Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the lesions of global glomerular sclerosis and arteriolar hyalinosis in 43 (29 females) insulin-dependent diabetes mellitus (IDDM) patients whose creatinine clearance (CCr) was greater than or equal to 45 ml/min/1.73 m2 and whose renal biopsies had at least 20 glomeruli available for study. These patients, ages 17 to 55 years, had IDDM for 7 to 32 (20 +/- 6, means +/- SD) years. CCr ranged from 47 to 139 (91 +/- 25) ml/min/1.73 m2 and urinary albumin excretion (UAE) from 5 to 3386 (median = 127) mg/24 hrs. Eighteen patients were hypertensive. Thus, these patients represented a broad clinical range from normal renal function through overt diabetic nephropathy. The percent of glomeruli which were globally sclerosed was strongly correlated with CCr (r = -0.64, P less than 0.0001) and log UAE (r = +0.67, P less than 0.001). Hypertension was more common in patients with more than 10% sclerosed glomeruli (chi square = 9.5, P less than 0.002). Percent sclerosed glomeruli was highly significantly correlated with the index of severity of the arteriolar hyalinosis lesion (r = +0.66, P less than 0.0001) and mesangial volume fraction (r = +0.61, P less than 0.0001). We hypothesize that arteriolar hyalinosis could contribute to global glomerular sclerosis through severe compromise of glomerular blood flow. Alternately, global glomerular sclerosis may result from marked mesangial expansion and capillary occlusion. However, in this broad range of patients it appeared that global glomerular sclerosis and mesangial expansion were not infrequently independent diabetic renal lesions which could contribute separately to the ultimate development of overt diabetic nephropathy.
 ...
PMID:Global glomerular sclerosis and glomerular arteriolar hyalinosis in insulin dependent diabetes. 192 Nov 45

The immunohistochemical localization of the extracellular matrix was examined in 31 cases with different degrees of human diabetic nephropathy using antisera to human collagen types I, III, IV, V, fibronectin, laminin, and basement-membrane-associated heparan sulfate proteoglycan (HSPG). In normal glomeruli, HSPG was predominantly localized in the glomerular basement membrane and in the mesangium, and to minor extent in the basement membranes of tubules and Bowman's capsule. Collagen IV and laminin were distributed in glomerular basement membrane and mesangium in minor amounts. Interstitial collagens usually do not occur within glomeruli except for collagen V which has a light microscopic glomerular distribution similar to collagen IV. In diabetic diffuse glomerulosclerosis, the enlarged mesangial matrix showed an increased staining reaction for collagen IV, V, laminin, and fibronectin whereas the staining pattern of HSPG was markedly reduced. Early, small nodular lesions in diabetic glomeruli were similarly positive for most of the basement membrane components, whereas HSPG remained absent. With an increase in the diameter of the noduli, however, the staining reaction for all basement membrane components diminished, whereas interstitial collagens V and III, but not collagen I, were present in these noduli in substantial amounts. These initial studies provide evidence that the changes in the glomerular matrix in diabetic nephropathy may be divided into distinct and progressing stages of lesions. The reduced amount of HSPG even in slight, early lesions may represent the morphologic correlate to the impaired filter function of the glomerular basement membrane.
 ...
PMID:Immunohistochemical localization of extracellular matrix components in human diabetic glomerular lesions. 192 5

The metabolic changes which accompany hyperglycemia in a person with diabetes are thought to cause renal hyperperfusion and intraglomerular hypertension, especially in the person with a predisposition to essential hypertension. Intraglomerular hypertension causing deposition of protein in the mesangium leads to glomerulosclerosis and renal failure. Screening for microalbuminuria can predict which type I diabetic patients will develop nephropathy. The decline in renal function in established diabetic nephropathy can be slowed with aggressive treatment of hypertension. The use of ACE inhibitors may also decrease intraglomerular hypertension. Whether similar treatment in the person with preclinical diabetic nephropathy would delay or prevent the onset of diabetic nephropathy is being investigated. Restricted protein intake, anti-platelet and rheolitic drugs may have a role in the treatment of established diabetic nephropathy. In end stage renal failure, renal transplantation is the treatment of choice. When transplantation cannot be performed, chronic ambulatory peritoneal dialysis is preferable to hemodialysis.
 ...
PMID:Diabetic nephropathy: changing concepts of pathogenesis and treatment. 200 Aug 93

