Should We Screen Preterm Infants for Nephrocalcinosis? An Evidence-based Decision

Shahirose S Premji; Majeeda Kamaluddeen


Pediatr Health. 2010;4(1):24-35. 

In This Article

Renal Function

Premature infants with nephrocalcinosis have been reported to have impaired GFR (i.e., chronic renal insufficiency) when compared with healthy children.[20,28] However, follow-up and comparison of GFR at a mean age of 4.7 years[26] and 7.5 years (SD ± 1 year)[28] with premature infants without nephrocalcinosis demonstrated no significant difference. It was not possible to predict GFR at follow-up based on the extent of nephrocalcinosis reported on ultrasound findings at term.[28] Porter et al. reported normal GFR in all premature infants with nephrocalcinosis who were assessed at a mean age of 6.9 years (range: 5.81–7.68 years).[29] By contrast, Jones et al. reported GFR to be low in premature infants with neonatal nephrocalcinosis.[27] As GFR was not measured in control premature infants, no inferences could be made with regard to whether the influencing factor is nephrocalcinosis or prematurity itself.[27]

Glomerular function was assessed by measuring GFR using the Schwartz formula (k*length in cm/serum creatinine in µmol/l, where k is adjusted for age)[20,26,28,29] or the modified Counahan–Barratt formula (GFR = [10 × height in cm]/plasma creatinine concentration in µmol/l).[27] In premature infants, use of the Schwartz formula is problematic as the k value for preterm infants at various ages is unknown and premature infants are likely to excrete low amounts of creatinine (owing to poor growth and muscle development).[20] Furthermore, normal values for GFR have not been established for premature infants.

Glomerular function was also assessed by measuring serum urea and creatinine and urine protein. An increase in serum urea and creatinine, evident during the neonatal period in infants with nephrocalcinosis relative to those without nephrocalcinosis, was no longer significant at 4 weeks of age[16] or at 6 weeks.[17] No significant differences in serum creatinine level were apparent at 2, 4 and 6 weeks of life when comparing premature infants with nephrocalcinosis to matched controls without nephrocalcinosis[4] and no significant difference was reported in serum urea and creatinine levels at a mean age of 4.7 years.[26] In contrast, Schell-Feith et al. reported a significant difference in serum creatinine levels at 4 weeks of life and at term between infants with and without nephrocalcinosis.[6] Two children had an albumin:creatinine ratio above 2.5 mg/mmol (3.9 and 4.5 mg/mmol, respectively) in the early morning urine specimens in the Jones et al. study,[27] and trace proteinuria determined by urine dipstick was found in a small number of patients at 1 year and 2 years of age in another study.[20] Only glomerular proteinuria can be detected with urine dipstick since with proximal tubular dysfunction low molecular weight proteins are excreted in fairly small quantities and cannot be detected with a urine dipstick. Nonetheless, in patients with hematuria, urine protein electrophoresis is a better measure of proteinuria as it minimizes false-positive results resulting from the release of hemoglobin into urine from red blood cell lysis.[31] False-positive findings may also result when the urine is alkaline or dilute, more importantly, proteinuria is a common finding in children, which may be a transient and benign condition.[103] Consequently, findings need to be interpreted with caution.[31]

Proximal tubular function was assessed by monitoring tubular reabsorption of phosphate, glucosuria and plasma bicarbonate levels.[28] Tubular reabsorption of phosphate per GFR (plasma phosphate [mmol/l] – urinary phosphate [µmol/l]*serum creatinine [mmol/l] divide by urinary creatinine [mmol/l]) was calculated by all studies[20,26,27,29] except Kist-van Holthe et al.,[28] where it was unclear how the outcome was calculated. Results from these various studies are inconsistent. Tubular phosphate reabsorption per GFR was found to be significantly lower in premature infants with nephrocalcinosis compared with 4–5 years reference values[27] and to premature infants without nephrocalcinosis at a mean age of 7.5 ± 1.0 years.[28] Limited inferences can be made from those studies[27,29] in which control infants did not have similar tests performed. In addition, there was no significant difference in other urinary biochemical variables between cases (i.e., with nephrocalcinosis)[29] before or after calcium load test.[27] The calcium load test compares urinary calcium:creatinine ratio pre- and post-administration of an oral dose of calcium (1 g/1.73 m2 of calcium, in the form of calcium Sandoz) in infants following overnight fast. Renal tubular dysfunction is suggested when urinary calcium:creatinine ratios are elevated during the fasting period[27,32] and after the oral dose of calcium.

Children with a history of nephrocalcinosis showed evidence of markers suggestive of proximal tubular dysfunction (e.g., higher urinary calcium and β2 microglobulin excretion[26] and lower tubular reabsorption of phosphate and raised β2 microglobulin:creatinine ratio[29]). No significant difference was reported in tubular reabsorption of phosphate and α1 microglobulin at 1 and 2 years of age when compared with a reference for healthy children[20] and no significant difference in tubular phosphate reasborption per GFR was evident between preterm infants with and without nephrocalcinosis.[26]

In the only study that monitored urinary glucose excretion in preterm infants, none of the infants had glucosuria, suggesting that tubular reabsorption of glucose may not be affected by neonatal nephrocalcinosis.[20]

Urine anion gap needs to be examined in conjuction with plasma bicarbonate to differentiate between proximal and distal tubular dysfunction.[28] At a mean age of 7.5 ± 1.0 years, significantly lower plasma bicarbonate levels were reported in preterm infants with neonatal nephrocalcinosis compared with those without neonatal nephrocalcinosis. Since the urine anion gap was inappropriately high in the former, distal tubular dysfunction (i.e., distal tubular acidification) was noted to be a long-term sequelae of neonatal nephrocalcinosis.[28] Despite an increase in duration of acidosis in those with more extensive nephrocalcinosis (i.e., hyperechogenecity filling the entire medullary pyramid), this was no longer significant at 3–5 years of age.[26] Although urine analysis revealed pH values to be relatively alkaline (pH 6.0–7.0) between LBW infants with and without renal calcification,[3] oral acetazolamide test, a convenient and sensitive proxy measure of distal tubular acidification, was abnormal at 3–5 years in only one infant (n = 20) with neonatal nephrocalcinosis. Hence, it was concluded that neonatal nephrocalcinosis does not markedly impact distal tubular acidification ability.[26]

The concentrating capacity of the distal tubules can be estimated by measuring urine osmolality following intranasal administration of desmopression. Urine osmolality post desmopressin in preterm infants (<32 weeks) at term-corrected age, when compared with reference ranges established for normal healthy term infants, was abnormal in four (n = 30) children at 1 year and in two children (n = 25) at 2 years.[20] Although early morning urine osmolality in premature infants with neonatal nephrocalcinosis was also reported to be significantly lower when compared with healthy children at 7.5 ± 1.0 years of age; no significant difference was present when compared with preterm infants without nephrocalcinosis.[28] Jones et al.[27] and Porter et al.[29] reported similar findings at 4–5 years of age and 5–7 years, respectively, using the desmopression test.

One can surmise that normal GFR is evident in most preterm infants with a history of nephrocalcinosis. There is no evidence to unequivocally suggest that proximal tubular dysfunction is a consequence of neonatal nephrocalcinosis in preterm infants. Neonatal nephrocalcinosis does not markedly impact distal tubular acidification or concentrating capacity. Renal dysfunction seen in preterm infants with neonatal nephrocalcinosis is also evident in preterm infants without nephrocalcinosis; hence, nephrocalcinosis cannot be the sole cause of renal dysfunction.[25]


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