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Nephrol Dial Transplant (2000) 15: 1575-1579
© 2000 European Renal Association-European Dialysis and Transplant Association

Renal function of children exposed to cyclosporin in utero

Patricia Lo Giudice1, Laurence Dubourg1,2, Aoumeur Hadj-Aïssa2, Marie-Hélène Saïd1, Olivier Claris3, Philippe Audra3, Xavier Martin4 and Pierre Cochat1,

1 Département de pédiatrie, 2 Service d'exploration fonctionnelle rénale, 3 Fédération femme-mère-enfant, 4 Service d’urologie et chirurgie de la transplantation, Hôpital Édouard Herriot and Université Claude Bernard, Lyon, France



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. The use of cyclosporin (CsA) has improved graft survival in transplant (Tx) patients despite its potential nephrotoxicity. Children born to transplanted women may present with intrauterine growth retardation (IUGR). On the basis of potential reduced nephron mass both in IUGR and in newborn experimental animals exposed to CsA in utero, we investigated the renal function of children >1 year of age born to women under maintenance immunosuppression, including CsA.

Methods. Fourteen children born to 12 Tx women (nine kidney, one pancreas-kidney, one heart, one liver) were investigated using inulin clearance (Cin), para-aminohippuric acid clearance (CPAH), microalbuminuria, and electrolyte reabsorption rate.

Results. Gestational age of the 14 infants was 34±3 weeks and birth weight 2018±620 g. During pregnancy, CsA trough blood level was 234±115 µg/l and plasma creatinine range was 96–136 µmol/l. Two children were excluded from the study because renal investigation led to a diagnosis of hereditary nephritis (one Alport syndrome, one familial dominant focal segmental glomerulosclerosis) that was retrospectively completed in the mother. Renal function tests were finally performed in 12 children at 2.6±1.8 years of age: BP 94±7/55±5 mmHg, Cin 117±28 ml/min/1.73 m2, CPAH 545±124 ml/min/1.73 m2, filtration fraction 0.23±0.03, microalbuminuria 4.2±3.5 mg/mmol. Electrolyte tubular reabsorption rates and urine concentrating capacity were normal.

Conclusion. These results suggest that in children born to transplanted women taking CsA, renal function develops normally despite prolonged exposure in utero.

Keywords: children; cyclosporin; nephrotoxicity; pregnancy; renal function



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Cyclosporin (CsA) is a major anticalcineurin agent widely used in organ transplantation; its use results in significantly improved patient and graft survival in kidney, heart, liver, pancreas, and intestine transplantation.

Several reports have shown that renal, endocrine, and sexual functions may return to normal after transplantation. In pregnant transplanted women, immunosuppressive therapy is generally maintained at the pre-pregnancy level, with appropriate adjustments according to standard parameters including CsA trough blood concentrations. Previous studies have shown that CsA crosses the placenta [1] and may accumulate in breast milk [2]. In addition, newborn infants exposed to CsA in utero often present with prematurity and/or low birth weight for gestational age [3–6].

Studies in experimental animals have demonstrated fetal toxicity, reduction of renal mass, and nephron deficit in association with high CsA doses [7–9]. Nevertheless, in humans, the incidence of neonatal complications and/or malformations are not increased [10].

On the basis of a potential reduced nephron mass both in intrauterine growth retardation (IUGR) and in newborn experimental animals exposed to CsA in utero, we investigated the renal function of children older than 1 year of age born to transplanted women receiving maintenance immunosuppression, including CsA.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Mothers
Fourteen children were delivered from 13 pregnancies in 12 organ-transplanted women who received an immunosuppression regime, including CsA, throughout their pregnancies. During pregnancy, the average CsA trough blood level was 234±115 (range 121–511) µg/l and the plasma creatinine (Pcr) range was 96–136 µmol/l. Pregnancy complications included systemic arterial hypertension (n=4), diabetes (n=1), and Salmonella infection (n=1). No allograft rejection was reported.

Children
Neonatal history was obtained for all 14 children and a complete physical examination was performed at the time of the renal function study. Two children were excluded because their renal investigation had led to a diagnosis of hereditary nephritis (one X-linked dominant Alport syndrome and one dominant focal segmental glomerulosclerosis); no other inherited condition was identified. Twelve children born to 10 women were finally studied (Table 1Go).


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  		Table 1. Cyclosporin-treated mothers' data during pregnancy

 

Methods
Whole-blood CsA concentration was assessed in mothers by enzyme-multi-immunoassay technique (EMIT) and Pcr was measured by an automated method with dialysis adapted from the Jaffé's reaction (Autoanalyzer Technicon, AAI-11 Bran-Lubbe, Plaisir, France). Renal function was assessed in children by measuring glomerular filtration rate (GFR) by inulin (polyfructosan) clearance (Cin), and effective renal plasma flow (ERPF) by para-aminohippuric acid (PAH) clearance (CPAH). After overnight fasting, the patients received a priming infusion of 30 mg/kg body weight (BW) polyfructosan (Inutest®) and 15 mg/kg BW sodium para-aminohippurate (Nephrotest®) made up to 30–60 ml with 0.9% NaCl given over 12 min. This was followed by a sustaining infusion of 0.33 mg/kg BW per min polyfructosan and 0.25 mg/kg BW per min PAH in 0.9% NaCl (Braun perfusor, 0.25–0.5 ml/min according to BW). After a 30-min equilibration period, two to four 30-min urine collections were performed, which sometimes required bladder catheterization in children who had not attained adequate micturition control. Blood samples were drawn at the midpoint of each urine collection. Plasma and urine creatinine, polyfructosan, and PAH were measured at each urine collection. Electrolyte tubular reabsorption rates and spontaneous urinary capacity tests were assessed concomitantly.

