Fetal renal failure (FRF) is a clinical syndrome that has several distinct causes but results in the inability to produce sufficient urine to maintain normal amniotic fluid volume, which is essential for normal fetal lung development. In FRF, the lack of amniotic fluid limits lung development and causes pulmonary hypoplasia, a life-threatening condition where the baby is unable to breathe on their own after birth.

The most common causes of fetal renal failure include bladder outlet obstruction (BOO) and resulting cystic renal dysplasia, bilateral multicystic kidney disease (MCDK), bilateral renal agenesis (BRA), unilateral renal agenesis and MCDK, and autosomal recessive polycystic kidney disease (ARPKD). The majority of cases of bladder outlet obstruction already have evidence of cystic renal dysplasia detectable by ultrasound at the time of presentation. Even with evidence of cystic renal dysplasia, the kidneys may produce sufficient urine to maintain amniotic fluid volume, which would allow lung development to proceed normally. In these cases, a fetal vesicocentesis is used to drain the bladder and assess the ability of the kidneys to produce urine is indicated. If rapid reaccumulation of urine in the fetal bladder is observed treatment of the bladder outlet obstruction would be indicated. However, if there is little urine produced this indicates there is fetal renal failure. In these cases treatment of the bladder outlet obstruction is futile and the lungs will remain profoundly hypoplastic and unable to support the baby after delivery.

In BRA the kidneys, ureters, and bladder are absent and once the transudation of fluid across the fetal skin ceases (usually <17 weeks), oligohydramnios and anhydramnios develop. The amniotic fluid in BRA is usually normal until ~17 weeks’ and then progressively fails as the maturation of the fetal skin prevents transudation of fluid. The complete absence of amniotic fluid which follows, prevents normal lung development.

MCDK is thought to be caused by a high-grade ureteral obstruction during the first trimester of pregnancy which disrupts the development of the kidney and results in a variable capacity for urine production. In bilateral MCDK the urine that is produced is often of poor quality and low volume and while the function of the kidney may be inadequate in utero, the volume of urine produced can vary and the resulting amniotic fluid volume may not be sufficient. In the most severe cases of bilateral MCDK, there is little to no urine production resulting in oligohydramnios or anhydramnios and the earlier in gestation this develops the worse the pulmonary hypoplasia.

In ARPKD, the genetic abnormality results in disordered renal development which can have a variable effect on the kidneys ability to produce urine which may present in utero or in postnatal life. In the most severe cases, ARPKD results in severely compromised renal function in utero leading to oligohydramnios, anhydramnios, and pulmonary hypoplasia.

The diagnosis of FRF is dependent on gestational age and findings and is primarily diagnosed with ultrasound with fetal MRI an important adjunct imaging modality. Fetal renal failure is a clinical syndrome characterized by oligohydramnios or anhydramnios due to the lack of urine production supporting amniotic fluid dynamics. At <17 weeks’ gestation the primary contributor to amniotic fluid volume is the transudation of fluid across the fetal skin, In normal development, fetal urine output at 16-17 weeks’ gestation becomes the predominant source of amniotic fluid when the maturation of the fetal skin prevents transudation of fluid across it. In BRA the complete absence of renal tissue and both ureters and the bladder confirms the diagnosis of FRF even if there is preserved amniotic fluid volume at < 17 weeks’ gestation. In contrast, in BOO with cystic renal dysplasia, there may be a variable amount of fetal urine produced. But do to the bladder outlet obstruction, the urine production can only be assessed by a fetal bladder tap and sonographic monitoring of the rapidity with which the bladder refills. Even in the presence of significant cystic renal dysplastic changes in the kidneys, if the production of urine is sufficient, treatment of the bladder outlet obstruction may restore amniotic fluid dynamics and support lung development. Renal dysplasia however, may be progressive, and while a fetus may initially respond to vesicoamniotic shunting or laser treatment of posterior urethral valves with normalization of amniotic fluid volume over time the urine production may fall resulting in olighydramnios or anhydramnios due to fetal renal failure.

It is essential to know the underlying cause of fetal renal failure for its prognostic significance, not only for the current pregnancy, but may also have implications for future pregnancies as in ARPKD. While a diagnosis of BRA, bilateral MCDK, BOO with cystic renal dysplasia may be evident from ultrasound alone, fetal MRI is a powerful adjunct to ultrasound and may be able to confirm the ultrasound findings or supply supplemental findings to support a specific diagnosis of the underlying etiology.

