| Abstract|| |
Acute kidney injury (AKI) is a complex disorder with clinical manifestations ranging from mild dysfunction to complete kidney failure. The published literature on the incidence and outcome of AKI in the critically ill neonatal population is scarce. The aim of this study was to evaluate the types, the associated risk factors and short-term outcome of AKI in the critically ill neonates. A cohort study was conducted including 100 critically ill neonates successively admitted to the Neonatal Intensive Care Unit. The inclusion criteria were a gestational age ≥28 weeks and body weight ≥1 kg. Exclusion criteria included those with multiple congenital anomalies or on drugs altering glomerular filtration rate or AKI developing postoperatively. Neonates were evaluated for the development of AKI [creatinine >1.5 mg/dL and/or blood urea nitrogen (BUN) >20 mg/dL] and were assigned as group A (who developed AKI) and group B (who did not develop AKI). Forty-one patients developed AKI (group A) among whom nine (22%) showed oliguric AKI. The most common risk factors among group A patients were sepsis (75.6%) and nephrotoxic drug administration (75.6%), followed by shock (39%). There were no statistically significant differences between both groups except for male sex predominance and necrotizing enterocolitis (NEC), which were significantly higher among group A (P <0.05). Use of continuous positive airway pressure (CPAP) ventilation was significantly higher in neonates without AKI (13.6% vs 0.0%, P = 0.02). The mortality rate among group A reached 51.2%. Various risk factors including gender, gestational age, birth weight, shock, NEC, sepsis, nephrotoxic drugs, oliguria and mechanical ventilation were studied as regards outcome of group A, and all factors except gender and oliguria proved to be significantly higher in deceased neonates. Male sex and NEC were important risk factors for developing AKI that was predominantly non-oliguric. CPAP ventilation may have a protective effect against AKI. The mortality rate was more than three times higher in the AKI group.
|How to cite this article:|
El-Badawy AA, Makar S, Abdel-Razek ARA, Abd Elaziz D. Incidence and risk factors of acute kidney injury among the critically ill neonates. Saudi J Kidney Dis Transpl 2015;26:549-55
|How to cite this URL:|
El-Badawy AA, Makar S, Abdel-Razek ARA, Abd Elaziz D. Incidence and risk factors of acute kidney injury among the critically ill neonates. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2019 May 22];26:549-55. Available from: http://www.sjkdt.org/text.asp?2015/26/3/549/157362
| Introduction|| |
Acute kidney injury (AKI) is a complex disorder and has clinical manifestations ranging from mild dysfunction to complete anuric kidney failure. The lack of a universal definition for AKI, till recently, has rendered comparative studies limited and harder to achieve.  AKI in the newborn is a common problem in the neonatal intensive care unit (NICU) and ranges from 6% to 24%. , Many underlying factors may contribute to AKI development, such as asphyxia, respiratory distress syndrome and urogenital anomalies.  In a full-term neonate, the kidney functions are not fully mature and functional maturation continues in the postnatal age. Under normal circumstances, the kidneys adapt to various endogenous and exogenous stresses. However, in sick neonates and in stressful conditions like sepsis and shock, the adaptive capacities of the kidney may be overcome, leading to renal dysfunction.  Permanent renal damage may develop in survivors of AKI in up to 40% of the cases.  The aim of this study was to investigate the incidence of AKI among sick neonates in a single tertiary center and to evaluate the risk factors that could be correlated with developing AKI. We assumed that the risk factors may include sepsis, shock and congestive heart failure, premature rupture of membrane, necrotizing enterocolitis (NEC), nephrotoxic drugs and mechanical ventilation.
| Materials and Methods|| |
This was a cohort study of 100 critically ill neonates admitted to Children's Hospital NICU, Cairo University, who were enrolled successively from August 2009 to February 2010. The basic inclusion criteria were admitted newborns with gestational age >28 week and body weight >1 kg. Exclusion criteria included neonates with multiple congenital anomalies, neonates with post-operative AKI, neonates on drugs altering the glomerular filtration rate (GFR) (e.g., angiotensin-converting enzyme inhibitors or indomethacin) and neonates with a maternal history of kidney failure. The study protocol was approved by the Cairo University Children's Hospital Investigational Review Board and was conducted in accordance with the University bylaws for human research. Verbal consent was taken from all newborns' legal guardians before enrollment.
