Kidney International, Vol. 63 (2003), pp. 2194–2199

CLINICAL NEPHROLOGY–EPIDEMIOLOGY–CLINICAL TRIALS

Hypocitraturia is one of the major risk factors fornephrocalcinosis in very low birth weight (VLBW) infants

PRZEMYSLAW SIKORA, BERNHARD ROTH, ANGELA KRIBS, DIETRICH V. MICHALK,ALBRECHT HESSE, and BERND HOPPE

Division of Pediatric Nephrology, University Children’s Hospital Cologne, Cologne, Germany; Division of Perinatology,University of Cologne, Cologne, Germany; and Division of Experimental Urology, Department of Urology,University of Bonn, Bonn, Germany

Hypocitraturia is one of the major risk factors for nephrocalci- is still a matter of debate, although it is definitively multi-nosis in very low birth weight (VLBW) infants. factorial [3–5]. Since Hufnagle et al [6] described the

Background. Very low birth weight (VLBW) infants are at association between long-term furosemide therapy andrisk to develop nephrocalcinosis (NC). NC may result fromrenal calcifications in preterm infants, additional clinicalspontaneous or therapy-induced imbalance between promoterspredisposing factors like other medications (e.g., dexa-and inhibitors of crystallization in the urine. However, data on

“normal” urinary excretions of these parameters in VLBW methasone, methylxantine), parenteral nutrition, long-infants are sparse. Therefore, we prospectively examined the term ventilation, oxygen dependency, decreased urineurinary excretion of calcium, oxalate, uric acid, and citrate in

output, and a lower gestational age have been incrimi-VLBW infants during the first 8 weeks of life.nated [1, 3–5]. Long-term follow-up in VLBW infantsMethods. Urine samples were collected once weekly in 124

VLBW infants. NC appeared in 16 infants, whose data were with NC had shown specific morbidity, with NC leadingseparately analyzed. The remaining 108 infants were divided to a decline of glomerular filtration rate (GFR) or to aninto subgroups: A, �1000 g (N � 53); and B, 1000 to 1500 g impairment of tubular function [7, 8].(N � 55). Random urine samples were analyzed and the results

NC is mostly due to either parenchymal calcium oxa-were expressed as molar creatinine ratios. Calcium/citrate andlate or calcium phosphate deposition [6, 9]. Therefore, NCoxalate/citrate expressed the risk for calcium oxalate crystalli-

zation. is considered to result, in analogy to the pathogenesis ofResults. In group A, citrate excretion was lower at weeks 2 urinary stone formation, from a spontaneous or therapy-

to 5 and 7; calcium/citrate was higher in weeks 2, 4, and 7;induced imbalance between promotors (e.g., calcium,oxalate/citrate was higher in weeks 3, 4, 7, and 8; and calcium/oxalate, uric acid) and inhibitors (e.g., citrate, magne-creatinine ratio was higher in week 4 (P � 0.05). Citrate/cre-

atinine ratios were low in nine infants with NC. Oxalate/creati- sium) of crystallization in the urine [4, 10]. Hence, evalu-nine and calcium/creatinine were elevated in five and calcium/ ation of these parameters seems to be helpful to assesscitrate was increased in nine infants with NC. the risk of NC and to eventually prevent it in this popula-Conclusion. Hypocitraturia is a major risk factor for NC

tion. However, apart of one report about urinary oxalatein VLBW infants, especially in those �1000 g. The urinaryexcretions in VLBW infants seem to depend on birth weight, excretion, there are no suitable longitudinal data on theage, and clinical condition. Hence, supplementation with alkali excretion of lithogenic and inhibitory substances incitrate may have a beneficial effect in the prevention of NC. VLBW infants [11]. Therefore, we prospectively exam-

ined the urinary excretion of calcium, oxalate, uric acid,and citrate in the population of VLBW infants during

Premature infants are known to have an increased the first 8 weeks of life. In addition, a group of smaller,risk for the development of nephrocalcinosis (NC). The

less mature infants was compared to a group of larger,incidence is particularly high in infants with a very low

more mature infants, as we expected significantly differ-birth weight (VLBW; �1500 g), but data published var-ent urinary concentrations of promotors/inhibitors ofied between 1.7% and 65% [1, 2]. The etiology of NCcrystal formation in either group.

