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Renal agenesis occurs when the ureteric bud fails to fuse with the metanephric blastema during embryogenesis, resulting in the absence of the nephron and often the ureter. Unilateral renal agenesis has an incidence of 1 in 1000 live births, whereas bilateral renal agenesis is less common, occurring in 1 in 3000 to 4000 pregnancies. Unilateral renal agenesis generally carries a very favorable prognosis, whereas bilateral renal agenesis is associated with a high rate of perinatal morbidity and mortality because of the absence of amniotic fluid leading to lethal pulmonary hypoplasia.
Definition
Renal agenesis is the absence of renal tissue due to a defect in early embryologic development. Both unilateral and bilateral renal agenesis are commonly associated with other congenital anomalies.
Ultrasound Findings
Although fetal kidneys can be visualized by ultrasound, inferior to the adrenals, by approximately 12 weeks of gestation,
this requires a detailed examination. The diagnosis of renal agenesis is typically made during an anatomy ultrasound examination in midgestation. The presence of amniotic fluid in the first trimester of pregnancy is not predictive of bilateral renal agenesis because early in gestation, amniotic fluid is placental in origin, and relatively normal amniotic volume can be present until approximately 16 to 18 weeks of gestation even in the absence of kidneys or renal function.
The initial sign of renal agenesis is an empty renal fossa. The absence of kidneys should be documented in the axial, sagittal, and coronal planes at the level of the spine below the stomach.
If unilateral renal agenesis is suspected, the possibility of a pelvic or ectopic kidney should be assessed. Hypertrophy of the visualized kidney is suggestive of unilateral renal agenesis.
The lack of amniotic fluid impedes ultrasonographic imaging; thus, diagnostic amnioinfusion has been reported as one technique to confirm the diagnosis. Additional ultrasound findings of renal agenesis include the “lying-down” adrenal sign (Figure 1), in which the adrenals appear large and flat instead of maintaining the normal “Y” configuration. The echogenic adrenal medulla between the cortex creates a layered appearance in the adrenal glands; they lack corticomedullary pyramidal differentiation and should not be confused with renal tissue. Color Doppler should be utilized to visualize the renal arteries originating from the aorta (Figure 2). The absence of renal artery flow at a 90° angle in the coronal plane
is confirmative and should not be confused with flow through the lumbar and adrenal arteries. Confirmation of the absence of a bladder is assisted by evaluating flow through the umbilical arteries. Parental renal ultrasonographic imaging is recommended because of the potential for an inherited etiology.
Figure 1Empty renal fossa with a “lying-down” adrenal sign (arrow)
A careful assessment should include a full evaluation of the urogenital system, including the genitalia. Bilateral renal agenesis with anhydramnios results in Potter syndrome. Features include a flat face with micrognathia, beaked nose, upslanted palpebral fissures, low-set ears, and joint contractures, such as talipes equinovarus. These deformations are secondary to anhydramnios and, in the absence of additional organ system anomalies, consistent with isolated bilateral renal agenesis. Clinically significant variants in multiple genes, including GREB1L,
ITA8, and FGF20, have been identified in cases of isolated renal agenesis and present with variable expressivity and penetrance.
Ultrasound findings that demonstrate cerebral, cardiovascular, gastrointestinal, or muscular systems can aid in the diagnosis of a chromosomal or syndromic etiology. Single-gene disorders include acro-renal-ocular syndrome (SALL4), branchio-oto-renal syndrome (EYA1), Pallister- Hall syndrome (GLI3), and Fraser syndrome (FRAS1, FEB2, and GRIP1).
A molecular genetic diagnosis is particularly useful for prognostic and recurrence risk counseling. Moreover, renal agenesis is associated with maternal environmental factors, including diabetes mellitus, smoking, and alcohol consumption. Diabetes mellitus as the etiology should be considered if identified anomalies suggest VACTERL (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities).
Differential Diagnosis
When renal agenesis is suspected, the presence of other normal or abnormal ectopic or pelvic kidneys should be excluded. It is important to rule out the possibility of preterm premature rupture of membranes and assess for structural anomalies of other organ systems. Fetal growth restriction is another etiology of early-onset anhydramnios, but if that is the primary reason for anhydramnios, kidneys are present. In the setting of unilateral renal agenesis, a second nonfunctioning kidney, such as a multicystic dysplastic kidney, could also result in anhydramnios and the misdiagnosis of bilateral renal agenesis.
Genetic Evaluation
Diagnostic testing with amniocentesis or chorionic villus sampling and chromosomal microarray analysis (CMA) should be offered when bilateral renal agenesis (or unilateral renal agenesis in the setting of other anomalies) is detected. In the setting of anhydramnios, in which amniocentesis is not feasible, testing can be done by placental biopsy. If ultrasound findings or screening test results are suggestive of a common aneuploidy, it is reasonable to initially perform karyotype analysis or fluorescence in situ hybridization, with reflex to CMA if these test results are normal. If there are additional anomalies, consanguinity, or a family history of a specific condition, gene panel testing or exome sequencing is sometimes useful because CMA does not detect single-gene (Mendelian) disorders. If exome sequencing is pursued, appropriate pretest and posttest genetic counseling by a provider experienced in the complexities of genomic sequencing is recommended. After appropriate counseling, cell-free DNA screening is an option for patients who decline diagnostic evaluation, particularly if a common aneuploidy is suspected and anhydramnios is present.
Pregnancy and Delivery Management
Isolated unilateral renal agenesis does not require any alteration in obstetrical management aside from appropriate genetic counseling. If associated anomalies are suggestive of a syndromic etiology or in the setting of bilateral renal agenesis, pregnancy termination should be offered. Shared patient decision-making requires a thorough evaluation and multidisciplinary counseling regarding prognosis.
Fetal therapy with serial amnioinfusions has been reported with a goal of allowing survival by reducing the risk of in utero fetal demise (IUFD) and neonatal pulmonary hypoplasia.
However, the benefit of this procedure in improving survival or morbidity is unknown, and this intervention should be considered investigational and offered only under research protocols, such as the prospective Eunice Kennedy Shriver National Institute of Child Health and Human Development-funded Renal Anhydramnios Fetal Therapy (RAFT) trial. This study is examining the natural history of bilateral renal agenesis and the safety, feasibility, and efficacy of serial amnioinfusions.
It is important to recognize that even if serial amnioinfusion allows improved survival because of better respiratory function, survivors will need to contend with the considerable challenges of absent renal function.
Prognosis
The prognosis for unilateral renal agenesis is favorable in the setting of normal amniotic fluid; however, the long-term prognosis of a hypertrophied unilateral kidney can include adult-onset renal dysfunction and hypertension. Bilateral renal agenesis is considered a life-limiting condition because of anhydramnios associated with IUFD and nonsurvivable neonatal respiratory failure. The RAFT trial may elucidate whether serial amnioinfusions are efficacious in improving outcomes.
Summary
Fetal renal agenesis is characterized by unilateral or bilateral absence of renal tissue. It is commonly associated with additional congenital anomalies as part of a chromosomal or syndromic condition. Targeted ultrasound examinations are recommended to improve counseling regarding an inherited condition. Appropriate genetic and prognostic counseling are recommended, including the likely lethality of bilateral renal agenesis.
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