- Email: [email protected]
Coronary Artery Calcification Score is Associated With Mortality in Japanese Hemodialysis Patients
ORIGINAL RESEARCH
Coronary Artery Calcification Score is Associated With Mortality in Japanese Hemodialysis Patients Yasuhiko Shimoyama, MD, PhD,* Yoshinari Tsuruta, MD, PhD,† and Toshimitsu Niwa, MD, PhD* Objective: Coronary artery calcification has been associated with higher mortality in coronary artery disease and chronic kidney disease. This study aimed to correlate coronary artery calcification score (CACS) with all-cause and cardiovascular mortalities in hemodialysis (HD) patients. Design, Setting, Subjects: A survival analysis was conducted in 200 HD patients. CACS was assessed by multidetector-row computed tomography and stratified as tertiles: group 1 (0105 U), group 2 (1101067 U), and group 3 (109415481 U). The duration of follow-up was 7 years and 4 months. Kaplan–Meier method and Cox proportional hazard analysis adjusted for age and HD duration were performed to examine the impact of CACS on survival. Main Outcome Measure: All-cause and cardiovascular mortalities were measured. Results: The cumulative all-cause and cardiovascular mortalities of group 1 were significantly lower than those of groups 2 and 3 (all-cause mortality: 7.6% vs. 43.3% and 52.2%, respectively, cardiovascular mortality: 3.0% vs. 22.4% and 26.9%, respectively). Cox proportional hazard analysis adjusted for age and HD duration revealed that all-cause and cardiovascular mortalities of group 1 were significantly lower than those of groups 2 and 3. Conclusion: CACS is helpful to predict prognosis of HD patients independently of age and HD duration. Ó 2012 by the National Kidney Foundation, Inc. All rights reserved.
C
ORONARY ARTERY DISEASE carries an enhanced risk of mortality in hemodialysis (HD) patients compared with that in general population.1,2 Vascular calcification has been recognized as a predictive factor of mortality, with a reported prevalence of 60% to 90% in chronic kidney disease (CKD) patients.3,4 Therefore, the early detection and treatment of coronary artery disease could improve the survival rate of HD patients. Abnormal mineral metabolism, such as
*Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Japan. †Department of Nephrology, Meiyo Clinic, Aichi, Japan. Financial Disclosure: The authors declare that they have no relevant financial interests. Address reprint requests to Toshimitsu Niwa, MD, PhD, Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 4668550, Japan. E-mail: [email protected] Ó 2012 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 doi:10.1053/j.jrn.2011.10.024
Journal of Renal Nutrition, Vol 22, No 1 (January), 2012: pp 139-142
hyperphosphatemia and calcium overload, and use of phosphate binders also have been associated with arterial media calcification with great impact on cardiovascular mortality in end-stage renal disease (ESRD).5 Noninvasive imaging approaches and calcification artery scores have been used to detect and measure vascular calcification. Multidetectorrow computed tomography is the most common method now available to quantify vascular calcification.6-8 Coronary artery calcification score (CACS) in asymptomatic subjects is a stronger predictor of myocardial infarction and coronary artery death than traditional risk factors such as age, smoking, and diabetes mellitus.9,10 The present study aimed to correlate CACS with all-cause and cardiovascular mortality in HD patients.
Materials and Methods Subjects This study included 200 Japanese subjects (110 men and 90 women) treated with HD at Meiyo 139
140
SHIMOYAMA ET AL
Clinic, Aichi, Japan.11 The mean age at start of this study was 60.0 6 13.1 (mean 6 standard deviation) years, ranging from 25 to 88 years, and the duration of HD was 9.25 6 8.37 (mean 6 standard deviation) years, ranging from 0.3 to 33.6 years.
Laboratory and CACS Measurement Blood samples were obtained after 12 hours of fasting. The following biochemical parameters were determined by standard laboratory methods based on Japan Society of Clinical Chemistry: red blood cell count, hematocrit, white blood cell count, platelet count, lactate dehydrogenase, alkaline phosphatase, total protein, albumin, total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, uric acid, Ca, P, Ca 3 P products. CACS was measured by using 16-row multidetector computed tomography (Aquilion 16, Toshiba Medical Systems Corporation, Tokyo, Japan) and was stratified as tertiles: group 1 (0105), group 2 (1101067), and group 3 (109415481). The HD patients were followed up for 7 years and 4 months. We measured all-
cause mortality and cardiovascular mortalities. Cardiovascular mortality includes deaths from heart disease, cerebrovascular disease, and peripheral artery disease.
