Induction and patterning of the metanephric nephron.

The functional unit of the mammalian metanephric kidney is the nephron: a complex tubular structure dedicated to blood filtration and maintenance of several important physiological functions. Nephrons are assembled from a nephron-restricted pool of mesenchymal progenitors over an extensive developmental period that is completed prior to (human), or shortly after (mouse), birth. An appropriate balance in the expansion and commitment of nephron progenitors to nephron formation is essential for normal kidney function. Too few nephrons increase risk of kidney disease later in life while the failure of normal progenitor differentiation in Wilm's tumor patients leads to massive growth of a nephroblast population often necessitating surgical removal of the kidney. An inductive process within the metanephric mesenchyme leads to the formation of a pretubular aggregate which transitions into an epithelial renal vesicle: the precursor for nephron assembly. Growth, morphogenesis and patterning transform this simple cyst-like structure into a highly elongated mature nephron with distinct cell types positioned along a proximal (glomerular) to distal (connecting segment) axis of functional organization. This review discusses our current understanding of the specification, maintenance and commitment of nephron progenitors, and the regulatory processes that transform the renal vesicle into a nephron.

The effect of vitamin A deficiency in maternal rats on tumor formation in filial rats.

PURPOSE: We established a vitamin A-deficient (VAD) model of pregnant rats to evaluate the effect of vitamin A deficiency in maternal rats on tumor formation in filial rats. METHODS: Ten pregnant Wistar rats were divided into 2 groups: (1) VAD group, 6 rats were given nonvitamin A diet from 2 weeks before mating till delivery and (2) normal diet (ND) group, 4 rats were given normal diet. Twenty random neonatal rats from each group were killed on the next day of delivery. The rest neonates were given normal diet for 1 year until killed. Serum levels of vitamin A, morphology of the kidney, incidence of tumor formation, and retinoid X receptor (RXR) alpha messenger RNA (mRNA) expression in renal tissue were assessed for the filial rats. RESULTS: Fifty-six and 49 neonatal rats were born for VAD group and ND group, respectively. The detection rate of nephrogenic rests (NRs) from neonates in VAD group (50%) was significantly higher than that in ND group (20%; P < .05). The incidence of nephroblastoma was 13.9% in filial rats of VAD group and 0% for ND group. The detection rate of NRs for filial rats of VAD group (30.6%) was significantly higher than that of ND group (6.9%; P < .01). The expression of RXRalpha mRNA in tumor tissue of the filial rats of VAD group (3.17 +/- 0.15) was significantly lower than that in kidney tissue of ND group (3.58 +/- 0.20; P < .01). CONCLUSION: Deficiency in vitamin A for pregnant rats resulted in renal dysplasia, increased NRs, and higher incidence of nephroblastoma.

Nephrogenic rests, nephroblastomatosis, and associated lesions of the kidney.

The fetal kidney is formed by the development of nephrons from fetal metanephric blastema surrounding the ureteric bud. The fetal renal tissue matures into normal renal parenchyma during gestation, but, occasionally, fetal tissue persists into infancy as microscopic foci called nephrogenic rests. Nephrogenic rests are found in approximately 1% of infant kidneys at autopsy. Nephrogenic rests are associated with an increased risk of Wilms tumor, and it is theorized that nephrogenic rests undergo neoplastic change into Wilms tumor. Fortunately, this transformation occurs in less than 1% of young children with nephrogenic rests. Nephrogenic rests are associated with many syndromes, including Beckwith-Wiedemann syndrome, hemihypertrophy, and sporadic aniridia. Children with identifiable syndromes, once diagnosed, should be screened for the development of Wilms tumor. Nephrogenic rests are associated with other lesions such as multilocular cystic nephroma and multicystic dysplasia, usually without malignant complications.

Primary extrarenal Wilms' tumor in the inguinal canal: case report and review of the literature.

