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PEDIATRICS: ANOMALIES OF THE KIDNEYS

Renal Embryology

Embryonic kidneys in order of their appearance:
1. Pronephros
  - Develops late in the 3rd week, and it completely regresses by the start of the 5th week
2. Mesonephros
  - Regresses partially by the 4th month
    - In males, the mesonephric tubules become the efferent ductules that serve as a link between the testicle and the mesonephric/Wolffian duct (WD) structures (the body and tail of the epididymis and vas deferens)
3. Metanephros
  - Becomes the permanent kidney.
- All 3 develop from the intermediate mesoderm.
  - The definitive kidney differentiates from the metanephric blastema, which is a specialized region of the intermediate mesoderm termed the metanephric mesenchyme
    - This process requires the reciprocal induction between the metanephric blastema and the ureteral bud
      - The metanephric blastema sends signals to the WD to initiate ureteric bud formation from its caudal end between 5-7 weeks’ gestation.
      - The ureteric bud evaginates and invades the metanephric blastema and branches repeatedly in a characteristic pattern to form the collecting duct system. The ureteral tips induce nephron differentiation in the adjacent mesenchyme, forming the mature metanephros
    - Although renal maturation continues to take place postnatally, nephrogenesis is essentially complete before birth at around 32-34 weeks’ gestation (CW11 p2826 "nephrogenesis is completed before birth at around 32 to 34 weeks of gestation"; CW12 p341 "By 34 to 36 weeks’ gestation, nephrogenesis is complete")
- The full term neonate has a glomerular filtration rate (GFR) of only 2 ml/minute.§
  - When this is normalized for body surface area of an adult, the GFR of a full term neonate is approximately 20 ml/min/1.73 m2
  - In an adult, GFR normally 100–120 ml/min/1.73 m2 (an average adult body surface area).

Anomalies of Number

Bilateral Renal Agenesis (BRA)

Much more common among males; 75% of patients with bilateral renal agenesis are male
Gross pathology

Ureters are almost always absent
Bladder is either absent or hypoplastic
Adrenal glands are usually positioned normally

Phenotypic Features

Infants look prematurely senile and have “a prominent fold of skin that begins over each eye, swings down in a semicircle over the inner canthus and extends onto the cheek”. This facial feature is a sine qua non of nonfunctioning renal parenchyma and suggests that its absence confirms the presence of at least one kidney
Anomalies of the external genitalia include absence of the scrotum and clitoral hypertrophy; testes are undescended in 43% of cases, penile development is usually normal
High incidence of anomalies of the Mullerian duct structures and ovaries
Uropathy-associated pulmonary hypoplasia appears to be a result of oligohydramnios rather than renal dysfunction

Prenatal diagnosis

Diagnosed by prenatal ultrasonography in the second and third trimesters, when severe oligohydramnios is noted and no renal parenchyma can be identified. Additional diagnostic findings include small lung volumes and chest diameter and abnormal adrenal gland appearance.
The characteristic Potter facies and the presence of oligohydramnios are pathognomonic.

Postnatal diagnosis

Regardless of the gestational age, infants void within the first 24 hours of life; after the first 24 hours, anuria without distention of the bladder suggests BRA
Post natal renal US is the most efficient way to identify the kidneys and bladder and to confirm the presence or absence of urine production.

Prognosis

About 40% of the affected neonates are stillborn
Of those neonates born alive, most do not survive beyond the first 24-48 hours because of respiratory distress

Unilateral Renal Agenesis

Renal aplasia is the most common cause of congenital solitary kidney.
Complete absence of one kidney occurs more frequently than BRA but is not easily detected on physical examination.
The largest study to date of neonates with an isolated single umbilical artery did not find an increased incidence of URA or other malformations
Incidence

Occurs 1 in 1100 births.
Males predominate (ratio 1.8:1), but lower proportion than bilateral renal agenesis
Absence of a kidney occurs more frequently on the left side

Genetic/Syndromic and Other Associations.

