The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants. Beneficial effects of the bioflavonoids curcumin and quercetin on early function in cadaveric renal transplantation: a randomized placebo controlled trial. A multivitamin infusion prevents lipid peroxidation and improves transplantation performance. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficiency: results of the HOPE study. A randomized double-blind trial of the use of human recombinant superoxide dismutase in renal transplantation. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. The antioxidant acetylcysteine reduces cardiovascular events in patients with end-stage renal failure: a randomized, controlled trial. Can renal dysfunction after infra-renal aortic aneurysm repair be modified by multi-antioxidant supplementation?
In a prospective randomized double-blind placebo-controlled trial, the effect of rh-SOD, given in a dose of 200 mg intravenously during surgery to cyclosporine-treated recipients of cadaveric renal allografts, on both acute and chronic rejection events as well as patient and graft survival was investigated by analyzing the patients' charts retrospectively. The results obtained show that rh-SOD exerts a beneficial effect on acute rejection events as indicated by a significant reduction of (1) first acute rejection episodes from 33.3% in controls to 18.5%, as well as (2) early irreversible acute rejection from 12.5% in controls to 3.7%. With regard to long-term results, there was a significant improvement of the actual 4-year graft survival rate in rh-SOD-treated patients to 74% (with a projected half-life of 15 years) compared with 52% in controls (with an extrapolated half-life of 5 years). The beneficial effect of rh-SOD observed in this trial is not fully understood, although one can assume that the effect is related to its antioxidant action on ischemia/reperfusion injury of the renal allograft, thereby potentially reducing the immunogenicity of the graft. In addition and in accordance with the "response-to-injury hypothesis" in the pathogenesis of general atherosclerosis, rh-SOD has the potential to mitigate free radical-mediated reperfusion injury-induced acute endothelial cell damage that potentially may contribute to the process of chronic obliterative rejection arteriosclerosis. The bioflavonoids quercetin and curcumin are renoprotective natural antioxidants. We wished to examine their effects on early graft function (EF).
                Between September 2002 and August 2004, 43 dialysis dependent cadaveric kidney recipients were enrolled into a study using Oxy-Q which contains 480 mg of curcumin and 20 mg of quercetin, started after surgery and taken for 1 month. They were randomized into three groups: control (placebo), low dose (one capsule, one placebo) and high dose (two capsules). Delayed graft function (DGF) was defined as first week dialysis need and slow function (SGF) as Cr >2.5 mg/dl by day 10. Category variables were compared by chi squared and continuous variables by Kruskal-Wallis.
                There were four withdrawals: one by patient choice and three for urine leak. The control group had 2/14 patients with DGF vs. none in either treatment group. Incidence of EF was control 43%, low dose 71% and high dose 93% (P=0.013). Serum creatinine was significantly lower at 2 days (control 7.6+/-2.1, low 5.4+/-0.6, high 3.96+/-.35 P=0.0001) and 30 days (control 1.82+/-.16, low 1.65+/-.09, high 1.33 +/-.1, P=0.03). Acute rejection incidence within 6 months was control 14.3%, low dose 14.3% and high dose 0%. Tremor was detected in 13% of high dose patients vs. 46% of others. Urinary HO-1 was higher in bioflavonoid groups.
                Bioflavonoid therapy improved early graft function. Acute rejection and neurotoxicity were lowest in the high dose group. These bioflavonoids improve early outcomes in cadaveric renal transplantation, possibly through HO-1 induction. The objective of this study was to test the hypothesis that ischemia reperfusion damage in kidney transplantation is associated with lipid peroxidation and that inhibition of lipid peroxidation by antioxidants improves the function of the transplanted kidney. Lipid peroxidation was assessed by measuring the plasma malonaldehyde content (as thiobarbituric acid reaction product) with high-performance liquid chromatography. Kidney function was assessed by plasma creatinine and creatinine clearance. Thirty patients of an ongoing series were randomly selected into two groups, with 14 controls and 16 patients in the antioxidant therapy group. Therapy consisted of two ampoules of Omnibionta (which contains vitamins C, E, A and B complex) diluted in 500 ml physiological sodium chloride, which was infused intravenously prior to reperfusion onset. No significant differences existed for the age of the patients in the control (43.00 +/- 9.86 years) and the therapy group (41.56 +/- 14.14 years) nor in the kidney preservation time, which was 24.12 +/- 8.73 and 18.43 +/- 9.97 hours in the control and therapy group, respectively. The controls showed a transient increase of plasma lipid peroxides as measured by malonaldehyde with a peak one hour after onset of reperfusion. Compared to the baseline value of 0.74 +/- 0.26 (mean +/- SD) the one hour malonaldehyde value increased to 1.46 +/- 0.22 nmol/ml (P < 0.001). In the therapy group the plasma malonaldehyde level did not increase, but slightly decreased by about 20% compared to the baseline value. The difference of plasma malonaldehyde between the two groups one hour after reperfusion onset was highly significant (P > 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS) Chronic kidney disease (CKD) associated with type 2 diabetes is the leading cause of kidney failure, with both inflammation and oxidative stress contributing to disease progression. Bardoxolone methyl, an oral antioxidant inflammation modulator, has shown efficacy in patients with CKD and type 2 diabetes in short-term studies, but longer-term effects and dose response have not been determined.
