Chapter 469. Renal Malformations

Renal malformations account for 30% to 50% of end-stage renal disease in children. Approximately one half of such cases are associated with lower urinary tract abnormalities. A spectrum of phenotypes exists and has been termed CAKUT (congenital abnormalities of the kidney and urinary tract). This chapter focuses on the epidemiology of these abnormalities and their etiologies, clinical manifestations, and aspects of clinical management.

Kidney malformation is classified at the clinical level by gross and microscopic anatomical features. One commonly used classification system is as follows:

• Renal agenesis—congenital absence of the kidney and ureter 
• Simple renal hypoplasia—small kidney with a reduced number of nephrons and normal renal architecture
• Renal dysplasia—presence of malformed kidney tissue elements
• Renal dysplasia/hypoplasia (hypodysplasia)—small, dysplastic kidney

Characteristic microscopic features of the dysplastic kidney (Fig. 469-1) include abnormal differentiation of mesenchymal and epithelial elements; a decreased number of nephrons; loss of corticomedullary differentiation; and the presence of dysplastic elements, including cartilage and bone. Dysplastic kidneys range in size from large distended kidneys with multiple large cysts to small kidneys, with or without cysts. A small dysplastic kidney without macroscopic cysts is often classified clinically as a hypoplastic/dysplastic kidney, since pathological examination, which provides a means to distinguish between simple hypoplasia and dysplasia, is not commonly performed during life. The multicystic dysplastic kidney (MCDK) is an extreme form of renal dysplasia.

The majority of renal malformations are detected during the antenatal period by fetal ultrasound and account for 20% to 30% of all anomalies detected. The incidence of renal and urinary tract malformations is 0.3 to 1.6 per 1000 liveborn and stillborn infants.1 Renal agenesis and dysplasia is 1.3- to 1.9-fold more common in males than in females.2 Fifty percent of individuals with a kidney malformation have a lower urinary tract anomaly. Of these, 25% have vesicoureteral reflux, 11% have ureteropelvic junction obstruction, and 11% are affected by ureterovesical junction obstruction.3 Renal malformations, other than mild antenatal pelviectasis, are associated with malformation of nonrenal tissues in about 30% of cases.1 There are over 100 syndromes associated with renal and urinary tract malformations. The most frequent syndromes are cited in Table 469-1. Bilateral renal agenesis occurs in 1 in 3000 to 10,000 births, while unilateral renal agenesis is estimated to have a prevalence of 1 in 1000. The incidence of unilateral dysplasia is 1 in 3000 to 5000 births (1:3640 for the MCDK) compared to 1 in 10,000 for bilateral dysplasia. Nine percent of first-degree relatives of patients with bilateral renal agenesis or bilateral renal dysgenesis have some type of renal malformation.4 The incidence of renal ectopia is 1 in 1000 autopsies, but the clinical recognition is estimated to be only 1 in 10,000 patients. Males and females are equally affected. Renal ectopia is bilateral in 10% of cases; when unilateral, there is a slight predilection for the left side. The incidence of fusion anomalies is estimated to be about 1 in 600 infants.

Over 30 genes have been identified in children with syndromic forms of renal malformation (Table 469-2). For a complete list of syndromes featuring renal malformations, the reader is referred to McKusick’s Online Mendelian Inheritance in Man(OMIM, http://www.ncbi.nlm. nih.gov/). Emerging evidence suggests that sporadic cases are associated with genetic mutations as well. Below, examples of genetic mutations associated with syndromic and nonsyndromic forms are discussed. The reader is also referred to Chapter 464, which covers the functions of these and other genes during renal development.