Key words: nephrocalcinosis, preterm infants, hypocitraturia.METHODS

Received for publication May 25, 2002During the study period (January 1999 through De-and in revised form August 28, 2002, and November 8, 2002

Accepted for publication January 14, 2003 cember 2001) a total of 375 preterm infants with a birthweight �1500 g were born in our hospital. Weekly urine 2003 by the International Society of Nephrology

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Sikora et al: Hypocitraturia in preterm infants 2195

collections for analysis of lithogenic and stone-inhibitory cinosis [12]. The study was approved by the local ethicscommittee and written consent was obtained by the par-parameters were started in all infants using plastic bags

(girls, boys) or 10 mL vials (boys). However, satisfactory ents before urine sampling. For statistical analysis, theMann-Whitney and Kruskal-Wallis tests were performedurine collections (more than four samples) during the

first 8 weeks of life could only be obtained in 124 VLBW using SPSS Software (SPSS, Chicago, IL, USA). P valuesof less than 0.05 were considered to be significant.infants (median birth weight, 1015 g; range, 380 to 1500 g)

of �34 weeks gestation age (median, 29 weeks; range,21 to 34 weeks). This was due to patient reasons (e.g.,

RESULTSproblems attaching plastic bags for urine collections due

The clinical data obtained in the preterm infants exam-to vulnerable skin), or early discharge of the pretermined are shown in Table 1. The time of mechanical venti-infants to secondary hospitals nearby the parents’ homes.lation and the dosage of specific medication was signifi-In addition, infants with renal anomalies, or renal insuf-cantly higher in the infants of group A and those withficiency, as well as infants with gastrointestinal or cardio-NC compared to the more mature infants of group Blogic diseases, were excluded from the study.(P � 0.01). There was no significant difference betweenTotal parenteral nutrition was started in all infants ongroup A and the infants with NC. No infant had prolongedthe second day of life with 4 g/kg body weight glucose andacidosis for more than 4 to 6 hours. The urinary molar cal-0.5 g/kg protein and was increased to the final amount ofcium/creatinine, oxalate/creatinine, uric acid/creatinine, ci-12 g/kg glucose and 2.5 g/kg protein at the end of thetrate/creatinine, calcium/citrate, and oxalate/citrate ratiosfirst week. Thereafter, it was tapered in favor of oralin preterm infants with birth weight �1000 g (group A)nutrition. Feeding was entirely oral at the end of theand 1000 to 1500 g (group B) during the first 8 weekssecond week of life. Calcium intake of the preterm in-of life are shown in Tables 2 and 3, respectively. Despitefants was adjusted to 120 mg/kg body weight/day andall efforts we were unable to obtain a complete weeklyphosphorus intake to 70 mg/kg body weight/day.series in every infant, hence the number of weekly urineAs we wanted to estimate “normal” values of the ex-analyses varies.cretion parameters, urine specimen from 16 infants who

Because the values were non-normally distributed, theydeveloped NC (median birth weight, 770 g; range, 415are expressed as median values and the range. We ob-to 1450 g) were separately analyzed. Hence, a total of 108served a definite effect of age on all ratios. In generalpreterm infants (57 girls and 51 boys) were included intocalcium/creatinine, oxalate/creatinine, and citrate/creati-the study to obtain data appropriate to use as normal levelsnine ratios were lower in the first 3 weeks of life thanin this group of infants. To evaluate the influence of thein weeks 6 to 8. The ratios of urinary citrate increasedbirth weight on the urinary parameters examined, the in-over time. The median values for uric acid/creatinine,fants were subsequently divided into subgroup A with 53calcium/citrate, and oxalate/citrate ratios were relativelyinfants �1000 g birth weight (median, 717 g; range, 380constant. There were no specific differences with regardto 990 g) and subgroup B with 55 infants weighing 1000to sex for any variable. As compared to group B, theto 1500 g at birth (median, 1306 g; range, 1010 to 1500 g).smaller infants (group A) had lower citrate/creatinineCalcium, oxalate, citrate and, since the year 2000, uricexcretions, which reached significance in weeks 2 to 5acid concentrations were weekly analyzed in random urineand 7 (P � 0.05) (Fig. 1C). Furthermore, infants fromsamples, and the results were correlated to creatinine ex-group A had higher calcium/citrate ratios in weeks 2, 4,cretion. To evaluate the risk for calcium oxalate crystalli-and 7 (P � 0.05) (Fig. 1E) and higher oxalate/citratezation, calcium/citrate and oxalate/citrate ratios were cal-ratios in weeks 3, 4, 7, and 8 (P � 0.05) (Fig. 1F). Inculated. Calcium concentration was measured by atomiccontrast, there was no systematic difference concerningabsorption spectroscopy (EFOX, Eppendorf, Germany),the calcium/creatinine, oxalate/creatinine, and uric acid/oxalate, citrate, and uric acid concentrations were mea-creatinine ratios.sured enzymatically using oxalate oxidase (Sigma, Tauf-

