The early predictive value of Cys-C, lactic acid, and urinary microglobulins in acute kidney injury following neonatal asphyxia

Introduction

Perinatal asphyxia remains a prevalent issue among newborns worldwide. Reports indicate that 1–2 cases of asphyxia occur per 1,000 live births in developed countries, while the incidence is significantly higher (5–15 per 1,000 live births) in low- and middle-income nation (1). Neonatal asphyxia refers to a pathological condition in which various factors during delivery prevent normal respiratory 12 function, leading to oxygen deprivation, acidosis, and impaired metabolic functions in infants. This condition ranks among the most common acute and critical emergencies in the neonatal perinatal period (2). It is one of the most common acute critical illnesses during the neonatal perinatal period. The body redistributes blood via the diving reflex to prioritize vital organs (e.g., heart, brain, adrenal glands), whereas renal blood flow decreases rapidly, increasing the risk of kidney damage. Studies have shown that approximately 70% of affected neonates develop multiple organ dysfunction, with high rates of cardiac, cerebral, and renal injuries (3). Owing to immature kidneys and poor hypoxia tolerance, neonates frequently develop acute kidney injury (AKI) after asphyxia.

AKI is a clinical syndrome characterized by a rapid short-term decline in renal function, mainly manifested as a decreased glomerular filtration rate (GFR). It has a high incidence and mortality rate in neonates, affecting 20% to 50% of critically ill infants (4). The risk of AKI is particularly prominent in perinatal asphyxia cases (5), especially for asphyxiated newborns, where factors such as hypoxia, acidosis, hypovolemia, use of vasoactive drugs, and mechanical ventilation significantly increase the risk of AKI (6,7). AKI not only causes water-electrolyte and acid-base imbalances but is also closely associated with neonatal multiple organ dysfunction, prolonged hospital stay, increased mortality, and a higher risk of long-term chronic kidney disease. Therefore, early identification and diagnosis of AKI are critical for timely intervention and improved outcomes.

Traditional AKI diagnosis mainly relies on serum creatinine (Scr) levels and changes in urine output. However, these indicators have limitations in neonates: Scr is affected by maternal creatinine levels and only increases when renal function declines by more than 50%, delaying early detection (8). In addition, reduced urine output (a key AKI indicator) can be influenced by non-renal factors such as dehydration or abnormal antidiuretic hormone secretion, leading to insufficient specificity (4). Consequently, there is an urgent need to explore more sensitive and specific early biomarkers to overcome the shortcomings of traditional indicators, providing scientific evidence for precise diagnosis and timely intervention of AKI in asphyxiated neonates (9).

In recent years, with advances in renal biomarker research, serum cystatin C (Cys-C), lactate, and a series of urinary microproteins [such as β2-microglobulin (β2-MG), transferrin (TRF), and α1-microglobulin (α1-MG)] have research hotspots for early AKI diagnosis due to their unique physiological characteristics and expression patterns in renal damage (10,11). As an endogenous GFR marker, Cys-C levels can rise early in the renal dysfunction and are less influenced by non-renal factors (11). Meanwhile, urinary microproteins (urinary β2-MG, urinary TRF, and urinary α1-MG) mainly reflect renal tubular reabsorption function. Their urinary excretion increases significantly when renal tubules are damaged, making them sensitive markers of tubular injury (9).

Given the complex pathophysiology of AKI in asphyxiated neonates (involving concurrent or sequential glomerular and tubular damage), a single biomarker cannot fully reflect renal injury. Thus, combining Cys-C (a glomerular function marker) with urinary microproteins (tubular function markers) may enable earlier, more comprehensive, and accurate AKI diagnosis. This study aims to explore the diagnostic value of serum Cys-C, blood lactic acid, urinary β2-MG, TRF, and α1-MG in detecting AKI after resuscitation in asphyxiated neonates, aiming to provide new clinical strategies to improve renal outcomes. We present this article in accordance with the STARD reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-790/rc).