Syndromes associated with URA:
- Turner syndrome
- Poland syndrome
- Branchio-oto-renal (BOR) syndrome
- DiGeorge anomaly (when associated with maternal insulin-dependent diabetes mellitus)
- VACTERL association (vertebral, imperforate anus, cardiac, tracheo-esophageal atresia, renal, and limb anomalies)
Maternal diabetes is associated with a 3x increased risk of renal agenesis and dysplasia
Congenital renal agenesis results from RET mutations that prevent or impede the embryonic development of RET-dependent structures

Embryology

The embryologic basis for URA and BRA is thought to be similar and it is most likely caused by the ureteric bud

Complete absence of a bud or aborted ureteral development prevents reciprocal induction, which is critical for the development of the metanephric blastema into the definitive adult kidney.
The metanephros is not likely to be responsible for the majority of cases

Prior to the increased use of prenatal ultrasound, a substantial number of cases thought to be URA were a dysplastic or multicystic dysplastic kidney (MCDK) that had involuted before birth
A plain film of the abdomen (or other radiographic study such as magnetic resonance imaging) showing the gas pattern of the splenic flexure in the left renal fossa suggests left renal agenesis, ectopia, or crossed ectopia, whereas the gas pattern of the hepatic flexure positioned in the right renal fossa suggests congenital absence of the right kidney.
Associated Genitourinary and Adrenal Anomalies

In autopsy studies of unilateral renal agenesis:
- Adrenal agenesis occurs in fewer than 10%, although the ipsilateral adrenal gland may be flattened or "lying down."
- The ureter is not normally developed, and the ipsilateral ureter is completely absent in approximately 60% of cases.
- The gonad is usually normal in both sexes.
- The head of the epididymis is normally formed because it is derived from the mesonephric tubules that link the mesonephric duct to the gonad.
Except for ectopia or malrotation, anomalies of the contralateral kidney are infrequent. However, abnormalities of the contralateral ureter are not uncommon, including ureteropelvic and ureterovesical junction obstruction in 11% and 7%, respectively and reflux in 30%
Reproductive tract abnormalities in females occur in ≥25-50% of cases compared with 10-15% in males.
Anomalies of the male

The testis and head of the epididymis, which contain the efferent ductules derived from the mesonephric tubules, are invariably present; WD structures (the body and tail of the epididymis, vas deferens, seminal vesicle, ampulla, and ejaculatory duct), are absent in ≈50%
Zinner syndrome (3):

Ipsilateral renal agenesis
Seminal vesicle cyst
Obstruction (atresia) of the ejaculatory duct

In males evaluated for infertility, the diagnosis of URA should be suspected when the vas deferens or body and tail of the epididymis are impalpable.
In children, URA should be considered when vasal and/or epididymal anomalies are incidentally found at the time of scrotal ultrasonography, herniorrhaphy, or orchiopexy.

Anomalies in the Female

≈1/4th-1/3rd of women with MD anomalies are found to have URA.
Depending on the timing of the embyrological insult, a variety of anomalies may result from incomplete Mullerian duct formation because of alterations in normal WD development.

Most common MD anomalies (2):
1. Unicornuate uterus with complete absence of the ipsilateral horn and fallopian tube
2. Bicornuate uterus with rudimentary development of the horn on the affected side
- Partial or complete midline fusion of the MD may result in a double (didelphys) or septate uterus with either a single or a duplicated cervix. Obstruction of one side of a duplicated system is not uncommon, and unilateral hematocolpos or hydrocolpos associated with a pelvic mass and/or pain has been described in pubertal girls
  - In rare instances, this anomalous condition has been mistaken for a large or infected Gartner duct cyst.
  - If the insult occurs early in the fourth week of gestation and affects both the wolffian duct and the ureteral bud, maldevelopment of the wolffian duct affects renal development, müllerian duct elongation, contact with the urogenital sinus, and subsequent fusion. Therefore, a didelphic uterus will form with obstruction of the horn and vagina on the side of the unilateral renal agenesis.
  - If the insult occurs after the 4th week, the wolffian duct and müllerian duct elongation and differentiation proceed normally and only the ureteral bud and metanephric blastema are affected, thereby resulting in isolated unilateral renal agenesis.

