- Email: [email protected]
Young Hemodialysis Patients Are Exposed to Hyperhomocysteinemia
RESEARCH BRIEFS
Young Hemodialysis Patients Are Exposed to Hyperhomocysteinemia Tsuneo Takenaka, MD, PhD,*† Yoshiaki Itaya, MD, PhD,* and Hiromichi Suzuki, MD, PhD† Objective: Homocysteine is one of the cardiovascular risk factors in hemodialysis (HD) patients. Studies were performed to assess the effects of folic acid on pulse wave velocity (PWV) in HD patients. Methods: In a cross-sectional study, plasma total homocysteine (tHcy) was measured in 49 patients on maintenance HD. Ten HD patients younger than 45 years old entered the prospective study. Monthly changes in PWV were compared before and during folic acid treatment. Results: Younger HD patients had higher tHcy (r ⫽ ⫺0.53, n ⫽ 49, P ⬍ .001). Patients who manifested myocardial ischemia (37 ⫾ 3 nmol/mL) possessed higher tHcy than those who did not (30 ⫾ 3 nmol/mL, P ⬍ .05). In prospective study, folic acid treatment (10 to 20 mg/d) failed to alter blood pressure and biochemical parameters, including lipids, calcium, phosphate, and parathormone. However, in association with a decrease in tHcy (46 ⫾ 5 to 27 ⫾ 3 nmol/mL, n ⫽ 10, P ⬍ .005), progressive increases in PWV (33 ⫾ 8 to 3 ⫾ 6 cm/sec/month, P ⬍ .01) were stopped. Conclusions: The present findings indicate that young HD patients are exposed to severe hyperhomocysteinemia, and suggest that relatively large doses of folic acid attenuate progressive increases in PWV of young or middle-age HD patients. © 2005 by the National Kidney Foundation, Inc.
H
EMODIALYSIS (HD) patients frequently have complications such as cardiovascular diseases, constituting major causes of death in this population.1 The prevention of arteriosclerotic diseases is important among HD patients because it may not only improve the life expectancy of the patients, but also decrease the total medical cost required for patients with end-stage renal diseases. Indeed, HD patients are commonly exposed to multiple cardiovascular risk factors, including dyslipidemia, hypertension, hyperhomocysteinemia, hyperparathyroidism, and calcium overload.1-6 Hyperhomocysteinemia constitutes a
*Shinjuku Suimei Clinic, Shinjuku, Tokyo. †Department of Medicine, Saitama Medical College, Iruma, Saitama, Japan. Address reprint requests to Hiromichi Suzuki, MD, PhD, Saitama Medical College, Department of Nephrology, 38 Morohongo Moroyama, Iruma Saitama 350-0495, Japan. E-mail: [email protected] © 2005 by the National Kidney Foundation, Inc. 1051-2276/05/1504-0009$30.00/0 doi:10.1016/j.jrn.2005.07.008
Journal of Renal Nutrition, Vol 15, No 4 (October), 2005: pp 435-440
significant cardiovascular risk factor, especially when the other risk factors are present.7 The pathology of arteriosclerosis includes atherosclerosis, Monckeberg medial sclerosis, and arteriolosclerosis.8 Arteriosclerosis in large- and medium-sized elastic and muscular arteries leads to ischemia of heart, brain, kidney, intestine, and extremities.2 Morphologic abnormalities in arteriosclerosis such as atheroma, fibrosis, and calcification are prone to elevate the stiffness of the vessel wall.2-6 Blacher et al9,10 have recently developed a noninvasive procedure to quantitate arterial stiffness. The Moens-Korteweg equation gives a theoretical basis that the square of pulse wave velocity (PWV) through the artery is directly related to its stiffness. This method affords repeated measurements of arterial stiffness easily. PWV predicts the cardiovascular survival of HD patients.10,11 Recent investigations have shown that angiotensin blockade, vitamin E, and lipid-lowering drugs including statins attenuate PWV in HD patients.11-13 Sevelamer, a phosphate binder containing neither calcium nor aluminium, also improves PWV in HD patients.14 435
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Our present data implicate that plasma total homocysteine (tHcy) varied from 15 to 74 nmol/mL among HD patients. Folic acid may ameliorate hyperhomocysteinemia. These observations prompted us to examine whether folic acid altered PWV in HD patients. In the present study, we measured PWV in young HD patients along with tHcy, lipids (total cholesterol [TC], triglyceride [TG], low- and high-density-lipoprotein cholesterol [LDL-C and HDL-C]), whole parathyroid hormone (PTH), and blood pressure.15
Methods Patients undergoing maintenance HD (4 h/session, 3 d/week) in our clinics entered into the study when they accepted informed consent according to the Declaration of Helsinki.16 A complete physical examination and medical history were taken. We recommended a daily protein intake of 1.2 g/kg and adequate watersoluble vitamins for all patients. Cross-sectional and prospective studies were carried out.
