Bilateral renal agenesis (BRA) is a fetal anomaly which leads to anhydramnios and resultant pulmonary hypoplasia. Historically, this anomaly was universally fatal early in the neonatal period due to the severity of the associated lung disease. Over the last 30 years, innovations in fetal therapies-specifically, serial amnioinfusions-have led to instances of infant pulmonary survival and initiation of postnatal dialysis, raising the possibility that early neonatal death may not be inevitable. Amnioinfusions are not without risk, and maternal complications can include prelabor rupture of membranes, preterm labor, infection, and bleeding. The data detailing neonatal outcomes are still limited and actively being collected. Two case series and one non-randomized clinical trial have supplied most of the known outcome data for infants with BRA after prenatal amnioinfusion. Although there are survivors reported in the literature, mortality remains high, with many deaths in infancy due to dialysis-associated sepsis. In addition, previously unknown morbidities have been documented in these infants, including neurologic injury. These challenges, in addition to the mechanical difficulties of providing dialysis to extremely small infants, can result in significant burdens for patients and their caregivers and moral distress for the health care team. The present review aims to explain the pathophysiology of BRA, detail the historical context and rationale for serial amnioinfusions to treat the pulmonary insufficiency associated with BRA, describe the available data regarding outcomes of infants born following prenatal amnioinfusions, discuss ethical issues surrounding this fetal intervention, and describe critical aspects of prenatal counseling for patients considering the intervention.

BACKGROUND: The optimal protocol for serial amnioinfusions to maintain amniotic fluid in pregnancies with early-onset fetal renal anhydramnios before 22 weeks is not known. We compared the performance of two different approaches.
METHODS: A secondary analysis was conducted of serial amnioinfusions performed by a single center during the external pilot and feasibility phases of the Renal Anhydramnios Fetal Therapy (RAFT) trial. During the external pilot, higher amnioinfusion volumes were given less frequently; in the feasibility study, smaller volume amnioinfusions were administered more frequently. Procedural details, complications, and obstetric outcomes were compared between the two groups using Pearson\'s χ2 or Fisher\'s exact tests for categorical variables and Student\'s t tests or Wilcoxon rank-sum tests for continuous variables. The adjusted association between procedural details and chorioamniotic separation was obtained through a multivariate repeated measure logistic regression model.
RESULTS: Eleven participants underwent 159 amnioinfusions (external pilot: 3 patients, 21 amnioinfusions; feasibility: 8 patients, 138 amnioinfusions). External pilot participants had fewer amnioinfusions (7 vs. 19.5 in the feasibility group, p = 0.04), larger amnioinfusion volume (750 vs. 500 mL, p < 0.01), and longer interval between amnioinfusions (6 [4-7] vs. 4 [3-5] days, p < 0.01). In the external pilot, chorioamniotic separation was more common (28.6% vs. 5.8%, p < 0.01), preterm prelabor rupture of membranes (PPROM) occurred sooner after amnioinfusion initiation (28 ± 21.5 vs. 75.6 ± 24.1 days, p = 0.03), and duration of maintained amniotic fluid between first and last amnioinfusion was shorter (38 ± 17.3 vs. 71 ± 19 days, p = 0.03), compared to the feasibility group. While delivery gestational age was similar (35.1 ± 1.7 vs. 33.8 ± 1.5 weeks, p = 0.21), feasibility participants maintained amniotic fluid longer.
CONCLUSIONS: Small volume serial amnioinfusions performed more frequently maintain normal amniotic fluid volume longer because of delayed occurrence of PPROM.

Our objective was to analyse the newest relevant data on worldwide prevalence and associated symptoms of renal agenesis (RA). This meta-analysis builds on previous systematic reviews to include bilateral RA, its symptoms and data on gender, unilateral RA and anomaly location prevalence. Review of available data included records in English and other languages from PubMed, Embase, ScienceDirect, Web of Science, SciELO, BIOSIS, Current Content Connect Korean Journal Database and Russian Citation Index and Google. A total of 15 641 184 patients were analysed in relation to the prevalence of RA. The pooled prevalence of RA was 0.03% (95% CI: 0.03%-0.04%). Based on 500 subjects, a pooled prevalence of 47.96% (95% CI: 31.55%-64.58%) for unilateral and 52.04% (95% CI: 35.42%-68.45%) for bilateral RA has been set. Our study presents the newest generalized findings on bilateral RA. There appears to be universal disease and symptom prevalence with minor differences between world regions, although quality of future observational research should include genomic data. This will provide even further insight into the prognosis of various renal anomalies and their etiologies.