Source: Wikipedia

Anomalies of other organ systems are found frequently in affected individuals. The more common sites involve the cardiovascular, gastrointestinal, and musculoskeletal systems.

Diagnosis and Radiographic Evaluation

≈90% of fetal kidneys associated with URA or MCDK undergo compensatory hypertrophy in utero which may lead to renal disease later in life

Supernumerary Kidney

The supernumerary kidney is a definitive accessory organ with its own collecting system, blood supply, and distinct encapsulated parenchyma.
The supernumerary kidney may be either completely separate or loosely attached to the kidney on the ipsilateral side.
The ureteral interrelationships on the side of the supernumerary kidney can be variable.

Anomalies of Ascent

Simple Renal Ectopia

More commonly diagnosed in females because they are more apt to undergo uroradiologic evaluation for urinary tract infection (UTI) and/or associated genital anomalies
The left side is affected slightly more than the right.
An ectopic kidney can be found in one of the following positions (5):
1. Pelvic (most common site)
2. Iliac
3. Abdominal
4. Thoracic
5. Contralateral or crossed
Embryology

The UB, arising from the WD at the end of the 4th week, grows cranial toward the urogenital ridge, acquiring a cap of metanephric blastema by the 5th week. The developing metanephric tissue and UB migrate cephalad. The entire process is completed by 8 weeks’ gestation.
Factors that may prevent the orderly ascent and rotation of the kidneys include UB maldevelopment, defective metanephric tissue that fails to induce ascent, genetic abnormalities, and maternal illnesses or teratogenic causes

Description and Associated Anomalies

The renal pelvis is usually anterior (instead of medial);
- As a result, 56% of ectopic kidneys have a hydronephrotic collecting system.
  - Of those with hydronephrosis:
    - 50% from obstruction of the ureteropelvic or the ureterovesical junction (70% and 30%, respectively)
    - 25% from reflux grade III or greater
    - 25% from the malrotation alone
Vesicoureteral reflux has been found in 30% of children with ectopic kidneys.
The incidence of genital anomalies in the patient with ectopia is about 15%.
The ureteric orifice is positioned normally, except for those unusual cases with ectopic ureters
In females, 20-66% have ≥1 of the following abnormalities of the reproductive organs:
1. Bicornuate or unicornuate uterus with atresia of one horn
2. Rudimentary or absent uterus and proximal and/or distal vagina
3. Duplication of the vagina
In males, 10-20% have a recognizable associated genital defect; undescended testes, duplication of the urethra, and hypospadias are the most common

Diagnosis

Most ectopic kidneys are clinically asymptomatic, except in cases of associated ectopic ureter.
- Thoracic kidneys are also usually asymptomatic

Prognosis

The ectopic kidney is no more susceptible to disease than the orthotopic kidney, except for the development of hydronephrosis or stones. This may be a result of the anteriorly placed pelvis and malrotation of the kidney, which may impair drainage of urine from a high insertion of the ureter to the pelvis or anomalous vasculature that partially obstructs one of the major calyces or the upper ureter.
May be an increased risk of injury from blunt abdominal trauma, because the low-lying kidney is not protected by the rib cage.

Anomalies of Form and Fusion

Horseshoe Kidney

Most common of all renal fusion anomalies
- Occurs in 0.25% of the population, more commonly in males
Consists of two distinct renal masses lying vertically on either side of the midline and connected at their respective lower poles by a parenchymatous or fibrous isthmus that crosses the midplane of the body

IVP in a patient with horseshoe kidney

Source: Wikipedia

Embryology

The abnormality occurs between 4-6 weeks’ gestation
Increased incidence of horseshoe kidneys in children with vertebral and neural tube defects

Description

The blood supply can be variable
In 95% of cases, the kidneys join at the lower pole
Migration is usually incomplete and it is thought that the inferior mesenteric artery prevents full ascent
The isthmus of a horseshoe kidney is located adjacent to the L3 and L4 vertebrae
The pelves and ureters of the horseshoe kidney are usually anteriorly placed
The calyces are normal in number
Because the kidney fails to rotate, the calyces point posteriorly, and the axis of each pelvis remains in the vertical or obliquely lateral plane.

