Invasive assessment of fetal renal abnormalities: urinalysis,fetal blood sampling and biopsy

There are a number of potential biochemcial markers that may have some role in predicting renal function postnatally. These include urinary sodium, calcium and β2‒microglobulin. The latter may also be measured in fetal serum. However, the accuracy of these parameters at a point in time is far from perfect as urinary tract obstruction is a progressive disease which may be best defined by repeated observations throughout pregnancy. Copyright © 2001 John Wiley & Sons, Ltd.     

Further predictors of renal dysplasia in fetal obstructive uropathy: Bladder pressure and biochemistry of ‘fresh’ urine

Urine was aspirated on two consecutive days from the dilated bladder of nine fetuses with lower urinary tract obstruction. Gestational age ranged from 17 to 35 weeks. Renal dysplasia was diagnosed histologically in four fetuses, whereas the other five had normal renal histology or only partial dysplasia. Urinary sodium (Na⁺) and osmolality (Osm) decreased significantly in the second urine sample 1 day after bladder emptying (median decrease: Na⁺ = −11.3 per cent; Osm= −13.3 per cent). Although there were no significant differences between fetuses with or without renal dysplasia, normalization of an initially raised urine Na ⁺ concentration occurred at the second sample in a fetus with partially normal renal histology, thus correcting a false-positive diagnosis of dysplasia. Bladder pressure was measured at the time of the first urine sampling in seven fetuses and in a further eight with bladder outlet obstruction undergoing a single urine aspiration at 18–28 weeks. Bladder pressure was increased above the reference range in 8 of 15 fetuses with urinary obstruction, but there was no correlation between pressure and the degree of impairment of renal function. Although no conclusive clinical guidelines can be drawn from this study for the evaluation of fetal renal function, these findings suggest that, in lower urinary tract obstruction, tubular reabsorption is impeded by the standing pressure in the urinary tract and that improvement of renal function may occur following relief of obstruction.     

In utero therapy for lower urinary tract obstruction

Lower urinary tract obstruction has a significant impact on neonatal and child health. Pulmonary hyperplasia and renal impairment could be direct or indirect consequences of this condition leading to significant morbidity and mortality. Evaluation of fetuses with suspected lower urinary tract obstruction is performed not only to confirm the diagnosis but also to assess renal prognosis. Ultrasound examination and urinary analysis aid in the evaluation of these fetuses. The decision to perform fetal intervention in these cases is a difficult one. Vesico‒amniotic fetal shunting, open fetal surgery and more recently endoscopic fetal surgery for this condition are available as possible modalities of fetal intervention. Case selection for fetal intervention is extremely important in order to both avoid unnecessary intervention in those unlikely to survive, and also to avoid procedure related complications in fetuses likely to do well without intervention. Vesico‒amniotic shunting has the advantage of bypassing the obstruction, however it is often associated with complications. Open fetal surgery is not usually recommended because of the complications and high fetal loss rate. Endoscopic surgery to visualise and treat the cause of lower urinary tract obstruction has been tried. Fetal endoscopic surgery is in its infancy and endoscopic procedures are limited to a few groups. This current review addresses evaluation, case selection and therapeutic options for lower urinary tract obstruction in utero. It also discusses the limited data against which the efficacy of the various options can be assessed. The current state of fetal intervention is detailed in the present review. Copyright © 2001 John Wiley & Sons, Ltd.     

Fetal surgery for severe lower urinary tract obstruction

Fetal interventions have been proposed for treatment of severe lower urinary tract obstruction (LUTO), as this condition is associated with high rates of perinatal mortality and postnatal renal impairment. The rationale for in utero treatment for those cases is based on the possibility of relieving the obstruction, improving the amniotic fluid volume, and preventing renal and bladder damage. Candidates for fetal intervention should be rigorously selected based on the confirmation of severe LUTO (dilated bladder and bilateral hydronephrosis), oligohydramnios or anyhydramnios and ‘favorable’ fetal urinalysis (dependent on gestational age). Nowadays there are two different therapeutic options with specific technical approaches. Vesico-amniotic shunting is an easier procedure, but with a higher frequency of related complications. Fetal cystoscopy can be used for diagnostic purpose and for treatment of posterior urethral valves, with suggestive advantage of allowing a more physiological release of the obstruction. According to the literature, estimated survival rates and postnatal normal renal function frequencies are approximately 40 and 50% after vesico-amniotic shunting and 75 and 65% after fetal cystoscopy, respectively. Copyright © 2011 John Wiley & Sons, Ltd.     

