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Brief Reports Indian Pediatrics 2000;37: 1102-1106 |
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Renal Insult in Asphyxia Neonatorum |
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Perinatal asphyxia can result in multisystem organ damage in a neonate. Circulatory response to asphyxia results in redistribution of blood flow towards the brain, heart and adrenals, and away from kidney, skin and the gastrointestinal tract. Hypo-perfusion with concommitant hypercapnia and acidosis contribute to organ damage, the extent of which is determined by the duration and severity of the insult. Perinatal asphyxia is the most common cause of neonatal renal failture(1). Renal functions should be carefully monitored in neonates with birth asphyxia(1-4). There are few published studies on renal functions in asphyxiated neonates from India. We have examined the incidence of renal failure in children asphyxiated at birth. Renal functional indices and urinary b2 microglobulin were also measured.
Term neonates born in King Edward Memorial hospital, Bombay, between March and December 1994 were studied. Criteria for inclusion were: (a) Apgar scores at 5 minutes of 5 or less in non-intubated babies, and 6 or less in intubated babies, (b) umbilical cord arterial pH less than 7.2 and/or pCO2 more than 50 mm of Hg, and (c) evidence of neurological abnormalities suggestive of hypoxic ischemic encephalopathy. Fifty neo-nates fulfilled the inclusion criteria (mean birth weight ± 2SD = 2.46 ± 1.23 kg, gestational age 38.4 ± 2.6 weeks). Nineteen normal term neo-nates who did not have meconium staining of liquor or other complications at birth were controls for urinary b2 microglobulin (mean birth weight 2.86 ± 0.63 kg and gestational age 38.1 ± 2.4 weeks). Neonates on treatment with aminoglycoside antibiotics were excluded. The study was approved by the Ethics Committee of the hospital and consent obtained from the parents before inclusion. The causes of birth asphyxia were antepartum hemorrhage, cord prolapse, eclampsia and meconium aspiration syndrome. Gestational age was determined by dates, ultrasound and Dubowitz criteria(5). Urinary output of all babies was monitored for 36 h if normal and till normalization if abnormal. Blood levels of urea nitrogen, creatinine and electrolytes were measured within the first 2 h of life, 12 h for the first 24 h and if abnormal continued every 12 h till normal. If these investigations were normal in the first 24 h, 2 more measurements were made every 24 h. Urine was collected by attaching test-tubes in boys and plastic diapers in girls. Urine was examined for pH, albumin and sugar, and microscopically for cells and casts. Urinary b2 microglobulin was estimated in the first urinary sample. Azotemia was defined as blood urea nitrogen greater than 20 mg/dl on at least 2 blood samples. Oliguria was defined as urinary output less than 1 ml/kg/h for 24 h or more. Serum creatinine was not used in the categorization since its levels in the first few days of life depend on maternal serum creatinine. Oliguric neonates were treated with 20 ml/kg of Ringers lactate solution followed by 2 mg/kg of frusemide. If there was an increase in urinary output to more than 1 ml/kg/h, the cause of oliguria was considered to be pre-renal. Otherwise intrinsic renal cause was presumed, and patients managed with fluid restriction to 400 ml/m2 of body surface area and, if indicated, peritoneal dialysis. Blood urea nitrogen was estimated by an enzymatic method using glutamate dehydro-genase and absorbance measured at 340 mm. Serum and urine creatinine were estimated by Jaffe’s method, electrolytes by flame photometry, urinary pH by dipstix paper, albumin by sulpho-salicylic acid method and sugar by Benedict’s method. Urinary b2 microglobulin was estimated by competitive radio-immunoassay using the IKBM1 kit (Diagnostic Products, Los Angeles, CA). Urinary samples were stored at –60°C after collection; samples with pH less than 6.5 were discarded(6). The mean values of urniary b2 micro-globulin, fractional excretion of sodium (FENa), renal failure index (RGI) and urine/plasma ratio of creatinine were calculated using standard formulae(17). Kruskal-Wallis test was used to compare means among various groups of patients (8,9). The levels of b2 microglobulin were normally distributed in controls, with mean level of 1186.32 ng/ml (95% confidence limit 1023.05 - 1349.58 ng/ml). Co-efficient of variation in normal b2 microglobulin values was 28.6%.