Associated Anomalies

Frequently found in association with other congenital anomalies

Genitourinary anomalies include hypospadias, undescended testes, bicornuate uterus, and a septate vagina
Other associated anomalies include duplication of the ureter, ectopic ureterocele, VUR

The high insertion of the ureter into the renal pelvis, its abnormal course anterior to the isthmus, and the anomalous blood supply to the kidney may individually or collectively contribute to the hydronephrosis.

UPJ obstruction, causing significant hydronephrosis, occurs in as many as 1/3 of individuals with horseshoe kidneys
In the modern era, frequently discovered incidentally, and their apparent hydronephrosis more often shows a non-obstructed pattern on radionuclide scanning.

Associated clinical conditions

Cystic disease and adult polycystic kidney disease
Stones
- Hypovolemia, hypercalciuria, and hypocitraturia were the most common metabolic defects
Because a horseshoe kidney is located above the pelvic inlet, it should not adversely affect pregnancy or delivery
60% of patients with horseshoe kidneys remained asymptomatic for an average of 10 years after discovery
Horseshoe kidney and coarctation of the aorta are seen in patients with Turner syndrome (45,XO). Therefore, in these patients, a karyotype should be obtained. Other stigmata of Turner syndrome may include lymphedema, shield chest, low hairline, and webbed neck.

Crossed Renal Ectopia with and without Fusion

When a kidney is located on the side opposite that in which its ureter inserts into the bladder, the condition is known as crossed ectopia.
90% of crossed ectopic kidneys are fused with their mate
- The superior pole of the ectopic kidney usually joins with the inferior aspect of the normal kidney.
Associated Anomalies

In all the types of fusion anomalies, the ureteral orifice associated with each kidney is usually orthotopic
The most common genital anomalies are cryptorchidism or absence of the vas deferens and vaginal atresia or a unilateral uterine abnormality
The highest incidence of associated anomalies occurs in children with solitary renal ectopia and involves both the skeletal system and genital organs.

Symptoms

Most individuals with crossed ectopic anomalies present no symptoms
An asymptomatic abdominal mass is the presenting sign in 1/3 of cases

Anomalies of Rotation

Between the 6th-9th week, normal rotation of the kidney toward the midline to attain its orthotopic position involves 90 degrees of ventromedial rotation so that the calyces point laterally and the pelvis faces medially. When this alignment is not exact, the condition is known as malrotation.
Malrotation is frequently associated with Turner syndrome

Anomalies of Renal Vasculature

Aberrant, Accessory, or Multiple Vessels

The correct term to describe any kidney supplied by >1 vessel is multiple renal arteries.
The terms anomalous vessels or aberrant vessels should be reserved for those arteries that originate from vessels other than the aorta or main renal artery.
The term accessory vessels denotes ≥2 arterial branches supplying the same renal segment.
Polar arteries or multiple renal arteries to the normally positioned kidney represent a failure of complete degeneration of all primitive vascular channels.
Description

Based on vascular supply, the renal parenchyma is divided into 5 segments:
1. Apical
2. Upper
3. Middle
4. Lower
5. Posterior
- The main renal artery divides initially into an anterior and posterior branch.
  - The anterior branch almost always supplies the upper, middle, and lower segments of the kidney.
  - The posterior branch invariably supplies the posterior and lower segments.
  - The vessel to the apical segment has the greatest variation in origin
    - Arises from:
      - Anterior division (43%)
      - Junction of the anterior and posterior divisions (23%)
      - Main-stem renal artery or aorta (23%)
      - Posterior division of the main renal artery (10%).