Statistical Analysis Kaplan–Meier method and Cox proportional hazard analysis adjusted for age and HD duration were used to examine the impact of CACS on survival. Significance was defined as a P value of ,.05. The analysis was done by using PASW statistics 18 (SPSS Japan Inc., Tokyo, Japan).
Results Table 1 shows general characteristics of HD patients. The average of CACS was 1299, and the median was 432. The patients of group 1 show young age, short HD duration, low systolic blood pressure, and high albumin compared with groups 2 and 3. During the study period of 7.3 years, 69 patients died, and the cumulative mortality was 34.5%. Thirty-five of 69 patients died of cardiovascular disease.
Table 1. General Characteristics of Subjects
n Age (year) HD duration (year) Systolic BP (mmHg) Diastolic BP (mmHg) Red blood cell (3106/mL) Hematocrit (%) White blood cell (3103/mL) Platelet (3103/mL) LDH (IU/L) ALP (IU/L) Total protein (g/dL) Albumin (g/dL) Total cholesterol (mg/dL) Triglyceride (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Uric acid (mg/dL) Calcium (mg/dL) Phosphorus (mg/dL) Ca 3 P (mg/dL)2 CACS
All
Group 1
Group 2
Group 3
200 60.0 6 13.1 9.25 6 8.37 143.3 6 24.0 75.4 6 13.8 3.26 6 0.38 31.6 6 3.2 5.76 6 1.73 181 6 56 349 6 71 167 6 76 6.99 6 0.45 4.12 6 0.37 168.6 6 37.3 133.1 6 94.3 44.0 6 12.6 98.5 6 30.1 8.28 6 1.29 8.53 6 0.93 5.88 6 1.15 50.4 6 11.8 1299 6 2183
66 51.2 6 11.9 7.17 6 6.98 133.5 6 19.5 75.0 6 13.3 3.33 6 0.40 31.9 6 3.1 5.89 6 1.46 187 6 52 343 6 78 155 6 59 7.08 6 0.45 4.22 6 0.40 170.4 6 39.3 142.2 6 77.8 43.6 6 13.1 98.4 6 33.4 8.57 6 1.29 8.43 6 0.83 5.88 6 1.00 49.5 6 9.9 24 6 31
67 63.1 6 11.6* 10.07 6 8.44* 145.0 6 23.2* 76.5 6 14.1 3.30 6 0.40 31.8 6 3.4 5.82 6 1.94 182 6 62 355 6 62 183 6 98 6.94 6 0.41 4.05 6 0.34* 167.8 6 36.3 121.6 6 66.4 44.5 6 12.5 99.0 6 30.1 8.26 6 1.22 8.48 6 0.95 5.89 6 1.10 50.2 6 12.1 482 6 284*
67 65.6 6 11.0* 10.48 6 9.23* 152.4 6 25.6* 74.6 6 14.2 3.16 6 0.31*,† 31.0 6 3.1 5.58 6 1.77 174 6 55 349 6 72 163 6 65 6.95 6 0.47 4.09 6 0.34* 167.6 6 36.8 135.6 6 127.5 44.0 6 12.5 98.1 6 27.2 8.02 6 1.32* 8.69 6 1.00 5.89 6 1.34 51.3 6 13.4 3372 6 2761*,†
HD, hemodialysis; LDH, lactate dehydrogenase; ALP, alkaline phosphatase; HDL, high-density lipoprotein; LDL, lowdensity lipoprotein; CACS, coronary artery calcification score. Data show means 6 standard deviation. *P , .05 versus group 1. †P , .05 versus group 2.
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CACS AND MORTALITY IN HD PATIENTS
Figure 1A shows survival curve of all-cause mortality. The cumulative all-cause mortality values of groups 1, 2, and 3 were 7.6%, 43.3%, and 52.2%, respectively. The mortality of group 1 was significantly lower than that of groups 2 and 3 (P 5 5.9 3 1025 and P 5 4.1 3 1026, respectively). Figure 1B shows survival curve of cardiovascular mortality. The cumulative cardiovascular mortality values of groups 1, 2, and 3 were 3.0%, 22.4%, and 26.9%, respectively. The mortality of group 1 was significantly lower than
that of groups 2 and 3 (P 5 .0039 and P 5 .0012, respectively). However, there were no significant differences in all-cause and cardiovascular mortalities between groups 2 and 3. Cox proportional hazard analysis adjusted for age and HD duration demonstrated that groups 2 and 3 showed higher all-cause mortality and higher cardiovascular mortality than group 1. (Table 2).
