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

The initial stages of diabetic nephropathy are characterized by glomerular hyperfiltration and hypertension, processes that have been linked to initiation and progression of renal disease. Renin angiotensin system (RAS) blockade is commonly used to modify the hyperfiltration state and delay progression of renal disease. Despite this therapy, many patients progress to ESRD, suggesting heterogeneity in the response to RAS modulation. The role of the RAS in the hyperfiltration state in adolescents with uncomplicated type 1 diabetes was examined, segregated on the basis of the presence of hyperfiltration. Baseline renal hemodynamic function was characterized in 22 patients. Eleven patients exhibited glomerular hyperfiltration (GFR>or=135 ml/min), and in the remaining 11 patients, the GFR was <130 ml/min. Renal hemodynamic function was assessed in response to a graded angiotensin II (AngII) infusion during euglycemic conditions and again after 21 d of angiotensin-converting enzyme (ACE) inhibition with enalapril. AngII infusion under euglycemic conditions resulted in a significant decline in GFR and renal plasma flow in the hyperfiltration group but not in the normofiltration group. After ACE inhibition, GFR fell but did not normalize in the hyperfiltration group; the normofiltration group showed no change. These data show significant differences in renal hemodynamic function between hyperfiltering and normofiltering adolescents with type 1 diabetes at baseline, after AngII infusion and ACE inhibition. The response to ACE inhibition and AngII in hyperfiltering patients suggests that vasodilation may complement RAS activation in causing the hyperfiltration state. The interaction between glomerular vasoconstrictors and vasodilators requires examination in future studies.
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PMID:Impact of renin angiotensin system modulation on the hyperfiltration state in type 1 diabetes. 1667 13

Type 2 diabetes mellitus (T2DM) is often accompanied by high blood pressure (BP) and the clustering of several cardiovascular risk factors, and is the most frequent cause of end-stage renal disease. The stages of development of overt nephropathy in T2DM patients range from an initial alteration in renal function with an increased GFR, followed by the development of microalbuminuria and macroalbuminuria or proteinuria, featuring an established diabetic nephropathy, which eventually progresses to end-stage renal disease. Early intervention is needed to prevent the development of diabetic nephropathy and requires effective control of the different risk factors, and in particular high BP. In the initial stages of the disease, strict BP control is crucial to prevent the development of initial renal and vascular damage. Adequate BP control is particularly difficult in T2DM patients and in most cases requires the use of combination therapy. Preterax, a fixed-dose combination of perindopril 2 mg and indapamide 0.625 mg, allows BP to be significantly reduced compared with conventional strategies; this combination can be uptitrated to BiPreterax when further BP control is needed. In the PREMIER study performed in T2DM over 12 months, the perindopril/indapamide combination brought about, in addition to excellent BP control, a significant reduction in urinary albumin excretion, compared with monotherapy with enalapril. In more advanced degrees of renal damage, higher doses of the fixed combination have to be considered. The pharmacological basis of the renoprotective effect of perindopril/indapamide is the demonstration that this combination prevented nephropathy as well as proteinuria in obese Zucker rats, independently of BP control. Strict BP control from the initial stages of nephropathy together with inhibition of the renin-angiotensin system is mandatory to prevent albuminuria. The fixed combination of perindopril/indapamide can greatly help clinicians in achieving the above goals, using Preterax in the early and BiPreterax in the late stages of nephropathy.
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PMID:Renal protection in diabetic patients: benefits of a first-line combination of perindopril-indapamide (Preterax). 1672 64

Functionally significant polymorphisms in endothelial nitric oxide synthase (eNOS) and reduced vascular eNOS activity have been associated with increased human diabetic nephropathy (DN), but the pathogenic role of eNOS deficiency in the development of DN has not yet been confirmed. This study characterizes the severity of DN in eNOS(-/-) mice that were backcrossed to C57BLKS/J db/db mice. Although the severity of hyperglycemia was similar to C57BLKS/J db/db mice, by 26 wk, eNOS(-/-) C57BLKS/J db/db mice exhibited dramatic albuminuria, arteriolar hyalinosis, increased glomerular basement membrane thickness, mesangial expansion, mesangiolysis, and focal segmental and early nodular glomerulosclerosis. Even more remarkable, eNOS(-/-) C57BLKS db/db exhibited decreases in GFR to levels <50% of that in eNOS(+/+) C57BLKS db/db, as confirmed by increased serum creatinine. In summary, eNOS(-/-) db/db mice provide the most robust model of type II DN that has been described to date and support a role for deficient eNOS-derived NO production in the pathogenesis of DN.
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PMID:Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. 1725 94

