ICURT PROCEEDINGS
Endocrine and Metabolic Changes Affecting Cardiovascular Disease in Dialysis Patients Tetsuo Shoji, MD, PhD,* Masanori Emoto, MD, PhD,† Yoshiki Nishizawa, MD, PhD,† and Masaaki Inaba, MD, PhD† Protein–energy wasting plays an important role in the increased risk of mortality from cardiovascular disease in people with end-stage renal disease. Because protein–energy wasting is a condition of imbalance between anabolism and catabolism, endocrine and metabolic alterations that regulate such balance should be the possible target of intervention. Subjects with end-stage renal disease exhibit various changes in thyroid function, gonadal hormones, adrenal androgen, glucose metabolism, dyslipidemia, fatty acid composition, cholesterol absorption, and vitamin D. In this article, we briefly review the association of these alterations with mortality and cardiovascular disease in hemodialysis patients. Although some of them may be the adaptive response to the catabolic condition, these observational data are useful for risk stratification of patients and also for providing new ideas for possible prevention. Ó 2014 by the National Kidney Foundation, Inc. All rights reserved.
R
ISK OF DEATH from cardiovascular disease (CVD) is markedly elevated in patients with chronic kidney disease (CKD), especially in those with end-stage renal disease. The extremely high risk of CVD death can be explained by the synergism of increased risk of incidence of CVD and increased risk of fatality after CVD events.1,2 Protein–energy wasting,3 not necessarily associated with inflammation, is an important predictor of increased risk of mortality in dialysis patients. Because protein–energy wasting is a condition of imbalance between anabolism and catabolism, endocrine and metabolic alterations that regulate such balance should be the possible target for possible intervention to improve the clinical outcome of these patients. In this article, we review epidemiologic association of some parameters of endocrine function and metabolism in CKD with CVD and mortality to search for interventional targets.
Thyroid Function Low T3 syndrome, or nonthyroidal illness syndrome, is a condition in which serum triiodothyroxin (T3) level is lowered, whereas compensatory increase of thyroid stimulating hormone from the pituitary gland does not occur in sick *
Department of Geriatrics and Vascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan. † Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan. Financial Disclosure: See Acknowledgments on page XXX. Address correspondence to Tetsuo Shoji, MD, PhD, Department of Geriatrics and Vascular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. E-mail:
[email protected] Ó
2014 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 http://dx.doi.org/10.1053/j.jrn.2014.10.018
Journal of Renal Nutrition, Vol -, No - (-), 2014: pp 1-3
patients including those with end-stage renal disease. According to several studies,4,5 low serum free T3 levels are independent predictor of all-cause mortality in dialysis patients. Because low T3 syndrome, by reducing basal metabolic rate, is considered as an adaptive response to catabolic conditions, replacement of T3 it is not recommended.
Gonadal Hormones Testosterone is one of the powerful anabolic hormones that increases muscle mass. Because sarcopenia is a condition associated with poor clinical outcomes, testosterone presumably is an important target for clinical research. Carrero et al6 reported that low serum testosterone was predictive of increased mortality in male dialysis patients.
Adrenal Androgen Dehydroepiandrosterone-sulfate (DHEA-S) is the most abundant steroid in serum, having anabolic properties. DHEA-S and DHEA are secreted from zona reticularis of the adrenal gland, and they are interconverted, and DHEA is metabolized into testosterone and estradiol. Because receptors specific to DHEA(-S) have not been identified, most of actions of DHEA(-S) is considered to be mediated by the androgen receptor and the estrogen receptor, in addition to the activation of the peroxisome proliferator–activated receptor-a, pregnane X receptor and other pathways. Kakiya et al.7 reported that hemodialysis patients had serum DHEA-S levels that were almost 50% lower than those of healthy controls, and that DHEA-S levels were different between male and female subjects, with lower levels in females. In their cohort, named DREAM (dialysis-related endocrine and metabolic changes affecting CVD), a low level of DHEA-S was found to be a significant 1
2
SHOJI ET AL
predictor of poor outcomes such as all-cause mortality, total CVD, and atherosclerotic CVD, even after adjustment for possible confounders, in male hemodialysis patients, but not in female patients.
Another trial with fish oil19 extended the time to occlusion and/or intervention of synthetic hemodialysis graft as a secondary end point.