Enrolled neonates were 60 males (60%) and 40 females (40%) with a mean gestational age of 35.9 ± 2.9 weeks (range 28-38). Patients were assigned into two groups: Group A that included 41 critically ill neonates who developed AKI and group B that included 59 cases who did not develop AKI. AKI was defined as serum creatinine (Cr) >1.5 mg/dL ,,, and/or blood urea nitrogen (BUN) >20 mg/dL 4 on two separate occasions at least 12 h apart.
For all 100 neonates, a detailed perinatal history including maternal illnesses, such as hypertension, diabetes mellitus and drug administration, mode of delivery, Apgar score at 1 and 5 min of delivery, history of cyanosis or convulsions were collected. Physical examination was carried out upon entry into the study with a thorough clinical examination of all systems. We recorded the administration of known nephrotoxic drugs (vancomycin, amikacin and gentamycin) during hospital stay in addition to the mode of ventilation if any [nasal continuous positive airway pressure (CPAP), synchronized intermittent mandatory ventilation (SIMV)]. The patient who was on CPAP then SIMV or SIMV then CPAP was considered as being on SIMV in the results.
The risk factors studied for the occurrence of AKI included sepsis, shock, heart failure, NEC, nephrotoxic drug administration and mechanical ventilation.
From patients who developed AKI (group A), the following laboratory tests were performed on the day of admission, on peak of renal impairment and on discharge: Complete blood count, C-reactive protein (CRP), BUN, Cr, Na, K, Ca and PO 4 . For group B, the same investtigations were carried out initially and on discharge only.
Peak renal impairment was defined as the point with highest Cr and or necessitating dialysis. Oliguria was defined as urine output <1 mL/kg/hr.  Urine output was monitored all through the study, but values recorded in the results were those during the peak of renal impairment, while in case of initiation of dialysis, urine output recorded was that of the 24 h preceding dialysis. GFR was measured using the Scwartz formula: Estimated GFR = (k × height)/serum creatinine, where k is a constant that equals 0.33 and 0.45 in prematures and full terms, respectively, in their first year of life. , On discharge, GFR was plotted against normal values for age in term and preterm neonates to evaluate whether they were discharged with normal or impaired GFR. ,
Sepsis was diagnosed on the basis of either a positive sepsis screen or a positive blood culture in symptomatic neonates. The screen was considered positive if two or more of the following were present: Immature/total (I: T) neutrophil ratio >0.2 (immature neutrophils include band cells + myelocytes + metamyelocytes, which increase as the bone marrow pushes even the premature cells into circulation to fight infection), micro-ESR >age in days + 2 mm or >15 mm, CRP >6 mg/dL, total leucocyte count <5000 cells/mm 3 .  NEC was assessed according to the modified Bell's staging criteria into three stages. 
Primary outcome variables were survival or death. The main secondary outcome variable for survivors included discharge with normal or impaired GFR.
| Statistical Analysis|| |
Data management and analysis were performed using SigmaStat program; version 3.5 (Systat Software Inc. San Jose, CA, USA). The numerical data were statistically presented in terms of median and interquartile range (IQR). Categorical data were summarized as percentages. Comparisons between numerical variables of groups were carried out using the Mann-Whitney rank sum test. Comparing categorical variables was performed by the chi square  or Fisher exact test for small sample size. Z-test (at a confidence interval of 95%) was used for comparing single proportions. All P-values are two tailed and considered significant when <0.05.
| Results|| |
The 100 critically ill neonates enrolled were 60% male and 40% female, with a median gestational age of 38 weeks (IQR: 34-38). The demographic and baseline data of the studied cases are illustrated in [Table 1].
