Di Xie

Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: A Randomized Controlled Study of Benazepril and Losartan in Chronic Renal Insufficiency

The Renoprotection of Optimal Antiproteinuric Doses (ROAD) study was performed to determine whether titration of benazepril or losartan to optimal antiproteinuric doses would safely improve the renal outcome in chronic renal insufficiency. A total of 360 patients who did not have diabetes and had proteinuria and chronic renal insufficiency were randomly assigned to four groups. Patients received open-label treatment with a conventional dosage of benazepril (10 mg/d), individual uptitration of benazepril (median 20 mg/d; range 10 to 40), a conventional dosage of losartan (50 mg/d), or individual uptitration of losartan (median 100 mg/d; range 50 to 200). Uptitration was performed to optimal antiproteinuric and tolerated dosages, and then these dosages were maintained. Median follow-up was 3.7 yr. The primary end point was time to the composite of a doubling of the serum creatinine, ESRD, or death. Secondary end points included changes in the level of proteinuria and the rate of progression of renal disease. Compared with the conventional dosages, optimal antiproteinuric dosages of benazepril and losartan that were achieved through uptitration were associated with a 51 and 53% reduction in the risk for the primary end point (P = 0.028 and 0.022, respectively). Optimal antiproteinuric dosages of benazepril and losartan, at comparable BP control, achieved a greater reduction in both proteinuria and the rate of decline in renal function compared with their conventional dosages. There was no significant difference for the overall incidence of major adverse events between groups that were given conventional and optimal dosages in both arms. It is concluded that uptitration of benazepril or losartan against proteinuria conferred further benefit on renal outcome in patients who did not have diabetes and had proteinuria and renal insufficiency.

Advanced Oxidation Protein Products Accelerate Atherosclerosis Through Promoting Oxidative Stress and Inflammation

Objective—Increased level of plasma advanced oxidation protein products (AOPPs) has been found in patients with uremia and nonuremic subjects with coronary artery disease. This study was conducted to test the hypothesis that AOPPs play a causal role in atherosclerosis. Methods and Results—Hypercholesterolemic (0.5% wt/wt diet) or normal rabbits received either repeated intravenous injections of AOPPs modified rabbit serum albumin (AOPPs-RSA) or unmodified RSA for 8 weeks. Compared with RSA- or vehicle-treated hypercholesterolemic rabbits, AOPPs-RSA–treated animals displayed increased atherosclerotic plaque area oxidized low-density lipoprotein (oxLDL) deposition, macrophage infiltration, and smooth muscle cell proliferation. Aortic sections from AOPPs-RSA–treated normal rabbits showed significant focal intima proliferation and mild Oil-Red-O staining lipid deposition in the affected areas, a phenomenon not observed in the RSA- or vehicle-treated controls. Plasma AOPPs levels in AOPPs-treated groups significantly increased in both hypercholesterolemic and normal rabbits compared with their relevant controls. Close correlations were found between plasma levels of AOPPs and the parameters of oxidative stress, eg, oxLDL and thiobarbituric acid reactive substances levels, or glutathione peroxidase activity. A highly significant correlation was also observed between plasma AOPPs and tumor necrosis factor (TNF)-α levels. Conclusions—This study provides in vivo evidence for a causal relationship between chronic AOPPs accumulation and atherosclerosis.

Advanced Oxidation Protein Products Activate Vascular Endothelial Cells via a RAGE-Mediated Signaling Pathway

The accumulation of advanced oxidation protein products (AOPPs) has been linked to vascular lesions in diabetes, chronic renal insufficiency, and atherosclerosis. However, the signaling pathway involved in AOPPs-induced endothelial cells (ECs) perturbation is unknown and was investigated. AOPPs modified human serum albumin (AOPPs-HSA) bound to the receptor for advanced glycation end products (RAGE) in a dose-dependent and saturable manner. AOPPs-HSA competitively inhibited the binding of soluble RAGE (sRAGE) with its preferential ligands advanced glycation end products (AGEs). Incubation of AOPPs, either prepared in vitro or isolated from uremic serum, with human umbilical vein ECs induced superoxide generation, activation of NAD(P)H oxidase, ERK 1/2 and p38, and nuclear translocation of NF-kappaB. Activation of signaling pathway by AOPPs-ECs interaction resulted in overexpression of VCAM-1 and ICAM-1 at both gene and protein levels. This AOPPs-triggered biochemical cascade in ECs was prevented by blocking RAGE with either anti-RAGE IgG or excess sRAGE, but was not affected by the neutralizing anti-AGEs IgG. These data suggested that AOPPs might be new ligands of endothelial RAGE. AOPPs-HSA activates vascular ECs via RAGE-mediated signals.