Glucose Metabolism
Cholesterol absorption appears to be increased in dialysis patients20 and in those with decreased glomerular filtration rate.21 Rogacev et al.20 showed that high cholesterol absorbers had a higher risk of all-cause mortality in their hemodialysis cohort.
Cholesterol Absorption Morioka et al.8 and Oomichi et al.9 are the first that reported that high hemoglobin A1c (HbA1c) levels were independent predictor of all-cause mortality in incident and prevalent hemodialysis patients, respectively, with type 2 diabetes mellitus. Recent larger studies10 revealed that both low and high HbA1c levels are associated with higher mortality risk in dialysis cohorts. The elevated risk associated with low HbA1c may be explained by reduced intake, bleeding, and others. In nondiabetic hemodialysis patients, insulin resistance may be related with CVD. Shinohara et al11 showed that a higher homeostasis model assessment index, an index of insulin resistance, was an independent predictor of CVDrelated mortality but not of non-CVD–related mortality in their hemodialysis cohort.
Dyslipidemia Lower serum cholesterol levels are known to predict higher risk of all-cause death in Western hemodialysis cohorts.12 Three trials failed to reduce the risk of CVD by treatment with a statin13,14 or statin-ezetimibe combination15 in hemodialysis patients. By contrast, in Japanese hemodialysis patients, the risk of incident myocardial infarction was higher in those with higher non–highdensity lipoprotein cholesterol levels and in those with lower high-density lipoprotein-cholesterol levels.16 There may be some difference in the pathology of vascular disease between Western and Japanese dialysis patients.
Fatty Acid Composition Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are in the n-3 (omega 3) polyunsaturated fatty acids (PUFAs), whereas arachidonic acid (AA) is in the n-6 (omega 6) family. Generally, AA-derived eicosanoids are proinflammatory, whereas EPA-derived eicosanoids are less inflammatory and antagonize the effects of AAderived counterparts. Also, DHA is the precursor of anti-inflammatory substances. Therefore, the ratios of EPA, DHA, or (EPA 1 DHA) to AA serve as the index for anti-inflammatory function of PUFAs. Shoji et al.17 measured serum PUFA profile showing that serum (EPA 1 DHA)-to-AA ratio was lower in hemodialysis patients than healthy controls. Also, a low (EPA 1 DHA)-to-AA ratio was an independent predictor of CVD events. EPA-to-AA ratio and DHA-to-AA ratio were also predictive of CVD risk in the hemodialysis cohort. A previous trial with n-3 PUFA in dialysis patients18 showed that risk of myocardial infarction was decreased, although it was not the primary endpoint.
Vitamin D and Calcium-Phosphate Homeostasis Vitamin D is one of the key players in the homeostasis of calcium and phosphate. In addition, vitamin D receptor activation appears to have nonskeletal functions that are potentially protective against CVD including suppression of the renin-angiotensin system, modulation of immune functions, and anti-inflammation. Thus, deficiency of active vitamin D may explain uremia-related complications at least partly. Shoji et al.22 reported that use of active vitamin D was associated with lower risk of CVD-related death in a cohort of 242 prevalent hemodialysis patients. As reviewed by others,23 later studies confirmed this observation reporting the use of vitamin D receptor activator (VDRA) was an independent predictor of all-cause mortality as the end point in much larger cohort of hemodialysis patients. In a cohort of 49,590 prevalent hemodialysis patients in the Japan Renal Data Registry conducted by the Japanese Society for Dialysis Therapy, the use of VDRA was associated with a low risk of all-cause mortality as previously reported. In addition, the use of VDRA was also associated with the risk of incident CVD as defined by composite of myocardial infarction, cerebral infarction, and cerebral hemorrhage, whereas it was not significantly associated with death after CVD events.
