Pediatric Nephrology

, Volume 25, Issue 2, pp 221–230 | Cite as

Nephrocalcinosis in preterm neonates

  • Eveline A. Schell-Feith
  • Joana E. Kist-van Holthe
  • Albert J. van der Heijden
Open Access
Educational Review


The prevalence of nephrocalcinosis (NC) in preterm neonates in recent reports is 7–41%. The wide range in prevalence is a consequence of different study populations and ultrasound equipment and criteria, in addition to a moderate interobserver variation. NC in preterm neonates has a multifactorial aetiology, consisting of low gestational age and birth weight, often in combination with severe respiratory disease, and occurs as a result of an imbalance between stone-promoting and stone-inhibiting factors. A limited number of histological studies suggest that calcium oxalate crystals play an important role in NC in premature neonates. In 85% of children resolution of NC occurs in the first years of life. Prematurity, per se, is associated with high blood pressure, relatively small kidneys, and (distal) tubular dysfunction. In addition, NC in preterm neonates can have long-term sequelae for glomerular and tubular function. Long-term follow-up of blood pressure and renal function of prematurely born children, especially with neonatal NC, is recommended. Prevention of NC with (low) oral doses of citrate has not resulted in a significant decrease in the prevalence of NC; a higher citrate dosage deserves further study. Future research pertaining to prevention of NC in preterm neonates is crucial.


Nephrocalcinosis Preterm neonate Low birth weight Renal ultrasound Aetiology Follow-up Prevention 


Nephrocalcinosis (NC), defined as renal calcification, was first described by Hufnagle et al. in 1982 in premature neonates who received long-term furosemide therapy [1].

NC in preterm neonates occurs as a result of imbalance between stone-promoting and stone-inhibiting factors. The aetiology of NC is multifactorial and comprehensive and will be discussed in detail.

As nephrogenesis is not completed until 34–36 weeks of gestation, the development of the kidneys, both anatomical and functional, is not completed at birth [2]. After birth, rapid changes in functional development occur. Injury to the kidneys in this period can affect renal function later in life [3]. There is growing evidence of an association of low birth weight with low nephron numbers and subsequent risk for adult cardiovascular disease and renal insufficiency [4]. However, full consensus has not been established, as recent studies do not fully support the hypothesis that low birth weight contributes to impaired kidney function, at least not until the age of 20–26 years [5, 6]. Nevertheless, development of NC in prematurely born children may carry an additional risk of compromising renal function later in life.

We will discuss prevalence, radiological and histological diagnosis, aetiology, natural course and long-term effects, in addition to prevention and treatment of NC in preterm neonates.

Prevalence of nephrocalcinosis

NC is diagnosed in 7–64% of preterm neonates with gestational age < 32 weeks or birth weight < 1,500 g [7, 8, 9, 10, 11, 12, 13, 14, 15, 16]. The wide range in prevalence of NC is a consequence of different study populations and ultrasound equipment and criteria, in addition to a moderate interobserver variation [12]. Recent studies have noted a slightly lower prevalence of 7–41% than in the original reports [12, 13, 14, 15, 16].

Diagnosis of nephrocalcinosis

Radiological evaluation

NC can be detected by conventional radiography, ultrasonography (Fig. 1) or computer tomography (CT). Ultrasonography is more sensitive than conventional radiography [17]. In rabbits with NC, ultrasound was more sensitive than CT (96% vs 64%), but CT was more specific than ultrasound (96% vs 85%) [18]. As CT involves a high radiation dose, it is unsuitable to detect NC in preterm neonates. Ultrasonography is a reliable method for screening and grading of young children with risk of NC, with good intra- and interobserver agreement (kappa coefficient, respectively, 0.80 and 0.76) [19]. Reproducibility of ultrasound in detecting NC in preterm neonates has a very good intra-observer agreement (kappa 0.84), but a moderate interobserver agreement (kappa 0.46) [12]. NC was located exclusively in the medulla in more than 95% of kidneys [12].
Fig. 1

a Renal ultrasound of a preterm neonate with moderate nephrocalcinosis, with small white flecks in the tip of the pyramids. b Ultrasound of kidney of a preterm neonate with severe nephrocalcinosis. White dots almost entirely fill the pyramids

However, increased medullary echogenicity in the preterm neonate is not exclusively found in NC, but also in other conditions, such as renal candidiasis, cytomegalovirus infection, acute renal failure, polycystic kidney disease, renal vein thrombosis, or as a transient spontaneously resolving phenomenon of unclear aetiology in the first postnatal week [20, 21, 22, 23, 24, 25, 26].

Histological evaluation

NC is defined as mineral precipitates located in the renal parenchyma. Knowledge of the pathological aspects of the ultrasound findings in preterm neonates is scarce. Histological examination of a few kidneys of preterm neonates with medullary echogenicity showed calcifications, located either within the tubules or in the interstitium, consisting of calcium oxalate or calcium phosphate crystals [1, 10, 27, 28, 29]. Renal histology of 44 infants and neonates who had died after intensive care treatment between 1972 and 1992 was compared with that of 64 infants and neonates who had died without intensive care treatment [29]. Intratubular calcium oxalate deposits were found in eight of the intensive care-treated patients, whereas two of these cases in addition showed intratubular calcium phosphate deposits, which, in one patient, extended into the interstitium. The patients without intensive care treatment, on the other hand, demonstrated minimal calcium phosphate microliths in two cases, but no oxalate crystals. This suggests that calcium oxalate crystals play an important role in NC in intensive care-treated patients.