The infants who developed NC had the lowest urinarykirchen, Germany), citrate lyase and the uricase methodcitrate concentrations, with citrate/creatinine values be-(Boehringer Mannheim, Mannheim, Germany), respec-ing as low as 0.08 mol/mol. Median citrate/creatininetively. Creatinine concentration was determined by alevels in the infants with NC increased from 0.52 forstandard kinetic Jaffe procedure.week one to 1.91 mol/mol at week 8. In nine infants withBlood gas analyses were performed daily during theNC the longitudinal follow-up showed urinary citrate/first 2 weeks of life and thereafter once a week or whencreatinine levels being generally lower (range, 0.08 toclinically indicated. Renal ultrasound examinations were0.37 mol/mol) than those obtained in the whole studyperformed at least every second week and always by thepopulation and in those �1000 g. In addition, increasedsame pediatric radiologist (Prof. Dr. G. Benz-Bohm).oxalate/creatinine and calcium/creatinine ratios wereHence, we were able to minimize the observer variability

reported for the sonographic diagnosis of nephrocal- found in five infants each and calcium/citrate ratios were

Sikora et al: Hypocitraturia in preterm infants2196

Table 1. Clinical data, time of mechanical ventilation, and dosage of medication in preterm infants included in the study

Group A Group B Infants with�1000 g 1000–1500 g nephrocalcinosis (NC)

Number of infants 53 55 16Gestation age weeks 26.4 (2.2)a 30.8 (1.0) 27.0 (1.8)a

Birth weight g 722 (156)a 1301 (157) 794 (271)a

Duration of ventilation days 8.6�11.2a 2.4 �4.7 9.1�6.9a

Dexamethasone dosage mg/kg 1.04 (1.53)b 0.16 (0.62) 1.3 (1.29)a

Furosemide dosage mg/kg 2.83 (5.77)b 0.53 (1.54) 7.07 (18.1)b

Theophylline dosage mg/kg 62.6 (55.8)a 18.6 (21.8) 74.0 (49.1)a

Coffeincitrate dosage mg/kg 294 (194)a 118 (88.8) 276 (99.8)a

Mean (� SD).aP � 0.001, bP � 0.05 (group A and infants with NC compared to group B, no statistical difference between group A and the infants with NC)

Table 2. Urinary calcium/creatinine (Ca/Cr), oxalate/creatinine (Ox/Cr), uric acid/creatinine (UA/Cr), citrate/creatinine (Cit/Cr), calcium/citrate (Ca/Cit), and oxalate/citrate (Ox/Cit) ratios in very low birth weight (VLBW) infants (�1000 g) in relation to age (� group A)

Age weeks

I II III IV V VI VII VIII

Ca/Cr mol/mol Median 0.78 1.48 1.40 1.55 1.00 1.16 1.80 1.33Range 0.23–2.24 0.29–6.53 0.09–5.66 0.38–5.40 0.24–4.30 0.32–4.20 0.67–6.70 0.45–8.90N 11 15 21 23 17 13 18 25

Ox/Cr mmol/mol Median 334 234 353 399 304 356 354 430Range 191–619 43–605 159–1258 70–1448 42–1098 258–600 205–1552 190–1740N 10 12 18 20 16 12 18 25

Cit/Cr mol/mol Median 0.70 0.40 0.65 1.10 1.32 1.88 1.61 2.16Range 0.24–1.47 0.12–1.65 0.04–2.96 0.35–3.10 0.11–3.30 0.78–2.84 0.07–3.61 0.66–5.30N 10 15 21 23 18 13 17 26

UA/Cr mol/mol Median 1.55 1.89 1.98 2.28 1.68 1.5 1.88 2.21Range 1.01–2.24 0.61–2.19 1.24–4.00 0.67–3.91 1.19–3.39 0.88–2.36 1.46–2.74 1.46–3.07N 5 6 6 9 8 5 8 11

Ca/Cit mol/mol Median 1.2 2.8 1.43 1.37 0.76 0.64 1.08 0.62Range 0.55–2.92 0.59–17.5 0.25–33 0.16–6.1 0.30–6.78 0.15–5.32 0.41–41.3 0.14–7.83N 10 15 21 23 17 13 17 26

