Serum creatinine in very low birth weight infants during their first days of life

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1 ORIGINAL ARTICLE Serum creatinine in very low birth weight infants during their first days of life (2006) 26, r 2006 Nature Publishing Group All rights reserved /06 $30 Department of Pediatrics, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA Objectives: Little is known about the relationship between gestational age (GA) or birth weight (BW) and serum creatinine (SCr) in very low birth weight (VLBW) infants. We sought to study postnatal SCr changes and determine if there is a correlation between GA or BW and SCr in VLBW infants, during their first days of life. Study Design: Medical records of all VLBW infants, who were admitted to our neonatal intensive care unit (NICU) between 1 May 1998 and 1 May 2001, were reviewed. Medical records were reviewed for: BW, GA, gender, race, APGAR scores, mechanical ventilation, use of medications, fluid intake, urinary output, protein intake, blood urea nitrogen (BUN) and SCr during the first days of life. Patients with anuria/oliguria, major congenital anomalies, low APGAR scores at 5 min, on high ventilator settings (on the oscillator), hemodynamically unstable (on pressors, inotropes) and on indomethacin and diuretics were excluded. Results: In total, 138 infants met our inclusion criteria. SCr was found to decrease postnatally, reaching a plateau on day 5 of life in all VLBW infants (repeated measure analysis of variance; P ¼ 0.004); however, there was a delay in the decrease of SCr in the subgroup of infants <29 weeks GA, and <1000 g BW. SCr (on day 5 of life) was also found to decrease with increasing GA and BW (Pearson correlation coefficient: (P ¼ 0.05) and (P ¼ 0.05) respectively). Conclusion: In VLBW infants SCr decreases significantly during the first days of life; however, in infants younger than 29 weeks GA or smaller than 1000 g BW there is a delay in the decrease of their SCr that extends beyond the first days of life. We also conclude that during the first days of life, and in VLBW infants SCr decreases with advancing GA and BW. (2006) 26, doi: /sj.jp ; published online 12 October 2006 Keywords: gestational age; very low birth weight; serum creatinine; postnatal age; infants; neonatal intensive care unit Correspondence: Dr MJ Mhanna, Department of Pediatrics, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109, USA mmhanna@metrohealth.org Financial supported: none. Received 4 May 2006; revised 14 August 2006; accepted 5 September 2006; published online 12 October 2006 Introduction Renal function is immature in very low birth weight (VLBW) and premature infants as compared to adults, 1 and serum creatinine (SCr) in newborn infants is elevated during the first week of life. 2 4 While in the immediate postnatal period the newborn SCr likely reflect maternal values, 2,4 further increase in the levels of SCr in premature infants have been attributed to increased tubular reabsorption of creatinine due to renal tubular immaturity and also to reduced creatinine clearance. 2,3 It has also been shown by several investigators that creatinine clearance and glomerular filtration rate (GFR) increase with postnatal age in premature infants, 5 8 and in the absence of urine creatinine measurements, SCr can be used to estimate GFR However, little is known about the relationship between gestational age/birth weight (GA/BW) and SCr in VLBW infants at birth following stabilization of their SCr. This study was conducted to determine postnatal SCr changes in VLBW infants and to determine if there is a correlation between GA or BW and SCr in VLBW infants, during their first days of life. Patients and methods Patients Medical records of all VLBW infants (p1500 g at birth) admitted to our neonatal intensive care unit (NICU) between 1 May 1998 and 1 May 2001 were identified by searching our electronic data base program. Medical records were reviewed for: GA, BW, length at birth, gender and race. Medical records were also reviewed for APGAR scores at 5 and 10 min of age, mechanical ventilation, continuous positive airway pressure (CPAP), daily fluid intake, urinary output, protein intake, blood urea nitrogen (BUN) and SCr during the first 6 days of life. Patients who were on the oscillator, and who received dopamine, dobutamine, indomethacin, gentamicin, xanthines (aminophylline, caffeine) and diuretics were also identified. Morning laboratory values were analyzed and hemolyzed samples were excluded. Hemolyzed samples were identified by the laboratory technicians. Morning laboratory values were collected

