Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
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Chronic hyperglycemia is the single most important pathogenic factor in the diabetic triad: retinopathy, glomerulopathy and neuropathy. But at equal serum glucose balance, diabetics are not equally at risk of microangiopathy. Hence the importance of timely screening of patients who should be convinced to accept the constraints and risk of perfect serum glucose balance or to whom specific therapy independent from serum glucose balance could be proposed. But at present, there is no genetic or immunologic marker allowing for the individual identification of at risk patients. Attention is thus directed towards factors which may be directly involved in the pathogenesis of diabetic microangiopathy: --Special sensitivity of vascular collagen to protein glycosylation which could be reflected in the involvement of tendon and aponeurotic collagen, --platelet abnormalities of which the exacerbating role appears to be confirmed by the significant efficacy of aspirin in the treatment of nonproliferative retinopathy in insulin-independent diabetics, --rheological abnormalities which might essentially be secondary to chronic hyperglycemia, --hormonal abnormalities, in particular hypersecretion of growth hormone and/or somatomedin C, whose role has long been suspected and could be established by therapeutic trials with new somatostatin analogues. But the most recent advances concern the study of hemodynamic factors. Irreversible organic diabetic microangiopathy is thought to be preceded by a phase of reversible functional microangiopathy, characterized by increased capillary blood flow, vascular dilatation, hyperpermeability and altered regulation of flow. Thus, diabetic glomerulopathy with decreased glomerular filtration is preceded by a phase of renal "hyperfunctioning" and irreversible proteinuria is the outcome of a progressive increase in microalbuminuria, reversible at least while the levels are not too high.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Screening of subjects at high risk for diabetic microangiopathies]. 264 89

Thirty of 45 (67%) streptozotocin-induced male Sprague-Dawley diabetic rats developed microalbuminuria that progressed to overt proteinuria with increased concentrations of IgG in their urine. 33% (15/45) never developed albuminuria or IgG proteinuria. These percentages did not correlate with glucose control since none of the animals were treated with insulin and all demonstrated the same degree of hyperglycemia. Indirect immunofluorescent antibody staining of frozen tissue sections from the kidneys of rats that developed overt proteinuria stained for IgM (67%), C3 (93%), IgG2b (93%) and IgG2c (60%). Non-proteinuric diabetic kidneys stained for IgM (80%), C3 (67%) IgG2b (67%) and IgG2c (87%). Control kidney sections demonstrated no consistent staining pattern. The occurrence and concentration of the different immunoglobulin isotypes, eluted from frozen sections with immune complex dissociating buffers, mimicked that which was observed by immunofluorescence. When urine or serum from the same rat or a rat of a different group was incubated with kidney sections eluted of all immunoglobulin, indirect immunofluorescent staining demonstrated antibody activity corresponding to the original staining pattern observed for each animal group prior to elution. The most consistent observation was that the diabetic rats that developed proteinuria were positive for IgG2b staining in their kidney sections; whereas, those that did not develop proteinuria stained predominantly for IgG2c. From this data, we suggest that the progression of diabetic nephropathy may depend on whether a specific IgG subclass response is elicited.
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PMID:Assessment of the role of the immunoglobulin isotypes in the development of diabetic nephropathy in untreated streptozotocin-induced diabetic rats. 269 1

The SHR/N corpulent (cp) rat is a genetically obese rat that develops hyperglycemia, hyperinsulinemia, and proteinuria. This study was designed to evaluate the effects of high carbohydrate (CHO) intake on renal function and structure in this animal model and to determine whether the renal effects are related to the type of CHO ingested. Two groups of 5-wk-old obese male SHR/N-cp rats and lean male littermates were fed diets containing 54% CHO in the form of sucrose or starch. After 12 wk, renal function parameters, including creatinine clearance, urinary glucose excretion, and urinary protein excretion, were measured. Renal morphology was evaluated by semiquantitative light and electron microscopy. On either diet, obese rats had significantly higher urinary glucose and protein excretions than their lean littermates. Mean creatinine clearance (ml/min) in obese rats did not differ significantly from values observed in lean rats. When corrected for body weight, creatinine clearance (ml.min-1.kg-1) tended to be lower in obese than in lean rats, but the difference was significant (P less than .02) only for obese and lean sucrose-fed animals. Obese rats fed sucrose compared with their obese counterparts fed starch had higher body weight (+8%, P less than .05), glucose excretion (+63%, P less than .02), and protein excretion (+242%, P less than .005). In obese rats, protein excretion correlated with glucose excretion (r = .71, P less than .01). Glomerular lesions consisting of mesangial expansion and intercapillary nodules were found in obese but not in lean rats. Moreover, obese rats fed sucrose had a significantly greater number of involved glomeruli than obese rats fed starch.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of carbohydrate intake on kidney function and structure in SHR/N-cp rats. A new model of NIDDM. 272 22