Discussion In the present study, the all-cause and cardiovascular mortalities of group 1 were significantly lower than those of groups 2 and 3. Further, Cox proportional hazard analysis adjusted for age and HD duration revealed that all-cause and cardiovascular mortalities of group 1 were significantly lower than those of groups 2 and 3. Thus, CACS is a marker independent of age and HD duration to predict survival of HD patients. Matsuoka et al.12 reported that there was a significant difference in the survival curves between low-CACS and high-CACS patients, and that cardiovascular events and infection were frequently observed in the high-CACS group. Fensterseifer et al.13 reported that age and serum albumin were individually significant variables affecting mortality in the Cox unadjusted model to predict death in 2 years of follow-up (CACS .400U). Our results are consistent with these previous observations. Matsuoka et al.12 and Fensterseifer et al.13 reported lower CACS median values in HD patients (200 U and 31.7 U, respectively) as compared with the present study (432 U). These differences could possibly be due to patient characteristics and HD duration. Mean age in our study was higher than that in the study of Matsuoka et al. and Fensterseifer et al. (60.0 6 13.1 vs. 55.9 6 13.6, 48.8 6 15.2 years, respectively). On the other hand, HD Table 2. Cox Proportional Hazard Analysis Adjusted for Age and HD Duration Adjusted Hazard Ratio P Value
Figure 1. Survival curves of all-cause mortality (A) and cardiovascular mortality (B), calculated by the Kaplan–Meier method, based on the baseline coronary artery calcification score.
All-cause mortality Group 2 versus group 1 Group 3 versus group 1 Cardiovascular mortality Group 2 versus group 1 Group 3 versus group 1
3.544 3.623
.012 .011
5.620 5.956
.026 .023
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SHIMOYAMA ET AL
duration in the present study was longer than that in these two studies (9.25 6 8.37 vs. 4.06 6 5.22 and 3.43 6 2.64 years, respectively). Mechanisms of vascular calcification could be multifactorial. The vascular calcification of HD patients is mainly due to calcium precipitation and hypertrophy of vascular wall. Secondary hyperparathyroidism, which is a common complication of HD patients, accelerates this calcification. Phosphorus control is the most important method to prevent secondary hyperparathyroidism14 and may be helpful in preventing coronary artery calcification. Tamashiro et al. showed the significant impact of dyslipidemia on CACS progression in HD patients.15 Uremic lipoprotein abnormalities may be an important factor in accelerated atherosclerosis in HD patients.16 Indoxyl sulfate, a uremic toxin, may be involved in progression of vascular calcification, as its administration to hypertensive rats accelerated aortic calcification.17 In conclusion, CACS is useful to predict the prognosis of HD patients independently of age and HD duration.
Practical Application CACS is a useful clinical index to predict prognosis in HD patients.
