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Body Composition and Cardiovascular Risk in Hemodialysis Patients
Body Composition and Cardiovascular Risk in Hemodialysis Patients Yoshiki Nishizawa, MD, PhD,* Tetsuo Shoji, MD, PhD,* and Eiji Ishimura, MD, PhD† Death rate is unacceptably elevated in end-stage renal disease patients treated with hemodialysis. Excessive body fat, or obesity, is the well-known risk factor for cardiovascular disease and other health problems in the general population. However, hemodialysis patients with a higher body mass index (BMI) have a lower risk of death, as shown by many studies. There are several explanations for the paradox of BMI in dialysis patients. First, although body mass is composed of fat mass and fat-free mass (lean mass), it is unknown which is more important, fat mass or lean mass, in predicting outcome of hemodialysis patients. Second, it is also possible that functions of adipose tissue are altered in renal failure so that accumulation of body fat leads to less atherogenicity and beneficial properties become predominant. Third, an increased fat mass may be protective against death after harmful events. In this article, we explore these possibilities using either the data of our own cohort of hemodialysis patients or the existing registry data of Japan. We conclude that in hemodialysis patients, fat mass rather than lean mass plays a protective role against mortality, that the fat mass–adipocytokine relationship is altered, and that a low BMI is associated with increased risk of fatality after cardiovascular events rather than the risk of occurrence of such events. © 2006 by the National Kidney Foundation, Inc.
M
ORTALITY RATE is unacceptably high in patients with renal failure treated with hemodialysis, and the risk of death from cardiovascular disease (CVD) is 10 to 30 times higher compared with that of the general population.1 To reduce such an elevated risk of death from CVD, we should attempt to control the risk factors contributing to mortality. However, previous epidemiologic studies in the dialysis population showed a strange relationship between risk factors and mortality risk. For example, a higher body mass index (BMI) is associated with a better survival in dialysis patients.2 In a recent review by Kalantar-Zadeh et al,3 death risk continues to decrease as BMI increases up to the highest category (⬎40) examined. This would not be easily *Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan. †Department of Nephrology, Osaka City University Graduate School of Medicine, Osaka, Japan. Address reprint requests to Yoshiki Nishizawa, MD, PhD, Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. E-mail: yynisizawa@med. osaka-cu.ac.jp © 2006 by the National Kidney Foundation, Inc. 1051-2276/06/1603-0015$32.00/0 doi:10.1053/j.jrn.2006.04.016
Journal of Renal Nutrition, Vol 16, No 3 ( July), 2006: pp 241-244
accepted by most physicians and other medical care providers because obesity is one of the established conditions associated with CVD and other health problems in the general population. Interestingly, such a paradoxical relationship has been also known for total cholesterol2,4 and blood pressure.5 Dialysis patients with a low cholesterol level or a low blood pressure have a high risk of all-cause and CVD mortality. These phenomena are called risk factor paradox6 or reverse epidemiology.7 The proper understanding of the reverse epidemiology is essential for the management of dialysis patients. In this article, we propose three possibilities that may explain the paradox of BMI in dialysis patients. The first possibility is that lean mass rather than fat mass may be more important. The second is a possible change in adipocyte function in renal failure. The third is that body fat may be protective against death after cardiovascular events. These possibilities are explored by using either the data of our own cohort of hemodialysis patients or the existing registry data of Japan.
Fat Mass or Lean Mass? Because body mass is composed of fat mass and fat-free mass (lean mass), BMI is affected by both of them. However, we tend to interpret changes 241
242
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in BMI as changes in body fat. The paradoxical and inverse relationship between BMI and mortality risk in dialysis patients may be explained by the change in lean mass rather than fat mass. To test this hypothesis, we evaluated the effects of fat and lean mass on outcome in a retrospective cohort of 808 hemodialysis patients who were examined with whole-body dual-energy X-ray absorptiometry (DEXA).8 Fat mass was directly measured by DEXA. Lean mass was defined as dry weight minus fat mass, because lean mass measured by DEXA is affected by excess body fluid. Fat mass and lean mass thus determined were standardized by height and expressed as fat mass index (FMI, measured in kg/m2) and lean mass index (LMI, measured in kg/m2), respectively. The mean follow-up period was 53 months. In this cohort, overall mortality was not predicted by LMI but by FMI independent of other confounding factors. Thus, increased fat mass rather than lean mass seemed to be protective against death in the dialysis patients. At least, increased fat mass did not predict increased risk of death from CVD in this cohort.