Methods

Clinical data

Neonates with asphyxia who were born and treated at our hospital from January 2023 to March 2025 were enrolled. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Jinjiang Municipal Hospital (Shanghai Sixth People’s Hospital Fujian) (No. JJSYYYXLL-2022096). Informed consent was taken from all the patients’ parents or legal guardians.

According to the criteria from Nelson Textbook of Pediatrics (19th edition) and the Chinese expert consensus on neonatal asphyxia diagnosis (12,13), neonates were divided into a mild asphyxia group (n=62) and a severe asphyxia group (n=23). There were 39 males and 46 females. Among them, 36 neonates with asphyxia had AKI, and 49 did not.

Inclusion criteria: (I) compliance with the diagnostic criteria for neonatal asphyxia; (II) complete clinical data and acceptance of relevant examinations; (III) approval by the Ethics Committee of Hospital, with informed consent signed by the parents or guardians of the asphyxiated neonates, and the researchers’ commitment to protect the content of the investigation and personal privacy of the subjects.

Exclusion criteria: (I) congenital renal dysplasia; (II) genetic metabolic diseases; (III) renal dysfunction caused by drugs, infections, jaundice, etc.

Data collection

Baseline data were collected, including gender, gestational age, birth weight, asphyxia severity, umbilical cord abnormalities (defined as cord entanglement, prolapse, compression, abnormal length, or abnormal blood flow), and maternal data [age, delivery mode, pregnancy complications: gestational diabetes mellitus (GDM), intrahepatic cholestasis of pregnancy (ICP), pregnancy-induced hypertension (PIH)], non-reassuring fetal status (NRFS, abnormal fetal heart rate monitoring or intrauterine hypoxia during labor), meconium-stained amniotic fluid (MSAF, amniotic fluid contaminated by fetal meconium under intrauterine hypoxia; classified into 3 grades: Grade I: light green thin amniotic fluid; Grade II: yellow-green turbid amniotic fluid; Grade III: dark brown-yellow thick particulate amniotic fluid), antenatal fever, chorioamnionitis, and premature rupture of membranes (PROM).

Laboratory index detection

Urine was collected from asphyxiated neonates within 24 hours after birth, and oliguria was defined as urine output less than 1 mL/kg/h. Fresh urine (10 mL) was collected using a urine collection bag and centrifuged at 1,500 r/min for 10 minutes. The HITACHI 7600 Automatic Analyzer was used to measure urinary TRF, β2-MGand α1-MG levels by immunoturbidimetry. The detection process was strictly carried out according to the standard operating procedures and the instructions of the reagent kit. Two milliliters of umbilical cord blood was collected, and serum levels of Cys-C and lactic acid were measured by immunoturbidimetry.

AKI diagnosis and grouping

AKI was diagnosed per Kidney Disease Improving Global Outcomes (KDIGO) criteria: (I) an increase in Scr of more than 26.5 µmol/L within 48 hours from the baseline at birth; (II) an increase in Scr to more than 1.5 times the baseline within 7 days; (III) urine output <0.5 mL/(kg·h) for more than 6 hours (14-16). All neonates were divided into AKI and non-AKI groups.

Statistical analysis

Neonates were grouped by AKI status. Continuous data (gestational age, birth weight, maternal age, laboratory indicators) were analyzed using t-tests; categorical data (gender, asphyxia severity, oliguria, umbilical cord abnormalities, delivery mode, intrauterine distress, MSAF, etc.) were analyzed using chi-square tests. The predictive value of blood lactic acid, urinary β2-MG, TRF, α1-MG, alone or in combination, for AKI was evaluated via receiver operating characteristic (ROC) curve analysis. P<0.05 was considered statistically significant.

Results

Basic characteristics of the study subjects

Among 85 asphyxiated neonates, 36 developed AKI (incidence: 42.35%). There were no significant differences between the AKI and non-AKI groups in gender, gestational age, birth weight, maternal age, delivery mode, maternal hypertension, MSAF, or intrauterine growth restriction (P>0.05). However, the AKI group had significantly higher rates of severe asphyxia, fetal distress, NRFS, umbilical cord abnormalities, and GDM than the non-AKI group (P<0.05) (Table 1).

