|Year : 2014 | Volume
| Issue : 2 | Page : 316-321
α2 -Microglobulin predicts renal injury in asphyxiated neonates
Fady Mohamed El-Gendy, Khalid Abd El-mo'men, Hassan Said Badr, Amira El-Sayed Mohammed
Department of Pediatrics, Faculty of Medicine, Menoufia University, Menoufia, Egypt
|Date of Submission||17-May-2013|
|Date of Acceptance||12-Sep-2013|
|Date of Web Publication||26-Sep-2014|
Amira El-Sayed Mohammed
MBBCh, Department of Pediatrics, Faculty of Medicine, Menoufia University, Menoufia
Source of Support: None, Conflict of Interest: None
The aim of the study was to predict early renal injury in asphyxiated neonates by measuring urinary level of b2 -microglobulin (b2 MG).
b2 MG has a molecular weight of 12 000 and it belongs to the light chain part of membrane-bound HLA antigens. It consists of two polypeptide chains, a heavy chain with antigenic structure and a light chain. Urinary b2 MG, specific urinary marker of renal tubular damage, can identify renal damage from asphyxia within 48 h of the insult.
This study included 50 asphyxiated newborns along with 35 weight-matched and gestational age-matched normal neonates as controls. First, voided urinary samples were collected within the first day of life and values of urinary b2 MG was determined by immunometric enzyme immunoassay.
In this study, we found that acute kidney injury occurred in 56% of asphyxiated neonates. The remaining 44% patients had subclinical tubular proteinuria. Urea and creatinine levels among patients were significantly higher on day 4 than on day 1. We found that, at the optimum cutoff level of 11.9 mg/ml of urinary b2 MG, the sensitivity, specificity, and accuracy of predicting renal injury in asphyxiated neonates were found to be 86, 68, and 74%, respectively.
Incidence of acute kidney injury in asphyxiated neonates was 56%. b2 MG is a sensitive and accurate marker of renal insult among these patients. Studies on other biomarkers such as NGAL, KIM-1, and cystatin C may be performed to evaluate their role in predicting renal injury.
Keywords: Asphyxia, b2 -microglobulin, renal injury
|How to cite this article:|
El-Gendy FM, El-mo'men KA, Badr HS, Mohammed AE. α2 -Microglobulin predicts renal injury in asphyxiated neonates. Menoufia Med J 2014;27:316-21
|How to cite this URL:|
El-Gendy FM, El-mo'men KA, Badr HS, Mohammed AE. α2 -Microglobulin predicts renal injury in asphyxiated neonates. Menoufia Med J [serial online] 2014 [cited 2020 Mar 30];27:316-21. Available from: http://www.mmj.eg.net/text.asp?2014/27/2/316/141689
| Introduction|| |
Perinatal asphyxia is an insult to the fetus or the newborn due to lack of oxygen (hypoxia) and/or lack of perfusion (ischemia) to various organs of sufficient magnitude and duration to produce more than fleeting functional and/or biochemical changes . It is estimated that around 23% of all newborn deaths are caused by birth asphyxia, with a large proportion of stillbirths . Asphyxia can occur before, during, or after birth because of various causes - for example, maternal placental abruption, umbilical cord prolapse, anemia, or shock to the newborn. Perinatal asphyxia can result in multisystem organ damage in a neonate, such as kidneys (50%), central nervous system (28%), cardiovascular system (25%), and lungs (23%). Kidneys are very sensitive to oxygen deprivation and irreversible cortical necrosis may occur due to prolonged renal insufficiency of hypoxic-ischemic episode. Perinatal asphyxia contributes to most of the neonatal renal failure. It may cause alterations in urinary protein excretion . Acute kidney injury (AKI) is a complex disorder that occurs with variable severity and in many clinical scenarios. Lack of universally recognized definition of AKI limited our ability to compare studies, predict clinical courses, and improve outcomes . The diagnosis of AKI is problematic, as current diagnoses rely on two functional abnormalities: functional changes in serum creatinine (Scr) [marker of glomerular filtration rate (GFR)] and oliguria. Both these are late consequences of injury and not markers of the injury itself . Early recognition of renal failure and the implementation of therapies aim at preventing or treating predictable complications . Biomarkers are currently being explored to differentiate between different causes of established AKI, to detect early AKI, and to prognosticate outcomes. Urinary b2 -microglobulin (b2 MG), specific urinary marker of renal tubular damage, can identify renal damage from asphyxia within 48 h of the insult . b2 MG is a low-molecular-weight protein normally filtered readily at the glomerulus and is totally reabsorbed and degraded by proximal tubular cells of the kidney; hence, elevation of urinary b2 MG is a sensitive and reliable early marker of tubular dysfunction .
