Published online March 1, 2007
PEDIATRICS Vol. 119 No. 3 March 2007, pp. 468-475 (doi:10.1542/10.1542/peds.2006-2639)
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ARTICLE

Is Nephrocalcinosis in Preterm Neonates Harmful for Long-term Blood Pressure and Renal Function?

Joana E. Kist-van Holthe, MD, PhDa, Paul H.T. van Zwieten, MDd, Eveline A. Schell-Feith, MD, PhDf, Harmien M. Zonderland, MD, PhDb, Herma C. Holscher, MD, PhDe, Ron Wolterbeekg, Sylvia Veen, MD, PhDa, Marijke Frolich, PhDc and Bert J. van der Heijden, MD, PhDf

a Departments of Pediatrics
b Radiology
c Clinical Chemistry, Leiden University Medical Center, Leiden, Netherlands
d Departments of Pediatrics
e Radiology, Haga Teaching Hospital, Juliana Children's Hospital, The Hague, Netherlands
f Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands
g Department of Medical Statistics, Rijksuniversiteit Leiden, Leiden, Netherlands


   ABSTRACT
TOP
 ABSTRACT
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. The aim of our study was to examine long-term effects of nephrocalcinosis in prematurely born children.

PATIENTS AND METHODS. Preterm neonates (gestational age <32 weeks) with (n = 42) and without (n = 32) nephrocalcinosis were prospectively studied at a mean age of 7.5 (±1.0) years.

RESULTS. Blood pressure did not differ in ex-preterm infants with and without nephrocalcinosis but was significantly higher than expected for healthy children. In comparison to healthy children, more ex-preterm infants with neonatal nephrocalcinosis had (mild) chronic renal insufficiency (glomerular filtration rate: <85 mL/min per 1.73 m2; 6 of 40); this is in contrast to ex-preterm infants without neonatal nephrocalcinosis (2 of 32). Tubular phosphate reabsorption and plasma bicarbonate were significantly lower in children with nephrocalcinosis compared with children without nephrocalcinosis. In addition, more ex-preterm infants with and without nephrocalcinosis than expected had low values for plasma bicarbonate and early-morning urine osmolality compared with healthy children. Kidney length of ex-preterm infants with and without nephrocalcinosis was significantly smaller than expected in healthy children of the same height. Nephrocalcinosis persisted long-term in 4 of 42 children but was not related to blood pressure, kidney length, or renal function.

CONCLUSIONS. Nephrocalcinosis in preterm neonates can have long-term sequelae for glomerular and tubular function. Furthermore, prematurity per se is associated with high blood pressure, relatively small kidneys, and (distal) tubular dysfunction. Long-term follow-up of blood pressure and renal glomerular and tubular function of preterm neonates, especially with neonatal nephrocalcinosis, seems warranted.

Key Words: nephrocalcinosis • renal failure • blood pressure • preterm infants • child

Abbreviations: GFR—glomerular filtration rate • TRP—tubular reabsorption of phosphate • SDS—SD score

Nephrocalcinosis, first described in preterm neonates in 1982 by Hufnagle, was initially attributed to long-term furosemide therapy for chronic lung disease.1 Since then, nephrocalcinosis was diagnosed in 7% to 64% of preterm neonates with gestational age <32 weeks or birth weight <1500 g.2–10 The wide range in prevalence of nephrocalcinosis is a consequence of different study populations and ultrasound equipment and criteria, in addition to a moderate interobserver variation.8 Nephrocalcinosis in preterm neonates occurs as a result of imbalance between stone-promoting and stone-inhibiting factors. The etiology of nephrocalcinosis is multifactorial, consisting of low gestational age and birth weight3,5–7,10,11; severe respiratory disease3,6,7,11,12; high intakes of calcium, phosphate,7,11 and ascorbic acid11; long duration of total parenteral nutrition6,7; as well as drugs with hypercalciuric adverse effects, eg, furosemide,1,7,10,12–15 corticosteroids,6,11,16,17 and methylxanthines.11,18 In addition, metabolic acidosis,9 hypocitraturia,7,11 hypercalciuria,1,7,9,11,18,19 high urinary oxalate/creatinine ratios,6,20 and high urate/creatinine ratios6,20 have all been associated with development of nephrocalcinosis in preterm neonates. Furthermore, a positive family history of kidney stones and white race have been found to be risk factors for nephrocalcinosis in preterm infants.4 Renal histology from autopsies of intensively treated neonates showed predominantly intratubular calciumoxalate and, in a minority of children, calcium phosphate deposits.4,21