Ox/Cit mol/mol Median 0.38 0.45 0.57 0.31 0.24 0.17 0.20 0.21Range 0.18–1.29 0.11–1.82 0.17–5.00 0.16–1.79 0.08–3.53 0.11–0.40 0.10–8.02 0.06–1.77N 8 12 18 20 16 12 17 25

Table 3. Urinary calcium/creatinine (Ca/Cr), oxalate/creatinine (Ox/Cr), uric acid/creatinine (UA/Cr), citrate/creatinine (Cit/Cr), calcium/citrate (Ca/Cit), and oxalate/citrate (Ox/Cit) ratios in very low birth weight (VLBW) infants (1000 to 1500 g) in relation to age (� group B)

Age weeks

I II III IV V VI VII VIII

Ca/Cr mol/mol Median 0.82 0.96 1.36 0.87 1.12 1.47 1.84 3.23Range 0.15–3.33 0.16–2.74 0.53–3.78 0.17–2.84 0.24–4.37 0.35–6.00 0.58–5.66 0.55–10.0N 28 24 28 20 24 20 14 15

Ox/Cr mmol/mol Median 248 241 284 327 348 308 319 480Range 100–1800 116–464 175–481 49–523 111–789 157–759 127–921 143–777N 25 21 25 20 23 19 13 13

Cit/Cr mol/mol Median 0.70 0.86 1.38 1.74 1.78 2.15 2.76 2.66Range 0.11–3.92 0.06–2.85 0.18–3.69 0.19–2.95 0.22–4.97 1.10–3.47 1.34–5.27 1.42–6.68N 27 24 28 20 24 19 14 12

UA/Cr mol/mol Median 1.45 0.98 1.32 1.37 1.53 1.47 1.37 1.54Range 0.38–10.4 0.58–1.73 0.57–1.61 0.21–2.54 0.73–2.29 0.95–2.23 0.88–2.58 1.01–2.23N 14 14 14 13 15 11 11 10

Ca/Cit mol/mol Median 1.04 0.84 0.98 0.62 0.69 0.74 0.66 0.94Range 0.22–6.29 0.25–8.70 0.29–9.52 0.09–2.54 0.14–1.46 0.19–3.01 0.38–1.43 0.24–3.48N 27 24 28 20 24 20 14 11

Ox/Cit mol/mol Median 0.37 0.26 0.25 0.22 0.20 0.16 0.13 0.09Range 0.07–1.80 0.07–4.06 0.07–2.33 0.02–1.26 0.06–1.92 0.05–0.41 0.04–0.27 0.06–0.49N 24 21 25 20 24 18 13 9

Sikora et al: Hypocitraturia in preterm infants 2197

Fig. 1. Median urinary calcium/creatinine (Ca/Cr) (A), oxalate/creatinine (Ox/Cr) (B ), citrate/creatinine (Cit/Cr) (C ), uric acid/creatinine (UA/Cr)(D ), calcium/citrate (Ca/Cit) (E ), and oxalate/citrate (Ox/Cit) (F ) ratios in very low birth weight (VLBW) infants with birth weight (BW) below(�) and above (�) 1000 g during the first 8 weeks of life. *Statistical differences P � 0.05.

elevated in nine infants with NC. However, the differ- to the lower GFR in immature kidneys. Another expla-nation relates it to the lithogenic effect of specific treat-ence did not reach statistical significance due to the largement modalities that are primarily used in smaller andrange and the limited number of infants with NC. Birthsicker preterm infants. Historically, furosemide-inducedweight was �1000 g in 13 of 16 infants with NC.hypercalciuria was considered to be the main risk factorfor the development of NC [2, 6, 7], but subsequently

DISCUSSION other hypercalciuric agents like corticosteroids [16],Preterm infants with a birth weight below 1500 g are methylxanthines [17], or parenteral nutrition [18] were