Inguinal and scrotal Wilms' tumors are extremely rare; only 15 cases have been reported to date. The authors report a case of inguinal Wilms' tumor (stage III), which occurred in a previously healthy 3 1/2-year-old boy who was staged and treated according to currently accepted National Wilms' Tumor Study III criteria. The exact embryological origin of this tumor has not been determined. However, there is evidence that the origin is more primitive than that of intrarenal Wilms' tumor.

Altered specificity of IGF2 promoter imprinting during fetal development and onset of Wilms tumour.

The specificity of IGF2 promoter imprinting was examined in embryonal tissues and Wilms tumour. In several fetal tissues of approximately 12 weeks gestation, IGF2 was found to be monoallelically expressed from all IGF2 promoters i.e. P1, P2, P3 and P4. However, in tissues of slightly older gestation age (15-17 weeks) relaxation of imprinting at the P1 promoter was evident, although the P2-P4 promoters remained imprinted. These data indicate that early in embryogenesis a population of cells exists in which all IGF2 promoters are imprinted, but that as development proceeds the imprinting of the P1 promoter is relaxed. The pattern of IGF2 promoter imprinting was also analysed in Wilms tumour. In some tumours, the pattern of promoter imprinting was identical to that found in early fetal kidney, indicating that this tumour originates within early embryonic kidney tissue. In contrast, in tumours in which relaxation of imprinting had occurred, imprinting relaxation affected all IGF2 promoters. This aberrant pattern of promoter imprinting, which was not detected in fetal kidney, provides further evidence that pathological relaxation of IGF2 imprinting is involved in the genesis of Wilms tumour.

Transcription factors in renal development: the WT1 and Pax-2 story.

The development of a complex, multicellular organ, such as the kidney, from two embryonic progenitor tissues requires the activation and suppression of transcription factors that regulate tissue and cell type-specific gene expression. From areas as diverse as fruit fly development and human cancer genetics, a number of important genes have been identified that help to orchestrate the early events of renal epithelium induction and differentiation. The Wilms' tumor-suppressor gene WT1 is critical for regulating the early response of the kidney mesenchyme to induction and may play multiple roles during the course of renal epithelial cell development and tumor formation. The Pax-2 gene is activated in the mesenchyme after induction and is necessary for condensation and perhaps proliferation of the induced cells. How these two important gene products exert their effects will be discussed in light of recent evidence on DNA binding, transcription repression, and protein interactions.

Growth factors in renal development.

The formation of all organs during embryogenesis, including the kidney, is dependent on the timed and sequential expression of a number of polypeptide growth factors. Synthesis and actions of one or more members of the insulinlike growth factor (IGF), epidermal growth factor/transforming growth factor-alpha (EGF/TGF-alpha), transforming growth factor-beta (TGF-beta), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), and nerve growth factor (NGF) families have been characterized in the developing metanephric kidney. Studies originating from a number of laboratories have defined the localization of growth factor mRNAs, receptors and peptides, have delineated patterns of growth factor synthesis, have established the growth factor-dependency of embryonic kidney development, and have identified abnormalities of growth factor-expression as potentially causative of aberrancies in metanephrogenesis. The results of these investigations are summarized in this review.

Nodular renal blastoma in kidney with multicystic dysplasia. Report of a case.

The clinico-pathologic association of nodular renal blastema, multicystic kidney and obstructive uropathy has been recently identified. We report on a female patient diagnosed as having unilater multicystic dysplasia by prenatal ultrasonography. The patient was nephrectomized at the age of 6 1/2 months. Examination of the resected kidney revealed multiple unilocular cysts in the cortex and hypoplasia of the homolateral ureter; histological study confirmed the presence of multiple cysts limited to the renal cortex, and revealed, among them, multiple cortical metanephric blastema cells islands. Our case supports a relationship between nodular renal blastema, cortical cysts and obstructive uropathy; ureter hypoplasia could cause intraluminal back pressure, with consequent abnormal development of the ampullae, normally endowed in nephronic anlagens induction, cystic tubular ectasia and persistence of nodular renal blastema. The peripheral location of renal nodular blastema and cysts supports a late error in nephrogenesis, at the time of formation of the last generation of nephrons.

