Risk Factors and Outcome of Nephrocalcinosis in Very Low Birth Weight Infants

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Original Article 대한주산회지제 26 권제 1 호, 2015 Korean J Perinatol Vol.26, No.1, Mar., Risk Factors and Outcome of Nephrocalcinosis in Very Low Birth Weight Infants
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Original Article 대한주산회지제 26 권제 1 호, 2015 Korean J Perinatol Vol.26, No.1, Mar., Risk Factors and Outcome of Nephrocalcinosis in Very Low Birth Weight Infants Ho Sung Kim, M.D., Kumi Jeong, M.D., Young Youn Choi, M.D., Ph.D., Eun Song Song, M.D., Ph.D. Department of Pediatrics, Chonnam National University Hospital, Gwangju, Korea Purpose: The aim of this study was to determine the incidence, risk factors, and long-term outcome of nephrocalcinosis in very low birth weight (VLBW) infants. Methods: A retrospective chart review was performed in VLBW infants between 2006 and 2012 in the neonatal intensive care unit. Results: The incidence of nephrocalcinosis in VLBW infants was 10.2%. By univariate analysis, oligohydramnios and use of antenatal steroids were more frequent in the nephrocalcinosis group. In the nephrocalcinosis group, the gestational age and birth weight were lower and there were more number of female infants. Also, the initial blood ph, the lowest systolic blood pressure, and urine output on the first day of life were lower and bronchopulmonary dysplasia, sepsis, and urinary tract infection were more prevalent in the nephrocalcinosis group. The use of dexamethasone or ibuprofen and the lowest levels of phosphorus, protein and albumin were significantly lower in the nephrocalcinosis group. By binary logistic regression analysis, the use of antenatal steroids, female sex, 5-minute Apgar score, duration of oxygen therapy and total parenteral nutrition, and the lowest albumin level were found to be significant risk factors for nephrocalcinosis. Overall, the resolution rate was 64.1% and 88.6% within 12 months and 18 months, respectively. Conclusions: The incidence of nephrocalcinosis in VLBW infants showed increasing trend. The risk factors of nephrocalcinosis were parameters for sick VLBW infants. Although the prognosis of nephrocalcinosis was relatively good, we should pay close attention to the development of complication. Key Words: Nephrocalcinosis, Very low birth weight infants, Incidence, Risk factors, Outcome Nephrocalcinosis (NC), defined as the deposition of calcium crystals in the renal parenchyma, occurs due to an imbalance between promoters and inhibitors of crystallization in urine. After first description of NC in adult by Dimopoulos et al. in 1971, 1 Hufnagle et al. 2 reported 10 premature infants of NC after long-term Received: 9 August 2014 Revised: 5 October 2014 Accepted: 21 October 2014 Correspondence to: Eun Song Song, M.D., Ph.D., Department of Pediatrics, Chonnam National University Hospital, 42, jebong-ro, Dong-gu, Gwangju , Korea Tel: , Fax: Copyrightc 2015 by The Korean Society of Perinatology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/license/ by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided that the original work is properly cited. The Korean Journal of Perinatology pissn eissn e-kjp.org furosemide therapy in Among different studies, the prevalence of NC ranged from 7 to 41% in very low birth weight (VLBW) infants with a gestational age less than 32 weeks. 3-9 The etiology of NC is multifactorial including low gestational age and birth weight. Male sex, family history, white race, mechanical ventilation, oxygen therapy, bronchopulmonary dysplasia (BPD), the use of furosemide, methylxanthine, dexamethasone, gentamicin, total parenteral nutrition (TPN), acidosis, hypercalcemia, hypophosphatemia, hypercalciuria, hyperoxaluria, hyperuricuria, and hypocitruria are associated with development of NC Most cases of NC resolves within one year; how Ho Sung Kim, et al. : - Risk Factors and Outcome of Nephrocalcinosis in VLBWI - ever, in the minority of patients, NC can persist for several years.9, 15-18, 20 Short-term compli cations include urinary tract infection (UTI), renal stone, hydronephrosis, hematuria, and colicky pain. Delayed renal growth, renal function impairment, and hypertension have been reported as the long-term complications. 