Incidence and risk factors associated with acute kidney injury in newborns affected by perinatal asphyxia

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Methods This retrospective study was conducted at the Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy. All neonates above 34 weeks of gestation diagnosed with hypoxic-ischemic encephalopathy (HIE) and treated with hypothermia, weighing more than 1800 grams, admitted from January 1, 2013, to December 31, 2022, were included. AKI was defined according to the neonatal KDIGO classification. Results A total of 76 neonates were enrolled: 13 (17%) with severe HIE. The incidence of AKI was 36%, with 64% of cases identified as a reduction in diuresis, 25% as changes in creatinine and oliguria, and only 10% as isolated creatinine elevation. The rate of AKI was significantly higher in infants with severe HIE (p < 0.001). Infants who developed AKI required more inotropes, had higher rates of serum hyponatremia (< 125 mEq/L) and were less likely to normalize lactate levels within 24 hours of birth. Conclusions In asphyxiated newborns, reduced kidney perfusion can cause kidney impairment in nearly 40% of those undergoing treatment. Enhancing the detection of AKI is crucial for improving patient outcomes. We recommend proactive monitoring of lactate trends, urinary output, and serum sodium levels to enable early interventions that protect kidney function and improve outcomes for these vulnerable infants. acute kidney injury AKI newborn perinatal asphyxia Figures Figure 1 Introduction Perinatal asphyxia is due to reduced fetal perfusion during labor, which results in severe hypoxemia and can lead to hypoxic-ischemic encephalopathy (HIE). Despite significant advancements in perinatal medicine over the past few decades, perinatal asphyxia remains a leading cause of mortality and disability in the neonatal period, with an estimated incidence of 1–2 cases for every 1,000 live newborns annually in developed countries. Therapeutic hypothermia (TH) has reduced mortality and improved neurodevelopmental outcomes in cases of moderate to severe HIE [ 1 , 2 , 3 ]. Although considerable research has focused on neurological damage, there is still a significant gap in our understanding of kidney damage in these patients. In cases of perinatal asphyxia, the body redistributes cardiac output to protect the heart and brain from ischemia, which further reduces the limited blood flow reaching the kidneys at birth. Additionally, in instances of hypoxemia, there is an increase in adenosine levels, which causes vasodilation of the kidney glomerular arterioles. This can reduce transglomerular pressure and lead to a decrease in the glomerular filtration rate. Recent studies report a wide variability in the incidence of acute kidney injury (AKI) in these patients largely due to differing definitions of AKI based on serum creatinine levels [ 4 , 5 ]. Additionally, even when AKI is identified, it is often not included in discharge letters or diagnosis codes. This omission leads to underestimating the issue and hampers appropriate follow-up. It is well established that experiencing a single episode of AKI can significantly increase the risk of developing chronic kidney disease later in life [ 6 ]. In 2015, a consensus statement of the Kidney Disease: Improving Global Outcomes (KDIGO) established a clear definition of neonatal acute kidney injury (AKI) [ 6 ]. KDIGO defined AKI as decreased urine output and elevated serum creatinine levels. The present study aimed to assess the incidence of AKI, defined as per KDIGO criteria, in neonates with HIE admitted to our unit between January 2013 and December 2022. Additionally, we analyzed the number of abnormal urine tests to ensure a more accurate assessment of AKI incidence and facilitate quicker diagnosis of kidney damage. Methods Study design and period This study retrospectively analyses data collected from the neonatal intensive care unit of Fondazione IRCCS San Gerardo dei Tintori in Monza, Italy, between January 1, 2013, and December 31, 2022. The ethics committee approved the study (approval number: 245). Study population All neonates diagnosed with perinatal asphyxia and admitted to our unit who received TH in the study period were included in the analysis. We excluded infants with gestational age < 35 weeks or birth weight < 1800 grams and infants with major malformations or chromosomal anomalies. We also excluded infants who died or were transferred to other hospitals in the first two days of life and infants with incomplete data. Unit policies for the management of perinatal asphyxia In our unit, all infants born with severe acidosis—defined as an arterial pH less than 7.0 or a base deficit greater than 12 or who required resuscitation for more than 10 minutes after birth—undergo a neurological assessment within the first 6 hours of life. This assessment includes an hourly Thompson score, and if the score exceeds 5, an amplitude-integrated electroencephalography (aEEG) is initiated. If the cerebral function monitoring (CFM) confirms a moderate to severe pattern, treatment with TH will be initiated. If the Thompson score is unavailable, which is often the case in outborn patients, the decision to begin therapeutic hypothermia is based solely on amplitude-integrated EEG (aEEG/CFM) findings. TH consists of cooling the infant to a core temperature of 33–34 °C within 6 hours after birth, maintaining this temperature for 72 hours, and then gradually re-warming at a rate of 0.5 °C per hour. From January 2013 to June 2018, we employed selective hypothermia using a Cool Cap; after that, we transitioned to whole-body hypothermia. Infants are closely monitored throughout the intervention, with serum urea and creatinine levels tested at least every 24 hours, alongside the liver and bone marrow function assessments. During hypothermia, newborns receive continuous aEEG monitoring. At the end of treatment, a neurological evaluation and cerebral MRI are performed to confirm the grade of encephalopathy. Data collection Data were extracted from the electronic clinical record form. AKI was defined according to the KDIGO criteria as an increase in serum creatinine and/or a reduction in urine output [7]. The nephrotoxic burden was defined as the use of at least three nephrotoxic medications within 24 hours or four or more days of intravenous aminoglycoside [8]. Hyponatremia was defined as a serum sodium concentration < 125 mEq/L. The Thompson score was given according to [9], and the highest score for a given patient was included in the analysis. Statistical analysis Continuous variables were expressed as median (Q1, Q3), and dichotomous variables as n (%). We compared infants who developed AKI versus those who did not, using the Mann-Whitney U test for continuous variables and the Fisher’s Exact test for dichotomous variables. The association between AKI of any stage and mortality was assessed using multivariable logistic regression, adjusting for severe HIE. We performed logistic regression to assess the association between early clinical and biochemical factors and the development of AKI. First, we built a model including all factors that differed