Introduction

Congenital abnormalities of the kidney and the urinary tract (CAKUT) are among the most frequent causes of antenatal consultation and occur in 1/500 live births [1]. The number of discovered gene defects related to CAKUT is constantly increasing, resulting in a complicated gene network [1, 2]. Epidemiologic data on renal outcome in children with congenital CAKUT are lacking even though pediatric nephrologists are being increasingly consulted. In this preliminary retrospective study we evaluated the outcome of children for whom an antenatal consultation was performed between January 2006 and February 2011 in one single pediatric nephrology center, with a particular focus on the outcome of children whose parents declined termination of pregnancy (TOP).

Patients and methods

To be eligible for the study, patients had to have been referred to the Pediatric Nephrology unit at Trousseau Hospital by the consulting obstetrician for an antenatal diagnosis of CAKUT without any other visible ultrasound abnormalities.

Data were collected from the mother’s pregnancy obstetrical file (including the systematic antenatal ultrasound screening at 12, 22, and 32 weeks gestational age), the patient file, and the radiology and biochemical units’ databases. We classified the patients into five groups according to their abnormalities: unilateral renal hypodysplasia, bilateral renal hypodysplasia, posterior urethral valves, multicystic dysplastic kidney, and isolated urologic abnormalities. The ultrasound evaluation was performed by an experienced radiologist on an Aplio XG ultrasound system (Toshiba, Tokyo, Japan) and the renal abnormalities evaluated as follows: (1) hypoplasia was defined as a kidney length smaller <2 SDS (standard deviation score) according to charts of fetal kidney size [3]; (2) dysplasia was suspected when the kidney was found to be hyperechogenic; (3) an oligohydramnios was suspected when the amniotic index (AI) was <8. When these data were not available, we used deep pocket measurements according to Queenan et al. [4]. TOP was proposed for bilateral renal abnormalities associated with oligohydramnios, which is considered to be a marker of early severe renal function impairment, or for bilateral renal abnormalities without oligohydramnios but with severe parenchyma abnormalities compatible with the development of end-stage renal disease (ESRD) during childhood.

Pathology examinations were performed in the fetal pathology unit of Trousseau hospital. The presence of functional renal parenchyma, pulmonary hypoplasia defined by a lung weight/body weight ratio <0.012, and the association of other morphological or histological abnormalities were assessed.

Results

Thirty-four cases of isolated CAKUT were found, for which 19 TOP were proposed; the parents refused TOP for ten of these patients (Table 1). TOP was proposed for the 12 patients for whom oligohydramnios was found and for the seven cases of bilateral renal hypodysplasia without oligohydramnios. No abortion was proposed for unilateral abnormalities nor for abnormalities of the urinary tracts without renal injury (Tables 1, 2). Among the ten patients for whom a TOP was refused, five died in the first month of life. The median creatinine level at 3 days of life was 162 (range 25–358)  μmol/L. The median time of hospitalization was 10 (range 2–80) days. The abnormalities seen on the prenatal ultrasounds were confirmed by postnatal exams. Oligohydramnios was found in the five patients who died. However, two of the five surviving patients also had an oligohydramnios. Among the three patients without oligohydramnios for whom ultrasound abnormalities had been considered severe enough to propose TOP, all had normal renal function at the age of 60, 55, and 15 months, respectively. One patient had an increased fetal beta-2 microglobulin blood level (9 mg/L); at the age of 29 months this patient had a normal serum creatinine level and significant proteinuria.

Table 1 Patient characteristics by category
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Table 2 Ultrasound parameters of patients for whom a termination of pregnancy was proposed
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For the five surviving patients, the median age at the time of analysis was 29 months. All five surviving patients had a normal serum creatinine level, three without proteinuria and two with intermittent proteinuria, with a maximum urinary creatinine level of 182 and 235 mg/mmol, respectively. Among these five patients none had hypertension or required anti-hypertension medication (Table 3).

Among the nine TOP, a pathologic examination was performed on six fetuses (Table 4): three had an echographic diagnosis of oligohydramnios and four had a pulmonary hypoplasia. All had abnormal nephron structure or at least a reduction in nephron number. Five had associated morphological abnormalities, such as hypertelorism, ventricular septum hypertrophia, incomplete small pulmonary scissure (2 patients), pseudocysts in the cortex of the adrenal glands (2 patients), accessory spleen, xiphoida bifida, and pulmonary anatomy abnormalities (2 patients). One patient had autosomal recessive polycystic kidney disease (ARPKD) with liver and pancreas fibrosis.