Cross-Sectional Study In February 2003 for 49 patients, biochemical parameters including tHcy were measured. Relationships between tHcy and clinical parameters, including electrocardiogram (ECG) and drinking habits, were determined. In the present study, we defined a drinker as a patient who drank alcohol more than 10 g/d at least once per week, and excluded a chance drinker. Prospective Study Because we had obtained an inverse relationship between age and tHcy in the first crosssectional study, 10 patients younger than 45 years old were selected for the second prospective study, and their PWV was assessed in March 2003. Blood pressure and biochemical parameters were measured at least bimonthly throughout the observation periods, and averages were calculated for each period (before and during folic acid treatment). Actual protein intake was estimated with protein catabolic rate.17 In September 2003, PWV and serum vitamins were assessed. Then, folic acid was prescribed. Three female patients took 10 mg folic acid daily, and 7 male patients took 20 mg. We have recently shown that angiotensin inhibitors, sevelamer, lipid-lowering
drugs, and dialysis membrane affect PWV.12,14 In March 2004, PWV and serum folic acid were measured for 10 patients, because no patient started or discontinued new medications or dialyzers. As described previously,12 PWV and ankle-brachial pressure index (ABI) were measured using an automated polygraph device (AT Form, Nihon Colin Co. Ltd, Tokyo. Japan) after HD sessions when the patients reached their own dry weights. PWV from the heart to the posterior tibial artery just above the ankle was considered, dividing the arterial length (estimated from patient’s height) by the time lag between the second heart sound (aortic closure) and the dicrotic notch of the arterial pressure. Recently, our observations have validated the usefulness of PWV from the heart to the tibial artery as a marker of arteriosclerosis in HD patients.12 PWV is inaccurately low as ABI is markedly decreased. Thus, the data from the patients who showed an ABI above 1.0 throughout the observation periods were used for final analysis. Data were expressed as mean ⫾ standard error of the mean. Linear regression analysis, Student t-tests, and analysis of variance followed by the Newman-Keuls test were used. P ⬍ .05 was considered statistically significant.
Results In the cross-sectional study, 49 patients (39 male and 10 female) were enrolled. Patient age and HD duration averaged 56 ⫾ 2 years old and 8 ⫾ 1 years, respectively. Eleven diabetic patients were included. Although there was no difference in tHcy between diabetic and nondiabetic HD patients, female HD patients (25 ⫾ 3 nmol/mL) had significantly lower tHcy than male patients (35 ⫾ 2 nmol/mL, P ⬍ .01). HD patients who had a medical history of ischemic heart disease or who showed ischemic ST-T changes in ECG manifested higher tHcy (37 ⫾3 nmol/mL, n ⫽ 22) than those who did not (30 ⫾ 3 nmol/mL, n ⫽ 27, P ⬍ .05). In addition, HD patients who drank alcohol manifested higher tHcy (37 ⫾ 3 nmol/mL, n ⫽ 27) than those who did not (29 ⫾ 2 nmol/mL, n ⫽ 22, P ⬍ .05). Surprisingly, there was an inverse correlation between tHcy and age. As shown in Figure 1, younger HD patients were exposed to a higher tHcy level (slope ⫽ ⫺0.61 ⫾ 0.14 nmol/mL/y, r ⫽ ⫺0.53, P ⬍ .001, n ⫽ 49).
FOLATE AND ARTERIAL STIFFNESS
Figure 1. Inverse relationship between age and plasma level of total homocysteine (tHcy). Slope ⫽ ⫺0.61 ⫾ 0.14 nmol/mL/y, r ⫽ ⫺0.53, P ⬍ .001, n ⫽ 49.
In the prospective study, the effects of folic acid were assessed. Mean age was 37 ⫾ 2 years old, and average HD duration was 8 ⫾ 1 years in these 10 patients. Two patients manifested ischemic ST-T changes, and the other two patients were defined as drinkers. As shown in Figure 2, the treatment with folic acid substantially decreased tHcy (46 ⫾ 5 to 27 ⫾ 2 nmol/mL, n ⫽ 10, P ⬍ .005) and increased serum folic acid (4.8 ⫾ 1.1 to
Figure 2. Temporal changes in total homocysteine (tHcy). *P ⬍ .005 between control and folic acid periods.
437
Figure 3. Folic acid stops progressive elevations in pulse wave velocity (PWV). Control and Folic Acid describe the baseline and folic acid periods, respectively. *P ⬍ .01.