References 1. Herzog CA, Ma JZ, Collins AJ. Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med. 1998;339:799-805. 2. Iseki K, Fukiyama K, for the Okinawa Dialysis Study Group. Long-term prognosis and incidence of acute myocardial infarction in patients on chronic hemodialysis. Am J kidney Dis. 2000;36: 820-825. 3. Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342:1478-1483. 4. Raggi P, Boulay A, Chasan-Taber S, et al. Cardiac calcification in adult hemodialysis patients. A link between end-stage renal
disease and cardiovascular disease? J Am Coll Cardiol. 2002;39: 695-701. 5. London GM, Gnerin AP, Marchais SJ, et al. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant. 2003;18: 1731-1740. 6. Becker CR, Kleffel T, Crispin A, et al. Coronary artery calcium measurement: agreement of multirow detector and electron beam CT. Am J Roentgenol. 2001;176:1295-1298. 7. Hong C, Becker CR, Schoepf UJ, et al. Coronary artery calcium: absolute quantification in non-enhanced and contrastenhanced multi-detector row CT studies. Radiology. 2002;223: 474-480. 8. Lembcke A, Hein PA, Dohmen PM, et al. Pictorial review: electron beam computed tomography and multislice spiral computed tomography for cardiac imaging. Eur J Radiol. 2006;57: 356-367. 9. Wong ND, Hsu JC, Detrano RC, et al. Coronary artery calcium evaluation by electron beam computed tomography and its relation to new cardiovascular events. Am J Cardiol. 2000;86: 495-498. 10. Raggi P, Cooil B, Cakuster TQ. Use of electron beam tomography data to develop models for prediction of hard coronary events. Am Heart J. 2001;141:375-382. 11. Shimoyama Y, Taki K, Mitsuda Y, Tsuruta Y, Hamajima N, Niwa T. KLOTHO gene polymorphisms G-395A and C1818T are associated with LDL cholesterol and uric acid in Japanese hemodialysis patients. Am J Nephrol. 2009;30:383-388. 12. Matsuoka M, Iseki K, Tamashiro M, et al. Impact of high coronary artery calcification score (CACS) on survival in patients on chronic hemodialysis. Clin Exp Nephrol. 2004;8:54-58. 13. Fensterseifer DM, Karohl C, Schvartzman P, Costa CA, Veronese FJ. Coronary calcification and its association with mortality in haemodialysis patients. Nephrology. 2009;14:164-170. 14. Hsu CH. Are we mismanaging calcium and phosphate metabolism in renal failure? Am J Kidney Dis. 1997;29:641-649. 15. Tamashiro M, Iseki K, Sunagawa O, et al. Significant association between the progression of coronary artery calcification and dyslipidemia in patients on chronic hemodialysis. Am J Kidney Dis. 2001;38:64-69. 16. Shoji T, Nishizawa Y, Kawagishi T, et al. Atherogenic lipoprotein changes in the absence of hyperlipidemia in patients with chronic renal failure treated by hemodialysis. Atherosclerosis. 1997; 131:229-236. 17. Adijiang A, Goto S, Uramoto S, Nishijima F, Niwa T. Indoxyl sulphate promotes aortic calcification with expression of osteoblast-specific proteins in hypertensive rats. Nephrol Dial Transplant. 2008;23:1892-1901.
Coronary Artery Calcification Score is Associated With Mortality in Japanese Hemodialysis Patients Yasuhiko Shimoyama, MD, PhD,* Yoshinari Tsuruta, MD, PhD,† and Toshimitsu Niwa, MD, PhD* Objective: Coronary artery calcification has been associated with higher mortality in coronary artery disease and chronic kidney disease. This study aimed to correlate coronary artery calcification score (CACS) with all-cause and cardiovascular mortalities in hemodialysis (HD) patients. Design, Setting, Subjects: A survival analysis was conducted in 200 HD patients. CACS was assessed by multidetector-row computed tomography and stratified as tertiles: group 1 (0105 U), group 2 (1101067 U), and group 3 (109415481 U). The duration of follow-up was 7 years and 4 months. Kaplan–Meier method and Cox proportional hazard analysis adjusted for age and HD duration were performed to examine the impact of CACS on survival. Main Outcome Measure: All-cause and cardiovascular mortalities were measured. Results: The cumulative all-cause and cardiovascular mortalities of group 1 were significantly lower than those of groups 2 and 3 (all-cause mortality: 7.6% vs. 43.3% and 52.2%, respectively, cardiovascular mortality: 3.0% vs. 22.4% and 26.9%, respectively). Cox proportional hazard analysis adjusted for age and HD duration revealed that all-cause and cardiovascular mortalities of group 1 were significantly lower than those of groups 2 and 3. Conclusion: CACS is helpful to predict prognosis of HD patients independently of age and HD duration. Ó 2012 by the National Kidney Foundation, Inc. All rights reserved.
