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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study tested the hypothesis that nitric oxide (NO)-mediated renal vasodilation due to the activity of the inducible nitric oxide synthase (iNOS) contributes to glomerular hyperfiltration in diabetic rats. Two weeks after induction of diabetes mellitus by streptozotocin, mean arterial BP (MAP), GFR (inulin clearance), and renal plasma flow (RPF) (para-aminohippurate clearance) were measured in conscious instrumented rats. Diabetic rats had elevated GFR (3129 +/- 309 microl/min versus 2297 +/- 264 microl/min in untreated control rats, P < 0.05) and RPF (10526 +/- 679 microl/min versus 8005 +/- 534 microl/min), which was prevented by chronic insulin treatment. Intravenous administration of 0.1 and 1 mg of L-imino-ethyl-lysine (L-NIL), an inhibitor of iNOS, did not affect MAP, GFR, or RPF, either in diabetic or control rats. A higher L-NIL dose (10 mg) increased MAP and decreased RPF in diabetic rats significantly (n = 6, P < 0.05), but not in controls (n = 6). In addition, 0.1 mg of NG-nitro-L-arginine methyl ester (L-NAME), a nonselective blocker of NOS isoforms, decreased GFR (2389 +/- 478 microl/min) and RPF (7691 +/- 402 microl/min) in diabetic animals to control levels, while renal hemodynamics in normoglycemic rats were not altered. Higher L-NAME doses (1 and 10 mg) reduced GFR and RPF in diabetic and control rats to identical levels. In glomeruli isolated from diabetic and control rats, neither iNOS mRNA nor iNOS protein expression was detected. In contrast, increased protein levels of endothelial constitutive NOS (ecNOS) were found in glomeruli of diabetic rats compared with controls. By immunohistochemistry, ecNOS but not iNOS staining was observed in the endothelium of preglomerular vessels and in diabetic glomeruli. These results support the notion that increased NO availability due to greater abundance of ecNOS contributes to the pathogenesis of glomerular hyperfiltration in early experimental diabetic nephropathy. In contrast, we found no functional or molecular evidence for increased glomerular expression and activity of iNOS in diabetic rats.
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PMID:Nitric oxide synthase isoforms and glomerular hyperfiltration in early diabetic nephropathy. 1061 42

Diabetic nephropathy is a serious long-term complication of diabetes characterized by persistent albuminuria (> 300 mg/24 h or 200 micrograms/min) associated with a decline in GFR, increasing arterial blood pressure, and high risk of cardiovascular morbidity and mortality. Diabetic nephropathy has become the leading cause of end stage renal disease in Europe, USA and Japan. There is a great inter-individual variation in the deterioration in GFR explained by genetic and non-genetic progression promoters (risk factors for losing GFR). In particular arterial blood pressure, glycaemic control, and albuminuria act as non-genetic promoters of progression. These factors are potentially modifiable. Genetic promoters of progression have also been identified, mainly the angiotensin converting enzyme insertion/deletion polymorphism. Knowledge of progression promoters can identify patients with a poor prognosis and direct therapy against modifiable risk factors, in particular hypertension and hyperglycaemia.
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PMID:[Risk factors in the progression of diabetic nephropathies]. 1101 33

Vascular endothelial growth factor (VEGF) is a cytokine that potently stimulates angiogenesis, microvascular hyperpermeability, and endothelium-dependent vasodilation, effects that are largely mediated by endothelial nitric oxide synthase (eNOS). The expression of VEGF is pronounced in glomerular visceral epithelial cells, but its function in renal physiology and pathophysiology is unknown. VEGF expression is upregulated by high ambient glucose concentrations in several cell types in vitro and in glomeruli of diabetic rats. To assess the role of VEGF in the pathophysiology of early renal dysfunction in diabetes, monoclonal anti-VEGF antibodies (Ab) were administered to control and streptozotocin-induced diabetic rats for 6 wk after induction of diabetes. Based on in vitro binding studies, an adequate serum VEGF inhibitory activity was achieved during the entire course of anti-VEGF Ab administration. Anti-VEGF Ab treatment but not administration of isotype-matched control Ab decreased hyperfiltration, albuminuria, and glomerular hypertrophy in diabetic rats. VEGF blockade also prevented the upregulation of eNOS expression in glomerular capillary endothelial cells of diabetic rats. Antagonism of VEGF had no effect on GFR and glomerular volume in control rats. These results identify VEGF as a pathogenetic link between hyperglycemia and early renal dysfunction in diabetes. Targeting VEGF may prove useful as a therapeutic strategy for the treatment of early diabetic nephropathy.
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PMID:Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. 1131 58

