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Title: Diabetic kidney : a study of diabetic microangiopathy by light and electron microscopy examination of percutaneous renal biopsies
Author: Ireland, John T.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1970
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Although there is an extensive literature concerning diabetic renal involvement, disagreement regarding the diffuse and nodular glomerular lesions, and uncertainty about their relationship to pyelonephritis and arteriolosclerosis, have obscured the pathogenesis of renal disease in diabetes. The general belief, however, that diabetics are more prone than non -diabetics to atheroma and other less specific changes in larger blood vessels in no way detracts from the concept that it is involvement of small blood vessels, and of capillaries in particular, which characterises the diabetic lesion. To investigate this problem a light and electron microscopy examination has been made of renal tissue obtained by percutaaeous biopsy from selected groups of patients representing different stages or clinical categories of diabetes and from healthy nondiabetics. Since reliable quantitative methods must be applied when electron microscopy is used to demonstrate cellular ultra - structure, and because the value of data based upon small biopsy samples is limited unless it can be shown that the tissue obtained is representative of that individual's glomerular population, statistical methods appropriate to small samples and free of assumptions concerning distribution have been used. Thus such non -parametric methods as the Mann- Whitney 'U' test or the Kolmogorov-Smirnov analysis of cumulative frequency distribution have been applied to both the measurement of glomerular capillary basement membrane thickness and to a technique of assessing on a quantitative basis, within the glomerular mesangium, the ratio of basement membrane substance to cellular cytoplasm which has been designated the Mesangial Index. Using these methods the mean glomerular capillary basement membrane thickness in nine non -diabetic subjects was 2,200 Å (Angstrom Units) and although the findings in four newly diagnosed juvenile diabetics were not significantly different from normal either in terms of basement membrane thickness or mesangial index, significant basement membrane thickening was found in seven of ten patients having diabetes secondary to haemochromatosis, chronic pancreatitis or pancreatic carcinoma. One of ten age-and duration-matched long-standing diabetics had no evidence of glomerular pathology after 23 years of insulin dependence. All other nine patients had unequivocal basement membrane thickening, however those without diabetic retinopathy had significantly lower mesnngial indices than patients having proliferative retinopathy. Thus in the latter patients there was attenuation of mesangial and endothelial cells with massive basement membrane accumulation. This aspect was studied further in six diabetics having advancing proliferative retinopathy by obtaining renal biopsy tissue before and one to two years after pituitary surgery. Successful pituitary ablation was followed by significant reduction in the thickness of the glomerular capillary basement membrane, restoration of atrophic endothelial and mesanginl cells to their normal appearance, persistence of morphological features suggesting over-activity of the epithelial cells and no improvement in the arteriolar lesion. Other light and electron microscopic features of the diabetic kidney have been reviewed and the above findings considered in relation to various clinical factors of significance in the diagnosis and assessment of diabetic renal disease. Current aspects of genetic, metabolic, immunological, endocrine and other factors of possible importance in the pathogenesis of diabetic small blood vessel disease have been considered in relation to the findings in this study. It is concluded that although the nodular glomerular lesion of Kimmelstiel and Wilson remains for the light microscopist the hallmark of diabetes in the kidney, usually it is found only in association with the more common diffuse glomerular changes, and with afferent and efferent arteriolosclerosis. Accompanying changes in the túbules and interstitial tissue which often in the past have been interpreted as chronic healed.pyelonephritis probably represent the end result of diabetic vascular lesions. It is suggested that the excessive basement membrane material found in the glomerular capillaries probably represents varying degress of its epithelial production or impaired mesangial turnover. The absence of glomerular lesions in newly diagnosed juvenile diabetics and the demonstration of basement membrane lesions in secondary diabetes suggests that the diabetic lesion is independent of the genetically determined diathesis to idiopathic diabetes but is due to some metabolic derangement aommon to both primary and secondary diabetes. The possibility that some components of diabetic microangiopathy can occur only in and be due to some as yet undefined aspect of the idiopathic disorder is, however, not excluded by these observations. Thus it is probable that diabetic nephropathy results from several separate though inter- related lesions each of which may be variously influenced by the metabolic disturbance, the inherited diabetic diathesis or pituitary activity. Although the idea of a specific diabetic microangiopathy is widely accepted, it is concluded that this simple concept probably conceals the complexity of the factors concerned in the pathogenesis of the various arteriolar and capillary lesions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available