Change in Plasma Adipocytokine Profile in Renal Failure Then, why did increased fat mass not predict CVD mortality in the dialysis patients, and why did it predict better survival? It may be that fat accumulation does not induce as much atherogenicity in the dialysis patients as in the general population. Because the atherogenic effects of adipose tissue are attributed, at least in part, to bioactive substances derived from adipose tissue (adipocytokines), we compared the plasma adipocytokine profile between hemodialysis and healthy control groups.9 We measured plasma leptin and adiponectin as well as body fat by DEXA. Adiponectin is a plasma protein secreted exclusively by adipocytes with atherogenic properties. Plasma adiponectin showed an inverse association with fat mass in the healthy subjects. Surprisingly, the plasma adiponectin level in the hemodialysis patients was 2 to 3 times increased, and it had no significant association with fat mass. In addition, the adiponectin–leptin ratio was elevated in the hemodialysis patients. These data show that the plasma adipocytokine profile is altered and less atherogenic in the dialysis pa-
tients, and that the fat mass–adiponectin relationship is almost lost in this patient group. These results do not contradict previous observations. Zoccali et al10 reported that a low adiponectin level predicted the incidence of CVD events in a cohort of hemodialysis patients. Also, they showed correlations of adiponectin with some of the metabolic parameters in the baseline study. Although they showed a weak correlation between adiponectin and BMI, they did not measure fat mass. We11 previously reported that no adiponectin fragments were detected in uremic serum on gel filtration followed by immunoblotting. All of these findings are consistent with the view that plasma adiponectin is apparently intact and functioning as an antiatherogenic factor. However, our data9 indicate that the relationship between fat mass and adiponectin is diminished in renal failure, suggesting the alterations in adipose tissue functions in renal failure.
Risk Factors for Event Occurrence and for Fatality After Events Some patients can survive repeated heart attacks, whereas some patients die after a single event of myocardial infarction. Clearly, risk of death from CVD has two components; one is the risk for incidence of an event, and the other is the risk for death (fatality) after the event.6,12 This consideration is important in understanding the epidemiologic data. For example, the relative risk of death from CVD in dialysis patients is in the range of 10 to 30.1 However, the relative risk of occurrence of myocardial infarction13 or stroke14 can only explain a several-times increase of the risk. This was simply because of the increased risk of death (fatality) after CVD events. Survival after acute myocardial infarction was much shorter in dialysis patients as compared with the general population. Time to 50% mortality after myocardial infarction was 1 month for Japanese dialysis patients, whereas it was 7.3 years for the background population.13 Also, the risk of death within 30 days after stroke is 3 to 4 times higher in the dialysis patients than the background population.14 The risk of death from CVD is the product of the risk of event occurrence and the risk of death after the event. Therefore, previously known risk factors for death from CVD may be categorized into either of the two groups;
BODY COMPOSITION AND CARDIOVASCULAR
one is the risk factors for the event occurrence, and the other is the risk factors for the fatality.6,12 A low BMI is a predictor of a high risk of death from all causes and CVD in dialysis populations.2 We had a question regarding whether BMI is a predictor for the event occurrence or for an increased risk of fatality after an event. We could not find direct evidence in the literature to answer this question. However, the existing data give interesting information. The Japanese Society for Dialysis Therapy published survival analyses involving more than 30,000 dialysis patients in the annual report as of December 31, 2001.15 According to the report, the risk of death from myocardial infarction or congestive heart failure in 1 year was elevated among dialysis patients in low BMI categories. In contrast, a low BMI was not significantly associated with the risk of occurrence of new myocardial infarction in 1 year. Similar data were reported in the same issue of the Japanese Society for Dialysis Therapy annual report that a low serum albumin level was associated with increased risk of death from myocardial infarction or congestive heart failure but not with the risk of occurrence of new myocardial infarction. Taken together, these data indirectly but strongly indicate that the elevated risk of CVD death in the lean subjects was mainly attributable to the elevated risk of fatality after events. We interpret these data to indicate that malnutrition itself does not promote atherosclerosis and CVD, but malnourished dialysis patients are prone to die at a higher rate.
