Role of Folic Acid in Atherosclerosis After Kidney Transplant: A Double-blind, Randomized, Placebo-controlled Clinical Trial

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1 Role of Folic Acid in Atherosclerosis After Kidney Transplant: A Double-blind, Randomized, Placebo-controlled Clinical Trial Mohsen Nafar, 1 Fatemeh Khatami, 2 Babak Kardavani, 1 Reza Farjad, 2 Fatemeh Pour-Reza-Gholi, 1 Ahmad Firouzan, 1 Akbar Kalantar, 3 Soudabeh Farhangi, Behzad Einollahi 4 Abstract Objectives: We investigated the effects of folic acid supplementation on plasma total homocysteine levels and carotid intima-media thickness after kidney transplant. Materials and Methods: Sixty patients who had undergone a kidney transplant were studied in this double-blind, randomized, placebo-controlled clinical trial. Those subjects were randomized to receive either 5 mg/d of oral folic acid or an equivalent dosage of placebo. The main outcome variables were the plasma total homocysteine level and carotid intima-media thickness (determined via B-mode sonography) at baseline and 2, 4, and 6 months after kidney transplant. We used independent and paired sample t tests for data analysis. Results: The mean age of the patients was 4.9 ± 1 years, and 32 of those subjects (58.2%) were men. In the control group, the plasma total homocysteine levels were 19 µmol/l at baseline, 18.7 µmol/l after 2 months, 19.3 µmol/l after 4 months, and 2 µmol/l after 6 months; and the carotid intima-media thickness measurements were.81 mm at baseline,.82 mm after 2 months,.84 mm after 4 months, and.85 mm after 6 months. In the folic acid group, the plasma total homocysteine levels were 18.5 µmol/l at baseline, 4.7 µmol/l after 2 months, 12.9 µmol/l after 4 months, and 1.9 µmol/l after 6 months; and the carotid intima-media thickness measurements were.73 mm at baseline,.73 mm after 2 months, From the 1 Urology Nephrology Research Center and the 2 Department of Kidney Transplantation, Shahid Labbafinejad Medical Center, Shaheed Beheshti University of Medical Sciences, Tehran, Iran; the 3 Iran University of Medical Sciences, Tehran, Iran; and the 4Baqiyatallah University of Medical Sciences, Tehran, Iran Address reprint requests to: Mohsen Nafar, MD, Department of Internal Medicine, Shahid Labbafinejad Medical Center, 9th Boustan, Pasdaran, Tehran, Iran Phone: Fax: nafar@ijkd.org Experimental and Clinical Transplantation (29) 1: mm after 4 months, and.71 mm after 6 months. Conclusions: Folic acid supplementation reduces both the plasma total homocysteine level and carotid intima-media thickness shortly after kidney transplant. Key words: Kidney transplant, Atherosclerosis, Homocysteine, Folic acid, Carotid intima-media thickness, Doppler, Ultrasonography Atherosclerosis and its consequences are the leading causes of morbidity and mortality after kidney transplant, and such problems decrease the overall success of kidney transplant with respect to the patient s longevity (1-3). However, a kidney transplant reduces the incidence of some cardiovascular morbidities such as left ventricular hypertrophy and volume overload (4). Prior studies have shown that, primarily because of various risk factors, a successful renal transplant may not completely normalize the risk of cardiovascular events or morphologic changes in vessel structure (5,6). One of the important risk factors that contributes to the development and progression of cardiovascular problems in kidney transplant recipients is homocysteine (Hcy) (7-9). Homocysteine is an intermediate product of methionine metabolism. An elevated level of Hcy has a negative effect on endothelial cells, coagulation factors, and platelet function (1-12) and could lead to adverse structural changes in carotid artery properties (13) that can be detected in several ways. One of the most frequently used and reliable markers for such changes is the carotid intima-media thickness as determined by B-mode Doppler sonography (14). Carotid intima-media thickness, which is useful in predicting cardiovascular outcome in several patient populations (14-16), appears to be a feasible, reliable, valid, and cost-effective method Copyright Başkent University 29 Printed in Turkey. All Rights Reserved.