36.9 ⫾ 4.2 ng/mL, P ⬍ .001). Although vitamin B6 and B12 influence the metabolism of homocysteine,18 we did not administer these vitamins because the 10 patients showed serum levels of both vitamins within normal or higher than normal values (B6, 33 ⫾ 10 ng/mL; B12, 802 ⫾ 169 pg/mL). The other biochemical parameters, which could modify PWV, remained unchanged during the control period and folic acid treatment.12 Folic acid did not alter lipids, including TC (178 ⫾ 6 to 178 ⫾ 7 mg/dL), LDL-C (97 ⫾ 6 to 99 ⫾ 7 mg/dL), TG (121 ⫾ 14 to 122 ⫾ 10 mg/dL), or HDL-C (49 ⫾ 4 to 52 ⫾ 4 mg/dL). Folic acid therapy did not influence serum calcium (9.8 ⫾ 0.2 to 9.9 ⫾ 0.2 mg/dL), phosphate (5.9 ⫾ 0.2 to 6.0 ⫾ 0.2 mg/ dL), or whole PTH (77 ⫾ 14 to 74 ⫾ 11 pg/mL). Protein catabolic rate was not modified by folic acid (1.07 ⫾ 0.05 to 1.08 ⫾ 0.06 g/kg/d). Figure 3 summarizes the changes in PWV during the control period and folic acid treatment. Although PWV was increased during the control period (from 1,373 ⫾ 101 to 1,569 ⫾ 91 cm/sec, P ⬍ .01), folic acid treatment stopped an elevation of PWV (to 1,584 ⫾ 100 cm/sec). Figure 4 illustrates the individual relationship between changes in both PWV and tHcy. The magnitude of decreases in PWV tended to become greater as the reductions in tHcy were
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Figure 4. Relationship between decreases in total homocysteine (changes in tHcy) and reductions in pulse wave velocity (changes in PWV).
larger (slope ⫽ 0.38 ⫾ 0.71 cm/sec/mo/nmol/ mL, r ⫽ 0.18). Because PWV correlates to blood pressure, especially systolic pressure,11 one would expect that an elevation of PWV at the end of control period might be caused by an increase in blood pressure. However, blood pressure at the time of PWV measurements averaged 138 ⫾ 5/74 ⫾ 2, 137 ⫾ 5/75 ⫾ 2, and 139 ⫾ 5/77 ⫾ 2 mm Hg in March 2003, September 2003, and March 2004, respectively. Thus, it is unlikely that the changes in PWV are attributable to variations in blood pressure.
Discussion Recent investigations have shown that hyperhomocysteinemia is an independent risk factor for vascular diseases and predicts the prognosis of ischemic heart disease.6,19 Homocysteine impairs endothelial cell function, participating in the pathogenesis of vascular diseases.20 Kidney function is a major determinant of tHcy in renal transplant recipients.21 In HD patients, plasma tHcy is commonly elevated partly because of folic acid deficiency.22 Folic acid is lost during highperformance HD. Thus, folic acid supplementation would decrease the high cardiovascular mor-
tality of HD patients. However, there is controversy in tHcy as a cardiovascular risk factor. Low tHcy is an indicator of poor outcome in HD patients, possibly because of protein-energy malnutrition.23 Hyperhomocysteinemia does not impair endothelial function in healthy subjects, who do not possess additional risk factors.7 Hyperhomocysteinemia shows a strong linkage to coronary artery disease in the general population.6,19 The present data show that HD patients with ischemic heart disease manifested a higher tHcy than those without ischemia. HD patients are exposed to multiple risk factors, such as hypertension, dyslipidemia, and calcium/phosphate disturbance.1,20 Furthermore, our previous data indicate that HD patients are exposed to excessive oxidative stress.16 In the presence of the other cardiovascular risk factors, hyperhomocysteinemia becomes a strong cardiovascular risk factor.7 Collectively, these observations suggest that tHcy seems to constitute a marker of ischemic heart disease also in HD patients. A large amount of alcohol consumption increases plasma homocysteine.24 Alcohol seems to impair folic acid absorption and alter its metabolism, thereby decreasing homocysteine breakdown. According to the JNC-VII guidelines for treatment of hypertension,25 ethanol consumption of 10 g/d may not be harmful for hypertensive patients with normal kidney function. However, our data indicated that tHcy was elevated in the drinker, and suggest that HD patients should restrict alcohol consumption more strictly than those with normal kidney function. Children with chronic renal failure on regular HD manifested high homocysteine levels.26 In the present study, we have shown that younger HD patients are exposed to higher tHcy. Furthermore, Oh et al27 showed that advanced coronary arteriopathy was seen in young adults with childhood-onset chronic renal failure, and coronary calcium score was correlated with hyperhomocysteinemia in this population. Forman et al28 reported that a large folic acid intake may reduce the risk of hypertension, especially in younger women. Taken together, these observations suggest that a high tHcy is an important therapeutic target for young HD patients to slow the progression of arteriosclerosis. Randomized, placebo-controlled study indicates that homocysteine-lowering treatment with folic acid and vitamin B6 in the healthy siblings of
