- Email: [email protected]
A case control analysis investigating risk factors and outcomes for nephrocalcinosis and renal calculi in neonates
Accepted Manuscript A case control analysis investigating risk factors and outcomes for nephrocalcinosis and renal calculi in neonates Melissa Huynh, Roderick Clark, Jenny Li, Guido Filler, Sumit Dave PII:
S1477-5131(17)30288-7
DOI:
10.1016/j.jpurol.2017.06.018
Reference:
JPUROL 2604
To appear in:
Journal of Pediatric Urology
Received Date: 5 January 2017 Revised Date:
1477-5131 1477-5131
Accepted Date: 29 June 2017
Please cite this article as: Huynh M, Clark R, Li J, Filler G, Dave S, A case control analysis investigating risk factors and outcomes for nephrocalcinosis and renal calculi in neonates, Journal of Pediatric Urology (2017), doi: 10.1016/j.jpurol.2017.06.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 PU FALL CONGRESS DALLAS 2016 A case control analysis investigating risk factors and outcomes for nephrocalcinosis and renal calculi in neonates
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Melissa Huynha, Roderick Clarka, Jenny Lib, Guido Fillerc,d,e, and Sumit Davea,c,*
Department of Surgery (Urology), Western University, London Ontario
b
Schulich School and Medicine & Dentistry, Western University, London Ontario
c
Department of Paediatrics (Nephrology), Western University, London, Ontario
d
Department of Medicine (Nephrology)
e
Department of Pathology & Laboratory Medicine, Western University, London Ontario
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a
* Corresponding author. Department of Surgery and Pediatrics, Western University, Room E2-650, 800 Commissioners Road East, London, Ontario, Canada, N6A 5W9. E-mail address: [email protected]
Summary Introduction: Studies on outcomes and risk factors for neonatal nephrocalcinosis (NC)
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and renal calculi (RC) are limited, and often do not include controls for comparison. We conducted a case–control analysis to identify risk factors associated with NC and/or RC in neonates and studied the natural course of these anomalies.
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Study design: Infants diagnosed with NC/RC on ultrasound within the first year of life and corresponding gestational age- and gender-matched controls were identified from the neonatal intensive care unit database at our institution over a 10-year period. Risk factors assessed included:
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low birth weight, small for gestational age, nephrotoxic drugs, respiratory support therapy, use of total parental nutrition (TPN), surgeries, history of UTIs, creatinine at presentation, and history of maternal hypertension. Unadjusted odds ratios were estimated. Chi square analysis was performed for binary variables and the Mann-Whitney U test for continuous variables. Outcomes examined include time to resolution of NC/RC, renal function, and hypertension. Results: We identified 22 cases of NC/RC with corresponding matched controls. Median follow-up was 28 months (IQR 0-122 months). History of urinary tract infections (UTI) was the only variable significantly associated with the presence of NC/RC (OR 5.62, 95% CI 1.12-31.1, p <0.013) (Table). All other known risk factors were comparable in both groups. There was no difference in
ACCEPTED MANUSCRIPT 2 the incidence of hypertension (OR 2.94, 95% CI 0.40-33.82, p=0.216) at diagnosis or last follow-up between the groups. Resolution of NC/RC was observed in 72.7%, during a median follow-up of 12.1 months. Mean urinary calcium/creatinine ratio for the NC/RC group was 2.3±1.5 at diagnosis and 0.96±0.8 at last follow-up.
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Discussion: Most NC/RC in infants resolve without surgical intervention but some infants require medical therapy and follow-up. Risk factors for NC/RC in neonates continue to be poorly defined because of the quality of studies available. Our study provides further adjustment for confounders but has a small sample size and is restricted to neonates from an intensive care unit.
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Conclusion: Most cases of NC/RC resolve spontaneously without surgical intervention. The mean time to resolution is 12.1 months, without untoward consequences in terms of hypertension. A history of UTIs is the only identified risk factor identified in this study which is associated with a
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significant increased risk of neonatal nephrocalcinosis and/or renal calculi. Larger prospective studies are warranted to confirm these findings.
KEYWORDS Renal stones;
Neonate; Case-control study
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Nephrocalcinosis;
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Table. Selected risk factors for NC/RC
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Controls (n=22) Cases (n=22) OR (95% CI) Ventilator support, days, median (IQR) 2 (0-38) 2.5 (0-28) -Nephrotoxic drug exposure 15 (68.1) 16 (72.7) 1.24 (0.28-5.61) Small for gestational age 8 (36.3) 6(27.2) 0.65 (0.14-2.81) Previous urinary tract infection 4 (18.1) 10 (45.4) 5.62 (1.12-31.1) Chi-square test for binary variables. Mann-Whitney U test for continuous variables.