Resolution of nephrocalcinosis commonly occurs in the first years of life.7,13–15,19,22 In a previous study, we found nephrocalcinosis persisted in only 15% of patients beyond 30 months of age.23 However, the question arises whether the presence of nephrocalcinosis in a preterm neonate has unfavorable long-term effects on blood pressure and renal function. Data on follow-up of renal function of preterms with nephrocalcinosis are scarce, involves small numbers of patients, and results are not always compared with a control group of preterms without nephrocalcinosis.7,13–15,22–25 Here, we present the largest prospective long-term follow-up study up to date of blood pressure and renal glomerular and tubular function in preterm neonates with and without neonatal nephrocalcinosis.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
General Outline
In our previous prospective observational study, 41% of 201 preterm neonates with gestational age <32 weeks developed nephrocalcinosis at term.11 The aim of the current study was to analyze long-term blood pressure and renal function and compare results of ex-preterm infants with and without neonatal nephrocalcinosis. In addition, children were checked for persistence of nephrocalcinosis and excretion of calcium, and citrate was measured. Patients were born between May 1996 and November 1998 at Leiden University Medical Center and Haga Teaching Hospital, Juliana Children's Hospital, Netherlands. All children alive with (n = 80) and without (n = 92) nephrocalcinosis at term were asked to participate in the study. Three children died, and children classified as having dubious nephrocalcinosis at term, defined as slight changes on renal ultrasound possibly but not unequivocally fitting nephrocalcinosis (n = 26), were excluded from the follow-up study.11 The ethics committee of both hospitals approved the study protocol. Informed consent was obtained after written information had been given.

Renal Function
Glomerular Function
Estimated glomerular filtration rate (GFR) was used to study renal function with a modified Schwartz formula (40 x length [cm]/serum creatinine [µmol/L]).26,27 Serum creatinine concentration was measured by means of a photometric method (Jaffé) on an automatic analyzer (Modular P 800, Hitachi, Tokyo, Japan at Leiden University Medical Center and Synchron LX20-pro, Beckman Coulter, Fullerton, CA, at Juliana Children's Hospital). Chronic renal insufficiency was defined as a GFR <85 mL/min per 1.73 m2.28 Urinary microalbumin was measured with an immunoturbidimetric assay on a fully automated Hitachi 911, and the variation coefficient ranged from 1.5% to 3.1% at different levels. The reference value for urine microalbumin/creatinine is <2.5 µg/µmol.

Tubular Function
Proximal tubular function was studied by means of tubular reabsorption of phosphate (TRP), plasma bicarbonate, and presence of glucosuria. Serum and urine phosphate concentration was measured on an automatic analyzer (Hitachi 747–100). Plasma bicarbonate was determined with a colorimetric assay on a fully automated Hitachi 911, with a variation coefficient of <2%. Urine anion gap (reference value: less than –20 to –50 mmol/L for adequate distal hydrogen ion production during metabolic acidosis) was used to differentiate between proximal and distal tubular acidosis. Urine glucose was tested semiquantitatively with a dipstick; a positive result corresponding to glucose was >0.3 g/L.

Distal tubular function was evaluated by means of early-morning urine osmolality and plasma bicarbonate in combination with urine anion gap. Urine osmolality was determined by testing freezing point depression.

Renal Ultrasound
Two pediatric radiologists, 1 in each center, performed ultrasound examinations with curved array broadband 5- to 12-mHz transducers, with additional imaging of details by means of small part transducers if possible (Toshiba Aplio, Toshiba, Zoetermeer, Netherlands, and ATL HDI 5000, Bethel, WA). Transverse and longitudinal images were obtained and length of the kidneys was measured. Nephrocalcinosis was defined as the presence of bright reflections in the medulla or cortex, reproducible in both transverse and longitudinal direction with or without acoustic shadowing. Small bright reflections (<2 mm) on renal ultrasound were classified as focal nephrocalcinosis and larger bright reflections (≥2 mm) were classified as extensive nephrocalcinosis.