Diabetic nephropathy(DN) is the leading cause of end-stage renal disease in Japan. Clinical course of DN is divided into five stages. Stage 1 is a pre-nephropathy stage. Stage 2 is the period with microalbuminuria. Stage 3A is the stage with persistent macroproteinuria and well preserved renal function. Strict glycemic control and antihypertensive treatment with ACE inhibitors are capable of inducing remission in stage 2 of DN and probably in stage 3A. GFR less than 60 ml/min and urinary protein excretion more than 1 g/day are regarded as stage 3B. Serum creatinine concentration increases in stage 4. Antihypertensive therapy and low protein diet are major options of therapy both in stage 3B and 4. Stage 5 is the period with renal replacement therapy. Survival rate of patients on HD due to DN still remains unsatisfactory. Only 30-50% of type 2 diabetic patients develop DN, suggesting that there are several factors other than hyperglycemia which induce DN. Prediabetic hypertension and parenteral hypertension are regarded as predictors of DN. Smoking, male gender, and advanced age might be risk factors of DN. Recently it was demonstrated that insertion/deletion(I/D) polymorphism of angiotensin converting enzyme gene is associated with DN. In addition polymorphisms of several genes seem to be associated with DN. Development of DNA tips will make it possible to determine a number of gene polymorphisms. Accumulations of the information on gene polymorphisms from many patients with or without DN are expected to contribute detection of patients at high risk of developing DN.
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PMID:[Diabetic nephropathy; clinical stage and prediction]. 1179 89

Prospective studies have established smoking as an independent risk factor for diabetic nephropathy, suggesting an adverse effect of smoking on glomerular structure and function. To test this hypothesis, this study evaluated GFR, metabolic profile, and smoking habits in 96 patients with type 2 diabetes and abnormal albumin excretion rate (AER). All patients underwent percutaneous kidney biopsy: mesangial fractional volume [Vv (mes/glom)] and glomerular basement membrane (GBM) width were estimated by electron microscopic morphometric analysis; interstitial fibrosis was estimated semiquantitatively by light microscopy. Forty-eight patients were smokers. Compared with nonsmokers, smokers had higher values of HbA(1c) (P = 0.002), AER (P = 0.026), GFR (P = 0.004), and GBM width (P = 0.002); moreover, GFR was higher in current smokers than in former smokers (P = 0.001), and GBM width was related to heavy smoking (F = 5.4; P = 0.006). Multiple linear regression analyses revealed that HbA(1c) was associated with fasting blood glucose (beta coef = 0.52; P < 0.001), smoking habit (beta coef = 0.31; P < 0.001), insulin therapy (beta coef = 0.22; P = 0.012), and male gender (beta coef = -0.20; P = 0.020); AER was related to Vv (mes/glom) (beta coef = 0.32; P = 0.003), GBM width (beta coef = 0.28; P = 0.016), and interaction between smoking habit and HbA(1c) (beta coef = 0.24; P = 0.040). GFR was negatively correlated with Vv (mes/glom) (beta coef = -0.57; P < 0.001) and age (beta coef = -0.29; P = 0.001) and positively correlated with GBM width (beta coef = 0.27; P = 0.012), heavy current smoking (beta coef = 0.24; P = 0.028), and HbA(1c) (beta coef = 0.28; P = 0.040); GBM width was explained by Vv (mes/glom) (beta coef = 0.53; P < 0.001), interaction between heavy smoking and HbA(1c) levels (beta coef = 0.25; P = 0.003), and diabetes duration (beta coef = 0.23; P = 0.010). Smoking habit did not affect the index of interstitial fibrosis. In conclusion, cigarette smoking affects glomerular structure and function in type 2 diabetes and may be an important factor for the onset and progression of diabetic nephropathy.
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PMID:Effects of cigarette smoking on glomerular structure and function in type 2 diabetic patients. 1239 43