Intervention Trials With VDRA A few interventional trials have been reported that addressed the possible effects of VDRA on cardiovascular system in subjects with CKD. Thadhani et al.24 performed a randomized controlled trial PRIMO in subjects with CKD stages 3 to 4 and found no significant effect on left ventricular mass index measured by magnetic resonance imaging. Wang et al.25 reported very similar observations in the OPERA trial in CKD stages 3 to 5 patients, with no significant effect on left ventricular mass index. Interestingly, CVD events as one of the secondary end points were less in the paricalcitol group than the placebo group in the PRIMO trial. Also, hospitalization as one of the adverse events was fewer in the paricalcitol group than the placebo group in the OPERA trial. We test the hypothesis that use of VDRA reduces CVD events in hemodialysis patients in our randomized
CARDIOVASCULAR DISEASES IN DIALYSIS PATIENTS
controlled trial J-DAVID (Japan Dialysis Active Vitamin D).26 A total of 976 prevalent hemodialysis patients with intact PTH level of 180 pg/mL or lower were randomly allocated to 1 of the 2 treatment arms; use of oral alfacalcidol with a starting dose of 0.5 mg/day or nonuse of any VDRA. The primary end point is the composite of coronary, cerebral, and peripheral artery events. The secondary end point is all-cause mortality. The subjects will be followed-up for 4 years until April 2015. The results will be analyzed by the intention-to-treatment approach.
Conclusions Some of the endocrine and metabolic alterations are independently associated with CVD in hemodialysis patients as shown by observational studies. These data may be useful in risk stratification of dialysis patients. Interventional trials are needed to show whether modification of the endocrine and metabolic changes in dialysis patients could improve their clinical outcomes.
Acknowledgments Y.N. and M.I. declare that they have no conflict of interest. Tetsu Shoji: Honoraria for lecturing from Astellas, Bayer, Chugai, Daiichi-Sankyo, Kowa, Kyowa Hakko Kirin, Mochida, MSD, Pfizer, Sanofi, Shionogi, Taisho, and Takeda. Masanori Emoto: Honoraria for lectures from Boehringer-Ingelheim, Eli Lilly, Tanabe-Mitsubishi; Joint research grants from Nikkiso; Scholarship grants from Boehringer-Ingelheim, Taisho-Toyama.
References 1. Nishizawa Y, Shoji T, Ishimura E, Inaba M, Morii H. Paradox of risk factors for cardiovascular mortality in uremia: is a higher cholesterol level better for atherosclerosis in uremia? Am J Kidney Dis. 2001;38(4 suppl 1):S4-S7. 2. Shoji T, Nishizawa Y. Chronic kidney disease as a metabolic syndrome with malnutrition–need for strict control of risk factors. Intern Med. 2005;44:179-187. 3. Fouque D, Kalantar-Zadeh K, Kopple J, et al. A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease. Kidney Int. 2008;73:391-398. 4. Zoccali C, Mallamaci F, Tripepi G, Cutrupi S, Pizzini P. Low triiodothyronine and survival in end-stage renal disease. Kidney Int. 2006;70:523-528. 5. Carrero JJ, Qureshi AR, Axelsson J, et al. Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J Intern Med. 2007;262:690-701. 6. Carrero JJ, Qureshi AR, Parini P, et al. Low serum testosterone increases mortality risk among male dialysis patients. J Am Soc Nephrol. 2009;20:613-620. 7. Kakiya R, Shoji T, Hayashi T, et al. Decreased serum adrenal androgen dehydroepiandrosterone sulfate and mortality in hemodialysis patients. Nephrol Dial Transplant. 2012;27:3915-3922. 8. Morioka T, Emoto M, Tabata T, et al. Glycemic control is a predictor of survival for diabetic patients on hemodialysis. Diabetes Care. 2001;24:909-913.
