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Background: Neonatal nephrocalcinosis (NC) and renal calculi (RC) are rare and the current literature lacks studies, which compare risk factors and outcomes between cases and controls. This study uses a case-control analysis to identify risk factors for NC/RC and assesses outcomes in these neonates.
Methods: After obtaining ethics approval, we performed a case-control analysis using the neonatal intensive care (NICU) database to identify all cases of NC/RC in infants between January 2002 and December 2014 diagnosed on ultrasound (US) within the first year of life. Age- and gender- matched controls were selected from the same database who had undergone US imaging during the same time period. We assessed the following risk factors in our 2 groups: prematurity (gestational age < 37 weeks), low birth weight (< 2500 g), small for gestational age (<10^th percentile weight), use of nephrotoxic drugs, respiratory factors (duration of ventilation, oxygen requirements, surfactant, antenatal steroid use), total parental nutrition, any surgeries, history of UTIs, creatinine at presentation, and history of maternal hypertension. Unadjusted odds ratios were estimated for these risk factors. A Chi-square analysis was performed for binary variables, while the Mann-Whitney U test was used for continuous variables. Outcomes assessed include time to resolution of NC/RC, renal function and blood pressure at last follow-up.
Results: During the study period, there were 68,901 births and 9256 neonates admitted to the NICU. We identified 26 cases of NC (n=16) or RC (n=14), or both). Twenty-two of the 26 cases had corresponding gender- and age-matched controls. Previous history of UTIs was the only variable that was significantly associated with the presence of NC/RC (OR 5.62, 95% CI [1.12, 31.1] p <0.013) (Table 1). At a median follow-up time of 28 months (range 0-122), there was no difference in the incidence of hypertension between the two groups (OR 2.94, 95% CI [0.40, 33.82], p=0.216). Thirteen (59.1%) patients in the NC/RC group received medical treatment. Of these, 6 received hydrochlorathiazide, 11 received citrate-based therapy, and 4 received both. Sixteen (72.7%) patients in the NC/RC group had resolution documented on ultrasound, with a median time of 12.1 months to resolution (range 0.5-50). The remainder had ongoing radiographic evidence of nephrocalcinosis or renal calculi at the end of the study period. The 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. There was no significant difference in creatinine at diagnosis or at last follow-up between the 2 groups.
Conclusion:
The majority of NC/RC in neonates resolve spontaneously with medical therapy without surgical intervention. The mean time to resolution is 12.1 months, without overt long-term renal consequences. The only risk factor predisposing to NC/RC was a previous history of UTIs. This study was limited by the small number of patients like other studies in the literature. Therefore, larger prospective studies, involving multiple centers are warranted to confirm these findings.

Table 1. Demographic characteristics of study population
	Controls (n=22)	Cases (n=22)	OR (95% CI)	P-value
Female gender	9 (40.9%)	8 (36.3%)	1.21 (0.30-4.85)	0.756
Birth weight (median, grams) (IQR)	1830 (970-3100)	1984 (1045-2610)	--	0.779
Gestational age at birth (median, days)	236.5 (189-266)	236.5 (189-267)	--	0.971
Low birth weight (<2500 g)	13 (59.0%)	15 (68.1%)	1.48 (0.36-6.13	0.530
Prematurity (<37 weeks)	13 (59.0%)	13 (59.0%)	1.0	1.0
Small for gestational age (<10th percentile)	8 (36.3)	6(27.2)	0.65 (0.14-2.81)	0.517
Multiple gestation	6 (27.2)	6 (27.2)	0.81 (0.17-3.88)	0.762
Ventilator support (median, days) (IQR)	2 (0-38)	2.5 (0-28)	--	0.883
Continuous positive airway pressure (median, days) (IQR)	0 (0-6)	1 (0-15)	--	0.508
Oxygen (median, days) (IQR)	1.5 (0-70)	5 (0-70)	--	0.660
Surfactant exposure	6 (27.2)	9 (40.9)	2.04 (0.47-9.16)	0.275
Previous urinary tract infection	4 (18.1)	10 (45.4)	5.62 (1.12-31.1)	0.013
Nephrotoxic drug exposure	15 (68.1)	16 (72.7)	1.24 (0.28-5.61)	0.741
Furosemide exposure	6 (27.2)	11 (50.0%)	2.66 (0.64-11.62)	0.121
Hydrochlorathiazide/Spironolactone exposure	1 (4.5%)	4 (18.1%)	4.66 (0.399-240.50)	0.154
Aminoglycoside exposure	11 (50.0%)	14 (81.8%)	1.75 (0.44-6.42)	0.361
Vancomycin exposure	11 (50.0%)	10 (45.4)	0.83 (0.21-3.18)	0.762
Meropenem exposure	6 (27.2)	1 (4.5%)	0.12 (0.002-1.25)	0.393
Indocid/Nonsteroidal anti-inflammatory drug 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)	0.750
Maternal hypertension	8 (36.3%)	6 (27.2)	1.37 (0.25-7.41)	0.667
Previous surgery	14 (81.8%)	9 (40.9%)	0.39 (0.09-1.55)	0.131