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NDT Advance Access originally published online on September 23, 2006
Nephrology Dialysis Transplantation 2007 22(1):96-103; doi:10.1093/ndt/gfl550
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The effect of intrauterine growth retardation on renal function in the first two months of life

Vasileios Giapros1, Photeini Papadimitriou1, Anna Challa2 and Styliani Andronikou1

1Neonatal Intensive Care Unit, Child Health Department and 2Research Laboratory of the Child Health Department, University of Ioannina, Greece

Correspondence and offprint requests to: V. Giapros, University of Ioannina, Medical School, Child Health Department, PO Box 1186, Ioannina, 45 110, Greece. Email: vgiapros{at}cc.uoi.gr



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Children born with growth retardation (GR) have a smaller nephron number and are at increased risk for the development of renal disease and hypertension in adult life. Data on the immediate post-natal development of renal function in neonates born with GR are limited and data on the effects of aminoglycosides (AGs) on renal function in these infants are lacking.

Methods. This was a prospective study of 81 preterm neonates with a mean gestational age of 32.5 weeks, 40 born with GR (small for gestational age, SGA) and 41 without GR (appropriate for gestational age, AGA). The infants were classified into 4 groups. Groups A (n = 21) and B (n = 20) consisted of AGA and SGA neonates, respectively, who received AGs, and groups C (n = 20) and D (n = 20) of AGA and SGA neonates, respectively, who did not receive AG treatment. Indices of renal function were: serum creatinine (SeCr), the fractional excretion of sodium (FENa), potassium (FEK), phosphorus (FEP), magnesium and uric acid (FEUA), the urinary calcium/creatinine ratio and the transtubular potassium gradient (TTKG).

Results. No differences were observed in the parameters examined between SGA and AGA neonates who did not receive AGs. Conversely, SGA infants who received AGs after birth (group B) exhibited higher values of SeCr 2 months later. Specifically, their mean ± SD value of SeCr (µmol/l) was 42 ± 05 compared with 33 ± 08 in group D, 35 ± 04 in group A and 33 ± 04 in group C (P < 0.01). These infants also had significantly higher values of TTKG than SGA infants without AG treatment (22 ± 9 vs 13 ± 3 in group D) and FEUA (60 ± 23 vs 35 ± 14 in group D). Their FENa and FEP were also inappropriately high despite having lower serum levels of Na and P.

Conclusion. Preterm SGA infants who had no need of AG treatment after birth have similar renal functional maturation than AGA preterm infants at 2 months of life, but preterm SGA infants who received AGs had indications of impaired glomerular and tubular function at this age.

Keywords: aminoglycosides; FENa; renal function; small for gestational age; transtubular potassium gradient (TTKG); tubular function



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Small for gestational age (SGA) neonates are a group of infants reported to have increased perinatal and long-term morbidity [1–3]. Epidemiological studies show that adults who were born SGA are at increased risk for the development of renal disease and hypertension [2,3]. Recent studies have shown that low birth weight (LBW) may be associated with a lower number of nephrons at birth [4,5]. Brenner and Chertow proposed that the link between LBW, adult hypertension and renal functional decline may be impaired nephrogenesis [6,7]. They suggested that the reduced number of glomeruli leads to hyperfiltration, which in turn leads to systemic hypertension, glomerular sclerosis and progressive deterioration of renal function [6,7].

Renal tubular function and glomerular function are immature at birth [8]. Preterm infants born before 34–36 weeks of gestational age (GA) have not completed formation of the structural units of the kidney, the nephrons; a process that continues after birth, up to the 36th week of corrected chronological age (CA) (CA = GA + post-natal age) [8]. Preterm kidneys must adapt post-natally in order to cope with the increased metabolic demands of the rapid growth in this period. This is achieved by functional and structural renal maturation [8]. In addition, SGA neonates have a numerically smaller nephron endowment [4,5]. Aminoglycosides (AGs), which are by far the most commonly administered nephrotoxic drugs during the neonatal period, may further compromise renal function in SGA infants.

There are only limited data on renal functional maturation in SGA infants immediately after birth [9], and none on the effects of AGs on renal tubular and glomerular function in SGA infants. As renal function is involved in long-term arterial blood pressure regulation, the question remains as to whether restricted intrauterine growth may affect renal function during the neonatal period.