                In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned 227 adults with CKD (defined as an estimated glomerular filtration rate [GFR] of 20 to 45 ml per minute per 1.73 m(2) of body-surface area) in a 1:1:1:1 ratio to receive placebo or bardoxolone methyl at a target dose of 25, 75, or 150 mg once daily. The primary outcome was the change from baseline in the estimated GFR with bardoxolone methyl, as compared with placebo, at 24 weeks; a secondary outcome was the change at 52 weeks.
                Patients receiving bardoxolone methyl had significant increases in the mean (±SD) estimated GFR, as compared with placebo, at 24 weeks (with between-group differences per minute per 1.73 m(2) of 8.2±1.5 ml in the 25-mg group, 11.4±1.5 ml in the 75-mg group, and 10.4±1.5 ml in the 150-mg group; P<0.001). The increases were maintained through week 52, with significant differences per minute per 1.73 m(2) of 5.8±1.8 ml, 10.5±1.8 ml, and 9.3±1.9 ml, respectively. Muscle spasms, the most frequent adverse event in the bardoxolone methyl groups, were generally mild and dose-related. Hypomagnesemia, mild increases in alanine aminotransferase levels, and gastrointestinal effects were more common among patients receiving bardoxolone methyl.
                Bardoxolone methyl was associated with improvement in the estimated GFR in patients with advanced CKD and type 2 diabetes at 24 weeks. The improvement persisted at 52 weeks, suggesting that bardoxolone methyl may have promise for the treatment of CKD. (Funded by Reata Pharmaceuticals; BEAM ClinicalTrials.gov number, NCT00811889.). A controlled trial reported cardiovascular benefits of vitamin E in terminal renal insufficiency. There are no data for renal insufficiency before the stage of terminal renal failure. We evaluated effects of vitamin E supplementation on cardiovascular and renal outcomes in 993 people with a serum creatinine > or =1.4 to 2.3 mg/dL.
                Post-hoc analysis of a randomized trial that compared treatment with natural source vitamin E (400 IU/day) to placebo in 9541 people, 993 of which had renal insufficiency. Participants had either known cardiovascular disease or diabetes and at least one additional coronary risk factor. Exclusion criteria included a serum creatinine > 2.3 mg/dL and dipstick-positive proteinuria. The primary study outcome after an average of 4.5 years was the composite of myocardial infarction, stroke, or cardiovascular death. Secondary outcomes included revascularizations, total mortality, and clinical proteinuria.
                In renal insufficiency, vitamin E supplementation had a neutral effect on the primary study outcome, on each component of the composite primary outcome, and on all secondary outcomes. Two hundred twenty-four primary outcomes, 23% of the vitamin E group and 22.1% of the placebo group, relative risk 1.03 (95% CI, 0.79-1.34; P= 0.82), were observed, and 585 secondary outcomes, including death in 17% and 18.8% of the vitamin E and placebo groups, respectively (RR 0.88, 95% CI, 0.66-1.18; P= 0.40). There was no effect of vitamin E on progression of proteinuria.
                In people with mild-to-moderate renal insufficiency at high cardiovascular risk, vitamin E at a dose of 400 IU/day had no apparent effect on cardiovascular outcomes. Oxygen free radical generation has been implicated as a possible mediator of the reperfusion injury postulated to occur following revascularization of the cold preserved and transplanted kidney. The superoxide radical (O2-) scavenger, superoxide dismutase, from bovine or recombinant (rh-SOD) sources, may ameliorate oxygen-free-radical mediated reperfusion injury of transplanted kidneys. To test this hypothesis, we performed a prospective, randomized, double-blind trial of the use of human rh-SOD in renal transplantation at three participating centers. Half of a 20 mg/kg solution of rh-SOD or placebo was administered as a bolus intravenous injection immediately prior to renal allograft reperfusion and the remainder as a peripheral intravenous infusion for 1 hr thereafter. Posttransplant renal function was determined using 99Tc-DTPA clearance to measure glomerular filtration rate at 48 +/- 24 hr and day 6 post-transplant. A two-tailed t test was used for pooled data, and analysis of variance was used to evaluate between center differences in outcome. One hundred and sixteen patients (58 rh-SOD and 58 placebo) were entered into the study. No adverse reactions to rh-SOD or placebo were noted. No differences were noted between rh-SOD and placebo groups with regard to GFR at 48 hr, serum creatinine or creatinine clearance at day 6, or percentage of patients with GFR < or = 10 ml/min or < or = 5 ml/min at 48 hr. The data did not vary when analyzed by center or in aggregate form, and no correlation was noted between storage time and GFR in either group. We conclude that data from this trial provide little basis for the use of rh-SOD as described to ameliorate reperfusion injury in transplanted kidneys. Excess cardiovascular mortality has been documented in chronic haemodialysis patients. Oxidative stress is greater in haemodialysis patients with prevalent cardiovascular disease than in those without, suggesting a role for oxidative stress in excess cardiovascular disease in haemodialysis. We investigated the effect of high-dose vitamin E supplementation on cardiovascular disease outcomes in haemodialysis patients with pre-existing cardiovascular disease.
