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Abstract Background: Free radical damage in conjuction with antioxidant deficiency has been observed in patients with chronic renal failure. In this larger study, we report whether treatment with antioxidant coenzyme Q10 can decrease progression or reverse chronic renal dysfunction and delay the need for dialysis. Design: A randomized, double-blind, placebo-controlled trial of coenzyme Q10 vs. placebo for a period of 12 weeks. Subjects and Methods: All patients with proven chronic renal failure with a history of declining renal function for at least the last 12 weeks were stratified into haemodialysis or no dialysis and blindly randomly divided into coenzyme Q10 (n=48) and control (n=49) subgroups with the help of computer-generated numbers. Results: Both coenzyme Q groups showed a significant decline in serum creatinine, blood urea nitrogen and a significant increase in creantine clearance and urine output compared with the placebo groups on dialysis and no dialysis over the 12 weeks of the trial, whereas the baseline values of these characteristics showed no significant difference between the concerned subgroups. The frequency of dialysis and the proportion of subjects taking dialysis were not significantly different at entry to the study. However, after 12 weeks, the number of subjects taking dialysis was significantly less in the antioxidant subgroup than the placebo subgroup (12 vs 24; p 0.02). Plasma levels of thiobarbituric acid reactive substances, diene conjugates and malondialdehyde, indicators of oxidative damage, showed a significant reduction where as antioxidant vitamins E and C and beta-carotene showed a significant increase in the antioxidant subgroups compared with the control groups. After 12 weeks of follow-up, all patients were alive. Conclusion: Treatment with coenzyme Q10 reduces serum creantine and blood urea nitrogen and increases creantine clearance and urine output in patients with chronic renal failure. This treatment also decreases the need for dialysis in patients on chronic dialysis. Approximately one-fifth of the patients showed no response to treatment. Keywords: renal failure, antioxidants, vitamins, haemodialysis. INTRODUCTION Evidence regarding the role of free radicals in renal injury has been derived predominantly from studies using a variety of antioxidants such as vitamins, superoxide dismutase, glutathione peroxidase and catalase [1-7]. Case-controlled studies [8, 9] indicate that there is a deficiency of antioxidant vitamin A, E and C and beta-carotene as well as coenzyme Q10 in patients with chronic renal failure with and without dialysis. However, not all studies have reported a deficiency of antioxidants in renal failure. Increased levels of thiobarbituric acid reactive substances (TBARS) and malondialdehyde (MDA), indicators of free radical damage, have also been described in patients with end-stage renal disease. Treatment with antioxidants may be more effective in the presence of antioxidant deficiency [3, 4]. It has been observed that vitamin E and isoflavon, which are potent antioxidants, may have beneficial effects in chronic renal damage [5-7, 10-14]. Vitamins C and E and coenzyme Q10 are important for cell growth, which poses the possibility that some antioxidant formulation may reverse renal dysfunction [13-15]. In this larger trial, we confirmed the findings of out previous study on the effect of coenzyme Q10 in patients with chronic renal failure during a follow-up of 12 weeks. SUBJECTS AND METHODS Patients with end-stage renal disease were recruited by placing advertisements in the newpapers that chronic renal failure may be showed by treatment with antioxidants and dialysis may be stopped in some patients. The diagnosis of chronic renal failure was based on available records indicating contracted kidneys, cortical thickness and persistent and progressive deterioration in renal function showing an increase in blood urea nitrogen and serum creantine in renal function showing an increase in blood urea nitrogen and serum creatinine and a decrease in creatinine clearance during the past 12 weeks to several years. The main criterion for inclusion in the study was a serum creantine and a decrease in creantine clearance during the past 12 weeks to several years. The main criterion for inclusion in the study was serum creantine level of 5mg dl ^{1 . Exclusion criteria were acute renal failure (n=9), obstructive uropathy (n=5), cancer (n=5), serious ill patients with marked acidosis, or shock and anuria (n=17).