In our previous experiments, a remarkable increase in urinary excretion of glucose was found in rats exposed to 821 ppm trichloroethylene for 12 wk. This was not accompanied with proteinuria, aminoaciduria, phosphaturia and definite histological changes in renal tubular structure. In order to ascertain the mechanism of the increase in urinary glucose excretion, blood glucose level and renal glucose reabsorption were studied in 10 male rats exposed to 783 ppm trichloroethylene for more than 3 wk. Another 10 male rats were studied as control. The following results were obtained: 1. Urine glucose of the trichloroethylene group increased after exposure for 2 wk. All the rats showed glycosuria (above 250 mg/dl) by the 4th week of exposure. 2. Plasma glucose levels were depressed by trichloroethylene to as low as 77% of that of the control group. Glycohemoglobin was similarly decreased. 3. Intravenous glucose tolerance tests (0.5 g/kg load) revealed that decreasing constant of plasma glucose (K value) was elevated by trichloroethylene, suggesting that induced hyperglycemia in the exposed rats improved more rapidly than in the controls. Trichloroethylene did not modify the secretion of insulin after glucose load, regardless of the depression in plasma insulin level before load. 4. Glucose titration tests revealed that tubular transport maximum for glucose (TmG) was decreased by trichloroethylene to as low as 46% of that of the control group. The ratio of TmG to glomerular filtration rate (the theoretical renal threshold for glucose) was also depressed to as low as 55% of that of the control group. The foregoing results indicate that trichloroethylene-induced glycosuria is attributable to deteriorated tubular reabsorption of glucose, and not to hyperglycemia. However, the mechanism for the selective disturbance of renal reabsorption of glucose is yet unknown.
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PMID:[Studies of trichloroethylene-induced glycosuria: blood glucose and renal glucose reabsorption in rats exposed to trichloroethylene]. 275 53

Little is known of the natural history of nephropathy in type 2 (non-insulin-dependent) diabetes, yet type 2 diabetes is a major cause of end-stage renal disease in the United States. The incidence rate of heavy proteinuria was determined in Pima Indians participating in a longitudinal population study of diabetes and its complications. Heavy proteinuria was defined by a urine protein (g/liter) to urine creatinine (g/liter) ratio greater than or equal to 1.0 (greater than or equal to 113 mg protein/nmol creatinine), a level which corresponds to a urine protein excretion rate of about 1 g/day. The incidence rates of proteinuria in diabetic Pimas were 4, 12, 37, and 106 cases/1,000 person-years at risk in the periods 0 to 5, 5 to 10, 10 to 15, and 15 to 20 years after the diagnosis of diabetes. The cumulative incidence rates were 2%, 8%, 23%, and 50% at 5, 10, 15, and 20 years, respectively. The duration of diabetes, severity of diabetes as determined by the degree of hyperglycemia and type of treatment, and blood pressure were risk factors for proteinuria. The presence of heavy proteinuria was strongly associated with the development of renal insufficiency, defined by serum creatinine greater than or equal to 2.0 mg/dl (greater than or equal to 177 mumol/liter). The incidence of proteinuria in type 2 diabetes in Pima Indians was as high as that reported in type 1 diabetes in other populations and represents a frequent, serious complication of the disease.
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PMID:Incidence of proteinuria in type 2 diabetes mellitus in the Pima Indians. 278 25

We studied the profile of nephropathy in 250 patients, 177 males and 73 females, with type 2 diabetes mellitus. The mean age was 55.9 +/- 8.8 years. Therapy for control of diabetes included diet alone in 1.6%, oral hypoglycaemic agents in 90.6% and insulin in 7.8%. Glycaemic control was satisfactory in 4.8%, fair in 41.2% and poor in 54.0%. Blood sugar values were normal without any therapy in 33 out of the 206 patients (16%) after the onset of renal insufficiency. The mean interval between the onset of diabetes and the appearance of proteinuria was 9.5 +/- 7.05 years. Proteinuria appeared within one year in 23 patients (9.2%), 1-5 years in 32 (12.8%), 6-10 years in 86 (34.4%) and more than 10 years in the remaining 109 patients (43.6%). Proteinuria was of nephrotic range in 17.6% of patients. Renal insufficiency was present in 206 (82.4%) patients and occurred 10.5 +/- 7.5 years after the detection of diabetes. Hypertension was present in 61.2% and was first detected 7.5 +/- 7.4 years after onset of diabetes. Endstage renal disease occurred 11.8 +/- 6.8 years after the onset of diabetes mellitus. Thus, clinical evidence of diabetic nephropathy is present in most patients with type 2 diabetes mellitus within a decade after the detection of diabetes. Subsequent progression to end-stage renal failure is rapid in the face of poorly controlled hypertension and hyperglycemia in the economically poor countries.
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PMID:Nephropathy in type 2 diabetes mellitus in Third World countries--Chandigarh study. 278 52