Changes in Fat Mass in Dialysis Patients Body fat increases after starting hemodialysis,16 and the increment is larger in those with a lower BMI and a lower serum albumin level, suggesting that malnutrition is improved during the first year of dialysis in these patients. However, male diabetic patients on dialysis tend to lose fat mass in the first year of dialysis treatment.17 On average, fat mass seems to increase for the initial 3 years of hemodialysis, but decreases thereafter.18 The decrease in fat mass was associated with an increased level of C-reactive protein,19 suggesting the fat mass loss is at least partly attributable to inflammation and wasting.
243
Conclusions As discussed above, increased fat mass does not seem hazardous for CVD in the dialysis population. Also, epidemiologic data indirectly suggest that body fat plays a protective role when dialysis patients experience CVD events. The paradox of BMI may arise in populations having an elevated risk of fatality who need sufficient energy for survival, such as dialysis patients, the elderly population,20 patients with congestive heart failure,21 and patients with acquired immunodeficiency syndrome.22 Although one study showed the change in the plasma adipocytokine profile in uremia, further studies are clearly needed to elucidate the mechanisms whereby adipose tissue exerts advantageous rather than disadvantageous influence on survival in some conditions. Also, we should seek strategies to improve nutritional status or to stop wasting in dialysis patients.
References 1. Levey AS, Beto JA, Coronado BE, et al: Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis 32:853-906, 1998 2. Degoulet P, Legrain M, Reach I, et al: Mortality risk factors in patients treated by chronic hemodialysis. Report of the Diaphane collaborative study. Nephron 31:103-110, 1982 3. Kalantar-Zadeh K, Abbott KC, Salahudeen AK, et al: Survival advantages of obesity in dialysis patients. Am J Clin Nutr 81:543-554, 2005 4. Lowrie EG, Lew NL: Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 15:458-482, 1990 5. Zager PG, Nikolic J, Brown RH, et al: “U” curve association of blood pressure and mortality in hemodialysis patients. Medical Directors of Dialysis Clinic, Inc. Kidney Int 54:561-569, 1998 6. Nishizawa Y, Shoji T, Ishimura E, et al: Paradox of risk factors for cardiovascular mortality in uremia: is a higher cholesterol level better for atherosclerosis in uremia? Am J Kidney Dis 38:S4-7, 2001 7. Kalantar-Zadeh K, Block G, Humphreys MH, et al: Reverse epidemiology of cardiovascular risk factors in maintenance dialysis patients. Kidney Int 63:793-808, 2003 8. Kakiya R, Shoji T, Tsujimoto Y, et al. Body fat mass and lean mass as predictors of survival in hemodialysis patients. Kidney Int (in press). 9. Shoji T, Shinohara K, Hatsuda S, et al: Altered relationship between body fat and plasma adiponectin in end-stage renal disease. Metabolism 54:330-334, 2005 10. Zoccali C, Mallamaci F, Tripepi G, et al: Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease. J Am Soc Nephrol 13:134-141, 2002
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11. Shoji T, Kimoto E, Shinohara K, et al: Molecular forms of adiponectin in uraemic plasma. Nephrol Dial Transplant 19: 1937-1938, 2004 12. Shoji T, Nishizawa Y: Chronic kidney disease as a metabolic syndrome with malnutrition—need for strict control of risk factors. Intern Med 44:179-187, 2005 13. Iseki K, Fukiyama K: Long-term prognosis and incidence of acute myocardial infarction in patients on chronic hemodialysis. The Okinawa Dialysis Study Group. Am J Kidney Dis 36:820-825, 2000 14. Iseki K, Fukiyama K: Clinical demographics and longterm prognosis after stroke in patients on chronic haemodialysis. The Okinawa Dialysis Study (OKIDS) Group. Nephrol Dial Transplant 15:1808-1813, 2000 15. Japanese Society for Dialysis Therapy: An overview of regular dialysis treatment in Japan (as of Dec 31, 2001). Tokyo, Japanese Society for Dialysis Therapy, 2002 16. Ishimura E, Okuno S, Kim M, et al: Increasing body fat mass in the first year of hemodialysis. J Am Soc Nephrol 12: 1921-1926, 2001