Branchio-Oto-Renal (Bor) Syndrome

BOR Syndrome, defined by the association of branchial (B), otic (O), and renal (R) anomalies, is an autosomal dominant disorder with incomplete penetrance and variable expressivity5 (OMIM 113650). However, individual patients may have only one or two of these major features in association with other minor features such as external ear anomalies, preauricular tags, or other facial abnormalities (eg, BO syndrome, OMIM 120502). Renal malformations include unilateral or bilateral renal agenesis; hypodysplasia; and malformation of the lower urinary tract, including vesicoureteral reflux, pyeloureteral obstruction, and ureteral duplication. Different renal malformations can be observed in the same family. The genes EYA1 and SIX1 are mutated in BOR syndrome.6,7 More than 50 different mutations in EYA1 have been identified. Variability of the phenotype in individuals with the same mutation limits accurate prediction of the type and severity of the renal malformation based on genetic testing. Heterozygous mutations in EYA1 or SIX1 have been associated with mutations in the GDNF and RET genes in a small number of affected kindreds.7 A SIX1 mutation has been found in association with a PAX2 mutation in two siblings with severe renal hypodysplasia that led to renal insufficiency during childhood and optic nerve coloboma. Interestingly, their father, who harbored only the PAX2 mutation, had a mild renal malformation with late-onset renal insufficiency and no ocular defect.8

Renal-Coloboma Syndrome (Rcs)

Renal coloboma syndrome (RCS), an autosomal dominant disorder, is characterized by renal hypoplasia, vesicoureteric reflux, and optic nerve coloboma. A wide range of renal and ocular malformations is observed in RCS. Renal hypoplasia and vesicoureteric reflux are most frequent, but multicystic dysplasia and pelviureteric junction obstruction have also been described.9 RCS is caused by mutations in PAX2,10 which encodes a transcription factor that belongs to the paired-box family of homeotic genes. Among the more than 30 mutations reported, the vast majority of the mutations are located in exons 2 and 3, which encode the DNA-binding domain. Despite this clustering of mutations, the RCS phenotype is highly variable even in patients harboring the same PAX2 mutation.

Renal Cyst and Diabetes Syndrome (Rcad)

RCAD is defined by the presence of renal hypodysplasia with cysts and diabetes mellitus. Occasional features include genital malformations. Diabetes mellitus, which is present in approximately 60% of all the cases reported, usually occurs before 25 years of age and is often associated with pancreatic atrophy.11 The presence of cysts is the most consistent feature of the renal phenotype, leading to the name renal cysts and diabetes syndrome. The cysts are usually cortical, bilateral, and small.12 Mutations in TCF2 encoding the transcription factor HNF1b are present in affected patients.13 Mutations in TCF2 are being increasingly identified in patients with renal hypoplasia and dysplasia, multicystic dysplastic kidneys, renal agenesis, horseshoe kidneys, pelviureteric junction obstruction, and clubbing and tiny diverticula of the calyces. When histology is available, the most specific finding is the presence of cortical glomerular cysts with dilatation of the Bowman spaces (glomerulocystic dysplasia). Other nonspecific lesions such as cystic renal dysplasia, interstitial fibrosis, or oligomeganephronia have also been reported. Antenatal presentation with enlarged hyperechoic kidneys seems to be a quite common finding.14 More than 50 mutations have been reported in TCF2. Most are located in the first four exons that encode the DNA-binding domain. In more than one third of the cases, the gene is entirely deleted. There is no correlation between the type of mutation and the phenotype. Importantly, deletions frequently arise de novo in the proband. As observed in other syndromes, phenotypic variability can be observed between families and in family members with the same mutation.

Townes-Brock Syndrome (Tbs)

TBS is an autosomal dominant malformation syndrome characterized by imperforate anus; preaxial polydactyly; or triphalangeal thumbs, external ear defects, sensorineural hearing loss, and, less frequently, kidney, urogenital, and heart malformations.15,16 REAR syndrome (renal-ear-anal-radial) has also been a term used to describe this condition.17 The gene mutated in human TBS is SALL1, a member of the Spalt family that is required for the normal development of the limbs, nervous system, kidney, and heart.18

Renal Tubular Dysgenesis (Rtd)

RTD is a severe perinatal disorder characterized by the absence or paucity of differentiated proximal tubules, early severe oligohydramnios, and perinatal death usually due to pulmonary hypoplasia and skull ossification defects.19 It may be acquired during fetal development or inherited as an autosomal recessive disease. Autosomal recessive renal tubular dysgenesis is genetically heterogeneous and linked to mutations in the genes that encode components of the renin-angiotensin system.20 This condition also occurs in fetuses exposed in utero to angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor antagonists.