Diabetic nephropathy (DN) is a late diabetic complication that comprises progressively increasing albuminuria, declining GFR, and increased cardiovascular risk. Only a minority of patients with diabetes (25 to 40%) develop nephropathy, and there is evidence that heritable genetic factors predispose these "at-risk" individuals to DN. Comparing variability among inbred mouse strains with respect to a specific phenotype can model interhuman variability, and each strain represents a genetically homogeneous system with a defined risk for nephropathy. C57BL/6 mice, which are relatively resistant to DN, were mutagenized using N-ethyl-N-nitrosourea and screened for mutants that developed excess albuminuria on a sensitizing type 1 diabetic background contributed by the dominant Akita mutation in insulin-2 gene (Ins2(Akita)). Two of 375 diabetic G1 founders were found to exhibit albumin excretion rates persistently 10-fold greater than albumin excretion rates in nonmutagenized Ins2(Akita) controls. This albuminuria trait was heritable and transmitted to approximately 50% of Ins2(Akita) G2 and G3 progeny, consistent with a simple, dominantly inherited trait, but was never observed in nondiabetic offspring. During the course of 1 yr, albuminuric Ins2(Akita) G2 and G3 progeny developed reduced inulin clearance with elevated blood urea nitrogen and plasma creatinine. Glomerular histology revealed mesangial expansion, and glomerular basement membrane thickening as determined by electron microscopy was enhanced in diabetic mutant kidneys. Hereditary albuminuric N-ethyl-N-nitrosourea-induced mutants were redesignated as Nphrp1 (nephropathy1) and Nphrp2 (nephropathy2) mice for two generated lines. These novel mutants provide new, robust mouse models of DN and should help to elucidate the underlying genetic basis of predisposition to DN.
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PMID:A sensitized screen of N-ethyl-N-nitrosourea-mutagenized mice identifies dominant mutants predisposed to diabetic nephropathy. 1715 34

Tight glycemic control can reduce progression of diabetic nephropathy (DN) while the histological changes may regress after pancreas transplantation. Clinical islet transplantation (CIT) can restore euglycemia but the effects of CIT and concomitant immunosuppression on renal function are not known. Renal function (modification of diet in renal disease estimated glomerular filtration rate [GFR]) is reported in 41 type 1 diabetes subjects followed for 29.8 (6-57) months after CIT who received sirolimus and tacrolimus. HbA(1c) improved by 3 months (6.1 +/- 0.5 vs. 8.1 +/- 1.3%, p < 0.001) and was sustained. Over 4 years estimated GFR (eGFR) declined (repeated measures ANOVA: p = 0.0011). The median rate of change in eGFR was -0.39 mL/min/1.73 m(2)/month but was highly variable (range: +1.62 to -2.79 mL/min/1.73 m(2)/month). Progression of albuminuria was observed in ten individuals while regression of microalbuminuria was observed in only one (chi square = 22.51, df = 4, p = 0.0002). Despite improved glycemia, CIT and concomitant immunosuppression, was associated with a fall in eGFR and progression of albuminuria over 4 years of observation. The rate of decline in eGFR was extremely variable and difficult to predict. The risk of progressive nephrotoxicity with decline in eGFR should be discussed with prospective CIT candidates and the risk: benefit ratio carefully considered in individuals with pre-existing renal impairment.
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PMID:Changes in renal function after clinical islet transplantation: four-year observational study. 1710 28

This study aimed to establish the time of initiation and the determinants of renal function decline in type 1 diabetes. Until now, such decline has been assumed to be a late-occurring event associated with proteinuria. A total of 267 patients with normoalbuminuria and 301 patients with microalbuminuria were followed for 8 to 12 yr. Linear trends (slopes) in GFR were estimated by serial measurement of serum cystatin C. Cases of early renal function decline were defined by loss in cystatin C GFR that exceeded -3.3%/yr, a threshold that corresponds to the 2.5th percentile of the distribution of GFR slopes in an independent nondiabetic normotensive population. Cases of early renal function decline occurred in 9% (mean slope -4.4; range -5.9 to -3.3%/yr) of the normoalbuminuria group and 31% (mean slope -7.1; range -23.8 to -3.3%/yr) of the microalbuminuria group (P < 0.001). Risk for early renal function decline depended on whether microalbuminuria regressed, remained stable, or progressed, rising from 16 to 32 and 68%, respectively (P < 0.001). In multivariate analysis, risk for decline was higher after age 35 yr or when glycosylated hemoglobin exceeded 9% but did not vary with diabetes duration, smoking, BP, or angiotensin-converting enzyme inhibitor treatment. Contrary to the existing paradigm of diabetic nephropathy, progressive renal function decline in type 1 diabetes is an early event that occurs in a large proportion of patients with microalbuminuria. Together with testing for microalbuminuria, clinical protocols using cystatin C to diagnose early renal function decline and track response to therapeutic interventions should be developed.
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PMID:Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes. 1736 Sep 46