significantly between infants who did and did not develop AKI; then, we performed stepwise elimination of factors that did not improve the prediction based on an algorithm that minimizes the AIC. Since the models aim to identify the most significant risk factors for the development of AKI, the severity of HIE was excluded as it is assessed at discharge, and the Thompson score was omitted due to frequent unavailability in outborn infants. Among resuscitation interventions at birth, we included only chest compression, which indicated the highest grade of asphyxia, to limit the risk of collinearity. Statistical analysis was performed using R 4.3.2 software. Results Between January 1, 2013, and December 31, 2022, 76 infants underwent active hypothermia for HIE, with 32 (42%) receiving whole-body cooling and 44 (58%) treated using a cooling cap. Of the included infants, 13 (17%) had severe HIE. Infants had a median (Q1, Q3) gestational age of 39.50 (38.21, 40.43) weeks, birth weight of 3150 (2783, 3510) g, and 37 (49%) were male. Twenty-six (36%) infants developed AKI, including 11 cases of AKI stage 1, 8 cases of AKI stage 2, and 7 cases of AKI stage 3. We did not observe a significant difference in the rate of AKI between infants receiving whole-body cooling and those treated using a cooling cap (p = 0.135). The rate of AKI was significantly higher in infants with severe HIE (p < 0.003). Table 1 summarizes the characteristics of the study population and compares key clinical factors between infants who did and did not develop AKI at any stage. Briefly, infants who developed AKI had significantly worse Thompson scores, a higher rate of severe HIE, required more intensive resuscitation at birth and ultimately had a higher mortality rate. The development of AKI added significantly (aOR = 1.16, p = 0.004) to the probability of death, even after adjusting for severe HIE (Table 2 ). Table 1 Characteristics of study participants Overall noAKI AKI p-value Number of cases 76 50 (66%) 26 (34%) Mode of delivery Cesarian section 37 (49%) 21 (42%) 16 (62%) 0.106 Prenatal events Fetal deceleration, n (%) 22 (29%) 16 (32%) 6 (23%) 0.416 Fetal bradycardia, n (%) 4 (5%) 1 (2%) 3 (12%) 0.077 Uterine rupture, n (%) 4 (5%) 2 (4%) 2 (8%) 0.494 Placental abruption/maternal hemorrhage, n (%) 10 (13%) 6 (12%) 4 (15%) 0.679 Cord prolapse, n (%) 4 (5%) 3 (6%) 1 (4%) 0.690 Shoulder dystocia, n (%) 9 (12%) 5 (10%) 4 (15%) 0.491 Neonatal characteristics GA, weeks 39.50 (38.21, 40.43) 39.64 (38.00, 40.39) 39.36 (38.75, 40.68) 0.638 BW, g 3150 (2783, 3510) 3180 (2813, 3500) 3120 (2670, 3613) 0.921 Female, n (%) 37 (49%) 22 (44%) 15 (58%) 0.257 Outborn, n (%) 40 (53%) 30 (60%) 10 (39%) 0.074 Apgar 5 4 (3, 6) 4 (3, 7) 4 (1, 5) 0.098 Cord pH 6.99 (6.86, 7.09) 6.99 (6.86, 7.10) 6.98 (6.83, 7.08) 0.588 Cord BE -14.5 (-18.3, -12.0) -13.3 (-17.0, -12.1) -15.6 (-19.8, -10.5) 0.367 Cord lactate 10.50 (8.25, 14.05) 10.00 (8.40, 14.05) 10.80 (7.90, 13.90) 0.874 Thompson* 8.0 (7.0, 11.5) 8.0 (6.5, 9.5) 12.0 (7.8, 16.0) 0.004 Whole body cooling, n (%) 32 (42%) 18 (36%) 14 (54%) 0.135 Resuscitation at birth Chest compressions, n (%) 29 (39%) 13 (27%) 16 (62%) 0.003 Epinephrine, n (%) 16 (21%) 7 (14%) 9 (35%) 0.041 Intubation, n (%) 43 (57%) 24 (48%) 19 (73%) 0.036 Neonatal outcomes Severe HIE 13 (17%) 3 (6%) 10 (39%) < 0.001 Death, n (%) 9 (12%) 0 (0%) 9 (35%) < 0.001 GA: gestational age; BW: birth weight; BE: base excess; HIE: hypoxic-ischemic encephalopathy; AKI: Acute Kidney Injury. Data are expressed as median (Q, Q3) or number (%). *: n = 59. Table 2 Relationship between AKI and mortality OR 95% CI p-value Severe HIE 1.85 1.64–2.09 < 0.001 AKI 1.16 1.05–1.27 0.004 HIE: hypoxic-ischemic encephalopathy; AKI: Acute Kidney Injury; OR: Odds Ratio; CI: confidence interval. Figure 1 shows the proportion of patients who developed different stages of AKI and the markers leading to the diagnosis based on KDIGO classification. Table 3 summarizes key risk factors for AKI and biochemical parameters likely associated with kidney function in infants who did and did not develop AKI. Infants who developed AKI required more inotropes (e.g. proxy for hypotension), had higher rates of serum hyponatremia and were less likely to normalize lactate levels within 24 hours of birth (e.g. proxy for kidney hypoperfusion). Table 3 Risk factors and key biochemical parameters by acute kidney injury noAKI AKI p-value Number of cases 50 (66%) 26 (34%) Risk factors Nephrotoxic burden, n (%) 36 (72%) 16 (62%) 0.352 Inotropes, n (%) 12 (24%) 13 (50%) 0.022 Sepsis, n (%) 4 (8%) 4 (15%) 0.320 Biochemical factors Hyponatremia, n (%) 3 (6%) 12 (46%) < 0.001 Lactate normalisation within 24 h, n (%) 15 (58%) 11 (22%) 0.002 Data are expressed as n (%). Table 4 shows the results of a multivariable logistic model including factors that differed significantly between patients who did and did not develop AKI. Hyponatremia was the factor that most strongly correlated with the development of AKI (aOR = 1.60, p < 0.001); the requirement of chest compressions at birth and lactates not normalizing within 24 hours after birth added significantly to the prediction of AKI development. Table 4 Multivariable logistic model of the probability of developing AKI OR 95% CI p-value Chest compressions 1.27 1.05–1.53 0.017 Hyponatremia 1.60 1.27–2.01 < 0.001 Lactate normalization within 24 h 0.79 0.65–0.96 0.022 OR: Odds Ratio; CI: confidence interval. Discussion In our population, the incidence of AKI in asphyxiated newborns undergoing hypothermic treatment was 36%. We found that chest compressions at birth, hypotension, and slow normalization of lactate levels are strongly associated with the occurrence of AKI. Previous studies reported AKI rates between 11 and 40% [ 10 , 11 , 12 ]. This wide range could be related to the different definitions of AKI, mainly using a creatinine-based definition. In our population, AKI was defined as an increase in creatinine, a decrease in urine output, or a combination of the two. Defining AKI only by creatinine augmentation can easily underestimate kidney injury because serum creatinine is a poor marker for AKI in the first period of life [ 13 ]. In our cohort, AKI defined by reduced urine output represents 64%, which is consistent with the result of the AWAKEN cohort [ 14 ], in which the proportion of AKI detected by oligo/anuria was almost 47%. Clinicians should pay more attention to urine output than to creatinine increase: serum creatinine could be a belated marker when irreversible kidney damage has already been established and nephron mass has already been lost. Additionally, serum creatinine levels represent maternal values for the initial 48–72 hours, potentially complicating the application of KDIGO criteria. Gupta et al. [ 11 ] have sought to modify the creatinine-based definition of AKI, characterizing it as a slow rate of creatinine decline. Their research has shown a significant correlation with the number of days patients require mechanical ventilation, the overall length of hospitalization, and the necessity for vasopressor drugs. This research highlights the need for a more complex definition of AKI, especially during the first days of life, that allows