3
9. Oomichi T, Emoto M, Tabata T, et al. Impact of glycemic control on survival of diabetic patients on chronic regular hemodialysis: a 7-year observational study. Diabetes Care. 2006;29:1496-1500. 10. Kim Y, Park JC, Molnar MZ, et al. Correlates of low hemoglobin A1c in maintenance hemodialysis patients. Int Urol Nephrol. 2013;45:1079-1090. 11. Shinohara K, Shoji T, Emoto M, et al. Insulin resistance as an independent predictor of cardiovascular mortality in patients with end-stage renal disease. J Am Soc Nephrol. 2002;13:1894-1900. 12. 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. 1990;15:458-482. 13. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353:238-248. 14. Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360:1395-1407. 15. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebocontrolled trial. Lancet. 2011;377:2181-2192. 16. Shoji T, Masakane I, Watanabe Y, Iseki K, Tsubakihara Y. Elevated non-high-density lipoprotein cholesterol (non-HDL-C) predicts atherosclerotic cardiovascular events in hemodialysis patients. Clin J Am Soc Nephrol. 2011;6:1112-1120. 17. Shoji T, Kakiya R, Hayashi T, et al. Serum n-3 and n-6 polyunsaturated fatty acid profile as an independent predictor of cardiovascular events in hemodialysis patients. Am J Kidney Dis. 2013;62:568-576. 18. Svensson M, Schmidt EB, Jorgensen KA, Christensen JH. N-3 fatty acids as secondary prevention against cardiovascular events in patients who undergo chronic hemodialysis: a randomized, placebo-controlled intervention trial. Clin J Am Soc Nephrol. 2006;1:780-786. 19. Lok CE, Moist L, Hemmelgarn BR, et al. Effect of fish oil supplementation on graft patency and cardiovascular events among patients with new synthetic arteriovenous hemodialysis grafts: a randomized controlled trial. JAMA. 2012;307:1809-1816. 20. Rogacev KS, Pinsdorf T, Weingartner O, et al. Cholesterol synthesis, cholesterol absorption, and mortality in hemodialysis patients. Clin J Am Soc Nephrol. 2012;7:943-948. 21. Sonoda M, Shoji T, Kimoto E, et al. Kidney function, cholesterol absorption and remnant lipoprotein accumulation in patients with diabetes mellitus. J Atheroscler Thromb. 2013;21:346-354. 22. Shoji T, Shinohara K, Kimoto E, et al. Lower risk for cardiovascular mortality in oral 1alpha-hydroxy vitamin D3 users in a haemodialysis population. Nephrol Dial Transplant. 2004;19:179-184. 23. Kovesdy CP, Kalantar-Zadeh K. Vitamin D receptor activation and survival in chronic kidney disease. Kidney Int. 2008;73:1355-1363. 24. Thadhani R, Appelbaum E, Pritchett Y, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. JAMA. 2012;307:674-684. 25. Wang AY, Fang F, Chan J, et al. Effect of paricalcitol on left ventricular mass and function in CKD–the OPERA trial. J Am Soc Nephrol. 2014;25:175-186. 26. Prospective, randomized, open-label, blinded-endpoint trial to examine the effect of active vitamin D on cardiovascular events in hemodialysis patients: Japan Dialysis Active Vitamin D trial (J-DAVID). https://upload. umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function5brows&action5brows&type 5summary&recptno5R000001456&language5E. Accessed March 10, 2014.
Endocrine and Metabolic Changes Affecting Cardiovascular Disease in Dialysis Patients Tetsuo Shoji, MD, PhD,* Masanori Emoto, MD, PhD,† Yoshiki Nishizawa, MD, PhD,† and Masaaki Inaba, MD, PhD† Protein–energy wasting plays an important role in the increased risk of mortality from cardiovascular disease in people with end-stage renal disease. Because protein–energy wasting is a condition of imbalance between anabolism and catabolism, endocrine and metabolic alterations that regulate such balance should be the possible target of intervention. Subjects with end-stage renal disease exhibit various changes in thyroid function, gonadal hormones, adrenal androgen, glucose metabolism, dyslipidemia, fatty acid composition, cholesterol absorption, and vitamin D. In this article, we briefly review the association of these alterations with mortality and cardiovascular disease in hemodialysis patients. Although some of them may be the adaptive response to the catabolic condition, these observational data are useful for risk stratification of patients and also for providing new ideas for possible prevention. Ó 2014 by the National Kidney Foundation, Inc. All rights reserved.
R
ISK OF DEATH from cardiovascular disease (CVD) is markedly elevated in patients with chronic kidney disease (CKD), especially in those with end-stage renal disease. The extremely high risk of CVD death can be explained by the synergism of increased risk of incidence of CVD and increased risk of fatality after CVD events.1,2 Protein–energy wasting,3 not necessarily associated with inflammation, is an important predictor of increased risk of mortality in dialysis patients. Because protein–energy wasting is a condition of imbalance between anabolism and catabolism, endocrine and metabolic alterations that regulate such balance should be the possible target for possible intervention to improve the clinical outcome of these patients. In this article, we review epidemiologic association of some parameters of endocrine function and metabolism in CKD with CVD and mortality to search for interventional targets.
