Pediatrics

Congenital anomalies/polycystic kidney disease

Overview: What every practitioner needs to know

Are you sure your patient has congenital anomalies/polycystic kidney disease? What are the typical findings for this disease?

Congenital anomalies of the kidney and urinary tract (CAKUT) occur in 1 in 500 births, account for the most cases of pediatric end-stage kidney disease (ESKD), and predispose an individual to hypertension and cardiovascular disease throughout life. While most cases of CAKUT are sporadic, familial clustering of CAKUT is common, emphasizing a strong genetic contribution to CAKUT origin. In addition, CAKUT occasionally develops in association with additional congenital anomalies outside the urinary tract.

Animal experiments demonstrate that alterations in genes critical for kidney development can cause experimental CAKUT. Understanding of the causes of CAKUT and the mechanisms underlying disease progression towards chronic kidney disease (CKD) and ESKD is essential for prediction of prognosis. Current nephroprotective treatment involves surgical intervention, management of hypertension, episodes of urinary tract infection and administration of supplements for renal support. Multidisciplinary research into molecular and genetic pathogenesis of CAKUT, with extension into translational studies, is aimed at improving long-term patient outcomes.

Typical Findings

CAKUT are diagnosed by antenatal ultrasonography (US) performed on 16-20 weeks of gestation or postnatally. Most common manifestations of CAKUT include:

Antenatal - oligohydramnios or variations in gross morphology of the kidney, ureter or bladder.

Postnatal - presence of palpable abdominal mass or single umbilical artery, feeding difficulties, decreased urine output, deficient abdominal wall musculature and undescended testes in a male infant.

What are the types of CAKUT?

Kidney anomalies:

Renal aplasia (agenesis) - Absence of one or both kidneys.

Renal hypoplasia - Decreased size of one or both kidneys by more than two standard deviations compared to the mean size by age.

Renal dysplasia - Presence of undifferentiated (immature) structures in kidney tissue, cysts, cartilage or fibrosis. (These changes are usually detected by histological examination of the kidney tissue.)

Renal hypodysplasia - Features of both hypoplasia and dysplasia are present.

Duplex kidney - Kidney has two separate collecting systems with either duplex ureter or a single ureter.

Horseshoe kidney - Fusion of the lower poles of two kidneys.

Ectopic kidney - Kidney moves across the midline or is located at abnormal position on the ipsilateral side.

Autosomal dominant polycystic kidney disease (ADPKD) - Presence of multiple macroscopic cysts in both kidneys, large kidney size.

Autosomal recessive polycystic kidney disease (ARPKD) - Presence of multiple microscopic cysts in both kidneys, large kidney size.

Multicystic dysplastic kidney (MCDK) - Nonreniform mass of macroscopic cysts and connective tissue.

Anomalies of the collecting system

Renal pelvis:

Hydronephrosis - Dilation of pelvis with or without dilation of calyces or loss of renal parenchyma.

Ureter:

Vesicoureteral reflux (VUR) - abnormal movement of urine from the bladder into the ureters or kidneys.

Ureterocele - Ureter balloons at its opening into the bladder, forming a sac-like pouch.

Ectopic ureter - Ureteral orifice is caudal to the normal insertion on the trigone of the bladder.

Megaureter - Ureter greater than 7 mm in diameter.

Bladder:

Diverticulum - A pouch or sac whose opening originates in a defect in the muscular layer of the bladder wall.

Bladder extrophy - An open inside out bladder with the inner surface exposed.

Urethra:

Posterior urethral valves - Membranous folds within the lumen of the posterior urethra that cause obstruction of urine flow.

Hypospadia - Ventral displacement of urethral meatus.

Epispadia - Dorsal displacement of urethral meatus.

Overview of normal kidney and urinary tract development

Permanent kidney, the metanephros, originates from embryonic tissue structure termed "intermediate mesoderm", begins to form in the fifth week of gestation and is fully formed before 37 weeks of gestation. Normal renal system development results from reciprocal inductive interactions between the ureteric bud (UB) and the mesenchyme, and is directed by complex interactions among diverse gene regulatory networks.

UB will outgrow from the nephric duct, a structure formed from within the intermediate mesoderm, invade the mesenchyme and undergo a series of branching events to form the renal collecting system (collecting ducts, renal calyces, pelvis and ureter), whereas the mesenchyme will give rise to all epithelial cells that form nephrons. Initial generations of UB branches are remodeled into the ureter, pelvis and calyces, whereas subsequent branches give rise to collecting ducts.

Proximal UB will form the ureter which will dissociate from the nephric duct to fuse with the bladder in the trigone, the muscular region located at the base of the bladder. The bladder and urethra begin to form from the urogenital sinus, an embryonic tissue structure distinct from the intermediate mesoderm, around the sixth week of gestation.

The resulting metanephric kidney consists of an average of 785,000 (range: 210,332-1,825,380) nephrons connected to a highly branched collecting duct system. Blood entering the nephron is filtered by the glomerulus, which consists of a capillary loop bound by mesangial cells, enveloped in podocytes, and enclosed by Bowman's capsule.

The filtrate flows from the glomerular space through the nephron tubule, consisting in sequence of the proximal tubule, loop of Henle, distal tubule and connecting tubule, which joins a collecting duct. All forms of CAKUT stem from faulty renal system development and are caused by disruption in genes that direct normal kidney organogenesis (Table I, Table II, Table III).

Table I.

Nonsyndromic human CAKUT )(Part 1)

Table II.

Glossary of genes (Part I)

Table III.

Syndromic CAKUT (Part 1)

Characteristics of CAKUT

Hydronephrosis:

Antenatal hydronephrosis is detected and graded based on fetal kidney US. Hydronephrosis can be transient or persistent. Postnatal hydronephrosis may manifest as a palpable abdominal mass or bladder, deficient abdominal wall musculature and undescended testes in a male infant with Prune-belly syndrome. UPJ, CAKUT and VUR are the most common causes of hydronephrosis.

Solitary kidney:

Solitary kidney may be due to a lack of contralateral kidney due to faulty embryonic renal system development or in utero regression of MCDK. Some cases may be accompanied by a single umbilical artery. Most patients with solitary kidney are asymptomatic. However, up to 50% of children develop hypertension and proteinuria.

Horseshoe and ectopic kidney:

Horseshoe kidney means fusion of two kidneys at one pole. In most cases fusion occurs at the lower poles and separate collecting systems are formed. Horseshoe kidneys are due to faulty renal ascent during renal system development, are located either in the pelvis or lower than usual and often have aberrant vascular supply. Ectopic kidney is due to faulty migration during renal system development.

Ectopic kidney may or may not be fused with contralateral kidney. Most cases of horseshoe or ectopic kidney are asymptomatic and detected accidentally with US. Some cases may be complicated by urinary tract obstruction, VUR, UTI or nephrolithiasis.

Renal hypodysplasia (RHD):

RHD represents a broad spectrum of CAKUT with or without renal cysts. One form of isolated renal hypoplasia is represented by oligomeganephronia, characterized by a reduction in number of nephrons, hypertrophic glomeruli and tubules.

One example of RHD with cysts is cystic dysplastic kidney (CDK). CDKs exhibit poorly differentiated, disorganized nephrons with cartilage. US of CDKs shows large echogenic kidneys with poor corticomedullary differentiation. Patients with Bardet-Biedl syndrome (BBS) (obesity, hypogenitalism in men, mental retardation, retinal dystrophy, polydactyly, RHD, polyuria and polydipsia) exhibit diffuse hyperechogenicity, loss of corticomedullary differentiation with or without macrocysts on US.