2 SCr in VLBW infants 756 during the first week of life between day 2 and 6. Day 2 of life was considered the first morning after the first 24 h of life. Our inclusion criteria consisted of all VLBW infants who were admitted to our NICU during the study period. Our exclusion criteria consisted of all patients with anuria/ oliguria, patients on indomethacin, amphotericin and diuretics, patients on high ventilator settings (on the oscillator), patients hemodynamically unstable on pressors and or inotropes (epinephrine, dobutamine and dopamine) and patients with major congenital anomalies. Patients with a low 5 min APGAR score (<5) were also excluded. Anuria was defined as a 24 h urinary output average of <1 ml/ kg/h during the first 6 days of life. SCr was determined by the Jaffe method, using the SYNCHRON LX 20 system. 13 The study was approved by our Institutional Review Board at MetroHealth Medical Center. Statistical analysis A repeated measure analysis of variance (ANOVA) was used to determine the difference of SCr, BUN, intravenous fluid intake and urinary output of all VLBW infants over time (during the first 6 days of life). A paired t-test (with Bonferroni correction) was used for comparison between different days (2, 3, 4 and 5) and day 6 of life. A Pearson test was used for correlation analysis between SCr and GA. A Pearson test was also used for correlation analysis between SCr and BW. Values were expressed as mean±s.d. or as mean±s.e. of the mean. P<0.05 was considered statistically significant. For nominal data the w 2 -test was used. To adjust for possible confounding, a logistic regression analysis was used. Variables known to alter SCr were entered in a logistic regression model using a decrease by X10% of SCr between day 2 and 6 of life as a classifying and dependent variable. However, only 138 infants met our inclusion criteria. The demographics of the 138 infants are summarized in Table 1. SCr decreased in VLBW infants during their first days of life (repeated measure ANOVA; P ¼ 0.004, n ¼ 138. Figure 1a), and there was a statistically significant differences (t-test with Bonferroni correction) between SCr on day 2 and 6 (±0.22 versus 7±0.22, respectively; P<0.001), and day 3 and 6 (±0.24 versus 7±0.22, respectively; P ¼ 0.001). However, there was no difference between SCr on day 4 and 6 (1±0.21 versus 7±0.22, respectively; P ¼ 0.063) or day 5 and 6 (8±0.21 versus 7±0.22, respectively; P ¼ 5). Serum BUN increased in VLBW infants during their first days of life (repeated measure ANOVA; P ¼ 0.004), and there was a statistically significant difference (paired t-test with Bonferroni correction) between serum BUN on day 2 and 6 of life (P ¼ 0.004, Figure 1b) a b Serum Creatinine in VLBW Infants During Their First Days of Life Serum Blood Urea Nitrogen in VLBW Infants During Their First Days of Life 17 Results During the study period, 1977 newborn infants were admitted to our NICU. Twenty eight percent (547/1977) were p32 weeks GA. BUN (mg/dl) Table 1 Patients demographics and characteristics Study population (n ¼ 138) Gestational age (range in weeks) 29.8±1.7 (25 32) Small for gestational age (%) 5/138 (3.6) Birth weight (range in g) 1179±214 ( ) Length (cm) 37.7±3.0 Male (%) 67/138 (48.5%) Caucasian (%) 54/138 (39%) Median APGAR at 5 min (quartiles) 8 (7 9) Median APGAR at 10 min (quartiles) 7 (7 8) Values are expressed as mean±s.d Figure 1 (a) SCr in VLBW infants during their first days of life. There is a decrease in SCr between day 2 and 6 of life (repeated measure ANOVA; P ¼ 0.004, n ¼ 138). Data is presented as mean±s.e. of the mean. Denotes a statistically significant difference (Pp0.01) with SCr on day 6 of life. (b) Serum BUN in VLBW infants during their first days of life. There is an increase in serum BUN between day 2 and 6 of life (repeated measure ANOVA; P<0.004, n ¼ 138). Data is presented as mean±s.e. of the mean. Denotes a statistically significant difference (Pp0.01) with Serum BUN on day 6 of life.

