Contributed by Antonio Alvarez-Mendoza MD, Terry L. Fox, MD and Dale S. Huff, MDFINAL DIAGNOSIS: -- RENAL TUBULAR DYSGENESIS (RTD)
DISCUSSION:
Since the original description of RTD in 1983 by Allanson (2), numerous subsequent reports have supported the theory of a disease with an autosomal recessive background (3,4,5,6,7). The most common scenario has been similar to the present case. The parents are unaffected and consanguinity has been described in some families (3,4,8,9). Often there is a family history of a previous prematurely born sibling with oligohydramnios that become apparent after the twentieth week (7). On physical examination all the patients have oligohydramnios sequence, anuria and respiratory failure. The diagnosis is establish at the autopsy. The characteristic anatomic feature is absence of proximal tubular differentiation confirmed by immunostain for Epithelial Membrane Antigen in all epithelial tubular structures. In the normal kidney, only the distal and collecting tubes are positive (6,7,5). Several other markers can be used to assess the presence or absence of proximal convoluted tubules such as Lysozyme; alpha 1-antitrypsin (8); Peanut Arachis hypogaea lectin, a marker of normal collecting ducts; and winged pea Tetragonolobus lotus lectin, a selective marker of proximal tubules (10,7). Microdissection of the nephrons has demostrated hypoplasia not restricted to the proximal convoluted tubules, but is present in all segments of the nephrons from the glomeruli to the collecting tubules (4,11).
Non familial, intrauterine acquired cases have been recognized recently. Intrauterine ischemia is probably the pathogenetic mechanism in these cases. Some are associated with severe congenital liver disease (12). In utero exposure to non-steroidal anti-inflammatory agents (NSAIDs) can induce renal dysgenesis in fetal monkeys and renal structural abnormalities in the developing human fetus, presumably due to decreased renal flow (13,14). Angiotensin converting enzyme (ACE) inhibitors administered during pregnancy can cause fetopathy with renal tubular dysgenesis and severely underdeveloped calvarial bones (15). The presumed mechanism again is the hypoxic effects of ACE inhibition on the renal microvasculature. In these ACE inhibitor induced cases of RTD, immunohistochemistry shows strong staining for renin in the preglomerular arteriole extending into the juxtaglomerular apparatuses at the glomerular hilum. This finding suggests that a large amount of renin causes increased local vasocontriction resulting in reduction of glomerular perfusion and ultrafiltration leading to oligohydramnios and postnatal oliguria (16). Due to the fact that angiotensin II is a renal tubular growth factor, an abnormality in its receptors may provide a link to the deficiency of tubular development that causes RTD (17). In our case there was no evidence of underdeveloped calvarial bones, but the juxtaglomerular apparatus showed a prominent macula densa. This correlates with the proposed hypothesis of increased local vasoconstriction as a cause of oliguria.
It is not clear whether the absence of recognizable proximal convoluted tubules signifies RTD because similar tubular changes might also be present in other conditions as a result of ischemia . Kidneys lacking normal appearing proximal tubules were found in 6 of 500 (1.2%) of perinatal autopsies where only one live born infant met the criteria for RTD (18). In this study the lack of recognizable renal proximal tubules most often was not a manifestation of RTD. It may be that renal tubular degeneration is due to renal hypoperfusion, as seen in twin-twin transfusion and acardia. Postnatally acquired atrophy of renal tubules can exhibit similar lectin staning pattern as RTD (1).
We feel that in our case there is an autosomic recessive pattern of inheritance. A contributing factor could be "ischemia"due to vascular thrombosis and decidual vasculopathy resulting in a small pacenta, 200 grams (10th percentile) . It is difficult to ascribe the ischemic changes in the placenta to the clinical history of 1 pack per day cigarette smoking in the mother. Schwartz raised the question of the possible effects of maternal cigarette smoking, alcohol intake and cocaine use during pregnancy on two siblings who died with changes of RTD (6). He postulated that repeated drug-related ischemic events with no frank arterial blockage could result in diffuse parenchymal changes.
The presence of renal venous thrombosis found in our case has also been described in other cases (3,19). It has been felt that venous thrombosis is not an event accounting for RTD. It is speculated that venous thrombosis could be secondary to a compression phenomenon associated with oligohydramnios.
Pulmonary hypoplasia is another common associated finding which is an important component of oligohydramnios sequence due to renal and non-renal causes. The pulmonary defect appears to be a deficiency of late fetal development during oligohydramnios (20,21). Although, in our case the lungs weigh was within the normal percentile (0.017 using Askenazi's definition of lung:body ratio) (22). During 23 hrs that this neonate survived, he developed hyaline membrane disease and early acute bronchopulmonary dysplasia, as usually happen in cases of pulmonary hypoplasia. Cases without hypoplasia are also well documented (23).
The prenatal diagnosis of RTD by ultrasonography should be suspected in cases of late onset oligohydramnios associated with a renal sonogram that shows kidneys of normal position and size without hydronephrosis or macroscopic cysts, but with indistinct corticomedullary junction (24).
In conclusion we feel the this case is an example of RTD with an autosomal recessive pattern of inheritance with associated lesions suggestive of a chronic reduction in utero placental perfusion.
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Contributed by Antonio Alvarez-Mendoza MD, Terry L. Fox, MD and Dale S. Huff, MD
