Congenital anomalies of the kidney and urinary tract--role of the loss of function mutation in the pluripotent angiotensin type 2 receptor gene.

PURPOSE: Recent studies of the human genome and genetic engineering experiments in mice revealed that congenital anomalies of the kidney and urinary tract commonly seen in newborns in various anatomical forms are polygenic disease, that is a disease caused by simultaneous defects in multiple genes. We discuss some possible genetic explanations of the classic theories of the formation of congenital kidney and urinary tract anomalies. MATERIALS AND METHODS: We reviewed classic and current theories regarding urinary tract development. Included in our review are recent results from our laboratory evaluating the genetic role of normal and abnormal urinary tract development. RESULTS: We observed a genetic abnormality that may explain many classic anatomical theories of congenital kidney and urinary tract anomalies. One of the genes involved in urinary tract ontogenesis is the angiotensin type 2 receptor gene, which is the "other" angiotensin receptor. While the type 1 receptor mediates essentially all known actions of angiotensin, including its hypertensive effect, relatively little is known about the angiotensin type 2 receptor. Careful dissection studies in mutant mouse embryos selectively lacking the angiotensin type 2 receptor gene revealed that this gene is pleiotropic, that is its defect causes not only ectopic ureteral budding from the wolffian duct, but also disturbance in other subsequent ontogenic events that are critical for the normal growth of the kidney and urinary tract. CONCLUSIONS: Many congenital anomalies of the kidney and urinary tract appear to share a common genetic cause. While these anomalies are caused by various genetic hits, abnormalities in the angiotensin type 2 receptor gene are often involved in this anomalous development. This review article offers a better understanding of the genetics involved in urinary tract development and ties some of the newly emerging genetic theories with classic anatomical theories.

How they begin and how they end: classic and new theories for the development and deterioration of congenital anomalies of the kidney and urinary tract, CAKUT.

CAKUT are problems that often require surgical intervention or, in the worst case, lead to renal failure and the need for dialysis and/or renal transplantation. It is believed that these anomalies share a common genetic cause and to date there has been no good animal model with which to study these abnormalities. Although the abnormal interaction between the ureteral bud and metanephric blastema leads to renal hypodysplasia, vesicoureteral reflux, and ectopic ureters to name a few, the genetic and biochemical modulation of urinary tract development is not understood. Studies using the mouse strain mutant for angiotensin type 2 (AT2) receptors have given new insight into this mystery. The animals show defective apoptosis of undifferentiated mesenchymal cells in the area surrounding the developing kidney and urinary tract. This abnormal apoptosis may well interfere with the normal interaction between the ureteral bud and metanephric blastema resulting in CAKUT. This abnormal interaction would theoretically lead to preexisting intrinsic abnormalities of the kidney, which are programmed and take effect early in embryonic development. In the worst cases, the renal abnormalities would lead to progressive deterioration of renal function. Undoubtedly, there are more genes and biochemical modulators involved in this process other than the RAS and AT2 receptors. Our current animal model gives new and unique possibilities with which to study development of the kidney and urinary tract and ultimately seek ways of preventing an often debilitating disease process.

Prune-belly syndrome: ongoing controversies regarding pathogenesis and management.

Classical prune-belly syndrome (also known as Triad syndrome, Eagle-Barrett syndrome, abdominal muscular deficiency syndrome) consists of a triad of anomalies: deficient abdominal wall musculature, urinary tract dilatation, and cryptorchidism. Although most investigators consider prune-belly syndrome a distinct entity, there is no consensus as to its pathogenesis despite extensive study of clinical cases and pathological material. Prognosis may vary from death in utero to a near-normal life expectancy. The lack of understanding of pathogenesis and wide range of severity result in dilemmas in treatment planning, and surgeons vary widely in their approach. This article discusses prune-belly syndrome, presents the currently favored hypotheses regarding its pathogenesis, and gives an overview of accepted management strategies.

Pathogenesis of the prune belly syndrome.

The triad of abnormalities of the prune belly syndrome may arise simply from the effects of early urethral obstruction or alternatively from a basic defect of the mesoderm from which the triad of abnormalities develops. The urethra and genital tract of 21 prune belly syndrome specimens and 23 specimens of Young's posterior urethral valves types 1 and 3 were compared in a study for differences in the pathological anatomy that may elucidate the controversy. The specimens were dissected and investigated radiographically and histologically. The seminal ducts and vesicles, and prostatic glands were abnormal in the prune belly syndrome specimens and normally developed in the posterior urethral valve specimens. We contest that this major difference stems from a primary defect of the intermediate and lateral plate mesoderm in the prune belly syndrome which would affect the embryogenesis not only of the mesonephric and paramesonephric ducts but also of the musculature of the abdominal wall and urinary organs, and that prune belly valves when present are intrinsic components of the mesodermal defect of the prune belly syndrome urethra.