Genetic predisposition to essential hypertension, as indicated by increased maximal velocity of Na+/Li+ countertransport in red cells, has been suggested as a marker for the risk of developing diabetic nephropathy. To evaluate the validity of this concept in non-insulin-dependent diabetics, we measured the maximal velocity of Na+/Li+ countertransport in red cells in 18 male diabetics suffering from proteinuria due to biopsy proven diabetic glomerulosclerosis (GFR: 51 [range 27 to 146] ml/min/1.73 m2), 17 male diabetics with normoalbuminuria, and in 18 sex-, age-, and body mass index-matched healthy control subjects. Na+/Li+ countertransport was identical in patients with and without diabetic nephropathy, 0.43 (0.24 to 0.92) versus 0.44 (0.20 to 0.83) mmol/(liter cells x hr), but was elevated compared to control subjects, 0.32 (0.09 to 0.73; P less than 0.05). Arterial blood pressure was elevated in patients with nephropathy (162/92 +/- 21/9 mm Hg) compared to normoalbuminuric patients (132/82 +/- 15/7) and control subjects (133/83 +/- 14/7 mm Hg; P less than 0.001). Our study does not support the hypothesis that the risk of diabetic nephropathy in non-insulin-dependent diabetes is associated with a genetic predisposition to hypertension. Diabetes per se seems to enhance Na+/Li+ countertransport activity.
 ...
PMID:Red cell Na+/Li+ countertransport in non-insulin-dependent diabetics with diabetic nephropathy. 200 27

Mice transgenic for growth hormone (GH) develop progressive glomerulosclerosis. The compositions of kidney extracellular matrix (ECM) and ECM mRNA were examined. The glomerulosclerotic areas in GH mice contained types I and IV collagen, laminin, and basement membrane heparan sulfate proteoglycan (HSPG), which increased with age. The type IV collagen, laminin B2, and HSPG mRNA levels in GH mice, measured by a solution hybridization RNase protection assay, were increased over normal littermates. These findings suggest that the accumulation of ECM components in the glomeruli of GH mice is regulated at the transcriptional level and that glomerulosclerosis is, in part, due to the excess production of ECM rather than simply a reduction in its turnover. The glomerular lesions in GH mice resemble diabetic nephropathy and may allow further dissection of the molecular basis of certain forms of glomerulosclerosis.
 ...
PMID:Glomerulosclerosis in mice transgenic for growth hormone. Increased mesangial extracellular matrix is correlated with kidney mRNA levels. 202 27

The precise pathogenesis of human diabetic kidney disease and the factors responsible for the susceptibility to it remain to be established. However, there is now evidence that renal disease clusters in families and that genetic factors are of central importance in determining liability. A predisposition to arterial hypertension has been suggested as playing a contributory role in the development of kidney disease. Genetically controlled hypertrophic processes may be implicated in the susceptibility to arterial wall damage and glomerular injury in diabetes. This suggestion derives from the observation that the fibroblasts of patients with diabetic nephropathy show a higher Na+/H+ antiport activity and a greater 3H-thymidine incorporation into DNA than fibroblasts of diabetic patients without nephropathy. The first sign of renal damage is the appearance of microalbuminuria and of a small elevation in arterial pressure, changes associated with significant mesangial expansion. Microalbuminuria is associated with abnormalities of lipoprotein profiles possibly as a consequence of insulin-resistance-induced hyperinsulinemia. It could be postulated that the environmental changes brought about by diabetes lead in susceptible individuals to increased systemic and intraglomerular pressure on the one hand and mesangial expansion on the other. These two processes would cause proteinuria and glomerulosclerosis. Lipid abnormalities would further aggravate the renal histological damage and, in combination with hypertension, contribute to the accelerated atherosclerosis typical of patients with diabetic kidney disease. A vicious circle would thus be triggered of reduction in renal function, more hypertension, more proteinuria, more glomerular obsolence, more hyperlipidemia and eventually end-stage renal failure or premature cardiovascular death.
 ...
PMID:Mechanisms of diabetic renal and cardiovascular disease. 207 90

Three cases are presented in which biopsy-proven diabetic nephropathy was found in nephrotic patients with no prior history of diabetes. One patient presented with advanced retinopathy and end-stage renal disease (ESRD), another with retinopathy and mild renal insufficiency, and a third with mild renal insufficiency alone. In each case, biopsy showed diffuse and nodular glomerulosclerosis with no evidence of kappa or lambda light chains. The patients had normal fasting serum glucose values, and two had normal oral glucose tolerance tests. Twenty-three similar cases in the literature were reviewed, and in most, some evidence of diabetes or hyperglycemia was found; five cases remained in which there was no evidence of hyperglycemia at any time. The cases reviewed included a disproportionate number of men (65%) and blacks (42%). It is concluded that diabetic nephropathy may exist in the absence of detectable hyperglycemia in a small number of extraordinarily susceptible individuals. Men and blacks appear to be at increased risk.
 ...
PMID:Diabetic nephropathy without hyperglycemia. 214 35