3 SCr in VLBW infants 757 a Intravenous Fluid intake ml/kg/day b Intravenous Fluid Intake in VLBW Infants During Their First Days of Life Urine Output in VLBW Infants During Their First Days of Life Serum Creatinine in VLBW Infants (<29 Weeks Gestational Age) During Their First Days of Life 5 5 Urine Output (ml/kg/h) Figure 2 (a) IVF intake in VLBW Infants during their first days of life. There is an increase in IVF intake between day 2 and 6 of life (repeated measure ANOVA; P<0.001). (b) Urine output in VLBW infants during their first days of life. There is an increase in urinary output between day 2 and 6 of life (repeated measure ANOVA; P ¼ 0.004). During the first days of life, there was a significant increase in intravenous fluid (IVF) intake (ANOVA; P<0.001, Figure 2a) and urinary output between day 2 and 6 of life (ANOVA; P ¼ 0.004, Figure 2b). In a subgroup analysis there was no statistically significant decrease in SCr in infants <29 weeks GA (ANOVA; P ¼ 0.076), whereas there was a significant decrease in SCr in infants 29 to 32 weeks GA during their first days of life (ANOVA, P ¼ 0.016, Figure 3). In another subgroup analysis there was no statistically significant decrease in SCr in infants <1000 g (ANOVA; P ¼ 0.298), whereas there was a significant decrease in SCr in infants 1000 to 1500 g during their first days of life (ANOVA, P ¼ 0.004, Figure 4). Following our first observation that SCr reached a plateau between the fourth and sixth day of life, we studied on the fifth day of life the relationships between SCr and GA, and SCr and BW. SCr on the fifth day of life was found to decrease with increasing GA (Pearson correlation coefficient: (P ¼ 0.05); Figure 5). On Serum Creatinine (mg/dl Serum Creatinine in VLBW Infants (29-32 Weeks Gestational Age) During Their First Days of Life Figure 3 SCr in VLBW infants during their first days of life. There is no change in SCr between day 2 and 6 of life in infants <29 weeks GA (repeated measure ANOVA; P ¼ 0.076), whereas there is a decrease in SCr between day 2 and 6 of life in infants 29 to 32 weeks GA (repeated measure ANOVA; P ¼ 0.016). Denotes a statistically significant difference (Pp0.01) with SCr on day 6 of life. the fifth day of life SCr was found also to decrease with increasing BW (Pearson correlation coefficient: (P ¼ 0.05). Figure 6). Table 2 shows patients characteristics on their fifth day of life. Among our patients, 89% (123/138) received gentamicin, 48% (66/138) received xanthines (aminophylline, and or caffeine), and 21% (29/138) remained mechanically ventilated (intubated) or on CPAP during the study period. To adjust for the use of gentamicin, xanthines and mechanical ventilation/cpap as possible confounding factors that can alter SCr levels; a logistic regression analysis was conducted. A X10% decrease in SCr (between day 2 and 6) was chosen as the dependent variable and use of gentamicin, xanthines or mechanical ventilation/cpap as independent variables. There was no statically significant effect 6

4 758 SCr in VLBW infants Serum Creatinine in < 1000 grams VLBW Infants During Their First Days of Life 1.20 Relationship Between Serum Creatinine and Gestational Age in VLBW Infants Seum Creatinine (mg/dl) Serum Creatinine in grams VLBW Infants During Their First Days of Life Figure 4 SCr in VLBW infants during their first week of life. There is no change in SCr between day 2 and 6 of life in infants <1000 g BW (repeated measure ANOVA; P ¼ 0.298), whereas there is a decrease in SCr between day 2 and 6 of life in infants 1000 to 1500 g BW (repeated measure ANOVA; P ¼ 0.004). Denotes a statistically significant difference (Pp0.01) with SCr on day 6 of life. of gentamicin, xanthines or mechanical ventilation/cpap on the change of SCr between day 2 and 6 of life (Table 3). The decrease by X10% of SCr was chosen because SCr dropped from on day 2 of life to 5 on day 6 of life (an approximate decrease of 10%). To determine if mechanical ventilation/cpap in younger infants (<29 weeks GA) is contributing to the higher SCr levels at day 6 of life a subgroup analysis was conducted. Fifty-six % (13/23) of ventilated infants on day 2 of life remained on mechanical ventilation/cpap on day 6 of life (in infants <29 weeks GA) versus 42% (16/38) of ventilated infants on day 2 of life remained on mechanical ventilation/cpap on day 6 of life (in infants X29 weeks GA; P ¼ 0.27). There was no significant difference in the percent of ventilated or treated with CPAP patients among younger or older infants during the study period Gestational Age (in weeks) Figure 5 Relationship between SCr (mg/dl) and GA (weeks) in VLBW infants. There is a decrease in SCr between p26 and 32 weeks GA, on day 5 of life. Pearson Correlation coefficient: (P ¼ 0.05, n ¼ 138). SCr values are presented in mean±s.d. and also in 10th, 50th and 90th percentiles. Diamonds represent the mean±s.d. values. The solid line represents the 50th percentile, and the dashed lines represent the 10th and 90th percentile Relationship Between Serum Creatinine and Birth Weight in VLBW Infants Birth Weight (in grams) Figure 6 Relationship between SCr (mg/dl) and BW (grams) in VLBW infants. There is a decrease in SCr between 450 to 750 g and 1251 to 1500 g groups. Pearson correlation coefficient: (P ¼ 0.05; n ¼ 138). SCr values are presented in mean±s.d. and also in 10th, 50th and 90th percentiles. Diamonds represent the mean±s.d. values. The solid line represents the 50th percentile, and the dashed lines represent the 10th and 90th percentile. Discussion We have shown in a large cohort of VLBW (459 to 1493 g) infants that SCr is elevated on the second day of life, and decreases postnatally to reach a plateau between the fourth and sixth day of life. However, in a subgroup analysis we found that SCr does not decrease significantly during the first 6 days of life in infants <29 weeks GA and <1000 g BW. We have also shown that infants SCr (on the fifth day of life) decreases with advancing GA and BW.