Atubular glomeruli (AG) have been described in several renal disorders. However, little attention has been paid to AG in diabetic nephropathy (DN). Preliminary studies suggested that tip lesions were frequently present in type 1 diabetic (D) patients with proteinuria. The aim of this study was to determine the frequency of AG and their possible relationship with tip lesions in DN. Renal biopsies from eight proteinuric type 1 D patients with normal to moderately reduced GFR (76 +/- 26 ml/min per 1.73 m(2)) and eight normal subjects were studied by light (LM) and electron microscopy (EM). Glomerular volume, volume of the glomerular corpuscle, which is tuft, and the fractional volumes of proximal, distal, and atrophic tubules per cortex were estimated using appropriate stereologic methods. Glomerulotubular junctions were examined on serial sections and classified into glomeruli attached to: normal tubules (NT); short atrophic tubules (SAT); long atrophic tubules (LAT); atrophic tubules with no observable glomerular opening (ATNO); and atubular glomeruli (AG). EM studies showed typical diabetic changes in biopsies, including increased GBM width (P < 0.00001) and mesangial fractional volume (P < 0.0001) and decreased filtration surface density (P < 0.01) compared with normal subjects. Seventeen percent of glomeruli in the D patients were atubular, and 51% were attached to atrophic tubules. Tip lesions were present in all SAT, 64% of LAT, 82% of ATNO, and only 9% of NT and were never observed in normal subjects. The relative volume of AG was smaller than glomeruli in other categories (P < 0.05). Fractional volume of proximal (P < 0.01) and distal (P <0.01) tubules per cortex were decreased, while fractional volume of cortical interstitium (P <0.00001) and atrophic tubules (P <0.01) were increased in D patients. Fractional volume of atrophic tubules, %AG, and percent of glomeruli with tip lesion explained 94% of the GFR variability in diabetic patients (P <0.05). Thus, AG and glomerulotubular junction abnormalities may be important in the development and progression of DN.
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PMID:Atubular glomeruli and glomerulotubular junction abnormalities in diabetic nephropathy. 1266 Mar 25

Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in diabetic patients. This study tested whether dual blockade of the renin-angiotensin system (RAS) with both an angiotensin-converting enzyme (ACE) inhibitor (ACE-I) and an Angiotensin-II receptor blocker (ARB) is superior to either drug alone in type I diabetic patients with diabetic nephropathy (DN). A randomized double-blind crossover trial was performed with 8-wk treatment with placebo, 20 mg of benazepril once daily, 80 mg of valsartan once daily, and the combination of 20 mg of benazepril and 80 mg of valsartan. Twenty type I diabetic patients with DN were included. At the end of each treatment period, albuminuria, 24-h BP, and GFR were measured. Eighteen patients completed the study. Placebo values were: albuminuria [mean (95% CI)], 701 (490 to 1002) mg/24 h; BP [mean (SEM)], 144 (4)/79 (2) mmHg, and GFR [mean (SEM)], 82 (7) ml/min per 1.73 m(2). Treatment with benazepril, valsartan, or dual blockade significantly reduced albuminuria and BP compared with placebo. Benazepril and valsartan were equally effective. Dual blockade induced an additional reduction in albuminuria of 43 % (29 to 54 %) compared with any type of monotherapy, and a reduction in systolic BP of 6 (0 to 13) mmHg and 7 (1 to 14) mmHg (versus benazepril and valsartan, respectively) and a reduction of 7 (4 to 10) mmHg diastolic compared with both monotherapies. GFR was reversibly reduced on dual blockade compared with monotherapy and placebo. All treatments were safe and well tolerated. In conclusion, dual blockade of the RAS may offer additional renal and cardiovascular protection in type I diabetic patients with DN.
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PMID:Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy. 1266 Mar 33

