Pediatrics

Renal hypoplasia/dysplasia/agenesis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has renal hypoplasia/dysplasia/agenesis? What are the typical findings for this disease?

Unilateral agenesis in neonates is an incidental finding. Patients may debut in adulthood with renal failure or hypertension, especially if there is contralateral pathology such as obstruction or reflux.

Signs and symptoms of bilateral renal hypoplasia/dysplasia depend on the severity of renal impairment. Commonly, these patients present with various stages of chronic renal disease.

Bi Bilateral renal agenesis is associated with Potter syndrome and is usually incompatible with life due to pulmonary insufficiency.

Congenital abnormalities affecting the kidney and the genitourinary tract are one of the most common structural birth defects, and may be responsible for significant morbidity and mortality.

Approximately 50% of babies with bilateral renal dysplasia or agenesis die before the age of 3 years due to pulmonary hypoplasia and/or renal compromise. Other abnormalities, despite originating during embryogenesis, may not be clinically apparent until adulthood (if at all in unilateral cases!), when patients may present with deteriorating renal function, especially hypertension.

Diagnosis and clinical classification of urinary tract abnormalities may be difficult due to phenotypic and clinical variability. Many investigators have opted to group urologic malformations under the label of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). Mutation in a single gene can have multiple and different effects on the development of the urogenital tract.

Classification

Renal Agenesis

Defined as unilateral or bilateral absence of kidneys. Bilateral cases are rare and a fatal event as they are associated with severe oligohydramnios and Potter syndrome: facial compression and severe pulmonary hypoplasia.

Renal hypoplasia and dysplasia

  • Renal hypoplasia is defined as a small kidney, which contains normal nephrons (qualitative) that are reduced in number (quantitative).

  • Renal dysplasia is defined as a small kidney with disorganized and maldifferentiated tissue (quantitative and qualitative).

  • Distinction between dysplasia and hypoplasia depends on histological examination of renal tissue.

  • In practice, the diagnosis of renal hypoplasia should be considered if:

    1. Renal size is reduced by two standard deviations from the mean for age and renal scarring is excluded by DMSA scan.

    2. Compensatory hypertrophy is identified in the contralateral kidney.

What other disease/condition shares some of these symptoms?

There are several multi-organ syndromes associated with renal agenesis and hypoplasia:

  • Miller-Dieker syndrome

  • DiGeorge syndrome

  • Brachio-oto-renal syndrome

  • Fanconi anemia

  • Fraser syndrome

  • Kallmann syndrome

  • Klinefelter syndrome

  • Rokitansky-Küster-Hauser syndrome

  • MURCS association (Müllerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia)

  • Poland syndrome

  • Renal cysts and diabetes syndrome

  • Townes-Broks syndrome

  • Williams-Beuren syndrome

  • Down syndrome

  • Velocardiofacial syndrome

  • Patau syndrome

  • Edward syndrome

  • Cat eye syndrome

  • Turner syndrome

Differential diagnosis of renal agenesis includes:

  • Ectopic kidney

  • Crossed fused ectopic kidney

  • Multicystic dysplastic kidney

Renal hypoplasia/dysplasia may be associated with:

  • Vesicoureteral reflux

  • Uretero-pelvic junction obstruction

  • Ectopic ureter

  • Polycystic kidney

What caused this disease to develop at this time?

  • · The development of the kidney begins during the 5th week of gestation from the interaction between two embryonic structures: 1) the metanephric blastema and 2) the ureteric bud.

  • · An aberrant interaction between these two structures leads to renal dysplasia/hypoplasia. On the other hand, the complete failure of the ureteric bud to interact with the metanephric blastema leads to renal agenesis.

  • · Mutations in different genes that encode transcription factors or cofactors that regulate critical steps in renal development have been associated with changes in nephrogenesis.

  • · Renal hypoplasia/dysplasia/agenesis may occur without apparent causes, but genetic factors and teratogens can contribute.

  • · Urinary obstruction has been associated with renal hypoplasia/dysplasia.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • · The principal aim once the diagnosis is established is to identify the entity and prevent ongoing damage to the remaining nephrons.

  • · Evaluation is done in a multidisciplinary fashion. In unilateral cases, serum creatinine and urea concentrations will be normal. In severe cases, renal function should be assessed. Serum creatinine and urea concentrations in the first 24 hours after birth will be the same as maternal concentrations except in the worst cases, where they may be elevated. Baseline glomerular filtration rate (GFR) may be calculated with the Schwartz formula. This is more accurate than serum BUN and creatinine. Assessment of electrolytes is essential. Hyponatremia is frequent in the presence of polyuria. Prompt sodium chloride supplementation is essential.

  • · Hyperkalemia due to reduced glomerular filtration, reduced tubular secretion, and associated metabolic acidosis can be life-threatening. Management depends on severity.

  • · Blood pressure (BP) should be compared with age-appropriate charts.

  • · Assessment by genetics should be considered if syndromic features are present.

Would imaging studies be helpful? If so, which ones?

  • · Renal agenesis/dysplasia/hypoplasia could be suspected antenatally with findings of absent or small kidney.

  • · Every case of antenatal diagnosis should be confirmed with a postnatal renal ultrasound. Ultrasound may also suggest hydronephrosis of the contralateral collecting system in unilateral cases, as both UPJ obstruction and megaureter are more common in this setting, and of course may adversely affect the remaining kidney.

  • · DMSA (technetium dimercaptosuccinic acid) scans can be useful in differentiating renal agenesis from an ectopic kidney. CT and MRI have also been used to establish its presence, but should be considered as secondary.

