KEY POINTS
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Congenital renal anomalies account for one-fourth of all congenital anomalies.
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Early pre- or postnatal detection can facilitate appropriate, timely management.
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Many infants will require coordinated, multispecialty treatment.
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Renal abnormalities are being increasingly recognized in four broad groups: (1) congenital anomalies of the kidney and the urinary tract (CAKUTs), such as renal agenesis, kidney hypodysplasia, and abnormalities of the draining systems; (2) functional disorders such as congenital nephrotic syndrome and renal tubular acidosis; (3) low nephron counts and glomerular volume, which may be an isolated condition or may be seen in association with CAKUT; and (D) inherited cystic disorders, which can be autosomal recessive or autosomal dominant.
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Infants with inherited renal abnormalities require long-term specialty care to assess both urologic and renal function.
Altered Development of the Kidneys and the Urinary Tract
The two kidneys begin developing at approximately the 3rd week, and despite some ethnic variation, they can each contain more than 1 million nephrons by the 36th week. The normal renal system filters waste and excess liquid from the blood, produces hormones that help strengthen bones, controls blood pressure, and directs the production of red blood cells. The filtered waste, in the form of urine, drains from the kidneys to the bladder through the ureters and is excreted from the bladder through the urethra. Prenatally, the fetal bladder may be first visible at 10 to 12 weeks’ gestation, and by midgestation, it fills and empties every 30 to 60 minutes. Fetal urine production begins by 9 to 10 weeks of gestation and increases by 14 to 16 weeks, such that after this point the bulk of amniotic fluid is made of fetal urine. ,
The kidneys and urinary tract often show birth defects that can affect the form and function of these organs. There are four major types of congenital renal abnormalities: (1) anatomic disruptions that are grouped together as the congenital anomalies of the kidney and the urinary tract (CAKUTs), such as renal agenesis, kidney hypodysplasia, and abnormalities of the draining systems , (the etiology of all CAKUTs is not yet clearly known, but genetic and environmental risk factors are being identified ; anomalies at the most severe end of the spectrum, such as renal agenesis, may be inconsistent with survival, but many less severe defects may remain asymptomatic until later childhood or even adulthood); (2) functional disorders such as congenital nephrotic syndrome and renal tubular acidosis; (3) low nephron counts and glomerular volume, , which may be an isolated condition or may be seen in association with CAKUT; (4) inherited cystic disorders, which can be autosomal recessive or autosomal dominant. Most patients with autosomal dominant polycystic kidney disease do not develop symptoms until adulthood, although some infants are now increasingly being identified earlier.
In this chapter, we seek to illustrate lesions involving the renal system, including pathologic alterations associated with various syndromes, and to analyze the more recent therapeutic interventions that may modify the natural history of some of these severe conditions. We have included evidence from our own clinical experience and from an extensive literature search in the databases PubMed, Embase, and Scopus. To avoid bias in identification of existing studies, key words were short-listed prior to the actual search, both from anecdotal experience and from PubMed’s Medical Subject Heading (MeSH) thesaurus.
Congenital Abnormalities of the Kidney and the Urinary Tract
The congenital anomalies of the kidney and the urinary tract, frequently grouped together and described using the acronym CAKUT, , comprise 20% to 30% of all major birth defects. , , More than 200 clinical syndromes currently include CAKUTs as a component of the phenotype. There are three major types:
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Renal abnormalities include uni- or bilateral renal agenesis, malpositioned kidney(s), renal hypoplasia, structural abnormalities with renal dysplasia, and anatomic abnormalities such as in horseshoe kidney.
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Ureters may show blockage at the ureteropelvic junction or the ureterovesicular junction with the formation of a ureterocele; vesicoureteral junction reflux; or ureteral duplication, where one of the two ureters may show reflux or obstruction.
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Downstream abnormalities may occur in the bladder and urethral valves. The bladder may not be visualized prenatally in the case of a bilateral severe kidney anomaly with no kidney function. A large bladder may result from either bladder outlet obstruction or may indicate neurogenic dysfunction with poor emptying capacity.
Any blockages in urinary flow can result in renal enlargement, as in hydronephrosis. These changes can start in utero and can be seen in prenatal sonography. The severity may vary; mild abnormalities can result in hydronephrosis or recurrent urinary tract infections, whereas the more severe ones can result in life-threatening kidney failure and end-stage renal disease.
The inheritance of CAKUTs is complex and not completely understood. These anomalies are seen at a frequency of 1 in 100 to 500 neonates, are familial in 10% to 20% of cases, can be uni- or bilateral, and constitute approximately 20% to 30% of all anomalies identified in the prenatal period. These conditions lead to 30% to 50% of all pediatric chronic kidney disease and are the most common cause of end-stage renal disease requiring renal replacement therapy in children.