Multicystic dysplastic kidney (MCDK):

Bilateral MCDKs are incompatible with life. Most MCDKs are unilateral. The cause of MCDK is unknown and disease is considered to be sporadic. MCDK may manifest as palpable abdominal mass. Kidneys are non-reniform, multiple macroscopic cysts are present, renal collecting system is usually atretic. VUR may be present in the contralateral kidney. MCDK can occur in maturity-onset diabetes of the young type 5 (MODY5), a disease caused by mutations in hepatocyte nuclear factor 1beta (HNF1beta) and characterized by early-onset diabetes mellitus.

Medullary sponge kidney (MSK):

MSK is characterized by the presence of cysts in medullary collecting ducts. The cause of MSK is unknown and therefore MSK is considered to be sporadic. Recent studies demonstrate presence of GDNF gene sequence variations in patients with MSK, suggesting a role for this gene in the pathogenesis of some cases of the disease.

Patients can be graded using a novel system based on IVP findings, which correlates with severity of disease. Most patients with MSK are asymptomatic. Symptomatic patients exhibit hematuria, nephrocalcinosis, abdominal or flank pain and UTI. US demonstrates increased echogenicity of the renal medulla.

Medullary cystic kidney disease (MCKD):

There are two types of MCDK: MCDK1 and MCDK2. Patients with MCDK1 present with slowly progressive CKD with minimal hematuria and/or proteinuria. Most patients with MCDK2 manifest gout, elevated serum uric acid levels and slow progression of CKD. Both types of MCKD are inherited in autosomal-dominant manner.

ADPKD:

ADPKD is due to mutations in either PKD1 gene encoding polycystin-1 (85% of affected individuals) or PKD2 encoding polycystin 2 (15% of affected individuals). Patients may manifest abdominal or flank pain, hypertension, proteinuria or UTI. Kidney US reveals uni- or bilateral multiple cysts usually in association with normal parenchyma. Extrarenal manifestations include polycystic liver disease and intracranial aneurysms.

Among individuals at 50% risk for ADPKD, diagnostic sensitivity of renal US at age of 30 years or younger is 95% for PKD1-related ADPKD and 67% for PKD2-related ADPKD.

ARPKD:

ARPKD is due to mutations in PKHD1 gene that encodes fibrocystin/polydactin. Most cases of ARPKD are diagnosed in the neonatal period based on the presence of bilateral palpable flank masses, enlarged echogenic kidneys with poor corticomedullary differentiation on US or magnetic resonance imaging (MRI), respiratory distress due to pulmonary hypoplasia, hypertension and history of oligohydramnios. Forty-five per cent of infants exhibit hepatomegaly and increased liver echogenicity. Older children may have kidney macrocysts, hepatomegaly and esophageal varices. Pathology reveals microcysts located predominantly in collecting ducts.

Patients and families should be informed on hereditary nature of ARPKD. Genetic counseling should explain that: the parents of an affected child are heterozygotes (i.e., carriers of one mutant allele); heterozygotes (carriers) are asymptomatic, each sibling of a proband has a 25% chance of inheriting the disease, a 50% chance of being a carrier and a 25% chance of not being a carrier and not having a disease; a child of an individual with ARPKD is a carrier of the disease.

Patients and families should be informed that there is no specific therapy to treat or prevent ARPKD. Chronic pain, respiratory compromise due to massively enlarged kidneys may require removal of one or both cystic kidneys and initiation of dialysis.

Nephronophthisis (NPHP):

NPHP consists of a group of autosomal recessive diseases that initially present with a urinary concentrating defect, polyuria, polydipsia and anemia, and subsequently require renal transplant. Renal fibrosis and corticomedullary junction cysts are observed. Renal US demonstrates small or normal size kidneys with increased echogenicity and with or without corticomedullary cysts. Extrarenal manifestations of NPHP include congenital hepatic fibrosis, structural cerebellar and midbrain anomalies and retinal degeneration (Senior-Loken syndrome).

Asphyxiating thoracic dystrophy is a feature of Jeune syndrome. Patients with Joubert syndrome exhibit ataxia due to cerebella vermis hypoplasia, polydactyly, hypotonia, developmental restriction. NPHP may be associated with Meckel-Gruber syndrome (central nervous system anomalies, cleft palate, polydactyly).

Simple renal cysts:

Isolated kidney cysts are sporadic in most cases. They may manifest with hematuria or abdominal/flank pain.

Glomerulocystic kidney disease (GCKD):

Most of GCKD is inherited in an autosomal dominant fashion. Histologically, GCKD is characterized by a predominance of glomerular cysts without tubular dilation. In infancy, GSKD can mimic ARPKD. Older children may present with flank pain, hematuria or hypertension.

Posterior urethral valves (PUV):

PUV result from aberrant development of the male urethra during embryonic life. PUV occur in 1 in 5000 to 8000 pregnancies and account for 19% of causes of urinary tract obstruction in newborn boys. Most cases of PUV are identified during prenatal US by the presence of dilated posterior urethra, dilated bladder and bilateral hydronephrosis in a male fetus with or without oligohydramnios. Presence of oligohydramnios in the second trimester of pregnancy is associated with a high perinatal mortality.

Neonates and infants present with respiratory distress due to pulmonary hypoplasia, poor urinary stream, straining or grunting during voiding, a palpable abdominal of flank mass, UTI or failure to thrive. Older boys may exhibit day-time and night-time urine incontinence and dysuria. Associated anomalies include VUR, bladder dysfunction with abnormally thickened bladder wall with diverticuli and trabeculations.

Diagnosis of PUV is established by VCUG which demonstrates dilated posterior urethra during the voiding phase and following removal of the urethral catheter. Additional findings on VCUG include a thick, trabeculated bladder wall with diverticuli. Up to 50% of patients have VUR.

Final diagnosis is established by cystoscopy. MAG3 or DMSA scan may be performed to assess differential kidney function, parenchymal or lower urinary tract anomalies. Serum creatinine and electrolytes should be assessed and abnormalities (e.g., hyperkalemia, metabolic acidosis) corrected. PUV need to be distinguished from urethral stricture.

Ureterocele:

A ureterocele is a cystic dilatation of the terminal ureter within the bladder and/or the urethra. In some cases, ureteroceles can be detected during prenatal US by the presence of hydronephrosis. Most ureteroceles are diagnosed postnatally by US during evaluation for UTI, palpable abdominal mass, lower abdominal pain or failure to thrive. US demonstrates a cystic intravesical mass. VCUG should be performed to identify the presence of VUR. Additional imaging and laboratory studies are tailored according to each specific case (e.g., MAG3 scan can evaluate differential kidney function and define urinary tract anatomy).

Vesicoureteral reflux (VUR):

VUR is the retrograde flow of urine from the bladder into the upper urinary tract. VUR is divided into primary and secondary.

Primary VUR is due to inadequate closure of the ureterovesical junction (UVJ) due to intrinsic UVJ defect. This may be due to a short intravesical tract of the terminal ureter within the bladder trigone. The trigone is a muscular structure located at the base of the bladder. When bladder fills with urine, the trigonal muscle helps compress the ureteral orifice within the bladder wall preventing back-flow of urine to the ureters or kidneys. Shortening of intravesical terminal ureter is due to formation of the ureteric bud too low on the nephric duct. In this case, terminal ureter (which is formed from the initial UB bud arising from the nephric duct) joins the bladder lateral or anterior (higher) to the normal insertion site causing VUR.

Secondary VUR is due to inability of the UVJ to close during bladder contraction as a result of abnormally elevated pressure in the bladder. Secondary VUR is most commonly due to anatomic (e.g., PUV, urethral stricture) or functional (e.g., neurogenic bladder) bladder outflow obstruction. VUR may be represented by hydronephrosis discovered during antenatal US. VUR presents postnatally with symptoms of UTI, febrile UTI or recurrent UTIs. Severity of VUR is graded based on the extent of retrograde filling and dilation of the renal collecting system as demonstrated by VCUG.

Grade I - Filling of the ureter with contrast without dilation.