5 SCr in VLBW infants 759 Table 2 Patients characteristics on day 5 of life Study population on day 5 of life (n ¼ 138) Mechanical ventilation (%) 23/138 (17%) 8±0.21 Serum BUN (mg/dl) 15.9±7.7 Protein intake (g/kg/d) 2.0±0.5 Fluid intake (ml/kg/d) 147.3±19.2 Urine output (ml/kg/h) 4.3±1.1 Values are expressed as mean±s.d. Abbreviation: BUN, blood urea nitrogen. Table 3 Adjusted odds ratio of risk factors associated with alteration of serum creatinine in VLBW infants Adjusted odds ratio Confidence interval P-values Xanthines Gentamicin Mechanical Ventilation/ CPAP Abbreviations: CPAP: continuous positive airway pressure; VLBW, very low birth weight. The high morbidity of VLBW infants during the first 2 days of life, and exposure to multiple agents that might impair renal function, make it very difficult to establish normal reference values of SCr during the first days of life. During the first 2 days of life the high level of SCr in newborn infants has been attributed to a combination of maternal creatinine levels, 1 immaturity of the glomerular filtration, and an increased tubular reabsorption of creatinine due to a possible back-flow of creatinine across leaky immature tubular and vascular structures. 2 Others have also reported reduced GFR values during the first 48 h of life secondary to the inability of premature kidneys to clear high SCr values. 3,14 To determine the relationship between SCr and GA, and SCr and BW in VLBW infants, SCr values of all VLBW infants were studied during their first days of life. The fifth day of life was chosen to study the relationship between SCr and GA or BW because SCr reached a plateau between the fourth and sixth day of life. Our findings are consistent with others; Bueva et al. 14 have shown in 11 patients (1001 to 1500 g) a decrease in SCr between day 1 to 2 and 8 to 9 (from 95±5 to 64±5 mmol/l, respectively). In a small number of patients divided between two groups of <30 weeks GA and 31 to 34 weeks GA, Vanpee et al. 8 have shown that postnatal development of renal function is also related to GA, and postnatal development of renal function is slower in premature infants than in full term infants. These authors have shown that: from the first to the fifth postnatal week, creatinine clearance (in ml/min/1.73 m 2 ) increased from 10 to 20 in infants <30 weeks GA at birth. Whereas, creatinine clearance increased from 15 to 30 in infants 31 to 34 week GA at birth. Their findings are also consistent with ours. In our study, we did not measure GFR in VLBW infants, however, we found in infants <29 weeks GA and <1000 g BW that SCr remained elevated during the first days of life most probably secondary to a low creatinine clearance in these extremely premature infants. The serum BUN also increased during the first week of life in our patients most probably secondary to the increase in protein intake between day 2 and 6 of life. On average our patients reached an intake of 2 g/kg/day of protein on their fifth day of life. IVF intake and urinary output increased during the first days of life as expected, secondary to fluid restriction during the first few days of life. Another explanation for the decrease in creatinine along with an increase in BUN could be related to an insufficient fluid or caloric intake in our patients or could be related to a progressive decrease in tubular back leak of creatinine (a hypothesis that cannot be tested without measurement of GFR). We have shown in our study that SCr decreases with advancing GA. Our findings are consistent with previous findings of Bueva et al. 14 who have shown that plasma creatinine concentration is significantly higher in preterm infants compared to term infants between the first and second day of life, and that creatinine clearance correlates with GA. In their study these authors assessed 66 term and preterm infants (1000 to 2500 g BW of which only 11 patients were 1001 to 1500 g), whereas in our study we evaluated 136 infants 25 to 32 weeks GA (<1500 g). In another study, Gallini et al. 6 have shown a correlation between serum SCr and postnatal age in 83 preterm infants <32 weeks GA. In their study there was no difference in SCr among infants of different GA at birth, but these authors found an inverse correlation between SCr and GA from the third day of life to the fifth week. During the first week of life the maximum value of SCr was significantly higher in the group of infants <27 weeks GA than infants who were 27 to 28 weeks, 29 to 30 weeks and 31 to 32 weeks. These findings are consistent with ours; we found that SCr, in infants <29 weeks GA and <1000 g BW, does not decrease significantly during the first week of life in comparison to infants 29 to 32 weeks GA and 1000 to 1500 g BW, respectively. There are limitations to our study. We conducted a retrospective review of our patients medical records; we did not measure creatinine clearance in order to determine if there is any correlation between creatinine clearance and GA or BW. We did not have prenatal medical records available for review. Any prenatal exposure to nephrotoxic medications such as prostaglandin inhibitors could have altered the results of our study. Another limitation to our study is the possibility of the presence of a silent PDA that could have affected renal perfusion and function. 