In the meantime, patients’ blood pressure was routinely checked (Dinamap®), as was proteinuria and renal ultrasound at the time of the renal function study. Results are expressed as mean±standard deviation (median; range). Informed consent was obtained from all parents.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Table 2Go displays the neonatal characteristics of the 12 study patients and the clinical data at the time of renal investigation. Preterm delivery occurred in 9/11 pregnancies (12 children) with a mean birth weight of 2018±620 g (2090; 1160–3280). The age at the time of renal investigation was 2.6 years (1.8; 1.0–6.9), BW 12.5±4.2 kg (11.7; 8.1–20.9), height 88.9±14.8 cm (82.5; 72.5–115.2). With respect to growth development, nine of the 12 children had normal body mass index (BW/height2) and the remaining three were in the lower range. All 12 children had normal psychomotor development.


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  		Table 2. Characteristics of children born to CsA-treated women

 
The results of renal function studies are summarized in Table 3Go. Electrolyte tubular reabsorption rates and urinary concentration capacity tests were normal. Plasma concentrations of sodium, potassium, chloride, calcium, and phosphate were normal, and no child had proteinuria. Figure 1Go shows individual GFR values plotted against chronological age compared to normal curves obtained from the literature [11]; for ethical reasons, there was no control group.


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  		Table 3. Renal function of in utero CsA-exposed children

 


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  		Fig. 1. GFR of children exposed to CsA in utero. Dashed lines, normal±SD GFR values reported in the literature [11]

 
Renal ultrasound examinations, including renal size, were within normal ranges.



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
CsA is a small neutral hydrophobic cyclic peptide of fungal origin, which is metabolized by the hepatic P-450 cytochrome system. Since its introduction, it has become a major immunosuppressive agent, widely used both in organ transplantation and autoimmune diseases [12]. However, its use is associated with a number of adverse events, such as nephrotoxicity, which may affect both native and transplanted kidneys. Two main forms of nephrotoxicity have been reported so far: acute reversible and chronic irreversible. Acute nephrotoxicity is haemodynamically mediated, i.e. an increase in renal vascular resistance is associated with a reduction in GFR and therefore in filtration fraction [13,14]; these are dose-dependent phenomena [15]. The chronic form is characterized by an irreversible renal dysfunction associated with morphological injury [16]. Tubular atrophy and interstitial fibrosis occur together with vascular hyalinosis and glomerulosclerosis, sometimes associated with microcalcifications and mitochondrial enlargement [17].

Nevertheless, the CsA era has been characterized by improved patient and graft survival, improved quality of life, and significant reductions in glucocorticoid dosage, which improvements have strongly favoured pregnancy in transplanted women [18]. However, because of substantial falls in serum CsA concentrations during pregnancy, the CsA requirements are usually increased [19,20]. Like other immunosuppressive agents, CsA crosses the placenta [1,21] and studies in placental cell lines have shown that it may cause selective impairment of taurine transport, whereas other maternofetal transport systems for glucose and amino acids are unaltered [22]. In addition, it has been shown that CsA accumulates in breast milk [2], although breast-fed infants of mothers taking CsA receive less than 300 µg CsA per day and absorb undetectable amounts [23].

The risk of fetal nephrotoxicity due to drugs administered to the mother has been investigated both in animal experiments and in humans. In utero aminoglycoside exposure has been studied in metanephric cell cultures and may be responsible for nephrogenesis alteration [24–26]. CsA does not influence the nephrogenesis induction process but it may alter the transformation of mesenchymal cells into epithelial cells [27], so that CsA may alter post-inductive processes.

Several reports have shown that children born to transplanted women often present with IUGR, low birth weight for gestational age, or prematurity [4–6] but the incidence of neonatal complications and/or malformations is not increased [10]. A positive correlation between birth weight and the final number of nephrons has been demonstrated in experimental animals; thus IUGR may be associated with a significant reduction in renal mass [28,29]. Such a pattern has been reported in humans [30,31], and may compromise long-term renal function [32].

In consideration of the potential additive effect of both IUGR and fetal exposure to CsA, one may speculate that the risk of altered GFR would increase in children born to pregnant women receiving CsA. Previous studies have produced reassuring short-and long-term data using simplified methods of GFR assessment, i.e. Pcr, creatinine clearance, or Schwartz formula [5,33]. However, since only minor alterations would be expected, more accurate methods for renal function assessment are required [34]. We found no significant impairment of renal function using Cin and CPAH in our study of children aged 1.0–6.9 years. Such encouraging results require confirmation by longitudinal evaluation into adulthood in a larger population, and validation with other nephrotoxic anticalcineurin agents.

In conclusion, in children born to transplanted women receiving CsA throughout pregnancy, renal function appears to develop normally despite prolonged CsA exposure in utero. These preliminary results should be confirmed in the long term by repeated GFR measurements and/or renal functional reserve assessment.



   Acknowledgments
 
The authors are grateful to all the transplant physicians who cared for the mothers and who kindly referred patients to us.



   Notes
 
Correspondence and offprint requests to: Pierre Cochat MD, Département de pédiatrie, Hôpital Edouard Herriot, F-69437 Lyon cedex 03, France. Back



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 19. 1.00
Accepted in revised form: 2. 5.00


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