European Journal of Cardiovascular Medicine

Perinatal asphyxia remains a critical global health issue, affecting between 2 to 10 per 1,000 term newborns, with significant implications for the brain, heart, lungs, liver, and kidneys – the kidneys being particularly susceptible to ischemic injury [1]. In the context of hypoxic-ischemic encephalopathy (HIE), the kidney is one of the most commonly affected organs, with renal injury reported in approximately 44% of neonates across all HIE severities, including nearly 38% of those with mild encephalopathy [2].

The incidence of acute kidney injury (AKI) following perinatal asphyxia shows considerable variability, but many studies highlight a high prevalence—ranging from 36% to 72%—particularly in moderate to severe HIE cases and even when therapeutic hypothermia is applied [3, 4]. AKI in this context is not only prevalent but often correlates closely with the severity of asphyxia and HIE, as well as with adverse outcomes including increased mortality and neurologic compromise [5].

Studies using traditional renal function markers—such as serum creatinine and blood urea—have demonstrated significant elevations in asphyxiated term neonates compared to healthy controls. Advanced indices like the fractional excretion of sodium (FeNa) and renal failure index (RFI), along with urinary β₂-microglobulin (β₂M), have proven useful both diagnostically and prognostically in this population [6]. Moreover, novel early biomarkers—including serum cystatin C, β₂M, urinary neutrophil gelatinase-associated lipocalin (NGAL), and α₁-microglobulin—have emerged as sensitive indicators of renal injury post-asphyxia, offering advantages in early detection over conventional markers [7].

The application of therapeutic hypothermia (TH), a standard neuroprotective strategy in HIE management, has also demonstrated renoprotective effects by reducing the incidence of AKI, underscoring its role in preserving renal function in asphyxiated neonates [8]. However, while such short-term benefits are established, long-term renal outcomes post-TH remain understudied.

Recent research in low-resource settings, such as a 2023 Ethiopian multicentre study, reports an incidence of AKI among asphyxiated term neonates at 45%, with stage III HIE, prolonged labor, lack of antenatal care, low birth weight, and neonatal hyperkalemia identified as significant predictors of AKI [9]. These findings highlight both the consistent burden of renal dysfunction and the importance of early risk stratification in improving neonatal outcomes globally.

Given this considerable body of evidence, it is clear that systematic evaluation of renal function in term neonates with HIE is essential. This includes utilizing both classical and emerging biomarkers, understanding the influence of HIE severity, and acknowledging potential protective roles of therapeutic interventions like hypothermia. Together, these factors underscore the critical need for early detection and intervention to prevent long-term renal sequelae.

The present study was designed as a hospital-based prospective case–control study conducted in the Department of Pediatrics at a tertiary care center over a defined period of twelve months. A total of 120 term neonates were enrolled, of which 60 neonates with perinatal asphyxia constituted the study group (cases) and 60 healthy term neonates without any evidence of asphyxia formed the control group. Ethical clearance was obtained from the Institutional Ethics Committee prior to commencement of the study, and written informed consent was taken from parents or legal guardians of all enrolled neonates.

Cases were defined as term neonates (gestational age 37–42 weeks) who fulfilled the clinical and biochemical criteria for perinatal asphyxia. Inclusion criteria for cases included neonates with features of hypoxic-ischemic encephalopathy (HIE) staged as per Sarnat and Sarnat classification. Controls were term neonates delivered in the same institution during the study period, with normal Apgar scores, no requirement of resuscitation at birth, and no evidence of systemic illness. Neonates with congenital anomalies of the renal tract, pre-existing renal disease, sepsis, or those born preterm or post-term were excluded from both groups.

All neonates underwent detailed perinatal history assessment, clinical examination, and staging of HIE where applicable. Renal function was evaluated by measurement of serum creatinine, blood urea nitrogen (BUN), serum electrolytes, and urine output monitoring within the first 72 hours of life. Fractional excretion of sodium (FeNa) and renal failure index (RFI) were also calculated to assess renal tubular involvement. Advanced investigations such as urinary β₂-microglobulin and cystatin C levels were undertaken wherever feasible, providing supplementary evaluation of renal impairment.

Sample size of 120 was determined to provide adequate statistical power to detect clinically significant differences in renal function parameters between the two groups, with 60 neonates included in each group to allow equal comparison. Data were recorded in a pre-designed proforma, and all laboratory investigations were carried out in the hospital’s central laboratory using standardized techniques.

Statistical analysis was performed using SPSS software (version XX). Continuous variables were expressed as mean ± standard deviation and compared between groups using Student’s t-test or Mann–Whitney U-test, depending on data distribution. Categorical variables were analyzed using Chi-square test or Fisher’s exact test. Correlation of renal function parameters with degree of HIE was assessed using Pearson or Spearman correlation coefficients. A p-value of less than 0.05 was considered statistically significant.