Advanced Oxidation Protein Products Promote Inflammation in Diabetic Kidney through Activation of Renal Nicotinamide Adenine Dinucleotide Phosphate Oxidase

The involvement of inflammatory processes has been recognized in development and/or progression of diabetic nephropathy. However, the mechanisms involved in the pathogenesis of renal inflammation have not been completely understood. In this study, we tested the hypothesis that accumulation of advanced oxidation protein products (AOPPs), which occurs in diabetes, may promote inflammatory responses in diabetic kidney. Streptozotocin-induced diabetic rats were randomized to iv injection of vehicle, native rat serum albumin (RSA), and AOPPs-modified RSA (AOPPs-RSA) in the presence or absence of oral administration of apocynin. A control group was followed concurrently. Compared with RSA- or vehicle-treated diabetic rats, AOPPs-RSA-treated animals displayed significant increase in renal macrophage infiltration and overexpression of monocyte chemoattractant protein-1 and TGF-beta1. This was associated with deteriorated structural and functional abnormalities of diabetic kidney, such as glomerular hypertrophy, fibronectin accumulation, and albuminuria. AOPP challenge significantly increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent superoxide generation in renal homogenates and up-regulated membrane expression of renal NADPH oxidase subunits p47(phox) and gp91(phox). All these AOPPs-induced perturbations in diabetic kidney could be prevented by the NADPH oxidase inhibitor apocynin. These data suggest that chronic accumulation of AOPPs may promote renal inflammation in diabetes probably through activation of renal NADPH oxidase.

Advanced Oxidation Protein Products Accelerate Renal Fibrosis in a Remnant Kidney Model

Accumulation of plasma advanced oxidation protein products (AOPP) has been found in patients with chronic kidney disease. However, the biologic consequences of AOPP consumption on progression of renal disease still are unclear. For testing of the hypothesis that AOPP accelerate progression of chronic kidney disease, Sprague-Dawley rats were subjected to five-sixths nephrectomy (5/6 Nx) or to sham operation. Rats in each group were randomly assigned in three subgroups (n = 30 in each group) and treated with repeated intravenous injections of AOPP-modified rat serum albumin (RSA), unmodified RSA, or vehicle for indicated period. Compared with RSA- or vehicle-treated 5/6 Nx rats, AOPP RSA-treated 5/6 Nx rats displayed greater proteinuria, higher serum creatinine, and lower creatinine clearance. AOPP challenge resulted in more renal hypertrophy, higher macrophage influx, and greater renal fibrosis in the remnant kidney. Chronic administration of AOPP in sham-operated rats increased urinary protein excretion and renal macrophage infiltration, but histologic renal fibrosis was not observed during the study period. AOPP treatment enhanced AOPP level in renal tissue. This was associated with marked increase of thiobarbituric acid reactive substances, decrease of glutathione peroxidase activity, and upregulated expression of monocyte chemoattractant protein-1 and TGF-beta1 in renal cortex. These data indicate that AOPP might be a new and potentially important mediator of renal fibrosis in the remnant kidney. Chronic accumulation of AOPP promotes renal fibrosis probably via a redox-sensitive inflammatory pathway.

Accumulation of advanced oxidation protein products induces podocyte apoptosis and deletion through NADPH-dependent mechanisms.

The accumulation of plasma advanced oxidation protein products (AOPPs) is prevalent in diverse disorders such as diabetes, metabolic syndromes, and chronic kidney disease. To study whether accumulated AOPPs have an important role in the progression of proteinuria and glomerulosclerosis, we chronically treated normal Sprague-Dawley rats with AOPP-modified rat serum albumin. Podocyte apoptosis was significantly increased coincident with the onset of albuminuria and preceded significant losses of glomerular podocytes. Increasing the amount of AOPPs in the media of conditionally immortalized podocytes rapidly triggered the production of intracellular superoxide by activation of NADPH oxidase and this, in turn, led to an upregulation of p53, Bax, caspase 3 activity, and apoptosis. Chronic inhibition of NADPH oxidase by apocynin prevented podocyte apoptosis, ameliorated podocyte depletion, and decreased albuminuria in AOPP-challenged rats. Our study demonstrates that accumulation of AOPPs promotes NADPH oxidase-dependent podocyte depletion by a p53-Bax apoptotic pathway both in vivo and in vitro.