p-value 0.883 0.741 0.517 0.013
Introduction The prevalence of nephrocalcinosis (NC) in preterm neonates is between 7% and 41% [1], and has been associated with hypertension, chronic kidney disease, and significantly smaller kidney lengths during childhood [2,3]. The proposed risk factors for NC include furosemide use [1,4–6], low birth weight [7], glucocorticoid use [8], parenteral nutrition [1,6], nephrotoxic medications [9], and
ACCEPTED MANUSCRIPT 3 prolonged oxygen supplementation or ventilation [8–10]. In addition, many studies have identified gestational age as associated with NC, although there is likely significant confounding between this and the other risk factors for NC/and or RC. Unfortunately, previous studies are observational, lack control groups, and focus on either risk factors or outcomes but not both. Therefore, we conducted a
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case-control analysis to determine the risk factors for NC and renal calculi (RC) comparing neonates with similar gestational age and studying whether the known risk factors retained
significance in a matched case-control analysis. In addition, we determined the clinical outcomes of these conditions. We hypothesized that the etiology of NC/RC in neonates is multifactorial
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Methods Study design and population
We conducted a retrospective matched case-control study for exposures and a retrospective
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matched cohort study for outcomes using our neonatal intensive care unit (NICU) database to identify all ultrasound (U/S)-proven cases of NC/RC in infants admitted to the NICU at a tertiary care centre between January 2002 and December 2014. Controls were matched 1:1 for gestational age and had a negative renal/bladder U/S for NC/RC during the same 6-month period as our cases. Four cases of NC/RC were excluded because of inability to find an appropriate matched control using our matching criteria. Drug exposures prior to the diagnosis of NC/RC were recorded. This
Outcome and exposures
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study is reported in accordance with the STROBE guidelines for observational studies [11].
Our main outcomes of interest were hypertension (defined using age, length, and gender
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standardized criteria) [12], renal function (defined with serum creatinine measurements), and time to resolution of NC/RC at follow-up. Follow-up time was calculated from the date of diagnosis to the date of last follow-up.
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Retrospective chart and discharge documents were reviewed to collect information on exposures identified in the literature predisposing to formation of NC/RC, including prematurity (gestational age <37 weeks), low birth weight (<2,500 g), small for gestational age (<10th percentile weight), use of nephrotoxic drugs, respiratory support usage (duration of ventilation, oxygen requirements, surfactant, antenatal steroid use), TPN use, any surgeries, history of UTIs, creatinine at presentation (IDMS traceable), and history of maternal hypertension. Statistical analysis
ACCEPTED MANUSCRIPT 4 Unadjusted odds ratios were estimated for the risk factors being investigated. A chi-square analysis was performed for binary variables, while the Mann-Whitney U test was used for continuous variables. Statistical analyses were carried out using Stata, v.11.2 software. Ethics approval
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This work received ethic approval through the Western University Human Research Ethics Board. Results
Between January 2002 and December 2014, there were 68,901 births and 9,256 neonates were admitted to the NICU. We identified 26 cases of NC or RC, or both. Sixteen of the 26 cases had NC
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alone, 14 had RC alone, and four patients had both NC and RC. Despite extensive review we could only match 22 of the 26 cases using our matching criteria who also had an ultrasound examination during the same time period. We therefore used these 22 cases and matched controls to perform our
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risk factor analysis and used the 26 patient cohort to study outcomes. Controls were well matched, with eight female controls and eight female cases, respectively, with a median gestational age of 236.5 days (IQR 189-266) for controls and 236.5 days (IQR 189-267) for cases (p 0.971) (Table 1). Median follow-up time was 28 months (IQR 0-122). In no case was there a positive family history of renal tubular acidosis, cystinuria, or hyperoxaluria. Exposures
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Birth weight, prematurity, and multiple gestation were not associated with a higher odds ratio of having NC/RC (Table 1). No demographic characteristics were associated with an increased odds ratio of NC or RC. Assessed characteristics included birth weight (cases 1,984 g, control 1,830 g, p
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0.779), prematurity (control 13/22, cases 13/22, p 1.0), or being a multiple gestation (control 6/22, cases 6/22, p 0.762). Respiratory therapy was not associated with an increased odds ratio of NC or RC. Assessed characteristics included ventilator support (p 0.883), CPAP exposure (p 0.508),
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oxygen support (p 0.660), or surfactant exposure (p 0.275). No medication exposure was associated with an increased odds ratio of NC or RC. Assessed medications included furosemide (p 0.121), hydrochlorothiazide or spironolactone (p 0.154), aminoglycoside (p 0.361), vancomycin (p 0.762), meropenem (p 0.393), or indomethacin or non-steroidal anti-inflammatory drugs (p 1.0). Among other exposures, only previous urinary tract infection was significantly associated with an increased odds ratio of NC or RC (OR 5.62, 1.12-31.1). Assessed characteristics also included TPN use (0.750), maternal hypertension (p 0.667), and previous surgery (p 0.667) (Table 1).
ACCEPTED MANUSCRIPT 5 We performed a descriptive analysis to assess for the possibility of concurrent multiple risk factors contributing towards NC/RC. We used a combination of primary risk factors identified in the literature to see if we could find an effect modifier or a combination of risk factors which were imbalanced in favor of our cases rather than the controls to suggest etiologic association. We found
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that our cases and controls were well balanced on the probability of having been exposed to both antenatal steroids and ventilation support (cases n=6, control n=5), TPN and ventilation support (cases n=7, control n=6), nephrotoxic exposure and ventilation support (cases n=2, control n=3), and low birth weight and nephrotoxic exposure (cases n=12, control n=8).
