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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2010  |  Volume : 21  |  Issue : 2  |  Page : 284-289
Nephrocalcinosis in very low birth weight infants

Pediatrics and Neonatology, Pediatric Nephrology, Radiology Department, Isfahan University of Medical sciences, Isfahan, Iran

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Date of Web Publication9-Mar-2010


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 Top

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. [1] The incidence of nephro­calcinosis varies between 16% and 64% depen­ding on different study populations and ultra­sonographic criteria. [2],[3],[4] Schell-Feith et al have demonstrated that ultrasonography (US) is ap­propriate for detecting NC in preterm babies, but better standardization is needed. [5] Short­term complications include renal stones with obstruction of the urinary tract, urinary tract infection, and glomerular and tubular dysfunc­tion. [6],[7],[8] Although a decrease in kidney function was considered as a long-term outcome in small-scale studies, [7],[8] 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. [9]

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. [5],[6] 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. [1],[2],[4],[6],[10]

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 Top

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. [11]

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. [12] Hyperphos­phaturia was confirmed the urinary P:creati­nine (UP/Ucr) ratio exceeded 1.2. [13] Hypocitra­turia was diagnosed if the urinary citrate/crea­tinine (Ucitrate/Ucr) ratio was less than 0.56 ± 0.04. [14] Metabolic acidosis was diagnosed if PH was less than 7.25 and HCO 3 ≤ 14 or base ex­cess (BE) :≤ - 6. [15]

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 Top

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 Top

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 Top

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%) [3] but similar to studies in United Kingdom [2] and Scandinavia. [16]

The pathogenesis of NC in VLBW infants appears to be multifactorial. [17] Extreme imatu­rity and the underdevelopment of renal func­tion may be the most important causes. [2],[3],[17]

Saarela et al [16] 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. [2],[3],[16] 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.[4] 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. [2],[4] This is explained by the decreasing urinary citrate ex­cretion, which is a known inhibitor of renal calcification, during severe respiratory disease. [18] 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, [19] Saarela et al [16] and Narendra et al [4] studies found an association between NC and postnatal dexamethasone, which may re­flect the severity of the respiratory disease and low gestation. [19] 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. [1],[3],[7],[16],[20],[21] However, in our study, none of the patients received furosemide. Neph­rotoxic antibiotic levels are strongly associated with NC independently of gestation. [4] Hyper­calciuria with therapeutic doses of gentamicin has been found in full term infants. [22] The renal toxicity of aminoglycoside is related to the fre­quency and duration of treatment rather than the actual serum toxic level. [23],[24] 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 [4] 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 [4] 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. [15] 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 [6] and compatible with White et al [25] results.

Transient hypophosphatemia was described by Narendra et al [4] in preterm neonate with NC within 2 weeks of birth. Hellstern et al [26] 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 [15] 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. [17],[20] Similar to Hein et al [15] 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 [6] and Ezzedeen [8] 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.