This study was designed to investigate the development of the glomerular and tubular function in SGA and appropriate for gestational age (AGA) preterm neonates in the first 2 months of life, and to study the effects on their renal function of AGs administered shortly after birth.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
The study population consisted of 81 preterm neonates with a GA of 28–34 weeks, born at the University Hospital of Ioannina and admitted immediately to the Neonatal Intensive Care Unit (NICU) of the same Hospital. This is a regional hospital covering the majority of deliveries (>85%) in the area of Northwest Greece. The GA at birth was assessed according to the mothers’ menstrual history and ultrasound (US) examination at 12–18 weeks of GA and confirmed by assessment of the babies’ maturity within 2 h of birth by neonatologists. Forty-one of the infants were categorized as AGA (BW 10th–90th percentile for GA) and 40 as SGA (BW < 10th percentile for GA) using the Gairdner and Pearson growth charts [10].

The AGA infants were classified into two subgroups; group A (n = 21) comprised those who received AG treatment and group C (n = 20) those who did not need AGs. The SGA infants also were classified into two groups; group B (n = 20) comprised those who received AG treatment and group D (n = 20) those who did not need AGs. The Scientific Committee of the University Hospital of Ioannina approved the study protocol and informed parental consent for participation of the infants was obtained.

Inclusion criteria
All preterm SGA neonates born between 28 and 34 weeks GA at this hospital during a period of 2 years were considered eligible for the study. AGA infants were selected to match with the SGA infants with respect to GA, gender, mode of delivery, parity and prenatal maternal steroid treatment. All infants included in the study were respiratory and metabolically stable: pH 7.25–7.40, PaO2 50–70 mmHg (6.6–9.2 kPa), PaCO2 < 55 mmHg (<7.31 kPa) and SBE < 10 mmol/l, and their diuresis was normal (1–4 ml/kg/h) during the study period. Infants with perinatal asphyxia, severe (grades III and IV) respiratory distress syndrome (RDS), hypotension, severe hyperbilirubinaemia or urinary infection were excluded, because these conditions can affect renal function [11]. All infants had a renal US study and those with abnormal findings were excluded. None of the infants received treatment with diuretics, corticosteroids, xanthines, dopamine–dobutamine, talazoline or indomethacin.

On the first day of life, the infants received either total parenteral nutrition (TPN) or a special formula for preterm neonates, depending on their clinical condition. TPN was substituted gradually the following days by oral feeding. Blood and 3 h urine samples were obtained in all groups at five study periods ranging from the third day of life to the 40th week of CA. Specifically, in the two groups of infants (A and B) who received AGs, blood and 3 h urine samples were obtained immediately before the infusion of the AG, on the third and the seventh day of treatment (first and second study periods, respectively) and 7 days following discontinuation of therapy (third study period). Two further samples were obtained at the CA of 36 and 40 weeks (fourth and fifth study periods). Serum and renal parameters in the untreated groups of AGA and SGA infants (C and D) were evaluated at the same post-natal ages. Blood and urine samples were all collected during routine procedures. In all infants, the daily and weekly intake of fluid, calories, protein, calcium (Ca), phosphorus (P), sodium (Na), potassium (K) and magnesium (Mg) were monitored throughout the study period. Urinalysis was performed for all neonates regularly.

AGs were administered to the infants in groups A and B along with cefotaxime for sepsis or suspected infection according to the Rodwell criteria [a haematological scoring system taking into consideration the following: total leucocyte count, total neutrophil count (PMN), immature PMN count, ratio of immature to total and immature to mature PMN, degenerative change in netrophils and platelet count] [12]. The AGs were administered intravenously over a 30 min period in a total volume of 5 ml distilled water. For infants aged 0–7 days the doses were 10 mg/kg of amikacin, and 3 mg/kg of gentamicin and netilmicin, every 24 h, while for infants aged >7 days the doses were 7.5 mg/kg of amikacin, and 2.5 mg/kg of gentamicin and netilmicin, every 12 h [13]. Trough and peak serum AG concentrations were obtained immediately before and 30 min after the drug administration, and doses were adjusted if necessary to maintain serum drug levels within the therapeutic range.