17. Okuno S, Ishimura E, Kim M, et al: Changes in body fat mass in male hemodialysis patients: a comparison between diabetics and nondiabetics. Am J Kidney Dis 38:S208-211, 2001 18. Ishimura E, Okuno S, Marukawa T, et al: Body fat mass in hemodialysis patients. Am J Kidney Dis 41:S137-141, 2003 19. Fujino Y, Ishimura E, Okuno S, et al: C-reactive protein is a significant predictor of decrease in fat mass in hemodialysis patients. Biomed Pharmacother 59:264-268, 2005 20. Kalmijn S, Curb JD, Rodriguez BL, et al: The association of body weight and anthropometry with mortality in elderly men: the Honolulu Heart Program. Int J Obes Relat Metab Disord 23:395-402, 1999 21. Kalantar-Zadeh K, Block G, Horwich T, et al: Reverse epidemiology of conventional cardiovascular risk factors in patients with chronic heart failure. J Am Coll Cardiol 43:14391444, 2004 22. Chlebowski RT, Grosvenor M, Lillington L, et al: Dietary intake and counseling, weight maintenance, and the course of HIV infection. J Am Diet Assoc 95:428-432; quiz 433-425, 1995
M
ORTALITY RATE is unacceptably high in patients with renal failure treated with hemodialysis, and the risk of death from cardiovascular disease (CVD) is 10 to 30 times higher compared with that of the general population.1 To reduce such an elevated risk of death from CVD, we should attempt to control the risk factors contributing to mortality. However, previous epidemiologic studies in the dialysis population showed a strange relationship between risk factors and mortality risk. For example, a higher body mass index (BMI) is associated with a better survival in dialysis patients.2 In a recent review by Kalantar-Zadeh et al,3 death risk continues to decrease as BMI increases up to the highest category (⬎40) examined. This would not be easily *Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan. †Department of Nephrology, Osaka City University Graduate School of Medicine, Osaka, Japan. Address reprint requests to Yoshiki Nishizawa, MD, PhD, Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. E-mail: yynisizawa@med. osaka-cu.ac.jp © 2006 by the National Kidney Foundation, Inc. 1051-2276/06/1603-0015$32.00/0 doi:10.1053/j.jrn.2006.04.016
Journal of Renal Nutrition, Vol 16, No 3 ( July), 2006: pp 241-244
accepted by most physicians and other medical care providers because obesity is one of the established conditions associated with CVD and other health problems in the general population. Interestingly, such a paradoxical relationship has been also known for total cholesterol2,4 and blood pressure.5 Dialysis patients with a low cholesterol level or a low blood pressure have a high risk of all-cause and CVD mortality. These phenomena are called risk factor paradox6 or reverse epidemiology.7 The proper understanding of the reverse epidemiology is essential for the management of dialysis patients. In this article, we propose three possibilities that may explain the paradox of BMI in dialysis patients. The first possibility is that lean mass rather than fat mass may be more important. The second is a possible change in adipocyte function in renal failure. The third is that body fat may be protective against death after cardiovascular events. These possibilities are explored by using either the data of our own cohort of hemodialysis patients or the existing registry data of Japan.
Fat Mass or Lean Mass? Because body mass is composed of fat mass and fat-free mass (lean mass), BMI is affected by both of them. However, we tend to interpret changes 241
242
NISHIZAWA ET AL
in BMI as changes in body fat. The paradoxical and inverse relationship between BMI and mortality risk in dialysis patients may be explained by the change in lean mass rather than fat mass. To test this hypothesis, we evaluated the effects of fat and lean mass on outcome in a retrospective cohort of 808 hemodialysis patients who were examined with whole-body dual-energy X-ray absorptiometry (DEXA).8 Fat mass was directly measured by DEXA. Lean mass was defined as dry weight minus fat mass, because lean mass measured by DEXA is affected by excess body fluid. Fat mass and lean mass thus determined were standardized by height and expressed as fat mass index (FMI, measured in kg/m2) and lean mass index (LMI, measured in kg/m2), respectively. The mean follow-up period was 53 months. In this cohort, overall mortality was not predicted by LMI but by FMI independent of other confounding factors. Thus, increased fat mass rather than lean mass seemed to be protective against death in the dialysis patients. At least, increased fat mass did not predict increased risk of death from CVD in this cohort.