Aetiology of nephrocalcinosis in preterm neonates

NC in preterm neonates has a multifactorial aetiology, consisting of low gestational age and birth weight [1, 7, 8, 9, 13, 14, 30], often in combination with severe respiratory disease [8, 13, 14, 30, 31], and it occurs as a result of an imbalance between stone-promoting and stone-inhibiting factors (Table 1). There is a clear correlation between prevalence of NC and low gestational age [7, 8, 9, 13, 14, 30]. Premature kidneys have relatively well-developed deep nephrons, with a long loop of Henle and probably low urine velocity. As a result, conditions are favourable for the formation of crystals, which can stick to the surface and grow and aggregate in the tubules. Under these circumstances stone-promoting factors such as hypercalciuria and hyperoxaluria, as described below, in combination with reduced stone-inhibiting factors like low urinary citrate excretion, can lead to NC.
Table 1

Aetiology of nephrocalcinosis in preterm neonates

Factors promoting nephrocalcinosis

Factors inhibiting nephrocalcinosis





 high calcium intake


 low phosphorus intake


 parenteral nutrition

stone-inhibiting macromolecules



  loop diuretics, methylxanthines, vitamin D



 Tamm-Horsfall protein?



 high precursor intake


ascorbic acid, glycine


parenteral nutrition


secondary hyperoxaluria


 fat malabsorption, high phosphorus intake




 Caucasian, male, family history of kidney stones


 nephrotoxic medication, e.g. gentamicin


Of course, other well-known causes of NC, such as primary hyperoxaluria, distal tubular acidosis, glucose–galactose malabsorption, Bartter’s syndrome, Williams’ syndrome, and hypophosphatasia, can also occur in preterm neonates [32, 33, 34, 35]. Here, we will focus on NC of prematurity.

Factors promoting nephrocalcinosis

Factors promoting nephrocalcinosis are shown in Table 1.


Mean urinary calcium/creatinine ratio in preterm neonates varies from 2.3–2.7 mmol/mmol, which is much higher than reference values for term neonates and older children (< 0.6–0.9 mmol/mmol) [30, 36]. On the other hand, considerable variation is reported, with much lower (median 0.31 mmol/mmol) as well as much higher (mean 4 mg/mg = 11.4 mmol/mmol) values [37, 38].


Several (early) studies indicated furosemide for chronic lung disease to be the most important aetiological factor in the development of NC in preterm neonates [1, 7, 39]. Reabsorption of calcium in the loop of Henle is primarily passive, driven by the gradient created by sodium chloride (NaCl) transport. Inhibition by furosemide of the Na+ K+-2Cl carrier in the apical membrane leads to a parallel reduction in the reabsorption of calcium and, hence, to hypercalciuria [40]. In preterm neonates calciuresis may be prolonged due to slower plasma clearance [41, 42]. However, development of NC has also been described in preterm neonates without furosemide therapy [8, 43].


Many preterm neonates receive glucocorticoids for treatment or prevention of chronic lung disease [44, 45, 46]. High doses of glucocorticoids can lead to osteopenia, hypercalciuria and nephrolithiasis. The pathogenesis relates to an imbalance between resorption and formation of bone. An association between dexamethasone treatment, high calcium excretion and NC is, indeed, found in preterm neonates [13, 30, 47, 48].


Caffeine and theophylline, both methylxanthines, are frequently prescribed to prevent apnoea in preterm neonates and are also known for their hypercalciuric effect. Urinary calcium excretion rose two- to ten-fold in preterm neonates treated with methylxanthines in comparison with a control group [49, 50]. In keeping with this concept, a significant correlation was noted between theophylline prescription and NC in preterm neonates [30]. Suggested mechanisms to explain the hypercalciuria are increased diuresis and natriuresis, increased prostaglandin synthesis, and antagonism of adenosine-mediated effects with a change in renal blood flow and glomerular filtration rate [49, 51].


Preterm neonates may experience periods of respiratory and/or metabolic acidosis. Acidosis results in a number of changes in adults that increase the risk of stone formation: increased urinary calcium as a result of bone buffering, decreased urinary citrate by increased reabsorption in the proximal tubule and decreased urinary pH [52]. Significantly more preterm neonates with NC show a tendency toward metabolic acidosis than those without NC [15].

Calcium intake

As 80% of calcium and phosphorus accumulate in the fetus between the 25th post-conceptional week and full term, the majority of bone accumulation in preterm neonates takes place after birth [53]. Consequently, to prevent rickets of prematurity, the recommended intake of calcium (100–160 mg/kg per day) is high in comparison with that for full-term neonates [54]. High calcium intake is confirmed as a risk factor for NC in preterm neonates [30].

Vitamin D intake

Vitamin D excess can result in hypercalcaemia and hypercalciuria. In order to prevent rickets, the intake of vitamin D in preterm neonates is relatively high. Recent guidelines advise an intake of 800–1,000 IU [54]. In spite of this, vitamin D has not been found to be a risk factor for NC. Vitamin D intake and vitamin 1,25(OH)2-vitamin D3 plasma levels were equal in preterm neonates compared with those without NC [30].

Phosphorus intake

Recommended phosphorus intake for preterm neonates is 60–90 mg/kg per day and is like calcium intake, high in comparison with that for term neonates [54]. Phosphorus intake can influence the risk of developing NC in two ways.

Low intake of phosphorus can result in hypophosphataemia. Hypophosphataemia leads to a rise in phosphorus reabsorption in the proximal tubules, an increase in calcium and phosphorus absorption from the bone, and an increase in renal production of 1,25(OH)2-vitamin D3. Vitamin D stimulates the intestinal absorption and resorption of calcium and phosphorus from the bone. The consequent increase in serum calcium induces suppression of parathormone release, which results in a further decrease in urine phosphate and an increase in calcium excretion in adults [55]. In line with this hypothesis, Hein et al. confirmed that significantly more preterm neonates with NC had transient hypophosphataemia and hypercalciuria than did preterm neonates without NC [15]. In contrast Schell-Feith et al. did not find a difference in serum phosphate between preterm neonates with and without NC [30].

In contrast, a high intake of phosphorus is also associated with NC in preterm neonates [11, 30]. In addition, a high intake of phosphorus can lead to secondary hyperoxaluria, as will be explained later.