Thirty six of 50 neonates with asphyxia had either oliguric or non-oliguric renal failure (Fig. 1). The overall mortality was 36.1% (13/36); mortality in the oliguric group was 31.8% (7/22) and in the non-oliguric group 42.8% (6/14). All 4 oliguric neonates who did not respond to Ringer lactate solution and frusemide survived. Three out of 14 neonates (21.4%) with no features of renal failure died.
Two neonates required peritoneal dialysis, one neonate each was from the oliguric and non-oliguric groups; both died subsequently. Six neonates required ventilatory support, of which 4 were oliguric and 2 had non-oliguric renal failure. Two oliguric neonates required inotropic support, of which one survived. Liver dysfunction in the form of elevated alanine transaminase, aspartate transaminase or hyperbilirubinemia was seen in 27 of the 50 neonates. Of these 15 had oliguric renal failure, 5 had non-oliguric renal failure and 7 had normal renal function. Table I shows the biochemical parameters in neonates with asphyxia. FENa and RFI were variable with no difference between the subgroups of asphyxiated neonates. Table I - Renal Parameters in Asphyxiated Neonates
Urine samples from 19 neonates could not be tested for b2 microglobulin as their urinary pH was <6.5 or the urine was exposed to room temperature for a long time. Mean (SD) urinary b2 microglobulin in 19 normal neonates was 1186.32 ng/ml (338.65) and in 31 asphyxiated neonates 1733.81 ng/ml (306.13); these differences were statistically significant (p >0.001).
Perinatal asphyxia is an important cause of neonatal renal failure. Monitoring of urinary output, urinalysis, and blood levels of urea nitrogen and creatinine helps in the diagnosis and management of renal failure. The higher mortality in non-oliguric neonates with renal failure is difficult to explain and is in constrast to previous studies(2,3). The fact that 18 of 22 oliguric neonates responded to a fluid challenge shows the predominance of pre-renal factors in the causation of oliguria, which compares well with previous studies(4). We could not derive any cut-off values for FENa and RFI to distinugish between pre-renal and intrinsic renal causes for renal failure. Proteinuria in tubular disease consists predominantly of proteins of low molecular weight(6,10). These proteins include b2 micro- globulin, retinol binding protein, lysozyme and immunoglobulin light chains that are freely filtered by the glomerulus and absorbed by the epithelial cells of the proximal convoluted tubule where they are degraded. In a normal kidney their absorption is nearly complete so only trace amounts of these proteins are excreted. When promixal tubular epithelium is damaged these proteins can be detected in the urine(11). Urinary excretion of b2 micro-globulin and retinol binding protein is highly specific for tubular disease whereas increased excretion of a1 microglobulin may also be seen in glomerular proteinuria. Renal tubular damage can be very sensitively detected by urinary estimation of b2 microglobulin, retinol binding protein and myoglobin excretion. Measuring urinary b2 microglobulin to study renal tubular damage is useful because (a) its excretion is affected by gestational age as low values are found even in preterm infants, (b) excretion is unaffected by urine flow rate, and (c) excretion is not a consequence of increased production as urinary and serum values do not correlate(12). We found statistically significant elevation of b2 microglobulin in the urine of asphyxiated neonates compared to controls. However, there were no statistically significant differences among the subgroups of asphyxiated neonates. Very high concentrations of urinary b2 microglobulin reported earlier(12) were not found in this study. We conclude that renal failure is common in neonates with birth asphyxia. The renal failure in most cases is pre-renal and responds to fluid administration. Urinary b2 microglobu-lin was increased in all asphyxiated neonates when compared to normal neonates. FENa, FRI and urine plasma ratio of creatinine were very variable and not useful in distinguishing between renal and pre-renal causes. Contributors: PVM designed the study, collected and analyzed the data and drafted the paper. PMP guided the design and co-ordinated the study. Funding:
The Diamond Jubilee Trust supported the cost of the kit for urinary b2
microglobulin.
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