Thyroid Function Low T3 syndrome, or nonthyroidal illness syndrome, is a condition in which serum triiodothyroxin (T3) level is lowered, whereas compensatory increase of thyroid stimulating hormone from the pituitary gland does not occur in sick *
Department of Geriatrics and Vascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan. † Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan. Financial Disclosure: See Acknowledgments on page XXX. Address correspondence to Tetsuo Shoji, MD, PhD, Department of Geriatrics and Vascular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. E-mail:
[email protected] Ó
2014 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 http://dx.doi.org/10.1053/j.jrn.2014.10.018
Journal of Renal Nutrition, Vol -, No - (-), 2014: pp 1-3
patients including those with end-stage renal disease. According to several studies,4,5 low serum free T3 levels are independent predictor of all-cause mortality in dialysis patients. Because low T3 syndrome, by reducing basal metabolic rate, is considered as an adaptive response to catabolic conditions, replacement of T3 it is not recommended.
Gonadal Hormones Testosterone is one of the powerful anabolic hormones that increases muscle mass. Because sarcopenia is a condition associated with poor clinical outcomes, testosterone presumably is an important target for clinical research. Carrero et al6 reported that low serum testosterone was predictive of increased mortality in male dialysis patients.
Adrenal Androgen Dehydroepiandrosterone-sulfate (DHEA-S) is the most abundant steroid in serum, having anabolic properties. DHEA-S and DHEA are secreted from zona reticularis of the adrenal gland, and they are interconverted, and DHEA is metabolized into testosterone and estradiol. Because receptors specific to DHEA(-S) have not been identified, most of actions of DHEA(-S) is considered to be mediated by the androgen receptor and the estrogen receptor, in addition to the activation of the peroxisome proliferator–activated receptor-a, pregnane X receptor and other pathways. Kakiya et al.7 reported that hemodialysis patients had serum DHEA-S levels that were almost 50% lower than those of healthy controls, and that DHEA-S levels were different between male and female subjects, with lower levels in females. In their cohort, named DREAM (dialysis-related endocrine and metabolic changes affecting CVD), a low level of DHEA-S was found to be a significant 1
2
SHOJI ET AL
predictor of poor outcomes such as all-cause mortality, total CVD, and atherosclerotic CVD, even after adjustment for possible confounders, in male hemodialysis patients, but not in female patients.
Another trial with fish oil19 extended the time to occlusion and/or intervention of synthetic hemodialysis graft as a secondary end point.
Glucose Metabolism
Cholesterol absorption appears to be increased in dialysis patients20 and in those with decreased glomerular filtration rate.21 Rogacev et al.20 showed that high cholesterol absorbers had a higher risk of all-cause mortality in their hemodialysis cohort.
Cholesterol Absorption Morioka et al.8 and Oomichi et al.9 are the first that reported that high hemoglobin A1c (HbA1c) levels were independent predictor of all-cause mortality in incident and prevalent hemodialysis patients, respectively, with type 2 diabetes mellitus. Recent larger studies10 revealed that both low and high HbA1c levels are associated with higher mortality risk in dialysis cohorts. The elevated risk associated with low HbA1c may be explained by reduced intake, bleeding, and others. In nondiabetic hemodialysis patients, insulin resistance may be related with CVD. Shinohara et al11 showed that a higher homeostasis model assessment index, an index of insulin resistance, was an independent predictor of CVDrelated mortality but not of non-CVD–related mortality in their hemodialysis cohort.
Dyslipidemia Lower serum cholesterol levels are known to predict higher risk of all-cause death in Western hemodialysis cohorts.12 Three trials failed to reduce the risk of CVD by treatment with a statin13,14 or statin-ezetimibe combination15 in hemodialysis patients. By contrast, in Japanese hemodialysis patients, the risk of incident myocardial infarction was higher in those with higher non–highdensity lipoprotein cholesterol levels and in those with lower high-density lipoprotein-cholesterol levels.16 There may be some difference in the pathology of vascular disease between Western and Japanese dialysis patients.
Fatty Acid Composition Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are in the n-3 (omega 3) polyunsaturated fatty acids (PUFAs), whereas arachidonic acid (AA) is in the n-6 (omega 6) family. Generally, AA-derived eicosanoids are proinflammatory, whereas EPA-derived eicosanoids are less inflammatory and antagonize the effects of AAderived counterparts. Also, DHA is the precursor of anti-inflammatory substances. Therefore, the ratios of EPA, DHA, or (EPA 1 DHA) to AA serve as the index for anti-inflammatory function of PUFAs. Shoji et al.17 measured serum PUFA profile showing that serum (EPA 1 DHA)-to-AA ratio was lower in hemodialysis patients than healthy controls. Also, a low (EPA 1 DHA)-to-AA ratio was an independent predictor of CVD events. EPA-to-AA ratio and DHA-to-AA ratio were also predictive of CVD risk in the hemodialysis cohort. A previous trial with n-3 PUFA in dialysis patients18 showed that risk of myocardial infarction was decreased, although it was not the primary endpoint.