Sodium intake

In children and adults sodium intake and excretion are linked to urinary calcium excretion and can result in hypercalciuria. Similarly, sodium excretion in preterm neonates is positively correlated with urinary calcium excretion [56]. Nonetheless, the correlation between sodium excretion and occurrence of NC in preterm neonates has not yet been studied.

Parenteral nutrition

In preterm neonates on parenteral nutrition urinary calcium/citrate ratio increased in the first 10 days of life, while in human-milk-fed infants this ratio decreased, which indicates a higher risk of renal calcifications in preterm neonates fed parenterally [57]. Narendra et al. confirmed that NC occurs more frequently in preterm neonates with longer duration of parenteral nutrition [13], while Schell-Feith et al. could not find such a correlation [30].


As NC in preterm neonates can consist of calcium oxalate precipitates, high urinary excretion of oxalate might be an important factor in the development of NC [1, 29]. Hoppe et al. demonstrated that preterm neonates excrete more oxalate in the first months of life than do full-term neonates [58]. An association with higher urine oxalate/creatinine ratio was found in preterm neonates with NC as opposed to those without NC by some [13, 59], but not by others [30].

Precursors of oxalate

Ascorbic acid and glycine are precursors of oxalate. This could be the reason why preterm neonates receiving parenteral nutrition that contains ascorbic acid and glycine excrete higher urinary oxalate than do neonates receiving a glucose and electrolyte solution in the first week of life [60]. Formula-fed preterm neonates have a higher excretion of oxalate than do human milk-fed preterm neonates. This can be explained either by the fact that in formula for preterm neonates there is a higher concentration of ascorbic acid than in human milk, or by the mechanism of secondary hyperoxaluria, described below [61].

Secondary hyperoxaluria

If calcium is bound to a compound in the gut, less calcium will be available for oxalate, and, therefore, oxalate will form complexes with sodium. In the intestines sodium–oxalate complexes are more readily absorbed than calcium–oxalate complexes. Thus, enteral oxalate absorption will increase and higher concentrations of oxalate will be excreted in the urine. One of these calcium-binding compounds in the gut is fat. Because fatty acid absorption is more effective in human milk-fed infants than in formula-fed infants, relative fat malabsorption can induce secondary hyperoxaluria in formula-fed neonates [61]. Moreover, phosphate can also form complexes with calcium in the gut and lead to secondary hyperoxaluria. In patients with hypophosphataemic rickets, high intake of phosphate has been described to lead to hyperoxaluria and NC, even in a normocalciuric state [62].

Parenteral nutrition seems to increase not only urinary calcium/citrate ratio (see above), but also urinary oxalate excretion in preterm neonates. Therefore, parenteral nutrition may be an additional factor in the pathogenesis of nephrocalcinosis [57, 60].


Demographic characteristics

NC occurs more often in Caucasians, male gender, and preterm neonates with a positive family history of kidney stones [10, 13].

Nephrotoxic medication, e.g. gentamicin, has also been found to be a risk factor for NC in preterm infants [13].

Factors inhibiting nephrocalcinosis

Factors inhibiting nephrocalcinosis are shown in Table 1.


Citrate is an important chelator of calcium stones, because it forms complexes with calcium that are more soluble than calcium oxalate and calcium phosphate. Preterm neonates on mechanical ventilation had a low urinary citrate excretion when compared with a control group [63]. Schell et al. confirmed a lower urine citrate/calcium ratio in preterm neonates with NC as opposed to those without NC [30]. Likewise, hypocitraturia was a major risk factor for NC in infants with very low birth weight, especially in those < 1,000 g [64]. In contrast, White et al. found similar values for urinary citrate in preterm neonates and healthy term babies. Furthermore, they found no association between urinary citrate and NC in preterm neonates [65]. A possible explanation for the lower excretion of citrate in some preterm neonates might be tubular reabsorption of citrate to compensate for episodes of respiratory and metabolic acidosis.


Magnesium is another low molecular weight chelator, which forms complexes with oxalate that are more soluble than calcium oxalate. The role of urinary magnesium excretion in the development of NC has not been studied in preterm neonates.

Stone-inhibiting macromolecules

Urine contains macromolecules, such as osteopontin, nephrocalcin and Tamm-Horsfall protein, which can inhibit the processes of nucleation, agglomeration and growth in vitro [66]. Osteopontin, a glycoprotein originally identified as a component of bone, has been associated with a variety of functions, including mineralization, signalling and cell adhesion. The ability of osteopontin to bind and coat calcium oxalate crystals in renal tubules suggests that osteopontin may play a role in the prevention of renal calcium oxalate accumulation [38]. Urinary osteopontin concentration is significantly lower in premature neonates than in adults [38]. However, levels do not differ from those of term infants; therefore, interpretation of these lower values in the aetiology of NC is still under debate, and additional studies are warranted. On the other hand, expression of crystal-binding molecules (hyaluronan and osteopontin) at the luminal surface of the distal tubular cells in preterm neonates precedes crystal retention at the distal nephron epithelium, the first step to NC [67]. Nephrocalcin and Tamm-Horsfall protein have not been studied in preterm neonates.


Thiazides, diuretics that inhibit sodium reabsorption in the distal tubules by blocking the thiazide sensitive Na+Cl co-transporter, are frequently administered to preterm neonates with chronic lung disease. Thiazides decrease urinary excretion of calcium. This hypocalciuric effect can either be caused by an increase in proximal reabsorption of sodium and calcium in reaction to distal natriuretic effect of thiazides, or by a direct stimulatory effect of thiazides on the distal reabsorption of calcium. Nevertheless, Toffolo et al. have described preterm neonates with chronic lung disease who were treated with thiazides and developed NC anyway [43].

Animal model for nephrocalcinosis

In an animal model NC occurred within a few days of extremely high (40 mg/kg) furosemide administration in weanling rats. Interestingly, NC in this model was not age dependent but reflected a property of the loop diuretic itself [68].