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Outcomes
Thirteen (59.1%) patients in the NC/RC group received medical treatment. Of these, six received hydrochlorathiazide, 11 received citrate-based therapy, and four received both. The mean urinary
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calcium/creatinine ratio for the NC/RC group was 2.3±1.5 at diagnosis and 0.96±0.8 at last followup. Ca:Cr ratio was >0.2 mmol/mmol in 21/21 of available cases. Sixteen (72.7%) patients in the NC/RC group had radiologic resolution documented on ultrasound, within a median follow-up duration of 12.1 months (IQR 0.5-50). The remainder had ongoing radiographic evidence of NC/RC. Five patients in the NC/RC group were initially found to have elevated blood pressures, but only one had persistent hypertension at the last follow-up visit. In the control group, two patients
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were initially hypertensive but were normotensive at the last follow-up visit. At a median follow-up time of 28 months, there was no difference in the prevalence of hypertension between the two groups (RR 2.94, 95% CI 0.40-33.82, p=0.216) (Table 2).
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Discussion
This case-control analysis investigates both risk factors and outcomes of nephrocalcinosis and renal calculi including both preterm and term infants. While we assessed several presumed risk factors
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for NC/RC in neonates identified in previous studies, only prior urinary tract infections was significantly associated with NC/RC in our case-control analysis. Furthermore, we found no difference between our infants with NC/RC and controls in incidence of hypertension. In addition, even though only 59% of NC/RC cases received medical therapy, most (72.7%) had resolution of their NC/RC at a median follow-up of 12.1 months. Hypercalciuria was the most common reason for medical intervention. Only three other matched cohort studies have been conducted in this population, but all had smaller sample sizes than our study and involved only preterm infants. Porter et al. examined urine biochemistry, renal function, and resolution of NC in 14 very low birth weight
ACCEPTED MANUSCRIPT 6 preterm infants. Patients were matched for birth weight, sex, and gestational age. No significant difference was identified in urinary parameters, and 75% of cases resolved at a median of 6.7 years, in keeping with our analyses [13]. Saarela et al. assessed 20 cases of neonatal NC matched for postnatal age and birth weight to investigate tubular and glomerular function. They found that some
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degree of renal tubular dysfunction, primarily increased urinary calcium and β-microglobulin was associated with NC, but did not seem to compromise GFR [3]. Giapros et al. found that kidney length was reduced in preterm neonates with NC, but eGFR was equivalent between preterm neonates with NC compared with controls. While these studies provide information regarding the
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potential sequelae of NC, they did not explore risk factors associated with the condition as in our analysis [14].
The only variable associated with NC/RC identified in our study was a prior history of UTIs.
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However, it is unclear whether or not UTIs predispose to NC/RC or vice versa, although it is well known that UTIs are a risk factor for urolithiasis in the adult population [15]. In contrast to our findings, Schell-Feith et al. did not find a difference in the incidence of UTI among 83 preterm infants with nephrocalcinosis (2.5%) compared with those without (4.4%) [1]. Our analysis did not show an association between furosemide and NC/RC despite its more established association in the literature [1,4–6]. This is probably a reflection of our sample size as
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furosemide usage was documented in 27% of our controls as opposed to 50% of our cases. In addition, 59% of our cases and controls were premature and it is possible that the adverse effect of furosemide would be more obvious in a population consisting only of premature babies. There have
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been a handful of studies documenting other risk factors including low birth weight [7], glucocorticoid use [8], parenteral nutrition [1,6], nephrotoxic medications [9], and prolonged oxygen supplementation or ventilation [8–10]. However, none of these were found to be in
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association with NC/RC in our study, which again may be a reflection of our small sample size or represent a lack of controls and confounding in the other studies showing these associations. The median time to resolution of NC/RC in our analysis was 12.1 months, with 72.7% of the patients achieving resolution at the end of the study period. A study by Schell-Feith et al. reported that nephrocalcinosis persisted for longer than 15 months in 34% and more than 30 months in 15%. The majority of NC/RC appear to resolve with conservative management, and none of the patients in our study required operative intervention. The prevalence of hypertension in the NC/RC group at last follow-up did not appear to be greater than that of the matched controls. While Kist-van Holthe et al. found that there was no
ACCEPTED MANUSCRIPT 7 difference in blood pressure in ex-preterm neonates with and without NC, the blood pressure was significantly higher than expected for healthy non-preterm children with NC [2]. Schell-Feith et al. found that over a third of preterm infants with NC had blood pressures above the 95th percentile at 2 years, although no control group was available for comparison [1].
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Other studies have examined long-term renal function associated with NC/RC. Nephrocalcinosis was not associated with renal compromise in the cohort studied by Porter et al. [13]. Similarly, Kist-van Holthe et al. found that mean GFR did not differ in those with or without NC in their preterm infant population. They did, however, note lower tubular phosphate
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reabsorption and plasma bicarbonate levels [2]. Renal dysfunction was observed in a small cohort of 11 preterm infants, but the decreased GFR was attributed to prematurity rather than the presence of renal calcifications [16].