| Methods|| |
This study was performed during the period from January 2012 to April 2013. Patients involved in the study were admitted to NICU in Ashmoun General Hospital. This study included 50 asphyxiated full-term neonates, with appropriate weight for gestational age, along with 35 normal full-term, gestational age-matched and weight-matched neonates with no asphyxia as controls. All cases and controls were subjected to the following: full detailed history taking, thorough clinical examination and assessment of Apgar score at 1 and 5 min, resuscitation in the delivery room, and investigations. Umbilical or arterial blood samples from cases and controls were obtained at the time of birth for arterial blood gas; venous blood samples were drawn within 6-12 h after delivery from cases and controls for complete blood count, C-reactive protein, urea, and creatinine. Other venous blood samples were taken from asphyxiated neonates on day 4 for remeasurement of urea and creatinine, in case of high urea or creatinine levels; they were measured daily until normalization or until discharge. Patients with high levels at discharge were followed up in outpatient clinic within 2 weeks; urine was collected from cases and controls by sterile urine-collecting bag attached to external genitalia to obtain the first voided urine sample. Urine was collected as soon as possible after voiding and was divided into two parts, one part for urine analysis and the other part was stored at -20°C until analyzed for b2 MG by immunometric enzyme immunoassay.
| Results|| |
In this study, we found that AKI (Scr > 1.5 mg/dl) occurred in 28 of the asphyxiated neonates (56%). The remaining 44% had subclinical tubular injury (diagnosed by increased urinary b2 MG level). Urea and creatinine levels were significantly higher on day 4 than on day 1 among the patients. We found that excretion of b2 MG in the first voided sample was significantly higher among patients (P < 0.001); there was significant negative correlation between its level and Apgar score at 1 min (P < 0.001). Two neonates with AKI died (4%) during the course of the study compared with no infants without AKI; one neonate was transferred for need of dialysis. Follow-up of the 25 patients with AKI who stayed until discharge showed that, when comparing their urea and creatinine levels at discharge with that on day 1, there was nonsignificant difference between them (P > 0.05), as urea and creatinine levels in most patients return to normal (between 14 and 21 days). Five patients with high urea and/or creatinine levels at discharge were followed up in outpatient clinic within 2 weeks after discharge, and there was nonsignificant difference in their urea and creatinine levels from those on day 1 (P > 0.05), at the optimum cutoff level of 11.9 mg/ml of b2 MG. The sensitivity, specificity, and accuracy of predicting renal injury in asphyxiated neonates were found to be 86, 68, and 74%, respectively; 21 patients (42%) had asphyxial encephalopathy grade I, three of them with AKI (6%) and 18 with no AKI (36%). Fifteen patients had asphyxial encephalopathy grade II (30%); all of them had AKI. Six patients had asphyxial encephalopathy grade III (12%); all of them also had AKI. A further five patients (10%) had transient cerebral irritability and feeding problems; only one of these infants developed AKI [Figure 1],[Figure 2] and [Figure 3] and [Table 1],[Table 2],[Table 3] and [Table 4].
|Table 1: Urea and creatinine levels on day 1, on day 4, at discharge, and postdischarge in group I|
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|Table 2: Comparison between the studied groups regarding their urinary α2MG of the first voided sample|
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|Table 3: Sensitivity and specificity of urine β2MG regarding acute renal failure|
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|Table 4: Comparison between the two subgroups of cases regarding Apgar at 1 and 5 min, pH at the time of birth, urea and creatinine levels on day 4, and β2MG in the first voided urinary sample|
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| Discussion|| |
The results of the study showed that 50 patients were suffering from hypoxic-ischemic encephalopathy; there were 36 male patients and 14 female patients, with gestational age of 38.8 ± 1.3 weeks, ranging between 37 and 41 weeks. In all, 33 neonates were delivered by normal vaginal delivery and 17 by cesarean section, with birth weight of 3.5 ± 0.9 kg, ranging between 2.5 and 4 kg. However, there were 35 control neonates, 23 male neonates, and 12 female neonates, with gestational age of 38.6 ± 1.3 weeks; 20 neonates were delivered by normal vaginal delivery and 15 by cesarean section, with birth weight of 3.6 ± 0.6 kg, ranging between 2.6 and 4.1 kg.