Ethanol extraction of Picrorhiza scrophulariiflora prevents renal injury in experimental diabetes via anti-inflammation action

There is evidence that inflammatory processes are involved in the development and/or progression of diabetic nephropathy. However, effective treatment for inflammation in the kidneys of diabetic is practically unknown. The rhizomes of Picrorhiza scrophulariiflora (PS) are a traditional medication long used to treat inflammatory diseases. The aim of the present study was to test the hypothesis that the ethanol extract of PS (EPS) may reduce inflammation in patients with diabetic kidneys. Streptozotocin-induced diabetic rats were randomly assigned to two groups treated with a gavage of either EPS or vehicle. A group of non-diabetic control rats was treated concurrently. Compared with vehicle-treated diabetic rats, EPS-treated animals displayed a significant decrease in renal macrophage infiltration and overexpression of chemokine (C-C motif) ligand 2 (CCL2) and TGFB1. This was associated with attenuation of the structural and functional abnormalities of early diabetic nephropathy, such as glomerular hypertrophy, mesangial expansion, and albuminuria. Administration of EPS significantly reduced NADPH oxidase-dependent superoxide generation and decreased expression of malondialdehyde and advanced oxidation protein products in diabetic kidney. These data suggest that EPS might improve diabetic nephropathy, probably through inhibition of redox-sensitive inflammation.

Accumulation of tissue advanced glycation end products correlated with glucose exposure dose and associated with cardiovascular morbidity in patients on peritoneal dialysis

OBJECTIVES Accumulation of tissue advanced glycation end products (AGEs) is a marker of cumulative glycemic and/or oxidative stress. Cutaneous AGEs levels measured by skin autofluorescence correlate well with cardiovascular outcomes in diabetes and hemodialysis (HD) patients. The present study aimed to compare tissue AGEs levels with peritoneal dialysis (PD) and HD patients and to evaluate the relationship between skin autofluorescence and cardiovascular morbidity in patients on PD. METHODS A total of 2388 maintenance dialysis patients (613 PD and 1775 HD) were enrolled in this cross-sectional study. Skin autofluorescence was measured non-invasively with an autofluorescence reader. Cardiovascular morbidity was defined as clinically diagnosed ischemic heart disease, heart failure, stroke or peripheral vascular disease from initiation of dialysis. RESULTS More than 90% of patients on both PD and HD had met current dialysis adequacy targets. Compared to HD group, PD patients receiving conventional glucose-containing dialyzate had significantly higher skin autofluorescence values in each category of age and dialysis duration, irrespective of the presence or absence of diabetes. In PD patients, skin autofluorescence values were strongly correlated with the duration of PD and glucose exposure dose and independently associated with cardiovascular morbidity. Multivariate analysis revealed that glucose exposure dose and skin autofluorescence were the strongest risk factors for cardiovascular morbidity in PD patients after adjustment by age, gender, and other classic- or uremic-related risk factors. CONCLUSIONS Accumulation of tissue AGEs provides a potential link between PD exposure of metabolic stress and progression of cardiovascular disease in patients on PD.

Acute and acute-on-chronic kidney injury of patients with decompensated heart failure: impact on outcomes

BackgroundAcute worsening of renal function, an independent risk factor for adverse outcomes in acute decompensated heart failure (ADHF), occurs as a consequence of new onset kidney injury (AKI) or acute deterioration of pre-existed chronic kidney disease (CKD) (acute-on-chronic kidney injury, ACKI). However, the possible difference in prognostic implication between AKI and ACKI has not been well established.MethodsWe studied all consecutive patients hospitalized with ADHF from 2003 through 2010 in Nanfang Hospital. We classified patients as with or without pre-existed CKD based on the mean estimated glomerular filtration rate (eGFR) over a six-month period before hospitalization. AKI and ACKI were defined by RIFLE criteria according to the increase of the index serum creatinine.ResultsA total of 1,005 patients were enrolled. The incidence of ACKI was higher than that of AKI. The proportion of patients with diuretic resistance was higher among patients with pre-existed CKD than among those without CKD (16.9% vs. 9.9%, P = 0.002). Compared with AKI, ACKI was associated with higher risk for in-hospital mortality, long hospital stay, and failure in renal function recovery. Pre-existed CKD and development of acute worsening of renal function during hospitalization were the independent risk factors for in-hospital death after adjustment by the other risk factors. The RIFLE classification predicted all-cause and cardiac mortality in both AKI and ACKI.ConclusionsPatients with ACKI were at greatest risk of adverse short-term outcomes in ADHF. Monitoring eGFR and identifying CKD should not be ignored in patients with cardiovascular disease.

Accumulation of circulating advanced oxidation protein products is an independent risk factor for ischaemic heart disease in maintenance haemodialysis patients.

Aim:  Whether the burden of advanced oxidation protein products (AOPP) accumulation, a marker of oxidative stress, is affected by dialysis modality remains unclear. We compared the serum levels of AOPP in patients on haemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) and tested the hypothesis that an accumulation of AOPP was an independent risk factor for cardiovascular disease.