The most severe forms of congenital anomalies of the kidney and urinary tract present in fetal life with early pregnancy renal anhydramnios and are considered lethal due to pulmonary hypoplasia without fetal therapy. Due to the high rate of additional structural anomalies, genetic abnormalities, and associated syndromes, detailed anatomic survey and genetic testing are imperative when stratifying which pregnancies are appropriate for fetal intervention. Restoring amniotic fluid around the fetus is the principal goal of prenatal treatment. The ongoing multi-center Renal Anhydramnios Fetal Therapy (RAFT) trial is assessing the safety and efficacy of serial amnioinfusions to prevent pulmonary hypoplasia so that the underlying renal disease can be addressed.

BACKGROUND: The advent of novel fetal interventions has increased interest in interventions for previously \"lethal\" anomalies such as bilateral renal agenesis or other congenital anomalies of the kidney and urinary tract (CAKUT) associated with in utero renal failure. While there have been rare reports of successful births following intervention in these cases, there is a paucity of data regarding the risks, benefits, and outcomes of intervention. To address this gap, this study presents our experience with fetal intervention for anatomic or functional renal agenesis.
METHODS: A retrospective review was conducted for patients referred to the Colorado Fetal Care Center (CFCC) between 2013 and 2019 for evaluation of CAKUT anomalies. Eligibility was determined by a multidisciplinary team. Amnioinfusion was scheduled prior to 24 weeks gestation, with normal saline or lactated ringers infused as needed to obtain a \"normal\" amniotic fluid volume. During this time period, a total of 5 cases received fetal amnioinfusion for treatment of bilateral renal agenesis or bladder outlet obstruction. All 5 cases reached birth. 3/5 cases expired on day one of life. 1/2 of the remaining infants expired at 3 months secondary to peritoneal dialysis failure. The remaining infant is 4 years. Developmentally, she is on track with cognitive and language skills but is behind with general motor skills. We observed a 30-day mortality of 60% and 1-year mortality of 80%.
CONCLUSIONS: Individuals carrying a pregnancy complicated by CAKUT anomalies face a difficult choice when considering intervention. Morbidity and mortality remain high at this stage of this evolving therapy, including difficulty with retaining infused intra-amniotic fluid >72 h and complications with peritoneal dialysis after birth. The surviving infant in this case series is 4 years. She currently awaits renal transplantation. These findings reinforce that treatment of these cases should remain experimental and large-scale multicenter trials are needed to determine the optimal indications for prenatal intervention.

Congenital abnormalities of the kidney and urinary tract (CAKUT) represent 20% of prenatally diagnosed congenital abnormalities. Although the majority of these abnormalities do not require intervention either pre or postnatally, there is a subset of patients whose disease is so severe that it may warrant intervention prior to delivery to prevent morbidity and mortality. These cases consist of patients with moderate lower urinary tract obstruction (LUTO) in which vesicocentesis, shunting or cystoscopy are options and patients with early pregnancy renal anhydramnios (EPRA) in whom amnioinfusion therapy may be an option. The main causes of EPRA are congenital bilateral renal agenesis (CoBRA), cystic kidney disease (CKD) and severe LUTO. Untreated, EPRA is universally fatal secondary to anhydramnios induced pulmonary hypoplasia. The evidence regarding therapy for LUTO is limited and the stopped early PLUTO (Percutaneous Shunting in Lower Urinary Tract Obstruction) trial was unable to provide definitive answers about patient selection. Evidence for EPRA therapy is also scant. Serial amnioinfusions have shown promise in cases of EPRA due to CoBRA or renal failure and this treatment modality forms the basis of the ongoing NIH funded RAFT (Renal Anhydramnios Fetal Therapy) trial. At present, there is consensus that treatment for EPRA should only occur in the setting of a clinical trial.