2 34 Mohsen Nafar et al / Experimental and Clinical Transplantation (29) 1: Exp Clin Transplant for use in population studies and clinical trials of atherosclerosis progression and regression (1). Prior studies have shown that a successful reduction in the plasma total homocysteine (thcy) level can lead to a decrease in carotid intima-media thickness and the incidence of cardiovascular events (3, 4, 17, 18). Some studies have shown that after kidney transplant, the level of thcy will increase gradually but never reaches a level within normal limits (1). It thus seems that the treatment of hyperhomocysteinemia after kidney transplant is beneficial (19). Supplementation with B vitamins and folic acid is the treatment of choice for hyperhomocysteinemia (2, 21) and could lead to a reduction in cardiovascular risk and carotid intimamedia thickness in the general population (11, 12, 21). However, there is not enough evidence to support the effectiveness of folic acid in treating hyperhomocysteinemia or decreasing the carotid intimamedia thickness after kidney transplant. We designed a double-blind, randomized, placebocontrolled clinical trial to investigate that issue in kidney transplant recipients. Materials and Methods Participants The duration of the study was from June 25 to March 26. A summary of the inclusion and exclusion criteria (Table 1) and a diagram showing enrollment and randomization (Figure 1) are included in this report. Patients who met the study criteria and were willing to participate were accepted as subjects. The subjects were patients with end-stage renal disease who had undergone a kidney transplant from a living unrelated donor. The mean age of the patients was 4.9 ± 1 years (age range, 25 to 62 years). There were 32 (58.2%) male subjects and 23 (41.8%) female subjects. Demographic data and baseline variables are presented in Table 2. All informed subjects provided their written consent to participate before the study, which was approved by the medical ethics research committee of the Shahid Behesti University of Medicine, was initiated. Study protocol This was a double-blind, randomized, placebocontrolled clinical trial. At enrollment, patients were randomly assigned to receive either folic acid 5 mg/d or placebo tablets. The duration of the study was 6 Table 1. Study inclusion and exclusion criteria Inclusion criteria 1. Hyperhomocysteinemia (ie, a total homocysteine level of > 12.5 µmol/l in men and > 11.5 µmol/l in women). 2. Age between 25 and 65 years. 3. No history of diabetes mellitus or cardiovascular disease such as myocardial infarction, stroke, coronary bypass surgery, congestive heart disease, etc. 4. Never cigarette smoking. 5. No current participation in other clinical studies on cardiac diseases. 6. No lipid-lowering treatment. 7. Not pregnant or breast-feeding. 8. No infection with the human immunodeficiency virus. 9. No infection with viral hepatitis. Exclusion criteria 1. Unstable transplanted kidney (eg, a creatinine level of > 3 mg/dl, a blood urea nitrogen level of > 5 mg/dl) 2. Cyclosporine intoxication according the values listed in the International Consensus Statement (37) 3. New onset of any severe disease (eg, myocardial infarction, stroke, diabetes mellitus, etc). Folic acid 3 participated 13 men 17 women 1 left the study 1 had graft rejection 76 patients were screened 6 underwent randomization 16 were excluded: 1 did not meet the criteria 2 changed the plan 4 refused to participate 4 left the study 1 had graft rejection 1 developed diabetes mellitus 2 died Figure 1. Enrollment and randomization of the study subjects Placebo 3 participated 2 men 1 women Table 2. Demographic and baseline variables of the study groups Variables Placebo group P Value Age (y) 4.2 ± ± 11.1 NS No. of men (%) 12 (41.4) 19 (76).14 HTN (%) 6 (2.7) 7 (28) NS CRF duration 4.6 ± ± 2.7 NS Dialysis duration 1.9 ± ±.8 NS thcy 18.5 ± ± 7.3 NS Folic acid 5.4 ± ± 6.4 NS Vit B ± ± NS FBS 76.4 ± ± 3.2 NS BUN 59.7 ± ± 19.9 NS Cr 11.1 ± ± 16.1 NS Total cholesterol ± ± TG ± ± 44.1 NS LDL 11.9 ± ± 26 NS HDL 61 ± ± 15.6 NS Systolic BP ± ± 13.3 NS Diastolic BP 77.9 ± ± 6.3 NS IMT.73 ± ±.19 NS Abbreviations: NS indicates not significant; HTN, hypertension; CRF, chronic renal failure; thcy, total homocysteine; FBS, fasting blood sugar; BUN, blood urea nitrogen; Cr, creatinine; TG, triglyceride; LDL; lowdensity lipoprotein; HDL, high-density lipoprotein; BP, blood pressure; and IMT, intima-media thickness.

