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Clinical factors related to the development and progression of renal lesions were studied in twenty-three diabetics by the use of serial renal biopsies or autopsy. The results were as follows: Most of the juvenile and intermediate type diabetics were poorly controlled, with the glomerular lesion progressing rather rapidly. In contrast, many cases of the adult type were able to be maintained under good control and the renal lesion neither developed nor progressed. Two of the adult type diabetics with poor control showed slowly and slightly progressing renal lesions. The progression of glomerular lesions was significantly related to the control of blood glucose, type of diabetes, age at onset, type of treatment, and degree of obesity, but not to the duration of diabetes or the length of the follow-up period. There was a significant correlation between the type of diabetes and the control of blood glucose over the years. Arteriolar lesions developed concurrently with the progression of the glomerular lesion. Retinopathy also had a tendency to develop in proportion to the progress of glomerular lesions although it was not statistically significant. We have discussed the clinical factors responsible for the progression of diabetic glomerulosclerosis and have suggested that the type of diabetes rather than the degree of control of blood glucose might be more important in determining the development and progression of diabetic glomerulosclerosis. Nevertheless, the possibility remains that successful control of blood glucose may prevent or retard the development of diabetic glomerulosclerosis.
Diabetes 1975 Jan
PMID:Onset and progression of diabetic glomerulosclerosis; a prospective study based on serial renal biopsies. 112 May 40

The pathophysiology of the microangiopathy of diabetes mellitus is poorly understood, and the relevance of carbohydrate intolerance remains uncertain. Four patients are presented with renal abnormalities suggestive of diffuse diabetic glomeruloscierosis. These patients have no evidence of carbohydrate intolerance by standard clinical technics. A familial incidence of diabetes mellitus and delayed insulin response to an oral glucose load support a classification of prediabetes or suspected diabetes mellitus for these patients. Early intercapillary nodule formation was seen in only two of the four patients. In the absence of this infrequent pathognomonic finding, an alternate approach to the diagnosis of diabetic glomerulosclerosis is suggested. Diffuse glomerular capillary basement membrane thickening, consistently present with diabetic glomerulosclerosis, is demonstrated by measurements utilizing the latex microsphere technic. The mean glomerular capillary basement membrane thickness of these patients was 4,403 A, compared with the control value of 3.098 A (P less than 0.001). Other pathologic findings suggestive of diabetic nephropathy include efferent arteriolosclerosis and linear immunofluorescence without electron dense deposits or inflammation. Skeletal muscle capillary basement membranes of all four patients also demonstrated significant thickening. The mean value for the patients was 1,510 A, as compared with a control value of 961 A (P less than 0.001). The importance of this muscle capillary basement membrane thickening to the diagnosis of diabetic microangiopathy is discussed. The pathologic alterations in the renal biopsy specimens and the demonstration of muscle capillary basement membrane thickening strongly suggest that diabetic glomerulosclerosis may occur in the absence of overt clinical carbohydrate intolerance.
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PMID:Diabetic glomerulosclerosis without glucose intolerance. 115 78

A 28 year old woman, with diabetes since age 18, had the nephrotic syndrome, hypertension and renal insufficiency. The initial renal biopsy specimen revealed diffuse glomerulosclerosis with early nodular changes. After an initial decline in renal function, her creatinine clearance progressively improved and has remained normal. Within 2 years she had a spontaneous remission of the nephrotic syndrome despite the presence of more pronounced nodular glomerular lesions. Although the renal hemodynamic functions were normal, certain tubular functions were impaired. Since we found no etiology for the nephrotic syndrome other than diabetic glomerulopathy, the complete remission of the nephrotic syndrome and improvement in renal function were very unusual events.
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PMID:Spontaneous remission of the nephrotic syndrome in diabetic nephropathy. 116 52