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There are several limitations of our study. It is retrospective; therefore, we were unable to control for confounders and are limited to data that were captured at the time of NICU admission. Further, because of this retrospective analysis, we cannot establish a temporal relationship between exposures and outcomes. We also used patient creatinine as a marker of kidney function within our population, although it would have been more robust to calculate eGFR. The length of patients with hypertension were recorded at birth, at the time of discharge from the NICU, and at the time of
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follow-up in the pediatric nephrology clinic. Patient length at time of follow-up was not available for all infants in the control group, aside from measurements at birth and NICU discharge, as they would not have required monitoring by the pediatric nephrologist. Patients in the control group
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often did not have any indication for urine studies, therefore urine biochemistry could not be compared between the groups. We also had a small sample size, much like many other studies in the literature and numbers for some parameters were small. We did not have information on the
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method of urine capture, which is unlikely to differ between our groups but there could be high levels of contamination. Also, our study did not include any children with congenital anomalies of the kidneys and urinary tract which is a limitation as the prevalence of nephrolithiasis could be higher and the outcomes less favorable within this population. Finally, our data were restricted to infants who were admitted to the NICU, therefore our conclusions cannot be applied to the healthy neonatal population in general. Conclusion Our findings demonstrate that most cases of NC/RC resolve spontaneously or with medical therapy, without the need for surgical intervention. There does not appear to be an increased incidence of
ACCEPTED MANUSCRIPT 8 renal compromise or elevated blood pressure associated with these conditions. Larger prospective multicenter studies are warranted as there continue to be conflicting data regarding risk factors for NC/RC in neonates. Conflict of interest
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None. Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors
1.
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References
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Nephrol. 2003; 18: 1102–1108. 2.
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DW, et al. Preterm neonates with nephrocalcinosis: natural course and renal function. Pediatr.
Kist-van Holthe JE, van Zwieten PHT, Schell-Feith EA, Zonderland HM, Holscher HC, Wolterbeek R, et al. Is nephrocalcinosis in preterm neonates harmful for long-term blood pressure and renal function? Pediatrics 2007; 119: 468–475.
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Saarela T, Lanning P, Koivisto M: Prematurity-associated nephrocalcinosis and kidney function in early childhood. Pediatr. Nephrol. Berl. Ger. 1999; 13: 886–890. Hufnagle KG, Khan SN, Penn D, Cacciarelli A, Williams P. Renal calcifications: a
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complication of long-term furosemide therapy in preterm infants. Pediatrics 1982; 70: 360– 363.
Downing GJ, Egelhoff JC, Daily DK, Alon U. Furosemide-related renal calcifications in the
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premature infant. A longitudinal ultrasonographic study. Pediatr. Radiol. 1991; 21: 563–565. 6.
Hoppe B, Hesse A, Neuhaus T, Fanconi S, Forster I, Blau N, Leumann E. Urinary saturation
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and nephrocalcinosis in preterm infants: effect of parenteral nutrition. Arch. Dis. Child. 1993; 69: 299–303. 7.
Karlowicz MG, Katz ME, Adelman RD, Solhaug MJ. Nephrocalcinosis in very low birth weight neonates: family history of kidney stones and ethnicity as independent risk factors. J. Pediatr. 1993; 122: 635–638.
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Chang H-Y, Hsu C-H, Tsai J-D, Li ST, Hung HY, Kao HA, et al. Renal calcification in very low birth weight infants. Pediatr. Neonatol. 2011; 52: 145–149.
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Narendra A, White M, Rolton H, Alloub ZI, Wilkinson G, McColl JH, Beattie J. Nephrocalcinosis in preterm babies. Arch. Dis. Child. Fetal Neonatal Ed. 2001; 85: F207– F213.
10. Short A, Cooke RW. The incidence of renal calcification in preterm infants. Arch. Dis. Child.
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1991; 66: 412–417. 11. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP; STROBE Initiative. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ 2007; 335: 806–808.
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12. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents: The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004; 114: 555–576.
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13. Porter E, McKie A, Beattie TJ, McColl JH, Aladangady N, Watt A, White MP. Neonatal nephrocalcinosis: long term follow up. Arch. Dis. Child. Fetal Neonatal Ed. 2006; 91: F333– F336.
14. Giapros V, Drougia A, Hotoura E, Papadopoulou F, Argyropoulou M, Andronikou S. Kidney growth in small-for-gestational-age infants: Evidence of early accelerated renal growth. Nephrol. Dial. Transplant. 2006; 21: 3422–3427.
32–36.
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15. Miano R, Germani S, Vespasiani G: Stones and Urinary Tract Infections. Urol. Int. 2007; 79:
16. Jones CA, King S, Shaw NJ, Judd BA. Renal calcification in preterm infants: follow up at 4-5
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years. Arch. Dis. Child. Fetal Neonatal Ed. 1997; 76: F185-189.