clinicians to detect any kidney impairment. It is evident that infants with severe HIE, coupled with extended resuscitation efforts, exhibit a significantly higher incidence of AKI. This observation reinforces the notion that the mechanisms leading to kidney damage are closely related to those causing cerebral injury. Given that kidney blood flow in newborns is markedly lower than in adults, perinatal asphyxia can severely compromise kidney perfusion. Moreover, in newborns, cerebral autoregulation is prioritised over kidney autoregulation, and this becomes even more pronounced in cooled infants. A NIRS study [ 15 ] highlighted that kidney oxygen saturation remains lower and more unstable compared to cerebral saturation during hypothermic treatments. This instability may be linked to blood pressure fluctuations; the combination of impaired kidney autoregulation and the administration of hypotensive agents, such as benzodiazepines, can result in significant hypotension that often requires inotropic support. In our cohort, the need for inotropes was strongly correlated with the development of AKI, underscoring the critical importance of vigilant monitoring and intervention. Our research has revealed a compelling positive correlation between the recovery time of lactate and the risk of AKI. Lactate serves as a crucial indicator of poor tissue perfusion, and it outperforms cord pH and base excess in predicting organ hypoperfusion and subsequent damage [ 16 ]. Notably, several studies have documented a link between high lactate levels in newborns and the severity of encephalopathy [ 17 ]. Furthermore, recent work by Bozkurt [ 18 ] and colleagues highlights that elevated lactate levels at 12 hours post-birth may significantly increase the risk of AKI. In our study, we investigated lactate trends during the first three days of life under TH and established a robust association between the timing of lactate normalization and the AKI risk. Based on these findings, we advocate for the consideration of lactate as a critical predictor of poor kidney outcomes. This could pave the way for improved fluid management strategies and the judicious use of inotropes to enhance kidney function. In our study cohort, we found that a significant majority, 73% of the neonates, exhibited moderate hyponatremia, defined by serum sodium levels falling below 131 mEq/L. Within this group, 40% of the infants demonstrated a more severe form of this condition, with serum sodium levels dropping below 125 mEq/L. To the best of our knowledge, such an observation has not been documented in prior research, underscoring the novelty of our findings. This situation prompts us to hypothesize that severe hyponatremia may serve as a predictor of adverse outcomes in affected infants, yet the intricate mechanisms behind sodium depletion remain largely elusive. Within the severely hyponatremic subgroup, we observed that 63% of the infants were diagnosed with AKI. This statistic raises the possibility that kidney impairment could be a contributing factor in the pathogenesis of sodium depletion, hinting at the complex interplay between kidney function and electrolyte balance. Unfortunately, the retrospective design of our study meant that routine urinalysis was not consistently conducted among the infants in our population. As a result, we were unable to fully support our hypothesis regarding urinary sodium loss, which limits our understanding of the underlying mechanisms. In a separate study, which examined a cohort of term infants who suffered from asphyxia, Karlo and colleagues noted that the fractional excretion of sodium was elevated in patients with AKI. Interestingly, when they categorized AKI into prerenal and intrinsic types, the previously observed positive correlation diminished, raising questions about the underlying causes of hyponatremia specifically in cases of prerenal AKI. Over the past few years, significant discussions have arisen concerning the appropriate management of fluid intake in this vulnerable population. It is evident that there is a notable scarcity of randomized controlled trials aimed at identifying the ideal volume of fluid for neonates at risk. While it has been established that an overload of fluids can lead to poorer clinical outcomes, it is equally important to consider scenarios involving acute intrapartum volume loss, such as maternal hemorrhage or uterine rupture. In such circumstances, strategically increasing fluid intake may play a vital role in preventing kidney injury and safeguarding the well-being of these fragile infants. The strengths of our study include a good sample size and the homogeneity of our participants. We implemented a consistent protocol for enrolling neonates in hypothermia treatment and utilized the same operators to analyze EEG, assess neurological conditions, and evaluate HIE grade. Additionally, despite the retrospective nature of this study, we have access to an electronic chart system that enables us to accurately retrieve information about the infants. Conversely, a limitation of our study is that it was conducted at a single center, which may affect the generalizability of our findings. Moreover, we lack information on the kidney function of asphyxiated infants who did not receive hypothermic treatment, which restricts our ability to draw broader conclusions. Conclusion In asphyxiated newborns, diminished kidney perfusion can lead to renal impairment in nearly 40% of those treated. Therapeutic hypothermia (TH) could improve short-term kidney function, but it is essential that we also enhance the detection of AKI. By prioritizing AKI detection, we can significantly improve patient outcomes and treatment effectiveness. We advocate for the proactive monitoring of lactate trends, urinary output, and serum sodium levels, which could facilitate early interventions to protect kidney function and foster better outcomes for these vulnerable infants. Declarations Acknowledgements We would like to thank all the nursing staff of our Neonatal Intensive Care Unit for their dedication and compassionate care of our patients. Disclosure Statements The authors have no conflicts of interest to declare. Financial Disclosure Statement The authors have no potential or actual interests to disclose. References Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2013 Jan 31;2013(1): CD003311. Acun C, Karnati S, Padiyar S, et al. Trends of neonatal hypoxic-ischemic encephalopathy prevalence and associated risk factors in the United States, 2010 to 2018. Am J Obstet Gynecol 2022; S0002-9378(22)004434. Abate BB, Bimerew M, Gebremichael B, et al. Effects of therapeutic hypothermia on death among asphyxiated neonates with hypoxic-ischemic encephalopathy: A systematic review and meta-analysis of randomized control trials. Plos One. 2021;16(2):e0247229. Hankins GD, Koen S, Gei AF, Lopez SM, Van Hook JW, Anderson GD. Neonatal organ system injury in acute birth asphyxia sufficient to result in neonatal encephalopathy. 