Natural course and long-term effects of nephrocalcinosis


Rarely, urolithiasis is found in former preterms with severe NC. Downing et al. describes two patients who needed nephrolithotomy for ureteral obstruction [69]. That urolithiasis is not a frequent finding in NC is also suggested by a large prospective study, where none of the patients with NC developed urolithiasis during a 2-year follow-up period [70]. Haematuria is not a characteristic of patients with NC, unless they have urolithiasis [70].

Persistence of nephrocalcinosis

In the majority of patients spontaneous resolution of NC occurs in the first years of life. However, persistence for several years has been described [11, 14, 69, 71, 72, 73, 74]. In the largest ongoing study of preterm neonates, NC persisted in 34%, 15% and 10% after 15 months, 30 months and 7.4 (± 1.0) years, respectively (Fig. 2) [70, 75].
Fig. 2

Persistence of nephrocalcinosis (NC) with time, n = 70 (continuous line) (95% confidence interval dotted line) [70]

Long-term consequences

Long-term consequences are shown in Table 2.

Blood pressure

Although there is evidence that low birth weight is an important factor in the development of hypertension and the metabolic syndrome in adults, prematurity did, but birth weight standard deviation score (SDS) did not, predict hypertension in a large cohort of 19-year-old former preterms (Table 2) [76, 77]. Likewise, blood pressure of children born preterm with and without NC did not differ when they were a mean age of 7.4 years. However, it was significantly higher than expected for healthy children, although only a minority of former preterms with (3/42) and without (2/31) NC in fact had a systolic blood pressure >95th percentile [75] (Table 2).
Table 2

Possible long-term effects of nephrocalcinosis and prematurity per se (TRP tubular reabsorption of phosphate)



Decreased glomerular filtration rate

Decreased glomerular filtration rate


High blood pressure

(Distal) renal tubular acidosis

Decreased renal growth

Decreased concentrating capacity

Decreased concentrating capacity



Renal growth

Decreased renal growth at the age of 20 years was noted in former preterms (gestational age < 32 weeks) compared to full-term born controls [5]. Likewise, the kidneys of patients with and without neonatal NC were significantly smaller than expected for healthy children of the same height [75]. It is hypothesized that preterm neonates are specifically at risk of renal growth impairment because nephrogenesis peaks at 32 weeks and continues until 36 weeks. So far as limited evidence suggests, NC does not further impair renal growth.

Glomerular function

Undoubtedly, the most important question is: does NC in very prematurely born children affect renal function in the long term? Several (early) studies comprising a limited number of selected children with preterm NC demonstrated reduced glomerular filtration rate (GFR) when they were aged between 1 year and 5 years [69, 71, 72]. In a prospective follow-up study, after 7.4 ± 1 years, significantly more children with NC (6/40, 15%) had low GFR (< 85 ml/min per 1.73 m2 body surface area) than did healthy children, this in contrast to children without neonatal NC (2/32, 6%), Fig. 3. However, there was no significant difference in GFR or microalbuminuria between the groups. Furthermore, no correlation between persistence of NC and low GFR was found, but the number former preterms with persisting NC (n = 4) was small [75]. This is in contrast with results of a study by Saarela et al., who found no significant difference in GFR at a mean age of 4.7 years between 20 former preterms with and 20 without NC in the neonatal period [73]. Hoppe et al. and Porter et al. also observed normal GFR after 3–6 years and 5.8–7.7 years, respectively, in 12 and 14 prematurely born children with NC [14, 74].
Fig. 3

Estimated GFR of former preterm infants with (n = 42) and without (n = 32) neonatal nephrocalcinosis at a mean age of 7.4 years. +NC with nephrocalcinosis, −NC without nephrocalcinosis. The asterisk indicates that significantly more children with neonatal nephrocalcinosis have (mild) chronic renal insufficiency than do healthy children, P < 0.0001. The dashed line shows glomerular filtration rate < 85 ml/min per 1.73 m2 body surface area [75]

In conclusion, long-term follow-up of preterm neonates with NC demonstrates normal renal function in most patients. However, an unfavourable effect on renal function is seen in a small number of children.

Proximal tubular function

How does NC affect long-term tubular function? Jones et al. studied 11 former preterms when they were aged 4–5 years with neonatal NC. They found low median TmP/GFR (tubular maximum of phosphate reabsorption corrected for glomerular filtration rate) in comparison with reference values [71]. Likewise, Saarela et al. observed a significantly higher urine β2-microglobulin/creatinine ratio in 20 children with NC than in 20 children without NC as preterm neonates, when they were a mean age of 4.7 years. However, in their study, tubular reabsorption of phosphate (TRP) did not differ significantly in children with and without NC [73]. In contrast, Downing et al. found significantly lower TRP (84 ± 2% versus 93 ± 1%, normal value > 85%) in former preterms at the age of 1–2 years with NC than in former preterms without NC [69]. Kist-van Holthe et al. also noted a significantly lower TRP in children with NC (n = 39) than in those without NC (n = 32) at a mean age of 7.4 ± 1 years. However, plasma phosphate was within normal limits in all children [75]. Therefore, the implication of low TRP in these patients is debatable. Glucosuria was not found in any of these children [75].

Considering these data, there is no firm evidence for proximal tubular dysfunction caused by neonatal NC in former preterms, with the exception of low TRP found in some patients (Table 2).

Distal tubular function

Downing et al. observed a lower ability to excrete hydrogen ions in the distal tubule in preterms with NC (n = 10) than in those without NC (n = 14) [69]. Median plasma bicarbonate level was significantly lower in a larger study of children with (n = 42) and without (n = 32) neonatal NC. Urine anion gap of the children with low plasma bicarbonate levels was inappropriately high, indicating distal rather than proximal tubular dysfunction [75]. On the other hand, Hoppe et al. noted no acidosis after a follow-up period of 3–6 years in 12 former preterms with neonatal NC [14].