439
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parents with premature atherothrombotic diseases is associated with a decreased occurrence of abnormal exercise ECG test results.29 However, Gonin et al18 reported that folic acid and vitamin B6 or B12 did not reduce homocysteinemia in HD patients. On the other hand, Righetti et al30 showed that although folic acid normalized homocysteine levels in only 12% of HD patients, there was a trend toward a decreased rate of cardiovascular events in folic acid–treated HD patients as compared with untreated ones. Our results are compatible with the latter, and indicate that folic acid did not normalize but reduced tHcy significantly. Blacher et al9 reported that hyperhomocysteinemia is associated with high lower-limb PWV. Zoungas et al31 described that the higher homocysteinemia was related to faster aortofemoral PWV. We previously showed that tHcy had a positive correlation with aortotibial PWV.12 We are unaware of any data regarding the effects of folic acid on PWV in HD patients. We have provided the first evidence that folic acid therapy for 6 months stopped the increase in PWV of young adult HD patients. This was associated with decreases in tHcy, which were higher in younger HD patients. Taken together, these observations indicate that folic acid constitutes an important treatment for slowing the elevation of PWV, especially in young adult HD patients, and suggest that tHcy contributes to the progression of arterial stiffness in HD patients. PWV is believed to be a surrogate risk factor for cardiovascular diseases. In HD patients, a higher PWV means a shorter survival.10,11 Homocysteine decreases the bioavailability of nitric oxide.20 Reductions in PWV by folic acid might reflect not only morphologic improvements of the arterial wall, but also functional ones. The present data have limitations. The prospective study is small and uses rather soft surrogate outcomes. However, our results suggest that folic acid could elicit a favorable outcome in young HD patients, and may form a basis for a larger, controlled, long-term, randomized trial.
Acknowledgements The authors thank Shingo Iwasaki, Eriko Oshima, Toru Kobayashi, and Kenji Takahashi for their excellent technical assistance. Parts of the contents of this manuscript were presented at the 49th annual meeting of Japanese Society of
Dialysis Therapy, and published as an abstract ( J Jap Soc Dial Ther 37:1045, 2004 [suppl 1]).
References 1. Sarnak MJ: Cardiovascular complications in chronic kidney disease. Am J Kidney Dis 41:11-17, 2003 (suppl 5) 2. Ross R: Atherosclerosis. N Engl J Med 340:115-126, 1999 3. Bakris GL: Angiotensin-converting enzyme inhibition to enhance vascular health. Am J Hypertens 14:264-269, 2001 4. Barenbrock M, Hausberg M, Kosch M, et al: Effect of hyperparathyroidism on arterial distensibility in renal transplant recipients. Kidney Int 54:210-215, 1998 5. Locatelli F, Cannata-Andia JB, Drueke TB, et al: Management of disturbances of calcium and phosphate metabolism in chronic renal insufficiency, with emphasis on the control of hyperphosphataemia. Nephrol Dial Transplant 17:723-731, 2002 6. Clarke R, Daly L, Robinson K, et al: Hyperhomocysteinemia: An independent risk factor for vascular disease. N Engl J Med 324:1149-1155, 1991 7. Woodman RJ, Celermajer DE, Thompson PL, et al: Folic acid does not improve endothelial function in healthy hyperhomocystenemic subjects. Clin Sci 106:353-358, 2004 8. Wisolar RW: Principles of the pathogenesis of atherosclerosis, in Braunwald E(ed): Heart Disease, 2nd ed. Philadelphia: Saunders, 1984, pp 1183-1204 9. Blacher J, Demuth K, Guerin AP, et al: Influence of biochemical alterations on arterial stiffness in patients with endstage renal disease. Artherioscler Thromb Vasc Biol 18:535-541, 1998 10. Blacher J, Guerin AP, Pannier B, et al: Impact of aortic stiffness on survival in end-stage renal disease. Circulation 99: 2434-2439, 1999 11. Guerin AP, Blacher J, Pannier B, et al: Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure. Circulation 103:987-992, 2001 12. Takenaka T, Kobayashi K, Suzuki H: Pulse wave velocity as an indicator of arteriosclerosis in hemodialysis