Vitamin D and Calcium-Phosphate Homeostasis Vitamin D is one of the key players in the homeostasis of calcium and phosphate. In addition, vitamin D receptor activation appears to have nonskeletal functions that are potentially protective against CVD including suppression of the renin-angiotensin system, modulation of immune functions, and anti-inflammation. Thus, deficiency of active vitamin D may explain uremia-related complications at least partly. Shoji et al.22 reported that use of active vitamin D was associated with lower risk of CVD-related death in a cohort of 242 prevalent hemodialysis patients. As reviewed by others,23 later studies confirmed this observation reporting the use of vitamin D receptor activator (VDRA) was an independent predictor of all-cause mortality as the end point in much larger cohort of hemodialysis patients. In a cohort of 49,590 prevalent hemodialysis patients in the Japan Renal Data Registry conducted by the Japanese Society for Dialysis Therapy, the use of VDRA was associated with a low risk of all-cause mortality as previously reported. In addition, the use of VDRA was also associated with the risk of incident CVD as defined by composite of myocardial infarction, cerebral infarction, and cerebral hemorrhage, whereas it was not significantly associated with death after CVD events.
Intervention Trials With VDRA A few interventional trials have been reported that addressed the possible effects of VDRA on cardiovascular system in subjects with CKD. Thadhani et al.24 performed a randomized controlled trial PRIMO in subjects with CKD stages 3 to 4 and found no significant effect on left ventricular mass index measured by magnetic resonance imaging. Wang et al.25 reported very similar observations in the OPERA trial in CKD stages 3 to 5 patients, with no significant effect on left ventricular mass index. Interestingly, CVD events as one of the secondary end points were less in the paricalcitol group than the placebo group in the PRIMO trial. Also, hospitalization as one of the adverse events was fewer in the paricalcitol group than the placebo group in the OPERA trial. We test the hypothesis that use of VDRA reduces CVD events in hemodialysis patients in our randomized
CARDIOVASCULAR DISEASES IN DIALYSIS PATIENTS
controlled trial J-DAVID (Japan Dialysis Active Vitamin D).26 A total of 976 prevalent hemodialysis patients with intact PTH level of 180 pg/mL or lower were randomly allocated to 1 of the 2 treatment arms; use of oral alfacalcidol with a starting dose of 0.5 mg/day or nonuse of any VDRA. The primary end point is the composite of coronary, cerebral, and peripheral artery events. The secondary end point is all-cause mortality. The subjects will be followed-up for 4 years until April 2015. The results will be analyzed by the intention-to-treatment approach.
Conclusions Some of the endocrine and metabolic alterations are independently associated with CVD in hemodialysis patients as shown by observational studies. These data may be useful in risk stratification of dialysis patients. Interventional trials are needed to show whether modification of the endocrine and metabolic changes in dialysis patients could improve their clinical outcomes.
Acknowledgments Y.N. and M.I. declare that they have no conflict of interest. Tetsu Shoji: Honoraria for lecturing from Astellas, Bayer, Chugai, Daiichi-Sankyo, Kowa, Kyowa Hakko Kirin, Mochida, MSD, Pfizer, Sanofi, Shionogi, Taisho, and Takeda. Masanori Emoto: Honoraria for lectures from Boehringer-Ingelheim, Eli Lilly, Tanabe-Mitsubishi; Joint research grants from Nikkiso; Scholarship grants from Boehringer-Ingelheim, Taisho-Toyama.