Comparison of creatinine, and urea nitrogen levels between AKI and non-AKI groups

There were no significant differences in Scr or urea nitrogen levels between the AKI and non-AKI groups (P>0.05) (Table 2).

Comparison of blood Cys-C, lactic acid, urinary β2-MG, TRF, α1-MG levels between AKI group and non-AKI group

Levels of Cys-C, lactic acid, urinary β2-MG, TRF, and α1-MG were significantly higher in the AKI group than in the non-AKI group (P<0.05) (Table 3).

Comparison of blood Cys-C, lactate, urinary β2-MG, TRF, α1-MG levels across different asphyxia severity grades

Levels of Cys-C, lactic acid, urinary β2-MG, TRF, α1-MG were significantly higher than those in the non-AKI group (P<0.05) (Table 4).

Predictive value of indicators for AKI (ROC curve analysis)

ROC curve analysis showed that the combined prediction of AKI using blood Cys-C, lactic acid, urinary β2-MG, TRF, and α1-MG had higher sensitivity and AUC than any single indicator, with comparable specificity (Table 5, Figure 1).

Figure 1 Predictive value of indicators for AKI (ROC curve analysis). ROC curve analysis showed that the combined prediction of AKI using blood Cys-C, lactic acid, urinary β2-MG, TRF, and α1-MG had higher sensitivity and AUC than any single indicator, with comparable specificity. Among the asphyxiated neonates included in this study, only three underwent therapeutic hypothermia; the remaining neonates did not. Given the limited number of subjects receiving hypothermia, subgroup analysis was not conducted. AKI, acute kidney injury; AUC, area under the curve; Cys-C, cystatin-C; ROC, receiver operating characteristic; TRF, transferrin; α1-MG, α1-microglobulin; β2-MG, β2-microglobulin.

Discussion

Studies report that neonatal asphyxia is a risk factor for AKI (17), and concurrent asphyxia and AKI significantly increases mortality and disability rates. Our findings show a 42.35% AKI incidence in asphyxiated neonates, confirming high AKI risk. Thus, early and accurate AKI identification is critical for targeted treatment, disease control, and reduced neonatal mortality.

AKI is a common severe complication in neonatal intensive care units (NICU). This study analyzed clinical data from 85 asphyxia neonates admitted to Jinjiang City Hospital (Fujian Branch of Shanghai Sixth People’s Hospital), revealing significantly higher serum Cys-C, lactate, urinary β2-MG, TRF, and α1-MG levels in the AKI group compared to the non-AKI group (P<0.05). These findings align with previous studies (10,11), strongly supporting the potential value of these biomarkers for early diagnosis of AKI following neonatal asphyxia, while providing new insights for clinical practice.

Traditionally, Scr and urine output used for pediatric AKI diagnosis and staging (14,18). However, these conventional diagnostic indicators have major limitations. Scr is affected by maternal creatinine, cleared slowly in neonates, and only increases when GFR decreases significantly, leading to delayed diagnosis (10). While reduced urine output is a key indicator of AKI, it may be affected by non-renal factors like dehydration or medication, resulting in insufficient specificity (5). Crucially, Scr reflects renal function rather than injury (19). Therefore, developing sensitive and specific early biomarkers has remained a key focus in research.

Our study found significantly elevated blood Cys-C, lactic acid, urinary β2-MG, TRF, and α1-MG levels in the AKI group, consistent with domestic and international literature, suggesting these markers are involved in AKI development in asphyxiated neonates. Cys-C is a low-molecular-weight (~13 kDa) cysteine protease inhibitor continuously produced and released into the bloodstream by all nucleated cells (20). It is freely filtered by the glomeruli and almost completely reabsorbed and metabolized in the proximal renal tubules without secretion. Thus, serum Cys-C is a reliable endogenous GFR marker, rising earlier and more sensitively than Scr in early renal impairment (21). Unlike Scr, Cys-C is less affected by non-renal factors (muscle mass, age, gender, inflammation, medication) (22).