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Table 1. Demographic characteristics of study population Birth weight, grams, median (IQR) Low birth weight (<2500 g) Prematurity (<37 weeks) Small for gestational age (<10th percentile) Multiple gestation Ventilator support, days, median (IQR) CPAP, days, median (IQR)
Controls (n=22)
OR (95% CI)
p-value
1830 (970–3100) 13 (59.0%) 13 (59.0%)
Cases (n=22) 1984 (1045– 2610) 15 (68.1%) 13 (59.0%)
–– 1.48 (0.36–6.13 1.0
0.77 0.53 1.0
8 (36.3) 6 (27.2)
6(27.2) 6 (27.2)
0.65 (0.14–2.81) 0.81 (0.17–3.88)
0.51 0.76
2 (0–38) 0 (0–6)
2.5 (0–28) 1 (0–15)
–– ––
0.88 0.50
ACCEPTED MANUSCRIPT 10 1.5 (0–70) 6 (27.2) 4 (18.1) 15 (68.1)
5 (0–70) 9 (40.9) 10 (45.4) 16 (72.7)
–– 0.66 2.04 (0.47–9.16) 0.27 5.62 (1.12–31.1) 0.01 1.24 (0.28–5.61) 0.74 2.66 (0.64– 6 (27.2) 11 (50.0%) 11.62) 0.12 HCTZ/spironolactone 4.66 (0.399– exposure 1 (4.5%) 4 (18.1%) 240.50) 0.15 Aminoglycoside exposure 11 (50.0%) 14 (81.8%) 1.75 (0.44–6.42) 0.36 Vancomycin exposure 11 (50.0%) 10 (45.4) 0.83 (0.21–3.18) 0.76 Meropenem exposure 0.12 (0.002– 6 (27.2) 1 (4.5%) 1.25) 0.39 Indocid/NSAID exposure 6 (27.2) 6 (27.2) 1.0 (0.21–4.65) 1.0 Total parenteral nutrition 14 (81.8%) 15 (68.1) 1.22 (0.29–5.31) 0.75 Maternal hypertension 8 (36.3%) 6 (27.2) 1.37 (0.25–7.41) 0.66 Previous surgery 14 (81.8%) 9 (40.9%) 0.39 (0.09–1.55) 0.13 CPAP = continuous positive airway pressure; HCTZ = hydrochlorothiazide; NSAID = non-steroidal anti-inflammatory drugs.
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Oxygen, days, median (IQR) Surfactant exposure Previous urinary tract infection Nephrotoxic drug exposure Furosemide exposure
Chi-square test for binary variables. Mann-Whitney U test for continuous variables.
OR (95% CI)
p-value
2
5
2.94 (0.40-33.82)
0.21
2
4
0
0.49
12.1
--
--
72.7
--
--
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Cases (n=22)
--
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Hypertension at diagnosis Hypertension resolved Mean time to resolution of renal calcifications (months) Percentage that had resolution of renal calcifications (%)
Control (n=22)
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Table 2. Clinical outcomes
--
S1477-5131(17)30288-7
DOI:
10.1016/j.jpurol.2017.06.018
Reference:
JPUROL 2604
To appear in:
Journal of Pediatric Urology
Received Date: 5 January 2017 Revised Date:
1477-5131 1477-5131
Accepted Date: 29 June 2017
Please cite this article as: Huynh M, Clark R, Li J, Filler G, Dave S, A case control analysis investigating risk factors and outcomes for nephrocalcinosis and renal calculi in neonates, Journal of Pediatric Urology (2017), doi: 10.1016/j.jpurol.2017.06.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 PU FALL CONGRESS DALLAS 2016 A case control analysis investigating risk factors and outcomes for nephrocalcinosis and renal calculi in neonates
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Melissa Huynha, Roderick Clarka, Jenny Lib, Guido Fillerc,d,e, and Sumit Davea,c,*
Department of Surgery (Urology), Western University, London Ontario
b
Schulich School and Medicine & Dentistry, Western University, London Ontario
c
Department of Paediatrics (Nephrology), Western University, London, Ontario
d
Department of Medicine (Nephrology)
e
Department of Pathology & Laboratory Medicine, Western University, London Ontario
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a
* Corresponding author. Department of Surgery and Pediatrics, Western University, Room E2-650, 800 Commissioners Road East, London, Ontario, Canada, N6A 5W9. E-mail address: [email protected]
Summary Introduction: Studies on outcomes and risk factors for neonatal nephrocalcinosis (NC)
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and renal calculi (RC) are limited, and often do not include controls for comparison. We conducted a case–control analysis to identify risk factors associated with NC and/or RC in neonates and studied the natural course of these anomalies.
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Study design: Infants diagnosed with NC/RC on ultrasound within the first year of life and corresponding gestational age- and gender-matched controls were identified from the neonatal intensive care unit database at our institution over a 10-year period. Risk factors assessed included:
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low birth weight, small for gestational age, nephrotoxic drugs, respiratory support therapy, use of total parental nutrition (TPN), surgeries, history of UTIs, creatinine at presentation, and history of maternal hypertension. Unadjusted odds ratios were estimated. Chi square analysis was performed for binary variables and the Mann-Whitney U test for continuous variables. Outcomes examined include time to resolution of NC/RC, renal function, and hypertension. Results: We identified 22 cases of NC/RC with corresponding matched controls. Median follow-up was 28 months (IQR 0-122 months). History of urinary tract infections (UTI) was the only variable significantly associated with the presence of NC/RC (OR 5.62, 95% CI 1.12-31.1, p <0.013) (Table). All other known risk factors were comparable in both groups. There was no difference in
ACCEPTED MANUSCRIPT 2 the incidence of hypertension (OR 2.94, 95% CI 0.40-33.82, p=0.216) at diagnosis or last follow-up between the groups. Resolution of NC/RC was observed in 72.7%, during a median follow-up of 12.1 months. Mean urinary calcium/creatinine ratio for the NC/RC group was 2.3±1.5 at diagnosis and 0.96±0.8 at last follow-up.
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Discussion: Most NC/RC in infants resolve without surgical intervention but some infants require medical therapy and follow-up. Risk factors for NC/RC in neonates continue to be poorly defined because of the quality of studies available. Our study provides further adjustment for confounders but has a small sample size and is restricted to neonates from an intensive care unit.