  • · DMSA scans are also used to assess differential renal function and cortical defects in renal dysplasia/hypoplasia.

  • · Vescicoureteral reflux is common. Thus, many advocate doing a voiding cystourethrogram (VCUG) with the thought that if reflux is present, a UTI could cause secondary renal damage

Confirming the diagnosis

A renal ultrasound in the minimum investigation. No generally agreed upon algorithm exists.

If you are able to confirm that the patient has renal hypoplasia/dysplasia/agenesis, what treatment should be initiated?

  • · Treatment depends of two factors: the degree of chronic renal disease and the presence of associated conditions that may worsen renal damage.

  • · Chronic renal disease is classified in five stages, depending on the glomerular filtration rate. Treatment is focused on preventing progression to stage 5, end-stage renal disease. Stage 5 renal failure requires renal replacement therapy, whether dialysis or renal transplantation.

  • · Renal hypoplasia and/or dysplasia is frequently associated with such urological conditions as vesicoureteral reflux, ureteropelvic or ureterovesical junction obstruction and ectopic kidneys. Treatment must be individualized accordingly.

What are the adverse effects associated with each treatment option?

N/A

What are the possible outcomes of renal hypoplasia/dysplasia/agenesis?

Prognosis is directly related to the presence and severity of chronic kidney disease. Approximately 10% of children with renal dysplasia/hypoplasia have a first-degree relative with urinary tract disease, suggesting a CAKUT (congenital anomalies of the kidney and urinary tract) association.

Cases detected antenatally are best managed in a multidisciplinary clinic with a urologist, nephrologist, geneticist and fetal medicine specialist, especially with severe bilateral abnormalities. Prenatal counseling is important. When perinatal death or early onset renal failure is likely, termination of pregnancy is an option for some parents.

Postnatally, if a bilateral abnormality results in oligohydramnios, delivery in a high-risk center should be encouraged due to the risk of pulmonary dysplasia and electrolyte and metabolic abnormalities.

Unilateral cases with normal amniotic fluid and a normal contralateral kidney should be managed as if two normal kidneys were present, i.e., in a standard maternity unit.

What causes this disease and how frequent is it?

  • Bilateral renal agenesis occurs in 0.1/1000 births. Unilateral cases are more common at 1:800-1200, although incidence is uncertain since unilateral renal agenesis is asymptomatic in the neonate.

  • Theincidence of unilateral renal dysplasia is approximately 1/1000births. Bilateral dysplasia occurs in approximately 1/5000 births.

  • The principal genes associated with renal agenesis, hypoplasia and dysplasia are shown in Table I.

Table I.

Principal genes associated with renal agenesis, hypoplasia, and dysplasia
Gene Kidney phenotype
FOXD1 Small, fused, undifferentiated kidney
EYA1 Absent kidneys
EMX2 Absent kidneys
HOXA11/HOXD11 Small or absent kidneys
LHX1 Absent kidneys
PAX2 Small or absent kidneys
WT1 Absent kidneys
AGTR2 Multiple urinary tract malformations
BMP4 Altered ureteric bud (UB) branching
BMP7 Disrupted nephrogenesis
WNT4 Undifferentiated kidneys
RET Absent kidneys, severe dysgenesis
GDNF Absent kidneys, severe dysgenesis
SIX1 Absent kidneys
SIX2 Small kidneys
SALL1 Absent kidneys
FGFR1/FGFR2 Absent kidneys
SLIT3 Small or absent kidneys
PBX1 Small or absent kidneys
FGF8 Small kidneys
RARA/RARB2 Small kidneys
LIM1 Absent kidneys

How do these pathogens/genes/exposures cause the disease?

N/A

Other clinical manifestations that might help with diagnosis and management

N/A

What complications might you expect from the disease or treatment of the disease?

N/A

Are additional laboratory studies available; even some that are not widely available?

N/A

How can this disease be prevented?

N/A

What is the evidence?

Hegde, S, Coulthard, MG. "Renal agenesis and unilateral nephrectomy: what are the risks of living with a single kidney?". Pediatr Nephrol. vol. 24. 2009. pp. 439-46.

Good reference for prognosis in unilateral renal agenesis

La Scola, C, Hewitt, I, Pasini, A. "Postnatal management of congenital bilateral renal hypodysplasia". J Matern Fetal Neonatal Med. vol. 23. 2010. pp. 97-100.

Very detailed paper about postnatal management of bilateral renal dysplasia/hypoplasia

Sanna-Cherchi, S, Caridi, G, Weng, PL. "Genetic approaches to human renal agenesis/hypoplasia and dysplasia". Pediatr Nephrol. vol. 22. 2007. pp. 1675-84.

Excellent article to understand the human genetic in renal hypoplasia/dysplasia/agenesis

Uetani, N, Bouchard, M. "Plumbing in the embryo: developmental defects of the urinary tracts". Clin Genet. vol. 75. 2009. pp. 307-17.

Didactic paper about renal embryogenesis

Winyard, P, Chitty, LS. "Dysplastic kidneys". Semin Fetal Neonatal Med. vol. 13. 2008. pp. 142-51.

Good reference for dysplastic kidneys

Woolf, AS, Hillman, KA. "Unilateral renal agenesis and the congenital solitary functioning kidney: developmental, genetic and clinical perspectives". BJU Int. vol. 99. 2007. pp. 17-21.

Review paper about unilateral renal agenesis

Ongoing controversies regarding etiology, diagnosis, treatment

Long-term follow-up studies of patients with renal hypoplasia/dysplasia/agenesis are needed to provide insight into prognostic factors identified antenatally. In the future, rapid genetic analysis may be possible.

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