reported to be at risk for the development of NC, how- linked with this condition. An influence of parenteralever, the incidence appears to be especially high in in- nutrition on the development of hyperoxaluria was alsofants below 1000 g [1, 4, 13]. Of the 16 premature infants reported [18, 19]. Finally, the gestational age (or birthwith NC diagnosed in our department in the last 3 years, weight)–dependent imbalance between promotors and13 (81%) had a birth weight below 1000 g, and the mean inhibitors of crystallization might play an additional role.birth weight of 16 premature infants with NC born in However, this hypothesis has not been tested in a popula-the previous period (1988 to 1998) was 1044 g [1]. In tion of very sick preterm infants. Our results show loweraccordance, the mean birth weight of infants with NC urinary citrate/creatinine ratios during the first 8 weeksranged between 800 g and 1100 g in the majority of studies of life in VLBW infants with a birth weight �1000 g[4, 14, 15]. In addition, the preterm infants developing than in those with birth weights of 1000 to 1500 g. Be-NC all had a gestational age �32 weeks [1]. So far, the cause citrate is a potent inhibitor of calcium oxalateincreased risk of NC in infants with a lower birth weight [20] and calcium phosphate [21] precipitation in urine,is not fully explained. According to Schell-Feith et al hypocitraturia could play an important role in the patho-[4, 10], it is the result of a higher susceptibility to hetero- genesis of NC in preterm infants as it does in stone

disease [22, 23].geneous crystallization and a reduced urine output due

Sikora et al: Hypocitraturia in preterm infants2198

Lower citrate/creatinine ratios in smaller preterm in- oxalate did not differ between the two groups, exceptfor a significantly higher calcium/creatinine ratio at 4fants could also be due to a relatively higher creatinine

excretion. However, the opposite is the case, as the latter weeks in the smaller infants. Results of earlier studiesconcerning these two main components of renal calcifi-increases significantly with postconceptional age [24].

Keeping in line is the finding of higher calcium/creatinine cation in infants with NC are conflicting [4, 5, 11, 28].Some authors reported an increased calcium excretionand oxalate/creatinine ratios. In contrast, the citrate/cre-

atinine ratios in the younger infants are lower indicating [4, 11], whereas other did not find it [5]. Similarly, oxalateexcretions were reported to be increased [5, 28] or nor-that urinary citrate excretion is indeed reduced.

The pathogenesis of the lower citrate excretion is not mal [4]. This might be simply explained by the heteroge-neity of the studied populations, especially with regardclear. A possible explanation could be a more pronounced

metabolic acidosis—one of the reasons for hypocitratu- to the medical care.Although the analysis of the urinary excretion of litho-ria—in smaller preterm infants [25]. In accordance, Mur-

phy and Mendoza [26] found lower urinary citrate/creati- genic and inhibitory substances in VLBW infants is im-portant, there are, apart from oxalate, no adjusted refer-nine ratios in premature infants with lung disease and

acidosis in comparison to nonacidotic controls. This re- ence values available [8]. Our data show that urinaryratios of these parameters in VLBW infants depend bothsult may explain the strong relationship between the

duration of ventilation or oxygen dependency and the on birth weight and postnatal age.Our results suggest that hypocitraturia is associatedincidence of NC reported by others [5, 11]. Hence, we

might speculate that the chance of more pronounced with an increased risk of NC in VLBW infants with abirth weight �1000 g during the first 8 weeks of life.periods of acidosis was higher in group A and in the

infants with NC, as the duration of ventilation was sig- Supplementation with alkali citrate may therefore havea beneficial effect in the prevention of NC in this popula-nificantly longer compared to group B. Repeated blood

gas analysis, however, did not express extended acidosis tion as is the case in calcium oxalate stone disease[30–34]. However, the effect of prophylactic treatmentin these infants.

Citrate excretion could also simply be age dependent, with alkali citrate in extremely low birth weight infantsshould first be examined in a controlled study.but we cannot exclude other influencing elements like

postnatal renal maturation, the clinical condition, andthe adaptation to nutritional and pharmacologic factors. ACKNOWLEDGMENTSSchell-Feith et al [4, 10] recently reported a lower urinary We thank the nurses of the neonatal intensive care unit and the

neonatology ward for their help in urine collections. Our special thankscitrate excretion in relation to calcium excretion in pre-belong to Prof. Ernst Leumann, Zurich, Switzerland, for his editorialterm infants with NC. This is in accordance with ourassistance and to Prof. Dr. Gabriele Benz-Bohm for performing the

results, as the infants who developed NC had the lowest ultrasound examinations.citrate levels overall and hence, the calcium/citrate ratio

Reprint requests to Bernd Hoppe, M.D., University Children’s Hospi-was elevated in 9 of 16 infants.tal, Division of Pediatric Nephrology, Josef-Stelzmann Str. 9, D-50924

We also found higher uric acid/creatinine ratios, par- Cologne, Germany.Email: Bernd.Hoppe@medizin.uni-koeln.deticularly in the 7th and 8th weeks of life and clearly

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