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Conclusion: Most cases of NC/RC resolve spontaneously without surgical intervention. The mean time to resolution is 12.1 months, without untoward consequences in terms of hypertension. A history of UTIs is the only identified risk factor identified in this study which is associated with a
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significant increased risk of neonatal nephrocalcinosis and/or renal calculi. Larger prospective studies are warranted to confirm these findings.
KEYWORDS Renal stones;
Neonate; Case-control study
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Nephrocalcinosis;
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Table. Selected risk factors for NC/RC
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Controls (n=22) Cases (n=22) OR (95% CI) Ventilator support, days, median (IQR) 2 (0-38) 2.5 (0-28) -Nephrotoxic drug exposure 15 (68.1) 16 (72.7) 1.24 (0.28-5.61) Small for gestational age 8 (36.3) 6(27.2) 0.65 (0.14-2.81) Previous urinary tract infection 4 (18.1) 10 (45.4) 5.62 (1.12-31.1) Chi-square test for binary variables. Mann-Whitney U test for continuous variables.
p-value 0.883 0.741 0.517 0.013
Introduction The prevalence of nephrocalcinosis (NC) in preterm neonates is between 7% and 41% [1], and has been associated with hypertension, chronic kidney disease, and significantly smaller kidney lengths during childhood [2,3]. The proposed risk factors for NC include furosemide use [1,4–6], low birth weight [7], glucocorticoid use [8], parenteral nutrition [1,6], nephrotoxic medications [9], and
ACCEPTED MANUSCRIPT 3 prolonged oxygen supplementation or ventilation [8–10]. In addition, many studies have identified gestational age as associated with NC, although there is likely significant confounding between this and the other risk factors for NC/and or RC. Unfortunately, previous studies are observational, lack control groups, and focus on either risk factors or outcomes but not both. Therefore, we conducted a
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case-control analysis to determine the risk factors for NC and renal calculi (RC) comparing neonates with similar gestational age and studying whether the known risk factors retained
significance in a matched case-control analysis. In addition, we determined the clinical outcomes of these conditions. We hypothesized that the etiology of NC/RC in neonates is multifactorial
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Methods Study design and population
We conducted a retrospective matched case-control study for exposures and a retrospective
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matched cohort study for outcomes using our neonatal intensive care unit (NICU) database to identify all ultrasound (U/S)-proven cases of NC/RC in infants admitted to the NICU at a tertiary care centre between January 2002 and December 2014. Controls were matched 1:1 for gestational age and had a negative renal/bladder U/S for NC/RC during the same 6-month period as our cases. Four cases of NC/RC were excluded because of inability to find an appropriate matched control using our matching criteria. Drug exposures prior to the diagnosis of NC/RC were recorded. This
Outcome and exposures
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study is reported in accordance with the STROBE guidelines for observational studies [11].
Our main outcomes of interest were hypertension (defined using age, length, and gender
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standardized criteria) [12], renal function (defined with serum creatinine measurements), and time to resolution of NC/RC at follow-up. Follow-up time was calculated from the date of diagnosis to the date of last follow-up.
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Retrospective chart and discharge documents were reviewed to collect information on exposures identified in the literature predisposing to formation of NC/RC, including prematurity (gestational age <37 weeks), low birth weight (<2,500 g), small for gestational age (<10th percentile weight), use of nephrotoxic drugs, respiratory support usage (duration of ventilation, oxygen requirements, surfactant, antenatal steroid use), TPN use, any surgeries, history of UTIs, creatinine at presentation (IDMS traceable), and history of maternal hypertension. Statistical analysis
ACCEPTED MANUSCRIPT 4 Unadjusted odds ratios were estimated for the risk factors being investigated. A chi-square analysis was performed for binary variables, while the Mann-Whitney U test was used for continuous variables. Statistical analyses were carried out using Stata, v.11.2 software. Ethics approval
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This work received ethic approval through the Western University Human Research Ethics Board. Results
Between January 2002 and December 2014, there were 68,901 births and 9,256 neonates were admitted to the NICU. We identified 26 cases of NC or RC, or both. Sixteen of the 26 cases had NC
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alone, 14 had RC alone, and four patients had both NC and RC. Despite extensive review we could only match 22 of the 26 cases using our matching criteria who also had an ultrasound examination during the same time period. We therefore used these 22 cases and matched controls to perform our
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risk factor analysis and used the 26 patient cohort to study outcomes. Controls were well matched, with eight female controls and eight female cases, respectively, with a median gestational age of 236.5 days (IQR 189-266) for controls and 236.5 days (IQR 189-267) for cases (p 0.971) (Table 1). Median follow-up time was 28 months (IQR 0-122). In no case was there a positive family history of renal tubular acidosis, cystinuria, or hyperoxaluria. Exposures
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Birth weight, prematurity, and multiple gestation were not associated with a higher odds ratio of having NC/RC (Table 1). No demographic characteristics were associated with an increased odds ratio of NC or RC. Assessed characteristics included birth weight (cases 1,984 g, control 1,830 g, p
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0.779), prematurity (control 13/22, cases 13/22, p 1.0), or being a multiple gestation (control 6/22, cases 6/22, p 0.762). Respiratory therapy was not associated with an increased odds ratio of NC or RC. Assessed characteristics included ventilator support (p 0.883), CPAP exposure (p 0.508),
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oxygen support (p 0.660), or surfactant exposure (p 0.275). No medication exposure was associated with an increased odds ratio of NC or RC. Assessed medications included furosemide (p 0.121), hydrochlorothiazide or spironolactone (p 0.154), aminoglycoside (p 0.361), vancomycin (p 0.762), meropenem (p 0.393), or indomethacin or non-steroidal anti-inflammatory drugs (p 1.0). Among other exposures, only previous urinary tract infection was significantly associated with an increased odds ratio of NC or RC (OR 5.62, 1.12-31.1). Assessed characteristics also included TPN use (0.750), maternal hypertension (p 0.667), and previous surgery (p 0.667) (Table 1).