The most common approach at centers around the country to the fetus diagnosed with fetal renal failure is to explain that nothing can be done for the baby, recommend prenatal genetic testing to rule out conditions that may have implications for future pregnancies, and to provide comfort care. At Connecticut Children’s Fetal Care Center, we take a more innovative approach to this challenging problem. Inappropriately counseled parents, a more aggressive approach to the management of fetal renal failure may be offered.

Medical professionals having a conversation

Mothers must first undergo a comprehensive series of fetal imaging to determine the underlying cause of the fetal renal failure including ultrasound (possibly following an amnioinfusion to better visualize the baby’s genitourinary system), fetal MRI and fetal echocardiography. The fetal MRI is an indispensable adjunct to ultrasound in assessing structural abnormalities in the fetus and determining the underlying cause of fetal renal failure. The fetal echocardiogram helps rule out structural heart disease and also allows a functional assessment of the fetal heart which in fetal renal failure is often associated with hypertensive cardiomyopathy.

Once the full diagnostic work up has been completed the mother undergoes a two-phase counseling process. In the first phase, the mother meets with the Maternal Fetal Medicine specialist, the fetal surgeon, and the fetal cardiologist to discuss the findings on imaging, the underlying diagnosis and prognosis, and an outline for treatment options and management of the pregnancy. The second phase of counseling is a series of consultations with a Neonatologist to discuss the risks of prematurity and the effects of fetal renal failure on pulmonary development and put in context the effects of prenatal treatment by serial amnioinfusion and the complexity of the baby’s postnatal course. The mother also meets with a Pediatric Nephrologist to discuss neonatal peritoneal dialysis and the challenges that these newborns face and the potential risks and complications that may arise before growing to a size that would allow renal transplantation and the criteria that must be met to be listed for transplantation.

We also recommend meeting with a member of the Pediatric Transplantation team to discuss the challenges specific to these babies in getting to transplantation, the need for lifelong immunosuppressive therapy to prevent transplant rejection and the life expectancy of a transplanted kidney. In cases of BRA, we also have the mother meet with a Pediatric Urologist, as the absence of the kidneys, ureters, and bladder presents a specific challenge in getting these babies ready to receive a kidney transplant requiring surgery to an ileal loop conduit prior to transplantation.

Lastly, we have the mother meet with the Maternal Fetal Medicine specialist and the Fetal Surgeon to discuss the options for serial amnioinfusion, either by needle or amnio port, and the potential obstetrical risks in this management approach. In addition, a psychosocial evaluation is performed to be certain the mother is a good candidate for the rigors of the stress of this treatment approach and that there are no contraindications to proceeding with prenatal treatment.

Fetal renal failure is treated by serial amnioinfusions to restore the amniotic fluid index using sterile IV fluid (Lactated Ringer’s solution) infusions. This can be accomplished by needle-based amnioinfusions or by the placement of an amnioport. All patients undergo an initial amnioinfusion to restore fluid around the baby for better songraphic visualization, obtain fluid for karyotype analysis and microarray and rule out preterm premature rupture of membranes (PPROM). If needle-based amnioinfusion is selected, the mother is seen for an ultrasound on a Monday, Wednesday, and Friday schedule, and amnioinfusion is performed whenever the AFI falls below 10 cm. Under ultrasound guidance, a needle is passed into the amniotic sac and an infusion of sterile Lactated Ringer’s solution is instilled to achieve an AFI of >12<15. Care is taken to avoid over-distention of the amnion which can predispose to PPROM. As the pregnancy progresses the volume of amnioinfusion can be slowly increased and the target AFI increases as the amnion becomes accustomed to amnioinfusion.