Grade II - Filling of the ureter and collecting system without dilation.

Grade III - Filling of the ureter and collecting system with mild dilation.

Grade IV - Filling of the ureter and collecting system with gross dilation and blunting of calyces.

Grade V - Filling of grossly dilated and tortuous ureter and collecting system with blunting of all calyces and loss of papillary impressions.

VUR grade I-II is considered mild, grade III- moderate and grade IV-V- severe.

One approach that may be used to evaluate for the presence of VUR in infants with history of hydronephrosis revealed by prenatal US is to perform early postnatal US. In the absence of severe hydronephrosis, postnatal US should be performed after the first week of life. VCUG is usually performed in symptomatic patients or patients with abnormal findings on US. Presence of grade III-V VUR requires evaluation of the extent of renal parenchymal damage and presence of obstruction. The extent of renal scarring is directly related to the grade of VUR.

Surveillance of VUR includes monitoring of growth, blood pressure, serum creatinine, proteinuria, symptoms of UTI or voiding dysfunction. Scheduled renal system imaging is performed based on the nature and extent of CAKUT. Radionuclide cystogram provides less radiation exposure, but is less sensitive than contrast VCUG.

Megaureter:

Megaureter may be primary or secondary. Primary megaureter is due to a functional or anatomical abnormality of the ureterovesical junction. Secondary megaureter results from abnormalities in the bladder or urethra (e.g., PUV). Almost 25% of the children referred to a pediatric urologist for obstructive uropathy suffer from an obstructive megaureter.

Most cases of megaureter are diagnosed by fetal ultrasonography which demonstrates dilated ureter, hydronephrosis and normal bladder. Postnatal presentation may be accompanied by abdominal pain, UTI, hematuria, palpable abdominal or flank mass or decreased renal function.

Ectopic ureter:

Ectopic ureter drains into the bladder at abnormally displaced location. Ectopic ureter is due to abnormally displaced spatial outgrowth of the ureteric bud (UB) from the nephric duct on weeks 5-6 of gestation in humans. Ectopic ureters may be associated with double ureters, double collecting systems or double kidneys. This is due to outgrowth of supernumerary UBs from the nephric duct leading to induction of two discrete mesenchymes.

Ectopic ureters may be associated with genitourinary or nongenitourinary anomalies (e.g., hypospadias, cloacal anomalies, anorectal, spinal cord and cardiac defects). Ectopic ureters causing obstruction are usually diagnosed on prenatal US which detects bladder outlet obstruction and hydronephrosis.

Postnatal symptoms include recurrent UTIs, dysuria, abdominal or flank pain and urinary incontinence in girls. Postnatal evaluation begins with kidney and bladder US followed by VCUG and dynamic renal scan with diuretic. Contrast vaginography can be used to detect the dysplastic kidney draining by a single ectopic ureter.

What other disease/condition shares some of these symptoms?

CAKUT are associated with extrarenal congenital anomalies in 1/3 of cases and are a part of 200 syndromes (Table III).

What caused this disease to develop at this time?

All cases of CAKUT are due to abnormal embryonic development of kidneys and urinary tract due to gene mutations, epigenetic modifications of chromatine, nutritional deficiencies or exposure to teratogens.

Gene mutations:

Mutations in the genes encoding for angiotensinogen, renin, angiotensin-converting enzyme (ACE) or angiotensin II AT1 receptor are associated with renal tubular dysgenesis (RTD). RTD is characterized by renal hypodysplasia and low systemic blood pressure. Majority of children with RTD die in the perinatal period due to anuria combined with pulmonary hypoplasia. Mutations in Pax2 cause Renal-Coloboma syndrome (optic nerve coloboma, hearing loss, renal hypoplasia and VUR). In addition, kidney volume is lower in infants heterozygoes for Pax2 AAA haplotype compared to more common homozygous GGG haplotype.

Nutritional deficiencies:

Maternal low-protein diet initiated at onset of pregnancy reduces nephron number and alters gene expression in the embryonic kidney in mice.

Teratogens:

Exposure to ACE inhibitors, angiotensin II AT 1 receptor antagonists, cyclosporine A, mycophenolate mofetil, cyclophosphamide, valproic acid, cocaine or alcohol during pregnancy.

Epigenetic modifications:

Disease or birth defect is caused by abnormally altered expression of the gene in the absence of mutations in this gene. This is due to aberrant gene methylation or acetylation. For example, some forms of Beckwith-Wiedemann syndrome (macroglossia, gigantism, visceromegaly, renal dysplasia and Wilm's tumor) are due to epigenetic imprinting of genes located on chromosome 11p15.5.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Prenatal evaluation:

When gross renal system anomalies are detected on prenatal US, the presence and severity of oligohydramnios and fetal growth should be assessed. History should evaluate maternal exposure to teratogens during pregnancy, family history of heritable renal diseases or multiorgan syndrome. Amniocenthesis can be performed to detect chromosomal abnormalities which are frequently associated with CAKUT, such as trisomy 18. Genetic counseling should be provided. Preimplantation genetic testing may be performed before pregnancy for families in which the disease-causing mutations have been identified.

Postnatal evaluation:

Should be tailored according to findings at prenatal evaluation.

Physical examination:

After delivery, the presence and degree of pulmonary hypoplasia should be assessed. Newborns with pulmonary hypoplasia may present with respiratory distress. The presence of a single umbilical artery or anomalies of the outer ear are associated with increased risk of CAKUT.

A palpable abdominal mass may suggest the presence of MCDK, severe hydronephrosis or neoplasm (e.g., Wilm's tumor).

Deficient abdominal wall musculature with cryptorchidism in a male newborn is characteristic of prune-belly syndrome.

Boys with PUV may exhibit poor urinary stream, straining and grunting during voids, urosepsis, a palpable distended bladder or failure to thrive.

Presence of flattened nose and ears, recessed chin and pseudoepicanthus may be due to Potter's syndrome.

Presence of gross morphologic alterations in other organ systems may point to the presence of multiorgan syndromes associated with CAKUT (Table III).

Ambiguous genitalia may be associated with Denys-Drash syndrome characterized by male pseudohermaphroditism and Wilm's tumor.

Hypertension may be due to renal artery stenosis, ARPKD or ADPKD.

Hypopigmented skin macules and angiofibromas are a feature of tuberous sclerosis complex (TSC). TSC may be associated with renal cysts due to concurrent mutations in PKD1 gene.

Renal hypoplasia may be a part of Branchio-oto-renal (BOR) syndrome (branchial cleft defects, ear pits, hearing loss) due to Eya1 gene mutation or Renal-coloboma syndrome.

Serum creatinine:

Renal function may be assessed by measuring serum creatinine which initially reflects maternal serum creatinine and declines during the first week of life in term infants and over 2 to 3 weeks in preterm infants to 0.2-0.5 mg/dL (18 to 35 micromol/L).

Long-term monitoring:

Long-term monitoring children with CAKUT involves monitoring diet, nutritional status, growth, blood pressure, serum creatinine, proteinuria (or microalbuminuria) and renal system imaging as indicated. New biomarkers are needed with greater sensitivity and specificity to follow changes in renal status before they become irreversible.

Would imaging studies be helpful? If so, which ones?

Renal US:

Should be performed within the first 24 hours after birth in newborns with bilateral pathology of the urinary tract, a history of oligohydramnios or a solitary dysplatic kidney discovered on antenatal US or with a distended bladder. In the presence of unilateral renal system defects, US may be performed after 48 hours of postnatal life. Serial US's can be performed to assess dynamics of renal system defects (e.g., change in kidney growth, structure, number and size of cysts). Doppler US can evaluate renal vascular flow, detect renal vein thrombosis or renal artery stenosis.

Voiding cystourethrography (VCUG):

VCUG is performed to assess bladder and urethral anatomy, identify and grade vesicoureteral reflux or hydronephrosis. VCUG can be performed with contrast agent or radionuclide. Contrast VCUG is more sensitive than radionuclide study, but provides a higher radiation exposure.

Dynamic renal radionuclide scans:

Dynamic renal scans utilize radiotracers [99mTc-mercaptotriglycylglycine (MAG-3) or 99mTc-diethylenetriamine pentaacetic acid (DTPA)]. Radiotracer is injected intravenously, is rapidly absorbed from the blood by proximal renal tubules and then rapidly secreted into the tubular lumen.

Dynamic renal scans can assess differential kidney function, identify urinary tract obstruction or gross renal systemanomaly (e.g., duplex collecting systems, hydronephrosis, horseshoe kidney, ectopic kidney) or renal artery stenosis. Furosemide is usually administered during these studies.

If washout of the radiotracer from the kidney occurs rapidly after furosemide administration (less than 15 minutes), the system is not obstructed. If washout is delayed (more than 20 minutes), obstructive uropathy is possible.

Because glomerular filtration rate (GFR) is low during neonatal period, more reliable results may be obtained by performing dynamic renal scans at about 8–12 weeks of age in most cases, but with severe pelvic dilatation (>40 mm), the first study can be undertaken earlier.

Static renal radionuclide scans:

Static renal scans utilize radiotracer 99mTc-dimercaptosuccinic acid (DMSA). Radiotracer is injected intravenously and is absorbed from the blood by proximal renal tubules. Most of absorbed DMSA accumulates over several hours in renal proximal tubules and only minimal amount is secreted into the urine. Static renal scan can assess kidney size, location, differential kidney function and renal scarring.

The detection of focal parenchymal abnormalities (renal scars, aberrant vascular supply) is the main indication for a static renal scan. In renal failure and/or bilateral dilatation, 99mTc-DMSA has proved essential in distinguishing between two equally affected kidneys or marked asymmetrical renal function.

Computerized tomography (CT):

CT with contrast has a higher sensitivity than that obtained with renal US for detection of kidney cysts, differentiation of a neoplastic lesion from a cyst (e.g., in von Hippel-Lindau disease characterized by renal cell carcinoma, renal cysts, pheochromocytoma and hemangioblastoma).

Notably, contrast CT may cause contrast-induced acute kidney injury. CT is recommended to better delineate the anatomy of the urinary tract, detect small urinary system stones or assess renal parenchyma (e.g., detect small renal cysts, tumors, hematomas or abscesses).

Magnetic resonance urography (MRU):

MRU can more clearly define the anatomy of CAKUT. Notably, use of gadolinium may cause nephrogenic systemic fibrosis. MRI is a valuable adjunct to ultrasound diagnosis of renal system anomalies, especially in cases of oligohydramnios. MRU is recommended to better define fine elements of renal parenchymal structure, identify cysts of small size (e.g., in ARPKD), monitor cyst volume and number in children with ADPKD and ARPKD.

If you are able to confirm that the patient has congenital anomalies/polycystic kidney disease, what treatment should be initiated?

Prenatal management

The type of intervention depends on the specific type of CAKUT/multiorgan malformation discovered. Prenatal counseling should be provided for any renal system anomaly identified. Presence of bilateral renal agenesis, oligohydramnios, severe anomaly of a single kidney with oligohydramnios, unfavorable results of amniocentesis may justify legal termination of pregnancy. Before a genetic test is offered for any potentially inherited disorders, its validity and clinical utility should be assessed.

Less severe defects require continued counseling during pregnancy and establishment of guidelines for the extent of initial postnatal care. Although surgical correction of select fetal renal system anomalies (e.g., obstructive hydronephrosis, PUV) may be attempted in specialized centers, such interventions are considered experimental. Randomized controlled trials are needed to evaluate whether vesicoamniotic shunting improves renal function and survival.

More studies are also needed to determine whether early delivery is beneficial in the presence of severe oligohydramnios and documented maturation of the lung in fetuses with CAKUT. Antenatal vesicoamniotic shunt placement makes no difference to the outcome and long-term results of patients with PUV.

In summary, antenatal surgical interventions in fetuses with CAKUT are associated with high risk of fetal and maternal morbidity without proven benefit for long-term outcome.

Postnatal management

Hydronephrosis:

If postnatal US demonstrates bilateral hydronephrosis, severity of hydronephrosis should be assessed, a VCUG should be performed to evaluate bladder anatomy and exclude VUR or PUV in boys. In the absence of VUR or PUV, a dynamic renal scan should be performed to exclude urinary tract obstruction [e.g., uretero-pelvic junction (UPJ) obstruction] and evaluate differential renal function.

Antibiotic prophylaxis with amoxicillin (20 mg/kg PO once a day) should be initiated to decrease the risk of urinary tract infection (UTI) and continued until the presence of VUR is excluded or in the presence of higher grades of hydronephrosis even in the absence of VUR.

Mild and moderate hydronephrosis can be assessed initially by US after the first week of life. Medical management is focused on correction of electrolyte and acid-base abnormalities, and maintenance of appropriate fluid balance.

Long-term management is tailored according to disease severity and course. Persistent moderate to severe hydronephrosis in the absence of VUR or bladder dysfunction typically requires annual renal US and dynamic renal scan. If differential kidney function is <35-40% on one side by MAG3 scan, the patient should be referred to a pediatric urologist to evaluate for a need of surgical correction.

Prognosis depends on severity of hydronephrosis, presence of uni-or bilateral hydronephrosis, cause of hydronephrosis (e.g., VUR versus obstruction), extent of renal parenchymal damage and renal function, differential renal function, comorbid conditions and other factors. Antibiotic prophylaxis of UTI should be initiated.

Indications for surgical correction, type of correction and its potential adverse effects are discussed with the family and patient in conjunction urologist and other subspecialties as needed.

Solitary kidney:

Serum creatinine should be measured, kidney size and structure should be assessed by US within several days after birth. Serial USs should be performed annually to assess kidney growth. Normal kidney function, size and structure of solitary kidney usually portend a favorable prognosis. Recent studies indicate that a solitary kidney is associated with a higher risk of dialysis later in life. Participation in contact sports is contraindicated.

Horseshoe and ectopic kidney:

Serum creatinine and blood pressure should be measured. The presence and degree of obstruction (hydronephrosis), VUR or Wilm's tumor should be assessed by US/VCUG. Normal anatomy of the uterus in girls should be confirmed with US. Careful physical examination should exclude the presence of cryptorchidism or hypospadia in boys. UTIs should be treated accordingly when present. Most patients have excellent prognosis without any interventions.

Renal hypodysplasia:

Isolated renal hypoplasia occurs infrequently and is most commonly associated with renal dysplasia. Management of renal hypodyslasia is generally supportive and includes serial imaging by US/VCUG, evaluation of serum creatinine, blood pressure and growth.

Growth hormone can be utilized to correct growth deficiency due to CKD. Renin-angiotensin system antagonists may be used to treat hypertension, slow the progression of CKD and attenuate proteinuria.

Urinary tract infection (UTI) should be treated with appropriate antibiotics. DMSA renal scan should be performed in case of UTI in patient with VUR or with recurrent UTIs to assess for renal scarring. CKD is managed according to CKD stage.

Hypotension and hyperkalemia observed in renal tubular dysgenesis may be treated initially with fludrocortisone. Extrarenal defects in syndromic renal hypodysplasia (e.g., BOR, renal-coloboma syndrome) should be managed accordingly. Progressive decline in kidney function may require renal replacement therapy.

Multicystic dysplastic kidney (MCDK):

MCDK often regresses during the first several years after birth. In the absence of contralateral kidney defects, hypertension or CKD, conservative management consists of serial USs to monitor healthy kidney growth. Most patients have excellent prognosis without any intervention.

Children with contralateral abnormalities are at risk for developing decreased kidney function, whereas a substantial number of patients with no obvious contralateral abnormalities have markers of renal injury. Therefore, systematic follow-up of all patients is recommended.

Medullary sponge kidney (MSK):

Symptomatic patients should be evaluated for hematuria or UTI, by a 24-hour urine collection for stone risk factors such as hypercalciuria, hyperoxaluria, increased excretion of uric acid or hypocitraturia. Management is tailored according to specific findings.

Optimal fluid intake, limitation of dietary sodium chloride intake and administration of potassium citrate may be used in patients with stone risk factors. Extracorporeal shock wave lithotripsy (SWL) be offered to patients with ureteral and kidney malformations. These patients should however be considered at high risk for recurrences and so they need to be carefully followed up. Most patients have excellent long-term prognosis.

Medullary cystic kidney disease (MCKD):

There is no specific treatment for MCDK1 or MCDK2. Patients who progress in CKD are treated accordingly to CKD stage. Allopurinol may be considered in patients with MCDK2 in the presence of gout. Some studies suggest that allopurinol may attenuate progression of CKD in patients with MCDK2.

ADPKD:

There is no specific treatment of ADPKD. Hypertension can be managed with ACE inhibitors, angiotensin II AT1 receptor- calcium channel- or beta-blockers.

Renin-angiotensin system blockers may cause hyperkalemia, an increase in serum creatinine and are contraindicated during pregnancy. More studies should be performed to determine with certainty whether renin-angiotensin system blockers slow progression of CKD and minimize cardiovascular morbidity and kidney injury in ADPKD.

CKD associated with dyslipidemia should be treated with statins. There is no evidence to support routine screening for intracranial aneurysm in asymptomatic patients with ADPKD. The annual rate of a decline in GFR is 4.4 to 5.9 ml/min/year ultimately leading to ESRD usually beyond pediatric age. PKD1 mutations cause more severe kidney disease associated with a 20-year earlier onset of ESRD compared with PKD2 mutations (54.3 years for PKD1, 74.0 years for PKD2). Kidney transplantation can be performed either before or after initiation of dialysis. Either PD or hemodialysis can be utilized if needed.

The choice of dialysis modality depends on multiple factors including large kidney and liver size. Intractable pain, renal cell carcinoma or need to accommodate renal allograft may require native nephrectomy. Tuberous sclerosis-associated renal angiomyolipomas can be treated with inhibitors of the mammalian target of rapamycin (mTOR) signalling pathway.

A number of novel therapeutic interventions are currently in clinical trial and may soon be available. Genetic testing, including preimplantation genetic testing, may be considered.

Patients and families should be informed on hereditary nature of ADPKD. Genetic counseling should explain that one parent of an affected child is homozygote (i.e., carrier of a mutant allele causing disease in the child). Each sibling of a proband has a 50% chance of inheriting the disease and a 50% chance of not being a carrier and not having a disease.

ARPKD:

Mechanical ventilation may be necessary for stabilization of respiratory function from massively enlarged kidneys. Unilateral or bilateral nephrectomy may be considered in select cases. Decreased renal function may require peritoneal dialysis.

Growth failure due to feeding intolerance or CKD may require supplemental feedings provided via nasogastric or gastrostomy tubes. Hypertension can be treated with renin-angiotensin system inhibitors or other anti-hypertensive agents.

Surveillance should include frequent monitoring of blood pressure, renal and hepatic function, serum electrolytes, nutritional and growth status, renal and hepatic US. Up to 30% of affected infants die within the first year of life. Ten-year survival of those who live beyond the first year of life is 82%.

Kidney transplantation is performed with progression of CKD.

Genetic counseling should explain that: the parents of an affected child are heterozygotes (i.e., carriers of one mutant allele); heterozygotes (carriers) are asymptomatic; each sibling of a proband has a 25% chance of inheriting the disease, a 50% chance of being a carrier and a 25% chance of not being a carrier and not having a disease; a child of an individual with ARPKD is a carrier of the disease. Preimplantation genetic testing may be performed before pregnancy for families in which the disease-causing mutations have been identified.

When clinical diagnostic criteria for ARPKD are met, genetic testing is usually not necessary to confirm the diagnosis. When clinical diagnostic criteria for ARPKD are not met, molecular testing for mutations in PKHD1 gene establishes the diagnosis in 82-85% of cases. Preimplantation genetic testing is possible if disease-causing alleles have been identified in the family or when linkage studies are informative.

Nephronophthisis (NPHP):

There is no specific treatment of NPHP. Imbalances in fluid and electrolyte homestasis should be corrected. Infantile, juvenile and adolescent forms of NPHP result in ESRD at median ages of 1, 13 and 19 years, respectively. Manifestations of CKD are managed accordingly to CKD stage. Renal transplantation is the method of choice.

Simple renal cysts:

Patients with normal renal functions and absence of comorbid CAKUT do not require specific therapy. In the presence of suspicion for neoplasms (e.g., renal cell carcinoma), CT or MRI can be performed.

Posterior urethral valves (PUV):

A transurethral catheter is placed to ensure urine outflow from the bladder followed by primary valve ablation during cystoscopy. Vesicostomy may be performed when PUV ablation is not possible. Medical management consists of correction of electrolyte abnormalities, respiratory distress, prevention and treatment of UTI and monitoring of kidney function.

Since a significant number of patients will develop progressive chronic kidney disease (CKD) and end-stage renal disease (ESRD), careful monitoring of renal and bladder function is continued following valve ablation throughout life.

Renal hypodysplasia associated with PUV represents a higher risk for dialysis later in life. The combination of pretreatment azotemia, VUR and UTI is highly predictive of a poor renal outcome. Despite timely surgical valve ablation, a significant number of patients will manifest urinary incontinence and progress to ESRD. Persistent bladder dysfunction requires clean intermittent bladder catheterization and/or pharmacotherapy.

Ureterocele:

Newborns should receive antibiotics for UTI prophylaxis until evaluation is completed, any associated obstruction/VUR is corrected or until resolution of VUR. All patients with ureteroceles require surgical correction. The type of surgical correction depends on specific type of associated CAKUT. Laparoscopic ipsilateral ureteroureterostomy is a safe and effective mode of surgical intervention with minimal complication. The long-term outcome after surgical correction of ureterocele is favorable.

Vesicoureteral reflux (VUR):

VUR can be treated with prophylactic antibiotics to prevent recurrent UTIs and renal scarring, treatment of comorbid conditions or surgical correction. Prophylactic antibiotics are usually administered in a single daily dose at bedtime. Amoxil (20 mg/kg/day) may be used in infants under 2 months of age. Trimethoprim, trimethoprin-sulfamethoxazole or nitrofurantoin can be used in infants over 2 months of age. In the absence of recurrent UTIs or voiding dysfunction, antibiotic prophylaxis may be discontinued in patients with persistent grade I-II VUR who are completely toilet trained.

Types of surgical correction of VUR:

Two surgical approaches can be used 1) Open surgical reimplantation and 2) Endoscopic injection of synthetic polymer beneath the mucosa of the ureterovesical junction through a cystoscope below the ureteral orifice (STING procedure). In open reimplantation, refluxing ureter is reimplanted by tunneling terminal ureter segment through the bladder wall muscle. This creates a new submucosal tunnel that is more likely to close completely during bladder muscle contraction, thereby preventing VUR. This procedure usually requires in-hospital admission.

Effectiveness of surgical correction of VUR:

Correction rates of 95 to 99% are reported following open surgical reimplantation for grades I to IV of VUR, with slightly lower success rate for grade V. The success rate for correcting VUR with a single injection by STING procedure depends on VUR grade as follows:

Grade I - 79%-89%

Grade II - 79%-83%

Grade III - 71%-72%

Grade IV - 59%-63%

Grade V - 51%-62%

The success rate of second injection with STING procedure after failed initial injection varies from 68% to 89%.