Previous studies of diabetic renovascular complications have measured morphologic changes in relatively few glomerular vessels by electron microscopy. The present study samples 20,000 to 80,000 glomeruli from each of ten nondiabetic and ten diabetic age- and sex-matched subjects. Glomeruli were isolated and fractionated by size with a sieving method. Three samples of glomeruli from each subject were analyzed for size, mass, and hydroxyproline content as an index of basement membrane collagen. Approximately 40 per cent of the glomeruli in each sample were isolated. Glomeruli comprised 94 per cent of the tissue elements present, and 92 per cent of the isolated glomeruli were intact. Diabetic glomeruli are larger than nondiabetic glomeruli (mean diameter +/- S.E.M. = 258 +/- 10 mu versus 196 +/- 6 mu) and heavier (499 +/- 63 ng. versus 232 +/- 16 ng.). Diabetic glomeruli have greater hydroxyproline content than nondiabetic glomeruli when content is expressed per glomerulus (21.9 +/- 3.3 ng. versus 7.1 +/- 0.5 ng.) and when expressed per milligram dry weight of glomeruli (44.0 +/- 2.4 mug. versus 31.6 +/- 1.9 mug.). Glomeruli from diabetics of longest duration show the greatest increases in mass and hydroxyproline values. A pathologist's semiquantitative estimation of diffuse glomerulosclerosis revealed a high correlation between hydroxyproline values and histologic determination of the extent of the renal lesion. These measurements allow quantification of basement membrane collagen and may be used to follow development of diabetic vascular complications.
Diabetes 1975 Dec
PMID:Quantification of collagen in renal glomeruli isolated from human nondiabetic and diabetic kidneys. 119 10

Crescents, defined as any proliferative or fibrous space occupying reaction of the parietal layer of Bowman's capsule, occur as a regular and integral feature of the glomerular changes of diabetes mellitus. The frequency of crescents and adhesions to the capsule increases with increasing total severity of diabetic glomerular and vascular disease in glomeruli with mild-moderate diffuse glomerulosclerosis (GS), severe diffuse GS, and nodular GA. The high frequency (greater than 90 per cent) of crescents and adhesions in glomeruli with exudative lesions is unrelated to over-all severity of diabetic renal disease. The 8.73 per cent of glomeruli with exudative lesions had 45 per cent of the total crescents observed. The mechanism of crescent formation in diabetes is probably similar to the proposed pathogenesis of crescents in other renal diseases. The underlying injury in the glomerular capillaries in diabetes is mainly the "exudative lesion." The percentage of diabetic glomeruli with crescents correlated better with blood urea nitrogen and creatinine that did the percentage of end stage glomeruli (a measure of severity of vascular disease), the percentage of diabetic glomeruli with severe diffuse GS, the percentage of diabetic glomeruli with nodular GS, or the percentage of diabetic glomeruli with exudative lesions. The percentage of diabetic glomeruli with crescents correlated better with severity of vascular disease than did any of the other diabetic glomerular changes. No correlation existed between incidence of crescents and "capsular drops."
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PMID:Crescents in diabetic glomerulopathy. Incidence and clinical significance. 120 85

Six patients without overt diabetes mellitus underwent renal biopsy for suspected glomerulonephritis. All were demonstrated to have diabetic glomerulosclerosis and subsequently were found to have abnormal glucose tolerance tests. Electron microscopy was critical in making the correct diagnosis in five of six patients. The reported cases represent 3% of a series of 200 patients who had a renal biopsy to evaluate possible glomerulonephritis. Renal manifestations of diabetes mellitus may antedate glycosuria and other more common presenting symptoms of this disease.
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PMID:Unsuspected diabetic glomerulosclerosis. 127 8

