| Abstract|| |
To determine the incidence and risk factors of nephrocalcinosis in preterm infants, we studied in a prospectively 64 preterm infants of birth weight :5 1500 g from February 2006 to November 2007. Data were collected on gestation, birth weight, gender and family history of renal calculi, respiratory support, and use of nephrotoxic drugs. The parameters of mineral metabolism were assessed in blood and spot urine samples at the end of 2 nd and 4 th weeks of age. Forty-nine babies completed the study, and nephrocalcinosis was observed in 13 (26.5%) babies and was bilateral in 7 (14.3%) infants. The mean age of diagnosis of nephrocalcinosis was 52.58 days (range 30-123 days). Gestational age, birth weight, and sex were not significantly associated with increased risk of nephrocalcinosis. The mean duration of ventilation was significantly less in babies with than without nephrocalcinosis (P= 0.020), and the mean levels of urine calcium and phosphate at 4 weeks of age, respectively (P= 0.013, P= 0.048). There were also significant differences in urine calcium/creatinine ratio (P= 0.001), mean plasma levels of calcium at 2 weeks of age (P= 0.047) and plasma levels of phosphate at 4 weeks of age (P= 0.016) between babies with and without nephrocalcinosis. Using logistic regression analysis, family history of renal stone (P= 0.002) and urine calcium/creatinine ratio (P= 0.011) were significant predictors of nephrocalcinosis. However, there were no significant differences in the length of stay in the intensive care unit, duration of total parenteral nutrition, and duration and cumulative doses of nephrotoxic drugs between these two groups. We conclude that the incidence of nephrocalcinosis was similar in our population to the previous studies. Family history of renal stone and urine calcium/ creatinine ratio are the major risk factors of nephrocalcinosis in very low birth weight neonates.
|How to cite this article:|
Nasseri F, Azhir A, Rahmanian S, Iranpour R, Adibi A. Nephrocalcinosis in very low birth weight infants. Saudi J Kidney Dis Transpl 2010;21:284-9
|How to cite this URL:|
Nasseri F, Azhir A, Rahmanian S, Iranpour R, Adibi A. Nephrocalcinosis in very low birth weight infants. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2023 Feb 9];21:284-9. Available from: https://www.sjkdt.org/text.asp?2010/21/2/284/60195
| Introduction|| |
Nephrocalcinosis (NC), diffuse deposition of calcium crystals in the parenchyma of the kidney, was first described in 1982 by Hufnagle et al in preterm babies.  The incidence of nephrocalcinosis varies between 16% and 64% depending on different study populations and ultrasonographic criteria. ,, Schell-Feith et al have demonstrated that ultrasonography (US) is appropriate for detecting NC in preterm babies, but better standardization is needed.  Shortterm complications include renal stones with obstruction of the urinary tract, urinary tract infection, and glomerular and tubular dysfunction. ,, Although a decrease in kidney function was considered as a long-term outcome in small-scale studies, , Porter et al found that a resolution of nephrocalcinosis occurred in 75% of the cases, and there was no evidence of renal dysfunction during the long-term follow up. 
Although a wide variety of renal, urologic, endocrine, and metabolic disorders was considered as an etiological factor for NC in adults and children, the exact etiology of NC in preterm neonates has not yet been fully clarified. , Low gestational age, low birth weight, use of nephrotoxic drugs such as aminoglycosides, male sex, length of assisted ventilation, hypercalciuria, and length of hospital stay were proposed as risk factors for NC in very low birth weight (VLBW) neonates. ,,,,
We aim from this prospective study to investigate the current incidence of nephrocalcinosis in a group of VLBW infants and to identify the possible causes and risk factors.
| Patients and Methods|| |
We studied prospectively neonates born with a birth weight of less than 1500 g who were treated in the neonatal intensive care unit at the university hospital, Isfahan, Iran from September 2006 to October 2007. The study protocol was approved by the local ethics committees, and informed written parental consent was obtained.