patients. Atherosclerosis 176:405-409, 2004 13. Ichihara A, Hayashi M, Ryuzaki M, et al: Fluvastatin prevents development of arterial stiffness in hemodialysis patients with type II diabetes mellitus. Nephrol Dial Transplant 17:15131517, 2002 14. Takenaka T, Suzuki H: New strategy to attenuate pulse wave velocity in haemodialysis patients. Nephrol Dial Transplant 20:811-816, 2005 15. Slatopolsky E, Finch J, Clay P, et al: A novel mechanism for skeletal resistance in uremia. Kidney Int 58:753-761, 2000 16. Takenaka T, Takahashi K, Kobayashi T, et al: Oxidized low density lipoprotein as a marker of atherosclerosis in hemodialysis patients. Clin Nephrol 58:33-37, 2002 17. Takenaka T, Itaya Y, Tsuchiya Y, et al: Fitness of biocompatible high-flux hemodiafiltration for dialysis-related amyloidosis. Blood Purif 19:10-14, 2001 18. Gonin JM, Nguyen H, Gonin R, et al: Controlled trials of very high dose folic acid, vitamin B12 and B6, intravenous folinic acid and serine for treatment of hyperhomocysteinemia in ESRD. J Nephrol 16:522-534, 2003 19. Nygard O, Nordrehaug JE, Refsum H, et al: Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 337:230-236, 1997
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20. Baigent C, Burbury K, Wheeler D: Premature cardiovascular disease in chronic renal failure. Lancet 356:147-152, 2000 21. Han H, Dwyer JT, Selhub J, et al: Determinants of plasma total homocysteine levels in Korean chronic renal transplant recipients. J Ren Nutr 10:202-207, 2000 22. Leblanc M, Pichette V, Geadah D, et al: Folic acid and pyridoxal-5=-phosphate losses during high-efficiency hemodialysis in patients without hydrosoluble vitamin supplementation. J Ren Nutr 10:196-201, 2000 23. Kalantar-Zadeh K, Block G, Humphreys MH, et al: A low, rather than a high, total plasma homocysteine is an indicator of poor outcome in hemodialysis patients. J Am Soc Nephrol 15:442-453, 2004 24. Halsted CH, Villanueva JA, Devlin AM, et al: Metabolic interactions of alcohol and folate. J Nutr 132:236-237, 2002 (suppl 8) 25. National High Blood Pressure Education Program Coordinating Committee: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 289:2560-2572, 2003
26. Farid FA, Faheem MS, Heshmat NM, et al: Study of the homocysteine status in children with chronic renal failure. Am J Nephrol 24:289-295, 2004 27. Oh J, Wunsch R, Turzer M, et al: Advanced coronary and carotid arteriopathy in young adults with children-onset chronic renal failure. Circulation 106:100-105, 2002 28. Forman JP, Rimm EB, Stampfer MJ, et al: Folate intake and the risk of incident hypertension. J Am Soc Nephrol 15: 354A, 2004 29. Vermeulen EG, Stehouwer CD, Twisk JW, et al: Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: A randomized, placebo-controlled trial. Lancet 355:517-522, 2000 30. Righetti M, Ferrario GM, Milani S, et al: Effects of folic acid treatment on homocysteine levels and vascular disease in hemodialysis patients. Med Sci Monit 9:19-24, 2003 31. Zoungas S, Branley P, Kerr PG, et al: Atherosclerosis and folic acid supplementation trial in chronic renal failure: Baseline results. Nephrology 9:130-141, 2004
Young Hemodialysis Patients Are Exposed to Hyperhomocysteinemia Tsuneo Takenaka, MD, PhD,*† Yoshiaki Itaya, MD, PhD,* and Hiromichi Suzuki, MD, PhD† Objective: Homocysteine is one of the cardiovascular risk factors in hemodialysis (HD) patients. Studies were performed to assess the effects of folic acid on pulse wave velocity (PWV) in HD patients. Methods: In a cross-sectional study, plasma total homocysteine (tHcy) was measured in 49 patients on maintenance HD. Ten HD patients younger than 45 years old entered the prospective study. Monthly changes in PWV were compared before and during folic acid treatment. Results: Younger HD patients had higher tHcy (r ⫽ ⫺0.53, n ⫽ 49, P ⬍ .001). Patients who manifested myocardial ischemia (37 ⫾ 3 nmol/mL) possessed higher tHcy than those who did not (30 ⫾ 3 nmol/mL, P ⬍ .05). In prospective study, folic acid treatment (10 to 20 mg/d) failed to alter blood pressure and biochemical parameters, including lipids, calcium, phosphate, and parathormone. However, in association with a decrease in tHcy (46 ⫾ 5 to 27 ⫾ 3 nmol/mL, n ⫽ 10, P ⬍ .005), progressive increases in PWV (33 ⫾ 8 to 3 ⫾ 6 cm/sec/month, P ⬍ .01) were stopped. Conclusions: The present findings indicate that young HD patients are exposed to severe hyperhomocysteinemia, and suggest that relatively large doses of folic acid attenuate progressive increases in PWV of young or middle-age HD patients. © 2005 by the National Kidney Foundation, Inc.
