Fetal and Perinatal Nephrology: Small but Mighty

Approximately 10,000 children and adolescents in the United States are living with kidney failure, according to the chronic kidney disease surveillance program of the Center or Disease Control and Prevention. More than 60% of them, and even more children in chronic kidney disease stages 1–4, have inborn diseases of the kidneys.¹ The wide availability of prenatal sonography and the continuously improving imaging quality has led to an increasing number of kidney malformations being diagnosed before birth, and, not surprisingly, more parents-to-be turn to fetal centers asking for advice. How should we counsel these families and what can we tell them about the prognosis of their babies? What are therapeutic approaches after or even before birth? Fetal nephrology is a challenging developing field in nephrology as postnatal outcomes range from asymptomatic follow-up to life-threatening situations in the first minutes of postnatal life. Severe bilateral congenital anomalies of the kidneys with antenatal impairment of kidney function may be associated with oligo-/anhydramnios during pregnancy and subsequent pulmonary hypoplasia. Predicting what is going to happen after birth and in the following months and years is challenging and may only be possible in rough sketches. There frequently remains some degree of uncertainty, and situations may even change throughout the course of a pregnancy. This insecurity can be a major psychological burden for expecting women and couples.

What are the main inborn conditions that we encounter in fetal nephrology? In this field we are dealing with a large and heterogeneous group of inborn kidney diseases. This includes rare monogenic diseases and syndromes and a group of related conditions referred to as congenital anomalies of the kidney and urinary tract (CAKUT) (Figure 1). CAKUT are by far the most frequent type of congenital malformations of the urogenital system in prenatal ultrasound screenings. They may also be monogenic (approximately 10%–20%), but most of them likely are of complex genetic, epigenetic, “environmental,” or toxic etiology.²

Figure 1: Examples of congenital kidney diseases, characteristic findings in prenatal and perinatal sonography, and effects on amniotic fluid.

Fortunately, many patients suffering from mild, for example, unilateral CAKUT subtypes, will remain asymptomatic throughout childhood and adolescence, albeit being at increased risk for chronic kidney disease throughout life. By contrast, other conditions of the CAKUT spectrum, such as lower urinary tract obstructions (LUTO)/posterior urethral valves or bilateral kidney dysplasia, and some monogenic diseases, such as autosomal recessive polycystic kidney disease or congenital nephrotic syndrome, are associated with substantial morbidity and mortality throughout the entire life, beginning even in the newborn period and even in highly experienced centers (Figure 1).

Some of the congenital kidney diseases may be suspected by (prenatal) ultrasound (e.g., autosomal recessive polycystic kidney disease), by characteristic biochemical imbalances (e.g., congenital nephrotic syndrome), or by syndromic involvement of other organs (e.g., Fraser syndrome). In many cases, a genetic analysis can confirm a clinical diagnosis and exclude phenocopies.³ However, genetics alone will not tell the whole story of a patient. Interpretation of genetic variants in “kidney genes,” especially in a prenatal context and CAKUT, has many pitfalls. Correlating the signs and symptoms underlying a clinical diagnosis with genetic findings, for example, detected in massive parallel sequencing approaches, is crucial for modern medicine. Variants in different genes may underlie an overlapping phenotypical spectrum but may be associated with different disease courses or variability of extrarenal findings. By contrast, different types of variants in the same gene can cause clinically very different phenotypes (e.g., ranging from isolated nephronophthisis to Meckel-Gruber syndrome in case of CEP290 variants). Thus, combining information on phenotype and genotype in modern nomenclature, as nicely demonstrated for the adult disorder autosomal dominant tubulointerstitial kidney disease, bears many advantages.

In this issue of Kidney360, Gonzalez et al.⁴ share experiences from 217 prenatal nephrology consultations over a 7-year period at Texas Children's Hospital Fetal Center, including a wide range of inborn conditions of the kidneys, which help us approach this evolving field of prenatal and perinatal nephrology. On the basis of chart reviews, the authors report maternal characteristics, prenatal sonography findings that led to the consultation, and postnatal outcomes. Given the fact that all these inborn conditions are rare, the authors' cohort of 130 patients with prenatal and postnatal data is large and informative.

What did Gonzalez et al.⁴ find? As a quaternary fetal center, they were confronted with all sonographically recognizable fetal kidney conditions. As expected for a quaternary center, there is an overrepresentation of more severe phenotypes. The most frequent pathology was LUTO, epidemiologically a very rare phenotype, which according to the authors may be owed to the fact that vesicoamnial shunting and maximal neonatal care are offered at their center. Sadly, even in this experienced quaternary center, approximately 50% of the babies with LUTO or bilateral kidney agenesis died in the prenatal (i.e., fetal demise or termination of pregnancy) or neonatal period, many of the delivered babies on their first day of life. Gestational age and outcome/benefit of the fetuses with shunting procedures are not further analyzed, but the data suggest that it was likely comparable with the findings of the Percutaneous shunting in Lower Urinary Tract Obstruction (PLUTO) trial revealing limited benefit for kidney survival.⁵ As recently shown, gestational age at the time of shunting may be important for the outcome of kidney disease.⁶ Importantly, of 73 babies discharged from the neonatal intensive care unit, only five were on kidney replacement therapy, which demonstrates that respiratory failure or the decision to change the therapy goal rather than dialysis were the limitations for survival.

Genetic counseling was offered to all and accepted by most couples. Prenatal genetic testing resulted in a molecular diagnosis in 5.7% of fetuses. Prenatal genetic testing was performed in >75% of the babies with LUTO to rule out chromosomal aberrations, which was necessary at Texas Children's Hospital before vesicoamnial shunting. Postnatal genetic testing helped to establish accurate diagnoses in several different phenotypes but also showed how challenging a correlation between clinical and genetic findings can be. The guidelines by the American College of Medical Genetics have helped to standardize and improve the interpretation of genetic variants by establishing strict criteria for causality, but they still should only be applied by qualified experts, who order and evaluate the best suitable genetic test for a specific phenotype and a given age.⁷ Thus, in summary, Gonzales et al.⁴ share valuable experiences. We can only join the authors in concluding that fetal nephrology is a complex field that requires the combined expertise from different disciplines, and we are confident that we will continue to learn and to improve care for the benefit of our youngest patients in nephrology.

Disclosures

M. Liebau reports the following: Employer: University Hospital of Cologne; Consultancy: Representing the University Hospital of Cologne, M. Liebau is a member of an advisory board for Otsuka Pharma; Advisory or Leadership Role: Representing the University Hospital of Cologne, M. Liebau is a member of an advisory board for Otsuka Pharma; and Other Interests or Relationships: Chair of the WG Inherited Kidney Diseases of the European Society for Pediatric Nephrology; CoChair WG CAKUT and Ciliopathies ERKNet; Scientific Advisory Committee PKD Foundation; Scientific Committee German PKD foundation. M. Liebau reports receiving funding from the German Research Council (DFG) for cell biological projects on ARPKD (DFG LI 2397/5-1). The remaining author has nothing to disclose.

Funding

This work was supported by research Grant No. 01GM2203B from the Bundesministerium für Bildung und Forschung (M.C. Liebau).