Fetal lower urinary tract obstruction: What should we tell the prospective parents?

Fetal lower urinary tract obstruction (LUTO), which often results in marked perinatal morbidity and mortality, is caused by a heterogeneous group of anatomical defects that lead to blockage of the urethra. The classic prenatal presentation of LUTO includes megacystis with hydronephrosis. While mild forms of the disease can be associated with favorable outcomes, more severe disease commonly leads to dysplastic changes in the fetal kidneys, and ultimately oligohydramnios, which can result in secondary pulmonary hypoplasia and renal failure at birth. The aim of this review is to provide practitioners with a general overview of the diagnosis and treatment of LUTO based on disease severity, along with some points to consider when counseling prospective parents of fetuses with this condition.     

Prenatal diagnosis: does it alter outcome?

The prenatal detection of urinary tract anomalies is changing paediatric practice but in many areas the impact on clinical outcome remains difficult to quantify. However it is already apparent that termination of pregnancy has reduced the numbers of infants with lethal pulmonary hypoplasia and renal dsyplasia who would previously have been liveborn but destined to succumb as neonates. Similarly, referrals of major non lethal abnormalities such as bladder exstrophy are declining as parents increasingly opt for termination. Fetuses at greatest risk of early onset postnatal renal failure can now be identified with considerable accuracy on prenatal ultrasound. Termination, prompted by quality of life considerations, could result in reduced numbers of infants and young children requiring end stage renal failure treatment in the first few years of life. Pre natal detection of anomalies such as PUJ obstruction and reflux undoubtedly provides an opportunity to avert functional deterioration and minimise urinary infection. But the proportion of children who genuinely benefit has proved difficult to assess. The prenatal detection of mild dilatation is of doubtful benefit in all but a minority of cases. Clinically significant underlying pathology is rare yet this common prenatal finding often generates disproportionate parental anxiety. Copyright © 2001 John Wiley & Sons, Ltd.     

Failure to detect fetal obstructive uropathy by second trimester ultrasound

The prenatal diagnosis, management and outcome of an hereditary obstructive uropathy is presented. Serial ultrasonic assessment of the fetal urinary tract was carried out from the early second trimester onward. Slight bilateral hydronephrosis as a first sign of obstructive uropathy was only established as late as 30 weeks of gestation. On the basis of weekly ultrasound scans, a conservative approach was adopted. In view of fetal maturity, labour was induced at 36 weeks resulting in the vaginal delivery of a male infant with moderate bilateral hydronephrosis. Neonatally, anuria developed due to bilateral obstruction of the ureters as a result of increasing bladder wall hypertrophy due to urethral valves. A bilateral uretero-cutaneostomy was carried out. The infant so far develops normally, and renal function is normal for age. Women at risk for fetal obstructive uropathy should have ultrasonic monitoring throughout pregnancy.     