If an amnioport is requested for amnioinfusion, the procedure is performed in the operating room under a regional anesthetic via an epidural catheter and IV sedation. A mini-laparotomy is performed to expose a small area of the fundus, or top, of the uterus. A purse-string suture is placed in the uterine wall through which an 18 gauge needle is passed into the amniotic sac, a “J” wire is passed through the needle and the needle is withdrawn. Over the wire, a dilator covered by a peel-away sheath is passed into the amniotic sac. The wire and the dilator are removed from the peel-away sheath and a silastic catheter is inserted via the sheath into the amniotic cavity. The intra-amniotic location of the catheter is confirmed by irriation with a sterile Lactated Ringer’solution. The pursestring suture is synched up, tied and secured to the silastic catheter to prevent it from being worked out of the uterus by normal uterine contractions. The uterine myometrium is then sutured over the top of the silastic catheter for 3 cm in a Witzel tunnel, again to prevent dislodgement by normal uterine contractions. The catheter is then tunneled through the abdominal wall up to the lower left chest of the mother where a counter incision has been made for the subcutaneous amnioport device to which the catheter is attached and secured. Amnioifusion is performed via the amnioport to confirm appropriate function. The mini-laparotomy and amnioport incisions are closed and the amnioport is accessed by insertion of a sterile Huber needle and covered by sterile central line dressing which allows access to the amnioport by connecting IV tubing. The port is “locked” with heparinized saline (100 u/ml) when de-accessed and not in use. The Huber needle requires changing at least once a week if it remains accessed. Ultrasound is performed on a Monday, Wednesday, and Friday schedule and an amnioinfusion performed is the AFI falls below 10 cm. This can be performed in the clinic after sterilely prepping and accessing the amnioport. The advantage of the amnioport is the risk of PPROM is primarily associated with its placement and not every amnioinfusion which is the case with needle-based amnioinfusion. The potential risks and complications are higher for the amnioport insertion compared to a single needle-based amnioinfusion, but subsequent amnioinfusion has less risk than the needle-based amnioinfusion.
Outcomes of Treatment of Fetal Renal Failure

If serial amnioinfusions can be consistently performed without developing PPROM and delivery occurs at a gestational age >30 weeks’, the pulmonary outcomes in this group have been excellent approaching 100%. Even so, most infants in this group require some respiratory support ranging from supplemental oxygen, and bubble CPAP, to intubation and ventilatory support. Pulmonary hypertension has been rare and mild when detected. The majority of infants are quickly weaned from oxygen, bubble CPAP, or ventilator support. In contrast, if PPROM develops precluding amnioinfusions, amnioinfusions are not consistently performed, or preterm delivery occurs <28 weeks’ gestation or with weight <1500 gm mortality is uniformly observed. Only 62% of treated fetuses met the criteria for peritoneal dialysis catheter placement primarily due to prematurity. Overall neonatal survival to 30 days of age was 75%. There were late deaths related to infectious complications and failure of the peritoneal membrane as a dialyzable membrane with long-term survival of 56%. All of these infants have complicated and protracted NICU stays.

In all pregnancies being treated for fetal renal failure by amnioinfusion, that the family is very aware that the baby must reach a minimum weight of 1500 gm in order to be a candidate for peritoneal dialysis catheter placement. If the baby is less than 1,500 gm at the time of delivery the comfort care alone is offered. In most cases, low-volume peritoneal dialysis is initiated within days of birth and the volume of dialysate is gradually increased. Because a 1500 gm premature infant with renal failure doesn’t heal well it is not uncommon to have to interrupt dialysis if a leak of peritoneal fluid develops. In these cases, we support the baby by performing continuous veno-venous hemofiltration (CVVH) via a large surgically placed internal jugular venous catheter (8-10 Fr) until the leak resolves and peritoneal dialysis can be resumed. Another common problem that these infants face is the development of peritoneal infection, which if mild and caught early, can be cleared by putting antibiotics in the dialysate fluid. If the baby fails to respond to peritoneal antibiotics, the peritoneal catheter must be removed and a course of IV antibiotics initiated. During this period the baby’s renal function is replaced by CVVH.

It is important that families understand how challenging it can be to care for a baby with renal failure. These infants are hypercoagulable and often develop deep venous thrombosis, particularly at sites of Broviac or CVVH catheter insertions requiring systemic anticoagulation with heparin which can predispose to bleeding complications. In addition, infections related to peritoneal dialysis catheters, endotracheal tubes, and central venous lines are common. Poor weight gain and compromised nutritional status are common in these babies and almost all will require placement of a feeding gastrostomy tube to supplement their nutrition.

If peritoneal dialysis in the NICU goes well the baby may be transitioned to an automatic cycler for peritoneal dialysis for which the baby’s PD catheter is hooked up only for 10-12 hours per day. Frequent follow-up with Pediatric Nephrology is essential to carefully monitor the baby with renal failure on peritoneal dialysis to address electrolyte imbalances, and fluid shifts and assure the baby’s nutrition is optimal.

While criteria for kidney transplantation in infants vary from center to center, most require a minimum weight of 10 kg to be achieved before considering them for evaluation for transplantation.

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