Multiple studies confirm Cys-C’s value in early neonatal AKI diagnosis. A study of asphyxiated neonates identified serum Cys-C as an effective early AKI predictor. An analysis of 60 critically ill neonates showed plasma Cys-C had superior early AKI predictive value (7). Plasma Cys-C levels were significantly higher in severe AKI than non-severe AKI, with marked differences on days 1 and 2 after onset (23). Hidayati et al. compared Cys-C and Scr and found Cys-C was a better renal biomarker for AKI assessment in critically ill neonates (24). Our results further confirm Cys-C’s sensitivity for early AKI diagnosis in asphyxiated neonates (P<0.05).

Neonatal asphyxia leads to systemic tissue hypoperfusion and reduced oxygen supply, causing cellular metabolism to shift from aerobic oxidation to anaerobic glycolysis, which generates substantial lactic acid. Consequently, elevated blood lactic acid levels directly reflect the severity of tissue hypoxia and metabolic dysfunction (25). When kidneys suffer hypoxic-ischemic injury, renal tubule epithelial cells become highly sensitive to oxygen deprivation, with metabolic disorders, oxidative stress, apoptosis, and necrosis directly impairing renal function (26). Specifically, lactic acid levels in the AKI group were significantly higher than those in the non-AKI group (P=0.000), indicating more severe tissue hypoxia and anaerobic metabolism in the AKI cohort (27). This significant difference suggests that higher lactic acid levels correlate with more severe hypoxia in newborns, potentially leading to more severe renal injury. Persistent or initial high lactic acid levels are considered important predictors of poor prognosis after neonatal asphyxia. Our study results further confirm that blood lactic acid levels in the AKI group were significantly higher than in the non-AKI group (P<0.05). Although lactic acid is not a renal-specific biomarker and can be affected by systemic hypoxia and other metabolic conditions, it still demonstrates high sensitivity for the early prediction of AKI in asphyxiated neonates, mainly reflecting the severity of global tissue hypoxemia and hypoperfusion.

β2-MG is a low-molecular-weight protein filtered by the glomeruli and nearly completely reabsorbed and degraded in the proximal renal tubules (28). β2-MG is a low-molecular-weight protein filtered by the glomeruli and nearly completely reabsorbed and degraded in the proximal tubules (28). Tubular dysfunction reduces β2-MG reabsorption, significantly increasing urinary β2-MG levels (10). Thus, urinary β2-MG is a sensitive tubular injury marker. Multiple studies confirm its value for early AKI prediction in asphyxiated neonates. Abdullah et al. found urinary β2-MG showed significant differences within 24 hours after birth in perinatal asphyxia neonates, with high diagnostic efficacy (10). Jalali et al. also investigated urinary β2-MG changes in renal dysfunction of asphyxiated neonates (28).

α1-MG is a low-molecular-weight protein with similar glomerular filtration and tubular reabsorption to β2-MG; elevated urinary levels indicate tubular injury. Our study found significantly higher urinary β2-MG and α1-MG levels in the AKI group (P<0.05), consistent with existing literature (9). Elevated urinary TRF (another tubular marker) further supports tubular damage from asphyxia in the AKI group. α1-MG and TRF share similar renal metabolic pathways: filtered by the glomeruli and reabsorbed/degraded in the proximal tubules. Tubular dysfunction reduces reabsorption, increasing urinary excretion.

Urinary TRF is an approximately 80 kDa plasma protein that is freely filtered by the glomerulus and reabsorbed in the proximal tubule via megalin-cubilin-mediated endocytosis (29). Owing to its low molecular weight and nearly complete tubular reabsorption, increasing evidence has indicated that urinary TRF can serve as a sensitive and relatively specific indicator of proximal tubular injury rather than primary glomerular dysfunction, supporting its utility as a reliable biomarker for tubular damage (30,31).