Of the 100 critically ill babies included in our study group, 41 developed AKI (group A) with BUN ranging from 4 to 254 mg/dL and Cr ranging from 0.1 to 14.6 mg/dL, while those who did not develop AKI constituted group B [Table 2]. In group A, neonates with low (normal) Cr had, on the other hand, serum BUN >20 mg/dL and suffered from pre-renal insults as shock and sepsis (their Cr: BUN >20). Of the 41 cases with AKI (group A), nine neonates (22%) were oliguric while the remaining 32 (78%) neonates were non-oliguric. No significant difference in median urine output was observed between group A (2 mL/kg/hr, ranging from 1.175 to 2.750 mL/kg/hr) and group B (2 mL/kg/hr, ranging from 1.725 to 2.600 mL//hr) (P = 0.2).
|Table 2: Comparison of the biochemistry profile between group A and group B.|
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Five patients (8.5%) of group B had elevated Cr on discharge (1.4 mg/dL in three cases and 1.5 mg/dL in two cases), but were not considered in the AKI group (Cr not >1.5 mg/dL and BUN not >20 mg/dL as previously defined as AKI). [Table 2] illustrates the differences in kidney functions and serum electrolytes between group A and group B.
A comparison of the risk factors between groups A and B is given in [Table 3]. The most common risk factors in group A were sepsis (75.6%) and nephrotoxic drug administration (75.6%), followed by shock (39%). However, there were no statistically significant differences between both groups except for male sex predominance and prevalence of NEC, which were significantly higher among group A (P <0.05). Presence of more than one risk factor was evident in all neonates of group A. It was observed that use of CPAP ventilation was significantly higher in neonates of group B (13.6% vs 0.0%, P = 0.02).
Among neonates who developed AKI, 21 (six girls and 15 boys; 51.2%) died during their hospital stay in the NICU, ten (24.4%) were discharged with normal kidney function and ten (24.4%) were discharged with impaired kidney function. A comparison of the outcome between groups A and B is summarized in [Table 4].
|Table 4: Comparison of outcome of critically ill neonates with and without AKI.|
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Various factors were studied in group A as regards the outcome (whether survival or death). Several factors were proved to be significantly higher in the deceased group while gender and oliguria did not affect the mortality. Sepsis was significantly more frequent in the patients who died than in those who survived (P = 0.03). Also, of 23 patients who needed mechanical ventilation, 18 died (44%). This rate was significantly higher than in those who did not need mechanical ventilation ( P ≤0.001) [Table 5].
|Table 5: Comparison of different risk factors between survivals and deaths in group A (n = 41).|
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| Discussion|| |
Many physiologic factors render the kidneys of neonates particularly susceptible to hypoperfusion, including low GFR, decreased intercortical perfusion, high renin activity and high renal vascular resistance. Sodium handling also is impaired with decreased Na re-absorption in the proximal tubules.  Thus, newborn infants are more susceptible to acute tubular necrosis or cortical necrosis.  Critically ill neonates are at a greater risk of having AKI as they are commonly exposed to nephrotoxic medications and have frequent infections that lead to multi-organ failure.  The present study has analyzed AKI in the critically ill newborn. It gives insight into the incidence, short-term outcome and the independent impact of AKI on outcome in the critically ill neonates.