Pathogenesis of megalourethra.

Idiopathic megalourethra in infants is an enlargement of the pendulous urethra with no evidence of distal obstruction. Two aborted fetuses at 14 and 19 weeks of gestational age exhibited megalourethra with definite complete distal obstruction. The urethras of these 2 fetuses were studied histologically confirming the presence of an uncanalized epithelial core in the glans obstructing the lumen of the patent urethra. Embryologically, this epithelial core is normal but early canalization achieves continuity with the lumen of the penile urethra. In these 2 fetuses canalization was arrested or delayed with complete obstruction of the urethra in the glans and dilatation of the pendulous urethra. In living children with this form of megalourethra the urethra of the glans is patent. Canalization of the epithelial core in the glans of the survivors may have been delayed rather than arrested and may be a cause of megalourethra.

Cloacal exstrophy: a report of 34 cases.

A clinical review is presented on 34 patients with cloacal exstrophy who were seen between 1963 and 1986. The patients were separated into 2 main groups: classical cloacal exstrophy (type I) and variant cloacal exstrophy (type II). In the classical cases 3 surface patterns were recognized: A-hemibladders confluent cranial to the bowel, B-hemibladders lateral to the bowel and C-hemibladders confluent caudal to the bowel. Surgical reconstruction was performed in 24 patients, with a 50 per cent survival rate. However, there was marked improvement in survival from 22 per cent between 1963 and 1978 to 90 per cent between 1979 and 1986.

Renal dysgenesis and cystic disease of the kidney: a report of the Committee on Terminology, Nomenclature and Classification, Section on Urology, American Academy of Pediatrics.

We believe that the confusion regarding abnormal renal development could be reduced by more precise terminology. Therefore, we suggest precise definitions for dysgenesis, hypoplasia, dysplasia, hypodysplasia, aplasia and agenesis of the kidney. We suggest the term reflux nephropathy be a generic label for any instance of abnormal renal morphology (gross or microscopic) associated with vesicoureteral reflux. Hypoplasia and hypodysplasia can be subclassified on the basis of associated urological criteria. There have been many previous attempts to classify cystic disease of the kidney but none has been accepted collectively by pathologists, urologists, nephrologists and radiologists. On the basis of known patterns of inheritance, a classification is outlined in which renal cystic disease is divided into 2 major groups: genetic and nongenetic. Each entity is discussed.

The Mayer-Rokitansky syndrome: pathogenesis, classification and management.

Agenesis of the vagina in karyotypic female subjects may be accompanied by other defects of the urogenital system. We describe 8 cases that exemplify nearly all variants in the group of müllerian and renal anomalies that we identify as the Mayer-Rokitansky syndrome. We trace the association of system defects to errors of formation of the wolffian body. This structure is the progenitor of the gonad and wolffian duct, which although temporary in the female subject, gives rise to the ureter and is the path finder of the müllerian system. Errors of formation or premature atrophy of the wolffian duct, or intrinsic müllerian organizers lead to the array of anomalies in this syndrome. Vaginal agenesis was found to be associated with müllerian, renal or ovarian defects in numerous embryological combinations. We propose a müllerian classification, and describe the current diagnostic modalities and techniques of surgery.

Covered anus with anocutaneous fistula: the muscular sphincters.

A rare specimen of a covered anus with anocutaneous fistula obtained from a newborn female baby was subjected to macroexamination and microexamination to determine the anatomy of the sphincters and the levatores musculature. The internal sphincter and the deep voluntary sphincters, albeit slightly modified, were well developed but the sphincters in the perineum were absent or rudimentary. The pelvic muscles were present even in the absence of the sacrum up to and including the second sacral vertebra.

Suggested terminology for duplex systems, ectopic ureters and ureteroceles.

Recommendations are made for the standardization of nomenclature describing duplex systems, ectopic ureters and ureteroceles. The elimination of some terms and redefinition of others are proposed in the hope to eliminate the ambiguity and confusion that exist currently.