The making of fetal surgery

Fetal diagnosis prompts the question for fetal therapy in highly selected cases. Some conditions are suitable for in utero surgical intervention. This paper reviews historically important steps in the development of fetal surgery. The first invasive fetal intervention in 1963 was an intra-uterine blood transfusion. It took another 20 years to understand the pathophysiology of other candidate fetal conditions and to develop safe anaesthetic and surgical techniques before the team at the University of California at San Francisco performed its first urinary diversion through hysterotomy. This procedure would be abandoned as renal and pulmonary function could be just as effectively salvaged by ultrasound-guided insertion of a bladder shunt. Fetoscopy is another method for direct access to the feto-placental unit. It was historically used for fetal visualisation to guide biopsies or for vascular access but was also abandoned following the introduction of high-resolution ultrasound. Miniaturisation revived fetoscopy in the 1990s, since when it has been successfully used to operate on the placenta and umbilical cord. Today, it is also used in fetuses with congenital diaphragmatic hernia (CDH), in whom lung growth is triggered by percutaneous tracheal occlusion. It can also be used to diagnose and treat urinary obstruction. Many fetal interventions remain investigational but for a number of conditions randomised trials have established the role of in utero surgery, making fetal surgery a clinical reality in a number of fetal therapy programmes. The safety of fetal surgery is such that even non-lethal conditions, such as myelomeningocoele repair, are at this moment considered a potential indication. This, as well as fetal intervention for CDH, is currently being investigated in randomised trials. Copyright © 2010 John Wiley & Sons, Ltd.     

Metabolism and water loss are not related to environmental heterogeneity in two mygalomorph spiders

Laboratory water flumes are artificial troughs of moving water widely used in hydraulic studies of fluvial systems to investigate real-world problems at smaller, more manageable scales. Water flumes have also been used to understand bone transportation sorting and bone orientation found in the fossil record using actual bones. To date, these studies have not involved scaled bones. A 1/12 scale model of a 21.8-m long skeleton of Apatosaurus, a long-necked sauropod dinosaur from the Late Jurassic, was used to explore three problems at Dinosaur National Monument (USA) that cannot be explained by tradition bone flume studies: (1) why there is an abrupt bend in articulated vertebrae, (2) why articulated dorsals are inverted relative to the pelvis, and (3) how bone jams form. The flume experiments established that (1) bed friction with the wing-like transverse processes of vertebrae resists the force of the water flow, whereas those vertebrae lacking the processes are free to pivot in the flow; (2) elevation of the dorsal vertebrae by the transverse processes subjects the vertebrae to the energy of the flow stream, which causes the vertebrae to flip. Computation fluid dynamics (CFD) software shows this flip was due to differential pressure on the upstream and downstream sides. (3) The formation and growth of bone clusters or jams (analogous to log jams in rivers) occur as transported bones pile against an initial obstruction and jammed bones themselves become obstacles. These preliminary studies show that scale models can provide valuable insights into certain taphonomic problems that cannot be obtained by traditional bone flume studies.

     

Megacystis-microcolon-intestinal hypoperistalsis syndrome in two male siblings

Two male sibs with severe congenital megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) are presented. Both had enlarged bladder and hydronephrosis due to reduced bladder emptying, decreased bowel motility, and malrotation of the colon. Repeated careful ultrasound examination of the urinary tract in the second sib failed to show significant bladder enlargement prior to 25 weeks' gestation, which has been considered to be a reliable prenatal diagnostic sign for MMIHS. Slight bilateral enlargement of the renal pelves was noted at 21 weeks' gestation, and this may represent the earliest prenatally-detectable observation in this disease. Although more females than males with this condition have been reported, our cases provide support for an autosomal recessive mode of inheritance with a similar recurrence risk for both sexes.     

Twin–twin transfusion syndrome: mathematical modelling

Twin–twin transfusion syndrome (TTTS) represents a pregnancy complication with a high risk for perinatal mortality and postnatal morbidity. Mathematical models have been utilized to examine the mechanisms of disease and potential treatment modalities. We developed four consecutive models based on pathophysiology mechanisms. Conceptually, these models remained simple, but with increased complexity in details. We present our models tutorially with the necessary equations expressed in words. The aetiology of TTTS was related to AV anastomoses from donor to recipient and their growth commensurate with placental growth. We assessed that natural growth of placenta and foetuses causes the diameter and length of the AV, as well as the AV's pressure gradient, to increase proportional to gestational age. The AV transfusion then increases faster than natural foetal growth. A progressively increasing discordance subsequently develops, not compensated for by foetal growth. A simulation is performed to show how this discordance in blood volumetric development causes successive discordances in other functions, particularly renal, circulatory, and cardio-vascular, resulting in disease progression to the various stages of TTTS. In conclusion, mathematical modelling of TTTS has provided an understanding of the sequence of events that leads to the various presentations of TTTS stages as well as the efficacy of therapies. Copyright © 2008 John Wiley & Sons, Ltd.     

