The effect of high-flux hemodialysis membranes on patient survival has not been unequivocally determined. In this prospective, randomized clinical trial, we enrolled 738 incident hemodialysis patients, stratified them by serum albumin Յ4 and Ͼ4 g/dl, and assigned them to either low-flux or high-flux membranes. We followed patients for 3 to 7.5 yr. Kaplan-Meier survival analysis showed no significant difference between high-flux and low-flux membranes, and a Cox proportional hazards model concurred. Patients with serum albumin Յ4 g/dl had significantly higher survival rates in the high-flux group compared with the low-flux group (P ϭ 0.032). In addition, a secondary analysis revealed that high-flux membranes may significantly improve survival of patients with diabetes. Among those with serum albumin Յ4 g/dl, slightly different effects among patients with and without diabetes suggested a potential interaction between diabetes status and low serum albumin in the reduction of risk conferred by high-flux membranes. In summary, we did not detect a significant survival benefit with either high-flux or low-flux membranes in the population overall, but the use of high-flux membranes conferred a significant survival benefit among patients with serum albumin Յ4 g/dl. The apparent survival benefit among patients who have diabetes and are treated with high-flux membranes requires confirmation given the post hoc nature of our analysis. 20: 645-654, 200920: 645-654, . doi: 10.1681 Patients who have stage 5 chronic kidney disease (CKD) and are on dialysis therapy have a high mortality rate, estimated between 14 and 26% in Europe and at 24% per year in the United States. 1 The accumulation of various retention solutes over a broad range of molecular weights and chemical composition is involved in the complex pathophysiology of uremia and, among other factors, implicated in the high mortality observed in CKD. 2 Because of their higher porosity, high-flux hemodialysis (HD) membranes have the capacity to remove retention solutes of higher molecular weight than do low-flux membranes, 3 which contain smaller pores. Whether this enhanced solute elimination of high-flux membranes translates J Am Soc Nephrol
Abstract. Diabetic nephropathy may be effectively prevented and treated by controlling glycemia and administering angiotensinconverting enzyme (ACE) inhibitors. However, strict metabolic control can be difficult, and ACE inhibitors may be poorly tolerated and only partially effective, particularly in diabetes mellitus type 2 (DM2), warranting the search for ancillary treatment. Sulodexide is a glycosaminoglycan, a new class of drug that has demonstrated nephroprotective activity in experimental investigations. The Di.N.A.S. study was a randomized, double-blind, placebo-controlled, multicenter, dose-range finding trial to evaluate the extent and duration of the hypoalbuminuric effect of oral sulodexide in diabetic patients. A total of 223 microalbuminuric and macroalbuminuric DM1 and DM2 patients with serum creatinine Յ150 mol/L and stable BP and metabolic control were recruited. They were randomly allocated to one of four groups: 50 mg/d, 100 mg/d, or 200 mg/d sulodexide daily or placebo for 4 mo (T0 to T4), with 4 mo of follow-up after drug suspension (T4 to T8). Treatment with 200 mg/d sulodexide for 4 mo significantly reduced log albumin excretion rate (logAER) from 5.25 Ϯ 0.18 at T0 to 3.98 Ϯ 0.11 at T4 (P Ͻ 0.05), which was maintained till T8 (4.11 Ϯ 0.13; P Ͻ 0.05 versus T0). Moreover, the sulodexideinduced percent reductions in AER at T4 were significantly different from the placebo value at T4 and approximately linear to dose increments (30% [confidence limits, 4 to 49%], P ϭ 0.03; 49% [30 to 63%], P ϭ 0.0001; and 74% [64 to 81%], P ϭ 0.0001 in the sulodexide 50, 100, and 200 mg/d groups, respectively. At T8, the sulodexide 200 mg/d group maintained a 62% (45 to 73%) AER significant reduction versus placebo (P ϭ 0.0001). Subanalysis by type of diabetes (DM1 versus DM2, microalbuminuric versus macroalbuminuric, or on concomitant ACE inhibitors versus not on ACE inhibitors) demonstrated similar findings. These effects were obtained without any significant variation in metabolic control and BP or serum creatinine. Very few adverse events were reported; none were serious. In conclusion, a 4-mo course of high doses of sulodexide significantly and dose-dependently improves albuminuria in DM1 and DM2 patients and micro-or macroalbuminuric patients with or without concomitant ACE inhibition. The effect on albuminuria is long-lasting and seemingly additive to the ACE inhibitory effect.Diabetes is the most common cause of end-stage renal disease (ESRD) in Western countries. In the United States, diabetes currently accounts for 44% of all new cases of ESRD (1). Despite advances in clinical care, the incidence of diabetes mellitus type 2 (DM2)-related cases of ESRD is rapidly increasing (2), and survival of DM-related ESRD patients on dialysis is markedly low (3,4).The anatomic hallmarks of diabetic nephropathy (DN) include thickening of the glomerular basement membrane (GBM) and mesangial expansion with hyalinosis both in the mesangium and capillary lumen. These lesions lead to glomerular fibrosis, which progressiv...