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Am J Perinatol 2019 DOI 10.1055/s-0039-1701024 Supplementary Files PedNephGraphicalAbstractHIE.pptx Cite Share Download PDF Status: Published Journal Publication published 19 Aug, 2025 Read the published version in Pediatric Nephrology → Version 1 posted Editorial decision: Major Revisions Needed 20 Jun, 2025 Reviewers agreed at journal 03 Jun, 2025 Reviewers invited by journal 03 Jun, 2025 Editor assigned by journal 03 Jun, 2025 First submitted to journal 03 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Tintori","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Luisa","lastName":"Ventura","suffix":""}],"badges":[],"createdAt":"2025-06-03 16:18:49","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6813243/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6813243/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00467-025-06926-8","type":"published","date":"2025-08-19T16:29:42+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84220486,"identity":"c5274a16-02be-4521-b938-5227097b1d40","added_by":"auto","created_at":"2025-06-09 11:33:10","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1602939,"visible":true,"origin":"","legend":"\u003cp\u003eProportion of infants by different AKI stages and different kidney injury 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11:25:10","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1522725,"visible":true,"origin":"","legend":"","description":"","filename":"PedNephGraphicalAbstractHIE.pptx","url":"https://assets-eu.researchsquare.com/files/rs-6813243/v1/aaa5cdfaf9dc6a1721acd5b0.pptx"}],"financialInterests":"","formattedTitle":"Incidence and risk factors associated with acute kidney injury in newborns affected by perinatal asphyxia","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePerinatal asphyxia is due to reduced fetal perfusion during labor, which results in severe hypoxemia and can lead to hypoxic-ischemic encephalopathy (HIE). Despite significant advancements in perinatal medicine over the past few decades, perinatal asphyxia remains a leading cause of mortality and disability in the neonatal period, with an estimated incidence of 1\u0026ndash;2 cases for every 1,000 live newborns annually in developed countries.\u003c/p\u003e \u003cp\u003eTherapeutic hypothermia (TH) has reduced mortality and improved neurodevelopmental outcomes in cases of moderate to severe HIE [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Although considerable research has focused on neurological damage, there is still a significant gap in our understanding of kidney damage in these patients.\u003c/p\u003e \u003cp\u003eIn cases of perinatal asphyxia, the body redistributes cardiac output to protect the heart and brain from ischemia, which further reduces the limited blood flow reaching the kidneys at birth. Additionally, in instances of hypoxemia, there is an increase in adenosine levels, which causes vasodilation of the kidney glomerular arterioles. This can reduce transglomerular pressure and lead to a decrease in the glomerular filtration rate.\u003c/p\u003e \u003cp\u003eRecent studies report a wide variability in the incidence of acute kidney injury (AKI) in these patients largely due to differing definitions of AKI based on serum creatinine levels [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Additionally, even when AKI is identified, it is often not included in discharge letters or diagnosis codes. This omission leads to underestimating the issue and hampers appropriate follow-up. It is well established that experiencing a single episode of AKI can significantly increase the risk of developing chronic kidney disease later in life [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn 2015, a consensus statement of the Kidney Disease: Improving Global Outcomes (KDIGO) established a clear definition of neonatal acute kidney injury (AKI) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. KDIGO defined AKI as decreased urine output and elevated serum creatinine levels.\u003c/p\u003e \u003cp\u003eThe present study aimed to assess the incidence of AKI, defined as per KDIGO criteria, in neonates with HIE admitted to our unit between January 2013 and December 2022. Additionally, we analyzed the number of abnormal urine tests to ensure a more accurate assessment of AKI incidence and facilitate quicker diagnosis of kidney damage.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003eStudy design and period\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study retrospectively analyses data collected from the neonatal intensive care unit of Fondazione IRCCS San Gerardo dei Tintori in Monza, Italy, between January 1, 2013, and December 31, 2022. The ethics committee approved the study (approval number: 245).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudy population\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll neonates diagnosed with perinatal asphyxia and admitted to our unit who received TH in the study period were included in the analysis. We excluded infants with gestational age \u0026lt; 35 weeks or birth weight \u0026lt; 1800 grams and infants with major malformations or chromosomal anomalies. We also excluded infants who died or were transferred to other hospitals in the first two days of life and infants with incomplete data.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eUnit policies for the management of perinatal asphyxia\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn our unit, all infants born with severe acidosis\u0026mdash;defined as an arterial pH less than 7.0 or a base deficit greater than 12 or who required resuscitation for more than 10 minutes after birth\u0026mdash;undergo a neurological assessment within the first 6 hours of life. This assessment includes an hourly Thompson score, and if the score exceeds 5, an amplitude-integrated electroencephalography (aEEG) is initiated. If the cerebral function monitoring (CFM) confirms a moderate to severe pattern, treatment with TH will be initiated. If the Thompson score is unavailable, which is often the case in outborn patients, the decision to begin therapeutic hypothermia is based solely on amplitude-integrated EEG (aEEG/CFM) findings. TH consists of cooling the infant to a core temperature of 33\u0026ndash;34 \u0026deg;C within 6 hours after birth, maintaining this temperature for 72 hours, and then gradually re-warming at a rate of 0.5 \u0026deg;C per hour. From January 2013 to June 2018, we employed selective hypothermia using a Cool Cap; after that, we transitioned to whole-body hypothermia. Infants are closely monitored throughout the intervention, with serum urea and creatinine levels tested at least every 24 hours, alongside the liver and bone marrow function assessments. During hypothermia, newborns receive continuous aEEG monitoring. At the end of treatment, a neurological evaluation and cerebral MRI are performed to confirm the grade of encephalopathy.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData collection\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eData were extracted from the electronic clinical record form. AKI was defined according to the KDIGO criteria as an increase in serum creatinine and/or a reduction in urine output [7]. The nephrotoxic burden was defined as the use of at least three nephrotoxic medications within 24 hours or four or more days of intravenous aminoglycoside [8]. Hyponatremia was defined as a serum sodium concentration \u0026lt; 125 mEq/L. The Thompson score was given according to [9], and the highest score for a given patient was included in the analysis.