Renal tubular function was assessed by examining the fractional excretion (FE) of Na (FENa), K (FEK), P (FEP), Mg (FEMg) and uric acid (FEUA). The urinary Ca excretion as the Ca/creatinine (UCa/UCr) ratio and the transtubular potassium gradient (TTKG) were also determined. The fractional excretion of the various substances (x) was calculated using the formula: FE(x) = Ux · SeCr/Sex · UCr, where Ux, Sex are the concentrations of any substance in the urine and serum, respectively, and UCr and SeCr are the concentrations of creatinine (Cr) in urine and plasma. The TTKG was calculated using the formula TTKG = [K] urine/(urine/plasma) osmolality x [K] venous blood [14]

Serial determinations of SeCr were performed throughout the study to assess the maturational changes in glomerular function. Measurements of Na, K, Ca, P, Mg, uric acid (UA) and Cr in serum and urine specimens were performed using the automatic analyser RA-100 (Technicon). The osmolality of urine and serum was calculated with a cryoscopic osmometer (Osmomat, Gonotec). Serum concentrations of the AGs were determined using the polarized immunofluorescence assay (System TDX, Abbott Laboratories). The inter- and intra-assay coefficients of variation were 1.02 and 2.5% for amikacin, 1.5 and 2.4% for gentamicin and 1.4 and 2% for netilmicin, respectively.

Statistical analysis
A sample size of 81 infants was calculated to be adequate for detecting a difference of one SD in blood and urine parameters between the AGA and SGA groups with a power of 88% at a significance level of 5% [15]. Differences were considered significant at a level of P < 0.05. The data were analysed using two-way repeated measurements analysis of variance (ANOVA). Testing the differences of BW-percentile classified groups (SGA, AGA) vs treatment or time groups yielded a statistically significant P-value (<0.05) and one-way ANOVA was subsequently performed. A logarithmic transformation was made in order to normalize the distribution of the values of the urinary variables. Values are expressed as means ± SD.



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Of the 54 preterm SGA neonates eligible to participate in the study during the 2-year period, the parents of 51 agreed for them to participate. Eleven of these were excluded during the course of the study because they did not meet the inclusion criteria and 40 finished the study. Forty-one preterm infants born AGA (matched controls) participated in the study. The clinical characteristics of the four groups of SGA and AGA neonates of the study are depicted in Table 1.


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  		Table 1. Clinical characteristics of the study groups of preterm neonates

 
Calories, protein, mineral and electrolyte intake was similar during the study period among the four groups (P = NS). Only in the first study period (third day), was the protein and mineral intake lower in group A than group C. During the following periods the mean intake of calories and protein varied as follows: calories (kcal/kg/day) from 131 ± 31 to 157 ± 7, protein (g/kg/day) from 3.7 ± 0.8 to 4.7 ± 0.6 (P = NS). The respective intake of minerals (mmol/kg/day) ranged as follows: Na, from 2.1 ± 0.9 to 2.8 ± 0.3; K, 2.8 ± 0.9 to 3.7 ± 0.2; Ca, 4.1 ± 1 to 4.8 ± 0.9; P, 2.5 ± 0.5 to 3.04 ± 0.5 and Mg, 0.57 ± 0.24 to 0.73 ± 0.16 (P = NS). Weight gain, urine output and blood pressure did not differ among the four groups throughout the study. AG treatment for suspected infection or sepsis was introduced during the first 48 h in all cases in groups A and B (Table 1). Three and four infants, respectively, of groups A and B needed a second course with another AG (Table 1). Serum levels of AGs were maintained within the therapeutic range and did not differ between the two groups A and B during the period of the treatment. The mean AGs serum levels (trough and peak, respectively) (µg/ml) in two groups ranged, for amikacin from 5.8 ± 4 to 6.4 ± 2 (trough) and 23 ± 4 to 26+6 (peak), for netilmicin from 1 ± 0.6 to 1.2 ± 0.6 (trough) and 7.1 ± 1.8 to 7.6 ± 2.4 (peak), and for gentamicin from 1.2 ± 0.4 to 1.3 ± 0.4 (trough) and 6.1 ± 2.4 to 7.2 ± 1.8 (peak).