15 We excluded patients with PDA who were symptomatic and who had an echocardiogram to confirm the diagnosis. We did not have cardiac echocardiograms carried out routinely to exclude patients with

6 760 SCr in VLBW infants silent PDA. We also excluded patients from our study who were on a high ventilator settings (such as on the oscillator), but we did not exclude patients who were on conventional mechanical ventilation. Any form of mechanical ventilation that increases intrathoracic pressure may impair venous return and renal perfusion. 15 However, in our logistic regression analysis mechanical ventilation or CPAP did not have any statistically significant effect on SCr during the study period. Also, in a subgroup analysis of our patients we did not find any difference in the percentage of patients who remained on mechanical ventilation/cpap during the entire study period between infants younger or older than 29 weeks. It will be difficult to recruit VLBW infants during their first days of life who are not in respiratory distress and on mechanical ventilation. Prospective, long-term studies are needed to explore the maturation of renal function in premature infants and to determine if there is a delay in renal maturation and function that extends beyond the neonatal period to infancy, childhood and or adulthood. With advancing technology, younger premature infants (<25 week GA) are surviving, future studies are also necessary to determine renal function and maturation at this very young age group. We conclude that in VLBW infants SCr decreases during the first days of life to reach a plateau between the fourth and sixth day of life (on average on the fifth day) most probably reflecting the infants own SCr than the mothers. However, in infants younger than 29 weeks GA or smaller than 1000 g at birth there is a delay in the decrease of their SCr that extends beyond the first 6 days of life. We also conclude that during the first days of life (on the fifth day of life), and in VLBW infants SCr decreases with advancing GA and BW. References 1 Chevalier RL. Developmental renal physiology of the low birth weight pre-term newborn. J Urol 1996; 156: Guignard JP, Drukker A. Why do newborn infants have a high plasma creatinine? Pediatrics 1999; 103(4): e49. 3 Miall LS, Henderson MJ, Turner AJ, Brownlee KG, Brocklebanck JT, Newell SJ et al. Plasma creatinine rises dramatically in the first 48 h of life in preterm infants. Pediatrics 1999; 104(6): Lao TT, Loong EP, Chin RK, Lam YM. Renal function in the newborn. Newborn creatinine related to birth weight, maturity and maternal creatinine. Gynecol Obstet Invest 1989; 28(2): Sonntag J, Prankel B, Waltz S. Serum creatinine concentration, urinary creatinine excretion and creatinine clearance during the first 9 weeks in preterm infants with a birth weight below 1500 g. Eur J Pediatr 1996; 155(9): Gallini F, Maggio L, Romagnoli C, Marrocco G, Tortorolo G. Progression of renal function in pretern neonates with gestational age p32 weeks. Pediatr Nephrol 2000; 15: van der Heijden AJ, Grose WF, Ambagtsheer JJ, Provoost AP, Wolff ED, Sauer PJ. Glomerular filtration rate in the preterm infant: the relation to gestational and postnatal age. Eur J Pediatr 1988; 148(1): Vampee M, Herin R, Zetterstrom R, Aperia A. Postnatal development of renal function in very low birthweight infants. Acta Paediatr Scand 1988; 77: Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am 1987; 34(3): Zacchello G, Bondio M, Saia OS, Largaiolli G, Vedaldi R, Rubaltelli FF. Simple estimate of creatinine clearance from plasma creatinine in neonates. Arch Dis Child 1982; 57(4): Brion LP, Fleischman AR, McCarton C, Schwartz GJ. A simple estimate of glomerular filtration rate in low birth weight infants during the first year of life: noninvasive assessment of body composition and growth. J Pediatr 1986; 109(4): Cicero FM, Okay Y, Araujo RJL. Relationship between plasma creatinine concentration and glomerular filtration in preterm newborn infants. Rev Hosp Clin Fac Med Sao Paulo 1999; 54(4): Bueva A, Guignard JP. Renal function in preterm neonates. Pediatr Res 1994; 36(5): Vampee M, Ergander U, Herin P, Aperia A. Renal function in sick, very low-birth-weight infants. Acta Paediatr 1993; 82: