Congenital Anomalies of the Kidney and Urinary Tract: A Clinical Review

Abstract

Purpose of review:

This review highlights the most common congenital anomalies of the kidney and urinary tract (CAKUT) that are encountered in pediatric practices. CAKUT are the most common cause of prenatally diagnosed developmental malformations and encompass a spectrum of disorders impacting lower urinary tract development as well as kidney development and function. In pediatric and adolescent populations, developmental abnormalities are the leading cause of end-stage kidney disease. The goal of this review is to provide pediatric providers a framework for appropriate clinical management as well as highlight when referral to subspecialty care is needed.

Recent findings:

While the exact etiologies of CAKUT are not completely defined, new evidence demonstrates that genetic and molecular changes impact embryonic kidney and urinary tract development. As a result, phenotypes and clinical outcomes may be affected.

Summary:

Because pediatric providers provide front-line care to children and adolescents with developmental kidney and urinary tract anomalies, updated knowledge of CAKUT pathogenesis, embryology, clinical management, and patient outcomes is needed. This manuscript reviews CAKUT etiologies and essential diagnostic, prognostic, and management strategies.

Introduction:

Congenital anomalies of the kidney and urinary tract (CAKUT) represent a broad range of disorders that result from developmental abnormalities of the lower urinary tract, urinary collecting system, disrupted embryonic migration of the kidney(s), or abnormal renal parenchymal development. Lower urinary abnormalities are identified in about 50% of affected patients and include vesicoureteral reflux (25%), ureteropelvic junction obstruction (11%), and ureterovesical junction obstruction (11%) [1, 2]. Kidney malformations are commonly identified in the antenatal period and account for 20-30% of all detectable anomalies [3, 2, 4]. Severity can range from mild antenatal pelviectasis to bilateral renal agenesis (Table 1). These disorders impact approximately 2% of all pregnancies and are often associated with additional developmental abnormalities or genetic syndromes (Table 2) [5]. Data from large registries show that CAKUT is a major cause of morbidity in pediatric and adolescent patient populations, accounting for 30-50% of end-stage kidney disease [2, 4]. The diagnosis and management of neonates, infants, and children with CAKUT occurs in diverse clinical arenas – including prenatal obstetrics, pediatric primary care offices, pediatric nephrology, and pediatric urology clinics. If undetected in childhood, CAKUT can present with renal problems in adulthood. These include hypertension, proteinuria, and renal impairment, which often require referral to adult nephrology [6, 7].

Table 1.

Phenotypic Spectrum of CAKUT

Renal agenesis

Renal dysplasia

Renal hypoplasia

Duplex kidney

Horseshoe kidney

Ureteropelvic junction obstruction

Duplication of the ureter

Vesicoureteral reflux

Ectopic Ureter

Table 2.

Human Genetic Syndromes with Defects in Renal Morphogenesis

Primary Disease	Kidney Phenotype	Gene	Reference
Alagille Syndrome	Cystic dysplasia	JAGGED1	[76]
Beckwidth-Wiedemann Syndrome	Medullary dysplasia	p57KIP2	[77]
Brachio-oto-renal (BOR) Syndrome	Unilateral or bilateral agenesis/dysplasia, hypoplasia, collecting duct anomalies	EYA1, SIX1	[78]
Frasier Syndrome	Agenesis, dysplasia	FRAS1	[79]
Hypothyroidism, Sensorineural Deafness, and Renal Anomalies (HDR) Syndrome	Dysplasia	GATA3	[80]
Kallman Syndrome	Agenesis	KAL1, FGFR1, PROK2, PROK2R	[81]
Renal-coloboma Syndrome	Hypoplasia, VUR	PAX2	[82]
Renal Cysts and Diabetes Syndrome	Medullary dysplasia	HNF1-ß	[83]
Smith-Lemli-Opitz Syndrome	Agenesis, dysplasia	DHCR7	[84]
Zellweger Syndrome	VUR, cystic dysplasia	PEX1	[85]

Table 2 adapted from: [86]

The pathogenesis of CAKUT is not well defined. While many CAKUT cases are sporadic, familial clustering is common, suggesting that CAKUT phenotypes are influenced by genetic factors [8]. Data indicate that approximately 20% of patients may have a genetic disorder that is usually not detected with standard clinical evaluations, implicating many different mutational mechanisms and pathologic molecular pathways [5]. A common genetic background with variable penetrance seems to play a role in the development of a spectrum of CAKUT disorders. However, autosomal dominant and autosomal recessive single-gene defects, polygenic inheritance, and large cytogenetic defects (i.e. copy number variations) have been associated with CAKUT [9–11]. Examples of single gene mutations or gene polymorphisms responsible for kidney and urinary tract morphogenesis are outlined below (Table 2). The emergence of high-throughput genomic approaches is expected to provide insight into the common and rare genetic determinants of diseases and provide opportunities for early diagnosis with genetic testing. The following manuscripts provide outstanding reviews [12, 13, 5, 11].

Embryonic Kidney Development:

In humans and other mammals, the kidneys develop through a multistep process, progressing from an anterior to posterior tract. The process begins with the formation of the nephric duct (embryonic day 22 in humans) in the intermediate mesoderm. The nephric duct extends caudally and induces kidney development in the adjacent mesoderm (Figure 1A). There are three stages or segments of embryonic kidneys that develop from the intermediate mesoderm: (A) the pronephros, (B) the mesonephros, and finally (C) the metanephros [14]. The metanephros, which becomes the mature kidney and is detectable around the fifth to sixth week of gestation, develops as the ureteric bud penetrates metanephric mesoderm and undergoes a series of divisions forming the collecting duct, major and minor calyces, renal pelvis and ureter (Figure 1B) [15, 14]. Primitive renal tubules also form from the metanephric mesoderm and as they mature, they become the glomerulus and Bowman’s capsule, the proximal convoluted tubule, loop of Henle, distal convoluted tubule, and collecting tubule [16]. Initially positioned in the pelvis or sacral region, the fetal kidney ascends to its adult position in the thoracolumbar (T12-L3) region in the retroperitoneal fossa. Once in the retroperitoneal fossa, the kidney rotates medially 90 degrees, to its final position by the 8th week of gestation [14].

Figure 1. Embryonic kidney and urinary tract development.

(A) Renal embryogenesis showing development and degeneration of the pronephros (left) and mesonephros (center), with induction of the ureteric bud and metanephric mesenchyme (right). (B) The initiating step in kidney development is the outpouching of the ureteric bud from the Wolffian duct. The stalk of the ureteric bud becomes the ureter (top). The ureteric bud undergoes repetitive branching to form the collecting tubules, major calices, and minor calices (middle). The end of each arched collecting tubule induces clusters of mesenchymal cells in the metanephrogenic blastema to undergo a mesenchymal-to-epithelial transformation that eventually develops into the mature nephron (bottom).

In the prenatal period, the kidney functions to maintain amniotic fluid. After 16 weeks of gestation, fetal urine becomes the primary source of amniotic fluid. Thus, amniotic fluid volume can also be an indicator of abnormal renal development. It is not until the postnatal period that the kidney begins to regulate fluid, electrolyte, and acid-base homeostasis as well as waste excretion [17]. The following sections highlight how aberrant kidney development leads to structural kidney and urinary tract disorders that are routinely encountered in clinical practice. In doing so, the following sections review diagnostic, prognostic, and management approaches to these conditions.

Renal agenesis

Renal agenesis refers to the complete loss of one or both kidneys without identifiable rudimentary tissue. Renal agenesis occurs with failure of metanephros formation and usually is associated with agenesis of the ipsilateral ureter [16, 14]. Causal heterogeneity has been shown, by both animal studies and clinical patient observations. Like many developmental kidney anomalies, renal agenesis is more prevalent in males than females [18]. Unilateral renal agenesis is usually asymptomatic and incidentally detected, whereas bilateral renal agenesis results in severe oligohydramnios and fetal or perinatal loss. Renal agenesis can be associated with anomalies of other organ systems, occurring in both contiguous (i.e. vertebrae, genital organs, intestines, anus) and in non-contiguous structures (i.e. limbs, heart, trachea, ear, central nervous system) [14, 6].

Fetal kidneys can be visualized with ultrasound as early as 10-12 weeks of gestation. Thus, renal agenesis is often diagnosed prenatally. Computed tomography and radionucleotide studies can be helpful in equivocal cases. With unilateral renal agenesis, the solitary kidney may show compensatory hypertrophy – measuring >95th percentile for gestational age [19, 20]. It is important to ensure that the non-visualized kidney is not in an ectopic location or dysplastic in appearance. Therefore, pelvic ultrasound is often warranted. Confirmatory testing includes magnetic resonance imaging.

When performing an initial evaluation on a patient with solitary kidney, a thorough history and physical examination should be obtained to evaluate for extra-renal congenital anomalies – including anosmia, hearing deficits, ear pits, coloboma, cleft lip or palate, single umbilical artery, syndactyly, microphallus, or cryptorchidism [6]. Multiple syndromes are associated with renal agenesis (Table 3). Prenatally, chromosomal microarray analysis has not been shown to be more beneficial than it would be for the general population [21]. Starting at birth, growth charts in these patients should be closely monitored for abnormal or poor growth, which can serve as a proxy for renal insufficiency.

Table 3.

Syndromes associated with unilateral or bilateral renal agenesis

Caudal Regression Syndrome

Cerebro-oculo-facial-skeletal Syndrome

CHARGE Association

DiGeorge Syndrome (22q11.2 deletion)

Fraser Syndrome

Mayer-Rokitasnsky-Kuster-Hauser Syndrome

Melnick-Fraser Syndrome

Potter Sequence (oligohydramnios)

Trisomy 13 and 18

Turner Syndrome

VACTERL

Velocardiofacial Syndrome

Table 3 adapted from: [87]

Long-term sequela includes chronic kidney disease that may develop after longstanding compensatory glomerular hyperfiltration. Therefore, blood pressure and urinalysis should be monitored to evaluate for elevated blood pressure and proteinuria. If either is detected, this may be an indication of injury to the solitary kidney and obtaining a serum creatinine is warranted in order to calculate the glomerular filtration rate (GFR) [22]. Overweight and obese patients have been found to have greater risk of progression of renal disease [23, 24]. According to 2012 American Academy of Pediatrics (AAP) guidelines, a solitary kidney is not an absolute indication to abstain from contact sports [25].

Ectopic Kidney

Ectopic kidneys, which are often pelvic in location, result from errors of ascent. Rare case reports exist of thoracic kidneys [26]. Ectopic kidneys can be unilateral or bilateral. Bilateral pelvic kidneys often fuse into a midline mass of renal tissue, with two distinct renal pelvises and a variable number of ureters – which is referred to as a pancake kidney. Cross fused ectopia refers to an ectopic kidney whose ureter crosses the midline. Ectopic kidneys are often hypoplastic and smaller in size. Consequently, the contralateral kidney may have compensatory hyperfiltration and hypertrophy [27, 14].

Ectopic and pelvic kidneys are often asymptomatic. Historically, there has been a higher incidence noted in autopsies than those found clinically. However, as ultrasound techniques improve, it is unclear how this paradigm has shifted. If an ectopic kidney is noted on prenatal ultrasonography, post-natal renal ultrasound is recommended to confirm the location of the pelvic kidney. Though some studies have shown no effects on blood pressure and renal function, annual serum creatinine measurements, urinalysis, and blood pressure monitoring are warranted for surveillance and preventive purposes [28]. Similar to renal agenesis, long-term sequela includes chronic kidney disease that develops after longstanding compensatory glomerular hyperfiltration. If changes in blood pressure and/or renal function are detected, this may be an indication of renal insufficiency [22].

Horseshoe kidney

Horseshoe kidney refers to a condition in which the kidneys are fused at the lower poles with a renal parenchymal or fibrous isthmus. The embryogenesis of horseshoe kidney with parenchymal isthmus is believed to be abnormal migration of nephrogenic cells. Most horseshoe kidneys are located in the pelvis at the lower vertebral levels. During kidney ascent, the connecting isthmus of the fused kidneys gets trapped behind the inferior mesenteric artery. Early fusion of the two kidneys may result in malrotation and a higher insertion point of the ureters leading to obstructive uropathy from a ureteropelvic junction obstruction [14, 16].

Horseshoe kidneys effect approximately 1 in every 500 live births and is more common in males. Horseshoe kidneys are typically asymptomatic and found incidentally on prenatal ultrasound; however, patients can have associated ureteropelvic junction obstruction leading to hydronephrosis, urinary tract infections (UTI), and/or nephrolithiasis. Horseshoe kidneys can be associated with other genitourinary anomalies as well as renal tumors – most commonly Wilm’s tumor [29, 30]. There is little evidence regarding preventive sonographic screening, but surgical resection is often difficult due to abnormal vasculature and location of the kidney [31].

Polycystic Kidney Disease

Cystic kidney diseases are a clinically and genetically heterogeneous group of disorders that may present in utero or be clinically silent into adulthood. Cystic kidney disease genes and their translated proteins have been identified, providing investigators with essential targets to investigate disease pathogenesis and sequelae [32, 33]. Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease, which results from mutations in the PKD1 (major) or PKD2 genes (minor). After diabetes mellitus and hypertension, ADPKD is the most common cause of end stage kidney disease [4]. By the age of 70, 50% of patients with ADPKD will require dialysis or kidney transplantation [34].

The diagnosis of ADPKD relies principally upon imaging of the kidney. Typical findings include large kidney with extensive cysts scattered bilateral (Figure 2). The presence of one cyst is adequate for the diagnosis in a child (0-5 years) with a known family history of ADPKD [35]. Because of cost and safety, ultrasonography is most commonly used as the imaging modality. In certain settings, genetic testing is required for a definitive diagnosis. Kidney size typically increases to more than five time normal in years prior to loss of kidney function. Measured kidney volume is the strongest predictor for the development of renal insufficiency [36]. Other renal manifestations that can occur include hypertension, UTI, urine concentrating defects, kidney stones, hematuria, proteinuria, and abdominal or flank pain. All of these complications relate directly to the extent of renal cyst involvement [37].

Figure 2. Ultrasonography of developmental kidney anomalies.

(A) A large left dilated renal pelvis (stars) and thin renal cortical tissue consistent with uretopelvic junction obstruction. (B) A multicystic dysplastic left kidney with multiple parenchymal non-communicating kidney cysts of varying size (*) and hyperechoic, dysplastic kidney tissue. (C) Autosomal dominant polycystic kidney disease with an enlarged kidney showing multiple large cortical cysts (*). (A-C) The white dashed line outlines the kidney parenchyma.

Histologically, renal cysts arise from renal tubular segments. These cysts progressively enlarge in all segments of the nephron and cause renal insufficiency [38]. Because ADPKD is a systemic disorder, patients can develop profound extrarenal cystic and non-cystic complications. Among the most important extrarenal manifestations seen in adults are cysts in other epithelial organs (i.e. liver and pancreas) and cardiovascular abnormalities such as mitral valve prolapse and cerebral berry aneurysms. In pediatric populations, these are rarely observed [38].

ADPKD treatment, which is typically overseen by a nephrologist, consists of medical management of chronic renal insufficiency, hypertension, UTI, and pain. Dialysis and kidney transplantation may eventually be needed, even in adolescent populations. Invasive procedures to manage pain consist of percutaneous cyst aspiration and sclerosis, open or laparoscopic cyst decompression, and laparoscopic denervation. Nephrectomy may be needed in patients with end stage kidney disease and uncontrolled pain, recurrent UTI, or extensively enlarged kidneys that interfere with future transplantation [37, 39].

Multicystic Dysplastic Kidney

Multicystic dysplastic kidney (MCDK) is a subset of renal dysplasia, where there is general structural disorganization of the renal parenchyma with many non-communicating cysts throughout the dysplastic kidney tissue (Figure 2). MCDK is one of the most common congenital urinary tract abnormalities with an incidence of up to 1 in 3,640 births [40]. It is typically sporadic, although familial cases have been reported. There is no laterality preference, and MCDK is slightly more prevalent in males. MCDK can be found in isolation, with other genitourinary abnormalities, or as part of a genetic syndrome [41].

Multiple theories exist regarding the development of a MCDK. The ureteric bud theory hypothesizes that MCDK is due to an abnormal connection of the ureteric bud with the mesenephric mesenchyme [42]. This theory has also been proposed for the pathogenesis of other renal disorders, including vesicoureteral reflux (VUR) and renal agenesis. Supporting this hypothesis, mutations in genes known to play a role in ureteric bud development including EYA1, SIX1, and PAX2 have been linked to MCDK, as well as other forms of renal dysplasia [43].

MCDK is often diagnosed by ultrasonography — two-thirds of cases are suspected prenatally [41]. While children and adolescents with unilateral MCDK do well, patients with bilateral MCDK frequently have oligohydramnios with resulting fetal demise, or end stage renal disease in childhood [40]. If MCDK is suspected on prenatal ultrasound, the prenatal diagnosis should be confirmed with a postnatal ultrasound. In addition to confirming the diagnosis, this initial postnatal ultrasound can screen for VUR, contralateral kidney abnormalities, and genital abnormalities [44–46]. On the contralateral side, low-grade VUR has been reported in up to 43% of patients with a MCDK. Ureteropelvic junction obstruction (UPJO), ureterovesical junction obstruction (UVJO), and ipsilateral structural abnormalities of the internal genitalia have also been reported [44–46]. A voiding cystourethrogram (VCUG) is not routinely recommended with diagnosis of a MCDK. Indications to perform a VCUG include an abnormal contralateral kidney, lower urinary tract abnormality, or development of a UTI due to risk of pyelonephritis and subsequent scarring in the solitary functioning kidney. Diuretic renograms can be used to evaluate the contralateral kidney for potential UPJO or UVJO when the renal pelvis is dilated ≥ 5mm with a negative VCUG, or > 10 mm with a VCUG showing the presence of VUR [47].

Generally, MCDKs tend to involute over time, with compensatory hypertrophy of the contralateral kidney (+2 standard deviations of the mean). The absence of compensatory hypertrophy should be investigated for pathologic conditions such as hypodysplasia. Complete MCDK involution has been reported in up to 74% of patients at two years of age [48]. Thus, serial ultrasounds should be performed to evaluate MCDK involution and growth of the contralateral kidney. The frequency of follow-up ultrasounds is debatable, but 4 weeks, 2 years, 5 years, and 10 years has been proposed [49].

Patients with “simple” MCDK (without other urinary tract abnormalities) generally have normal or near-normal renal function. Conversely, 50% of patients with “complex” MCDK (bilateral MCDK, unilateral with contralateral anomalies) show evidence of renal impairment [40]. Thus, serum creatinine should be obtained at diagnosis, 2 years of age, and 5 years of age, to monitor for progression of chronic kidney disease [48]. While blood pressure should be monitored with all clinic visits in older children with MCDK (> 3 years of age), there is little evidence to support they have an increased risk of hypertension. Routine abdominal exams should also be done at well child checks to monitor for abdominal masses that could be due to hydronephrosis or tumor [50].

In the past, nephrectomy of the MCDK was often performed due to the presumed risk of Wilms tumor or other malignant transformation. However, data now suggest that the rate of Wilms tumor is very low and routine nephrectomy is no longer indicated [51]. Nephrectomy may be considered in MCDK patients that have refractory hypertension. However, nephrectomy may only resolve hypertension 25-50% of the time [50].

Vesicoureteral Reflux

VUR is the retrograde flow of urine from the bladder to the kidneys. VUR has been implicated in renal injury before birth as well as in the postnatal development of UTI, pyelonephritis, and further renal damage. The overall incidence of VUR is unknown, as a VCUG is not routinely performed in healthy children. However, VUR has been detected in 8-50% of children, and 36-49% of infants and newborns who underwent a VCUG after presenting with a UTI [52]. The majority of patients with VUR are diagnosed after developing a febrile UTI. Additionally, VUR is often diagnosed when a prenatal ultrasound shows hydronephrosis or hydroureter, in children with unilateral MCDK, or children having significant bladder dysfunction [53–56].

There are multiple potential etiologies leading to the development of VUR, including anatomic anomalies, disrupted cellular signaling, and genetic defects [57, 43, 58]. One hypothesis suggests that during embryologic development the ureteric bud arrives at the urogenital sinus relatively early, causing a lateral and proximal displacement of the ureteral meatus. This results in a shorter intravesical submucosal length of the ureter – predisposing the patient to reflux [52].

The gold standard for the diagnosis of VUR is the VCUG. VCUG is an invasive test and requires urethral catheterization and either fluoroscopy or administration of a radionuclide. This is also the modality that is used to identify the grade of reflux. Grading has been standardized by the International Reflux Study and is categorized as grade I to grade V, with grade V being the most severe. [59] While ultrasound is not sensitive for the detection of VUR, it is the first imaging modality used to look for other renal or urologic abnormalities, including ureteral or renal pelvis dilation seen in high grades of VUR [60]. The American Academy of Pediatrics recommends routine ultrasound screening for children less than 24 months with a febrile UTI [61]. Technetium 99 m Dimercaptosuccinic Acid Renal Scan (DMSA Renal Scan) can be used to look for the presence of renal scars, which may occur due to reflux nephropathy or pyelonephritis [62].

Many children, especially those with low-grade VUR, will outgrow it – likely due to the lengthening of the submucosal ureteral segment as the child grows [63]. The potential for the spontaneous VUR resolution is the basis for conservative non-operative management. Factors that increase the chance of VUR resolution include non-white race, low-grade VUR, absence of voiding dysfunction, and absence renal scarring [64]. Ureteral dilation, increased age at presentation, and bilateral VUR decrease the probability of VUR resolution [65].

Clinical follow-up of VUR is warranted because VUR is believed to be the primary risk factor for pyelonephritis and subsequent renal scarring. Various factors influence the probability of scarring in children with VUR and UTI. These include severity of reflux, age in which VUR patient develops a UTI, delay in treatment, bacterial virulence, genetics, and immune dysfunction [66–69]. After acute pyelonephritis, renal scarring takes about 1-2 years to develop [70, 71]. The pathogenesis of renal scarring after acute pyelonephritis is not well defined. The process is an inflammatory response that is initiated by the presence of bacteria and triggers renal parenchymal damage [72, 66]. Renal parenchymal damage can cause proteinuria, hypertension, and chronic kidney disease.

Management of VUR is divided into medical and surgical treatment. Medical management is based on the observation that low-grade VUR will resolve spontaneously. Medical management may involve treatment of bowel and bladder dysfunction, correcting metabolic disorders stemming from renal insufficiency, blood pressure control, reduction of proteinuria, and serial radiological follow-up. Select patient populations may benefit from daily antibiotic UTI prophylaxis. Surgical management may be considered with co-existing upper or lower urinary tract anomalies or recurrent UTI. The detailed role of medical and surgical VUR management is beyond the scope of this review and have been highlighted elsewhere [68, 73, 74].

Conclusions:

CAKUT are a collection of different disease entities impacting the kidney and/or urinary tract. Despite significant variation in phenotype and clinical implications, CAKUT shares a common genetic basis and molecular signaling that affect kidney development [75]. Since many of these congenital anomalies are hereditary, advances in prenatal diagnostics, imaging, genetic testing, laboratory surveillance, and medical management have improved the prognosis and quality of life in affected families.