Intraobserver and interobserver agreement of ultrasound for the detection of nephrocalcinosis in preterm neonates by the 2 pediatric radiologists were previously found to be good ({kappa} value: 0.84) and moderate ({kappa} value: 0.46), respectively.8 Kidney length was compared with values for healthy children of the same height.29

Miscellaneous
Blood pressure was measured 3 times using an oscillometric device (Critikon Dynamap, GmbH, München, Germany). The lowest value was used and compared with values for healthy children of the same gender, age, and height.30 Urine analysis was performed by dipstick; if the dipstick was positive for hemoglobin or leukocytes, microscopy was performed. Urine calcium, creatinine, and citrate were measured on an automatic analyzer (Hitachi 747-100).

Statistics
Statistical significance of the variables was tested using {chi}2 at a 5% significance level. {chi}2 tests were also used to assess the fit of theoretical distributions specified by population percentiles. Group differences in baseline variables were tested by using {chi}2 tests and independent samples t tests. All computations were conducted in SPSS 12.0 (SPSS Inc, Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patients
A total of 42 (53%) of 80 patients with nephrocalcinosis and 32 (35%) of 92 patients without nephrocalcinosis at term participated in the study. One patient without nephrocalcinosis at term is excluded because of cystic kidney disease. The remaining patients refused to participate in the study or were lost to follow-up. Patient characteristics are depicted in Table 1. There was no significant difference in gestational age or in birth weight between children with nephrocalcinosis at term participating (Table 1) and not participating (28.7 ± 1.9 weeks and 1136 ± 302 g; n = 38; P = .35) in the follow-up study. Likewise, there was no significant difference in gestational age or in birth weight between children without nephrocalcinosis at term participating (Table 1) and not participating (29.3 ± 1.7 weeks and 1264 ± 313 g; n = 58; P = .49) in the follow-up study.


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  		TABLE 1 Patient Characteristics, Blood Pressure, and Renal Function of Ex-preterm Infants With (NC+) and Without (NC–) Neonatal Nephrocalcinosis

 
Growth and Blood Pressure
Weight for height (SDS) and height (SDS) of the patients are depicted in Table 1. Systolic and diastolic blood pressure did not differ significantly in both groups but was significantly higher than expected for healthy children (Table 1). None of the children received antihypertensive medication at follow-up. Birth weight SDS was not related to high blood pressure (systole: P = .13; diastole: P = .41).

Glomerular Function
In comparison to healthy children, more ex-preterm infants with neonatal nephrocalcinosis had (mild) chronic renal insufficiency (GFR <85 mL/min per 1.73 m2) than expected (6 of 40; P < .0001); this is in contrast to ex-preterm infants without neonatal nephrocalcinosis (2 of 32; P = .18). However, mean GFR was not significantly different in ex-preterm infants with nephrocalcinosis compared with infants without neonatal nephrocalcinosis (Table 1; Fig 1). Patients with (mild) chronic renal insufficiency did not have relevant concomitant medical problems. The degree of nephrocalcinosis at term (18 of 42 had focal nephrocalcinosis, and 24 of 42 had extensive nephrocalcinosis) did not predict glomerular function at follow-up (P = .62).


Figure 1
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  		FIGURE 1 Long-term GFR of ex-preterm infants with and without neonatal nephrocalcinosis. a Significantly more children with neonatal nephrocalcinosis have (mild) chronic renal insufficiency compared with healthy children, P < .0001. The dotted line indicates GFR <85 mL/min per 1.73 m2.

 
Urine albumin excretion did not differ significantly between both groups. Furthermore, values in either group were within the reference range compared with values for healthy children from literature (Table 1).

Tubular Function
Proximal and distal tubular function are shown in Table 2. Plasma bicarbonate is classified under distal tubular function because the urine anion gap of all patients with low plasma bicarbonate was more than –20 mmol/L, indicating inadequate distal hydrogen ion production during metabolic acidosis. Tubular function of children with extensive nephrocalcinosis at term (24 of 42) did not differ significantly from children with focal nephrocalcinosis (18 of 42).


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  		TABLE 2 Long-term Tubular Function and Urinary Solute Excretion of Premature Infants With (NC+) and Without (NC–) Neonatal Nephrocalcinosis

 
Urine Analysis
Urinary excretion of calcium and citrate are depicted in Table 2. No patient had (microscopic) hematuria.

Renal Ultrasound
Kidney length of ex-preterm infants with and without neonatal nephrocalcinosis is depicted in Table 3. 25 Kidneys of patients with as well as without neonatal nephrocalcinosis were significantly smaller than expected for healthy children, with the exception of left kidneys of children without neonatal nephrocalcinosis, which showed only a trend in being smaller (P = .054).