Abstract-The renin-angiotensin-aldosterone system plays an important role in blood pressure regulation by influencing salt-water homeostasis and vascular tone. The purpose of the present study was to search for associations of single nucleotide polymorphisms on 3 major candidate genes of this system with the plasma concentrations of the corresponding renin-angiotensin-aldosterone system components considered as quantitative phenotypes. Genotyping was performed in 114 normotensive subjects for different variants of the angiotensinogen (AGT) gene (C-532T, G-6A, M235T), the angiotensin I-converting enzyme (ACE) gene [4656(CT) 2/3 ], the aldosterone synthase (CYP11B2), and the type 1 angiotensin II receptor (AT1R) gene (A1166C) by hybridization with allele-specific oligonucleotides (ASO) or enzymatic digestion of polymerase chain reaction products. Plasma levels of AGT, ACE, angiotensin II (Ang II), aldosterone, and immunoreactive active renin were measured according to standard techniques. Platelet binding sites for Ang II were analyzed by the binding of radioiodinated Ang II to purified platelets. B max and K D values of the Ang II binding sites on platelets of each individual were calculated to examine a possible relationship between these parameters and the AT1R genotype. A highly significant association of the ACE 4656(CT) 2/3 variant with plasma ACE levels was observed (PϽ0.0001). ANOVA showed a significant effect of the AGT C-532T polymorphism on AGT plasma levels (Pϭ0.017), but no significant effect was detectable with the other AGT polymorphisms tested, such as the G-6A or the M235T. A significant effect association was also found between the C-344T polymorphism of the CYP11B2 gene and plasma aldosterone levels, with the T allele associated with higher levels (Pϭ0.02 Key Words: angiotensinogen Ⅲ angiotensin-converting enzyme Ⅲ angiotensin II Ⅲ aldosterone Ⅲ polymorphism Ⅲ blood pressure S ingle nucleotide biallelic polymorphisms are powerful tools when used to search for a linkage disequilibrium between a marker genotype and a disease, mainly of multifactorial origin. With these markers, candidate genes of the renin-angiotensin-aldosterone system (RAAS), including those of angiotensinogen (AGT), the angiotensin I-converting enzyme (ACE), and type I angiotensin (Ang) II receptor (AT1R), have been investigated in association studies with cardiovascular diseases, such as hypertension or myocardial infarction. As examples of these associations, the ACE insertion/deletion (I/D) polymorphism was found associated with myocardial infarction, cardiac hypertrophy after physical exercise, and Alzheimer disease, 1,2 and the AGT or AT1R genes were found to be associated with hypertension. 3,4 Therefore, it is of interest to establish relationships between these marker genotypes and intermediate phenotypes related to the disease and to the gene tested to understand the physiopathology of these associations, thus helping to clarify inconsistent results issued from some association studies. Among these observations, the st...
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