When we compared the demographic data of patients and controls, we found that there was no significant difference between the studied groups regarding gestational age, sex, birth weights, or modes of delivery (P > 0.05).
Several previous studies have shown that urinary concentrations of some biomarkers are dependent on gestational age in infants without AKI; this might be secondary to the inability of immature tubules to reabsorb these proteins in underdeveloped kidney. Controlling for this important confounder is necessary to insure that the association between urine biomarkers and AKI is not simply a reflection of tubular maturation ,,.
Hence, we chose full-term neonates of at least 37 weeks (mean 38.8 ± 1.3 and 38.6 ± 1.3 for cases and controls, respectively) to exclude that elevation of biomarkers is not due to tubular immaturity.
However, Aggarwal et al.  and Askenazi et al.  made a regression analysis on the studied neonates and examined asphyxiated neonates of at least 34 weeks, depending on the fact that nephrogenesis is completed at 34 weeks .
Results of complete blood count (regarding Hb%, platelets, and white blood cell counts) and urine analysis (regarding red blood cells and pus cells in the first urine sample) were not significantly different between cases and controls (P > 0.05). We did not find hematuria in asphyxiated neonates in contrast to results of Rashid et al.  and Robson  who reported hematuria in 11% of asphyxiated neonates.
Blood urea and Scr levels had been elevated significantly in asphyxiated patients on day 4 when compared with results on day 1 (21.8 ± 4.9 and 0.82 ± 0.2 mg/dl for urea and creatinine, respectively, on day 1 and 35.2 ± 14.7 and 1.42 ± 0.6 mg/dl for urea and creatinine, respectively, on day 4) (P < 0.001). This is in agreement with the studies by Aggarwal et al. , Ashraf et al. , and Mohan and Pai .
It is explained by Askenazi et al.  who reported that Scr may not change until 25-50% of kidney function has already been lost. Vladislav et al.  as well as Voskaridou et al.  reported that Scr did not rise until about 50% of renal functions had been lost, as Scr is insensitive for detection of small decrease in GFR because of the nonlinear relationship between its plasma concentration and GFR .
We depend in this study on the definition of AKI as increased Scr greater than 1.5 mg/dl ; it occurred in 28 of the 50 asphyxiated neonates (56%). Two newborns with AKI died (mortality rate 4%) compared with none of those without AKI.
At discharge, there were five patients who still had Scr greater than 1.5 mg/dl (20%).
Follow-up of these five patients in outpatient clinic shows that only one patient (20%) still had high creatinine (>1.5 mg/dl).
This is in agreement with the study by Aggarwal et al.  who showed in a case-control analysis (matching for gestational age and birth weight in otherwise healthy newborns) that the incidence of AKI in infants with 5-min Apgar scores of 6 or less was 56 versus 4% in controls. They noted that clinical markers of asphyxia were better predictors of adverse outcomes than were renal function tests.
Similarly, Gupta et al.  found a 47% incidence of AKI and 14.1% mortality in infants with Apgar scores of 6 or less.
Askenazi et al.  defined AKI as a rise in Scr of at least 0.3 mg/dl or a Scr elevation of at least 1.7 mg/dl persisting for 3 days, and they reported mortality in two (22%) of the nine infants studied with AKI compared with no infants without AKI.
Agras et al.  explored AKI (Scr > 1.5 mg/dl) in the general critically ill neonatal population and found that the incidence of AKI was 47% and the mortality rate was 25%.
Rashid et al.  also reported 40% AKI incidence among asphyxiated patients and 7.33% mortality rate.
Higher incidence was found by Ganavi , 75.0 versus 4.0% in nonasphyxiated controls, and Hankins et al.  also reported 72% incidence of AKI where only babies with asphyxia severe enough to cause encephalopathy were included.
Kaur et al.  found that AKI developed in 9.1% infants with moderate asphyxia and in 56% infants with severe asphyxia, making a total incidence of 41.7%.
Karlowicz and Adelman  compared term infants with severe asphyxia with similar infants with moderate asphyxia scores. They found that AKI (Scr > 1.5 mg/dl) occurred in 61% of infants with severe asphyxia compared with 0% in those with moderate asphyxia. All these studies report over 50% of AKI cases to be nonoliguric, which highlights the insensitivity of oliguria to predict AKI in neonates.