Vascular endothelial growth factor (VEGF) is an important mediator in maintaining normal kidney functions. In addition, several lines of evidence suggest that upregulation of VEGF in glomeruli may be associated with or cause renal dysfunction such as diabetic nephropathy. For elucidation of the pathologic consequences of high levels of VEGF in glomeruli, transgenic (Tg) rabbits that express human VEGF(165) isoform in both kidney and liver under the control of the human alpha-1-antitrypsin promoter were generated and characterized. With the use of heterozygous Tg rabbits and their littermates aged 8 to 55 wk, renal functions and structures were investigated. Compared with control rabbits, Tg rabbits exhibited progressive proteinuria with increased GFR at the early stage and decreased GFR at the later stage. Histologic examinations revealed that Tg rabbit kidneys were characterized by considerable glomerular hypertrophy as a result of increased proliferation of both glomerular capillaries and mesangial cells accompanied by prominent podocyte hypertrophy. With increasing age starting from 20 wk, Tg rabbit kidneys showed prominent formation of microaneurysms and capillary proliferation at the vascular pole area. At a later stage (55 wk), many glomeruli showed sclerosis and tuft collapse with the formation of glomerular cysts on a background of tubular atrophy and interstitial fibrosis. This study provides the first evidence that increased expression of VEGF in glomeruli directly causes the glomerular hypertrophy that is associated with proteinuria, suggesting that VEGF exerts multiple effects on the glomerular pathophysiologic processes.
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PMID:Increased expression of vascular endothelial growth factor in kidney leads to progressive impairment of glomerular functions. 1755 51

In 2005, the acceptance rate for renal replacement therapy (RRT) in adults in the UK was 108 per million population (pmp). This was derived from complete data for adults in the UK, as data were obtained separately from the five English renal units not currently returning to the Registry. In addition, 87 children started RRT (see Chapter 13) giving a total incidence of 110 pmp. From 2001 to 2005 there has been an 7.3% rise in the acceptance numbers in those 42 renal units with full reporting throughout that period. In the UK, for adults in 2005, the crude acceptance rates in Local Authorities (LA) varied from 0 (in two very small LA areas in Scotland and Northern Ireland) to 271 pmp; the standardized rate ratios for acceptance varied from 0 to 2.76. Excluding the two areas with null returns, 20 areas had significantly low ratios, all of them in England. Thirty had significantly high ratios, seven in Northern Ireland, four in Scotland, three in Wales and seven in London. Over the period 2001-2005, 25 areas had a significantly low standardized acceptance rate; 24 in England and one in Scotland. All except one of these had ethnic minority populations of <10%. Thirty-seven had high standardized acceptance rates, seven in Scotland where ethnicity data were not available, 14 from areas with ethnic minority populations in excess of 10%, and 12 were in Wales or the Southwest of England. The median age of patients starting RRT in England has increased from 63.8 years in 1998 to 65.2 years in 2005. The median age of incident non-White patients is significantly lower at 56.8 years. In England, the acceptance rate is highest in the 75-79 age band at 408 pmp, as in Scotland at 580 pmp; in Wales the peak is in the 80-84 age band at 525 pmp, as in Northern Ireland with a rate of 825 pmp. Diabetic renal disease (20%) remains the most common specific primary renal disease. There was a significant positive correlation between the percentage of incident RRT patients with diabetic renal disease and the percentage of non-Whites in the incident cohort. Haemodialysis (HD) was the first modality of RRT in 76% of patients, peritoneal dialysis (PD) in 21% and pre-emptive transplant in 3%. In 1998, the proportion whose first modality was HD was 58% and this continues to increase. By day 90, 8% had died, a further 1% had stopped treatment or been transferred out leaving 91% of the original cohort on RRT. Of these, 71% were on HD, 26% on PD and 3% had received a transplant. Data on first referral to a nephrologist were available from 22 centres for the period 2000-2005 (for a total of 5611 patients and 59 centre-years). In 2005, the mean percentage of patients referred late (<90 days before dialysis initiation) was 30% (centre range 13-48%). This was similar to the value in 2000. Patients referred late were older, a higher proportion of them were male, a lower proportion non-White, and a lower proportion with no recorded comorbidity. Patients with polycystic kidney disease and diabetic nephropathy tended to be referred early compared with the whole incident cohort and those with uncertain aetiology and no recorded diagnosis referred late. Estimated GFR (eGFR) at the start of RRT appears to be higher in older than younger patients. eGFR is significantly lower in those referred late compared with those referred earlier and this is especially marked in the older patients. The geometric mean eGFR of all patients starting RRT rose from 6 in 1997 to above 7.5 in 2003, since when it has remained stable.
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PMID:New adult patients starting renal replacement therapy in the UK in 2005 (chapter 3). 1772 40