3 Mohsen Nafar et al / Experimental and Clinical Transplantation (29) 1: months. Patients and study personnel were unaware of the study group assignments, laboratory measurements, and carotid imaging findings. Before the study was initiated, the subjects were treated with a standard immunosuppression regimen consisting of triple therapy (prednisone, mycophenolate mofetil, and cyclosporine microemulsion formulation. We performed laboratory examinations and radiographic measurement at baseline and 2, 4, and 6 months after kidney transplant. Outcome measures To measure the carotid intimal-media thickness, we used longitudinal B-mode Doppler sonography (Hitachi EUB-565, Hitachi Co, Tokyo, Japan) in 12 carotid segments (the near and far walls of the left and right common carotid arteries, the carotid bifurcation, and the internal carotid artery) with the patient supine. To measure the carotid intima-media thickness, we first identified the carotid arteries by means of a transverse scan and then rotated the probe 9º, which resulted in the creation of 2 parallel lines that showed the intima and media-adventitia. The distance between those 2 lines provided the index of the intima-media thickness. The carotid intima-media thickness measurement for each specific site revealed the maximum carotid thickness. All examinations were performed by a single trained ultrasonographer. The mean of those 12 measures of the carotid intima-media thickness was used as the value for carotid intima media thickness for each patient. Laboratory assessments We used a radioimmunoassay to measure the subjects plasma total homocysteine level. The samples for that test were obtained after the subjects had been fasted of food for 12 hours. We also measured the levels of serum folic acid, vitamin B12, lipids (triglyceride, cholesterol, high-density lipoprotein, low-density lipoprotein), serum cyclosporine, blood urea nitrogen, and creatinine. Statistical analyses We used the mean and standard deviation and the relative frequencies, based on the variable types, to describe our studied variables. To compare the measurements of carotid intima-media thickness and the values of thcy in the 2 study groups, we used the independent sample t test. To compare each cited variable in each group with the respective baseline value, we used the paired sample t test. The differences between the 2 groups with respect to the relative prevalence of the nominal variables were studied by means of the chi-square test. A P value of <.5 was considered statistically significant. Results Except for the total cholesterol level, all other measured variables did not differ between the treated and control groups. Supplementation with folic acid caused a significant increase in the plasma folic acid level in the treated group (from 5.4 ± 3.1 mmol/l at baseline to 7.9 ± 4.4 mmol/l, 8.9 ± 4.4, mmol/l and 1.2 ± 4.5 mmol/l at 2, 4, and 6 months, respectively; P value for each interval compared with baseline, <.5). There was no significant change in the plasma level of folic acid in the control group. During the first 2 months of study, the level of thcy decreased significantly in the folic acid group (from 18.5 ± 7 µmol/l to 14.7 ± 3.8 µmol/l, P <.1). Such a significant decrease did not occur in the control group (Figure 2). The thcy level in the folic acid group was significantly lower than that in the control (P =.6). At 2 months, the carotid intimamedia thickness was slightly higher than the baseline level in the control group, but that increase was not statistically significant. The carotid intima-media thickness in the folic acid group did not change significantly from the baseline level. The increase in the carotid intima-media thickness in the control group at 2 months made the difference of carotid intima-media thickness between folic acid and control group to a significant level (P =.44) (Figure 3). Plasma homocysteine (µmol/l) * 2* 12.9* 1.9* Baseline Time after kidney transplantation (months) Figure 2. Total homocysteine levels in the study subjects Abbreviations: thcy, total homocysteine; FA, folic acid. *Significant at P <.5 between the 2 groups. Significant at P <.5 from the baseline measure.