Etiology of Wilms' tumor.

Present knowledge of the pathogenesis of Wilms' tumor can be used to plan further epidemiologic investigations in a logical manner. Table 3 summarizes the epidemiologic evidence presently available that implicates various exposures. The proportion of cases of Wilms' tumor that arise from germline mutations is unknown. Future case-control studies could contribute to providing such information by systematically collecting and preserving constitutional genetic material from cases and their parents and neoplastic genetic material from their tumors. The studies that have demonstrated germline mutations so far have involved small numbers of subjects, being the equivalent of "case reports" (36, 37, 45-47, 50, 53). The techniques of molecular biology will be necessary to distinguish germline mutations or equivalent events that have been transmitted by parents from those that have arisen de novo. (Since it has already been shown that phenotypically unaffected parents can transmit relevant mutations to offspring who become affected (45, 46), the presence or absence of phenotypic abnormalities in the parents cannot be used to infer whether germinal mutations have arisen de novo.) Such studies will be laborious and expensive. The best strategy to minimize cost and labor would be restriction on age; the cases diagnosed relatively early in life (before the age of 2-3 years) are more likely to have arisen from germline mutations than those diagnosed later (34). The existence of de novo germline mutations relevant to the development of Wilms' tumor should prompt epidemiologists to search for causal exposures before conception. Preliminary evidence suggests that males have a higher germinal mutation rate (48). On the basis of the epidemiologic evidence to date, Olshan et al. have suggested the following: "paternal preconceptional exposures may play a more important role in the etiology of Wilm's tumor than maternal factors"(8,p.943). Pathologic and molecular biologic studies have shown that Wilm's tumor arises from nephrogenic rests that represent renal stem cells, the development of which has been arrested before normal differentiation occurs (2,44). Exposures that occur during intrauterine life are likely to be relevant to this process; these can be studied with epidemiologic methods, and clues have emerged (7,86,89). It is important to realize, however, that the fetus may be exposed in utero to substances to which the mother was exposed prior to conception, if these substances are excreted slowly or not at all, such as the persistent organochlorine pesticides (96,98). Study of the determinants of the growth behavior of nephrogenic rests (persistence, regression, generalized growth, or malignant transformation (2)) may be possible only in an animal model of Wilm's tumor, if one can be found in which nephroblastoma arises from nephrogenic rests. Ethylnitrosurea, an alkylating agent, causes renal tumors identical to Wilm's tumor in the opossum when given early in postnatal life (103) and in the rabbit when given transplacentally (104). Nephroblastoma in animals is one of the very few types of tumors that is inducible by chemicals via the transplacental route. This mode of induction should be regarded as as an etiologic possibility in humans as well as animals (105). As Hard, however, has pointed out, "nodular renal blastema [now known as nephrogenic rests] or nephroblastomatosis...have [sic] never been described in conjunction with nephroblastoma of animals" (105,p.184). the renal stem cells that give rise to Wilm's tumor normally disappear 4-6weeks prior to birth (19). If they persist after birth, as nephrogenic rests or otherwise, postnatal exposures could contribute to the development of Wilm's tumor. Cases diagnosed later, especially those presenting with lower stage disease, are more likely to have arisen from mutations occurring after birth. Potential carcinogens in children's diet and the home environment are worthy of close study.

The molecular genetics of Wilms tumor: a paradigm of heterogeneity in tumor development.