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  		TABLE 3 Kidney Length Related to Patient Height at Long-term Follow-up of Ex-preterm Infants With (NC+) and Without (NC–) Neonatal Nephrocalcinosis

 
Nephrocalcinosis persisted long-term in 4 (10%) of 42 children. Persistence of nephrocalcinosis was not related to blood pressure or kidney length. Only 1 child with persisting nephrocalcinosis had (mild) chronic renal insufficiency (GFR: 68 mL/min per 1.73 m2). No child had low TRP or plasma bicarbonate, and only 1 had slightly decreased early-morning urine osmolality (675 mOsm/kg water). All 4 children with persisting nephrocalcinosis at long-term follow-up had a urinary calcium/creatinine ratio within the reference range, and only 1 child had a low urine citrate/creatinine ratio (0.07 mmol/mmol).

One child with neonatal nephrocalcinosis passed a few small kidney stones until the age of 3 years. At long-term follow-up, he had persistent nephrocalcinosis but no kidney stones.


   DISCUSSION
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
General
With improvement of medical science and technical possibilities in the care of very prematurely born neonates, quality of life of surviving children becomes increasingly important. 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.31,32 Development of nephrocalcinosis in prematurely born children may carry an additional risk of further compromising renal function later in life.

In our previous prospective observational study, 41% of 201 preterm neonates with gestational age of <32 weeks developed nephrocalcinosis at term.11 Here, we prospectively studied blood pressure, renal function, and long-term persistence of nephrocalcinosis in the same cohort of children and compared results with a control group of ex-preterm infants without nephrocalcinosis. Selection in follow-up of patients did not find place, other than by the willingness of children and their parents to participate in the study. This is reflected by the finding that children participating did not differ in gestational age or in birth weight from those not participating in the study. Children classified as having dubious neonatal nephrocalcinosis were not included in the follow-up study to get a clear picture of the influence of nephrocalcinosis on renal function.

Blood Pressure
Blood pressure in our study did not differ in ex-preterm infants with and without nephrocalcinosis but was significantly higher than expected for healthy children, although only a minority (3 [7%] of 42 with and 2 [6%] of 31 without nephrocalcinosis) had systolic blood pressure more than the 95th percentile (Table 1). This is in concert with the current concept that high blood pressure is increasingly seen in follow-up of preterms into (young) adulthood and is a risk factor for hypertension later in life.33 Although there is evidence that low birth weight is an important factor in the development of hypertension and metabolic syndrome in adults, prematurity did but birth weight SDS did not predict hypertension in a large cohort of 19-year-old ex-preterm infants.33,34 Similarly, in our study there was no correlation between high blood pressure and birth weight SDS. Concluding, in our study, prematurity per se is associated with high blood pressure.

Renal Ultrasound
Long-term follow-up data on nephrocalcinosis in ex-preterm infants are scarce. Studies in a limited number of patients show persistence of nephrocalcinosis in 4 of 10, 5 of 9, 6 of 26, 5 of 11, 4 of 16, 2 of 26, and 3 of 12 after 1 to 2 years, 21 ± 15 months, 2 years, 4 to 5 years, 3 to 6 years, 6 years, and 5.8 to 7.7 years, respectively.7,13–15,22,24,25 We observed only 10% nephrocalcinosis in ex-preterm infants after a longer follow-up period of 7.4 (±1.0) years. This fits in well with our previous findings of 34% and 15% persistence of nephrocalcinosis after 15 and 30 months, and the concept of spontaneous resolution of nephrocalcinosis in time.23

Furthermore, we established that kidneys of patients with as well as without neonatal nephrocalcinosis were significantly smaller than expected for healthy children of the same height, with the exception of left kidneys of children without neonatal nephrocalcinosis, which showed only a trend in being smaller (P = .05). This is in concert with the study of Keijzer-Veen,35 who found decreased kidney growth in 51 preterms (gestational age: <32 weeks) compared with 30 term born controls at the age of 20 years. 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.