                Haemodialysis patients with pre-existing cardiovascular disease (n=196) aged 40-75 years at baseline from six dialysis centres were enrolled and randomised to receive 800 IU/day vitamin E or matching placebo. Patients were followed for a median 519 days. The primary endpoint was a composite variable consisting of: myocardial infarction (fatal and non-fatal), ischaemic stroke, peripheral vascular disease (excluding the arteriovenous fistula), and unstable angina. Secondary outcomes included each of the component outcomes, total mortality, and cardiovascular-disease mortality.
                A total of 15 (16%) of the 97 patients assigned to vitamin E and 33 (33%) of the 99 patients assigned to placebo had a primary endpoint (relative risk 0.46 [95% CI 0.27-0.78], p=0.014). Five (5.1%) patients assigned to vitamin E and 17 (17.2%) patients assigned to placebo had myocardial infarction (0.3 [0.11-0.78], p=0.016). No significant differences in other secondary endpoints, cardiovascular disease, or total mortality were detected.
                In haemodialysis patients with prevalent cardiovascular disease, supplementation with 800 IU/day vitamin E reduces composite cardiovascular disease endpoints and myocardial infarction. Patients with end-stage renal failure have increased oxidative stress and show elevated cardiovascular mortality. Whether increased cardiovascular events can be prevented by the administration of antioxidants is unknown.
                We evaluated the effects of acetylcysteine, a thiol-containing antioxidant, on cardiovascular events in patients undergoing hemodialysis. A prospective, randomized, placebo-controlled trial was conducted between October 1, 1999, and September 30, 2001, in 134 patients (76 male and 58 female) with a mean age of 62+/-16 years (mean+/-SD) who had been undergoing maintenance hemodialysis for a minimum of 3 months 3 times weekly in an ambulatory center. Median (range) follow-up was 14.5 (1 to 24) months. Patients were randomly assigned either to receive acetylcysteine (600 mg BID) or placebo. The primary end point was a composite variable consisting of cardiac events including fatal and nonfatal myocardial infarction, cardiovascular disease death, need for coronary angioplasty or coronary bypass surgery, ischemic stroke, peripheral vascular disease with amputation, or need for angioplasty. Secondary end points included each of the component outcomes, total mortality, and cardiovascular mortality. A total of 18 (28%) of the 64 hemodialysis patients assigned to acetylcysteine group and 33 (47%) of the 70 hemodialysis patients assigned to control group had a primary end point (relative risk, 0.60 [95% CI, 0.38 to 0.95], P=0.03). No significant differences in secondary end points or total mortality were detected.
                In hemodialysis patients, treatment with acetylcysteine (600 mg BID) reduces composite cardiovascular end points. Renal failure after lower torso ischemia is a serious problem, partly caused by hypotension and indirect reperfusion injury. This injury is partly due to the formation of oxygen free radicals by activated neutrophils. This injury results in albuminuria and renal function impairment. There are indications that free radical damage in indirect reperfusion injury can be diminished by administering extra antioxidants before and during reperfusion.
                In this prospective randomised study we have looked at the influence of a multi-antioxidant supplementation on renal function in patients undergoing an elective open infrarenal abdominal aneurysm repair. The patients received either standard treatment (n=22) or standard treatment with additional antioxidants perioperatively (Allopurinol, vitamin E and C, N-acetylcysteine and mannitol). For renal function we have looked at the albumin/creatinine ratio in urine and 24 hr creatinine clearance.
                Despite significantly increased serum total antioxidant capacity, the group receiving extra antioxidants showed no decrease in the albumin/creatinine ratio in urine. There was however a significantly higher creatinine clearance in this group at day 2.
                The results indicate that the diminished renal function after infrarenal aneurysm repair may be influenced by antioxidant therapy.
Although antioxidant therapy does not reduce the risk of cardiovascular and all-cause death or major cardiovascular events in people with CKD, it is possible that some benefit may be present, particularly in those on dialysis. However, the small size and generally suboptimal quality of the included studies highlighted the need for sufficiently powered studies to confirm this possibility. Current evidence suggests that antioxidant therapy in predialysis CKD patients may prevent progression to ESKD; this finding was however based on a very small number of events. Further studies with longer follow-up are needed for confirmation. Appropriately powered studies are needed to reliably assess the effects of antioxidant therapy in people with CKD.