Most studies found no difference in early morning urine osmolality between former preterms with and without NC [14, 69, 74, 75]. On the other hand, two studies demonstrated early morning urine osmolality to be significantly lower in former preterms than in healthy children [6, 71]. However, test results indicating impaired concentrating ability after desmopressin was found in 4/30 children with neonatal NC at 1 year and in 2/25 at 2 years [70]. In conclusion, NC in preterm neonates can have long-term sequelae, mainly for distal tubular acidification. Furthermore, some tubular defects (e.g. reduced early morning osmolality) cannot solely be attributed to NC but are also seen in former preterms without neonatal NC.


Hypercalciuria is frequently seen in former preterms with neonatal NC. Significantly more (9/41, 22%) children with neonatal NC had hypercalciuria after a mean age of 7.4 years than expected for healthy children, in contrast to former preterms without NC (2/32, 6%) [75]. This is in keeping with the findings of other smaller studies in which hypercalciuria with or without NC is described in former preterms (Table 2) [69, 71, 73, 74, 78].

Prevention and treatment of nephrocalcinosis in preterm neonates

In children with hypercalciuria, urinary calcium excretion decreases after administration of thiazides [79]. Nevertheless, a study in rats showed that, once established, NC caused by furosemide is not affected by thiazide therapy, in spite of its anti-calciuric effect [80]. The effect of thiazides on the natural course of NC in former preterm neonates has not yet been studied.

Children with primary hyperoxaluria have been treated successfully with sodium citrate [81]. Citrate supplementation in preterm neonates for prevention of NC from day 7 until term at a dose of 0.52 mmol/kg per day did decrease the urinary calcium/citrate ratio and was safe. Although a positive trend, no significant decrease in the prevalence of NC was found [82]. Prevention of NC with higher citrate dosage in preterm neonates deserves further study.

The balance between high intake of protein, phosphate, calcium and vitamin D for accretion of tissues on the one hand, and the risk of renal damage on the other hand, remains delicate, implying that, also in the newly developed guidelines for preterm neonates, attention to the development of NC is warranted.


Prevalence of NC of prematurity varied from 7–41% in the different populations studied. NC in preterm neonates has a multifactorial aetiology, consisting of low gestational age and birth weight, often in combination with severe respiratory disease, and occurs as result of an imbalance between stone-promoting and stone-inhibiting factors. Although spontaneous resolution of NC occurs in most children, some are at risk of renal damage later in life, validating the screening for NC of preterm neonates. Long-term follow-up of preterm neonates, especially with NC, is warranted. Further research pertaining to prevention of NC is necessary.


