Renal tubular dysgenesis

RTD is characterised by absence or incomplete differentiation of the proximal tubules, early and persistent anuria, and ossification disorders of the skull. Oligohydramnios caused by reduced fetal urine production can be observed from around the 20th week of pregnancy and persist throughout gestation. The absence of amniotic fluid leads to fetal compression and reduced intrauterine mobility, resulting in the Potter sequence with facial anomalies, excess skin, contractures, and lung hypoplasia.

The early appearance of fetal anuria is contrasted by the absence of major abnormalities of the kidneys or urinary tract on ultrasound examination. The kidneys are normal or slightly enlarged, with or without discrete hyperechogenicity or loss of corticomedullary differentiation.

The disease is always severe. Most patients die in utero or shortly after birth from respiratory distress, persistent anuria and refractory arterial hypotension. Rare survivors show chronic kidney disease or end-stage renal failure from birth.

RTD is described as a rare and severe fetal disorder. Most affected patients die in utero or shortly after birth.

RTD can be acquired during fetal development or inherited in an autosomal-recessive manner. Secondary RTD due to other concomitant diseases has been described in the donor in fetal transfusion syndrome, in fetuses with congenital haemochromatosis, after maternal therapy with renin–angiotensin system (RAS) blockers during pregnancy, as well as in congenital heart disease or renal artery stenosis.

The hereditary form is genetically heterogeneous and is associated with pathogenic variants in genes encoding the main components of the renin–angiotensin system: AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme) and AGTR1 (angiotensin II receptor type 1/AT1).

The renin-angiotensin system controls extracellular volume and maintains peripheral resistance, blood pressure, blood flow, and kidney function. It consists of angiotensinogen synthesised by the liver and cleaved in the circulation by renin, an aspartyl protease produced in the kidney. The resulting peptide angiotensin I is converted by the ectoenzyme ACE into angiotensin II (ANG II), the end product of activation of the RAS cascade. ANG II, an active octapeptide, binds to two different receptors, AT1 and AT2. AT1 mediates the vasopressive effect of ANG II, while AT2 has the opposite effect. ANG II exerts negative feedback control on renin production. Thus, the absence or ineffectiveness of ANG II leads to an overproduction of renin.

Causative variants lead either to a lack of production (alterations in AGT, REN or ACE) or to a lack of efficacy (alterations in AGTR1) of ANG II. ACE variants are causative in 65.5% of cases, REN variants in 20%, AGT variants in 8.5%, and AGTR1 variants in 6%. In contrast to secondary forms, no reduction in intrauterine growth has been observed in connection with the genetic form of RTD. In all cases, renal hypoperfusion occurs.

The hereditary form of Renal tubular dysgenesis is inherited in an autosomal-recessive manner.

Diagnosis of autosomal-recessive RTD is initially based on medical history, clinical findings, pathological examination, and exclusion of secondary forms of the disease. Abnormal renal renin expression may indicate an underlying genetic cause. Molecular genetic confirmation is important to enable genetic counselling, assessment of recurrence risk and, if appropriate, prenatal diagnosis.

Secondary forms of RTD associated with fetal transfusion syndrome, congenital haemochromatosis, maternal renin–angiotensin system blocker therapy, congenital heart disease or renal artery stenosis must be excluded.

• Gubler et al. 2014, Pediatr Nephrol 29:51
• Gribouval et al. 2012, Hum Mutat 33:316
• Kim et al. 2012, Clin Kidney J 5:56