Bilateral renal agenesis (BRA) is a lethal con genital anomaly caused by the failure of normal development of both kidneys early in embryonic development. Oligohydramnios on fetal ultrasonography reveals BRA. Although the exact causes are not clear, BRA is associated with mutations in many renal development genes. However, molecular diagnostics do not pick up many clinical patients. Nephronectin (NPNT) may be a candidate protein for widening diagnosis. It is essential in kidney development, and knockout of Npnt in mice frequently leads to kidney agenesis or hypoplasia.
A consanguineous Han family experienced three cases of induced abortion in the second trimester of pregnancy, due to suspected BRA. Whole-exome sequencing (WES)-based homozygosity mapping detected underlying genetic factors, and a knock-in mouse model confirmed the renal agenesis phenotype.
WES and evaluation of homozygous regions in II:3 and II:4 revealed a pathologic homozygous frameshift variant in NPNT (NM_001184690:exon8:c.777dup/p.Lys260*), which leads to a premature stop in the next codon. The truncated NPNT protein exhibited decreased expression, as confirmed in vivo by the overexpression of WT and mutated NPNT. A knock-in mouse model homozygous for the detected Npnt mutation replicated the BRA phenotype.
A biallelic loss-of-function NPNT mutation causing an autosomal recessive form of BRA in humans was confirmed by the corresponding phenotype of knock-in mice. Our results identify a novel genetic cause of BRA, revealing a new target for genetic diagnosis, prenatal diagnosis, and preimplantation diagnosis for families with BRA.

BACKGROUND: Bilateral renal agenesis (BRA) is a lethal diagnosis, specifically meaning that natural survival beyond birth is not expected secondary to pulmonary hypoplasia. Limited contemporary data are available about intervention and the impact of restoring amniotic fluid volume in relation to the risk for lethal pulmonary hypoplasia and other factors that might influence survival in cases of fetal BRA.
OBJECTIVE: We report the largest series of patients undergoing fetal intervention and postnatal care for BRA at a single comprehensive fetal center.
METHODS: All patients with fetal BRA were reviewed from January 2004 to November 2017. Maternal and neonatal data were collected in an institutional review board-approved retrospective review.
RESULTS: From 2014 to 2017, 20 singleton pregnancies with isolated fetal BRA were evaluated and 14 had amnioinfusion. Eight had serial infusions. Of those, there were 6 neonatal deaths. There were 2 neonatal survivors beyond 30 days; however, both died of sepsis on dialysis. One of these survivors received amnioinfusions by percutaneous approach and one via amnioport. There were no survivors to transplantation.
CONCLUSIONS: Fetal intervention via amnioinfusion may promote pulmonary survivorship after birth, but postnatal survival remains poor. Future studies must place an emphasis on standardizing the postnatal approach to this patient population.

Autosomal-recessive SLOS is caused by mutations in the DHCR7 gene. It is defined as a highly variable complex of microcephaly with intellectual disability, characteristic facies, hypospadias, and polysyndactyly. Syndrome diagnosis is often missed at prenatal ultrasound and fetal autopsy METHODS: We performed autopsies and DHCR7 gene analyses in eight fetuses suspected of having SLOS and measured cholesterol values in long-term formalin-fixed tissues of an additional museum exhibit RESULTS: Five of the nine fetuses presented classical features of SLOS, including four cases with atrial/atrioventricular septal defects and renal anomalies, and one with additional bilateral renal agenesis and a Dandy-Walker cyst. These cases allowed for diagnosis at autopsy and subsequent SLOS diagnosis in two siblings. Two fetuses were mildly affected and two fetuses showed additional holoprosencephaly. These four cases and the exhibit had escaped diagnosis at autopsy. The case with bilateral renal agenesis presented a novel combination of a null allele and a putative C-terminus missense mutation in the DHCR7 gene CONCLUSIONS: In view of the discrepancy between the prevalence of SLOS among newborns and the carrier frequency of a heterozygous DHCR7 gene mutation, the syndrome-specific internal malformation pattern may be helpful not to miss SLOS diagnosis in fetuses at prenatal ultrasound and fetal autopsy.

Bilateral renal agenesis is associated with severe oligohydramnios and was considered incompatible with postnatal life due to severe pulmonary hypoplasia. The use of renal replacement therapy was limited by significant morbidity and mortality associated with dialysis in very young infants with major pulmonary pathology. In the United States, there is a tremendous controversy about whether or not the use of prenatal amniotic fluid infusions provides a benefit to fetuses with bilateral renal agenesis. One of the critical issues identified is that there are, as yet, no children reported who had achieved long-term survival. Previous reports all indicated these children died shortly after birth or after unsuccessful peritoneal dialysis. We present two infants with a prenatal diagnosis of bilateral renal agenesis whose mothers elected to undergo prenatal amnioinfusions. One was born at 28 weeks with a birthweight of 1230 g and the other born at 34 weeks with a birthweight of 1940 g. We present the details of both cases, with initial management on chronic peritoneal dialysis, which started shortly after birth, as a bridge to living related kidney transplants.