UTI prophylaxis versus surgical correction of VUR:

Spontaneous resolution of VUR over time occurs in most children with grades I to III VUR and some children with grades IV to V VUR. Spontaneous resolution of VUR occurs in 91% of patients with VUR grade I-III and in 18 to 26% patients with VUR grade IV-V. Grade is the strongest predictor of VUR resolution, with high-grade VUR being much less likely to resolve.

Other factors that negatively influence resolution include lower bladder volume or pressure at onset of reflux, older age, female sex, bilateral VUR, ureteral duplication, abnormal or scarred kidneys, and bladder dysfunction. Comparable outcome is observed with either antibiotic prophylaxis of UTI or surgical correction of VUR in terms of the risk of renal scarring, CKD or hypertension regardless of the VUR grade.

In view of the high likelihood of spontaneous resolution of grades I to III VUR and inconclusive data comparing the effectiveness of UTI prophylaxis versus surgical correction of VUR in children, the benefits and potential adverse effects of these two treatment modalities should be discussed with the family and patients. Surgical correction of VUR is usually reserved for patients who are unlikely to undergo spontaneous resolution of VUR and are at risk for developing renal scarring.

Surveillance of VUR:

Long-term management includes monitoring of patient's growth and blood pressure, serum creatinine to assess renal function and annual renal US to monitor kidney growth, extent of renal collecting system dilation and parenchymal structure. Monitoring of VUR is accomplished by either contrast VCUG or radionuclide cystography.

The interval for these studies depends on dynamics of renal function, course of VUR and extent of hydronephrosis observed on renal US. In general, it is reasonable to perform VCUG every 1 to 2 years if needed. DMSA renal scan is performed in patients with break-through UTIs, abnormal or worsening kidney function, poor kidney growth as documented by renal US, and in patients with grades III to V VUR. Presence of comorbid conditions may require additional investigations (e.g., urodynamic studies in patients with bladder dysfunction). Symptoms that suggest break-through UTIs or unexplained fever should be promptly identified and treated.

Megaureter:

US shows a grossly dilated ureter (>7 mm in fetuses and children under 12 years of age), where there may or may not be VUR and normal bladder. The kidney function is usually preserved. VCUG and MAG3 renal scan are usually performed to document whether megaureter is associated with VUR or obstruction. It is important to exclude ureterocele or other bladder anomaly.

Thick and trabeculated bladder wall suggests bladder dysfunction. X-ray of the lower spine may be performed to exclude occult spinal dysraphism.

MRI may be required to exclude spinal cord pathology. In the absence of severe oligohydramnios, careful monitoring is implemented in the antenal period. Postnatal treatment depends on the exact nature of underlying abnormalities and renal function. Asymptomatic infants with non-obstructed, non-refluxing megaureter or in the presence of mild VUR (grades I-III) do not require surgical reconstruction.

All patients with megaureter will benefit from UTI prophylaxis with amoxicillin (20 mg/kg/day) or trimethoprim-sulfametoxazole (2 mg/kg/day, not recommended in infants under 2 months of age).

Patients exhibiting recurrent UTIs, pyelonephritis, hematuria, persistent flank pain, decreased kidney function, obstruction or high-grade VUR (IV-V) usually require surgical correction. Ureteric stenting provides an alternative to early surgery in patients with primary non-refluxing megaureter. Robotic laparoscopic reconstruction with ureteric reimplantation in primary symptomatic obstructive megaureter is effective. The long-term outcome of primary megaureter is favorable with mainly conservative treatment of UTI as the most common complication. Adverse outcome is more closely related to congenital kidney hypoplasia than to degree of obstruction.

Ectopic ureter:

Patients with ectopic ureters require surgical correction. Laparoscopic ipsilateral ureteroureterostomy is effective. The long-term outcome following surgical correction is excellent.

What are the adverse effects associated with each treatment option?

Antenatal surgical interventions:

Antenatal bladder drainage for congenital lower urinary tract obstruction may confer a high residual risk of poor postnatal renal function necessitating renal replacement therapy. Another potential adverse effect is premature delivery.

Amniocentesis:

Amniotic fluid leakage, increased rate of respiratory distress and orthopedic malformations in infants after birth, increased risk of mother-to-infant transmission of infections and fetal loss.

STING procedure:

Although the majority of children do not have serious or clinically significant adverse effects after endoscopic polymer injection for correction of VUR, some patients develop urosepsis and obstructive acute renal failure.

What are the possible outcomes of congenital anomalies/polycystic kidney disease?

Antenatally detected CAKUT

Presence of bilateral renal agenesis, oligohydramnios, severe anomaly of a single kidney with oligohydramnios, unfavorable results of amniocentesis may justify legal termination of pregnancy. Less severe defects require continued counseling during pregnancy and establishment of guidelines for the extent of initial postnatal care.

Postnatal CAKUT

Hydronephrosis:

Idiopathic prenatal hydronephrosis resolves spontaneously in most cases when the renal pelvic anterior-posterior diameter is less than 12 mm, but is less frequent when dilation is greater than 12 mm.

Solitary kidney:

Long-term prognosis in the absence of comorbid CAKUT or renal dysfunction is usually excellent. Patients and families should be counseled on necessity to avoid contact sports.

Horseshoe and ectopic kidney:

Most patients have excellent prognosis without specific treatment. Caution should be exercised regarding participation in contact sports.

Renal hypodysplasia (RHD):

Prognosis depends on the presence of uni- or bilateral RHD, extent of kidney injury and comorbid conditions. RHD in the absence of surgically correctable CAKUT is managed conservatively. Patients and families should be informed about risk of recurrent UTIs, hypertension, chronic kidney and cardiovascular disease, and potential need of renal replacement therapy with progression of CKD. Patients with syndromic RHD should be evaluated by pediatric geneticist.

Multicystic dysplastic kidney (MCDK):

Most cases of unilateral MCDK resolve uneventfully without any specific therapy. Patients with solitary contralateral kidney should refrain from participation in contact sports. Families should be informed on likely sporadic nature of the disease.

Medullary sponge kidney (MSK):

MSK has an excellent prognosis. Patients and families should be informed on possibility of developing abdominal or flank pain, hematuria, nephrocalcinosis and nephrolithiasis.

Medullary cystic kidney disease (MCKD):

MCDK is characterized by the development of slowly progressive CKD and onset of ESRD between 20 to 70 years of age.

ADPKD:

Each patient with PKD has a substantial risk to progress to ESRD. PKD1 mutations cause onset of ESRD at mean age of 54.3 years, whereas PKD2 mutations cause ESRD at mean age of 74.0 years.

ARPKD:

Up to 30% of affected infants die within the first year of life. Ten-year survival of those who live beyond the first year of life is 82%. Renal replacement therapy and kidney transplantation may be required.

Nephronophthisis (NPHP):

Patients and families should be informed that there is no specific therapy to treat or prevent NPHP. Infantile, juvenile and adolescent forms of NPHP result in ESRD at median ages of 1, 13 and 19 years, respectively, and require renal replacement therapy.

Simple renal cysts:

Isolated renal cysts are sporadic. Prognosis is excellent without any specific treatment.

Posterior urethral valves (PUV):

Families should be informed that despite timely surgical valve ablation, significant number of patients will manifest urinary incontinence and progress to ESRD. Persistent bladder dysfunction may require timed voiding every 2 hours, bladder catheterization, biofeedback, medical management, performance of vesicostomy or bladder augmentation and scheduled renal system imaging.

Ureterocele:

Patients will require antibiotic prophylaxis of UTI and surgical correction of ureterocele. Long-term prognosis following surgical correction of ureterocele is excellent.