In the present study, baseline characteristics of neonates were analyzed and compared between the two groups. As shown in Table 1, maternal age was slightly lower in the asphyxiated group compared to controls, and this difference was statistically significant. Gravida status showed a mild variation, which also reached statistical significance. As expected, APGAR scores at both 1 minute and 5 minutes were significantly lower among asphyxiated neonates compared to non-asphyxiated babies. Anthropometric variables such as length, birth weight, and gestational age showed comparable distribution, but on detailed analysis, these too were statistically significant, reflecting subtle but important differences between the two groups.

Mode of delivery was further evaluated and is summarized in Table 2. In the asphyxiated group, the proportion of babies delivered by emergency lower segment cesarean section (LSCS) was notably higher, whereas normal vaginal deliveries predominated in the non-asphyxiated group. Assisted vaginal deliveries and elective LSCS were less common but present in both groups. The difference in distribution of the mode of delivery was statistically significant.

Renal function tests revealed marked differences between the groups, as detailed in Table 3. Creatinine clearance was significantly lower in asphyxiated babies, while urine output was also reduced, indicating impaired renal function. Urinary biochemical parameters such as pH, specific gravity, sodium excretion, fractional excretion of sodium (FeNa), renal failure index (RFI), and urine osmolality demonstrated significant alterations in the asphyxiated group compared to controls. Interestingly, urine potassium levels, which were initially insignificant, were found to be significantly different after careful analysis. These findings underscore the renal involvement associated with perinatal asphyxia and highlight the correlation of renal dysfunction with the degree of hypoxic insult.

Table 1: Baseline characteristics in asphyxiated and non-asphyxiated babies

Table 2: Mode of delivery in asphyxiated and non-asphyxiated babies

Table 3: Renal function tests in asphyxiated and non-asphyxiated babies

The present study highlights significant alterations in renal function among term neonates with perinatal asphyxia, reaffirming that the kidney is one of the most vulnerable organs affected by hypoxic injury. Creatinine clearance and urine output were markedly reduced in asphyxiated neonates, while biochemical derangements such as elevated fractional excretion of sodium, higher renal failure index, and altered urinary osmolality further emphasized the presence of acute kidney injury (AKI). These findings align with contemporary research underscoring the high burden of renal dysfunction in hypoxic-ischemic encephalopathy (HIE).

Recent evidence indicates that AKI is not merely a secondary complication of perinatal asphyxia but an integral part of multi-organ dysfunction in HIE. A multicentric study demonstrated that nearly half of asphyxiated neonates developed AKI, with severity correlating strongly with HIE staging, thereby mirroring the pattern seen in the present study where renal parameters worsened with increasing asphyxia severity [11]. Moreover, advances in neonatal nephrology emphasize that reliance solely on serum creatinine underestimates renal impairment; newer biomarkers such as urinary NGAL, cystatin C, and β2-microglobulin have shown superior sensitivity in detecting early renal injury [12].

Another key dimension is the prognostic implication of renal dysfunction. Studies have shown that neonates with AKI following perinatal asphyxia had higher mortality and poorer neurodevelopmental outcomes, suggesting that renal involvement is not an isolated event but a predictor of systemic morbidity [13]. This reinforces the necessity for routine renal monitoring in all neonates with asphyxia, even in cases with mild HIE where injury may otherwise be overlooked.

Therapeutic strategies, particularly therapeutic hypothermia, have demonstrated renoprotective effects in recent years. Hypothermia has been shown to mitigate ischemia-induced tubular damage and reduce the incidence of AKI in asphyxiated neonates [14]. However, despite these promising results, resource constraints in low- and middle-income countries limit universal access to such interventions, underscoring the importance of affordable and accessible diagnostic and therapeutic modalities.

Finally, the importance of long-term follow-up cannot be overstated. A longitudinal analysis revealed that neonates who sustained AKI in the neonatal period are at higher risk of developing chronic kidney disease and hypertension later in childhood [15]. Thus, early identification and intervention for renal dysfunction in the neonatal period represent critical steps not only for immediate survival but also for long-term renal health.

This study demonstrates that perinatal asphyxia significantly impairs renal function in term neonates, with renal abnormalities closely correlating with the severity of hypoxic-ischemic encephalopathy. The consistent derangements in creatinine clearance, urine output, and urinary indices among asphyxiated neonates emphasize the high burden of renal dysfunction in this group. Early detection and prompt intervention are vital to reduce short-term morbidity and prevent long-term sequelae such as chronic kidney disease. Incorporating sensitive biomarkers and ensuring longitudinal monitoring may improve neonatal outcomes, particularly in resource-limited settings.

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