Genetic Causes of Isolated (Nonsyndromic) Renal Malformation

In the majority of children with renal malformation, neither a syndrome nor a Mendelian pattern of inheritance is obvious. It has recently become apparent that mutations in genes that control renal development can be identified in many such patients. For example, analysis of a cohort of 100 patients with renal hypodysplasia and renal insufficiency demonstrated that 16% had mutations in one gene encoding for a transcription factor. The majority of mutations were identified in TCF2 (especially in the subset with kidney cysts) and PAX2. EYA1 and SALL1 mutations were found in single cases.8 Some of the mutations that were identified in these genes were de novo mutations, which explains the sporadic appearance of renal malformations. Careful analysis of patients with TCF2 and PAX2 mutations revealed the presence of extrarenal symptoms in only half; this supports previous reports that TCF2 and PAX2 mutations can be responsible for isolated renal tract anomalies or at least CAKUT malformations with minimal extrarenal features.12,21 This study demonstrates that subtle extrarenal symptoms in syndromal renal malformations can easily be missed.

Mutations in RET, which encodes a tyrosine kinase cell surface receptor, have been detected in patients with renal malformations. These mutations (Y791F and S649L) have also been detected in individuals with medullary thyroid carcinoma (MTC). None of the patients or their carrier relatives had clinical evidence of MTC at the time of the study. A low penetrance of renal malformation was suggested by minimal or no renal phenotypes in most carrier relatives.

The widespread use and sensitivity of fetal ultrasound has increased the prenatal diagnosis of renal malformations. The sensitivity of prenatal ultrasound screening for renal malformations is about 82%, and the mean time at which these malformations are detected is 23 weeks gestation.1 In general, urinary tract malformations detected antenatally are isolated and present as mild hydronephrosis with no therapeutic consequences. Parents should be reassured. In contrast, bilateral forms of renal agenesis, severe dysgenesis, bilateral ureteric obstruction, or obstruction of the bladder outlet or the urethra can cause severe oligohydramnios as early as 18 weeks. Because amniotic fluid is critical to lung development, oligohydramnios as early as the second trimester can result in lung hypoplasia, a potentially fatal disorder. The oligohydramnios sequence, termed Potter’s syndrome, in its most severe form consists of a typical facial appearance characterized by pseudoepicanthus; recessed chin; posteriorly rotated, flattened ears and flattened nose; decreased fetal movement; clubfoot and clubhand; hip dislocation; joint contractures; and pulmonary hypoplasia. Severe renal malformations are usually the cause of oligohydramnios, which gives rise to the facial and limb deformities and impairs normal lung development. However, nonurinary causes such as amniotic fluid leakage and placental pathology could provoke oligohydramnios with the same consequences.

The renal prognosis can be evaluated antenatally, with poor outcome likely when there is severe oligohydramnios and small, hyperechogenic kidneys. Antenatal diagnosis and assessment of the renal prognosis are important for considering early termination in cases of fatal or eventually severe renal disease and to prepare parents and medical staff for the likelihood of neonatal renal insufficiency. Other organ malformations should be sought carefully, and if detected, a karyotype should be done.

The clinical presentation of renal malformation in the postnatal period depends on the amount of functioning renal mass, the presence of bilateral urinary tract obstruction, and the occurrence of urinary tract infection. Bilateral renal agenesis or severe dysplasia is likely to present soon after birth with decreased renal function. This may be accompanied by oliguria. Alternatively, patients may present with a flank mass or an asymptomatic abnormality detected by renal imaging.

A detailed history and careful physical examination should be carried out on all infants with an antenatally detected renal malformation. An early renal ultrasound (within 24 hours of life) is recommended for newborns with a history of oligohydramnios, progressive antenatal hydronephrosis, distended bladder on antenatal sonograms, and bilateral severe hydroureteronephrosis. In male infants, a distended bladder and bilateral hydroureteronephrosis may be secondary to posterior urethral valves, a condition that requires immediate renal imaging and clinical intervention. In general, unilateral anomalies do not require urgent investigation after birth. Rather, renal ultrasound is recommended after the first 72 hours of life, because urine output gradually increases over the first 24 to 48 hours of life as renal plasma flow and glomerular filtration rate increase. Thus, the degree of urinary tract dilatation can be underestimated if performed during this period of transition.

