Renal Tubular Dysgenesis, a Not Uncommon Autosomal Recessive Disorder Leading to Oligohydramnios

Abstract

Renal tubular dysgenesis is a clinical disorder that is observed in fetuses and characterized by the absence or poor development of proximal tubules, early onset and persistent oligohydramnios that leads to the Potter sequence, and skull ossification defects. It may be acquired during fetal development or inherited as an autosomal recessive disease. It was shown recently that autosomal recessive renal tubular dysgenesis is genetically heterogeneous and linked to mutations in the genes that encode components of the renin-angiotensin system. This study analyzed the clinical expression of the disease in 29 fetus/neonates from 18 unrelated families and evaluated changes in renal morphology and expression of the renin-angiotensin system. The disease was uniformly severe, with perinatal death in all cases as a result of persistent anuria and hypoxia related to pulmonary hypoplasia. Severe defects in proximal tubules were observed in all fetuses from 18 gestational weeks onward, and lesions also involved other tubular segments. They were associated with thickening of the renal arterial vasculature, from the arcuate to the afferent arteries. Renal renin expression was strikingly increased in 19 of 24 patients studied, from 13 families, whereas no renal renin was detected in four patients from three families. Angiotensinogen and angiotensinconverting enzyme were absent or present in only small amounts in the proximal tubule, in correlation with the severity of tubular abnormalities. No specific changes were detected in angiotensin II receptor expression. The severity and the early onset of the clinical and pathologic expression of the disease underline the major importance of this system in fetal kidney function and development in humans. The identification of the disease on the basis of precise histologic analysis and the research of the genetic defect now allow genetic counseling and early prenatal diagnosis. (1) in two stillborn siblings who had developed fetal anuria that resulted in oligohydramnios and the Potter phenotype. Fetal urine is the major constituent of amniotic fluid, especially after 18 to 20 gestational weeks, and estimation of its abundance is the best approach for evaluation of fetal kidney function. Oligohydramnios, whatever the cause, leads to fetal compression and decreased intrauterine motility, resulting in the Potter sequence that includes redundant skin, facial dysmorphia with large and flattened low-set ears, limb positioning

Effect of Drugs on Renal Development

“…An important example in the light of drug effects is renal tubular dysgenesis (14). This is characterized by kidneys of normal size and appearance on ultrasound, but without any urine production or clearance.…”

“…Genetic knockout mice of the angiotensin II type 1 receptor or angiotensinogen have both resulted in an atrophic renal papilla (29), underlining the role of the RAS in renal development. Several clinical and frequently lethal sequelae have been described of RAS blocking during development, including renal insufficiency, oligohydramnion with hypoplastic lungs and respiratory insufficiency, and limb contractures (14). Kidney analysis of neonatal ACEI-or ARB-treated rats confirms the atrophy of the renal papilla together with tubular alterations such as fibrosis, atrophy, and urinary concentration impairment (32), but it also shows a reduction in nephron numbers (33).…”

Inherited renal tubular dysgenesis: the first patients surviving the neonatal period

“…ACE-inhibitor, angiotensin II receptor antagonist, nonsteroidal antiinflammatory drug (8,10,11), twin-to-twin transfusion syndrome, major cardiac malformations (3) and severe liver disease (5). A recent series on autosomal recessive RTD showed a uniformly severe course characterised by early onset oligohydramnios, persistent fetal anuria, pulmonary hypoplasia, severe refractory arterial hypotension and perinatal death (7). Other features were also described, such as skull hypoplasia of the membranous bones resulting in wide cranial sutures and large fontanels.…”

Ontogeny of angiotensin-converting enzyme 2

“…Use of ACE inhibitors or AT 1 R antagonists during fetal life, as well as mutations in the genes encoding angiotensinogen, renin, ACE, and AT 1 R in humans, are associated with renal tubular dysgenesis (9). Genetic inactivation of angiotensinogen, renin, ACE, or AT1R in mice causes abnormal glomerular and renal vascular development, pelvic dilation (hydronephrosis), and hypoplastic papilla (10).…”