Renal Artery Aneurysm (RAAs)

Overall incidence 0.1-0.3%
Classified: saccular, fusiform, dissecting, and arteriovenous

The saccular aneurysm, a localized outpouching that communicates with the arterial lumen by a narrow or wide opening, is the most common type
When the aneurysm is located at the bifurcation of the main renal artery and its anterior and posterior divisions, or at one of the more distal branchings, it is considered to be congenital in origin and is called the fusiform type

Diagnosis and Evaluation
- History and Physical Exam
  - History
    - Most RAAs are silent, especially in children.
    - Many asymptomatic RAAs are diagnosed during an evaluation of hypertension
  - Physical Exam
    - Diagnosis is suspected when a pulsatile mass is palpated in the region of the renal hilum or when a bruit is heard on abdominal auscultation
- Imaging
  - A wreathlike calcification in the area of the renal artery or its branches (30%) is highly suggestive.
Management
- Indications for intervention (7):
  1. Rapidly expanding
  2. Female and considering pregnancy (rupture during pregnancy is a likely possibility)
  3. Renal artery aneurysm > 2.0cm (some sources say >2.5cm)
  4. Symptoms (uncontrolled hypertension from renal artery stenosis, flank pain, hematuria)
  5. Renal ischemia/infarction (resulting from embolization from the aneurysm)
  6. Incomplete ringlike calcification is present
  7. Arteriovenous fistula is present
- Options: endovascular vs. surgical repair
  - In young patients, surgical repair may be preferred as endovascular stent may require lifelong anti-coagulation

Renal Arteriovenous Fistula

Classified: congenital vs. acquired
- Congenital
  - <25% of all renal arteriovenous fistulas (AVFs) are congenital.
  - They are identifiable by their cirsoid configuration and multiple communications between the main or segmental renal arteries and venous channels.
  - Although congenital, they rarely present clinically before the third or fourth decade.
  - Females are affected three times as often as males
  - Right kidney is involved slightly more often than the left.
  - The lesion is usually located in the upper pole (45% of cases), but not infrequently it may be found in the mid-portion (30%) or in the lower pole (25%) of the kidney.
- Acquired
  - Results from a congenital aneurysm eroding into an adjacent vein
Often requires surgical intervention

Anomalies of the Collecting System

Calyceal Diverticulum

A calyceal diverticulum is a cystic cavity within the kidney that is lined by urothelium and communicates with a calyx or, less commonly, with the renal pelvis through a narrow isthmus.
The incidence based on excretory urography is ≈4.5 per 1000
Upper calyx most frequently affected
Small diverticula are usually asymptomatic
Infection, milk of calcium or true stone formation are complications of stasis or obstruction that can produce symptoms
The diagnosis is suggested on ultrasonography but is confirmed on CT scan or MRU
Patients who are asymptomatic do not require treatment but should be followed periodically with ultrasonography.
Laparoscopy by a retroperitoneal approach for marsupialization of the diverticulum, fulguration of the epithelial lining, and percutaneous marsupialization/ablation are treatment options.

Hydrocalycosis

Hydrocalycosis is a rare cystic dilation of a major calyx with a demonstrable connection to the renal pelvis

Megacalycosis

Megacalycosis is defined as nonobstructive enlargement of calyces resulting from malformation of the renal papillae
The calyces are generally dilated and malformed and may be increased in number.
The renal pelvis is not dilated, nor is its wall thickened, and the ureteropelvic junction is normally funneled without evidence of obstruction. The ureter is usually normal.
Occurs predominantly in males with a ratio of 6:1 and has been found only in Caucasians.
Bilateral disease has been seen almost exclusively in males, whereas segmental unilateral involvement occurs only in females
Diuretic renography shows a normal pattern for uptake and washout of the isotope
Long-term follow-up of patients with this anomaly does not usually show progression of the anatomic or functional status of the kidney

Infundibulopelvic Stenosis

Most likely forms a link between cystic dysplasia of the kidney and the grossly hydronephrotic kidney.
Usually bilateral and is commonly associated with vesicoureteral reflux, suggesting an abnormality of the entire UB

References

Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 130