Table 3 Follow-up data of surviving patients for whom termination of pregnancy was declined by the parents
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Table 4 Fetal pathology data
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An ultrasound control was performed after birth for seven of the 15 patients. The antenatal diagnosis was confirmed in six of these seven patients; in the seventh patient, the abnormality was found to be bilateral, whereas the prenatal exam had found it to be unilateral. Serum creatinine and proteinuria were checked in only two patients and found to be normal at 5 months and 3 years of age, respectively.

Discussion

Oligohydramnios has been found to be independently associated with a poor renal outcome [5]. In our study, among the seven patients born alive with oligohydramnios, five died in the first month of life. However, if there are no abnormalities other than the renal ones and no early oligohydramnios, which exposes the patient to pulmonary hypoplasia, nephrologic management is still possible and has to be discussed with the parents.

Even though the requirement of neonatal peritoneal dialysis and renal transplantation after the first year of life is regularly discussed with the parents in such clinical settings, it had not been performed in our patients. Kemper et al. found similar results in ten patients with oligohydramnios, in which only one patient required peritoneal dialysis and another preemptive renal transplantation after a 2.5-year follow-up [6].

Patients without oligohydramnios had normal renal function after long-term (1–5 years) follow-up, the ultrasound scan revealing severe abnormalities and the TOP proposal. This strengthens the concept that oligohydramnios is a risk factor for early renal failure and that in its absence it is very difficult to evaluate the duration of time to progress to end-stage renal failure. Nevertheless, the considerable phenotypic changes over time for many patients makes pre-natal counseling extremely difficult since although abnormalities often worsen over time, on rare occasions improvement has also been observed.

An increased blood or amniotic fluid beta-2-microglobulin level has been reported to be associated with a poor renal outcome [7]. However, in a meta-analysis which evaluated the intrinsic validity of beta-2-microglobulin dosage, Morris et al. demonstrated that it was of little diagnostic help, especially in amniotic fluid with poor specificity [positive predictive value +2.92, confidence interval (CI) 1.28–6.67; negative predictive value −0.53, 95% CI 0.24–1.17] [8]. Moreover, the beta-2-microglobulin level has been found to be increased in several fetal infections, such as cytomegalovirus and toxoplasmosis [9]. Therefore, the beta-2-microglobulin level seems to be of limited value in the context of a TOP. In our study, the fetal beta-2-microglobulin blood level was tested in only one case, in which it had increased to 9 mg/L, associated with an oligohydramnios. The parents refused a TOP, and the patient had severe neonatal renal failure but did not require dialysis. The renal function recovered, and this patient had a normal serum creatinine level with a proteinuria of 235 mg/mmol urinary creatinine at the age of 2.5 years.

The follow-up of patients for whom no TOP had been proposed was difficult since approximately 50% of patients were lost to follow-up. This jeopardizes data interpretation. Nevertheless, the great importance of a long-term follow-up of those patients should be emphasized as morphological presentation of CAKUT (i.e., development of contralateral lesions) may change over time, and hyperfiltration lesions with secondary development of proteinuria may occur despite the initial absence of pathologic urinary and blood parameters. Sanna-Cherchi et al. [10] evaluated the renal outcome of patients with CAKUT at 30 years of age. In this study, the authors followed 312 patients with an antenatal or postnatal diagnosis of CAKUT and found ESRD in 58 patients (19%) by the age of 30 years if all types of CAKUT were taken into account. Even in groups considered at low risk of ESRD and for whom a TOP is usually not proposed, the patients had a worse outcome than generally expected: among 27 patients initially diagnosed with unilateral hypodysplasia, four patients required dialysis at the age of 30 years. Even though parents with fetuses carrying unilateral lesions have to be reassured, it seems to be of extreme importance to organize a long-term follow-up of those patients in order to be able to initiate a nephroprotective strategy in the case that microalbuminuria or hypertension develops. The limits of sonographic and biologic prognosis factors leads to a discussion of the possibility of pre-conception genetic counseling since the number of genes known to be implicated in CAKUT is steadily increasing. However, most mutations are of autosomic dominant inheritance with an extreme variability in phenotype, which makes the prediction of severe kidney dysfunction impossible.

In conclusion, in the ten patients with severe CAKUT, for whom TOP was refused by the parents, five had a normal serum creatinine level at a median age of 29 months. This result demonstrates the difficulty in evaluating renal outcome in such patients. No single predictive factor seems to have enough specificity to motivate a TOP proposal, even the presence of an oligohydramnios. This finding suggests the need of long-term follow-up studies and new predictive markers.