When inherited, most CAKUTs follow an autosomal dominant pattern with reduced penetrance. Some anomalies show an autosomal recessive pattern. In many cases, the inheritance pattern is unknown or the condition may not be inherited. Some patients may have nonmotile ciliopathies and other syndromes associated with renal malformations, such as Meckel–Gruber, short rib, Bardet–Biedl, asplenia/polysplenia, hereditary renal adysplasia, Zellweger, trisomies, the VACTER-L association (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities), Potter, caudal dysplasia, and sirenomelia. A list of the best-known genes involved in CAKUTs is provided in Table 61.1 .
| Type of Malformation | Renal Phenotype | Gene | Cause |
|---|---|---|---|
| Renal agenesis | Absence of the ureter and kidney | RET , GDNF , FGF20 , FRAS1 , FREM2 | Lack of interaction between the ureteric bud and MM |
| Renal hypoplasia | Reduced number of ureteric bud branches and nephrons; small kidney size, often associated with dysplasia | Pax2 , Sall1 , Six2 , BMP4 , HNF1B , UMOD | Aberrant interaction between ureteric bud and MM |
| Renal dysplasia | Reduced number of ureteric bud branches and nephrons; undifferentiated stromal and mesenchymal cells, cysts, or cartilage | PAX2 , HNF1B , UMOD , Nphp1 BMP4 , Six2 , XPNPEP3 | Aberrant interaction between ureteric bud and MM |
| MCDK | Absent glomeruli and tubules | HNF1B , UPIIIA , PEX26 , ELN , HNF1B , ALG12 , FRG1 , FRG2 , CYP4A11 | Aberrant interaction between ureteric bud and MM |
| Duplex ureters | Duplex ureters and kidneys or duplex ureters and collecting systems | Robo2 , FoxC1 , FoxC2 , BMP4 | Supernumerary ureteric bud budding from the MD |
| Horseshoe kidney | Kidneys are fused at inferior lobes and located lower than usual | HNF1B | Defects in renal capsule |
| VUR | Urine refluxes to various degrees from bladder up into the collecting system | PAX2 , ROBO2 , SIX1 , SIX5 , SOX17 , TNXB , CHD1L , TRAP1 | Aberrant insertion of ureter into bladder wall |
| Renal tubular dysgenesis | Absence of or incomplete differentiation of proximal tubule | ACE , AGT , AGTR1 , REN | Impaired tubular growth and differentiation |
Renal Agenesis
Unilateral kidney agenesis is a relatively frequent, multifactorial anomaly. Most cases result from the involution of a multicystic dysplastic kidney or as a primary developmental anomaly. Sometimes, it may reflect an earlier renal infarction due to inadequate vascular supply or an involuted unilateral dysplastic kidney. The clinical outcomes of infants with a solitary functioning kidney are generally favorable if there are no other forms of CAKUT. Some infants are at risk for hyperfiltration injury and may require follow-up. However, the surviving kidney in most patients will undergo compensatory hypertrophy, which is due to an increase in nephron hypertrophy, not a change in nephron number.
Bilateral renal agenesis is considered a form of CAKUT. Historically this was considered to be a fatal condition, incompatible with extrauterine life. There are reports of amnioinfusion to support lung development, and studies are currently underway to assess this intervention and its outcomes. It is critical to note that even if lung development is adequate, the neonate will have end-stage kidney disease, and amnioinfusions increase the risk for preterm delivery, both of which will contribute to morbidity and mortality. ,
Renal Ectopia
Ectopic kidneys can be located anywhere in the body other than the typical renal fossa and may be noted prenatally, postnatally, or later if imaging is obtained for another purpose. The most frequently noted site is the pelvis, and very rarely, the thorax.
Similar to horseshoe kidneys, crossed-fused renal ectopia is also a fusion anomaly and results in both kidneys being located on one side. The ureter of the ectopically located kidney inserts orthotopically into the bladder, on the original side.
Multicystic Kidney Dysplasia
Kidneys with multicystic kidney dysplasia show areas with abnormal tissue organization and multiple noncommunicating cysts, which may be of variable size and location. These affected regions do not have function; some cysts may involute over time, but many persist. Some cases also show a dilated renal outflow tract, although it may be unclear whether this dilatation is yet another primary developmental abnormality or is a secondary manifestation related to compression from the cysts. In these cases, functional scanning using dimercaptosuccinic acid (DMSA) or mercaptoacetyltriglycine (MAG3) can help determine the likely effectiveness of intervention.
Horseshoe Kidney or Renal Fusion
In most cases, the kidneys are fused at the lower pole ( Fig. 61.1 ). These anomalies have been associated with trisomy 18 and male gender. Anatomically, fused kidneys may be positioned lower than normal and may have associated ureteropelvic junction (UPJ) obstruction; the clinical manifestations may include urinary tract infections, abdominal mass, and/or hematuria.
The treatment is surgical. Some infants may be treatable with transperitoneal laparoscopy, which may permit exploration of the pyelocalyceal system and detection of anatomic anomalies such as crossing vessels, and if needed, procedures such as pyeloplasty.