H
EMODIALYSIS (HD) patients frequently have complications such as cardiovascular diseases, constituting major causes of death in this population.1 The prevention of arteriosclerotic diseases is important among HD patients because it may not only improve the life expectancy of the patients, but also decrease the total medical cost required for patients with end-stage renal diseases. Indeed, HD patients are commonly exposed to multiple cardiovascular risk factors, including dyslipidemia, hypertension, hyperhomocysteinemia, hyperparathyroidism, and calcium overload.1-6 Hyperhomocysteinemia constitutes a
*Shinjuku Suimei Clinic, Shinjuku, Tokyo. †Department of Medicine, Saitama Medical College, Iruma, Saitama, Japan. Address reprint requests to Hiromichi Suzuki, MD, PhD, Saitama Medical College, Department of Nephrology, 38 Morohongo Moroyama, Iruma Saitama 350-0495, Japan. E-mail: [email protected] © 2005 by the National Kidney Foundation, Inc. 1051-2276/05/1504-0009$30.00/0 doi:10.1016/j.jrn.2005.07.008
Journal of Renal Nutrition, Vol 15, No 4 (October), 2005: pp 435-440
significant cardiovascular risk factor, especially when the other risk factors are present.7 The pathology of arteriosclerosis includes atherosclerosis, Monckeberg medial sclerosis, and arteriolosclerosis.8 Arteriosclerosis in large- and medium-sized elastic and muscular arteries leads to ischemia of heart, brain, kidney, intestine, and extremities.2 Morphologic abnormalities in arteriosclerosis such as atheroma, fibrosis, and calcification are prone to elevate the stiffness of the vessel wall.2-6 Blacher et al9,10 have recently developed a noninvasive procedure to quantitate arterial stiffness. The Moens-Korteweg equation gives a theoretical basis that the square of pulse wave velocity (PWV) through the artery is directly related to its stiffness. This method affords repeated measurements of arterial stiffness easily. PWV predicts the cardiovascular survival of HD patients.10,11 Recent investigations have shown that angiotensin blockade, vitamin E, and lipid-lowering drugs including statins attenuate PWV in HD patients.11-13 Sevelamer, a phosphate binder containing neither calcium nor aluminium, also improves PWV in HD patients.14 435
436
TAKENAKA ET AL
Our present data implicate that plasma total homocysteine (tHcy) varied from 15 to 74 nmol/mL among HD patients. Folic acid may ameliorate hyperhomocysteinemia. These observations prompted us to examine whether folic acid altered PWV in HD patients. In the present study, we measured PWV in young HD patients along with tHcy, lipids (total cholesterol [TC], triglyceride [TG], low- and high-density-lipoprotein cholesterol [LDL-C and HDL-C]), whole parathyroid hormone (PTH), and blood pressure.15
Methods Patients undergoing maintenance HD (4 h/session, 3 d/week) in our clinics entered into the study when they accepted informed consent according to the Declaration of Helsinki.16 A complete physical examination and medical history were taken. We recommended a daily protein intake of 1.2 g/kg and adequate watersoluble vitamins for all patients. Cross-sectional and prospective studies were carried out.
Cross-Sectional Study In February 2003 for 49 patients, biochemical parameters including tHcy were measured. Relationships between tHcy and clinical parameters, including electrocardiogram (ECG) and drinking habits, were determined. In the present study, we defined a drinker as a patient who drank alcohol more than 10 g/d at least once per week, and excluded a chance drinker. Prospective Study Because we had obtained an inverse relationship between age and tHcy in the first crosssectional study, 10 patients younger than 45 years old were selected for the second prospective study, and their PWV was assessed in March 2003. Blood pressure and biochemical parameters were measured at least bimonthly throughout the observation periods, and averages were calculated for each period (before and during folic acid treatment). Actual protein intake was estimated with protein catabolic rate.17 In September 2003, PWV and serum vitamins were assessed. Then, folic acid was prescribed. Three female patients took 10 mg folic acid daily, and 7 male patients took 20 mg. We have recently shown that angiotensin inhibitors, sevelamer, lipid-lowering
drugs, and dialysis membrane affect PWV.12,14 In March 2004, PWV and serum folic acid were measured for 10 patients, because no patient started or discontinued new medications or dialyzers. As described previously,12 PWV and ankle-brachial pressure index (ABI) were measured using an automated polygraph device (AT Form, Nihon Colin Co. Ltd, Tokyo. Japan) after HD sessions when the patients reached their own dry weights. PWV from the heart to the posterior tibial artery just above the ankle was considered, dividing the arterial length (estimated from patient’s height) by the time lag between the second heart sound (aortic closure) and the dicrotic notch of the arterial pressure. Recently, our observations have validated the usefulness of PWV from the heart to the tibial artery as a marker of arteriosclerosis in HD patients.12 PWV is inaccurately low as ABI is markedly decreased. Thus, the data from the patients who showed an ABI above 1.0 throughout the observation periods were used for final analysis. Data were expressed as mean ⫾ standard error of the mean. Linear regression analysis, Student t-tests, and analysis of variance followed by the Newman-Keuls test were used. P ⬍ .05 was considered statistically significant.