Vesicoureteral reflux (VUR):

Prognosis depends on the grade of VUR. Grades I to III of primary VUR are likely to resolve spontaneously, whereas grades IV to V of VUR will most likely require surgical correction of VUR. Prolonged administration of antibiotics for UTI prophylaxis is usually recommended. There is a strong genetic predisposition to primary VUR with 27% of siblings of a patient with VUR and 35% of children of a parent with VUR having VUR.

Megaureter:

The long-term outcome of primary megaureter is favorable with mainly conservative treatment of UTI as the most common complication. Patients exhibiting recurrent UTIs, pyelonephritis, hematuria, persistent flank pain, decreased kidney function, obstruction or high-grade VUR (IV-V) usually require surgical correction.

Ectopic ureter:

Patients with ectopic ureters require surgical correction. The long-term outcome following surgical correction is excellent.

What causes this disease and how frequent is it?

Many forms of syndromic and non-syndromic human CAKUT are due to mutations in genes that play an important role in renal system development (Table I, Table II,Table III). However the cause of most nonsyndromic cases of CAKUT is unknown. The overall prevalence rate of CAKUT is 1 in 500 live births.

Hydronephrosis:

Congenital ureteropelvic junction obstruction (UPJ), posterior urethral valves (PUV) and VUR are the most common causes of hydronephrosis. Fetal hydronephrosis occurs in 0.5% to 1% of pregnancies. Congenital hydronephrosis has an overall prevalence of 1 in 1,000 live births.

Solitary kidney:

Solitary kidney may result for agenesis of the contralateral kidney or regression of the contralateral kidney (e.g., regression of unilateral MCDK). Unilateral renal agenesis occurs in 0.008% of fetuses and in 1 in 5,000 newborns. Bilateral renal agenesis occurs in 0.013% of fetuses and in 1 in 30,000 newborns.

Horseshoe and ectopic kidney:

Horseshoe kidney is due to abnormal fusion and lack of normal ascent of kidneys during embryonic development. The exact molecular mechanisms that account for horseshoe kidney in humans are unknown. Horseshoe kidney occurs in 1 in 1,000 newborns. Ectopic kidney is due to aberrant migration during embryonic development. Ectopic kidney occurs in 1 in 5,000 children.

Renal hypodysplasia (RHD):

RHD is due to suboptimal interactions among the ureteric bud, mesenchyme and stroma during metanephric kidney development on weeks 5-36 of gestation in humans. RHD is associated with mutations in renal developmental genes such as HNF1 beta, Eya1, Six1, Six2, BMP4, Sall1, and Pax2. Renal hypoplasia is found in 0.2% of neonates, among which most cases are unilateral, and is highly associated with VUR. Most of the affected individuals in this study were boys. Renal hypoplasia is associated with Ret gene polymorphism.

Multicystic dysplastic kidney (MCDK):

Although most cases of MCDK are considered to be sporadic, select cases may be associated with mutations in HNF1 beta gene. MCDK occurs in 0.3 to 1 in 1,000 live births. Unilateral MCDK is reported in 0.014% of fetuses in Europe.

Medullary sponge kidney (MSK):

The cause and prevalence of MSK are unknown. However, MSK is diagnosed in 12%-20% of patients evaluated for nephrolithiasis.

Medullary cystic kidney disease (MCKD):

The cause of MCDK1 is unknown. Most cases of MCDK2 characterized by an autosomal-dominant inheritance are due to mutations in UMOD gene which encodes protein uromodulin. MCKD is a rare disease and exact prevalence is unknown.

ADPKD:

ADPKD is due to mutations in either PKD1 gene encoding polycystin-1 (85% of affected individuals) or PKD2 encoding polycystin 2 (15 % of affected individuals). ADPKD occurs in 1 in 500 live births.

ARPKD:

ARPKD is due to mutations in PKHD1 gene that encodes fibrocystin/polydactin. ARPKD is observed in 1 in 10,000 to 40,000 live births.

Nephronophthisis (NPHP):

Mutations in eighteen different recessive genes (NPHP1 to NPHP18) have been identified as causing NPHP. Proteins encoded for by NPHP1-NPHP18 are involved in the function of primary cilia/basal body complex, a sensory complex that transfers information from the extracellular environment to the cell interior.

Posterior urethral valves:

PUV occur as a result of aberrant cloacal/urogenital sinus development. The exact molecular mechanisms that account for PUV remain to be determined. PUV are observed in 0.003% of fetal US.

Ureterocele:

Although the exact molecular mechanisms accounting for ureterocele remain to be determined, ureterocele is most likely due do aberrant fusion of the ureter with the cloaca and its derivatives (urogenital sinus and bladder). Ureterocele occurs in 1 in 500 children.

VUR:

Despite presence of VUR in ROBO2/SLIT2- mutant mice, these gene mutations are very rarely associated with familial non-syndromic primary VUR in children. The prevalence of postnatal VUR in infants with hydronephrosis revealed by prenatal US is 21% . Twenty-seven per cent of siblings of a patient with VUR and 35% of children of a parent with VUR have VUR.

Despite strong genetic predisposition for primary VUR in children, VUR appears to be a genetically heterogeneous disorder and further studies are needed to identify specific genetic mutations causing primary VUR.

Megaureter:

Megaureter may result from a segmental developmental delay of smooth muscle formation in the terminal ureter at about 20 weeks of gestation. Megaureter occurs in 3.5 in 1,000 live births.

Ectopic ureter:

Ectopic ureter is due to abnormally displaced spatial outgrowth of theureteric bud (UB) from the nephric duct on weeks 5-6 of gestation in humans. The exact prevalence of ectopic ureter in children is unknown.

Prune belly syndrome:

The cause of prune belly syndrome is unknown. The incidence of prune belly syndrome is 3.8 cases/100,000 live births.

How do these pathogens/genes/exposures cause the disease?

Genetics of CAKUT

All forms of CAKUT stem from faulty renal system development and are caused by disruption in genes that direct normal kidney organogenesis.

Animal models have provided evidence that interruption of specific molecular pathways at certain stages of renal system development can lead to specific types of CAKUT (Table I, Table II, Table III). For example, lack of interaction of the UB with the mesenchyme will result in renal agenesis. Aberrant interactions between the UB and mesenchyme will cause renal hypodysplasia. Disruptions in tubular and collecting duct patterning may lead to PKD.

In utero environment and CAKUT

Emerging evidence demonstrates an important role for the intrauterine environment and fetal programming in the pathogenesis of CAKUT and predisposition for later kidney disease.

Factors that influence intrauterine environment and are associated with CAKUT include uteroplacental insufficiency, vitamin A deficiency, low protein diet, hyperglycemia, cocaine, alcohol, dexamethasone.

The underlying genetic and molecular mechanisms that cause CAKUT in response to suboptimal in utero environment are largely unknown. A better understanding of pathogenesis of CAKUT that occur under these conditions will advance diagnosis, prevention and treatment of CAKUT and prevent associated cardiovascular morbidity.

How can congenital anomalies/polycystic kidney disease be prevented?

Behavioral factors:

Families should be consulted on potential association of maternal smoking or alcohol use with CAKUT in offspring.

Genetic counseling:

Identification of genetic mutations helps affected individuals and their families to understand why a given form of CAKUT has occurred and what is the risk for their offspring to develop this or other form of CAKUT. Such information is often gratefully received. Genetic testing is, however, a complex process which requires considerations of appropriateness, limitations and implications of the test for the patients and their families.

Before a genetic test is used, its analytic ability (i.e., the accuracy of a test in identifying a particular disease) and clinical utility (i.e., the impact of a genetic test on patient outcome) should be assessed. Genetic counseling should be undertaken first in collaboration with a pediatric nephrologist, clinical geneticist and obstetrician.

Nutrition:

Families should be informed regarding potential association of maternal low protein diet and vitamin A deficiency during pregnancy with CAKUT in their offspring.

