Renal tubular dysgenesis

Renal tubular dysgenesis is a severe inherited disorder of fetal renal development characterised by the absence or marked depletion of proximal tubules. Onset is prenatal, with foetal anuria producing oligohydramnios in the second or third trimester and triggering the Potter sequence. Affected neonates typically present with anuria, profound arterial hypotension refractory to volume expansion and vasopressors, and pulmonary hypoplasia; the condition is usually lethal in the neonatal period from renal failure, respiratory insufficiency, and circulatory collapse. Survival beyond the neonatal period has been reported in a minority of cases, and atypical milder presentations with progressive chronic kidney disease in childhood or adolescence have been described.

Due to insufficient data, no reliable statement on prevalence can currently be made. The condition is described as very rare.

Renal tubular dysgenesis is caused by biallelic germline pathogenic variants in genes encoding components of the renin-angiotensin system: ACE (accounting for ~64% of families in the largest reported cohort), REN, AGT, and AGTR1. The resulting loss of angiotensin II generation or signalling produces foetal hypotension and impaired renal perfusion. Evidence from organoids indicates that proximal tubule dysgenesis is primarily a non-cell-autonomous consequence of delayed angiogenesis at a critical developmental window.

Renal tubular dysgenesis is inherited in an autosomal recessive manner. Parents of an affected child are obligate heterozygous carriers, and the recurrence risk in each subsequent pregnancy is 25%. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

Renal tubular dysgenesis is diagnosed primarily by molecular genetic testing. Prenatal ultrasound typically shows oligohydramnios with structurally normal-appearing foetal kidneys; postnatal findings include anuria, refractory hypotension, and pulmonary hypoplasia. Renal histology demonstrates absence or severe depletion of proximal tubules.

• Establishing the molecular diagnosis confirms the clinical suspicion, clarifies the underlying cause, and ends the diagnostic odyssey for the affected family.
• A confirmed molecular diagnosis is a prerequisite for targeted medical care, enabling individualised clinical management to be planned by the treating physicians in consultation with the affected individual or their family.
• Once the familial pathogenic variants are known, testing of at-risk family members can clarify carrier status and inform reproductive counselling.

• Tseng MH, Huang SM, Huang JL, Fan WL, Konrad M, Shaw SW, et al. Autosomal recessive renal tubular dysgenesis caused by a founder mutation of angiotensinogen. Kidney Int Rep. 2020;5(11):2042-51. doi:10.1016/j.ekir.2020.08.011. PMID:; PMCID:PMC7609895.
• Pode-Shakked N, Slack M, Sundaram N, Schreiber R, McCracken KW, Dekel B, et al. RAAS-deficient organoids indicate delayed angiogenesis as a possible cause for autosomal recessive renal tubular dysgenesis. Nat Commun. 2023;14(1):8159. doi:10.1038/s41467-023-43795-x. PMID:; PMCID:PMC10710424.
• Vincent KM, Alrajhi A, Lazier J, Bonin B, Lawrence S, Weiler G, et al. Expanding the clinical spectrum of autosomal-recessive renal tubular dysgenesis: two siblings with neonatal survival and review of the literature. Mol Genet Genomic Med. 2022;10(5):e1920. doi:10.1002/mgg3.1920. PMID:; PMCID:PMC9034669.
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