Congenital Renal Abnormalities

Renal Embryology

The kidney develops in the pelvis and migrates cranially. Three separate renal systems form in sequence, giving rise to the kidney, in association with the urinary tract and urogenital system:

• Pronephros:
  • Non-functional vestigial renal structure found in the cervical area
  • Appears in the 3rd week
  • Disappears by the 4th week
• Mesonephros:
  • 4th week: Excretory units, composed of capillaries, the Bowman’s capsule, and the collecting tubule connected to the Wolffian ducts, form. 
  • Derived from the intermediate mesoderm in the upper thoracic to the lumbar area
  • Functional for some time in utero
  • Mostly disappears; a small portion remains part of the final renal system:
    • Fuses with the cloaca to create the bladder
    • In boys, gives rise to a portion of the genital system
• Metanephros:
  • 5th week: develops caudally in relation to the mesonephros 
  • Renal parenchyma differentiates from the mesoderm similarly to the mesonephros.
  • The collecting duct system:
    • Initially appears as a stalk and bud (blastema) derived from the mesonephric duct close to the cloaca
    • Later forms the ureter, renal pelvis, and calyces and merges with the metanephric tissue, creating the collecting tubules
    • Tips of the collecting tubules interact with the metanephric tissue → nephrons.
    • 20th week: Entire collecting system has been formed.
    • 32nd–36th weeks: All nephrotic units have formed, but continue to mature after birth.
• Renal ascent:
  • Caused by growth of lumbar and sacral regions 
  • Blood supply is from arteries coming off the aorta.
  • As the kidney arises, new arteries arise, while old arteries disappear.
  • 9th week: Left kidney is at the level of T11–L2. Right kidney is at the level of T12–L2/3.

Disorders of the Renal Parenchyma

Introduction

Renal embryologic disorders affecting the size, the shape, or the structure of kidney parenchyma (renal dysgenesis):

• Renal agenesis: absence of renal tissue due to a disruption during embryologic renal development
• Renal hypoplasia: small kidneys with a decreased number of functioning nephrons
• Renal dysplasia: focal or diffuse abnormalities of the nephron architecture; can be:
  • Non-cystic (simple renal dysplasia)
  • Cystic dysplasia: characterized by the formation of cysts
    • Multicystic dysplastic kidneys (MCDK): cystic dysplasia involving the entire kidney
    • Autosomal recessive polycystic kidney disease (ARPKD)

Renal agenesis

• Pathophysiology:
  • Interruption of the embryologic development of the ureteric bud, or metanephric blastema 
  • True renal agenesis includes an absent ipsilateral ureter and bladder hemitrigone.
  • Bilateral renal agenesis is incompatible with life.
• Epidemiology:
  • Incidence of unilateral renal agenesis: ~1 in 500–1,000 births
  • ↑ in infants with a single umbilical artery.
  • Boys ＞ girls
  • Common associations include:
    • Boys: absent ipsilateral vas deferens
    • Girls: Müllerian duct abnormalities 
• Etiology:
  • Genetic predisposition (e.g., mutations in genes responsible for renal development, RET and GDNF)
  • Syndrome association:
    • Associated with vertebral anomalies, anal atresia, and cardiac anomalies (VACTERL)
    • Mayer-Rokitanski-Kuster-Hauser: vaginal aplasia, uterine abnormalities
    • DiGeorge’s syndrome: palate defects, cardiac abnormalities, absent thymus
  • Associated maternal risk factors:
    • Maternal diabetes
    • Maternal obesity
    • Young maternal age
    • Maternal smoking
    • Maternal ethanol consumption during pregnancy
    • Teratogen exposure (e.g., retinoic acid, cocaine)
• Clinical presentation: 
  • Prenatal:
    • Routine-monitoring ultrasound findings include oligohydramnios and an absent bladder and kidney.
    • Genetic testing in cases with a high prenatal index of suspicion
    • Left kidney is more often absent.
  • Postnatal:
    • Often discovered during evaluation for other anomalies 
    • Incidental discovery on ultrasound
    • May have recurrent urinary tract infections (UTIs) or hypertension
    • Pulmonary hypoplasia due to a lack of amniotic fluid production may be a sign.
  • Potter’s syndrome: 
    • Bilateral renal agenesis, pulmonary hypoplasia resulting from oligohydramnios 
    • Facial abnormalities: widely separated eyes, prominent epicanthal folds, broad and compressed nose, and low-set ears 
    • Other abnormalities: club foot, leg bowing, diaphragmatic hernia, eye anomalies (e.g., cataract, lens prolapse), cardiovascular abnormalities (e.g., ventricular septal defect, patent ductus arteriosus, tetralogy of Fallot)
    • Potter’s syndrome may also be associated with cystic renal dysplasia, obstructive uropathy, ARPKD, renal hypoplasia, and medullary dysplasia.  
• Management: 
  • Children with a solitary kidney have a high risk for chronic kidney disease (CKD):
    • Monitor the contralateral kidney for hypertrophy.
    • Long-term follow-up for hypertension and proteinuria
    • Kidney function testing
  • Avoiding contact sports is controversial.