First and early second-trimester diagnosis of fetal urinary tract anomalies using transvaginal sonography

Urinary tract anomalies are common. Prenatal diagnosis is important and enables either special obstetric management or termination of pregnancy and probably in the future, intrauterine intervention. Transvaginal sonography (TVS) allows visualization of the normal and anomalous fetal urinary tract at an early stage. One thousand nine hundred and forty women were examined via TVS at an early stage of pregnancy between 10 and 16 weeks from the last menstrual period (LMP) and 35 anomalies (1·8 per cent) were clearly identified: 29 cases of low urinary tract obstruction, 2 cases of multicystic dysplastic kidney, 2 cases of polycystic kidney (infantile type), 1 case of double collecting system, and 1 case of horseshoe kidney. Potter syndrome could be ruled out in three patients who had delivered fetuses suffering from this anomaly in previous pregnancies. The concise and early identification of anomalies makes TVS an important aid in the hands of the obstetrician, ultrasonographer, and neonatologist.     

Severe bilateral renal disease: Correlation of antenatal and autopsy findings

We report 20 infants with severe bilateral renal disease examined by prenatal ultrasound and by autopsy. In 17, the prenatal and pathologic diagnoses correlated well. Although the prenatal and autopsy findings differed in the three remaining cases, the autopsy confirmed the presence of severe bilateral renal abnormalities. All 20 pregnancies were complicated by oligohydramnios, which was severe in 60 per cent. Most of these fetuses had malformation of other organ systems. This series supports the utility of prenatal ultrasound examinations, but emphasizes the need for postnatal evaluation of congenital renal disease including pathologic examination of tissue when possible for correct classification and genetic counselling.     

Duplex systems

Duplex kidneys occur in 0.8% of the general population, many of whom are asymptomatic. Children with duplex kidneys may be prone to urinary tract infections because of vesico-ureteric reflux or obstruction. Surgical management is usually required once symptoms occur. Increasing numbers of duplex kidneys are now prenatally diagnosed by ultrasound, resulting in the development of early postnatal strategies to try and reduce morbidity. Copyright © 2001 John Wiley & Sons, Ltd.     

Normal and abnormal development of the urogenital tract

An understanding of the normal development of the urogenital tract, at both the structural and molecular level, gives an insight into the mechanisms involved in renal pathology. In this review we will outline embryology of normal and abnormal renal development and discuss the function of some of the key regulatory molecules which have been described recently. Copyright © 2001 John Wiley & Sons, Ltd.     

Maternal genetic disorders and fetal development

With improvements in early diagnosis and management of genetic diseases, more women with genetic disorders are reaching reproductive age and becoming pregnant. While pregnancy can have a significant impact on a woman's health when there is an underlying genetic disorder, there can also be fetal effects, including embryopathy, fetal growth restriction, and brain injury. Some maternal genetic disorders are associated with adverse perinatal outcomes, including a high risk of perinatal loss and preterm birth. In this article, we review several maternal genetic disorders associated with fetal risk that are important for clinicians and patients to understand and manage appropriately. These include phenylalanine hydroxylase (PAH) deficiency and other inborn errors of metabolism, tuberous sclerosis complex, myotonic dystrophy, cystic fibrosis, Turner syndrome, sickle cell disease, and connective tissue disorders.     