C
ORONARY ARTERY DISEASE carries an enhanced risk of mortality in hemodialysis (HD) patients compared with that in general population.1,2 Vascular calcification has been recognized as a predictive factor of mortality, with a reported prevalence of 60% to 90% in chronic kidney disease (CKD) patients.3,4 Therefore, the early detection and treatment of coronary artery disease could improve the survival rate of HD patients. Abnormal mineral metabolism, such as
*Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Japan. †Department of Nephrology, Meiyo Clinic, Aichi, Japan. Financial Disclosure: The authors declare that they have no relevant financial interests. Address reprint requests to Toshimitsu Niwa, MD, PhD, Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 4668550, Japan. E-mail: [email protected] Ó 2012 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 doi:10.1053/j.jrn.2011.10.024
Journal of Renal Nutrition, Vol 22, No 1 (January), 2012: pp 139-142
hyperphosphatemia and calcium overload, and use of phosphate binders also have been associated with arterial media calcification with great impact on cardiovascular mortality in end-stage renal disease (ESRD).5 Noninvasive imaging approaches and calcification artery scores have been used to detect and measure vascular calcification. Multidetectorrow computed tomography is the most common method now available to quantify vascular calcification.6-8 Coronary artery calcification score (CACS) in asymptomatic subjects is a stronger predictor of myocardial infarction and coronary artery death than traditional risk factors such as age, smoking, and diabetes mellitus.9,10 The present study aimed to correlate CACS with all-cause and cardiovascular mortality in HD patients.
Materials and Methods Subjects This study included 200 Japanese subjects (110 men and 90 women) treated with HD at Meiyo 139
140
SHIMOYAMA ET AL
Clinic, Aichi, Japan.11 The mean age at start of this study was 60.0 6 13.1 (mean 6 standard deviation) years, ranging from 25 to 88 years, and the duration of HD was 9.25 6 8.37 (mean 6 standard deviation) years, ranging from 0.3 to 33.6 years.
Laboratory and CACS Measurement Blood samples were obtained after 12 hours of fasting. The following biochemical parameters were determined by standard laboratory methods based on Japan Society of Clinical Chemistry: red blood cell count, hematocrit, white blood cell count, platelet count, lactate dehydrogenase, alkaline phosphatase, total protein, albumin, total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, uric acid, Ca, P, Ca 3 P products. CACS was measured by using 16-row multidetector computed tomography (Aquilion 16, Toshiba Medical Systems Corporation, Tokyo, Japan) and was stratified as tertiles: group 1 (0105), group 2 (1101067), and group 3 (109415481). The HD patients were followed up for 7 years and 4 months. We measured all-
cause mortality and cardiovascular mortalities. Cardiovascular mortality includes deaths from heart disease, cerebrovascular disease, and peripheral artery disease.
Statistical Analysis Kaplan–Meier method and Cox proportional hazard analysis adjusted for age and HD duration were used to examine the impact of CACS on survival. Significance was defined as a P value of ,.05. The analysis was done by using PASW statistics 18 (SPSS Japan Inc., Tokyo, Japan).
Results Table 1 shows general characteristics of HD patients. The average of CACS was 1299, and the median was 432. The patients of group 1 show young age, short HD duration, low systolic blood pressure, and high albumin compared with groups 2 and 3. During the study period of 7.3 years, 69 patients died, and the cumulative mortality was 34.5%. Thirty-five of 69 patients died of cardiovascular disease.
Table 1. General Characteristics of Subjects
n Age (year) HD duration (year) Systolic BP (mmHg) Diastolic BP (mmHg) Red blood cell (3106/mL) Hematocrit (%) White blood cell (3103/mL) Platelet (3103/mL) LDH (IU/L) ALP (IU/L) Total protein (g/dL) Albumin (g/dL) Total cholesterol (mg/dL) Triglyceride (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Uric acid (mg/dL) Calcium (mg/dL) Phosphorus (mg/dL) Ca 3 P (mg/dL)2 CACS