Genetic testing in children with renal malformations should be preceded by a thorough clinical evaluation for extrarenal symptoms, including eye, ear, and metabolic anomalies. The presence of nonrenal anomalies increases the likelihood of detecting a specific genetic abnormality (Table 469-3). In addition, mutations in genes that are usually associated with syndromes can occur in patients with isolated renal malformations.

Unilateral Renal Agenesis

A diagnosis of unilateral renal agenesis depends on the certainty that a second kidney does not exist in the pelvis or some other ectopic location. Since absence of one kidney induces compensatory hypertrophy in the existing kidney, the presence of a large kidney on one side suggests the possibility of unilateral renal agenesis. This condition is associated with contralateral urinary tract abnormalities, including ureteropelvic junction obstruction and vesicoureteral reflux in 20% to 40% of the cases. Thus, imaging of the contralateral side by ultrasonography and a voiding cystourethrogram is suggested. Managing affected patients involves determining the functional status of the contralateral kidney. A normal contralateral kidney is associated with an excellent long-term renal functional outcome. Since some studies have revealed that a substantial proportion of patients will develop proteinuria and hypertension in the long term, affected individuals should have their blood pressure measured and their urine periodically tested for protein throughout life.

Renal Hypoplasia

Unless associated with other malformations, renal hypoplasia can be asymptomatic. Unilateral hypoplasia is often discovered as an incidental finding during an abdominal sonogram or other imaging study. In contrast, patients with bilateral renal hypoplasia are at risk for decreased renal function and chronic kidney disease.

Renal Dysplasia

The dysplastic kidney is generally smaller than normal. However, cystic elements can contribute to large kidney size, the most extreme example being the multicystic dysplastic kidney. During the antenatal period, unilateral disease is likely to be discovered as an incidental finding. This may also be the case for bilateral renal dysplasia unless it is associated with oligohydramnios. After birth, bilateral renal dysplasia may limit glomerular filtration, causing renal failure that is usually progressive. Postnatal ultrasonography of the dysplastic kidney is characterized by increased echogenicity, loss of corticomedullary differentiation, and cortical cysts. Renal dysplasia is strongly associated with dilatation of the upper and lower urinary tract and with vesicoureteric reflux and posterior urethral valves. Accordingly, imaging of the lower urinary tract should be performed to determine whether these abnormalities are present.

Multicystic Dysplastic Kidney (MCDK)

The MCDK appears on ultrasonography as a large cystic nonreniform mass in the renal fossa; by palpation, MCDK appears as a flank mass. The MCDK is nonfunctional, a condition that can be demonstrated by imaging with MAG3 or DTPA radionuclide scanning. The MCDK is usually unilateral. If bilateral, it is fatal. Complications of MCDK include hypertension (0.01–0.1%), Wilms tumor, and renal cell carcinoma. However, the incidence of these disorders is extremely low. In 25% of cases, the contralateral urinary tract is abnormal. Contralateral abnormalities can include rotational or positional anomalies, renal hypoplasia, vesicoureteric efflux, and ureteropelvic junction obstruction. Contralateral uteropelvic junction (UPJ) obstruction occurs in 5% to 10% of cases.

Gradual reduction in renal size and eventual resolution of the mass of the MCDK is common. At 2 years, an involution in size has been noted by ultrasound in up to 60% of the affected kidneys. Complete disappearance of the MCDK can occur in a minority of patients (3–4%) by the time of birth, and in 20% to 25% by 2 years. Increase in the size of MCDK can be seen in some cases. The contralateral kidney shows compensatory hypertrophy by ultrasound evaluation.