Mohan and Pai  also defined azotemia as blood urea nitrogen level greater than 20 mg/dl in at least two blood samples; they found that the incidence of AKI in asphyxiated newborns was 72%, and the overall mortality rate was 36.1%.
Indeed, AKI varies with definition interpretation . Scr-based definitions have significant shortcomings when defining AKI, mainly because Scr provides an estimate of function, not injury. Thus, the current Scr-based definitions of AKI is likely not 100% accurate in detecting AKI .
Therefore, excretion of many low-molecular-weight proteins such as b2 MG, myoglobin, retinol binding protein, and N-acetyl-b-glucosaminidase has been used to detect renal tubular dysfunction .
When comparing urinary b2 MG in the first voided sample between patients and controls, we found highly significant increase in its excretion in cases compared with controls (12.5 ± 2.9 mg/ml for cases and 0.2 ± 0.4 mg/ml for controls) (P < 0.001).
This is in agreement with the studies by Aggarwal et al. , Askenazi et al. , and Mohan and Pai .
Banupriya et al.  reported a significantly higher (P < 0.01) urinary protein excretion rate as assessed from urinary protein-creatinine ratio in perinatal asphyxia cases compared with controls.
Among the patients, there were 28 patients who had AKI (Scr > 1.5 mg/dl) (group Ia), and they had increased level of excreted urinary b2 MG (12.9 ± 3.1 mg/ml); the remaining 22 patients had no AKI (normal urea and creatinine levels) (group IIb), but they also showed increased level of urinary b2 MG (11.9 ± 2.6 mg/ml). This suggests that subclinical tubular damage was present in those neonates, and this is important to be diagnosed to administer the appropriate fluid and electrolyte replacement. Apgar scores at 1 and 5 min and pH at the time of birth were significantly lower in group Ia than in group Ib (P < 0.001). Blood urea and Scr at day 4 were significantly higher in group Ia than in group Ib (P < 0.001).
This is in agreement with the study by Robert et al. , who reported subclinical proximal tubular injury in asphyxiated neonates by increased excretion of urinary b2 MG.
There was highly significant negative correlation between level of b2 MG and Apgar score at 1 min (P < 0.001).
This is in agreement with the studies by Banupriya et al.  and Banerjee et al. .
The renal damage in perinatal asphyxia, which is very common, might be a cause of loss of selectivity of protein excretion by the kidney; impairment of tubular reabsorption due to ischemic damage might also contribute to the appearance of proteins in urine ,.
The optimum cutoff level of b2 MG was 11.9 mg/ml. Forty-two patients were above this level and eight patients were below it. None of controls were above this level. At this cutoff level, the sensitivity, specificity, and accuracy of predicting renal injury in asphyxiated neonates were found to be 86, 68, and 74%, respectively.
When comparing levels of urea for patients with AKI at discharge (23.4 ± 8.1 mg/dl) and after discharge (27.0 ± 5.7 mg/dl) with those at day 1 (21.8 ± 4.9 mg/dl), there was no significant difference (P > 0.05).
In addition, when comparing levels of creatinine for these patients at discharge (0.99 ± 0.4 mg/dl) and after discharge (1.12 ± 0.3 mg/dl) with those at day 1 (0.82 ± 0.2 mg/dl), there was nonsignificant difference (P > 0.05).
This is in agreement with the study by Bhat et al. , who showed a favorable outcome in patients with AKI with resolution of tubular abnormalities and normal Scr level within 6 weeks, and with the study by Rashid et al.  who said that renal parameters normalize in all neonates by 2 months of age.
In contrast, Stapleton et al.  suggested residual renal dysfunction in at least 40% of neonates with acute renal failure.
In addition, Askenazi et al.  reported that over 50% of children have at least one sign of chronic kidney disease 3-5 years after the initial event.
In this study, 42 patients (84%) had asphyxial encephalopathy with various degrees; 24 (48%) of them had AKI and 18 (36%) had no AKI. A further five patients (10%) had transient cerebral irritability and feeding problems; only one of these infants developed AKI.
A lower incidence was reported by Shah and Singh  who reported that 30% of newborns with birth asphyxia presented with various stages of hypoxic-ischemic encephalopathy, and the incidence was higher in the low Apgar score group, and Nilufar et al.  also observed neurological sequelae in 28% of asphyxiated babies.
| Conclusion|| |
- Incidence of AKI in asphyxiated neonates was 56%.
- α2 MG is a sensitive and accurate marker of renal insult among those patients.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]