Glomerular Function
Undoubtedly, the most important question is, does nephrocalcinosis in very prematurely born children affect growth and function of kidneys in the long-term? To date, only small numbers of patients have been studied. Furthermore, most studies probably concern selected populations of prematurely born children. The first study to address this question was performed by Ezzedeen et al.14 Four of 9 children with nephrocalcinosis as preterm neonate had low GFR at a mean age of 21 (SD: 15) months (20, 25, 52, and 65 mL/min per 1.73 m2, respectively). At 1 to 2 years, Downing et al36 also found significantly lower mean GFR in 10 children with nephrocalcinosis as preterm neonates (84 ± 8 mL/min per 1.73 m2) compared with 2 groups without nephrocalcinosis but with (n = 10; 109 ± 5 mL/min per 1.73 m2) or without furosemide medication (n = 7; 103 ± 7 mL/min per 1.73 m2) in the neonatal period. Jones et al24 studied 11 children at the age of 4 to 5 years with nephrocalcinosis as preterm neonates. She found a median GFR of 61 mL/min per 1.73 m2 (range: 46–79 mL/min per 1.73 m2), which is low compared with reference values for healthy children. This is in contrast with Saarela et al,25 who found no significant difference in GFR at a mean age of 4.7 years between 20 preterms with and 20 without nephrocalcinosis in the neonatal period. Hoppe et al7 and Porter et al22 also observed normal GFR after 3 to 6 and 5.8 to 7.7 years, respectively, in 12 and 14 prematurely born children with nephrocalcinosis.

We previously reported mean estimated GFR of 110 (SD: 34) and 132 (SD: 34) mL/min per 1.73 m2 after 1 and 2 years in the same population of preterm neonates with nephrocalcinosis studied here. At that time, none of the children at 1 year and only 2% of the children at 2 years of age had low values for GFR compared with healthy subjects.23 Here, we extended the follow-up period to mean 7.4 ± 1 years and, in addition, studied preterm neonates without neonatal nephrocalcinosis as a control group. Significantly more children in the nephrocalcinosis group (6 of 40 [15%]) had low GFR compared with healthy children; this is in contrast to children without neonatal nephrocalcinosis (2 of 32 [6%]; Fig 1). However, there was no significant difference in GFR or microalbuminuria between both groups. Interestingly, the degree of nephrocalcinosis at term (focal or extensive) did not influence glomerular function at follow-up. Furthermore, no correlation between persistence of nephrocalcinosis and low GFR was found, but the number ex-preterm infants with persisting nephrocalcinosis (n = 4) is small. We conclude that long-term follow-up of preterm neonates with nephrocalcinosis demonstrates an unfavorable effect on renal function in some children.

Proximal Tubular Function
If neonatal nephrocalcinosis in preterms has long-term sequelae for glomerular function, how does nephrocalcinosis affect tubular function? Jones et al24 studied 11 ex-preterm infants at the age of 4 to 5 years with neonatal nephrocalcinosis. She found a low median tubular phosphate reabsorption/100 mL glomerular filtration rate compared with reference values. Likewise, Saarela et al25 also observed a significantly higher urine β2-microglobulin/creatinine ratio in 20 children with compared with 20 children without nephrocalcinosis as preterm neonates at a mean age of 4.7 years. However, in his study TRP did not differ significantly in children with and without nephrocalcinosis. In contrast, Downing et al36 found significantly lower TRP (84 ± 2% vs 93 ± 1%; P < .05) in preterm children at the age of 1 to 2 years with nephrocalcinosis compared with preterms without nephrocalcinosis. In our study, TRP also was significantly lower in children with compared with without nephrocalcinosis (Table 2). However, plasma phosphate was within reference limits in all children. Therefore, the implication of low TRP in these patients is debatable. We did not observe glucosuria in any of the children.

These findings are in concert with our previous study where we found normal tubular phosphate reabsorption/100 mL glomerular filtration rate and urine {alpha}1-microglobulin in ex-preterm infants with neonatal nephrocalcinosis after 1 and 2 years follow-up.23 Considering these data, our study does not support firm evidence for proximal tubular dysfunction caused by neonatal nephrocalcinosis in ex-preterm infants.

Distal Tubular Function
Downing et al36 observed lower ability to excrete hydrogen ions in the distal tubule in preterms with (n = 10) compared with without (n = 14) nephrocalcinosis. In another study, distal tubular acidification was measured by using an oral acetazolamide test, in which the response was abnormal in 1 of 20 children with nephrocalcinosis as opposed to none without neonatal nephrocalcinosis.25 On the other hand, Hoppe et al.7 noted no acidosis after a follow-up period of 3 to 6 years in 12 preterms with neonatal nephrocalcinosis. In our study, we found median plasma bicarbonate was significantly lower in children with versus without neonatal nephrocalcinosis (Table 2). The urine anion gap of the children with low plasma bicarbonate was inappropriately high, indicating distal rather than proximal tubular dysfunction.