In Germany, 36% of all new chronic dialysis patients have diabetic nephropathy. The majority are type 2 diabetics. Early intervention has the greatest effect. Incipient nephropathy can be diagnosed by evidence of microalbuminuria (30-300 mg albumin/g creatinine). Proteinuria on the standard test strip (>300 mg/g) indicates manifest nephropathy followed by progressive renal failure. Important cofactors for progression are hypertension, hyperglycemia, and smoking. Low normal blood pressure levels (<130/80 mmHg without and <125/75 mmHG with proteinuria) based on ACE inhibitors/AT1 blockers are the goal. Combination therapies are frequently necessary. This can often reverse microalbuminuria. Chronic renal failure requires special attention (e.g. bone metabolism, anemia, acidosis). Timely initiation of renal replacement therapy (GFR <15 ml/min) reduces morbidity and mortality. In addition to hemo- and peritoneal dialysis, early kidney and in individual cases of type 1 diabetes combined kidney/pancreas transplantation is appropriate.
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PMID:[Diagnostics and therapy of diabetic nephrology]. 1273 10

Elevated systemic blood pressure is one of the most important risk factor of diabetic nephropathy. The aim of the study was to estimate the influence of systemic blood pressure on renal function in children and adolescents with type 1 diabetes mellitus. Fifty-nine patients without evidence of arterial hypertension were recruited. In all patients 24-hour automatic blood pressure monitoring and renal examination (GFR, ERPF, FF, renoscintigraphy, urinary albumin excretion) were performed. The patients were divided into three groups according to blood pressure load: group I (less than 40% of systolic blood pressure--SBP and diastolic blood pressure--DBP values above 90th percentile for sex, age, height and body weight)--26 persons, group II (more than 40% DBP above 90th percentile)--25 persons, group III (more than. 40% SBP and DBP above 90th percentile)--8 persons. The study suggests that 24-hour automatic blood pressure monitoring is useful for early detection of increased blood pressure in diabetic children and adolescents. The patients with elevated both systolic and diastolic blood pressures had more frequently glomerular hyperfiltration. The persons with elevated only diastolic blood pressure had the lowest glomerular filtration and filtration fraction.
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PMID:[The influence of systemic blood pressure on renal function in children and adolescents with type 1 diabetes mellitus]. 1291 96

The impact of polymorphisms in the genes coding for angiotensinogen (M235T), ACE (ID), and angiotensin II type 1 receptor (A(1166)-->C) on decline in GFR and doubling of s-creatinine or development of ESRD in patients with type 1 diabetes and diabetic nephropathy (DN) was tested. From 1985, all patients (n = 169) who had established diabetic nephropathy and were treated with angiotensin-converting enzyme inhibition (ACE-I) were identified consecutively at Steno Diabetes Center. Patients were followed for a median of 6 yr (range, 3 to 15 yr), with nine (range, three to 29) measurements of GFR ((51)Cr-EDTA). In a Cox proportional hazards model corrected for other risk factors, the D allele (ACE/ID) was associated with time to doubling of s-creatinine/ESRD (rate ratio, 1.81 per allele; 95% confidence interval, 1.09 to 3.03; P = 0.02). A new interaction hypothesis was generated demonstrating that the following variables were associated with accelerated decline in GFR: albuminuria (estimate, 2.12 ml/min per yr per 10-fold increase in albuminuria; P < 0.001), mean BP (estimate, 0.88 ml/min per yr per 10 mmHg; P = 0.02), hemoglobin A(1c) (estimate, 0.54 min/min per yr per 1%; P = 0.02), and number of M (M235T)/D (ID)/A (A(1166)-->C) alleles (estimate, 0.45 ml/min per yr per allele; P = 0.049). Number of M/D/A alleles also influenced time to doubling of s-creatinine or ESRD. In this study of patients with type 1 diabetes, the D allele of the ACE/ID polymorphism in addition to nongenetic risk factors independently accelerated progression of DN during ACE-I. Interaction between polymorphisms in the renin-angiotensin system also influenced the loss of kidney function. This new genetic interaction model needs to be confirmed in future studies.
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PMID:Genetic variation in the Renin-Angiotensin system and progression of diabetic nephropathy. 1456 94


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