Change in Plasma Adipocytokine Profile in Renal Failure Then, why did increased fat mass not predict CVD mortality in the dialysis patients, and why did it predict better survival? It may be that fat accumulation does not induce as much atherogenicity in the dialysis patients as in the general population. Because the atherogenic effects of adipose tissue are attributed, at least in part, to bioactive substances derived from adipose tissue (adipocytokines), we compared the plasma adipocytokine profile between hemodialysis and healthy control groups.9 We measured plasma leptin and adiponectin as well as body fat by DEXA. Adiponectin is a plasma protein secreted exclusively by adipocytes with atherogenic properties. Plasma adiponectin showed an inverse association with fat mass in the healthy subjects. Surprisingly, the plasma adiponectin level in the hemodialysis patients was 2 to 3 times increased, and it had no significant association with fat mass. In addition, the adiponectin–leptin ratio was elevated in the hemodialysis patients. These data show that the plasma adipocytokine profile is altered and less atherogenic in the dialysis pa-
tients, and that the fat mass–adiponectin relationship is almost lost in this patient group. These results do not contradict previous observations. Zoccali et al10 reported that a low adiponectin level predicted the incidence of CVD events in a cohort of hemodialysis patients. Also, they showed correlations of adiponectin with some of the metabolic parameters in the baseline study. Although they showed a weak correlation between adiponectin and BMI, they did not measure fat mass. We11 previously reported that no adiponectin fragments were detected in uremic serum on gel filtration followed by immunoblotting. All of these findings are consistent with the view that plasma adiponectin is apparently intact and functioning as an antiatherogenic factor. However, our data9 indicate that the relationship between fat mass and adiponectin is diminished in renal failure, suggesting the alterations in adipose tissue functions in renal failure.
Risk Factors for Event Occurrence and for Fatality After Events Some patients can survive repeated heart attacks, whereas some patients die after a single event of myocardial infarction. Clearly, risk of death from CVD has two components; one is the risk for incidence of an event, and the other is the risk for death (fatality) after the event.6,12 This consideration is important in understanding the epidemiologic data. For example, the relative risk of death from CVD in dialysis patients is in the range of 10 to 30.1 However, the relative risk of occurrence of myocardial infarction13 or stroke14 can only explain a several-times increase of the risk. This was simply because of the increased risk of death (fatality) after CVD events. Survival after acute myocardial infarction was much shorter in dialysis patients as compared with the general population. Time to 50% mortality after myocardial infarction was 1 month for Japanese dialysis patients, whereas it was 7.3 years for the background population.13 Also, the risk of death within 30 days after stroke is 3 to 4 times higher in the dialysis patients than the background population.14 The risk of death from CVD is the product of the risk of event occurrence and the risk of death after the event. Therefore, previously known risk factors for death from CVD may be categorized into either of the two groups;
BODY COMPOSITION AND CARDIOVASCULAR
one is the risk factors for the event occurrence, and the other is the risk factors for the fatality.6,12 A low BMI is a predictor of a high risk of death from all causes and CVD in dialysis populations.2 We had a question regarding whether BMI is a predictor for the event occurrence or for an increased risk of fatality after an event. We could not find direct evidence in the literature to answer this question. However, the existing data give interesting information. The Japanese Society for Dialysis Therapy published survival analyses involving more than 30,000 dialysis patients in the annual report as of December 31, 2001.15 According to the report, the risk of death from myocardial infarction or congestive heart failure in 1 year was elevated among dialysis patients in low BMI categories. In contrast, a low BMI was not significantly associated with the risk of occurrence of new myocardial infarction in 1 year. Similar data were reported in the same issue of the Japanese Society for Dialysis Therapy annual report that a low serum albumin level was associated with increased risk of death from myocardial infarction or congestive heart failure but not with the risk of occurrence of new myocardial infarction. Taken together, these data indirectly but strongly indicate that the elevated risk of CVD death in the lean subjects was mainly attributable to the elevated risk of fatality after events. We interpret these data to indicate that malnutrition itself does not promote atherosclerosis and CVD, but malnourished dialysis patients are prone to die at a higher rate.
Changes in Fat Mass in Dialysis Patients Body fat increases after starting hemodialysis,16 and the increment is larger in those with a lower BMI and a lower serum albumin level, suggesting that malnutrition is improved during the first year of dialysis in these patients. However, male diabetic patients on dialysis tend to lose fat mass in the first year of dialysis treatment.17 On average, fat mass seems to increase for the initial 3 years of hemodialysis, but decreases thereafter.18 The decrease in fat mass was associated with an increased level of C-reactive protein,19 suggesting the fat mass loss is at least partly attributable to inflammation and wasting.
243
Conclusions As discussed above, increased fat mass does not seem hazardous for CVD in the dialysis population. Also, epidemiologic data indirectly suggest that body fat plays a protective role when dialysis patients experience CVD events. The paradox of BMI may arise in populations having an elevated risk of fatality who need sufficient energy for survival, such as dialysis patients, the elderly population,20 patients with congestive heart failure,21 and patients with acquired immunodeficiency syndrome.22 Although one study showed the change in the plasma adipocytokine profile in uremia, further studies are clearly needed to elucidate the mechanisms whereby adipose tissue exerts advantageous rather than disadvantageous influence on survival in some conditions. Also, we should seek strategies to improve nutritional status or to stop wasting in dialysis patients.