4 36 Mohsen Nafar et al / Experimental and Clinical Transplantation (29) 1: Exp Clin Transplant Carotid Intima-Media Thickness (mm) *.73* 19.3* 12.9* 2* 1.9* Time after kidney transplant (mo) Figure 3. Changes in intima-media thickness after kidney transplant in the study subjects *Significant at P <.5 between the 2 groups. Significant at P <.5 from the baseline measure. After 4 months of study, the level of thcy continued to decrease in the folic acid group and reached 12.9 ± 2.6 µmol/l, which was significantly lower than the baseline value (P <.1). The level of thcy, which reached 19.3 ± 6.8 µmol/l in the control group, had not changed significantly from the baseline value at that time. Again, the level of thcy in the folic acid group was significantly lower than that in the control group (P =.7). The carotid intima-media thickness in the folic acid group decreased to.72 ±.1 mm, which was significantly lower than the baseline thickness (P =.42). The carotid intima-media thickness had increased significantly from the baseline thickness in the control group and reached.84 ±.2 mm (P =.24). There was also a significant difference between the carotid intima-media thickness in the folic acid and that in the control group (P =.7) At the end of the study (ie, 6 months after the study initiation), the thcy values and carotid intimamedia thickness in the folic acid group were significantly lower than baseline (1.9 ± 2.1,.71 ±.1 µmol/l; P <.1 and P =.11, respectively). In the control group, the thcy level reached 2 ± 6.9 µmol/l, which was not significantly higher than baseline (P =.342). The carotid intima-media thickness in the control group reached.85 ±.2 mm, which was significantly higher than baseline (P =.3). When we compared the 2 groups, we found that thcy values and carotid intima-media thickness were both significantly lower in the folic acid group than in the control group (P <.1 and P =.3; respectively). During the study, the lipid profile (ie, the levels of total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides) was not significantly different nor from the baseline measure in each group, neither between the folic acid and control group (Figure 4) Total cholesterol (mg/dl) Low-density lipoprotein (mg/dl) Baseline Baseline Baseline Baseline Figure 4. Changes in the lipid profile of the study subjects Triglyceride (mg/dl) High-density lipoprotein (mg/dl)

5 Mohsen Nafar et al / Experimental and Clinical Transplantation (29) 1: Discussion In our study, we observed that folic acid, when administered in a dosage of 5 mg/d to patients who had undergone a kidney transplant, reduced both the thcy level to a significant degree (which was detected after 2 months of therapy) and the carotid intima-media thickness. That decrease continued throughout the study. The carotid intima-media thickness also decreased in the folic acid group during the study, and that decrease was significant after 4 months of folic acid treatment. In the control group, however, the total homocysteine level and carotid intima-media thickness increased during the study. The increase in the carotid intima-media thickness was significant 4 months after the kidney transplant. Although the level of thcy might be expected to decrease after a kidney transplant, a study by Suwelack and colleagues showed no significant decrease in that level during the first 12 months of follow-up after kidney transplant in a subgroup of patients with baseline thcy values similar to those in our patients (13). In another study of patients who underwent a kidney transplant and were monitored for up to 252 months, Sobki and colleagues found that there was a significant correlation between the thcy level and the posttransplant interval (22). This suggests that the thcy level increases gradually after a kidney transplant; thus patients with a transplanted kidney might be expected to have higher a thcy level than that in the healthy population. This finding was found in similar studies, such as that performed by Marcucci and colleagues, who found that hyperhomocysteinemia is highly prevalent after kidney transplant (23). We found similar results, and in our study, a gradual and nonsignificant increase in the level of thcy occurred in the control group. In a study on change in the carotid intima-media thickness after a kidney transplant, De Lima and colleagues found that 12 months after surgery, the carotid morphological parameters had increased above baseline, but that increase was not significant (5). Forty months after a successful kidney transplant, the carotid intima-media thickness in their subjects had significantly decreased (5). In another study, there was no improvement in the carotid intima-media thickness of the patients 1 year after a kidney transplant (24). In other research, Jogestrand and colleagues (25) and Suwelack and colleagues (26) compared carotid artery characteristics in patients who had undergone a kidney transplant with those in healthy individuals. Those authors found that a short time after kidney transplant, the levels of carotid atherosclerosis markers were significantly increased. In our study, 4 months after a kidney transplant, the carotid intimamedia thickness in the control group was significantly higher than baseline. That increase was also observed in the sixth month of the study. Our results are similar to those of previous