All
Group 1
Group 2
Group 3
200 60.0 6 13.1 9.25 6 8.37 143.3 6 24.0 75.4 6 13.8 3.26 6 0.38 31.6 6 3.2 5.76 6 1.73 181 6 56 349 6 71 167 6 76 6.99 6 0.45 4.12 6 0.37 168.6 6 37.3 133.1 6 94.3 44.0 6 12.6 98.5 6 30.1 8.28 6 1.29 8.53 6 0.93 5.88 6 1.15 50.4 6 11.8 1299 6 2183
66 51.2 6 11.9 7.17 6 6.98 133.5 6 19.5 75.0 6 13.3 3.33 6 0.40 31.9 6 3.1 5.89 6 1.46 187 6 52 343 6 78 155 6 59 7.08 6 0.45 4.22 6 0.40 170.4 6 39.3 142.2 6 77.8 43.6 6 13.1 98.4 6 33.4 8.57 6 1.29 8.43 6 0.83 5.88 6 1.00 49.5 6 9.9 24 6 31
67 63.1 6 11.6* 10.07 6 8.44* 145.0 6 23.2* 76.5 6 14.1 3.30 6 0.40 31.8 6 3.4 5.82 6 1.94 182 6 62 355 6 62 183 6 98 6.94 6 0.41 4.05 6 0.34* 167.8 6 36.3 121.6 6 66.4 44.5 6 12.5 99.0 6 30.1 8.26 6 1.22 8.48 6 0.95 5.89 6 1.10 50.2 6 12.1 482 6 284*
67 65.6 6 11.0* 10.48 6 9.23* 152.4 6 25.6* 74.6 6 14.2 3.16 6 0.31*,† 31.0 6 3.1 5.58 6 1.77 174 6 55 349 6 72 163 6 65 6.95 6 0.47 4.09 6 0.34* 167.6 6 36.8 135.6 6 127.5 44.0 6 12.5 98.1 6 27.2 8.02 6 1.32* 8.69 6 1.00 5.89 6 1.34 51.3 6 13.4 3372 6 2761*,†
HD, hemodialysis; LDH, lactate dehydrogenase; ALP, alkaline phosphatase; HDL, high-density lipoprotein; LDL, lowdensity lipoprotein; CACS, coronary artery calcification score. Data show means 6 standard deviation. *P , .05 versus group 1. †P , .05 versus group 2.
141
CACS AND MORTALITY IN HD PATIENTS
Figure 1A shows survival curve of all-cause mortality. The cumulative all-cause mortality values of groups 1, 2, and 3 were 7.6%, 43.3%, and 52.2%, respectively. The mortality of group 1 was significantly lower than that of groups 2 and 3 (P 5 5.9 3 1025 and P 5 4.1 3 1026, respectively). Figure 1B shows survival curve of cardiovascular mortality. The cumulative cardiovascular mortality values of groups 1, 2, and 3 were 3.0%, 22.4%, and 26.9%, respectively. The mortality of group 1 was significantly lower than
that of groups 2 and 3 (P 5 .0039 and P 5 .0012, respectively). However, there were no significant differences in all-cause and cardiovascular mortalities between groups 2 and 3. Cox proportional hazard analysis adjusted for age and HD duration demonstrated that groups 2 and 3 showed higher all-cause mortality and higher cardiovascular mortality than group 1. (Table 2).
Discussion In the present study, the all-cause and cardiovascular mortalities of group 1 were significantly lower than those of groups 2 and 3. Further, Cox proportional hazard analysis adjusted for age and HD duration revealed that all-cause and cardiovascular mortalities of group 1 were significantly lower than those of groups 2 and 3. Thus, CACS is a marker independent of age and HD duration to predict survival of HD patients. Matsuoka et al.12 reported that there was a significant difference in the survival curves between low-CACS and high-CACS patients, and that cardiovascular events and infection were frequently observed in the high-CACS group. Fensterseifer et al.13 reported that age and serum albumin were individually significant variables affecting mortality in the Cox unadjusted model to predict death in 2 years of follow-up (CACS .400U). Our results are consistent with these previous observations. Matsuoka et al.12 and Fensterseifer et al.13 reported lower CACS median values in HD patients (200 U and 31.7 U, respectively) as compared with the present study (432 U). These differences could possibly be due to patient characteristics and HD duration. Mean age in our study was higher than that in the study of Matsuoka et al. and Fensterseifer et al. (60.0 6 13.1 vs. 55.9 6 13.6, 48.8 6 15.2 years, respectively). On the other hand, HD Table 2. Cox Proportional Hazard Analysis Adjusted for Age and HD Duration Adjusted Hazard Ratio P Value
Figure 1. Survival curves of all-cause mortality (A) and cardiovascular mortality (B), calculated by the Kaplan–Meier method, based on the baseline coronary artery calcification score.