Serum and renal parameters
Serum creatinine
The most remarkable differences in SeCr were observed in group B (SGA infants who received AGs) in comparison with all the other groups. In this group, SeCr was lower than in group D of SGA infants during the first period of the study (Table 2). At the fourth study period (36 weeks of CA), in the SGA infants, SeCr was higher in group B than in group D (P < 0.05) (Table 2). This difference became more significant at 40 weeks of CA (fifth study period) (P < 0.001).


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  		Table 2. Serum values of potassium (SeK), phosphate (SeP) and creatinine (SeCr) in the study groups of preterm neonates

 
Serum electrolytes and uric acid
Significant differences in SeK and SeP levels were observed between the various groups, as depicted in Table 2. No differences were observed between the various groups in SeCa, SeNa and SeMg throughout the study and their mean values (mmol/l) varied: SeCa from 2.2 ± 0.15 to 2.5 ± 0.1; SeNa from 137 ± 3 to 143 ± 3 and SeMg from 0.66 ± 0.08 to 0.78 ± 0.08. Only at 40 weeks was SeNa higher in group D compared to group B (140 ± 1 vs 138 ± 2, P < 0.05). SeUA (µmol/l) was high in all groups at the first study period, varying between 226 ± 59 and 250 ± 101, and declined thereafter to between 89 ± 18 and 107 ± 47. At 40 weeks SeUA was higher in group D SGA infants compared to group B (124 ± 47 vs 89 ± 12, P < 0.01).

Urinary parameters
The main finding in the urinary parameters was an increase in TTKG and FEUA at 40 weeks CA in group B infants compared to the other three groups (Table 3), in spite of lower SeK (Table 2) and SeUA levels. Inappropriately high FEP and FENa (Table 4), despite their significant lower serum levels (P < 0.001 and 0.05, respectively, Table 2) were also observed in this group at the same study period. At this period urine osmolality (UOsm) was lower in group B than in groups A and C (P < 0.05), although fluid intake did not differ among the four groups. The mean values of UOsm (mosmol/kg) for the groups A,B,C and D, respectively, were 145 ± 90, 101 ± 50, 154 ± 53 and 139 ± 42.


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  		Table 3. Fractional potassium excretion (FEK), transtubular potassium gradient (TTKG) and fractional excretion of uric acid (FEUA) in the study groups of neonates

 

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  		Table 4. Fractional excretion of sodium (FENa), phosphate (FEP) and magnesium (FEMg), and urinary calcium to creatinine ratio (UCa/UCr) in the study groups of preterm neonates

 
Tables 5 and 6 (See online supplementary data) depict the respective intakes and serum levels of all examined parameters and Table 7 (See online supplementary data) depict serum AGs levels.



   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
It has been postulated that serial determinations of SeCr in the neonatal period are a reliable indicator of renal function as they represent the glomerular filtration rate (GFR) [16]. The results of the present study indicate that the SeCr values in preterm SGA infants with a mean GA of 32.6 weeks who did not receive AGs post-natally were similar to those of AGA infants during the whole study period. The SeCr levels showed a normal decline after birth in this SGA group, following a similar pattern to that of the AGA groups, and the SeCr values in these groups were close to those reported recently by Gallini et al. [17] in preterm infants. These findings imply that either glomerular function is not impaired in this group of SGA infants up to the second month of life or that a compensatory process of hypertrophy or accelerated renal growth may take place [18]. It was recently reported that most preterm SGA neonates of a GA similar to the babies of this study exhibit accelerated renal growth as estimated by US during the first months of life [19].

Scarce clinical data are available regarding maturation of renal function in preterm SGA infants. In the single published study no difference was found in SeCr between two groups of AGA and SGA preterm infants during the first 2 weeks of life, and GFR estimation, based on 6 h urine collections, was lower in SGA infants in the same period [9]. Experimental studies in rats showed that intrauterine growth retardation (GR) was accompanied by a nephron deficit that may not be fully compensated for within the first weeks after birth, despite compensatory hypertrophy, and that overall renal function was impaired [20]. Other authors studying piglets have shown impaired secretory capacity in SGA compared to AGA animals in the immediate post-natal period [21].