The exact incidence of neonatal AKI is unknown. Although published studies estimate that the incidence of AKI in critically ill neonates is lower than that in our study (between 8% and 24%),  higher rates were reported in asphyxiated neonates with low Apgar scores ≤6 at 5 min (47-56% vs 4% in controls). ,
It is worth noticing that AKI was mainly non-oliguric in the current study (oliguria was found only in 22%) and no significant difference in median urine output was observed in newborns with and without AKI. Other previous studies reported the presence of nonoliguric AKI to be over 50%, ,, while Mathur and colleagues reported up to 85% of AKI patients to be non-oliguric.  Non-oliguria as well was not correlated with outcome (mortality or survival) in our study. This confirms the non-innocent nature of AKI in sick neonates where a high index of anticipation should be raised in spite of good urine output, especially in the presence of other risk factors.  Different studies reported a higher incidence of non-oliguric AKI in asphyxiated neonates and recommended to monitor serum Cr daily and not to be satisfied with adequate urine output in asphyxiated neonates.  Nonoliguric AKI, in part, could be attributed to the associated tubular injury accompanying AKI in vulnerable neonatal kidneys,  which also may explain the discrepancy in the rise of creatinine and BUN without a concomitant rise of K and phosphorus.
Among 41 newborns of group A, almost half of them died. Survivors were equally divided between complete recovery and persistently impaired GFR on discharge. Different studies report poor survival in neonatal AKI. Agras et al reported a 25% hospital mortality rate for neonates with AKI,  while Gupta et al reported a 14.1% mortality in infants with Apgar scores ≤6. 
This work aimed at studying the underlying risk factors in neonatal AKI. The development of AKI among the critically ill neonates seems multi-factorial as the same risk factors in the same setting may affect newborns differently. Investigators suggested that the presence of underlying genetic risk factor(s) promoting the development of AKI including the combination of polymorphisms of tumor necrosis factor-alfa, interleukin (IL) 1b, IL6 and IL10 genes that might lead to a greater inflammatory response and the development of AKI in some neonates with infection. 
In our study, we observed a significant male sex predominance as a risk factor among cases that developed AKI; the male-female ratio was (1.5:1). This was in line with the results of Mortazavi and colleagues,  who reported the male-female ratio to be 2:1 in neonates with AKI. The high frequency of AKI in boys may be due to the higher susceptibility of boys to some perinatal disorders like sepsis and respiratory distress syndrome. 
The occurrence of NEC and mode of ventilation were other significant risk factors of AKI among our cases, while gestational age, birth weight, sepsis, nephrotoxic drugs, congestive heart failure, premature rupture of membranes (PROM) and perinatal asphyxia were not significant risk factors of AKI in the critically ill neonates. This was in line with Mathur and colleagues,  who reported similar results among septic cases who developed AKI. Although not statically significant, sepsis was the most common risk factor (75.6%) followed by nephrotoxic drug administration (75.6%) and shock (39%). Similar results were reported by Pereira et al  and Mortazavi et al. 
In addition, there was a non-significant difference between AKI and non-AKI neonates as regards prevalence of mechanical ventilation in our study, which is not consistent with previous studies. ,, Nevertheless, it was observed that use of CPAP ventilation was significantly higher in neonates without AKI (13.6% vs. 0.0%, P = 0.02), raising the possibility of being a protective factor against AKI in the critically ill babies. However, a recent study reported a higher prevalence of CPAP among cases with AKI. 
Our study has some limitations, including it being a single-center study and lacking a reliable consistent definition of AKI in the neonatal population. A larger population is needed to properly estimate the prognostic predictors. Another limiting factor is lacking follow-up data of patients who were discharged and hence data about the long-term outcome is lacking.
| Conclusion|| |
Male sex and NEC were important risk factors for developing AKI among our critically ill babies. CPAP may have a protective effect against AKI. AKI was predominantly nonoliguric. The mortality rate was more than three times higher in neonates with AKI, which demands a greater awareness of this entity among practitioners and better management of this condition. Low gestational age, low birth weight, low weight at presentation, shock, sepsis, nephrotoxic drugs and mechanical ventilation were proved to be significant risk factors in deceased neonates. Large multicenter prospective studies are needed to have clear definitions and to better understand the risk factors, incidence, independent outcomes and mechanisms that lead to poor shortand long-term outcomes.
Conflict of Interest: None
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Dr. Samuel Makar
Department of Pediatrics, New Children's Hospital, Cairo University, Cairo
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]