16,17,21,22 A few studies that addressed the risk factors of NC have been reported in Korea, but there is no long-term follow-up data yet. The aim of this study was to determine the incidence, risk factors, and long-term outcome of NC in VLBW infants. Subjects and Methods 1. Subjects A retrospective chart review was performed in 688 infants of birth weight less than 1,500 g who were admitted between January 2006 and December 2012 in the neonatal intensive care unit of Chonnam National University Hospital, Gwangju, Korea. One hundred seventy-eight infants [43 infants who were discharged before 4 weeks of life, 11 infants who were transferred to other hospitals, 84 infants who died due to severe congenital anomaly or severe prematurity, and 40 infants who did not undergo renal ultrasonography (US)] were excluded. The remaining 510 infants were enrolled in this study; the NC group included 52 infants, and the control group included 458 infants. Renal US was performed by a consultant radiologist. The indication of US was hypercalcemia, or hypercalciuria (urinary calcium-creatinine ratio 0.8), 26 or presence of calcium crystals in urinalysis. Additionally, renal US was routinely preformed in VLBW infants before discharge. NC was defined as at least one bright reflection in the medulla or cortex that was reproducible in both transverse and longitudinal directions on renal US Date collection Maternal data such as age, preterm premature rupture of membranes (PPROM), diabetic disease, hypertensive disease, histologic chorioamnionitis, and use of antenatal steroids were recorded. Gestational age, birth weight, gender, Apgar scores at 1 minute and 5 minutes, ph in the first arterial or venous blood gas analysis, lowest systolic blood pressure (measured by noninvasive blood pressure or invasive arterial blood pressure) and urine output on the first day after birth were investigated. Morbidity data include the presence of patent ductus arteriosus (PDA), BPD, bacterial sepsis, fungal sepsis, and UTI. With respect to the treatment profile, duration of mechanical ventilation, oxygen therapy, TPN and phototherapy, and the postnatal day at initial trophic feeding were obtained. The frequency of surfactant, dexamethasone, indomethacin, ibuprofen, and furosemide, and the duration of use of furosemide, gentamicin, cefotaxime, ampicillin, fluconazole, and theophylline were recorded. The highest and lowest levels of serum calcium and phosphate, blood urea nitrogen (BUN), creatinine, protein, and albumin levels were recorded from the data of every 2 week interval. Follow-up renal US was performed every one to three months in patients with NC at the out-patient department. In addition, we obtained the data of the presence of UTI, renal function impairment, and hypertension in the medical records. 3. Statistical analysis Data were analyzed by Statistical Program for the Social Science (SPSS) version 22.0, and P values less than 0.05 were considered statistically significant 김호성등 : - 극소저체중출생아에서신석회화증의위험요인과예후 - Continuous variables were compared using the Mann-Whitney U test. Non-continuous variables were compared using the X 2 test or Fisher s exact test. To identify statistically meaningful data in the univariate analysis, a binary logistic regression analysis was performed as the multivariate analysis. Results 1. Incidence The overall incidence of NC in VLBW infants was 10.2% with an increasing tendency in every year. The incidence of NC differed depending on the birth weight, occurring in 15.4% below 750 g, 28.8% between g, 48.1% between 1,000-1,249 g, 7.7% between 1,250-1,499 g. The average time of diagnosis was 68.4 days of life (range days of life). All cases in the NC group showed deposition of calcium salts in the medulla of the kidney. Among the 52 VLBW infants in the NC group, 48 cases had bilateral NC (92.3%) and 4 cases had unilateral NC (7.7%, 2 cases in the left kidney, and 2 cases in the right kidney). 