Renal hypoplasia

• Pathophysiology:
  • Small kidneys (＜50% than expected for age) 
  • Fewer-than-normal nephrons and calyces
  • Large glomeruli and tubules (hypertrophy to compensate)
  • Over time, patients develop end-stage renal disease (ESRD).
• Epidemiology:
  • Incidence of 1 in 400 live births
• Etiology:
  • Vascular abnormalities: 
    • Renal hypoperfusion in utero leads to hypoplasia.
  • Genetic disorders: 
    • Over 200 associated syndromes
    • Mutation in key regulatory genes in renal development
• Clinical presentation:
  • Unilateral: 
    • Diagnosed incidentally during evaluation for hypertension or urinary complaints
    • Neonates may present with failure to thrive.
  • Bilateral:
    • History of polyuria, polydipsia, and/or urinary abnormalities 
    • Development of ESRD in the 1st decade of life
• Diagnosis: 
  • Prenatal: 
    • Found through routine screening ultrasound by 3 months’ gestation
  • Postnatal: 
    • Renal ultrasound of suspected cases
    • Can be further confirmed by histology but rarely performed
• Management:
  • Unilateral:
    • Periodic follow-up by ultrasound and urinalysis to monitor compensatory hypertrophy of the unaffected kidney
  • Bilateral:
    • May require human growth hormone (rHGH) to allow appropriate growth
    • Angiotensin-converting enzyme (ACE) inhibitors to slow the progression to ESRD
    • Renal transplant for patients with advanced disease

Renal dysplasia

• Epidemiology:
  • 2–4 per 1,000 births
  • Boys-to-girls ratio:
    • Bilateral 1.3:1
    • Unilateral 2:1
• Classification:
  • Simple renal dysplasia
  • Cystic renal dysplasia
• Etiology: 
  • Primarily due to the incorrect differentiation of renal tissue caused by:
    • Embryonic ureteral buds arise in incorrect locations, leading to the incorrect differentiation of renal tissue.
    • Obstructive uropathy in gestation
• Clinical presentation:
  • Unilateral: 
    • Diagnosed incidentally during evaluation for another dysmorphism
  • Bilateral:
    • Found to have renal failure at birth or will develop renal failure soon after
    • Associated urinary abnormalities lead to frequent UTI, hematuria, and abdominal pain.
• Diagnosis: 
  • Prenatal: 
    • Found through routine screening ultrasound by 3 months’ gestation
  • Postnatal: 
    • Renal ultrasound of suspected cases 
• Management:
  • At risk for CKD:
    • Blood pressure should be closely monitored.
    • Yearly urinalysis
    • Urine function tests in patients with proteinuria/hypertension
• MCDK:
  • Most common cause of an abdominal mass in newborns
  • Usually unilateral (polycystic kidney disease is often bilateral)
  • Bilateral is incompatible with life.
  • May be diagnosed during prenatal ultrasound
  • May be asymptomatic and diagnosed incidentally on imaging
  • Complete cyst regression occurs by 7 years in half of cases.
  • Annual follow-up with ultrasound and blood pressure monitoring is recommended.

ARPKD

• Epidemiology: 
  • Incidence varies from 1:10,000 to 1:40,000 live births.
• Etiology:
  • An autosomal recessive disorder caused by the polycystic kidney and hepatic disease 1 (PKHD1) gene 
  • Affects: kidneys, lungs, and liver; rarely, the brain
• Clinical presentation:
  • Neonatal period or early infancy:
    • Typically presents with abdominal distension with bilateral flank masses 
    • Other associations: pulmonary hypoplasia and respiratory distress, spontaneous pneumothorax, Potter’s syndrome, hypertension, impaired renal function, failure to thrive, polyuria, polydipsia, ESRD
  • Infants and children:
    • Typically has a mixed renal-hepatic presentation
    • Often present with hepatosplenomegaly, signs of portal hypertension (prominent periumbilical veins, thrombocytopenia, and gastroesophageal varices), ascending cholangitis, choledochal cysts
    • Renal manifestations may be absent or similar to those in the neonatal period.
• Diagnosis:
  • Prenatal ultrasound: 
    • Oligohydramnios
    • Absence of urine in the bladder
  • Postnatal ultrasound:
    • Bilaterally enlarged, uniformly hyperechogenic kidneys with poor corticomedullary differentiation and multiple cysts
    • Hepatosplenomegaly with a hyperechoic liver and dilatation of the peripheral intrahepatic and main bile ducts
  • Molecular genetic testing confirms the diagnosis.
• Management:
  • Aggressive ventilatory support
  • Supportive treatment with the multidisciplinary team:
    • Antihypertensive medications (ACE inhibitors)
    • Diuretics for edema
    • Osteopenia management
    • Palliative unilateral/bilateral nephrectomy
    • Dialysis
    • Renal and/or hepatic transplantation
  • Pre-implantation genetic testing with in vitro fertilization in families with a history of ARPKD

Disorders of Renal Positioning

Renal ectopia and non-rotation

• Definition:
  • Renal ectopia: abnormal ascent of the kidneys during embryonic development
  • Renal non-rotation: abnormal rotation of the kidneys
• Epidemiology:
  • Incidence of renal ectopia: 1 in 900 births
  • Incidence of renal non-rotation: 1 in 2,000 autopsies
• Clinical presentation:
  • Usually asymptomatic
  • May have a higher incidence of UTI, urinary obstruction, or kidney stones
  • Ectopic kidney may be found in the pelvis, the thorax, or the contralateral side. 
  • Blood supply is variable.
• Diagnosis:
  • Antenatal or postnatal renal ultrasound
  • Voiding cystourethrogram (VCUG) and serial serum creatinine may be necessary if there is evidence of kidney injury.

Kidney fusion

• Definition: fusion of the lower poles of the kidney (horseshoe kidney)
• Epidemiology:
  • Incidence of 1 in 400–500 births 
  • Associated with Turner’s syndrome
  • Wilms’ tumor, stone disease, hydronephrosis, and MCDK are more common in horseshoe kidneys.
• Clinical presentation and management:
  • Hydronephrosis is a common finding (80% of cases).
  • Many patients are asymptomatic and require no treatment.