Bilateral Renal Agenesis

Bilateral renal agenesis is defined as complete absence of both kidneys and ureters, resulting from their failure to form.

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The incidence of bilateral renal agenesis is 1:240 stillbirths, and about 1:3000 livebirths.^1,2 It occurs about three times more frequently in males. It is also more common in twins than in singletons.

Bilateral renal agenesis is due either to failure of the development of the ureteric bud, or to a defect of its interaction with the metanephric blastema.³  In cases of renal agenesis, the defect occurs before day 35 of embryogenesis. Genes related to the induction and development of the ureteric bud, and possibly involved in case of renal agenesis, are WT1, GDNF, RET, PAX2.³. As their role in human bilateral renal agenesis has not been yet clearly defined, prenatal diagnosis should be based just on imaging techniques.

Cases of renal agenesis related to teratogenic exposure to alcohol, cocaine, thalidomide and warfarine have been reported; diabetes mellitus could also be related to this condition.³

Absence of both kidneys makes it impossible for the fetus to produce urine, causing oligo/anhydramnios. Anhydramnios causes mechanical compression of the chest, and impaired development of the lungs, resulting in pulmonary hypoplasia. A typical facial appearance (Potter’s facies) and limbs abnormalities are the other characteristic features of bilateral renal agenesis. This deformation sequence is known as the oligo/anhydramnios sequence or Potter sequence.

Chromosomal abnormalities are not common in fetuses with bilateral renal agenesis, with an association of 1-5%.^{3, 4} Bilateral renal agenesis has been reported mainly in association with trisomy 7, 10, 21, 22 and microdeletion of 22q11. Extra-renal anomalies are associated with bilateral renal agenesis in more than one third of the cases.³ They include mainly cardiac, cerebral, urogenital and skeletal malformations, and are often one of the features of a more complex syndrome.⁵

Renal agenesis could be the main sign of more than 40 different syndromes.³

The most common syndromes and associations are:

• Fraser syndrome(renal agenesis, laryngeal atresia, cryptophthalmos, and syndactyly)
• VA(C)TER(L) association (renal agenesis, vertebral anomalies, anal atresia, cardiac abnormalities, trachea-esophageal fistula and limb anomalies)
• Caudal regression syndrome (renal agenesis, sacral agenesis, lumbar vertebral anomalies and femoral hypoplasia)
• Sirenomelia (renal agenesis,fusion of the lower limbs, anal atresia, vertebral anomalies and genital anomalies)
• Cerebro-oculo-facial-skeletal syndrome (renal agenesis, microcephaly, micrognathia and joint contractures)
• Otocephaly (renal agenesis,agnathia, microstomia, holoprosencephaly and cleft lip/palate.)^{3, 4}

Another typical association is with hypertrophic cardiomyopathy. The ventricular septum and walls are thickened. Pericardial effusion is possible in these cases.

Renal agenesis is often associated with genital anomalies; Mullerian duct derivatives (uterus, vagina) could be abnormal or atretic in females, as well as Wolffian duct derivatives (seminal vescicles, vas deferens) in males.

X-linked, autosomal dominant and recessive inheritance have been reported for renal agenesis.⁶ If renal agenesis is isolated, the empiric risk of recurrence is 3-4%, whereas if it is one sign of a syndrome, the risk of recurrence is obviously the risk associated with the underlying syndrome. The finding of a renal agenesis in one of the parent increases the recurrence risk to 15-20%³, as this means that there is a potential gene for the hereditary renal abnormality, carried by one of the parents.

Sonographic diagnosis of bilateral renal agenesis is based on the impossibility of visualizing the kidneys and the bladder, associated with severe oligohydramnios after the 16th week of gestation. In these cases, it is important not to mistake the adrenal glands for the kidneys. In fact, when imaging the renal fossae, kidneys should be differentiated from the adrenal glands. Due to the absence of the kidneys, these glands sometimes appear merely rounder than normal and fill the renal fossa⁷ in what has been termed the “lying down” adrenal sign⁸, making the diagnosis of bilateral renal agenesis difficult. The features that may help in differentiating the adrenal glands from the kidneys are as follows: the adrenal glands are smaller and oblong, and (in contrast to the renal medulla), the adrenal medulla is hyperechoic rather than hypoechoic.

However, the lack of an acoustic window, due to the severe oligohydramnios, can make diagnosis challenging in some cases. Although amnio-infusion has been proposed as a diagnostic aid, it is generally sufficient to employ color/power Doppler to confirm the absence of the renal arteries, a feature consistent with the diagnosis of bilateral renal agenesis.^4,9

In cases of bilateral renal agenesis, the differential diagnosis should include other conditions possibly responsible for severe oligohydramnios: severe bilateral renal disease, urethral obstruction, severe FGR and rupture of the membranes.