Results In the cross-sectional study, 49 patients (39 male and 10 female) were enrolled. Patient age and HD duration averaged 56 ⫾ 2 years old and 8 ⫾ 1 years, respectively. Eleven diabetic patients were included. Although there was no difference in tHcy between diabetic and nondiabetic HD patients, female HD patients (25 ⫾ 3 nmol/mL) had significantly lower tHcy than male patients (35 ⫾ 2 nmol/mL, P ⬍ .01). HD patients who had a medical history of ischemic heart disease or who showed ischemic ST-T changes in ECG manifested higher tHcy (37 ⫾3 nmol/mL, n ⫽ 22) than those who did not (30 ⫾ 3 nmol/mL, n ⫽ 27, P ⬍ .05). In addition, HD patients who drank alcohol manifested higher tHcy (37 ⫾ 3 nmol/mL, n ⫽ 27) than those who did not (29 ⫾ 2 nmol/mL, n ⫽ 22, P ⬍ .05). Surprisingly, there was an inverse correlation between tHcy and age. As shown in Figure 1, younger HD patients were exposed to a higher tHcy level (slope ⫽ ⫺0.61 ⫾ 0.14 nmol/mL/y, r ⫽ ⫺0.53, P ⬍ .001, n ⫽ 49).
FOLATE AND ARTERIAL STIFFNESS
Figure 1. Inverse relationship between age and plasma level of total homocysteine (tHcy). Slope ⫽ ⫺0.61 ⫾ 0.14 nmol/mL/y, r ⫽ ⫺0.53, P ⬍ .001, n ⫽ 49.
In the prospective study, the effects of folic acid were assessed. Mean age was 37 ⫾ 2 years old, and average HD duration was 8 ⫾ 1 years in these 10 patients. Two patients manifested ischemic ST-T changes, and the other two patients were defined as drinkers. As shown in Figure 2, the treatment with folic acid substantially decreased tHcy (46 ⫾ 5 to 27 ⫾ 2 nmol/mL, n ⫽ 10, P ⬍ .005) and increased serum folic acid (4.8 ⫾ 1.1 to
Figure 2. Temporal changes in total homocysteine (tHcy). *P ⬍ .005 between control and folic acid periods.
437
Figure 3. Folic acid stops progressive elevations in pulse wave velocity (PWV). Control and Folic Acid describe the baseline and folic acid periods, respectively. *P ⬍ .01.
36.9 ⫾ 4.2 ng/mL, P ⬍ .001). Although vitamin B6 and B12 influence the metabolism of homocysteine,18 we did not administer these vitamins because the 10 patients showed serum levels of both vitamins within normal or higher than normal values (B6, 33 ⫾ 10 ng/mL; B12, 802 ⫾ 169 pg/mL). The other biochemical parameters, which could modify PWV, remained unchanged during the control period and folic acid treatment.12 Folic acid did not alter lipids, including TC (178 ⫾ 6 to 178 ⫾ 7 mg/dL), LDL-C (97 ⫾ 6 to 99 ⫾ 7 mg/dL), TG (121 ⫾ 14 to 122 ⫾ 10 mg/dL), or HDL-C (49 ⫾ 4 to 52 ⫾ 4 mg/dL). Folic acid therapy did not influence serum calcium (9.8 ⫾ 0.2 to 9.9 ⫾ 0.2 mg/dL), phosphate (5.9 ⫾ 0.2 to 6.0 ⫾ 0.2 mg/ dL), or whole PTH (77 ⫾ 14 to 74 ⫾ 11 pg/mL). Protein catabolic rate was not modified by folic acid (1.07 ⫾ 0.05 to 1.08 ⫾ 0.06 g/kg/d). Figure 3 summarizes the changes in PWV during the control period and folic acid treatment. Although PWV was increased during the control period (from 1,373 ⫾ 101 to 1,569 ⫾ 91 cm/sec, P ⬍ .01), folic acid treatment stopped an elevation of PWV (to 1,584 ⫾ 100 cm/sec). Figure 4 illustrates the individual relationship between changes in both PWV and tHcy. The magnitude of decreases in PWV tended to become greater as the reductions in tHcy were
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Figure 4. Relationship between decreases in total homocysteine (changes in tHcy) and reductions in pulse wave velocity (changes in PWV).
larger (slope ⫽ 0.38 ⫾ 0.71 cm/sec/mo/nmol/ mL, r ⫽ 0.18). Because PWV correlates to blood pressure, especially systolic pressure,11 one would expect that an elevation of PWV at the end of control period might be caused by an increase in blood pressure. However, blood pressure at the time of PWV measurements averaged 138 ⫾ 5/74 ⫾ 2, 137 ⫾ 5/75 ⫾ 2, and 139 ⫾ 5/77 ⫾ 2 mm Hg in March 2003, September 2003, and March 2004, respectively. Thus, it is unlikely that the changes in PWV are attributable to variations in blood pressure.
