Immunocytochemical Studies of the Developmental Biology and Pathology of the Human Kidney

Fleming, Stewart (1988) Immunocytochemical Studies of the Developmental Biology and Pathology of the Human Kidney. MD thesis, University of Glasgow.

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This thesis describes my study of normal and abnormal differentiation in the human kidney. Firstly, I have used immunocytochemical techniques to map the appearance of differentiation markers during renal organogenesis. I have shown that at the stage of tubular induction the induced cells underwent transferrin dependent proliferation. Simultaneously there was a change in intermediate filament phenotype from vimentin to cytokeratin. Tubular epithelium continued to express cytokeratins during development but in the glomerular epithelium cytokeratin expression was transient and was lost during glomerular maturation. As tubular development progressed the segregation of proximal and distal tubular epithelium was marked by the expression of different cell surface antigens, brush border antigen in the proximal tubule and epithelial membrane antigen in the distal tubule. Further developmental progress was accompanied by the appearance of new maturation markers such as ferritin, alpha-1-antitrypsin and carbonic anhydrase C. It is the ureteric bud which induces tubulogenesis from the metanephric blastema. During this process the ureteric bud expressed a specialised group of cell surface carbohydrates, which have been shown to be important in cell interactions during other embryogenic processes. These molecules were lost as the ureteric bud differentiated to the collecting duct epithelium. Changes in the extracellular matrix, vascular tree and juxta-glomerular apparatus have also been described. I have concluded this first part of the study by formulating a classification of the cell markers according to the developmental stage and site at which they first appeared. I have then used the same markers to study differentiation in different types of renal dysplasia and renal neoplasms. These are diseases in which differentiation may be abnormal. In the cases of renal dysplasia I identified two different types of abnormality of differentiation. Firstly, the different components of the nephron showed evidence of developmental arrest. There was morphological immaturity and a failure of all segments of the nephron to express various maturation markers. Secondly, in the mesenchymal compartment heterologous differentiation into non-renal tissues such as cartilage and fat was a frequent occurrence. The renal neoplasms also showed different forms of abnormal differentiation. The tubular elements of nephroblastoma expressed cytokeratins and either epithelial membrane antigen or brush border antigen but did not express the mature tubular markers such as carbonic anhydrase C and ferritin. The mesenchyme of some cases contained morphologically and immunologically detectable heterologous tissues particularly skeletal muscle. I have provided immunocytochemical evidence that the type B tubules in nephroblastoma are derived from the ureteric bud and grow into the tumours from the adjacent kidney. It has previously been proposed that renal cell carcinomas arise from the proximal tubule, but I have herein shown that these tumours co-express markers of both proximal and distal tubular epithelium. Similar results have been seen in regenerative epithelium. Neoplastic epithelial cells in the majority of renal cell carcinomas expressed both the vimentin and cytokeratin types of intermediate filament protein. The proliferation of the renal tumours has been studied by the monoclonal antibodies Ki 67 and HB 21 . Renin containing cells have been found in a proportion of both of the main types of renal neoplasm. These were characteristically seen in a perivascular distribution. During the course of the study a distinct type of renal carcinoma was identified. I have called this tumour collecting duct carcinoma because the tumour cells had the same cytokeratin phenotype and cell surface markers as normal collecting duct epithelium. Finally I have discussed these various results in the context of our present knowledge of cell commitment and differentiation in the kidney and other tissues. The lack of heterologous epithelial differentiation in renal pathology has suggested that the commitment to renal differentiation persists in disease states. The renal connective tissues showed no such commitment and heterologous differentiation in this cell compartment was relatively common.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: Medicine, Developmental biology, Pathology
Date of Award: 1988
Depositing User: Enlighten Team
Unique ID: glathesis:1988-77903
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 30 Jan 2020 15:48
Last Modified: 30 Jan 2020 15:48

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