  1. 1.
    Hufnagle KG, Khan SN, Penn D, Cacciarelli A, Williams P (1982) Renal calcifications: a complication of long-term furosemide therapy in preterm infants. Pediatrics 70:360–363PubMedGoogle Scholar
  2. 2.
    Chevalier RL (1996) Developmental renal physiology of the low birth weight pre-term newborn. J Urol 156:714–719CrossRefPubMedGoogle Scholar
  3. 3.
    Rodriguez-Soriano J, Aguirre M, Oliveros R, Vallo A (2005) Long-term renal follow-up of extremely low birth weight infants. Pediatr Nephrol 20:579–584CrossRefPubMedGoogle Scholar
  4. 4.
    Barker DJ (1990) The fetal and infant origins of adult disease. BMJ 301:1111CrossRefPubMedGoogle Scholar
  5. 5.
    Keijzer-Veen MG, Kleinveld HA, Lequin MH, Dekker FW, Nauta J, de Rijke YB, van der Heijden BJ (2007) Renal function and size at young adult age after intrauterine growth restriction and very premature birth. Am J Kidney Dis 50:542–551CrossRefPubMedGoogle Scholar
  6. 6.
    Kistner A, Celsi G, Vanpee M, Jacobson SH (2000) Increased blood pressure but normal renal function in adult women born preterm. Pediatr Nephrol 15:215–220CrossRefPubMedGoogle Scholar
  7. 7.
    Jacinto JS, Modanlou HD, Crade M, Strauss AA, Bosu SK (1988) Renal calcification incidence in very low birth weight infants. Pediatrics 81:31–35PubMedGoogle Scholar
  8. 8.
    Short A, Cooke RW (1991) The incidence of renal calcification in preterm infants. Arch Dis Child 66:412–417CrossRefPubMedGoogle Scholar
  9. 9.
    Sheu JN, Chen CH, Lue KH, Chen JY, Tsau YK, Chen JH (1993) Renal calcification in very low birth weight infants. Am J Nephrol 13:6–11CrossRefPubMedGoogle Scholar
  10. 10.
    Katz ME, Karlowicz MG, Adelman RD, Werner AL, Solhaug MJ (1994) Nephrocalcinosis in very low birth weight neonates: sonographic patterns, histologic characteristics, and clinical risk factors. J Ultrasound Med 13:777–782PubMedGoogle Scholar
  11. 11.
    Saarela T, Vaarala A, Lanning P, Koivisto M (1999) Incidence, ultrasonic patterns and resolution of nephrocalcinosis in very low birthweight infants. Acta Paediatr 88:655–660CrossRefPubMedGoogle Scholar
  12. 12.
    Schell-Feith EA, Holscher HC, Zonderland HM, Kist-Van Holthe JE, Conneman N, van Zwieten PH, Brand R, van der Heijden AJ (2000) Ultrasonographic features of nephrocalcinosis in preterm neonates. Br J Radiol 73:1185–1191PubMedGoogle Scholar
  13. 13.
    Narendra A, White M, Rolton H, Alloub Z, Wilkinson G, McColl J, Beattie J (2001) Nephrocalcinosis in preterm babies. Arch Dis Child Fetal Neonatal Ed 85:F207–F213CrossRefPubMedGoogle Scholar
  14. 14.
    Hoppe B, Duran I, Martin A, Kribs A, Benz-Bohm G, Michalk DV, Roth B (2002) Nephrocalcinosis in preterm infants: a single center experience. Pediatr Nephrol 17:264–268CrossRefPubMedGoogle Scholar
  15. 15.
    Hein G, Richter D, Manz F, Weitzel D, Kalhoff H (2004) Development of nephrocalcinosis in very low birth weight infants. Pediatr Nephrol 19:616–620CrossRefPubMedGoogle Scholar
  16. 16.
    Ketkeaw K, Thaithumyanon P, Punnahitananda S (2004) Nephrocalcinosis in very low birth weight infants: a single center experience. J Med Assoc Thai 87 [Suppl 2]:S72–S77Google Scholar
  17. 17.
    Alon U, Brewer WH, Chan JC (1983) Nephrocalcinosis: detection by ultrasonography. Pediatrics 71:970–973PubMedGoogle Scholar
  18. 18.
    Cramer B, Husa L, Pushpanathan C (1998) Nephrocalcinosis in rabbits—correlation of ultrasound, computed tomography, pathology and renal function. Pediatr Radiol 28:9–13CrossRefPubMedGoogle Scholar
  19. 19.
    Dick PT, Shuckett BM, Tang B, Daneman A, Kooh SW (1999) Observer reliability in grading nephrocalcinosis on ultrasound examinations in children. Pediatr Radiol 29:68–72CrossRefPubMedGoogle Scholar
  20. 20.
    Shultz PK, Strife JL, Strife CF, McDaniel JD (1991) Hyperechoic renal medullary pyramids in infants and children. Radiology 181:163–167PubMedGoogle Scholar
  21. 21.
    Chiara A, Chirico G, Comelli L, De Vecchi E, Rondini G (1990) Increased renal echogenicity in the neonate. Early Hum Dev 22:29–37CrossRefPubMedGoogle Scholar
  22. 22.
    Herman TE, Siegel MJ (1991) Pyramidal hyperechogenicity in autosomal recessive polycystic kidney disease resembling medullary nephrocalcinosis. Pediatr Radiol 21:270–271CrossRefPubMedGoogle Scholar
  23. 23.
    Riebel TW, Abraham K, Wartner R, Müller R (1993) Transient renal medullary hyperechogenicity in ultrasound studies of neonates: is it a normal phenomenon and what are the causes? J Clin Ultrasound 21:25–31CrossRefPubMedGoogle Scholar
  24. 24.
    Starinsky R, Vardi O, Batasch D, Goldberg M (1995) Increased renal medullary echogenicity in neonates. Pediatr Radiol 25 [Suppl 1]:S43–S45PubMedGoogle Scholar
  25. 25.
    Streitman K, Toth A, Horvath I, Tálosi G (2001) Renal injury in perinatal hypoxia: ultrasonography and changes in renal function. Eur J Pediatr 160:473–477CrossRefPubMedGoogle Scholar
  26. 26.
    Makhoul IR, Soudack M, Smolkin T, Sujov P, Epelman M, Eisenstein I, Magen D, Zelikovic I (2005) Neonatal transient renal failure with renal medullary hyperechogenicity: clinical and laboratory features. Pediatr Nephrol 20:904–909CrossRefPubMedGoogle Scholar
  27. 27.
    Downing GJ, Egelhoff JC, Daily DK, Alon U (1991) Furosemide-related renal calcifications in the premature infant. A longitudinal ultrasonographic study. Pediatr Radiol 21:563–565CrossRefPubMedGoogle Scholar
  28. 28.
    Karlowicz MG, Katz ME, Adelman RD, Solhaug MJ (1993) Nephrocalcinosis in very low birth weight neonates: family history of kidney stones and ethnicity as independent risk factors. J Pediatr 122:635–638CrossRefPubMedGoogle Scholar
  29. 29.