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical analysis\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eContinuous variables were expressed as median (Q1, Q3), and dichotomous variables as n (%). We compared infants who developed AKI versus those who did not, using the Mann-Whitney U test for continuous variables and the Fisher\u0026rsquo;s Exact test for dichotomous variables. The association between AKI of any stage and mortality was assessed using multivariable logistic regression, adjusting for severe HIE. We performed logistic regression to assess the association between early clinical and biochemical factors and the development of AKI. First, we built a model including all factors that differed significantly between infants who did and did not develop AKI; then, we performed stepwise elimination of factors that did not improve the prediction based on an algorithm that minimizes the AIC. Since the models aim to identify the most significant risk factors for the development of AKI, the severity of HIE was excluded as it is assessed at discharge, and the Thompson score was omitted due to frequent unavailability in outborn infants. Among resuscitation interventions at birth, we included only chest compression, which indicated the highest grade of asphyxia, to limit the risk of collinearity. Statistical analysis was performed using R 4.3.2 software.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eBetween January 1, 2013, and December 31, 2022, 76 infants underwent active hypothermia for HIE, with 32 (42%) receiving whole-body cooling and 44 (58%) treated using a cooling cap. Of the included infants, 13 (17%) had severe HIE.\u003c/p\u003e \u003cp\u003eInfants had a median (Q1, Q3) gestational age of 39.50 (38.21, 40.43) weeks, birth weight of 3150 (2783, 3510) g, and 37 (49%) were male. Twenty-six (36%) infants developed AKI, including 11 cases of AKI stage 1, 8 cases of AKI stage 2, and 7 cases of AKI stage 3. We did not observe a significant difference in the rate of AKI between infants receiving whole-body cooling and those treated using a cooling cap (p\u0026thinsp;=\u0026thinsp;0.135). The rate of AKI was significantly higher in infants with severe HIE (p\u0026thinsp;\u0026lt;\u0026thinsp;0.003).\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the characteristics of the study population and compares key clinical factors between infants who did and did not develop AKI at any stage. Briefly, infants who developed AKI had significantly worse Thompson scores, a higher rate of severe HIE, required more intensive resuscitation at birth and ultimately had a higher mortality rate. The development of AKI added significantly (aOR\u0026thinsp;=\u0026thinsp;1.16, p\u0026thinsp;=\u0026thinsp;0.004) to the probability of death, even after adjusting for severe HIE (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of study participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003enoAKI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAKI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of cases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 (66%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (34%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMode of delivery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCesarian section\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (49%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (62%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.106\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrenatal events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFetal deceleration, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (29%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.416\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFetal bradycardia, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.077\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUterine rupture, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.494\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlacental abruption/maternal hemorrhage, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.679\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCord prolapse, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.690\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShoulder dystocia, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.491\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeonatal characteristics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGA, weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39.50 (38.21, 40.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39.64 (38.00, 40.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39.36 (38.75, 40.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.638\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBW, g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3150 (2783, 3510)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3180 (2813, 3500)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3120 (2670, 3613)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.921\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (49%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (44%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (58%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.257\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutborn, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (53%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (39%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.074\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApgar 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (3, 6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (3, 7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (1, 5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.098\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCord pH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.99 (6.86, 7.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.99 (6.86, 7.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.98 (6.83, 7.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.588\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCord BE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-14.5 (-18.3, -12.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-13.3 (-17.0, -12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-15.6 (-19.8, -10.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.367\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCord lactate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.50 (8.25, 14.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.00 (8.40, 14.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.80 (7.90, 13.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.874\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThompson*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.0 (7.0, 11.