} Treatment The test agent, coenzyme Q10, is marked as a health product in most industrialized countries. The placebo capsules containing inert fiber were supplied from our laboratory. All patients in the treatment group (group A) were given two capsules three times daily. The placebo capsules (two capsules, three times daily) containing inert fiber were administered to all patients in the placebo group B. The placebo group did not self-administer coenzyme Q10. The test capsules were identical in size, shape and colour for both groups and were provided to patients in identical containers marked group A or group B. Compliance was monitored by counting the number of capsules returned by the patients on follow-up visits or each day during hospitalization. All other advice on treatment was similar in both groups. Both groups met a physician for check-ups who was blind to the groups. Study Design All patients with the available record off diagnosis of chronic renal failure were prospectively studied for 4 weeks while receiving all other supportive treatment, during which laboratory and clinical data were obtained to confirm the diagnosis of chronic renal failure. The study was approved by the ethics committee of human studies in our center. After written informed consent, all patients with the diagonisis of chronic renal failure were stratified into those on haemodialysis and dialysis and then each subgroup was randomized by the pharmacist with the help of computer-generated numbers in blocks of 10 into intervention and control groups. The physician examining the patients and the technician analysing the blood were blind to the treatment groups. The coenzyme Q group (n=48) received coenzyme Q10 (180 mg day ^{1, two capsules, three times daily) and the placebo group (n=49) received inert fiber cellulose (3 g day} 1, two capsules, three times daily) for a period of 12 weeks. All other treatments, such as furosemide, iron, calcium, vitamin D _{3, erythropoietin and blood transfusion as well as anti-hypertensive drugs, were administered to both groups. All patients were followed weekly for 4 weeks and then every 4 weeks for 12 weeks. Both groups were also encouraged to decrease the frequency or stop dialysis if there was an increase in urine output and a decrease in serum creantine of more than 2 mg dl ^{-1 without any symptoms indicating any complications.}} Study Methods In all patients, clinical, ultrasonographic, radiological and laboratory data were recorded at admission before entry to the study. Hypertension was defined as blood pressure 140/90 mm Hg and hypotension as systolic blood pressure 90 mm Hg. Blood pressures were measured after 5 min rest, with the patient resting comfortably in the supine position and second measurement was considered for this study. Phase V Korotkoff sounds were recorded for diastolic blood pressure. Hypertension was treated when blood pressure was 140 mmHg systolic and or 90mmHg diastolic with an attempt to maintain blood pressure 135/85mmHg. Smoking was completely stopped by all patients. Heart enlargement was defined as a dialted heart on radiological, and echocardiographic examination. Clinical data, complications, and drug intake were recorded for 12 weeks by an interviewer who was unaware of the treatment groups. Urine output per 24 hours was recorded from 7 a.m. daily in all patients during the follow-up of 12 weeks. Haemodialysis was advised when serum creatinine was 9.0 mg dl ^{-1 with or without other complications such as coma, acidosis and acute pulmonary oedema, heart failure and/or hyperkalameia (serum potassium 6.0mEq 1} -1 ). Peritoneal dialysis is not commonly performed in India due to increased rate of infections. Laboratory Data A blood sample (for plasma/serum) was drawn in the morning after at least 10 hours of fasting at entry to the study and then at 4, 8 and 12 weeks of follow-up, for a blood count, hemoglobin, urea nitrogen, glucose, creatinine, sodium, potassium, vitamins E and C, beta-carotene, TBARS, diene conjugates and MDA [16-20]. MDA is a type of TBARS. A urine analysis and creatinine clearance were also performed in all patients. The laboratory personnel analyzing the blood were blind to the treatment groups. The blood was stored at -4 C and analysed in the afternoon of the same day. Heparin plasma was used for the analysis of cvarious biochemical markers at oxidative damage and serum was used for creatinine and electrolytes. A recently modified colorimetric method for a quantitative assay of TBARS in the plasma, free of interference from sialic acids, was used [19, 20]. The thiobarbituric acid was dissolved in sodium sulphate and both the liberation of TBARS and a colour reaction were performed simultaneously. Lipid