A case of central pontine myelinolysis (CPM) followed by hyperglycemia and hypoglycemia was reported. The case was 53-year-old female. Diabetes mellitus was found when she was 32 years old, insulin therapy was started at 37 years of age. Since she was 50 years old, proteinuria and ankle edema had developed and she was admitted to The Keihin Hospital. The peritoneal dialysis (PD) was performed next year, followed by the hemodialysis (HD). In January 1978, strange movements and the disturbance of her consciousness were occurred during PD, then blood glucose level showed over 1,800 mg/dl and serum osmolarity was over 390 mosm/KgH2O. Then she was diagnosed as non-ketotic hyperosmolar coma. After that, during HD and PD, hyperglycemia (approximately 1,200 mg/dl) and hypoglycemia (approximately 40 mg/dl) developed frequently. She died soon after HD on 19th December 1979. The autopsy disclosed bilateral atrophic kidneys due to diabetic changes and atrophic pancreas. Gross neuropathological findings revealed a few small infarcts at the putamen and the globus pallidus, however, other area were observed to be normal. The most remarkable change in microscopical finding was nearly symmetrical demyelinative lesion in the center of the basis pontis. The nerve cells and axon cylinders were relatively well preserved in the demyelinative lesion. The hyaline degeneration was observed in the arterial wall, however, any arterial obstruction was not found. Recent studies would suggest that the electrolyte disturbance, such as hyponatremia, may lead to CPM, particularly when this disturbance was rapidly corrected. On the other hand, CPM induced by diabetic coma has been reported, however, its pathogenesis has been unclear.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Central pontine myelinolysis followed by frequent hyperglycemia and hypoglycemia--report of an autopsy case]. 280 35

Six risk factors for severe visual loss despite panretinal (scatter) photocoagulation were identified by analyzing data collected during the first 5 years after randomization in the Diabetic Retinopathy Study. Proportional hazards regression revealed NVD (neovascularization on/around the optic disc) to be the most important risk factor. The risk of severe visual loss rose with increasing NVD, hemorrhages/microaneurysms, retinal elevation, proteinuria, and hyperglycemia and fell with increasing "treatment density." These results are similar to previous DRS findings on untreated eyes. The importance of "treatment density" as an independent predictor of visual outcome is a new finding and lends support to the common clinical practice of repeating photocoagulation if initial treatment does not reduce or stabilize retinal neovascularization.
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PMID:Factors associated with visual outcome after photocoagulation for diabetic retinopathy. Diabetic Retinopathy Study Report #13. 291 11

The antihypertensive effect of enalapril maleate, a new converting enzyme inhibitor, was evaluated in a multiclinic, double-blind, randomized study in patients with mild to moderate essential hypertension. The analyses were done in two ways, with patients who violated the entry criteria of the protocol excluded, and according to the intention to treat principle. Enalapril in dosages of 10 to 40 mg daily administered alone or concomitantly with hydrochlorothiazide was compared to propranolol (80 to 240 mg daily) alone or concomitantly with the diuretic. The study showed that enalapril significantly lowered both systolic and diastolic blood pressure. At each timepoint measured in the course of 26 weeks of therapy, the patients in the enalapril group consistently had greater decreases in blood pressure than patients in the propranolol group although not always significantly. The enalapril treatment group had a decrease in the mean arterial blood pressure of 22.2 mmHg compared to the propranolol group of 17.9 mmHg at the end of the study. These results were similarly independent of the way the data were analyzed. Fewer patients in the enalapril group required the addition of hydrochlorothiazide to maintain optimal control of blood pressure. Enalapril was found to be safe and well tolerated over the long-term of 48 weeks. Side effects such as leukopenia and taste perversions believed to be sulfhydryl-related were not encountered. The occurrence of rash and proteinuria was rare. Thiazide-induced hypokalemia, hyperuricemia and hyperglycemia appeared to be attenuated by enalapril. The favorable efficacy and side-effect profile provide the basis for enalapril to be a drug of choice when initiating antihypertensive therapy.
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PMID:Long-term enalapril--a new converting enzyme inhibitor--in the treatment of mild to moderate essential hypertension, results of a worldwide multiclinic study. Comparing two ways of analyzing data. 300 72

Two groups of adult male Munich-Wistar rats and a third group of nondiabetic age-matched and weight-matched normal control rats underwent micropuncture study 1 mo, and morphologic studies 14 mo, after induction of streptozotocin diabetes or sham treatment. All animals were fed standard rat chow. Diabetic rats received daily ultralente insulin to maintain stable moderate hyperglycemia (approximately 350 mg/dl). In addition, one group of diabetic rats was treated with the angiotensin I converting enzyme inhibitor, enalapril, 15 mg/liter of drinking water. Average kidney weight, whole kidney and single-nephron glomerular filtration rate, and glomerular plasma flow rate were elevated to similar values in both groups of diabetic rats, relative to normal control rats. Non-enalapril-treated diabetic rats exhibited significant elevations in mean glomerular capillary hydraulic pressure and transcapillary hydraulic pressure gradient, compared with the other groups studied, and only this group eventually developed marked and progressive albuminuria. Likewise, histological examination of the kidneys at 14 mo disclosed a high incidence of glomerular structural abnormalities only in non-enalapril-treated diabetic rats. These findings indicate that prevention of glomerular capillary hypertension in rats with diabetes mellitus effectively protects against the subsequent development of glomerular structural injury and proteinuria. This protection is afforded despite pronounced hyperglycemia and elevated levels of glucosylated hemoglobin, further supporting our view that hemodynamic rather than metabolic factors predominate in the pathogenesis of diabetic glomerulopathy.
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PMID:Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. 301 62


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