    McCormick FC, Brady K, Keen CE (1996) Oxalate nephrocalcinosis: a study in autopsied infants and neonates. Pediatr Pathol Lab Med 16:479–488PubMedGoogle Scholar
  30. 30.
    Schell-Feith EA, Kist-van Holthe JE, Conneman N, van Zwieten PH, Holscher HC, Zonderland HM, Brand R, van der Heijden BJ (2000) Etiology of nephrocalcinosis in preterm neonates: association of nutritional intake and urinary parameters. Kidney Int 58:2102–2110CrossRefPubMedGoogle Scholar
  31. 31.
    Woolfield N, Haslam R, Le Quesne G, Chambers HM, Hogg R, Jureidini K (1988) Ultrasound diagnosis of nephrocalcinosis in preterm infants. Arch Dis Child 63:86–88CrossRefPubMedGoogle Scholar
  32. 32.
    Cumming WA, Ohlsson A (1984) Nephrocalcinosis in Bartter’s syndrome. Demonstration by ultrasonography. Pediatr Radiol 14:125–126CrossRefPubMedGoogle Scholar
  33. 33.
    Barcia JP, Strife CF, Langman CB (1997) Infantile hypophosphatasia: treatment options to control hypercalcemia, hypercalciuria, and chronic bone demineralization. J Pediatr 130:825–828CrossRefPubMedGoogle Scholar
  34. 34.
    Mathias RS (2000) Rickets in an infant with Williams syndrome. Pediatr Nephrol 14:489–492CrossRefPubMedGoogle Scholar
  35. 35.
    Pahari A, Milla PJ, van WG (2003) Neonatal nephrocalcinosis in association with glucose-galactose malabsorption. Pediatr Nephrol 18:700–702CrossRefPubMedGoogle Scholar
  36. 36.
    Karlen J, Aperia A, Zetterstrom R (1985) Renal excretion of calcium and phosphate in preterm and term infants. J Pediatr 106:814–819CrossRefPubMedGoogle Scholar
  37. 37.
    Giapros VI, Papaloukas AL, Andronikou SK (2007) Urinary mineral excretion in preterm neonates during the first month of life. Neonatology 91:180–185CrossRefPubMedGoogle Scholar
  38. 38.
    Rockwell GF, Morgan MJ, Braden G, Campfield TJ (2007) Preliminary observations of urinary calcium and osteopontin excretion in premature infants, term infants and adults. Neonatology 93:241–245CrossRefPubMedGoogle Scholar
  39. 39.
    Pope JC 4th, Trusler LA, Klein AM, Walsh WF, Yared A, Brock JW 3rd (1996) The natural history of nephrocalcinosis in premature infants treated with loop diuretics. J Urol 156:709–712CrossRefPubMedGoogle Scholar
  40. 40.
    Rose B, Post T (2001) Clinical physiology of acid-base and electrolyte disorders, 5th edn. McGraw-Hill, New York, p 449Google Scholar
  41. 41.
    Mirochnick MH, Miceli JJ, Kramer PA, Chapron DJ, Raye JR (1988) Furosemide pharmacokinetics in very low birth weight infants. J Pediatr 112:653–657CrossRefPubMedGoogle Scholar
  42. 42.
    Peterson RG, Simmons MA, Rumack BH, Levine RL, Brooks JG (1980) Pharmacology of furosemide in the premature newborn infant. J Pediatr 97:139–143CrossRefPubMedGoogle Scholar
  43. 43.
    Toffolo A, Trevisanuto D, Meneghetti S, Talenti E, Zacchello G, Zanardo V (1997) Non-furosemide-related renal calcifications in premature infants with bronchopulmonary dysplasia. Acta Paediatr Jpn 39:433–436PubMedGoogle Scholar
  44. 44.
    Halliday HL, Ehrenkranz RA (2001) Delayed (> 3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev CD001145Google Scholar
  45. 45.
    Halliday HL, Ehrenkranz RA (2001) Early postnatal (< 96 hours) corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev CD001146Google Scholar
  46. 46.
    Halliday HL, Ehrenkranz RA (2001) Moderately early (7–14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev CD001144Google Scholar
  47. 47.
    Kamitsuka MD, Williams MA, Nyberg DA, Fox KA, Lee DL, Hickok D (1995) Renal calcification: a complication of dexamethasone therapy in preterm infants with bronchopulmonary dysplasia. J Perinatol 15:359–363PubMedGoogle Scholar
  48. 48.
    Cranefield DJ, Odd DE, Harding JE, Teele RL (2004) High incidence of nephrocalcinosis in extremely preterm infants treated with dexamethasone. Pediatr Radiol 34:138–142CrossRefPubMedGoogle Scholar
  49. 49.
    Zanardo V, Dani C, Trevisanuto D, Meneghetti S, Guglielmi A, Zacchello G, Cantarutti F (1995) Methylxanthines increase renal calcium excretion in preterm infants. Biol Neonate 68:169–174CrossRefPubMedGoogle Scholar
  50. 50.
    Mazkereth R, Laufer J, Jordan S, Pomerance JJ, Boichis H, Reichman B (1997) Effects of theophylline on renal function in premature infants. Am J Perinatol 14:45–49CrossRefPubMedGoogle Scholar
  51. 51.
    Gouyon JB, Guignard JP (1987) Renal effects of theophylline and caffeine in newborn rabbits. Pediatr Res 21:615–618CrossRefPubMedGoogle Scholar
  52. 52.
    Rose B, Post T (2001) Clinical physiology of acid-base and electrolyte disorders, 5th edn. McGraw-Hill, New York, p 313Google Scholar
  53. 53.
    Tsang R, Lucas A, Uauy R, Zlotkin S (1993) Calcium, magnesium and vitamin D. In: Nutritional needs of the preterm infant: scientific basis and practical guidelines. Williams and Wilkins, New York, p 135Google Scholar
  54. 54.
    Rigo J, Pieltain C, Salle B, Senterre J (2007) Enteral calcium, phosphate and vitamin D requirements and bone mineralization in preterm infants. Acta Paediatr 96:969–974CrossRefPubMedGoogle Scholar
  55. 55.
    Rose B, Post T (2001) Clinical physiology of acid-base and electrolyte disorders, 5th edn. McGraw-Hill, New York, pp 201–202Google Scholar
  56. 56.
    Bert S, Gouyon JB, Semama DS (2004) Calcium, sodium and potassium urinary excretion during the first five days of life in very preterm infants. Biol Neonate 85:37–41CrossRefPubMedGoogle Scholar
  57. 57.
    Hoppe B, Hesse A, Neuhaus T, Fanconi S, Forster I, Blau N, Leumann E (1993) Urinary saturation and nephrocalcinosis in preterm infants: effect of parenteral nutrition. Arch Dis Child 69:299–303CrossRefPubMedGoogle Scholar
  58. 58.