peroxidation begins with the formation of a lipid free radical which rearranges to form a diene. Partial oxidation results in the formation of a lipid peroxy which rearranges to form a diene. Partial oxidation results in the formation of a lipid peroxy radical which takes up a hydrogen atom resulting in the formation of TBARS. MDA is a breakdown product of unsaturated fatty acids. Increases in the plasma levels of TBARS and MDA and diene conjugates are indicators of enhanced oxidative stress and cell damage [18-20]. However, there is considerable disagreement regarding the reliability of various tests to measure oxidant and antioxidant effects. Ascorbic acid was assayed at 520 mm with 2, 4-dinitrophenyl hydrazine forming red bishydrazone having a coefficent of variation of 5.4%. Vitamin A and beta-carotene were separated in diethylether and the beta-carotene level was obtained at 46 nm using a standard curve [16, 17]. Vitamin E was extracted into n-hexane and analysed with ferric chloride/D a-a dipridyl reagent. The coefficients of variation for vitamin E and C and beta-carotene were 4.5, 4.1 and 2.2%, respectively. Statistical Analysis The two-sample t-test using one-way analysis of variance and the Z-score for proportions were used to measure the statistical significance between the two groups. Turkeys post-hoc test was also conducted for multiple comparisons. Only a P value 0.05 and a two-tailed t-test were considered significant. Data were analysed on the basis of intention to treat. RESULTS We studied 133 patients with end-stage renal failure who responded to our advertisement. After excluding 36 patients, 97 were randomized to coenzyme Q10 (n=48) and placebo groups (n=49). Table 1 shows the data for the four subgroups indicating that mean age, body weight and body mass index showed no significant difference between the subgroups (antioxidant-dialysis vs. Placebo-dialysis and antioxidant-no dialysis vs. placebo-no dialysis). The proportions of male subjects and of low hemoglobin, hypertension, type II diabetes mellitus and bilateral contracted kidneys were comparable in the selected subgroups. Treatment given before the trial indicated that the percentage of subjects given dialysis (haemodialysis), furosemide, erthropoietien and blood transfusions for anameia was comparable in the two groups. However, during the 12 weeks trial period, subjects were given haemodialysis significantly less in the coenzyme Q subgroup than the control subgroup. The total number of haemodialyses performed in the last week before entry to the study was comparable in the two groups. However, total numbers of dialyses preformed in the last week after entry to the study during follow-up were significantly less in the coenzyme Q group compared with the control subgroup (Table 1). Of 48 patients in the coenzyme Q group, nine stopped their dialyses, and 30 showed a significant reduction in serum creatinine. Among patients who stopped dialysis, four decreased their dialysis from twice weekly to once weekly after 4 weeks and stopped dialysis after 8 weeks of treatment. The remaining five patients stopped dialysis after 8 weeks of treatment. Only nine (19%) out of 48 patients showed no response to treatment with coenzyme Q10. The total number of dialyses in the last 12 weeks before entry to the study was comparable in the two groups (720 vs. 744). However, the overall number of dialyses during the 12 weeks of follow-up after entry to the study was significantly lower in the antioxidant group A than control group B (380 vs. 751, p 0.01). Other treatments were similar (Table 1). The number of subjects with furosemide treatment was also higher in the antioxidant group than the control group. Anti-hypertensive drugs were amlodipine (20 vs. 18), beta-blockers (13 vs. 15) and minipress (21 vs. 20). Table 2 shows that baseline laboratory data in the four subgroups showed no significant difference between the subgroups. Serum creatinine and blood urea nitrogen were significantly higher in the haemodialysis subgroup compared with no dialysis subgroup (Table 2). Treatment with coenzyme Q10 was associated with significant reductions in blood urea nitrogen and serum creatinine with an increase in creatinine clearance and urine output in the antioxidant subgroups compared with the control subgroups (Table 3). The dose of erthropoietin and the incidence of anameia showed no significant difference. Plasma levels of TBARS, MDA and diene conjugates, indicators of oxidative damage, were higher and antioxidant vitamins E and C and beta-carotene were lower in all the subgroups without any significant groups differences at entry to the study