Renal disease is one of the most common and severe complications of diabetes mellitus. The hallmark of the disease, glomerulosclerosis, is characterized by an accumulation of extracellular matrix in the mesangial areas, leading to progressive obliteration of the vascular spaces. The role of the metabolic derangements of diabetes mellitus in the development of these lesions is incompletely understood. One of the consequences of hyperglycemia is the formation of advanced glycosylation end products (AGEs), which result from a series of rearrangements secondary to nonenzymatic reaction of glucose with proteins. Specific receptors for proteins modified by AGEs, present in several cell types, were recently described in human and rat mesangial cells. Furthermore, exposure of mesangial cells to AGEs was followed by an increase in fibronectin production. In the present study we show evidence that mouse mesangial cells exhibit an increase in collagen type IV mRNA and peptide synthesis after exposure to AGEs. Antibodies to AGE receptors prevent this increase, indicating that the response is AGE-receptor-mediated. In addition, anti-platelet-derived growth factor abrogates the AGE response, suggesting that platelet-derived growth factor acts as an intermediate factor. Transcription assay reveals that the elevated mRNA levels are due to an increase in the transcription rate, rather than to an increase in the stability of the message. Finally, the mRNAs coding for laminin and heparan sulfate proteoglycan are also increased after exposure to AGE, whereas glyceraldehyde 3-phosphate dehydrogenase mRNA levels remain constant. The increase in extracellular matrix mRNAs seen in the current study suggests that AGE formation in vivo may be one of the metabolic events leading to the development of diabetic glomerulosclerosis.
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PMID:Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation end products is mediated via platelet-derived growth factor. 131 71

The duration of diabetes mellitus and presence of hyperglycaemia appear to be important in the development of diabetic nephropathy. The presence of nodular glomerulosclerosis is thought to be pathognomonic of the condition. We report two patients with histological features of diabetic glomerulosclerosis who did not have diabetes mellitus. The discussion reviews the literature and concludes that diabetic glomerulosclerosis with normal glucose tolerance is very rare and that most cases are due to overt diabetes mellitus or a degree of glucose intolerance. However, cases with only minimal glucose intolerance suggest that factor(s) other than hyperglycaemia are responsible for diabetic renal damage.
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PMID:Diabetic glomerulosclerosis without diabetes mellitus--two case reports and a review of the literature. 132 76

Characteristic pathological changes in the glomeruli in diabetic nephropathy include expansion of the mesangial matrix and thickening of the glomerular basement membrane (GBM). Using an acellular digestion technique combined with scanning electron microscopy, the three-dimensional ultrastructural changes in glomerular extracellular matrices were studied in rats with diabetic glomerulopathy. Diabetes was induced by the intravenous injection of streptozotocin and morphological analyses were performed 3, 6 and 11 months after the injection. Expansion of mesangial area and GBM thickening became evident with time. After treatment with the series of detergents, all cellular components were completely removed leaving the extracellular matrices intact. In normal controls, the mesangial matrix appeared as fenestrated septa with oval or round stomata between the glomerular capillaries. In diabetic glomerulopathy, expansion of mesangial matrix and narrowing of the mesangial fenestrae were observed. These changes in the mesangial matrices seem to play a vital role in the progression of glomerulosclerosis in rat diabetes. A subendothelial thin layer of the GBM was continuous with the mesangial matrix. One cause of GBM thickening in streptozotocin diabetes may be expansion of the mesangial matrix into the peripheral GBM.
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PMID:Glomerular extracellular matrices in rat diabetic glomerulopathy by scanning electron microscopy. 135 71

Hypertension and diabetes mellitus are strongly associated conditions from epidemiologic, genetic, and pathophysiologic points of view. The prevalence of hypertension is high in patients with diabetes, and, conversely, many patients with essential hypertension are glucose intolerant. Proteinuria appears in 40-50% of patients with insulin-dependent diabetes mellitus and 20-30% of patients with non-insulin-dependent diabetes mellitus. Progressive renal failure occurs in 30-40 and 3-8% of patients, respectively, hypertension being a leading factor in its rate of progression. In various animal experiments, ACE inhibitors are able to prevent proteinuria and glomerular sclerosis, presumably by lowering transglomerular capillary pressure. In the diabetic human, ACE inhibitors are powerful antihypertensive drugs, devoid of metabolic side effects. Clinical studies indicate that ACE inhibitors reduce proteinuria and possibly slow the rate of decline in renal function. Such an effect is not observed with beta-blockers. Large-scale studies are needed to confirm this very important hypothesis.
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PMID:Angiotensin-converting enzyme inhibition and diabetic nephropathy. 138 63


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