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.0 (6.5, 9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.0 (7.8, 16.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003e0.004\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhole body cooling, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (54%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.135\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResuscitation at birth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChest compressions, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (39%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (27%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (62%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003e0.003\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpinephrine, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (35%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003e0.041\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntubation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43 (57%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (48%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (73%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003e0.036\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeonatal outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere HIE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (39%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003e\u0026lt;\u0026thinsp;0.001\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (35%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003e\u0026lt;\u0026thinsp;0.001\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eGA: gestational age; BW: birth weight; BE: base excess; HIE: hypoxic-ischemic encephalopathy; AKI: Acute Kidney Injury. Data are expressed as median (Q, Q3) or number (%). *: n\u0026thinsp;=\u0026thinsp;59.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRelationship between AKI and mortality\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere HIE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.64\u0026ndash;2.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAKI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.05\u0026ndash;1.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eHIE: hypoxic-ischemic encephalopathy; AKI: Acute Kidney Injury; OR: Odds Ratio; CI: confidence interval.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the proportion of patients who developed different stages of AKI and the markers leading to the diagnosis based on KDIGO classification. Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e summarizes key risk factors for AKI and biochemical parameters likely associated with kidney function in infants who did and did not develop AKI. Infants who developed AKI required more inotropes (e.g. proxy for hypotension), had higher rates of serum hyponatremia and were less likely to normalize lactate levels within 24 hours of birth (e.g. proxy for kidney hypoperfusion).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRisk factors and key biochemical parameters by acute kidney injury\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003enoAKI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAKI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of cases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50 (66%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (34%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRisk factors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNephrotoxic burden, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (72%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (62%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.352\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInotropes, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e0.022\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSepsis, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.320\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiochemical factors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyponatremia, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e\u0026lt;\u0026thinsp;0.001\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLactate normalisation within 24 h, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (58%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e0.002\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eData are expressed as n (%).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the results of a multivariable logistic model including factors that differed significantly between patients who did and did not develop AKI. Hyponatremia was the factor that most strongly correlated with the development of AKI (aOR\u0026thinsp;=\u0026thinsp;1.60, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001); the requirement of chest compressions at birth and lactates not normalizing within 24 hours after birth added significantly to the prediction of AKI development.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariable logistic model of the probability of developing AKI\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChest compressions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.05\u0026ndash;1.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyponatremia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.27\u0026ndash;2.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLactate normalization within 24 h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.65\u0026ndash;0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eOR: Odds Ratio; CI: confidence interval.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our population, the incidence of AKI in asphyxiated newborns undergoing hypothermic treatment was 36%. We found that chest compressions at birth, hypotension, and slow normalization of lactate levels are strongly associated with the occurrence of AKI.\u003c/p\u003e \u003cp\u003ePrevious studies reported AKI rates between 11 and 40% [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. This wide range could be related to the different definitions of AKI, mainly using a creatinine-based definition. In our population, AKI was defined as an increase in creatinine, a decrease in urine output, or a combination of the two. Defining AKI only by creatinine augmentation can easily underestimate kidney injury because serum creatinine is a poor marker for AKI in the first period of life [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In our cohort, AKI defined by reduced urine output represents 64%, which is consistent with the result of the AWAKEN cohort [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], in which the proportion of AKI detected by oligo/anuria was almost 47%. Clinicians should pay more attention to urine output than to creatinine increase: serum creatinine could be a belated marker when irreversible kidney damage has already been established and nephron mass has already been lost. Additionally, serum creatinine levels represent maternal values for the initial 48\u0026ndash;72 hours, potentially complicating the application of KDIGO criteria. Gupta et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] have sought to modify the creatinine-based definition of AKI, characterizing it as a slow rate of creatinine decline. Their research has shown a significant correlation with the number of days patients require mechanical ventilation, the overall length of hospitalization, and the necessity for vasopressor drugs. This research highlights the need for a more complex definition of AKI, especially during the first days of life, that allows clinicians to detect any kidney impairment.