compared with normal values observed in our laboratory in Indians (Table 2) [8]. Antioxidant vitamin E and C and beta-carotene showed a significant increase and TBARS, MDA and diene conjugates showed a significant reduction in the antioxidant subgroups compared with the control subgroups after the 12 weeks of the trial. Changes in sodium and potassium were not significant. All patients of the intervention and control subgroups were alive at 12 weeks of follow-up. DISCUSSION The present trial shows that treatment with antioxidant coenzyme Q10 in patients with end-stage renal failure was associated with a significant decline in serum creatinine and blood urea nitrogen with an increase in creatinine clearance and urine output after 12 weeks of follow-up in the coenzyme Q subgroups compared with the control subgroups in patients on haemodialysis or no dialyses (Table 3). No published evidence is available to demonstrate the role of antioxidants in patients with chronic renal failure. Therefore, we cannot compare our results with other studies. Coenzyme Q10 administration was associated with significant benefit in 11 patients with chronic renal failure compared with the control group in one pilot study [14]. It is therefore possible that in patients with chronic renal failure on haemodialysis or no dialysis, treatment with coenzyme Q10 may be beneficial. In our pilot study [14], we discussed the presence of antioxidant vitamin and coenzyme Q deficiency in patients with chronic renal failure. This study [14] showed that treatment with coenzyme Q10 (n=11) was associated with a significant decline in serum creatinine and blood urea and an increase in creatinine clearance and urine output during a follow-up of 4 weeks. In the second study [9], the deficiency in serum coenzyme Q10 was greater in patients on haemodialysis compared with those not receiving this form of therapy. In both studies, lipid peroxidation products such as TBARS and conjugated dienes were higher in uraemic subjects compared with healthy controls. In an earlier experience, Mervyn observed low tissue levels of vitamin E and coenzyme Q10 in post-mortem kidneys (Len Mervyn, Lamberts, Kent, UK, personal communication, 1955) of patients with nephritis compared with healthy kidneys. Low levels of serum vitamin E were found in renal failure subjects on a conservative regimen including dietary restrictions. It is possible that lower concentrations of coenzyme Q10 and vitamin E may contribute to increased oxidative damage resulting in uraemic toxicity and a greater risk of cancer and coronary artery disease. Plasma levels of minerals, red blood cell vitamin E as well as the enzymers glutathione peroxidase and catalase were studied in 54 renal disease patients who had varying degrees of kidney dysfunction [21]. Plasma levels of zinc and red blood cell vitamin E were inversely associated with poor renal function and the lipid peroxidation product MDA was higher. TABLE 1. Clinical characteristics [mean standard deviation of n (%) of subjects in the coenzyme Q10 and control groups

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Coenzyme Q10 group (n = 48) Control group (n = 49) Haemodialysis No dialysis (n = 21) (n =27) (n =24) (n =25) Mean age (years) 51.5 11.8 46.8 12.4 48.4 13.1 46.3 11.7 Body weight (kg) 57.0 9.6 58.8 13.6 56.0 11.5 56.8 12.3 Body mass index (kgm ^{-2 )} 21.0 3.0 22.3 3.1 20.0 2.4 20.8 3.0 Men 16 (76.2) 18 (66.6) 17 (70.8) 18 (72.0) Low haemoglobin ( 10g%) 21 (100.0) 23 (85.2) 20 (83.3) 19 (76.0) Hypertension ( 140/90mmHg) 19 (90.4) 14 (51.8) 18 (75.0) 20 (80.0) Diabetes mellitus (known) type II 8 (38.1) 7 (25.9) 9 (37.5) 9 (36.0) Bilateral contracted kidneys (ultrasonography) Aeitology of renal failure Diabetes mellitus type II 9 (33.3) 8 (33.3) Hypertension 3 (14.2) 2 (7.4) 3 (12.5) 2 (8.0) Chronic glomerulonephritis 6 (28.5) Chronic pyelonephritis 2 (9.5) 2 (18.5) 2 (8.3) 2 (12.0) Unknown Treatment received before the trial Total no. dialyses in the last week before entry 46 (219) - 54 (225) Furosemide (40-120 mg day ^{1 )} 5 (23.8) 24 (88.8) 25 (100) Blood transfusion 17 (80.9) 16 (59.2) 22 (91.6) 14 (56.0) Erythropoietin (2000-4000 units week ^{1 )} 20 (95.2) 13 (48.1) Treatment given during the trial Total no. of dialyses in the week after entry 24 (114)* 62 (258) Haemodilysis 12 (57.0)* 24 (100) Furosemide (40-120 mg dl ^{-1 )} 29 (95.2) 25 (92.6) 20 (83.2) 21 (87.5) 15 (60.0) Erthropoietin (2000-4000 units week ^{-1 )} 23 (95.8) *p 0.01 by chi-square test. P values were obtained by comparison of each coenzyme Q subgroup with concerned control subgroup on haemodialysis and no dialysis. monebaggassemonebaggasseTABLE 2.