The evidence that genes on chromosome 11 are involved in Wilms tumor development is convincing; however, it is also evident that the mechanisms of tumorigenesis are more complex than the two-mutation model originally proposed. Potentially several genetic loci participate in Wilms tumor development. This should not be too surprising considering the complexity of pathways regulating growth and differentiation in nephrogenesis. It is possible that these various genes act at different points in the differentiation pathway and disruption of their normal function contributes to tumorigenesis. In fact, these loci may interact with one another in tumor formation. Certain types of genetic alterations may be the rate-limiting steps, but other changes may also contribute or be necessary for tumor development. Homozygous inactivation of specific genes, combinations of mutated alleles, and relaxation of genetic imprinting, or even interactions between different mutated alleles may all be part of the process for individual tumors. It has been found that some patients with the WAGR syndrome who are hemizygous for WT1 at 11p13 have in addition loss of heterozygosity within 11p15, and a sporadic tumor has been shown to have a WT1 mutation and loss of heterozygosity at loci at both 11p15 and 11p13 (59,85). These observations suggest the potential for interaction among the various Wilms tumor loci. Not only are there likely to be a number of different genetic loci linked to Wilms tumor development, but the mechanisms underlying altered gene function may be more variable than originally believed. It is probably not correct to think of Wilms tumor as a homogeneous entity. Mutations at different loci or various combinations of genetic lesions could well be responsible for the different categories of Wilms tumors. This apparent genetic complexity of Wilms tumor development is a concept that can very likely be applied to many other types of neoplasms. A complete understanding of Wilms tumorigenesis awaits identification of all members of the Wilms tumor gene family and the functional significance of their alterations.

Wilms' tumour: reconciling genetics and biology.

Wilms' tumour, a paediatric malignancy of the kidney, is a striking example of the relationship between aberrant development and cancer. Several different genetic loci have been implicated in the aetiology of the tumour; genomic imprinting also plays a role. One Wilms' tumour predisposition gene (WT1), encoding a zinc finger protein, is expressed in a limited set of tissues, including developing nephrons and gonads. The biology and genetics of Wilms' tumour underline the developmental relationship between kidneys and gonads.

The nephroblastomatosis complex and its relationship to Wilms' tumor.

Nephroblastomatosis (NB), a persistence of abnormal embryonal renal tissue beyond 36 weeks' gestation, is often associated with Wilms' tumor. The exact relationship of NB to the development of Wilms' tumor is unclear. Four cases are presented that elucidate the entire morphological spectrum of this disease. Analyses of these cases suggest these conclusions: (1) the NB complex is a spectrum of lesions from benign multifocal nodular renal blastema, resembling residual nephrogenic zones of immature fetal kidney, to Wilms' tumor; (2) infantile NB is a premalignant variant of Wilms' tumor with a favorable outcome usually, when treated early; (3) neonatal nephromegaly requires a complete evaluation and follow-up imaging; persistence mandates biopsy; (4) "second-look" laparotomy is unnecessary with state-of-the-art imaging; and (5) standardization of terminology is essential.

The candidate Wilms' tumour gene is involved in genitourinary development.

Wilms' tumour is an embryonic kidney tumour thought to arise through aberrant mesenchymal stem cell differentiation and to result from loss of function of a 'tumour suppressor' gene(s). Both sporadic and syndrome-associated Wilms' tumours are accompanied by an increased frequency of abnormalities of the urinary tract and genitalia. Deletional analysis of individuals with the WAGR syndrome (for, Wilms' tumour, aniridia, genitourinary abnormalities and mental retardation) showed that a Wilms' tumour gene lies at chromosomal position 11p13. This led to the isolation of a candidate Wilms' tumour gene, encoding a zinc-finger protein which is likely to be a transcription factor. To gain insight into the role of this candidate gene in normal development and tumorigenesis, we have now performed in situ messenger RNA hybridization on sections of human embryos and Wilms' tumours. The candidate Wilms' tumour gene is expressed specifically in the condensed mesenchyme, renal vesicle and glomerular epithelium of the developing kidney, in the related mesonephric glomeruli and in cells approximating these structures in tumours. The other main sites of expression are the genital ridge, fetal gonad and mesothelium. These data suggest that (1) this candidate is indeed a Wilms' tumour gene, (2) the associated genital abnormalities are pleiotropic effects of mutation in the Wilms' tumour gene itself, in support of recent genetic analysis, and (3) this gene has a specific role in kidney development and a wider role in mesenchymal-epithelial transitions.

Lectin histochemical studies on renal tumors.