In case of sever renal disease, the kidneys are visible and usually abnormal (e.g. bilateral multicystic kidneys, infantile polycystic renal disease); the bladder outlet obstruction is usually associated with a megacystis. In the presence of severe FGR, oligohydramnios and an empty bladder are associated, but the fetal growth rate is reduced, and the umbilical artery velocimetry is usually abnormal. In case of rupture of the membranes, the main feature is oligohydramnios: a normal bladder can be usually visualized, and this can be helpful to exclude bilateral renal agenesis.^{4, 10}

Suring the first trimester screening, when the amniotic fluid would still be normal in case of bilateral renal agenesis, the routine visualization of the fetal bladder could help to exclude this malformation. The lack of visualization of the bladder could help identification of high-risk cases. Oligohydramnios after 16 weeks would raise strong suspicion of a severe renal problem. This readily detectable sign should be considered as a hint to check the fetal renal fossae and pelvis. For this reason, the best time to assess the kidneys is after 16 weeks, during the anomaly scan (19-21 weeks), when diagnosis of bilateral agenesis of kidneys is usually feasibile. On the other hand, it has to be remarked that oligohydramnios is the main limiting factor to a proper examination of the renal anatomy, as it significantly reduces the ultrasound visualization of the fetal structures. This is why some authors would suggest amnio-infusion as a possible option to improve the ultrasound visualization and detection.¹¹

Ultrasound diagnosis has been reported to be possible in the first trimester, using a transvaginal scan.¹²

The outcome of bilateral renal agenesis is uniformly fatal, due to the associated severe pulmonary hypoplasia. In addition to provoking the typical Potter sequence (Potter facies, deformation of hands and feet, etc.), severe oligohydramnios induces lethal pulmonary hypoplasia. Both the compression of the fetal chest by the uterine walls, and the absence of amniotic fluid, arrest pulmonary development: one-third of fetuses die in utero and the remaining two-thirds die immediately after birth due to severe pulmonary hypoplasia.^{4, 13}

Although the association with chromosomal anomalies is not considered to be high, some authors advise karyotyping¹⁴, especially in cases associated with other malformations, to help to estimate the recurrence risk. No surgical treatment is currently available for bilateral renal agenesis. Due to the invariably bad prognosis, termination of pregnancy can be offered.¹⁵

1. Cardwell MS. Bilateral renal agenesis: clinical implications. South Med J. 1988 Mar; 81(3):327-8.

2. Potter EL. Normal and abnormal development of the kidney. Year book medical publishers, Chicago, 1972.

3. Evans JA. Urinary tract. In: Stevenson RE, Hall JG. Human Malformations and Related Anomalies, second edition. Oxford. Oxford University Press. 2006: 1161-90.

4. Paladini D, Volpe P. Ultrasound of Congenital Fetal Anomalies. Informa Healthcare, 2007.

5. EUROSCAN Study Group: Wiesel A, Queisser-Luft A, Clementi M, Bianca S, Stoll C. Prenatal detection of congenital renal malformations by fetal ultrasonographic examination: an analysis of 709,030 births in 12 European countries. Eur J Med Genet. 2005 Apr-Jun;48(2):131-44.

6. Bianchi D, Crombleholme T, D' Alton M, Malone F. Fetology: Diagnosis and Management of the Fetal Patient. Second Edition. McGraw Hill Professional, 2010; 589-95.

7. Droste S, Fitzsimmons J, Pascoe-Mason J, Shepard TH, Mack LA. Size of the fetal adrenal in bilateral renal agenesis. Obstet Gynecol. 1990 Aug;76(2):206-9.

8. Hoffman CK, Filly RA, Callen PW. The "lying down" adrenal sign: a sonographic indicator of renal agenesis or ectopia in fetuses and neonates. J Ultrasound Med. 1992 Oct;11(10):533-6.

9. DeVore GR. The value of color Doppler sonography in the diagnosis of renal agenesis. J Ultrasound Med. 1995 Jun;14(6):443-9.

10. Twining P. Genitourinary Malformation. In: Nyberg DA, McGahan JP, Pretorius DH, Pilu G (eds): Diagnostic Imaging of Fetal Anomalies. Lippincott Williams & Wilkins, Philadelphia, 2003: 610-14.

11. Gembruch U, Hansmann M. Artificial instillation of amniotic fluid as a new technique for the diagnostic evaluation of cases of oligohydramnios. Prenat Diagn. 1988 Jan;8(1):33-45.

12. Bronshtein M, Amit A, Achiron R, Noy I, Blumenfeld Z. The early prenatal sonographic diagnosis of renal agenesis: techniques and possible pitfalls. Prenat Diagn. 1994 Apr;14(4):291-7.

13. Nagase H, Ishikawa H, Nishikawa T, Kurosawa K, Itani Y, Yamanaka M. Prenatal management of the fetus with lethal malformation: from a study of oligohydramnios sequence. Fetal Pediatr Pathol. 2011;30(3):145-9.

14. Gruskin D, Kanil E, Rimoin D. Congenital disorders of the urinary tract. In: Rimoin D, Connor JM, Pyeritz RE, Korf BR, eds. Emery and Rimoin’s Principles and Practice of Medical Genetics, 4th edn. Edinburgh. Churchill-Livingstone. 2002: 1659–743.

15. Gramellini D, Fieni S, Kaihura C, Piantelli G, Verrotti C. Antepartum amnioinfusion: a review. J Matern Fetal Neonatal Med. 2003 Nov; 14(5):291-6.

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