Managing patients with MCDK has shifted from routine nephrectomy to observation and medical therapy. Because of the risk of associated anomalies in the contralateral kidney, the possibility of vesicoureteral reflux should be evaluated and blood pressure should be measured. Renal ultrasound is generally recommended at an interval of 3 months for the first year of life and then every 6 months up to involution of the mass, or at least up to 5 years. Compensatory hypertrophy of the contralateral kidney is expected and should be monitored by renal ultrasound.

Renal Ectopia

Normally, the kidneys lie on either side of the spine in the lumbar region and are located in the retroperitoneal renal fossae. Rapid caudal growth during embryogenesis results in migration of the developing kidney from the pelvis to the retroperitoneal renal fossa. With ascension comes a 90o rotation from a horizontal to a vertical position, with the renal hilum finally directed medially. Migration and rotation are complete by 8 weeks of gestation.

Simple congenital ectopy refers to a low-lying kidney that failed to ascend normally. An ectopic kidney that lies over the pelvic brim or in the pelvis is termed a pelvic kidney. Less commonly, the kidney may lie on the contralateral side of the body, a state that is termed crossed ectopy without fusion. Clinical presentation can be asymptomatic or symptomatic. An ectopic kidney is frequently discovered as an incidental finding during routine antenatal sonography. Symptomatic presentation occurs with urinary tract infections. On examination, an abdominal mass may be palpable. Other presenting features include hematuria, incontinence, renal insufficiency, and hypertension. Renal ectopia is highly associated with urological abnormalities. Vesicoureteral reflux is the most common, occurring in 20% of crossed renal ectopia and 30% of simple renal ectopia. In bilateral simple renal ectopia, the incidence is as high as 70%. Other associated urological abnormalities include contralateral renal dysplasia (4%), cryptorchidism (5%), and hypospadias (5%). Reduced renal function in the ectopic kidney is commonly observed by radionuclide scan. Female genital anomalies such as agenesis of the uterus and vagina or unicornuate uterus have also been associated with ectopic kidneys. Other anomalies described include adrenal, cardiac, and skeletal anomalies. Clinical assessment should therefore include a careful physical examination for other anomalies. Renal ultrasonography will help with diagnosis and with defining the underlying anatomy. A voiding cystourethrogram (VCUG) should be undertaken, particularly if there is hydronephrosis, given the risk of vesicoureteral reflux and obstruction. A dimercaptosuccinic acid (DMSA) scan is also recommended to assess for differential renal function.

Renal Fusion

Renal fusion is defined as the fusion of two kidneys. The most common fusion anomaly is the horseshoe kidney, in which fusion occurs at one pole of each kidney, usually the lower one. The fused kidney may be located in the midline (symmetric horseshoe kidney) or laterally (asymmetric horseshoe kidney). In a crossed fused ectopic kidney, the kidney from one side has crossed the midline to fuse with the kidney on the other side. Fusion is thought to occur before the kidneys ascend from the pelvis to their normal dorsolumbar position. This is usually between the fourth to ninth week of gestation. As a result, fusion anomalies seldom assume the high position of normal kidneys. The blood supply may be abnormal, such as from the iliac arteries. Abnormal rotation is also associated with early fusion of the developing kidneys.

The pelvis of each kidney lies anteriorly; therefore, the ureter traverses over the isthmus of a horseshoe kidney or over the anterior surface of the fused kidney. Ureteric compression may occur due to external compression by a traversing aberrant artery. The majority of patients may be asymptomatic. Some, however, develop obstruction that presents with loin pain, hematuria, and may be associated with urinary tract infections due to urinary stasis or vesicoureteric reflux. Renal calculi may occur in up to 20% of cases. Other associated urological anomalies include ureteral duplication, ectopic ureter, and retrocaval ureter. Genital anomalies such as bicornuate or septate uterus, hypospadias, and undescended testes have also been described. Associated nonrenal anomalies involve the gastrointestinal tract (anorectal malformations such as imperforate anus, malrotation, and Meckel diverticulum), the central nervous system (neural tube defects), and the skeleton (rib defects, clubfoot, or congenital hip dislocation). Investigations should include static imaging (renal ultrasound), functional imaging (DMSA scan), and a VCUG.