2. Univariate analysis of risk factors 1) Baseline characteristics of mothers and their infants Compared with the control group, oligohydramnios and use of antenatal steroids were more frequent in the NC group. There was no significant difference in maternal age, PPROM, diabetic disease, histologic chorioamnionitis, and hypertensive disease in two groups (Table 1). The NC group had lower gestational age and birth weight than the control group. NC developed predominantly in female infants in our study. Also, the Table 1. Baseline characteristics of mothers and their infants Variables NC group (n=52) Control group (n=458) P-value Mother Age (years), mean (range) 31.5 (19-40) 31.3 (17-45) 0.38 Oligohydramnios (AFI 5), n (%) 7 (13.5) 27 (5.9) 0.04 Use of antenatal steroids, n (%) 37 (71.2) 243 (54.3) 0.04 PPROM ( 18 hours) 12 (23.1) 150 (32.8) 0.08 GDM or overt DM, n (%) 4 (7.7) 16 (3.5) 0.09 Histologic chorioamnionitis 20 (38.5) 151 (33.0) 0.65 Hypertensive diseases*, n (%) 11 (21.2) 97 (21.2) 1.00 Infants GA (weeks), mean (range) 27.6 ( ) 29.6 ( ) 0.01 BW (g), mean (range) (470-1,480) 1,186.1 (570-1,490) 0.01 Small for gestational age, n (%) 10 (19.2) 74 (16.2) 0.57 Female, n (%) 32 (61.5) 210 (45.9) min Apgar score, mean (range) 4.5 (0-10) 5.2 (0-10) min Apgar score, mean (range) 6.4 (1-10) 7.4 (1-10) 0.01 Initial blood ph, mean (range) 7.28 ( ) 7.32 ( ) 0.04 Lowest systolic BP on day 1 (mmhg), mean (range) 35.0(21-65) 39.3 (21-75) 0.01 Urine output on day 1 (ml/kg/hr), mean (range) 2.1 ( ) 2.8 ( ) 0.01 Abbreviations: NC, nephrocalcinosis; AFI, amniotic fluid index; PPROM, Preterm premature rupture of membranes; GDM, Gestational diabetes mellitus; DM, diabetes mellitus; GA, gestational age; BW, birth weight;bp, blood pressure. *Hypertensive diseases include pregnancy induced hypertension, preeclampsia, eclampsia and chronic hypertension. Ho Sung Kim, et al. : - Risk Factors and Outcome of Nephrocalcinosis in VLBWI - 5-minute Apgar score, the initial blood, the lowest systolic BP and urine output on the first day of life were lower in the NC group (Table 1). 2) Morbidity The incidence of BPD, bacterial sepsis, fungal sepsis, and UTI was significantly higher in the NC group, but there was no significant difference in the incidence of PDA between the two groups (Table 2). 3) Supportive care and drug treatment The duration of mechanical ventilation, oxygen therapy, and TPN support was significantly longer in the NC group. Compared to the control group, initial Table 2. Morbidities among very low birth weight infants Variables NC group (n=52) Control group (n=458) P- value PDA, n (%) 40 (76.9) 269 (58.7) 0.11 BPD, n (%) 33 (63.5) 188 (41.0) 0.02 Bacterial sepsis, n (%) 25 (48.1) 156 (34.1) 0.03 Fungal sepsis, n (%) 13 (25.0) 39 (8.5) 0.01 Urinary tract infection, n (%) 27 (51.9) 157 (34.3) 0.01 Abbreviations: NC, nephrocalcinosis; PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia. trophic feeding was started later in the NC group. The frequency of use of dexamethasone and oral ibuprofen was significantly higher in the NC group. But, there was no difference in the frequency of use of surfactant, intravenous indomethacin, and furosemide between two groups. The infants in the NC group were treated with cefotaxime and fluconazole for a significantly longer duration than the control group, but there was no significant difference in the duration of use of furosemide, gentamicin, and ampicillin between the two groups (Table 3). 