ACCEPTED MANUSCRIPT 5 We performed a descriptive analysis to assess for the possibility of concurrent multiple risk factors contributing towards NC/RC. We used a combination of primary risk factors identified in the literature to see if we could find an effect modifier or a combination of risk factors which were imbalanced in favor of our cases rather than the controls to suggest etiologic association. We found
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that our cases and controls were well balanced on the probability of having been exposed to both antenatal steroids and ventilation support (cases n=6, control n=5), TPN and ventilation support (cases n=7, control n=6), nephrotoxic exposure and ventilation support (cases n=2, control n=3), and low birth weight and nephrotoxic exposure (cases n=12, control n=8).
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Outcomes
Thirteen (59.1%) patients in the NC/RC group received medical treatment. Of these, six received hydrochlorathiazide, 11 received citrate-based therapy, and four received both. The mean urinary
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calcium/creatinine ratio for the NC/RC group was 2.3±1.5 at diagnosis and 0.96±0.8 at last followup. Ca:Cr ratio was >0.2 mmol/mmol in 21/21 of available cases. Sixteen (72.7%) patients in the NC/RC group had radiologic resolution documented on ultrasound, within a median follow-up duration of 12.1 months (IQR 0.5-50). The remainder had ongoing radiographic evidence of NC/RC. Five patients in the NC/RC group were initially found to have elevated blood pressures, but only one had persistent hypertension at the last follow-up visit. In the control group, two patients
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were initially hypertensive but were normotensive at the last follow-up visit. At a median follow-up time of 28 months, there was no difference in the prevalence of hypertension between the two groups (RR 2.94, 95% CI 0.40-33.82, p=0.216) (Table 2).
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Discussion
This case-control analysis investigates both risk factors and outcomes of nephrocalcinosis and renal calculi including both preterm and term infants. While we assessed several presumed risk factors
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for NC/RC in neonates identified in previous studies, only prior urinary tract infections was significantly associated with NC/RC in our case-control analysis. Furthermore, we found no difference between our infants with NC/RC and controls in incidence of hypertension. In addition, even though only 59% of NC/RC cases received medical therapy, most (72.7%) had resolution of their NC/RC at a median follow-up of 12.1 months. Hypercalciuria was the most common reason for medical intervention. Only three other matched cohort studies have been conducted in this population, but all had smaller sample sizes than our study and involved only preterm infants. Porter et al. examined urine biochemistry, renal function, and resolution of NC in 14 very low birth weight
ACCEPTED MANUSCRIPT 6 preterm infants. Patients were matched for birth weight, sex, and gestational age. No significant difference was identified in urinary parameters, and 75% of cases resolved at a median of 6.7 years, in keeping with our analyses [13]. Saarela et al. assessed 20 cases of neonatal NC matched for postnatal age and birth weight to investigate tubular and glomerular function. They found that some
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degree of renal tubular dysfunction, primarily increased urinary calcium and β-microglobulin was associated with NC, but did not seem to compromise GFR [3]. Giapros et al. found that kidney length was reduced in preterm neonates with NC, but eGFR was equivalent between preterm neonates with NC compared with controls. While these studies provide information regarding the
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potential sequelae of NC, they did not explore risk factors associated with the condition as in our analysis [14].
The only variable associated with NC/RC identified in our study was a prior history of UTIs.
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However, it is unclear whether or not UTIs predispose to NC/RC or vice versa, although it is well known that UTIs are a risk factor for urolithiasis in the adult population [15]. In contrast to our findings, Schell-Feith et al. did not find a difference in the incidence of UTI among 83 preterm infants with nephrocalcinosis (2.5%) compared with those without (4.4%) [1]. Our analysis did not show an association between furosemide and NC/RC despite its more established association in the literature [1,4–6]. This is probably a reflection of our sample size as
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furosemide usage was documented in 27% of our controls as opposed to 50% of our cases. In addition, 59% of our cases and controls were premature and it is possible that the adverse effect of furosemide would be more obvious in a population consisting only of premature babies. There have
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been a handful of studies documenting other risk factors including low birth weight [7], glucocorticoid use [8], parenteral nutrition [1,6], nephrotoxic medications [9], and prolonged oxygen supplementation or ventilation [8–10]. However, none of these were found to be in
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association with NC/RC in our study, which again may be a reflection of our small sample size or represent a lack of controls and confounding in the other studies showing these associations. The median time to resolution of NC/RC in our analysis was 12.1 months, with 72.7% of the patients achieving resolution at the end of the study period. A study by Schell-Feith et al. reported that nephrocalcinosis persisted for longer than 15 months in 34% and more than 30 months in 15%. The majority of NC/RC appear to resolve with conservative management, and none of the patients in our study required operative intervention. The prevalence of hypertension in the NC/RC group at last follow-up did not appear to be greater than that of the matched controls. While Kist-van Holthe et al. found that there was no
ACCEPTED MANUSCRIPT 7 difference in blood pressure in ex-preterm neonates with and without NC, the blood pressure was significantly higher than expected for healthy non-preterm children with NC [2]. Schell-Feith et al. found that over a third of preterm infants with NC had blood pressures above the 95th percentile at 2 years, although no control group was available for comparison [1].
