Srinivasjois et al. reported that a postnatal age ≥ 7 days at the start of indomethacin treatment is a predictor of significant rise in the level of SCr in extremely preterm neonates, compared with infants who were treated within their first seven days of life [40]. This group postulated that prolonged compromise of renal perfusion due to the aortic steal phenomenon is associated with a significant PDA, as well as with higher likelihood of hypovolemia/dehydration among infants beyond their first weeks of life [40]. The other reasons why AKI make have been significantly lower in our prophylaxis cohort include: 1) low availability of Cr values in the 1st day of life in our cohort, 2) difficulties in capturing a “rise” in SCr on the 1st day when Cr is known to peak and then decrease naturally over the first week in premature infants [41], 3) inability to capture UO based AKI accurately within the first day of life during NSAID exposure, especially in the context of the predominance of UO based AKI identified in the symptomatic treatment cohort and 4) a lower total dose compared to the symptomatic treatment group. A further study with a larger sample size, the use of more novel urinary AKI biomarkers outside of SCr and UO, and documentation of both cardiac output and renal perfusion by Near Infrared Spectroscopy is needed to address these postulations.
There are several limitations associated with this pilot study. Firstly, this is a relatively small retrospective study evaluating AKI with a sample size of 70 patients. Secondly, decisions concerning the treatment regimen, including the day of initiation and total doses, were at the discretion of attending physicians and not completely standardized. A minority of infants (8/70, 11%) in our cohort received ibuprofen, which might carry less nephrotoxic side effects, but we were not able to ascertain any differences in AKI risk with ibuprofen vs indomethacin. Lastly, it is challenging to quantify UO in the early days of life among small premature infants due to the risk of mixing of urine and meconium. Furthermore, the UO criteria and thresholds of defining AKI are not well validated in the most premature infants, which make the direct comparisons of results from various studies difficult.
Having said that, this is one of the few studies evaluating the impact of NSAID therapy on AKI incidence with a description of the course of AKI among preterm infants. A standardized evidence-based monitoring regimen of preterm infants exposed to NSAIDs and/or other nephrotoxic medications in NICU is desperately needed, as a systematic surveillance program to identify high-risk infants can prevent nephrotoxic-induced AKI and has the potential to prevent short and long-term consequences of AKI in critically ill infants [42]. Our study revealing a high signal of NSAID related AKI coupled with the lack of SCr monitoring has motivated further collaborative clinical, research, and quality improvement work between the nephrology and neonatology teams at our center to improve the renal health of these vulnerable infants in the short and long term.