Twenty-three nonobese KK mice with abnormal tolerance to glucose, hyperinsulinemia with insulin resistance and human diabetic-like nephropathy were treated with either saline (12 mice) or glipizide, an oral hypoglycemic compound, 1 mg/kg, (11 mice) from 120 to 360 days of age. These mice develop significant increases in mesangial volume and matrix by 40 days of age. Oral glucose tolerance (OGTT), glucosyltransferase and N-acetyl-beta-glucosaminidase (enzymes involved in synthesis and degradation of kidney glycoproteins, respectively) in the kidney and serum, 24-hr proteinuria, and light microscopy studies of the kidney were performed. Glipizide-treated mice improved their OGTT. There was no difference in body weight; however, a 16% decrease (P less than 0.05) in kidney weight was observed in glipizide-treated mice. Both enzymes were significantly increased in the kidneys of mice treated with glipizide. No difference in serum enzymes was found between the two groups of mice. About 58% of the saline-treated mice had moderate glomerulosclerosis. By contrast, only 27% of glipizide-treated mice had moderate glomerulosclerosis. Also, a significant decrease in proteinuria was found in glipizide-treated mice. These data suggest that glipizide improves glucose metabolism, decreases kidney size, prevents kidney glycoprotein and mesangial matrix accumulation, and reduces proteinuria in type II diabetic KK mice. This indicates that good glycemic control prevents further progression of established diabetic nephropathy in animals.
 ...
PMID:Diabetic microangiopathy in KK mice. VI. Effect of glycemic control on renal glycoprotein metabolism and established glomerulosclerosis. 214 55

At present the pathogenesis of diabetic nephropathy remains unresolved. Clearly lack of insulin, with its associated disorders of carbohydrate, protein, and/or lipid metabolism, initiates the process which eventually leads to the characteristic histologic picture of diabetic nephropathy. The disturbance in cellular metabolism per se could directly injure the kidney by altering the energy needs of the cell or by leading to the accumulation of cellular toxins (ie, polyols) or by causing the deficiency of key cellular metabolites (ie, myoinositol). Elevation of the plasma glucose concentration enhances the glycosylation of proteins, which in turn can lead to glomerular basement membrane thickening, loss of charge selectivity, and direct cellular damage. The multiple disturbances in intermediary metabolism are associated with increased levels of and/or enhanced sensitivity to a variety of growth factors, including IGF-I and angiotensin, and this could lead to glomerular hypertrophy. An increase in the filtered load and subsequent reabsorption of electrolytes and metabolites also could contribute to renal hypertrophy. In all animal models of nephropathy, including diabetes, glomerular hypertrophy has been shown to be the best correlate of glomerular sclerosis, proteinuria, and progressive renal deterioration. The potential mechanisms by which glomerular hypertrophy can lead to renal histologic damage were discussed previously. By increasing the luminal diameter, glomerular hypertrophy also would be expected to augment wall tension and thereby increase intraglomerular pressure. Derangements in cellular metabolism or altered sensitivity to angiotensin also can directly elevate the intraglomerular pressure and lead to structural renal damage. In this schema, elevated intraglomerular pressure is but one of many pathogenic factors that contribute to the development of diabetic glomerulopathy and albuminuria. The precise role of increased glomerular pressure in the evolution of diabetic nephropathy remains uncertain at present. In rats, severe diabetic nephropathy can occur without an increase in Pgc, while in humans, hyperfiltration does not appear to be a predictor of proteinuria and renal dysfunction. Lastly, it is likely that a variety of other factors, including the coagulation system, plasma/cell lipid levels, prostaglandins, etc, also play a role in the pathogenesis of diabetic nephropathy. According to the outline presented in Figure 1, it is unlikely that any single factor will be sufficient to explain the development of diabetic glomerulosclerosis. Ultimately, the origin of diabetic nephropathy in IDDM must be traced to insulin lack, with its associated derangements in cellular metabolism. Therefore, the importance of tight glucose control should not be underemphasized.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Hyperfiltration and diabetic nephropathy: is it the beginning? Or is it the end? 219 Feb 80

Kidney disease, characterized by proteinuria and glomerular lesions, is a common complication of spontaneous diabetes mellitus in many animal species. It occurs in animals with hypoinsulinemia, hyperinsulinemia, or impaired glucose tolerance. The renal functional and structural abnormalities in spontaneously diabetic animals resemble human diabetic nephropathy in many respects. Mesangial expansion and glomerular basement membrane thickening, two structural hallmarks of diabetic glomerulopathy in humans, are the most frequently encountered lesions in animals. In addition, a nodular form of mesangial expansion that resembles but is not identical with human nodular glomerulosclerosis or the Kimmelstiel-Wilson lesion has been observed in some animal models. Other abnormalities, such as exudative hyaline lesions and arteriolar hyalinosis, have also been noted occasionally in other models. Although diabetic animals may develop kidney disease that resembles human diabetic nephropathy, no single animal model develops renal changes identical to those seen in humans. Nonetheless, animal models with spontaneous diabetic kidney disease may be useful for investigating the mechanisms of development of diabetic nephropathy and the effects of various treatment modalities on the progression of renal disease.
 ...
PMID:Animal models of spontaneous diabetic kidney disease. 219 83


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>