\u003c/p\u003e \u003cp\u003eIt is evident that infants with severe HIE, coupled with extended resuscitation efforts, exhibit a significantly higher incidence of AKI. This observation reinforces the notion that the mechanisms leading to kidney damage are closely related to those causing cerebral injury. Given that kidney blood flow in newborns is markedly lower than in adults, perinatal asphyxia can severely compromise kidney perfusion. Moreover, in newborns, cerebral autoregulation is prioritised over kidney autoregulation, and this becomes even more pronounced in cooled infants. A NIRS study [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] highlighted that kidney oxygen saturation remains lower and more unstable compared to cerebral saturation during hypothermic treatments. This instability may be linked to blood pressure fluctuations; the combination of impaired kidney autoregulation and the administration of hypotensive agents, such as benzodiazepines, can result in significant hypotension that often requires inotropic support. In our cohort, the need for inotropes was strongly correlated with the development of AKI, underscoring the critical importance of vigilant monitoring and intervention.\u003c/p\u003e \u003cp\u003eOur research has revealed a compelling positive correlation between the recovery time of lactate and the risk of AKI. Lactate serves as a crucial indicator of poor tissue perfusion, and it outperforms cord pH and base excess in predicting organ hypoperfusion and subsequent damage [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Notably, several studies have documented a link between high lactate levels in newborns and the severity of encephalopathy [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Furthermore, recent work by Bozkurt [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] and colleagues highlights that elevated lactate levels at 12 hours post-birth may significantly increase the risk of AKI. In our study, we investigated lactate trends during the first three days of life under TH and established a robust association between the timing of lactate normalization and the AKI risk. Based on these findings, we advocate for the consideration of lactate as a critical predictor of poor kidney outcomes. This could pave the way for improved fluid management strategies and the judicious use of inotropes to enhance kidney function.\u003c/p\u003e \u003cp\u003eIn our study cohort, we found that a significant majority, 73% of the neonates, exhibited moderate hyponatremia, defined by serum sodium levels falling below 131 mEq/L. Within this group, 40% of the infants demonstrated a more severe form of this condition, with serum sodium levels dropping below 125 mEq/L. To the best of our knowledge, such an observation has not been documented in prior research, underscoring the novelty of our findings. This situation prompts us to hypothesize that severe hyponatremia may serve as a predictor of adverse outcomes in affected infants, yet the intricate mechanisms behind sodium depletion remain largely elusive. Within the severely hyponatremic subgroup, we observed that 63% of the infants were diagnosed with AKI. This statistic raises the possibility that kidney impairment could be a contributing factor in the pathogenesis of sodium depletion, hinting at the complex interplay between kidney function and electrolyte balance. Unfortunately, the retrospective design of our study meant that routine urinalysis was not consistently conducted among the infants in our population. As a result, we were unable to fully support our hypothesis regarding urinary sodium loss, which limits our understanding of the underlying mechanisms. In a separate study, which examined a cohort of term infants who suffered from asphyxia, Karlo and colleagues noted that the fractional excretion of sodium was elevated in patients with AKI. Interestingly, when they categorized AKI into prerenal and intrinsic types, the previously observed positive correlation diminished, raising questions about the underlying causes of hyponatremia specifically in cases of prerenal AKI.\u003c/p\u003e \u003cp\u003eOver the past few years, significant discussions have arisen concerning the appropriate management of fluid intake in this vulnerable population. It is evident that there is a notable scarcity of randomized controlled trials aimed at identifying the ideal volume of fluid for neonates at risk. While it has been established that an overload of fluids can lead to poorer clinical outcomes, it is equally important to consider scenarios involving acute intrapartum volume loss, such as maternal hemorrhage or uterine rupture. In such circumstances, strategically increasing fluid intake may play a vital role in preventing kidney injury and safeguarding the well-being of these fragile infants.\u003c/p\u003e \u003cp\u003e The strengths of our study include a good sample size and the homogeneity of our participants. We implemented a consistent protocol for enrolling neonates in hypothermia treatment and utilized the same operators to analyze EEG, assess neurological conditions, and evaluate HIE grade. Additionally, despite the retrospective nature of this study, we have access to an electronic chart system that enables us to accurately retrieve information about the infants.\u003c/p\u003e \u003cp\u003eConversely, a limitation of our study is that it was conducted at a single center, which may affect the generalizability of our findings. Moreover, we lack information on the kidney function of asphyxiated infants who did not receive hypothermic treatment, which restricts our ability to draw broader conclusions.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn asphyxiated newborns, diminished kidney perfusion can lead to renal impairment in nearly 40% of those treated. Therapeutic hypothermia (TH) could improve short-term kidney function, but it is essential that we also enhance the detection of AKI. By prioritizing AKI detection, we can significantly improve patient outcomes and treatment effectiveness. We advocate for the proactive monitoring of lactate trends, urinary output, and serum sodium levels, which could facilitate early interventions to protect kidney function and foster better outcomes for these vulnerable infants.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank all the nursing staff of our Neonatal Intensive Care Unit for their dedication and compassionate care of our patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure Statements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial Disclosure Statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no potential or actual interests to disclose.