Duplex Kidneys
The term duplex kidney indicates the presence of duplicated ureters or a duplicated collecting system ( Fig. 61.2A ). Such duplications comprise a spectrum of disorders that range from incomplete changes in a small segment of the ureter to complete doubling of the ureter(s), where two ureteral tubes join at the bladder. Incomplete duplication may involve a bifid collecting system. Complete ureteral duplication is when there are two separate ureters that continue and enter the urinary bladder. ,
A ureterocele is a cystic dilation of the ureter at the bladder entrance (see Fig. 61.2B ). These anomalies may follow an autosomal dominant inheritance with incomplete penetrance. The risk of infections, including pyelonephritis, may be increased. , Conjoint ureters may be more frequent than complete ureteral duplication and may have a female predilection. In some cases, a duplex system may be associated with hydronephrosis, obstruction, reflux, and infections, which may lead to chronic renal disease.
Prenatally Diagnosed Hydronephrosis
Antenatal urinary tract dilation is diagnosed in 1% to 5% of all pregnancies. As many as 36% to 80% of the less severe cases recover postnatally, but the most severely afflicted infants may not. Mutations in the hepatocyte nuclear factor 1B (HNF1B) gene are identified in up to 50% infants with kidney anomalies. , Other frequently detected mutations include those in the paired box gene 2 (PAX2) and the eyes absent homolog 1 (EYA1) genes. A schematic diagram for the loss of renal function in obstructive nephropathy is shown in Fig. 61.3 .
The postnatal management of antenatally diagnosed hydronephrosis is not fully resolved yet. The severity of the urinary tract dilation in the third trimester can be classified in several ways ( Figs. 61.4 and 61.5 ). However, mild hydronephrosis is likely to be transient; <5% of infants will develop vesicoureteral reflux (VUR) or urinary tract infections. These infants do not require antibiotic prophylaxis, and the first postnatal ultrasound may be safely delayed for 1 to 2 weeks. In the subgroup with severe hydronephrosis, about 20% will have VUR and 10% to 40% will likely develop urinary tract infections during infancy. Even in the absence of VUR, children with severe hydronephrosis are at risk of urinary tract infections. The need for a voiding cystourethrogram (VCUG) and antibiotic prophylaxis in moderate to severe hydronephrosis is controversial.
Ureteropelvic Junction Obstruction
UPJ obstruction is one of the most frequently seen CAKUTs; the incidence may vary somewhere between 1 in 1000 to 1500 newborns and is a common cause of antenatal hydronephrosis. Longstanding obstruction may lead to pyelonephritis, hydronephrosis, and renal failure. The pathophysiology of UPJ obstruction is unknown, but some possibilities have been noted:
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Obliteration-recanalization: transient obliteration of the developing ureteric duct (future ureter) followed by recanalization. This hypothesis has lost some support.
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Developmental abnormalities with insertion anomalies of the ureters, ureteral muscular hypertrophy, and/or peripelvicalyceal fibrosis.
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Extrinsic obstruction by abnormal blood vessels: the developing ureters may have a positional kink or compression due to abnormal large vessels.
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Genetic anomalies: this is a possibility; homozygous and heterozygous Id2 mutations in rodents have been associated with hydronephrosis due to congenital UPJ obstruction. It is more frequent in males and unilateral, in the right kidney that is positioned higher.
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Some investigators have suggested a role of smooth muscle cell apoptosis and defective neural development in congenital UPJ obstruction.
UPJ obstruction results from intrinsic stenosis, fibrosis, or a crossing vessel leading to ureteral compression. Less severe cases are often asymptomatic and may not be identified during infancy. Most infants do not require surgery in the neonatal period, except those with severe abnormalities without a normal contralateral kidney or in cases of bilateral UPJ obstruction. Surgery may be needed if the renal function, size of the kidney, or drainage parameters are worsening over time. The best practice for unilateral cases with a normal contralateral kidney is still not defined. Some cases related to genetic abnormalities/familial CAKUT need evaluation.
Primary Megaureter
Megaureter refers to an enlarged ureter, which may be due to an intrinsic abnormality, external obstruction, or VUR. Many cases resolve during the first 1 to 3 years of age, but infants with megaureter are still at risk for pyelonephritis and kidney scarring. Thus infants with megaureters with VUR are often treated with prophylactic antibiotics. Secondary megaureters due to a neurogenic bladder or urethral issues such as posterior urethral valves may have to be treated for the specific etiology. Ureterovesical junction obstruction may result from a primary obstructive process or secondarily in cases of bladder hypertrophy, often associated with bladder outlet obstruction.
Vesicoureteral Reflux
VUR is the retrograde flow of urine from the bladder upward into the ureters and kidneys, resulting from anomalous anatomy of the ureterovesical junction. VUR is graded by VCUG on a scale of 1 to 5 ( Fig. 61.6 ). The degree of vesicoureteral reflux is poorly correlated with the degree of urinary tract dilation seen on ultrasound, and therefore, voiding studies are required for assessment. Severe VUR and pyelonephritis can increase the risk of kidney scarring. High-grade VUR can also lead to bladder dysfunction over time.