Babies born with major congenital anomalies or those who died or were transferred before the end of the study period were excluded. Data were recorded on gender, gestational age, birth weight, family history of renal calculi, duration of assisted ventilation and the number of days on total parentral nutrition, length of stay in hospital, and cumulative dose of treatment with frusemide, aminoglycoside, vancomycin, theophylline and dexamethasone. Plasma concentrations of calcium, phosphate, alkaline phosphatase were recorded at the end of 2 nd and 4 th weeks of life. Urinary calcium, phosphate, citrate and creatinine were measured in spot urine samples at the same time. Random urinary calcium/creatinine, phosphate/creatinine, citrate/creatinine ratios and calcium/citrate ratios were measured at 2 nd and 4 th weeks of life. Acid base status was determined with daily arterial blood gas during the first week of age.
The ultrasound examination was performed by a single consultant radiologist using state of the art equipment with a 7.5 MHz small-part transducer at the age of 4 weeks or at term. Nephrocalcinosis was diagnosed as type 3 or 4 using the calcification score of Pohlandt and Muller. 
Plasma electrolytes, including calcium (Ca) and phosphate (P), alkaline phosphatase were measured using a Technicon auto-analyzer. Urinary Ca, P, citrate, and creatinine were measured with the Vitrous 250 analyzer.
A urine Ca/creatinine ratio > 0.85 was considered to represent hypercalciuria.  Hyperphosphaturia was confirmed the urinary P:creatinine (UP/Ucr) ratio exceeded 1.2.  Hypocitraturia was diagnosed if the urinary citrate/creatinine (Ucitrate/Ucr) ratio was less than 0.56 ± 0.04.  Metabolic acidosis was diagnosed if PH was less than 7.25 and HCO 3 ≤ 14 or base excess (BE) :≤ - 6. 
All patients were fed according to the standard regimen of the ward: If possible, oral alimentation was started within the first days with the mother's milk. Human milk was supplemented with fortifier, when the babies received 100 mL/kg/day breast milk. In addition, a supplement of vitamin D (400 units) was started on day 10.
| Statistical Analysis|| |
Data were analyzed by SPSS (version 15) software. The means of the continuous parameters of the babies with and without nephrocalcinosis were compared by the student's test while the chi-squared for non-parametric data. P values < 0.05 were accepted as significant. Variables were entered into a multivariate analysis, namely binary logistic regression, to determine whether a small number of explanatory variables may be particularly important for discrimination between babies in both groups.
| Results|| |
A total of 64 eligible babies were identified; 4 babies died and 11 did not have the term ultrasound scan, which resulted in 49 babies who completed the study.
Fifteen (30%) babies had abnormal ultrasounds and 12 (24.5%) had NC. Unilateral pelvicaliceal dilation was detected in three babies. The mean age for the diagnosis of NC was 52.58 days (range 30-123 days). The NC was bilateral in 7 (14.3%) and unilateral in 6 (12.2%) infants.
[Table 1] shows that gestational age, birth weight, sex and family history of renal calculi were not significantly associated with an increased risk of NC. Eight (16%) neonates had BW < 1000 gram, and only 2 of them were diagnosed as NC. There were 6 babies of gestational age > 31-34 weeks and birth weight below 1500 g, and only one developed NC. There was a positive history of renal stone in her family.
Three (25%) babies with NC were ventilated compared with 11 (29%) of those without. The mean duration of ventilation was 3 days for babies with NC compared with 6.73 days for those without [P= 0.02, 95% CI (0.711, 6.472)]. We did not find any significant correlation between the use of medications such as aminoglicoside, vancomycin, theophylline and their cumulative doses with NC even when administered concomitantly.
Thirty-two babies without NC and 11 babies with NC received TPN; the mean duration of TPN days were 15.7 and 13.8, respectively, (P= 0.335). In addition, the mean duration of hospitalization in infants with and without NC was 26.7 and 28.0 days, respectively, (P= 0.630).
[Table 2] shows the means of the urinary and serum parameters in VLBW infants with and without nephrocalcinosis at 2 nd and 4 th week of life. There was a significant difference in the medium levels of plasma calcium at 2 weeks of age and plasma phosphate at 4 weeks of age between babies with and without NC, respectively, (P= 0.047, P= 0.016). There was a significant difference of the mean levels of urine Ca and P between babies with and without NC at the 4 th week of age, respectively, (P= 0.013, P= 0.048), and of calcium/creatinine ratio (P= 0.001). However, there was no significant difference of the urine level of citrate between babies with and without NC at 2 nd and 4 th weeks of age.