During neonatal asphyxia resuscitation, hypoxic-ischemic injury is one of the primary and predominant causes of AKI (9). AKI in asphyxiated neonates is multifactorial and may also involve iatrogenic factors such as hemodynamic instability, fluid therapy, and medication exposure. Hypoxic-ischemic damage primarily affects proximal tubular epithelial cells, causing cellular dysfunction, necrosis, and even shedding, thereby impairing tubular reabsorption function.

Urinary TRF increases early in AKI, often preceding the decline in GFR or elevation of Scr, allowing identification of early tubular dysfunction (32). It can reflect the severity of tubular damage and help distinguish tubular from glomerular injury. Although large-scale studies in neonates remain limited, TRF has shown predictive value in multiple renal injury models. Combined with other tubular markers such as NGAL, KIM-1 and β2-MG, TRF further improves the early diagnostic performance for AKI.

The significant elevation of urinary α1-MG and TRF in the AKI group provides direct evidence of hypoxic-ischemic tubular damage in asphyxiated neonates. Early elevation of these tubular markers suggests tubular injury may precede or coincide with glomerular dysfunction, creating an early intervention window for AKI. AKI pathophysiology is complex, involving glomerular and tubular damage. Cys-C mainly reflects glomerular filtration; blood lactic acid reflects tissue hypoxia; urinary β2-MG, TRF, and α1-MG reflect tubular reabsorption. Combining these multi-dimensional biomarkers enables comprehensive assessment of glomerular filtration, tubular reabsorption, and tissue hypoxia, providing complete renal function data, overcoming single-biomarker limitations, and improving diagnostic accuracy.

ROC curve analysis showed the combined five indicators (Cys-C, lactic acid, β2-MG, TRF, α1-MG) predicted AKI with sensitivity of 75%, specificity of 98%, and AUC of 0.909—all higher than single indicators, with comparable specificity. This confirms that combined detection improves AKI predictive efficacy in asphyxiated neonates. Single-indicator prediction risks missed diagnosis in complex cases; multi-indicator combination comprehensively assesses glomerular and tubular injury, evaluating renal dysfunction severity and enhancing prediction accuracy. The optimal cutoff values were: Cys-C 1.9 ng/mL, lactic acid 7.7 mmol/L, β2-MG 3.25U/L, TRF 0.24 ng/mL, α1-MG 4.4 mg/L. Levels above these cutoffs indicate the highest AKI risk. Clinically, combined detection of these indicators allows comprehensive evaluation of glomerular and tubular dysfunction, overcoming single-biomarker limitations and improving early AKI diagnostic sensitivity and specificity.

Dynamic monitoring of these early biomarkers helps clinicians identify high-risk neonates earlier and implement timely renal protection (optimizing fluid management, avoiding nephrotoxic drugs, correcting acid-base imbalances, improving tissue oxygenation). Early effective intervention reduces AKI incidence and severity, decreases complications, and improves clinical outcomes.

This study used single-time-point testing rather than longitudinal dynamic monitoring, so the exact timing of early marker elevation remains unclear. The relatively small sample size means the optimal cutoff values are exploratory and preliminary, requiring large-scale validation before clinical application.

Conclusions

Serum Cys-C, lactic acid, urinary β2-MG, TRF, and α1-MG are significantly elevated in asphyxiated neonates with AKI. Each indicator predicts AKI risk, and the five-indicator combination improves predictive efficacy. This combination enables earlier identification of high-risk neonates, guides early intervention, and improves AKI prognosis. These indicators can serve as auxiliary biomarkers for early clinical AKI diagnosis in asphyxiated neonates, with clinical application and promotion value.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-790/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-790/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-790/prf

Funding: This study was supported by the Hospital-level Project of Jinjiang Municipal Hospital (Shanghai Sixth People’s Hospital Fujian) (No. 2022LC03), Quanzhou City Science & Technology Program of China (No. 2023NS097), and the Open Research Project of Fujian Key Laboratory of Neonatal Diseases.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-790/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Jinjiang Municipal Hospital (Shanghai Sixth People’s Hospital Fujian) (No. JJSYYYXLL-2022096). Informed consent was taken from all the patients’ parents or legal guardians.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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