Discussion Recent investigations have shown that hyperhomocysteinemia is an independent risk factor for vascular diseases and predicts the prognosis of ischemic heart disease.6,19 Homocysteine impairs endothelial cell function, participating in the pathogenesis of vascular diseases.20 Kidney function is a major determinant of tHcy in renal transplant recipients.21 In HD patients, plasma tHcy is commonly elevated partly because of folic acid deficiency.22 Folic acid is lost during highperformance HD. Thus, folic acid supplementation would decrease the high cardiovascular mor-
tality of HD patients. However, there is controversy in tHcy as a cardiovascular risk factor. Low tHcy is an indicator of poor outcome in HD patients, possibly because of protein-energy malnutrition.23 Hyperhomocysteinemia does not impair endothelial function in healthy subjects, who do not possess additional risk factors.7 Hyperhomocysteinemia shows a strong linkage to coronary artery disease in the general population.6,19 The present data show that HD patients with ischemic heart disease manifested a higher tHcy than those without ischemia. HD patients are exposed to multiple risk factors, such as hypertension, dyslipidemia, and calcium/phosphate disturbance.1,20 Furthermore, our previous data indicate that HD patients are exposed to excessive oxidative stress.16 In the presence of the other cardiovascular risk factors, hyperhomocysteinemia becomes a strong cardiovascular risk factor.7 Collectively, these observations suggest that tHcy seems to constitute a marker of ischemic heart disease also in HD patients. A large amount of alcohol consumption increases plasma homocysteine.24 Alcohol seems to impair folic acid absorption and alter its metabolism, thereby decreasing homocysteine breakdown. According to the JNC-VII guidelines for treatment of hypertension,25 ethanol consumption of 10 g/d may not be harmful for hypertensive patients with normal kidney function. However, our data indicated that tHcy was elevated in the drinker, and suggest that HD patients should restrict alcohol consumption more strictly than those with normal kidney function. Children with chronic renal failure on regular HD manifested high homocysteine levels.26 In the present study, we have shown that younger HD patients are exposed to higher tHcy. Furthermore, Oh et al27 showed that advanced coronary arteriopathy was seen in young adults with childhood-onset chronic renal failure, and coronary calcium score was correlated with hyperhomocysteinemia in this population. Forman et al28 reported that a large folic acid intake may reduce the risk of hypertension, especially in younger women. Taken together, these observations suggest that a high tHcy is an important therapeutic target for young HD patients to slow the progression of arteriosclerosis. Randomized, placebo-controlled study indicates that homocysteine-lowering treatment with folic acid and vitamin B6 in the healthy siblings of
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parents with premature atherothrombotic diseases is associated with a decreased occurrence of abnormal exercise ECG test results.29 However, Gonin et al18 reported that folic acid and vitamin B6 or B12 did not reduce homocysteinemia in HD patients. On the other hand, Righetti et al30 showed that although folic acid normalized homocysteine levels in only 12% of HD patients, there was a trend toward a decreased rate of cardiovascular events in folic acid–treated HD patients as compared with untreated ones. Our results are compatible with the latter, and indicate that folic acid did not normalize but reduced tHcy significantly. Blacher et al9 reported that hyperhomocysteinemia is associated with high lower-limb PWV. Zoungas et al31 described that the higher homocysteinemia was related to faster aortofemoral PWV. We previously showed that tHcy had a positive correlation with aortotibial PWV.12 We are unaware of any data regarding the effects of folic acid on PWV in HD patients. We have provided the first evidence that folic acid therapy for 6 months stopped the increase in PWV of young adult HD patients. This was associated with decreases in tHcy, which were higher in younger HD patients. Taken together, these observations indicate that folic acid constitutes an important treatment for slowing the elevation of PWV, especially in young adult HD patients, and suggest that tHcy contributes to the progression of arterial stiffness in HD patients. PWV is believed to be a surrogate risk factor for cardiovascular diseases. In HD patients, a higher PWV means a shorter survival.10,11 Homocysteine decreases the bioavailability of nitric oxide.20 Reductions in PWV by folic acid might reflect not only morphologic improvements of the arterial wall, but also functional ones. The present data have limitations. The prospective study is small and uses rather soft surrogate outcomes. However, our results suggest that folic acid could elicit a favorable outcome in young HD patients, and may form a basis for a larger, controlled, long-term, randomized trial.
Acknowledgements The authors thank Shingo Iwasaki, Eriko Oshima, Toru Kobayashi, and Kenji Takahashi for their excellent technical assistance. Parts of the contents of this manuscript were presented at the 49th annual meeting of Japanese Society of
Dialysis Therapy, and published as an abstract ( J Jap Soc Dial Ther 37:1045, 2004 [suppl 1]).
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