Prenatal diagnosis of an intra-abdominal sacrococcygeal teratoma

The prenatal diagnosis of a presacral (type IV) sacrococcygeal teratoma (SCT) is described. The initial ultrasound appearance was suggestive of a lower urinary tract obstruction, but further ultrasonic examination and radiological imaging using contrast medium led to the diagnosis of SCT. This is the first prenatal diagnosis of a totally intra-abdominal SCT.     

Etiology and management of early pregnancy renal anhydramnios: Is there a place for serial amnioinfusions?

Early pregnancy renal anhydramios (EPRA) comprises congenital renal disease that results in fetal anhydramnios by 22 weeks of gestation. It occurs in over 1 in 2000 pregnancies and affects 1500 families in the US annually. EPRA was historically considered universally fatal due to associated pulmonary hypoplasia and neonatal respiratory failure. There are several etiologies of fetal renal failure that result in EPRA including bilateral renal agenesis, cystic kidney disease, and lower urinary tract obstruction. Appropriate sonographic evaluation is required to arrive at the appropriate urogenital diagnosis and to identify additional anomalies that allude to a specific genetic diagnosis. Genetic evaluation variably includes karyotype, microarray, targeted gene testing, panels, or whole exome sequencing depending on presentation. Patients receiving a fetal diagnosis of EPRA should be offered management options of pregnancy termination or perinatal palliative care, with the option of serial amnioinfusion therapy offered on a research basis. Preliminary data from case reports demonstrate an association between serial amnioinfusion therapy and short-term postnatal survival of EPRA, with excellent respiratory function in the neonatal period. A multicenter trial, the renal anhydramnios fetal therapy (RAFT) trial, is underway. We sought to review the initial diagnosis ultrasound findings, genetic etiologies, and current management options for EPRA.     

Prenatal genetic considerations of congenital anomalies of the kidney and urinary tract (CAKUT)

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute 20% of all congenital malformations occurring in one in 500 live births. Worldwide, CAKUT are responsible for 40% to 50% of pediatric and 7% of adult end-stage renal disease. Pathogenic variants in genes causing CAKUT include monogenic diseases such as polycystic kidney disease and ciliopathies, as well as syndromes that include isolated kidney disease in conjunction with other abnormalities. Prenatal diagnosis most often occurs using ultrasonography; however, further genetic diagnosis may be made using a variety of testing strategies. Family history and pathologic examination can also provide information to improve the ability to make a prenatal diagnosis of CAKUT. Here, we provide a comprehensive overview of genetic considerations in the prenatal diagnosis of CAKUT disorders. Specifically, we discuss monogenic causes of CAKUT, associated ultrasound characteristics, and considerations for genetic diagnosis, antenatal care, and postnatal care.     

Prenatal diagnosis of multiple acyl-CoA dehydrogenase deficiency: association with elevated α-fetoprotein and cystic renal changes

We report the occurrence of multiple acyl-CoA dehydrogenase deficiency (MADD) in two consecutive pregnancies in a young, Caucasian, non-consanguineous couple. In the first pregnancy, the maternal serum α-fetoprotein was elevated. A sonogram showed growth delay, cystic renal disease, and oligohydramnios; the parents decided to terminate the pregnancy. Postmortem examination confirmed the cystic renal disease and showed hepatic steatosis, raising the suspicion of a metabolic disorder. The diagnosis of MADD was made by immunoblot studies on cultured fibroblasts. In the subsequent pregnancy, a sonogram at 15 weeks' gestation showed an early growth delay but normal kidneys. The maternal serum and amniotic fluid concentrations of α-fetoprotein were elevated, and the amniotic fluid acylcarnitine profile was consistent with MADD. In vitro metabolic studies on cultured amniocytes confirmed the diagnosis. A follow-up sonogram showed cystic renal changes. These cases provide additional information regarding the evolution of renal changes in affected fetuses and show a relationship with elevated α-fetoprotein, which may be useful in counseling the couple at risk. MADD should be considered in the differential diagnosis of elevated α-fetoprotein and cystic renal disease. Early growth delay may be an additional feature. Copyright © 2001 John Wiley & Sons, Ltd.