Using binary logistic regression test model, the strongest indicators of nephrocalcinosis were: family history of renal calculi (P= 0.049) and urine calcium/creatinine ratio at 2 nd week of age (P= 0.034).
| Discussion|| |
Our results demonstrate low incidence of NC in VLBW infants. The incidence of NC vary in different studies, perhaps reflecting variations in ultrasonic identification of NC, improvements in neonatal intensive care, particularly the antenatal use of steroids and surfactant and improved nutrition approaches. The incidence of NC was lower (22.4%) in our study compared to the earlier studies (64%)  but similar to studies in United Kingdom  and Scandinavia. 
The pathogenesis of NC in VLBW infants appears to be multifactorial.  Extreme imaturity and the underdevelopment of renal function may be the most important causes. ,,
Saarela et al  revealed that NC was identified three times more often in the VLBW infants with BW < 1000 g than in those with BW > 1000 g. Furthermore, several studies indicating an increased risk of NC in smaller and more premature infants. ,, However, we did not find NC to be associated with low gestational age and low birth weight, which could be explained by the fact that the majority of our neonates weighed more than 1000 gm.
In only one study, male sex was reported to be significantly associated with NC. In agreement with other studies, we did not find similar association.
Duration of ventilation and oxygen therapy was shown to be significantly associated with renal calcification in VLBW infants. , This is explained by the decreasing urinary citrate excretion, which is a known inhibitor of renal calcification, during severe respiratory disease.  Nevertheless, urinary citrate excretion was not decreased significantly in the babies with NC in our study, which may be due to lower duration of ventilation and oxygen therapy in them.
Cranefield et al,  Saarela et al  and Narendra et al  studies found an association between NC and postnatal dexamethasone, which may reflect the severity of the respiratory disease and low gestation.  However, we did not find such association in our study, which is probably due to less the use of postnatal dexamethasone in our patients.
There is controversy about the role of furosemide in NC. ,,,,, However, in our study, none of the patients received furosemide. Nephrotoxic antibiotic levels are strongly associated with NC independently of gestation.  Hypercalciuria with therapeutic doses of gentamicin has been found in full term infants.  The renal toxicity of aminoglycoside is related to the frequency and duration of treatment rather than the actual serum toxic level. , In our study, the mean duration and cumulative dose of aminoglicoside was lower in the babies with than without NC; however, the blood levels of aminoglicoside were not measured. Furthermore, dissimilar to Narendra et al  study, the risk of NC was not greater when vancomycin was administered concurrently with aminoglicoside in our study.
TPN was not significantly associated with NC in our study. However, Narendra et al  found that the duration of TPN was significantly longer in babies with than those without NC.
High urinary calcium/citrate ratio was considered to be a risk factor for the development of NC.  We did not find any significant association of low urinary citrate or high urine ratios of calcium/citrate at 2 nd and 4 th weeks of age with NC. Our findings were in contrast to Schell-Fieth et al  and compatible with White et al  results.
Transient hypophosphatemia was described by Narendra et al  in preterm neonate with NC within 2 weeks of birth. Hellstern et al  illustrated that a significant urinary phosphate excretion in the presence of low serum phosphate was observed in VLBW infants during the first weeks of life. Increased urinary excretion of phosphate within 2 weeks of life was found in premature infants with NC by Hein et al  study. In disagreement with these studies, we found NC to be associated with higher serum and urinary phosphate at the 4 th week of age of our patients; the higher urinary excretion of phosphate may indicate low renal phosphate threshold, disturbed mineralization and higher concentration of phosphate in the TPN solution. An elevated urinary calcium excretion is a major factor contributing to the pathophysiology of NC. , Similar to Hein et al  study, our premature babies with NC showed an increased urinary calcium excretion at the 4 th weeks of age.
High values of serum calcium in premature infants with NC were observed in Schell-Feith  and Ezzedeen  studies. In contrast to their results, we found that NC was associated with lower serum calcium at the 2 nd week of age.
In conclusion, the incidence of NC was compatible with the previous studies; it was particularly associated with family history of renal stone and high urine calcium/creatinine ratio. We have found a new association of NC with increased urinary excretion of phosphate and hyperphosphatemia at the 4 th week of age and hypocalcemia at the 2 nd week of age. Further studies are required on the preventive role of inhibitors of urinary calcification in these high risk neonates.
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Pediatrics Department, Alzahra Hospital, Isfahan University of Medical Sciences, Soffe Blvd, Isfahan
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2]