    Hoppe B, Hesse A, Neuhaus T, Fanconi S, Blau N, Roth B, Leumann E (1997) Influence of nutrition on urinary oxalate and calcium in preterm and term infants. Pediatr Nephrol 11:687–690CrossRefPubMedGoogle Scholar
  59. 59.
    Berard E, Dageville C, Bekri S, Boutté P, Coussement A, Mariani R (1995) Nephrocalcinosis and prematurity: importance of urate and oxalate excretion. Nephron 69:237–241CrossRefPubMedGoogle Scholar
  60. 60.
    Campfield T, Braden G (1989) Urinary oxalate excretion by very low birth weight infants receiving parenteral nutrition. Pediatrics 84:860–863PubMedGoogle Scholar
  61. 61.
    Campfield T, Braden G, Flynn-Valone P, Clark N (1994) Urinary oxalate excretion in premature infants: effect of human milk versus formula feeding. Pediatrics 94:674–678PubMedGoogle Scholar
  62. 62.
    Reusz GS, Latta K, Hoyer PF, Byrd DJ, Ehrich JH, Brodehl J (1990) Evidence suggesting hyperoxaluria as a cause of nephrocalcinosis in phosphate-treated hypophosphataemic rickets. Lancet 335:1240–1243CrossRefPubMedGoogle Scholar
  63. 63.
    Murphy JL, Mendoza SA (1990) Decreased urinary citrate in premature infants with lung disease. Child Nephrol Urol 10:76–80PubMedGoogle Scholar
  64. 64.
    Sikora P, Roth B, Kribs A, Michalk DV, Hesse A, Hoppe B (2003) Hypocitraturia is one of the major risk factors for nephrocalcinosis in very low birth weight (VLBW) infants. Kidney Int 63:2194–2199CrossRefPubMedGoogle Scholar
  65. 65.
    White MP, Aladangady N, Rolton HA, McColl JH, Beattie J (2005) Urinary citrate in preterm and term babies. Early Hum Dev 81:319–323CrossRefPubMedGoogle Scholar
  66. 66.
    Khan SR, Kok DJ (2004) Modulators of urinary stone formation. Front Biosci 9:1450–1482CrossRefPubMedGoogle Scholar
  67. 67.
    Verhulst A, Asselman M, De Naeyer S, Vervaet BA, Mengel M, Gwinner W, D, Haese PC, Verkoelen CF, De Broe ME (2005) Preconditioning of the distal tubular epithelium of the human kidney precedes nephrocalcinosis. Kidney Int 68:1643–1647CrossRefPubMedGoogle Scholar
  68. 68.
    Osorio AV, Alon MM, Nichols MA, Alon US (1998) Effect of age on furosemide-induced nephrocalcinosis in the rat. Biol Neonate 73:306–312CrossRefPubMedGoogle Scholar
  69. 69.
    Downing GJ, Egelhoff JC, Daily DK, Thomas MK, Alon U (1992) Kidney function in very low birth weight infants with furosemide-related renal calcifications at ages 1 to 2 years. J Pediatr 120:599–604CrossRefPubMedGoogle Scholar
  70. 70.
    Schell-Feith EA, Kist-van Holthe JE, van Zwieten PH, Zonderland HM, Holscher HC, Swinkels DW, Brand R, Berger HM, van der Heijden BJ (2003) Preterm neonates with nephrocalcinosis: natural course and renal function. Pediatr Nephrol 18:1102–1108CrossRefPubMedGoogle Scholar
  71. 71.
    Jones CA, King S, Shaw NJ, Judd BA (1997) Renal calcification in preterm infants: follow up at 4–5 years. Arch Dis Child Fetal Neonatal Ed 76:F185–F189CrossRefPubMedGoogle Scholar
  72. 72.
    Ezzedeen F, Adelman RD, Ahlfors CE (1988) Renal calcification in preterm infants: pathophysiology and long-term sequelae. J Pediatr 113:532–539CrossRefPubMedGoogle Scholar
  73. 73.
    Saarela T, Lanning P, Koivisto M (1999) Prematurity-associated nephrocalcinosis and kidney function in early childhood. Pediatr Nephrol 13:886–890CrossRefPubMedGoogle Scholar
  74. 74.
    Porter E, McKie A, Beattie TJ, McColl JH, Aladangady N, Watt A, White MP (2006) Neonatal nephrocalcinosis: long term follow up. Arch Dis Child Fetal Neonatal Ed 91:F333–F336CrossRefPubMedGoogle Scholar
  75. 75.
    Kist-van Holthe JE, van Zwieten PH, Schell-Feith EA, Zonderland HM, Holscher HC, Wolterbeek R, Veen S, Frolich M, van der Heijden BJ (2007) Is nephrocalcinosis in preterm neonates harmful for long-term blood pressure and renal function? Pediatrics 119:468–475CrossRefPubMedGoogle Scholar
  76. 76.
    Keijzer-Veen MG, Finken MJ, Nauta J, Dekker FW, Hille ET, Frölich M, Wit JM, van der Heijden AJ, Dutch POPS-19 Collaborative Study Group (2005) Is blood pressure increased 19 years after intrauterine growth restriction and preterm birth? A prospective follow-up study in The Netherlands. Pediatrics 116:725–731CrossRefPubMedGoogle Scholar
  77. 77.
    Barker DJ (1992) The fetal origins of adult hypertension. J Hypertens [Suppl 10]:S39–S44PubMedGoogle Scholar
  78. 78.
    Jones CA, Bowden LS, Watling R, Ryan SW, Judd BA (2001) Hypercalciuria in ex-preterm children, aged 7–8 years. Pediatr Nephrol 16:665–671CrossRefPubMedGoogle Scholar
  79. 79.
    Reusz GS, Dobos M, Tulassay T, Miltényi M (1993) Hydrochlorothiazide treatment of children with hypercalciuria: effects and side effects. Pediatr Nephrol 7:699–702CrossRefPubMedGoogle Scholar
  80. 80.
    Knoll S, Alon US (2000) Effect of thiazide on established furosemide-induced nephrocalcinosis in the young rat. Pediatr Nephrol 14:32–35CrossRefPubMedGoogle Scholar
  81. 81.
    Leumann E, Hoppe B, Neuhaus T (1993) Management of primary hyperoxaluria: efficacy of oral citrate administration. Pediatr Nephrol 7:207–211CrossRefPubMedGoogle Scholar
  82. 82.
    Schell-Feith EA, Moerdijk A, van Zwieten PH, Zonderland HM, Holscher HC, Kist-van Holthe J, van der Heijden BJ (2006) Does citrate prevent nephrocalcinosis in preterm neonates? Pediatr Nephrol 21:1830–1836CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s) 2008

Authors and Affiliations

  • Eveline A. Schell-Feith
    • 1
  • Joana E. Kist-van Holthe
    • 2
    • 2
  • Albert J. van der Heijden
    • 3
  1. 1.Department of PediatricsRijnland ZiekenhuisLeiderdorpThe Netherlands
  2. 2.Department of PediatricsLeiden University Medical CenterLeidenThe Netherlands
  3. 3.Department of PediatricsErasmus MC-Sophia Children’s HospitalRotterdamThe Netherlands

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