All-cause mortality Group 2 versus group 1 Group 3 versus group 1 Cardiovascular mortality Group 2 versus group 1 Group 3 versus group 1
3.544 3.623
.012 .011
5.620 5.956
.026 .023
142
SHIMOYAMA ET AL
duration in the present study was longer than that in these two studies (9.25 6 8.37 vs. 4.06 6 5.22 and 3.43 6 2.64 years, respectively). Mechanisms of vascular calcification could be multifactorial. The vascular calcification of HD patients is mainly due to calcium precipitation and hypertrophy of vascular wall. Secondary hyperparathyroidism, which is a common complication of HD patients, accelerates this calcification. Phosphorus control is the most important method to prevent secondary hyperparathyroidism14 and may be helpful in preventing coronary artery calcification. Tamashiro et al. showed the significant impact of dyslipidemia on CACS progression in HD patients.15 Uremic lipoprotein abnormalities may be an important factor in accelerated atherosclerosis in HD patients.16 Indoxyl sulfate, a uremic toxin, may be involved in progression of vascular calcification, as its administration to hypertensive rats accelerated aortic calcification.17 In conclusion, CACS is useful to predict the prognosis of HD patients independently of age and HD duration.
Practical Application CACS is a useful clinical index to predict prognosis in HD patients.
References 1. Herzog CA, Ma JZ, Collins AJ. Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med. 1998;339:799-805. 2. Iseki K, Fukiyama K, for the Okinawa Dialysis Study Group. Long-term prognosis and incidence of acute myocardial infarction in patients on chronic hemodialysis. Am J kidney Dis. 2000;36: 820-825. 3. Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342:1478-1483. 4. Raggi P, Boulay A, Chasan-Taber S, et al. Cardiac calcification in adult hemodialysis patients. A link between end-stage renal
disease and cardiovascular disease? J Am Coll Cardiol. 2002;39: 695-701. 5. London GM, Gnerin AP, Marchais SJ, et al. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant. 2003;18: 1731-1740. 6. Becker CR, Kleffel T, Crispin A, et al. Coronary artery calcium measurement: agreement of multirow detector and electron beam CT. Am J Roentgenol. 2001;176:1295-1298. 7. Hong C, Becker CR, Schoepf UJ, et al. Coronary artery calcium: absolute quantification in non-enhanced and contrastenhanced multi-detector row CT studies. Radiology. 2002;223: 474-480. 8. Lembcke A, Hein PA, Dohmen PM, et al. Pictorial review: electron beam computed tomography and multislice spiral computed tomography for cardiac imaging. Eur J Radiol. 2006;57: 356-367. 9. Wong ND, Hsu JC, Detrano RC, et al. Coronary artery calcium evaluation by electron beam computed tomography and its relation to new cardiovascular events. Am J Cardiol. 2000;86: 495-498. 10. Raggi P, Cooil B, Cakuster TQ. Use of electron beam tomography data to develop models for prediction of hard coronary events. Am Heart J. 2001;141:375-382. 11. Shimoyama Y, Taki K, Mitsuda Y, Tsuruta Y, Hamajima N, Niwa T. KLOTHO gene polymorphisms G-395A and C1818T are associated with LDL cholesterol and uric acid in Japanese hemodialysis patients. Am J Nephrol. 2009;30:383-388. 12. Matsuoka M, Iseki K, Tamashiro M, et al. Impact of high coronary artery calcification score (CACS) on survival in patients on chronic hemodialysis. Clin Exp Nephrol. 2004;8:54-58. 13. Fensterseifer DM, Karohl C, Schvartzman P, Costa CA, Veronese FJ. Coronary calcification and its association with mortality in haemodialysis patients. Nephrology. 2009;14:164-170. 14. Hsu CH. Are we mismanaging calcium and phosphate metabolism in renal failure? Am J Kidney Dis. 1997;29:641-649. 15. Tamashiro M, Iseki K, Sunagawa O, et al. Significant association between the progression of coronary artery calcification and dyslipidemia in patients on chronic hemodialysis. Am J Kidney Dis. 2001;38:64-69. 16. Shoji T, Nishizawa Y, Kawagishi T, et al. Atherogenic lipoprotein changes in the absence of hyperlipidemia in patients with chronic renal failure treated by hemodialysis. Atherosclerosis. 1997; 131:229-236. 17. Adijiang A, Goto S, Uramoto S, Nishijima F, Niwa T. Indoxyl sulphate promotes aortic calcification with expression of osteoblast-specific proteins in hypertensive rats. Nephrol Dial Transplant. 2008;23:1892-1901.