Medications:

Families should be informed that a number of medications, when taken during pregnancy, may cause CAKUT. These medications include, but may not be limited to: aminoglycosides, cyclosporin A, prostaglandin synthetase inhibitors, ACE inhibitors and angiotensin II receptor blockers, dexamethasone, furosemide, antiepileptic drugs, adriamycin, cyclophosphamide and mycophenolate mofetil.

What is the evidence?

Song, R, Yosypiv. "Genetics of Congenital Anomalies of the Kidney and Urinary Tract". Pediatric Nephrology. vol. 26. 2011. pp. 353-64.

Renkema, KY, Winyard, PJ, Skovorodkin, IN, Levtchenko, E, Hindryckx, A, Jeanpierre, C. "Novel perspectives for investigating congenital anomalies of the kidney and urinary tract (CAKUT)". Nephrol Dial Transplant. vol. 26. 2011. pp. 3843-51.

Sanghvi, KP, Merchant, RH, Gondhalekar, A, Lulla, CP, Mehta, AA, Mehta, KP. "Antenatal diagnosis of congenital renal malformations using ultrasound". J Trop Pediatr. vol. 44. 1998. pp. 235-40.

Costantini, F, Kopan, R. "Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development". Dev Cell. vol. 18. 2010. pp. 698-712.

Kerecuk, L, Schreuder, MF, Woolf, AS. "Renal tract malformations: perspectives for nephrologists". Nat Clin Pract Nephrol. vol. 4. 2008. pp. 312-25.

Bisceglia, M, Galliani, CA, Senger, C, Stallone, C, Sessa, A. "Renal cystic diseases: a review". Adv Anat Pathol. vol. 13. 2006. pp. 26-56.

Torres, VE, Harris, PC. "Autosomal dominant polycystic kidney disease: the last 3 years". Kidney Int. vol. 76. 2009. pp. 149-68.

Guay-Woodford, LM, Desmond, RA. "Autosomal recessive polycystic kidney disease: the clinical experience in North America". Pediatrics. vol. 111. 2003. pp. 1072-80.

Freedman, AL, Johnson, MP, Gonzalez, R. "Fetal therapy for obstructive uropathy: past, present...future?". Pediatr Nephrol. vol. 14. 2000. pp. 167-76.

"Medical versus surgical treatment of primary vesicoureteral reflux: report of the International Reflux Study Committee". Pediatrics. vol. 67. 1981. pp. 392-400.

Wiesel, A, Queisser-Luft, A, Clementi, M, Bianca, S, Stoll, C. "Prenatal detection of congenital renal malformations by fetal ultrasonographic examination: an analysis of 709,030 births in 12 European countries". Eur J Med Genet. vol. 48. 2005. pp. 131-44.

de Bruyn, R, Marks, SD. "Postnatal investigation of fetal renal disease". Semin Fetal Neonatal Med. vol. 13. 2008. pp. 133-41.

Abdelazim, IA, Abdelrazak, KM, Ramy, AR, Mounib, AM. "Complementary roles of prenatal sonography and magnetic resonance imaging in diagnosis of fetal renal anomalies". Aust N Z J Obstet Gynaecol. vol. 50. 2010. pp. 237-41.

Kitchens, DM, Herndon, CD. "Prenatal intervention for lower urinary tract obstruction". Scientific World Journal. vol. 9. 2009. pp. 390-2.

Sanna-Cherchi, S, Ravani, P, Corbani, V, Parodi, S, Haupt, R, Piaggio, G. "Renal outcome in patients with congenital anomalies of the kidney and urinary tract". Kidney Int. vol. 76. 2009. pp. 528-33.

Routh, JC, McGee, SM, Ashley, RA, Reinberg, Y, Vandersteen, DR. "Predicting renal outcomes in children with anterior urethral valves: a systematic review". J Urol. vol. 184. 2010. pp. 1615-19.

Sidhu, G, Beyene, J, Rosenblum, ND. "Outcome of isolated antenatal hydronephrosis: a systematic review and meta-analysis". Pediatr Nephrol. vol. 21. 2006. pp. 218-24.

Weber, S, Moriniere, V, Knüppel, T, Charbit, M, Dusek, J, Ghiggeri, GM. "Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study". J Am Soc Nephrol. vol. 17. 2006. pp. 2864-70.

James, CA, Watson, AR, Twining, P, Rance, CH. "Antenatally detected urinary tract abnormalities: changing incidence and management". Eur J Pediatr. vol. 157. 1998. pp. 508-11.

Ongoing controversies regarding etiology, diagnosis, treatment

Etiology

Most cases of known syndromic forms of CAKUT, renal tubular dysgenesis or certain types of polycystic kidney diseases are causally linked to mutations in specific genes ( Table I, Table II, Table III). The cause of most cases of isolated non-syndromic CAKUT is unknown. These types of CAKUT are assumed to be sporadic (multifactorial) and occur as a result of combination of epigenetic and environmental factors affecting genetically susceptible individuals.

Diagnosis

CAKUT represent a clinically challenging array of diseases because of their diversity, difficulties of making precise histological diagnoses while the patient is alive and pre- or postnatal onset. Milder cases of CAKUT can be clinically benign (e.g., ectopic kidney, mild unilateral hydronephrosis or primary VUR). Other cases of CAKUT can be devastating, resulting in acute renal failure, death due to pulmonary failure or extrarenal anomalies (e.g., renal tubular dysgenesis, bilateral renal agenesis, posterior urethral valves).

Prevention

Select forms of CAKUT which are due to mutation in known genes (e.g., ADPKD, ARPKD) can be predicted based on genetic counseling and diagnosed in utero by amniocentesis or before conception by preimplantation genetic testing. The main factor that leads to decision to terminate pregnancy is poor renal function and/or severe renal tract outflow obstruction which manifest by the presence of oligohydramnios. The presence of multiorgan anomalies or gross chromosomal aberrations might also drive the decision to terminate pregnancy in fetuses with CAKUT.

Treatment

Whether prenatal decompression of obstructed urinary tracts is beneficial is unclear. There is no evidence of improvement in renal outcomes with surgical decompression of fetal bladders by use of vesico-amniotic shunts. Prospective trials are in progress to determine whether such prenatal surgery is beneficial.

Given that progression of CKD in children with diverse forms of CAKUT correlates with proteinuria, several studies investigated the effect of low protein diet and renin-angiotensin system blockers on the course of CKD due to CAKUT. Low protein diet did not alter the progression of CKD in children with renal hypodysplasia compared to control group.

Several studies demonstrated that blockade of the renin-angiotensin system with ACE inhibitor lowers blood pressure and attenuates proteinuria in children with CAKUT. In contrast, other studies reported that ACE inhibitors have no significant beneficial effect on the progression of CKD in children with renal hypodysplasia. Randomized prospective studies are needed to investigate the efficacy of ACE inhibitors on the progression of CKD in children with CAKUT.

Given the broad spectrum of CAKUT in children and variable clinical impact of different forms of renal system anomalies ranging from mild clinically asymptomatic cases to severe kidney injury manifesting before or after birth, each patient with CAKUT requires individualized clinical management.

Because morbidity in mild cases of CAKUT may not manifest until later in life, these patients should be closely followed throughout life. Medical monitoring should include diet, nutritional status, growth, blood pressure, renal function, proteinuria and urinary tract imaging.

New biomarkers are needed to better assess disease progression and therapeutic strategies to slow progression of renal injury. Genetic counseling is recommended for all patients with familial cases of CAKUT or newly diagnosed forms of CAKUT that suggest presence of genetic anomalies. Introduction of more sensitive array-based methods that allow to screen for multiple gene mutations and unravel a complex network of molecular interactions will help to determine and predict occurrence and consequences of CAKUT.

Finally, establishment of shared large biorepositories of patients with CAKUT for molecular, genetic and translational studies will have a major impact on designing novel strategies to predict, prevent and manage CAKUT.

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