Histochemical characteristics on lectin binding of 16 cases of nephroblastoma and of 57 cases of renal cell carcinoma were studied on those of six embryonal and fetal kidneys in 4 to 24 gestational weeks and in six normal adult kidneys using four biotinylated lectins (PNA, LTA, SBA and UEA-1), which show segment specific binding for normal nephron. In normal nephrogenesis, Gal beta 1-3 GalNAc (PNA receptor) appeared at first in developing tubuli of the metanephros at 10 gestational weeks, and remained positive in proximal tubuli of 13 gestational weeks, where the Lewis X antigen (LTA receptor) emerged. In adult kidneys, Gal beta 1-3 GalNAc distributed along distal tubuli and collecting ducts and not in proximal tubuli. Type 2 H antigen (UEA-1 receptor) was confined to collecting ducts. In nephroblastomas, positive reaction to these lectins were almost exclusively confined to tubular structures. Gal beta 1-3 GalNAc was constantly positive there. Intensely positive stain of Lewis X antigen was observed in three cases of histologically well differentiated type. Lewis X antigen positive tubuli co-expressed Gal beta 1-3 GalNAc. There were six type 2 H antigen positive cases showing differentiation toward ureteric bud or collecting ducts. In view of the cell surface glycosylation, regular differentiation of fetal renal tubuli was also retained in nephroblastomas according to their degree of histological differentiation. In renal cell carcinoma, Gal beta 1-3 GalNAc was positive in 49% (28/57) and Lewis X antigen was positive in 54% (31/57). Type 2 H antigen was completely negative. In contrast to the nephroblastoma, there was no correlation between histological features and lectin binding patterns in renal cell carcinoma.

Pronephros and mesonephros--Cohnheim revisited.

Erroneous quotations in the literature and Cohnheim's statement, in his Lectures on General Pathology, that the Wolffian body or mesonephros is the first anlage of the urogenital system prompted this description of the growth of our knowledge of the early development of the kidney. Some of the pertinent older literature is reviewed, and the concept of the holonephros, as opposed to the trinephric view of kidney development, is discussed. Emphasis is placed on the decreasing functional significance of the pronephros with evolutionary development, to the extent that the role of the pronephros in the human is questioned. Cohnheim's seemingly erroneous reference to the development of the kidney is shown to be merely a reflection of the views current at his time.

Wilms' tumour as a paradigm for the relationship of cancer to development.

Wilms' tumour or nephroblastoma is one of the commonest solid paediatric malignant diseases, accounting for 8% of childhood cancers. The tumour arises through aberrant differentiation of metanephric mesenchyme and thus represents a paradigm for the relationship of cancer and development. There is considerable heterogeneity in the pathology of Wilms' tumour and several genes have been implicated in its aetiology. One of these genes, located at chromosome 11p13, is categorised as a 'tumour suppressor' gene since loss of function can lead to malignancy. It has not been possible as yet to correlate the involvement of a particular locus with a subset of tumour pathology. The recently cloned Wilms' tumour gene encodes a putative transcription factor which is likely to activate or repress the expression of other genes in kidney development. We have shown by in situ hybridization that expression of this gene is restricted to specific cell types within the developing kidney. It is also expressed in a limited range of embryonic tissues, including the gonad, spleen and mesothelium. With the benefit of this new information, we speculate on the part played by this gene in normal kidney development, in tumorigenesis and in other aspects of Wilms' tumour; these include associated congenital abnormalities, genetic predisposition to second tumours and inheritance of Wilms' tumour.

[Congenital anomalies of the urogenital tract in patients with a Wilm's tumor]. / Congenitale afwijkingen van de tractus urogenitalis bij patiënten met een Wilms-tumor.

133 patients in whom a Wilms' tumour had been diagnosed between 1971 and 1986 were evaluated retrospectively for presence of congenital anomalies of the genitourinary tract. These were detected in 51 patients, 38.3%. A comparison was made between the incidence of each detected malformation in the patient group and in the general population. Some anomalies seemed to have a high association with the nephroblastoma; sharing the same basic embryological disorder is suggested as a possible explanation for this association.