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Other studies have examined long-term renal function associated with NC/RC. Nephrocalcinosis was not associated with renal compromise in the cohort studied by Porter et al. [13]. Similarly, Kist-van Holthe et al. found that mean GFR did not differ in those with or without NC in their preterm infant population. They did, however, note lower tubular phosphate
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reabsorption and plasma bicarbonate levels [2]. Renal dysfunction was observed in a small cohort of 11 preterm infants, but the decreased GFR was attributed to prematurity rather than the presence of renal calcifications [16].
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There are several limitations of our study. It is retrospective; therefore, we were unable to control for confounders and are limited to data that were captured at the time of NICU admission. Further, because of this retrospective analysis, we cannot establish a temporal relationship between exposures and outcomes. We also used patient creatinine as a marker of kidney function within our population, although it would have been more robust to calculate eGFR. The length of patients with hypertension were recorded at birth, at the time of discharge from the NICU, and at the time of
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follow-up in the pediatric nephrology clinic. Patient length at time of follow-up was not available for all infants in the control group, aside from measurements at birth and NICU discharge, as they would not have required monitoring by the pediatric nephrologist. Patients in the control group
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often did not have any indication for urine studies, therefore urine biochemistry could not be compared between the groups. We also had a small sample size, much like many other studies in the literature and numbers for some parameters were small. We did not have information on the
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method of urine capture, which is unlikely to differ between our groups but there could be high levels of contamination. Also, our study did not include any children with congenital anomalies of the kidneys and urinary tract which is a limitation as the prevalence of nephrolithiasis could be higher and the outcomes less favorable within this population. Finally, our data were restricted to infants who were admitted to the NICU, therefore our conclusions cannot be applied to the healthy neonatal population in general. Conclusion Our findings demonstrate that most cases of NC/RC resolve spontaneously or with medical therapy, without the need for surgical intervention. There does not appear to be an increased incidence of
ACCEPTED MANUSCRIPT 8 renal compromise or elevated blood pressure associated with these conditions. Larger prospective multicenter studies are warranted as there continue to be conflicting data regarding risk factors for NC/RC in neonates. Conflict of interest
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None. Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors
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References
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Table 1. Demographic characteristics of study population Birth weight, grams, median (IQR) Low birth weight (<2500 g) Prematurity (<37 weeks) Small for gestational age (<10th percentile) Multiple gestation Ventilator support, days, median (IQR) CPAP, days, median (IQR)
Controls (n=22)
OR (95% CI)
p-value
1830 (970–3100) 13 (59.0%) 13 (59.0%)
Cases (n=22) 1984 (1045– 2610) 15 (68.1%) 13 (59.0%)
–– 1.48 (0.36–6.13 1.0
0.77 0.53 1.0
8 (36.3) 6 (27.2)
6(27.2) 6 (27.2)
0.65 (0.14–2.81) 0.81 (0.17–3.88)
0.51 0.76
2 (0–38) 0 (0–6)
2.5 (0–28) 1 (0–15)
–– ––
0.88 0.50
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5 (0–70) 9 (40.9) 10 (45.4) 16 (72.7)
–– 0.66 2.04 (0.47–9.16) 0.27 5.62 (1.12–31.1) 0.01 1.24 (0.28–5.61) 0.74 2.66 (0.64– 6 (27.2) 11 (50.0%) 11.62) 0.12 HCTZ/spironolactone 4.66 (0.399– exposure 1 (4.5%) 4 (18.1%) 240.50) 0.15 Aminoglycoside exposure 11 (50.0%) 14 (81.8%) 1.75 (0.44–6.42) 0.36 Vancomycin exposure 11 (50.0%) 10 (45.4) 0.83 (0.21–3.18) 0.76 Meropenem exposure 0.12 (0.002– 6 (27.2) 1 (4.5%) 1.25) 0.39 Indocid/NSAID exposure 6 (27.2) 6 (27.2) 1.0 (0.21–4.65) 1.0 Total parenteral nutrition 14 (81.8%) 15 (68.1) 1.22 (0.29–5.31) 0.75 Maternal hypertension 8 (36.3%) 6 (27.2) 1.37 (0.25–7.41) 0.66 Previous surgery 14 (81.8%) 9 (40.9%) 0.39 (0.09–1.55) 0.13 CPAP = continuous positive airway pressure; HCTZ = hydrochlorothiazide; NSAID = non-steroidal anti-inflammatory drugs.
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Oxygen, days, median (IQR) Surfactant exposure Previous urinary tract infection Nephrotoxic drug exposure Furosemide exposure
Chi-square test for binary variables. Mann-Whitney U test for continuous variables.
OR (95% CI)
p-value
2
5
2.94 (0.40-33.82)
0.21
2
4
0
0.49
12.1
--
--
72.7
--
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Cases (n=22)
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Hypertension at diagnosis Hypertension resolved Mean time to resolution of renal calcifications (months) Percentage that had resolution of renal calcifications (%)
Control (n=22)
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Table 2. Clinical outcomes
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