   References Top

1.Hufnagle KG, Khan SN, Penn D, Cacciarelli A, Williams P. Renal calcification a complica­tion of long-term furosemide therapy in pre­term infants. Pediatrics 1982;70(3):360-3  Back to cited text no. 1      
2.Short A, Cooke RW. The incidence of renal calcification in preterm infants. Arch Dis Child 1991;66(4):412-7.  Back to cited text no. 2      
3.Jacinto JS, Modanlou HD, Crade M, Strauss AA, Bosu SK. Renal calcification in very low birth weight infants. Pediatrics 1988;81(1):31­5.  Back to cited text no. 3      
4.Narendra A, White MP, Rolton HA, et al. Nephrocalcinosis in preterm babies. Arch Dis Child Fetal Neonatal Ed 2001;85(3):F207-13.  Back to cited text no. 4      
5.Schell-Feith EA, Holscher HC, Zonderland HM, et al. Ultrasonographic features of nephrocal­cinosis in preterm neonates. Br J Radiol 2000; 73(875):1185-91.  Back to cited text no. 5      
6.Schell-Feith EA, van-K, Holthe JE, et al. Etio­logy of nephrocalcinosis in preterm neonates: Association of nutritional intake and urinary parameters. Kidney Int 2000;58(5):2102-10.  Back to cited text no. 6      
7.Downing GJ, Egelhoff JC, Daily DK, Thomas MK, Alon U. Kidney function in very low birth weight infants with furosemide-related renal calcifications at ages 1 to 2 years. J Pediatr 1992;120(4):599-604.  Back to cited text no. 7      
8.Ezzedeen F, Adelman R, Ahlfors CE. Renal calcification in preterm infants: Pathophysio­logy and longterm sequelae. J Pediatr 1988; 113(3):532-9.  Back to cited text no. 8      
9.Porter E, McKie A, Beattie TJ, et al. Neonatal nephrocalcinosis: Long term follow up. Arch Dis Child Fetal Neonatal 2006;91(5):333-6.  Back to cited text no. 9      
10.Dayer Zamara VM, Sauve SR, Yee W, Inci­dence, risk factors and longterm outcome of nephrocalcinosis in infants born weighing 1250g or less in Southern Alberta, Canada. Paediatr Res 1999;45(4)Part2:241.  Back to cited text no. 10      
11.Pohlandt F, Muller M. Renal echogenicity in VLBW infants supplemented with Ca and P to prevent bone demineralization. Pediatr Res 1987;22(2):233.  Back to cited text no. 11      
12.Hooman N, Honarpisheh A. The effect of phototherapy on urinary calcium excretion in newborns. Pediatr Nephrol 2005;20(9):1363-4.  Back to cited text no. 12      
13.Beth AV, Katherine MD, Ira DD. The kidney and urinary tract. In: Martin RJ, Fanaroff AA, Walsh MC. Neonatal - Perinatal Medicine. Diseases of the fetus and infants. 8th ed. Philadelphia: Mosby, 2006;1674  Back to cited text no. 13      
14.Cillo ACP, Cattini H, Boim MA, Schor N. Evaluation of lithogenic elements in urine of healthy newborns. Pediatr Nephrol 2001;16 (12):1080-3.  Back to cited text no. 14      
15.Hein G, Richter D, Manz F, Weitzed D, Kalhoff H. Developmental nephrocalcinosis in very low birth weight infants. Pediatr Nephrol 2004;19(6):616-20.  Back to cited text no. 15      
16.Saarela T, Vaarala A, Lanning P, Koivisto M. Incidence, ultrasonic patterns and resolution of nephrocalcinosis in very low birth weight infants. Acta Paediatr 1999;88(6):655-60.  Back to cited text no. 16      
17.Adams ND, Rowe JC. Nephrocalcinosis. Clin Perinatol 1992;19(1):179-95.  Back to cited text no. 17      
18.Murphy JL, Mendoza SA. Decreased urinary citrate in premature infants with lung disease. Child Nephrol Urol 1990;10(2):76-80.  Back to cited text no. 18      
19.19 Cranefield DJ Odd DE Harding JE Teele RL High incidence of nephrocalcinosis in extremely preterm infants treated with dexamethasone. Pediatr Radiol 2004;34(2):138-42.  Back to cited text no. 19      
20.Pope JC 4 th , Trusler LA, Klein AM, Walsh WF, Yared A, Brock JW 3 rd . The natural his­tory of nephrocalcinosis in premature infants treated with loop diuretics. J Urol 1996;156(2 Pt 2):709-12.  Back to cited text no. 20      
21.Katz ME, Karlowicz MG, Adelman RD, Werner AL, Solhaug MJ. Nephrocalcinosis in very low birth weight neonates: Sonographic patterns, histologic characteristics, and clinical risk factors. J Ultrasound Med 1994;13(10): 777-82.  Back to cited text no. 21      
22.Andronikou S, Giapros VI, Cholevas VI, Papa­dopoulou ZL. Effect of aminoglycoside the­rapy on renal function in full-term infants. Pediatr Nephrol 1996;10(6):766-8.  Back to cited text no. 22      
23.Parsons PP, Garland HO, Harpur ES, Old S. Acute gentamicin-induced hypercalciuria and hypermagnesiuria in the rat: Dose-response relationship and role of renal tubular injury. Br J Pharmacol 1997;122(3):570-6.  Back to cited text no. 23      
24.Frame PT, Phair JP, Watanakunakorn C, Ban­nister TW. Pharmacologic factors associated with gentamicin nephrotoxicity in rabbits. J Infect Dis 1977;135(6):952-6.  Back to cited text no. 24      
25.White MP, Aladangady N, Rolton HA, McColl JH, Beattie J. Urinary citrate in preterm and term babies. Early Hum Dev 2005;81(2):191­5.  Back to cited text no. 25      
26.Hellstern G, Poschl J, Linderkamp O. Renal phosphate handling of premature infants of 23­25 weeks gestational age. Pediatr Nephrol 2003;18(8):756-8.  Back to cited text no. 26      

Correspondence Address:
Fatemeh Nasseri
Pediatrics Department, Alzahra Hospital, Isfahan University of Medical Sciences, Soffe Blvd, Isfahan
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Source of Support: None, Conflict of Interest: None

PMID: 20228514

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