4) Laboratory findings on admission, 2nd weeks, and 4th weeks of life During the hospitalization period, the lowest values of serum phosphate, protein, and albumin were significantly lower in the NC group, and the highest serum value of BUN was higher in the NC group than in the control group. At 2 weeks of life, the values of serum phosphate, protein, and albumin were significantly lower in the NC group, while the value of serum creatinine was higher in the NC group. Table 3. Supportive care and drug treatment Variables NC group (n=52) Control group (n=458) P-value Mechanical ventilation (days), mean (range) 28.8 (0-154) 11.9 (0-150) 0.01 Oxygen therapy (days), mean (range) 50.7 (0-196) 26.3 (0-235) 0.01 Initial trophic feeding (day of life), mean (range) 4.7 (1-34) 2.5 (0-23) 0.01 TPN (days), mean (range) 37.5 (5-106) 25.4 (0-116) 0.01 Phototherapy (days), mean (range) 12.5 (4-31) 13.7 (0-66) 0.14 Surfactant, n (%) 46 (88.5) 330 (72.1) 0.11 Dexamethasone, n (%) 18 (34.6) 91 (19.9) 0.01 Indomethacin, n (%) 3 (5.8) 84 (18.3) 0.32 Ibuprofen, n (%) 20 (38.4) 89 (19.4) 0.01 Furosemide, n (%) 27 (51.9) 193 (42.1) 0.23 Furosemide (days), mean (range) 4.5 (0-70) 2.1 (0-89) 0.12 Gentamicin (days), mean (range) 0.9 (0-17) 0.6 (0-21) 0.11 Cefotaxime (days), mean (range) 17.0 (0-71) 11.3 (0-52) 0.01 Ampicillin (days), mean (range) 14.3 (0-82) 10.3 (0-64) 0.07 Theophylline (days), mean (range) 27.9 (0-103) 25.4 (0-102) 0.88 Fluconazole (days), mean (range) 6.1 (0-44) 3.4 (0-41) 0.03 Abbreviations: NC, nephrocalcinosis; TPN, total parenteral nutrition. 김호성등 : - 극소저체중출생아에서신석회화증의위험요인과예후 - At 4 weeks of life, the value of serum albumin was significantly lower, while the value of serum creatinine was higher in the NC group than in the control group. But, neither the highest and lowest values of total and ionized calcium, nor the values of total and ionized calcium at 2 weeks and 4 weeks was different between the two groups (Table 4). 3. Significance of risk factors by multivariate analysis Binary logistic regression was used as the multivariate analysis. NC was selected as a dependent variable, and the variables with statistical significance (P 0.05) were selected as independent variables. As a result, use of antenatal steroids [P 0.01, odds ratio (OR) 7.112, 95% confidence interval (CI) ], female sex (P=0.03, OR 0.161, 95% CI ), 5-minute Apgar score (P=0.01, OR 1.503, 95% CI ), duration of oxygen therapy (P=0.01, OR 1.039, 95% CI ), duration of TPN support (P=0.02, OR 0.947, 95% CI ), and lowest albumin level during the hospitalization period (P 0.01, OR , 95% CI ) were the strongest risk factors for NC (Table 5). Table 4. Laboratory findings on admission, 2nd weeks, and 4th weeks of life Variables NC group (n=52) Control group (n=458) mean (range) mean (range) P-value During admission Total calcium (mg/dl), highest 10.4 ( ) 9.6 ( ) 0.58 Total calcium (mg/dl), lowest 7.2 ( ) 6.8 ( ) 0.74 Ionized calcium (meq/l), highest 3.0 ( ) 2.9 ( ) 0.09 Ionized calcium (meq/l), lowest 2.0 ( ) 2.1 ( ) 0.43 Inorganic phosphorus (mg/dl), highest 7.4 ( ) 7.5 ( ) 0.48 Inorganic phosphorus (mg/dl), lowest 3.0 ( ) 3.5 ( ) 0.01 BUN (mg/dl), highest 35.7 ( ) 25.1 ( ) 0.03 Creatinine (mg/dl), highest 1.17 ( ) 1.2 ( ) 0.87 Protein (g/dl), lowest 3.8 ( ) 4.1 ( ) 0.01 Albumin (g/dl), lowest 2.6 ( ) 2.7 ( ) nd week Total calcium, mg/dl 9.4 ( ) 8.8 ( ) 0.65 Ionized calcium, mg/dl 2.5 ( ) 2.7 ( ) 0.17 Inorganic phosphorus, mg/dl 4.4 ( ) 4.9 ( ) 0.03 BUN, mg/dl 19.0 ( ) 11.6 ( ) 0.07 Creatinine, mg/dl ( ) 0.6 ( ) 0.02 Protein, g/dl 4.6 ( ) 4.9 ( ) 0.01 Albumin, g/dl 3.2 ( ) 3.4 ( ) 0.01 4th week Total calcium, mg/dl 9.0 ( ) 8.4 ( ) 0.68 Ionized calcium, mg/dl 2.5 ( ) 2.4 ( ) 0.61 Inorganic phosphorus, mg/dl 5.4 ( ) 6.1 ( ) 0.13 BUN, mg/dl 7.4 ( ) 6.7 ( ) 0.73 Creatinine, mg/dl 0.4 ( ) 0.3 (0-3.0) 0.03 Protein, g/dl 4.5 ( ) 4.7 ( ) 0.07 Albumin, g/dl 3.3 ( ) 3.4 ( ) 0.04 Abbreviations: NC, nephrocalcinosis; BUN, blood urea nitrogen Ho Sung Kim, et al. : - Risk Factors and Outcome of Nephrocalcinosis in VLBWI - Table 5. Significance of risk factors by binary logistic regression analysis Subject P-value Odd ratio 95% Confidence Interval Lower Upper Use of antenatal steroids Female Five-minute Apgar score Oxygen therapy (days) TPN (days) Albumin (lowest) level during admission Abbreviations: BPD, bronchopulmonary dysplasia; TPN, total parenteral nutrition. Fig. 1. Renal ultrasonographic findings at two months of life showed nephrocalcinosis in both kidneys (a maximum diameter of 3.5 mm in the left kidney) with normal renal echogenicity and size (upper two). At four and a half months of life, diffuse nephrocalcinosis (large calculi in the left kidney) and decreased size of both kidneys, more marked in the left kidney (left 2.8x1.4 cm, right 8x8 cm) with loss of corticomedullary differentiation suggesting chronic renal parenchymal disease was noted (lower two). 4. Prognosis Follow-up renal US was performed in 45 VLBW infants. We couldn t collect the data of 7 cases that were lost to follow-up. Among these 45 VLBW infants, NC was resolved in 13 infants (28.9%, 13/45) by 6 months after discharge. NC was resolved in other 12 and 7 infants by 12 months and 18 months, respectively, and the resolution rate at 12 months and 18 months was 55.6% (25/45) and 71.1% (32/45), respectively. In 4 infants, NC resolved by 18 months of age, so the total resolution rate was 80.0% (36/45). NC persisted but mildly decreased in size in the remaining 9 infants at the time of last follow-up. The average period of recovery was 10.3 months (44.1 weeks) in 36 VLBW infants. During long-term follow-up, pyelonephritis and renal stones occurred in two VLBW infants each. One preterm female infant of 27 weeks gestational age and weighing 850 g had diagnosed the bilateral NC 김호성등 : - 극소저체중출생아에서신석회화증의위험요인과예후 - with multiple stones (maximum diameter 3.5 mm) at 2 months of life (Fig. 1A). She experienced a cardiac tamponade but was successfully resuscitated at 6 days of life. Transiently, her renal function decreased. Not only progression of renal atrophy was observed in the left kidney without regression of NC (Fig. 1B), but also renal function impairment was noted in the 99m Tc-MAG3 renal scan. She was followed up at the out-patient department for 7 years with conservative medical treatment for hypertension (systolic blood pressure 96 mmhg / diastolic blood pressure 74 mmhg) and chronic renal failure (BUN 32.0 mg/dl, creatinine 2.3 mg/dl). Discussion The incidence of NC in this study is 10.2%, which was coincide with that previously reported. 3-9 The varying prevalence of NC is considered to be due different study populations and era, development in the sensitivity of ultrasound equipment, and workmanship of the observer. 27 In several reports, the incidence of NC showed a decreasing trend with development in care of preterm infants, 6,20,24 but this study showed an increasing tendency for NC. This finding is suspected to be due to an increase birth rate in infants with low gestational age and birth weight and survival of them, and active evaluation of VLBW infants with close attention to NC. Renal US was performed by a consultant radiologist in charge of pediatric specialty, and the sonographic diagnostic criteria and the policy to check renal US remain constant above mentioned during study period. The risk factors for NC are different among reports, and the most important risk factors are gestational age and birth weight At a low gestational age, the lower glomerular filtration ratio and the shorter loop of Henle lead to slow urinary transition, while the sensitivity for heterogeneous crystallization is high, which result in decreased calcium excretion and increased calcification. Also, during the neonatal period, VLBW infants are exposed more frequently and for a longer time to multiple risk factors associated with treatment. 28 In this study the NC group had lower gestational age and birth weight than the control group. The NC group also had lower 5 minute Apgar score, initial blood ph, the lowest systolic blood pressure and urine output on the first day of life than the control group. These findings are related clinical characteristics of low gestational age and
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