The results of the present study showed that the SGA preterm neonates who received AGs during the first days after birth had considerably higher SeCr levels about 2 months later, at a CA of 40 weeks. This group of infants had 21% higher SeCr levels, in comparison not only with the SGA infants who did not receive AGs, but also with AGA infants who did not receive AG treatment. In the immediate post-natal period GFR is based on the function of the medullar nephrons, which are mature and receive a major fraction of the renal blood flow [8,22]. The more recently formed nephrons in the superficial cortex have little contribution [8,22]. It has been shown in studies on puppies that AG administration early in life affects mainly the medullary nephron function [23]. Any damage at this site during the first days of life could be offset by the subsequent development of more superficial nephrons [23]. It is tempting to speculate that preterm SGAs, having possibly a lower number of superficial nephrons, are unable to offset the compromised renal function caused by AG administration early in life. In addition, a direct adverse effect of AGs on the nephrogenesis process cannot be excluded in this group [24]. These factors render them unable to exhibit the normal decline in SeCr observed in the other groups.

FEK and TTKG are both useful indices of K handling by the kidney [25]. FEK is considered as an index that estimates renal K transport along the whole nephron. TTKG reflects K handling in the collecting duct, where free water is reabsorbed and K is excreted under aldosterone stimulation. TTKG might be a better indicator of renal K excretion during the neonatal period [14,25]. SGA neonates who received AGs exhibited an altered pattern of TTKG, showing very low TTKG during AG treatment, in accordance with the observed lower serum K levels in this group at this period, and a gradual increase thereafter. A late increase in TTKG with a concomitant decrease in UOsm was observed in this group of SGA infants at 40 weeks CA. At this age, SGA infants who had received AGs had a mean TTKG value almost double that of the other groups of SGA and AGA infants. This increase in TTKG was observed in spite of significantly lower SeK values in this group, and might be attributed to a tubular functional or structural lesion caused by AGs.

Urinary UA also increased gradually in SGA infants receiving AGs and at 40 weeks CA was almost double that of the SGA infants not receiving AG. FENa also remained higher in AG-treated SGA neonates throughout the study period. Urinary P excretion at 36 and 40 CA weeks, although similar among the four groups, seems to be inappropriately high in the SGA infants who received AGs, taking into consideration their significantly lower SeP levels at that period.

The urinary levels of Ca and Mg were similar in SGA and AGA infants and were unaffected by AG administration, except in the first week of life. During the first period of the study (third day of AG treatment) the excretion of these ions were higher in the AG-treated groups, a finding consistent with the findings of previous reports on AG administration in preterm infants [26,27].

In the SGA infants receiving AGs, the coexistence of increased TTKG with high urinary UA and P and Na, despite their significant lower serum values compared to the other study groups, implies a state of ‘tubulopathy’ in these neonates, possibly attributable to the combined effects of being SGA and having early AG exposure.

The study design and its inclusion criteria minimized the possibility that other perinatal factors may have affected renal function. The group of SGA infants who received AGs was comparable to the three other groups of SGA and AGA infants in all respects. This study did not include neonates with GA <28 weeks because this age group often has a complicated perinatal period and therefore it is difficult to attribute any disturbance of renal function solely to administered drugs.

Subtle tubular disturbances have been reported in children and adults born SGA, but there are no studies on the long-term effect of AGs on tubular function in this group [28–30]. Monge et al. [29] observed elevated calciuria and NAG excretion in children born with LBW between 4 and 12 years of age. Young male adults born with BW <2500 g were found to have higher FENa, partially attributable to a concomitant increase in blood pressure [28]. A recent study in children born preterm, but not SGA, has shown a correlation between AG administration during the neonatal period and increased Ca excretion during childhood, implying long-term tubular derangements [31]. Further studies are needed to delineate the course of the derangements in tubular function observed in the neonates of this study later in life.

AGs are possibly the commonest antibiotics to be administered during the neonatal period. The findings of the present study imply that renal functional maturation in SGA infants born preterm may be compromised by early administration of AGs. Glomerular and tubular function may both be affected, despite maintenance of drug levels within the normal therapeutic range. Long-term follow-up of renal function in this subgroup of SGA neonates is needed.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Received for publication: 17. 5.06
Accepted in revised form: 16. 8.06


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