In a clinic-based, cross-sectional study of 320 type 2 diabetic patients, we staged the level of diabetic nephropathy (normoalbuminuric, microalbuminuric and macroalbuminuric stage) and estimated GFR based on serum creatinine and cystatin C (CysC). Serum creatinine and CysC levels were 0.91+/-0.21 mg/dL and 0.87+/-0.26 mg/L, respectively. Correlation coefficients between CysC-GFR and each of the creatinine-based GFR measurements (MDRD-GFR, Cockcroft-Gault-GFR, and CLcr) were 0.589, 0.569, and 0.479 (p<0.001). Serum CysC was significantly lower in normoalbuminurics (0.83+/-0.22) than in microalbuminurics and macroalbuminurics (0.94+/-0.33 and 1.05+/-0.28; p=0.004 and p<0.001). Of the estimations of GFR, significant differences among the groups were found on CysC-GFR and CLcr. CysC-GFR (mL/min) was statistically lower in macroalbuminurics (79.5+/-30.5) than in normoalbuminurics (104.3+/-30.9, p=0.01). The logistic regression analyses showed that retinopathy, A1C, CysC, diabetic duration, and CysC-GFR were indicators to predict the development of microalbuminuria. Serum CysC seems to be more accurate serum marker than serum creatinine in evaluating a prognostic stage of type 2 diabetic nephropathy. Our study suggests that, in Korean type 2 diabetic patients, CysC-based GFR might be more valuable than creatinine-based GFR in the prediction of the microalbuminuric stage.
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PMID:The comparison of cystatin C and creatinine as an accurate serum marker in the prediction of type 2 diabetic nephropathy. 1782 97

Recent studies questioned the existence of a specific renoprotective effects of ACE-inhibitors (ACE-i) and angiotensin receptor blockers (ARBs) besides their blood pressure lowering effect. In the ALLHAT study patients were randomly assigned to receive chlorthalidone, amlodipine and lisinopril. Results showed that, even in patients with reduced GFR, neither lisinopril nor amlodipine was superior to chlorthalidone in reducing the rate of development of ESRD or a 50% or greater decrement in GFR. Because of inclusion criteria the ALLHAT population was selected as at low risk for renal outcomes. Moreover, over 50% of the patients who were randomized to lisinopril either never received the medication or received the lower possible dose. Casas et al selected RCT comparing ACE-i and ARBs with other regimens. They concluded that ACE-i and ARBs are not more renoprotective that can be explained by lowering of blood pressure (BP) in diabetic nephropathy, while in non diabetic kidney disease a blood pressure independent renoprotective effect is uncertain. They made a very heterogeneous selection of trials that was dominated by the ALLHAT study; the analysis was not based on individual patient data. The Benedict Study showed that in hypertensive, normoalbuminuric patients with type 2 diabetes, BP reduction and ACE-i therapy both independently may prevent microalbuminuria. ACE-i therapy is particularly effective when BP is poorly controlled. We conclude that the recommendation of the Guidelines to use ACE-i and/or ARBs as first-line antihypertensive drugs for renoprotection in patients with diabetic and non diabetic kidney disease is still valid.
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PMID:[Antihypertensive therapy and renoprotection: do we really need to block the renin-angiotension system?]. 1788 9


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