studies (23, 27, 28) showing that supplementation with folic acid lowers elevated levels of thcy in the short term and over time. We found, as have other authors who reported on the role of folic acid supplementation in reducing carotid intima-media thickness and the incidence of cardiovascular accidents (28-3), that folic acid therapy is similarly useful after a kidney transplant. In their study of 1 kidney transplant recipients, Austen and colleagues found that after 3 months of therapy with folic acid and despite a significant decrease in the thcy level, there was no significant change in the brachial artery intima-media thickness of their subjects (31). Ours findings were similar. We observed no change in the subjects carotid intima-media thickness during the first 4 months of the study, and it was only later that we noted a reduction in the carotid intima-media thickness in the folic acid group. It seems that folic acid therapy must be administered for several months before its beneficial effects occur. The changes in carotid intima-media thickness seemed not to be the effect of other factors such as age, the duration of chronic renal failure, or hemodialysis therapy because there was no significant difference associated with those factors in our 2 study groups. Our subjects had no history of cardiovascular disease, diabetes mellitus, or cigarette smoking, all of which could affect the carotid intima-media thickness of the participants. We also observed no significant difference or change in the lipid profile of our subjects before and during the study. We can thus with more confidence attribute the changes in carotid intima-media thickness to the alterations that occurred in the subjects thcy levels as a result of folic acid treatment. Because of the high prevalence of cardiovascular events that occur during early posttransplant months (32), we agree that aggressive intervention is needed

6 38 Mohsen Nafar et al / Experimental and Clinical Transplantation (29) 1: Exp Clin Transplant during the first year after a kidney transplant to prevent the development of a cardiovascular event (33). We believe that the beneficial effects of a kidney transplant on atherosclerotic indices do not occur for several months after surgery and that during that interval, patients have a relatively greater risk of experiencing a cardiovascular event. Because of the adverse sequelae of having undergone a kidney transplant (eg, recurrent hospitalizations or infections and the effects of immunosuppressive therapy), it seems wise not to impose a greater risk of cardiovascular accidents on such patients, especially when those events could be prevented by using a simple treatment like administration of folic acid. Other interventions (eg, steroid-free immuno - suppressive therapy [34] or a reduction in the cyclosporine dose [35]), which are useful in reducing the plasma thcy level and the risk of cardiovascular disease, should also be considered when possible. Our study has some limitations. The relatively small sample size is a major limitation in generalizing the results. Also, the brief follow-up limited our ability to determine the long-term effects of our intervention on the patient population studied. The power of our study lies in our use of valid measures and methods to evaluate atherosclerotic status and to determine the subjects plasma level of thcy. In summary, we found that administering supplementary folic acid 5 mg/d after kidney transplant led to a reduction in the subjects plasma thcy level and reduced carotid intima-media thickness. Those findings were detectable shortly after treatment with supplementary folic acid was initiated. References 1. 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7 Mohsen Nafar et al / Experimental and Clinical Transplantation (29) 1: Till U, Röhl P, Jentsch A, et al. Decrease of carotid intima-media thickness in patients at risk to cerebral ischemia after supplementation with folic acid, Vitamins B6 and B12. Atherosclerosis. 25;181(1): Marcucci R, Zanazzi M, Bertoni E, et al. Vitamin supplementation reduces the progression of atherosclerosis in hyperhomo cysteinemic renal-transplant recipients. Transplantation. 23;75(9): Austen SK, Fassett RG, Geraghty DP, et al. Folate supplementation fails to affect vascular function and carotid artery intima media thickness in cyclosporin A-treated renal transplant recipients. Clin Nephrol. 26;66(5): Chuang P, Gibney EM, Chan L, et al. Predictors of cardiovascular events and associated mortality within two years of kidney transplantation. Transplant Proc. 24;36(5): Laurés AS, Gómez E, Baltar J, et al. Risk factors for cardiovascular disease during the first 2 years after renal transplantation. Transplant Proc. 25;37(9): Libetta C, Sepe V, Zucchi M, et al. Influence of methylprednisolone on plasma homocysteine levels in cadaveric renal transplant recipients. Transplant Proc. 26;38(9): Wong W, Tolkoff-Rubin N, Delmonico FL, et al. Analysis of the cardiovascular risk profile in stable kidney transplant recipients after 5% cyclosporine reduction. Clin Transplant. 24;18(4): Levy G, Thervet E, Lake J, et al. Consensus on Neoral C(2): Expert Review in Transplantation (CONCERT) Group. Patient management by Neoral C(2) monitoring: an international consensus statement. Transplantation. 22;73(9 Suppl):S12-S18. [Note: Reference 37 is cited in Table 1.]