References 1. Levey AS, Beto JA, Coronado BE, et al: Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis 32:853-906, 1998 2. Degoulet P, Legrain M, Reach I, et al: Mortality risk factors in patients treated by chronic hemodialysis. Report of the Diaphane collaborative study. Nephron 31:103-110, 1982 3. Kalantar-Zadeh K, Abbott KC, Salahudeen AK, et al: Survival advantages of obesity in dialysis patients. Am J Clin Nutr 81:543-554, 2005 4. Lowrie EG, Lew NL: Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 15:458-482, 1990 5. Zager PG, Nikolic J, Brown RH, et al: “U” curve association of blood pressure and mortality in hemodialysis patients. Medical Directors of Dialysis Clinic, Inc. Kidney Int 54:561-569, 1998 6. Nishizawa Y, Shoji T, Ishimura E, et al: Paradox of risk factors for cardiovascular mortality in uremia: is a higher cholesterol level better for atherosclerosis in uremia? Am J Kidney Dis 38:S4-7, 2001 7. Kalantar-Zadeh K, Block G, Humphreys MH, et al: Reverse epidemiology of cardiovascular risk factors in maintenance dialysis patients. Kidney Int 63:793-808, 2003 8. Kakiya R, Shoji T, Tsujimoto Y, et al. Body fat mass and lean mass as predictors of survival in hemodialysis patients. Kidney Int (in press). 9. Shoji T, Shinohara K, Hatsuda S, et al: Altered relationship between body fat and plasma adiponectin in end-stage renal disease. Metabolism 54:330-334, 2005 10. Zoccali C, Mallamaci F, Tripepi G, et al: Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease. J Am Soc Nephrol 13:134-141, 2002
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11. Shoji T, Kimoto E, Shinohara K, et al: Molecular forms of adiponectin in uraemic plasma. Nephrol Dial Transplant 19: 1937-1938, 2004 12. Shoji T, Nishizawa Y: Chronic kidney disease as a metabolic syndrome with malnutrition—need for strict control of risk factors. Intern Med 44:179-187, 2005 13. Iseki K, Fukiyama K: Long-term prognosis and incidence of acute myocardial infarction in patients on chronic hemodialysis. The Okinawa Dialysis Study Group. Am J Kidney Dis 36:820-825, 2000 14. Iseki K, Fukiyama K: Clinical demographics and longterm prognosis after stroke in patients on chronic haemodialysis. The Okinawa Dialysis Study (OKIDS) Group. Nephrol Dial Transplant 15:1808-1813, 2000 15. Japanese Society for Dialysis Therapy: An overview of regular dialysis treatment in Japan (as of Dec 31, 2001). Tokyo, Japanese Society for Dialysis Therapy, 2002 16. Ishimura E, Okuno S, Kim M, et al: Increasing body fat mass in the first year of hemodialysis. J Am Soc Nephrol 12: 1921-1926, 2001
17. Okuno S, Ishimura E, Kim M, et al: Changes in body fat mass in male hemodialysis patients: a comparison between diabetics and nondiabetics. Am J Kidney Dis 38:S208-211, 2001 18. Ishimura E, Okuno S, Marukawa T, et al: Body fat mass in hemodialysis patients. Am J Kidney Dis 41:S137-141, 2003 19. Fujino Y, Ishimura E, Okuno S, et al: C-reactive protein is a significant predictor of decrease in fat mass in hemodialysis patients. Biomed Pharmacother 59:264-268, 2005 20. Kalmijn S, Curb JD, Rodriguez BL, et al: The association of body weight and anthropometry with mortality in elderly men: the Honolulu Heart Program. Int J Obes Relat Metab Disord 23:395-402, 1999 21. Kalantar-Zadeh K, Block G, Horwich T, et al: Reverse epidemiology of conventional cardiovascular risk factors in patients with chronic heart failure. J Am Coll Cardiol 43:14391444, 2004 22. Chlebowski RT, Grosvenor M, Lillington L, et al: Dietary intake and counseling, weight maintenance, and the course of HIV infection. J Am Diet Assoc 95:428-432; quiz 433-425, 1995