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eJacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2013 Jan 31;2013(1): CD003311.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAcun C, Karnati S, Padiyar S, et al. Trends of neonatal hypoxic-ischemic encephalopathy prevalence and associated risk factors in the United States, 2010 to 2018. Am J Obstet Gynecol 2022; S0002-9378(22)004434.\u003c/li\u003e\n \u003cli\u003eAbate BB, Bimerew M, Gebremichael B, et al. Effects of therapeutic hypothermia on death among asphyxiated neonates with hypoxic-ischemic encephalopathy: A systematic review and meta-analysis of randomized control trials. Plos One. 2021;16(2):e0247229.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eHankins GD, Koen S, Gei AF, Lopez SM, Van Hook JW, Anderson GD. Neonatal organ system injury in acute birth asphyxia sufficient to result in neonatal encephalopathy. Obstet Gynecol. 2002 May;99(5 Pt 1):688-91.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003evan Wincoop M, de Bijl-Marcus K, Lilien M, van den Hoogen A, Groenendaal F. Effect of therapeutic hypothermia on renal and myocardial function in asphyxiated (near) term neonates: A systematic review and meta-analysis.. PLoS One. 2021 Feb 25;16(2):e0247403.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eRobinson CH et al. Long-Term Kidney Outcomes after Pediatric Acute Kidney Injury. J Am Soc Nephrol 2024 Nov 1;35(11):1520-1532.\u003c/li\u003e\n \u003cli\u003eKidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012; 2:1\u0026ndash;138.\u003c/li\u003e\n \u003cli\u003eStoops C, Stone S, Evans E, et al (2019) Baby NINJA (Nephrotoxic Injury Negated by Just-in-Time Action): Reduction in Nephrotoxic Medication-Associated Acute Kidney Injury in the Neonatal Intensive Care Unit. J Pediatr 215:223\u003c/li\u003e\n \u003cli\u003eThompson CM, Puterman AS, Linley LL, Hann FM, van der Elst CW, Molteno CD, Malan AF. The value of a scoring system for hypoxic ischaemic encephalopathy in predicting neurodevelopmental outcome. Acta Paediatr. 1997;86:757\u0026ndash;761\u003c/li\u003e\n \u003cli\u003eSelewski DT, Jordan BK, Askenazi DJ, Dechert RE, Sarkar S. Acute kidney injury in asphyxiated newborns treated with therapeutic hypothermia. J Pediatr 2013;162:725-729.e1\u003c/li\u003e\n \u003cli\u003eGupta C, Massaro AN, Ray PE. A new approach to define acute kidney injury in term newborns with hypoxic ischemic encephalopathy. Pediatr Nephrol 2016;31:1167-78.\u003c/li\u003e\n \u003cli\u003eNour I. Selective head cooling and acute kidney injury in neonates with hypoxic ischemic encephalopathy J Neonatal Perinatal Med. 2020;13(1):21-30.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eGallo D et al. Early Acute Kidney Injury in Preterm and Term Neonates: Incidence, Outcome, and Associated Clinical Features. Neonatology. 2021;118(2):174-179.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAWAKEN Acute Kidney Injury in Neonatal Encephalopathy: An Evaluation of the AWAKEN Database. Pediatr Nephrol. 2019 January ; 34(1): 169\u0026ndash;176. doi:10.1007/s00467-018-4068-2\u003c/li\u003e\n \u003cli\u003eChock VY, Frymoyer A, Yeh CG, Van Meurs KP. Renal Saturation and Acute Kidney Injury in Neonates with Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia. J Pediatr. 2018 Sep;200:232-239.e1.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDaSilva S. Clinical value of a single postnatal lactate measurement after intrapartum asphyxia. Acta Paeditr 2000; 89(03):320-323\u003c/li\u003e\n \u003cli\u003eShah S. Postnatal lactate as an early predictor of short-term outcome after intrapartum asphyxia. J Perinatol 2004 24(01): 16-20\u003c/li\u003e\n \u003cli\u003eBozkurt Y. Acute kidney injury in neonates with perinatal asphyxia receiving therapeutic hypothermia. Am J Perinatol 2019 DOI 10.1055/s-0039-1701024\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"acute kidney injury, AKI, newborn, perinatal asphyxia","lastPublishedDoi":"10.21203/rs.3.rs-6813243/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6813243/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eTo evaluate the incidence and potential predisposing factors for the development of acute kidney injury (AKI) in asphyxiated neonates undergoing hypothermic treatment.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective study was conducted at the Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy. All neonates above 34 weeks of gestation diagnosed with hypoxic-ischemic encephalopathy (HIE) and treated with hypothermia, weighing more than 1800 grams, admitted from January 1, 2013, to December 31, 2022, were included. AKI was defined according to the neonatal KDIGO classification.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 76 neonates were enrolled: 13 (17%) with severe HIE. The incidence of AKI was 36%, with 64% of cases identified as a reduction in diuresis, 25% as changes in creatinine and oliguria, and only 10% as isolated creatinine elevation. The rate of AKI was significantly higher in infants with severe HIE (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Infants who developed AKI required more inotropes, had higher rates of serum hyponatremia (\u0026lt;\u0026thinsp;125 mEq/L) and were less likely to normalize lactate levels within 24 hours of birth.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn asphyxiated newborns, reduced kidney perfusion can cause kidney impairment in nearly 40% of those undergoing treatment. Enhancing the detection of AKI is crucial for improving patient outcomes. We recommend proactive monitoring of lactate trends, urinary output, and serum sodium levels to enable early interventions that protect kidney function and improve outcomes for these vulnerable infants.\u003c/p\u003e","manuscriptTitle":"Incidence and risk factors associated with acute kidney injury in newborns affected by perinatal asphyxia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-09 11:25:06","doi":"10.21203/rs.3.rs-6813243/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revisions Needed","date":"2025-06-20T11:43:07+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-06-04T00:36:08+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-03T20:34:30+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-03T19:15:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Nephrology","date":"2025-06-03T12:18:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c95740b4-a659-4ec6-bdc0-a765a294412d","owner":[],"postedDate":"June 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-25T16:37:34+00:00","versionOfRecord":{"articleIdentity":"rs-6813243","link":"https://doi.org/10.1007/s00467-025-06926-8","journal":{"identity":"pediatric-nephrology","isVorOnly":false,"title":"Pediatric Nephrology"},"publishedOn":"2025-08-19 16:29:42","publishedOnDateReadable":"August 19th, 2025"},"versionCreatedAt":"2025-06-09 11:25:06","video":"","vorDoi":"10.1007/s00467-025-06926-8","vorDoiUrl":"https://doi.org/10.1007/s00467-025-06926-8","workflowStages":[]},"version":"v1","identity":"rs-6813243","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6813243","identity":"rs-6813243","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}