References 1. Nishizawa Y, Shoji T, Ishimura E, Inaba M, Morii H. Paradox of risk factors for cardiovascular mortality in uremia: is a higher cholesterol level better for atherosclerosis in uremia? Am J Kidney Dis. 2001;38(4 suppl 1):S4-S7. 2. Shoji T, Nishizawa Y. Chronic kidney disease as a metabolic syndrome with malnutrition–need for strict control of risk factors. Intern Med. 2005;44:179-187. 3. Fouque D, Kalantar-Zadeh K, Kopple J, et al. A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease. Kidney Int. 2008;73:391-398. 4. Zoccali C, Mallamaci F, Tripepi G, Cutrupi S, Pizzini P. Low triiodothyronine and survival in end-stage renal disease. Kidney Int. 2006;70:523-528. 5. Carrero JJ, Qureshi AR, Axelsson J, et al. Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J Intern Med. 2007;262:690-701. 6. Carrero JJ, Qureshi AR, Parini P, et al. Low serum testosterone increases mortality risk among male dialysis patients. J Am Soc Nephrol. 2009;20:613-620. 7. Kakiya R, Shoji T, Hayashi T, et al. Decreased serum adrenal androgen dehydroepiandrosterone sulfate and mortality in hemodialysis patients. Nephrol Dial Transplant. 2012;27:3915-3922. 8. Morioka T, Emoto M, Tabata T, et al. Glycemic control is a predictor of survival for diabetic patients on hemodialysis. Diabetes Care. 2001;24:909-913.
3
9. Oomichi T, Emoto M, Tabata T, et al. Impact of glycemic control on survival of diabetic patients on chronic regular hemodialysis: a 7-year observational study. Diabetes Care. 2006;29:1496-1500. 10. Kim Y, Park JC, Molnar MZ, et al. Correlates of low hemoglobin A1c in maintenance hemodialysis patients. Int Urol Nephrol. 2013;45:1079-1090. 11. Shinohara K, Shoji T, Emoto M, et al. Insulin resistance as an independent predictor of cardiovascular mortality in patients with end-stage renal disease. J Am Soc Nephrol. 2002;13:1894-1900. 12. 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. 1990;15:458-482. 13. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353:238-248. 14. Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360:1395-1407. 15. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebocontrolled trial. Lancet. 2011;377:2181-2192. 16. Shoji T, Masakane I, Watanabe Y, Iseki K, Tsubakihara Y. Elevated non-high-density lipoprotein cholesterol (non-HDL-C) predicts atherosclerotic cardiovascular events in hemodialysis patients. Clin J Am Soc Nephrol. 2011;6:1112-1120. 17. Shoji T, Kakiya R, Hayashi T, et al. Serum n-3 and n-6 polyunsaturated fatty acid profile as an independent predictor of cardiovascular events in hemodialysis patients. Am J Kidney Dis. 2013;62:568-576. 18. Svensson M, Schmidt EB, Jorgensen KA, Christensen JH. N-3 fatty acids as secondary prevention against cardiovascular events in patients who undergo chronic hemodialysis: a randomized, placebo-controlled intervention trial. Clin J Am Soc Nephrol. 2006;1:780-786. 19. Lok CE, Moist L, Hemmelgarn BR, et al. Effect of fish oil supplementation on graft patency and cardiovascular events among patients with new synthetic arteriovenous hemodialysis grafts: a randomized controlled trial. JAMA. 2012;307:1809-1816. 20. Rogacev KS, Pinsdorf T, Weingartner O, et al. Cholesterol synthesis, cholesterol absorption, and mortality in hemodialysis patients. Clin J Am Soc Nephrol. 2012;7:943-948. 21. Sonoda M, Shoji T, Kimoto E, et al. Kidney function, cholesterol absorption and remnant lipoprotein accumulation in patients with diabetes mellitus. J Atheroscler Thromb. 2013;21:346-354. 22. Shoji T, Shinohara K, Kimoto E, et al. Lower risk for cardiovascular mortality in oral 1alpha-hydroxy vitamin D3 users in a haemodialysis population. Nephrol Dial Transplant. 2004;19:179-184. 23. Kovesdy CP, Kalantar-Zadeh K. Vitamin D receptor activation and survival in chronic kidney disease. Kidney Int. 2008;73:1355-1363. 24. Thadhani R, Appelbaum E, Pritchett Y, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. JAMA. 2012;307:674-684. 25. Wang AY, Fang F, Chan J, et al. Effect of paricalcitol on left ventricular mass and function in CKD–the OPERA trial. J Am Soc Nephrol. 2014;25:175-186. 26. Prospective, randomized, open-label, blinded-endpoint trial to examine the effect of active vitamin D on cardiovascular events in hemodialysis patients: Japan Dialysis Active Vitamin D trial (J-DAVID). https://upload. umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function5brows&action5brows&type 5summary&recptno5R000001456&language5E. Accessed March 10, 2014.