Downing et al36 found no difference in early-morning urine osmolality between ex-preterm infants with and without nephrocalcinosis after 1 to 2 years. In another study, 12 preterm infants with neonatal nephrocalcinosis had early-morning urine osmolality within the reference range after a follow-up period of 3 to 6 years.7 Likewise, Porter et al22 noted early-morning urine osmolality that was within the reference range in 14 children with and 14 children without neonatal nephrocalcinosis at a mean age of 6.9 years. However, we previously found impaired desmopressin test in 4 of 30 ex-preterm infants with neonatal nephrocalcinosis at 1 year and 2 of 25 at 2 years.23In our current study, early-morning urine osmolality did not differ between children with and without neonatal nephrocalcinosis, but likewise was significantly lower in both groups compared with healthy children. However, it is difficult to rule out that some of the children were not fasting when collecting the early-morning urine sample. In concert with our study, Jones et al24 found no significant difference in renal concentrating capacity after desmopressin in children with and without nephrocalcinosis. Equally, she found the mean concentrating capacity was below that of reference values.

Interpreting all these data, nephrocalcinosis in preterm neonates can have long-term sequelae mainly for distal tubular function. However some tubular defects cannot solely be attributed to nephrocalcinosis but are also seen in ex-preterm infants without neonatal nephrocalcinosis (low early-morning urine osmolality and plasma bicarbonate).

Hypercalciuria
We found significantly more (9 of 41 [22%]) children with hypercalciuria in the group with neonatal nephrocalcinosis than expected in healthy children; this is in contrast to ex-preterm infants without nephrocalcinosis (2 of 32 [6%]). In addition, the urinary calcium/citrate ratio was significantly higher at long-term follow-up in children with compared with without neonatal nephrocalcinosis (Table 2). Hypercalciuria is indeed frequently seen in ex-preterm infants with neonatal nephrocalcinosis. At 1 to 2 years of age, the urine calcium/creatinine ratio was significantly higher in 10 preterms with (0.94 ± 0.23 mmol/mmol) compared with 10 preterms without (0.45 ± 0.17 mmol/mmol) nephrocalcinosis.36 Similarly, the urine calcium/creatinine ratio was significantly higher in 20 children with (0.68 [± 0.45] mmol/mmol) versus 20 children without (0.34 [±0.23] mmol/mmol) neonatal nephrocalcinosis at a mean age of 4.7 years.25 On the other hand, Jones et al24 found no difference in calciuria in ex-preterm infants with (n = 11) and without (n = 17) nephrocalcinosis at 4 to 5 years of age, but both groups contained more children than expected with high calcium excretion: 27% and 29%, respectively. Likewise, she found higher urinary calcium excretion in 7- to 8-year-old ex-preterm infants compared with healthy controls.37 Porter et al22 also noted evidence of hypercalciuria in 2 of 14 children with as well as in 4 of 14 children without neonatal nephrocalcinosis at long-term follow-up, suggesting prematurity might be a risk factor.

Furthermore, in our study, the urine citrate/creatinine ratios in both groups were significantly lower than expected in healthy children (reference value: >0.3 mmol/mmol, 0.51 g/g). Then again, there is no clear consensus in the literature on the cutoff level for healthy children (Table 2).38


   CONCLUSIONS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Nephrocalcinosis in preterm neonates can have long-term sequelae for glomerular and tubular function (low plasma bicarbonate, high urine calcium/citrate ratios). Furthermore, prematurity per se is associated with high blood pressure and relatively small kidneys, as well as (distal) tubular dysfunction (low plasma bicarbonate and early-morning urine osmolality). Long-term follow-up of blood pressure and renal function of prematurely born children, especially with neonatal nephrocalcinosis, seems warranted. Future research pertaining to prevention of nephrocalcinosis in preterm neonates is needed.


   ACKNOWLEDGMENTS
 
We gratefully acknowledge financial support by the Dutch Kidney Foundation.


   FOOTNOTES
 
Accepted Nov 9, 2006.

Address correspondence to Joana E. Kist-van Holthe, Department of Pediatrics, Leiden University Medical Center, PO Box 9600, 2300RC Leiden, Netherlands. E-mail: j.kist{at}lumc.nl

The authors have indicated they have no financial relationships relevant to this article to disclose.

Dr Zonderland's current affiliation is Department of Radiology, Academic Medical Center, Amsterdam, Netherlands.


   REFERENCES
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics

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