Archives of Medical Research 44 (2013) 628e632

ORIGINAL ARTICLE

Vascular Calcification in Mexican Hemodialysis Patients Enrique Rojas-Campos,a Rebeca Herrera-Llamas,a Jose L. Monta~ nez-Fernandez,a,b  A. Avila-Baray,d and Petra Martınez-Martınez,a,c Jorge Andrade-Sierra,a,c Angel a Alfonso M. Cueto-Manzano a

Medical Research Unit in Renal Diseases, Specialty Hospital, CMNO, IMSS, Guadalajara, Mexico b Service of Nephrology, Regional General Hospital No. 110, IMSS, Guadalajara, Mexico c Department of Nephrology, Specialty Hospital, CMNO, IMSS, Guadalajara, Mexico d Department of Radiology, Specialty Hospital, CMNO, IMSS, Guadalajara, Mexico Received for publication August 22, 2013; accepted October 22, 2013 (ARCMED-D-13-00460).

Background and Aims. Vascular calcification (VC) is a predictor of poor survival and cardiovascular outcome in end-stage renal disease (ESRD) patients; however, there is scarce information of VC in Latin America, and virtually no data in our setting. We undertook this study to evaluate the prevalence and characteristics of VC in a hemodialysis (HD) population from western Mexico and to determine possible associated factors. Methods. This was a cross-sectional study performed in 52 patients. VC was evaluated using plain X-ray films (Adragao’s score) of hands and pelvis; clinical and biochemical variables were also collected. Statistical analysis was carried out with Student t and c2 tests performed as appropriate and logistic regression to determine predictors of VC. Results. Mean age was 43 years, 48% were female, 23% had diabetes mellitus (DM), and median time on dialysis was 46 months. Percentage prevalence was 52% with a mean calcification score of 2.0  2.6; 23% of patients had severe calcification. VC was present in about 23e37% among the different vascular territories evaluated (radial, digital, femoral and iliac). Patients with calcification were significantly older, had a higher frequency of DM, higher alkaline phosphatase and lower HDL lipoproteins than those without VC. In the multivariate analysis, VC in these patients was significantly predicted only by an older age (OR [95% CI]: 1.15 [1.01e1.31], p 5 0.04); lower HDL-cholesterol and higher alkaline phosphatase were marginal predictors. Conclusions. Half of our HD patients had VC. Territories of radial, iliac, femoral and digital arteries were roughly equally affected, and 25% of patients had a calcification considered as severe. Older age was the only significant predicting variable for VC, with low HDL-cholesterol and high alkaline phosphatase as marginal predictors. Ó 2013 IMSS. Published by Elsevier Inc. Key Words: Vascular calcification, Hemodialysis, Diabetes, Cardiovascular disease.

Introduction Cardiovascular mortality in patients with end-stage renal disease (ESRD) is several times higher compared to the general population (1). Vascular calcification (VC) is highly

Address reprint requests to: Dr. Alfonso M. Cueto-Manzano, Unidad de Investigaci on Medica en Enfermedades Renales, Hospital de Especialidades, CMNO, IMSS, Belisario Domınguez No 1000, Col. Independencia, Guadalajara, Jalisco, Mexico; Phone: (þ52) (33) 3668300, ext 32204; FAX: (+52) (33) 36245050; E-mail: [email protected]

prevalent in maintenance dialysis patients and has been associated with an increased risk of cardiovascular and all-cause mortality (2e4). Prevalence of VC is even higher in pre-dialysis and kidney transplant patients than in the general population (2e5). Vascular calcification can affect intimal or media wall as well as vessels of different anatomic sites and size (5). However, all VC types have been associated with high mortality in ESRD patients (6e10); additionally, the severity of VC has been associated with the number of cardiovascular events in these kinds of patients (6).

0188-4409/$ - see front matter. Copyright Ó 2013 IMSS. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.arcmed.2013.10.018

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Table 1. Demographic and clinical results Variable Number of patients Age (years) Gender, n (%) Male/Female Diabetes mellitus, n (%) Diabetes evolution (years) Time on dialysis (months) Weight (kg) BMI (kg/m2) SBP (mmHg) DBP (mmHg)

Value 52 43  18 27 (52): 25 (48) 12 (23) 21 (5e34) 46 (2e156) 64.2  14.2 24.4  4.4 144  28 78  16

BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure. Data are shown as mean  SD or median (interquartile range).

In spite of the above, there is limited information in this regard in Latin American populations and virtually no information in our setting. Therefore, the aim of this study was to evaluate the prevalence and characteristics of VC in a hemodialysis (HD) population from western Mexico and to determine possible associated factors.

Figure 1. Percentage prevalence of vascular calcification in the sample of HD patients.

groups. Logistic regression (using presence of vascular calcification as dependent variable in a backward conditional method) was done to determine the possible predictors of VC. Statistical analyses were performed with SPSS software package, v.17 (SPSS, Inc., Chicago, IL).

Results Patients and Methods This is a cross-sectional study performed from July to December 2010 in 52 prevalent HD patients from the Hospital de Especialidades, CMNO, IMSS, Guadalajara, Mexico. Patients were included disregarding age, gender, cause of ESRD, vascular access and time on HD. Vascular calcification was evaluated by means of plain X-rays of pelvis and hands performed in the Department of Radiology of the same hospital and evaluated only by one trained physician who was blinded to patient characteristics. To measure VC, Adragao’s score was employed (6) in which the presence or absence of linear calcifications in iliac/femoral arteries and radial/digital arteries are graded as 1 or 0 points, respectively. The maximum score is 8 points (all vascular territories calcified) and the minimum is 0 (no-vascular territory calcified). Using this index, the presence of VC $3 has been associated with lower survival and higher cardiovascular hospitalizations (7). Biochemical and clinical variables were collected at the time of the study. Biochemical variables included serum glucose, urea, creatinine, total, HDL- and LDL-cholesterol, triglycerides, albumin, calcium, phosphorus, PTH and alkaline phosphatase. Clinical variables included age, gender, body mass index, systolic and diastolic blood pressure, presence and duration of diabetes mellitus (DM) and hypertension.

Demographic and clinical results are shown in Table 1. Mean age was 43 years, gender distribution was almost equal, and DM was the original cause of ESRD in almost 25% of patients. Half of the patient sample had VC (Figure 1) and the mean calcification score was 2.0  2.6. From those with VC, 56% had a high-risk calcification index ($3 points) (Figure 2). Comparison of Patients With and Without Vascular Calcification Patients with vascular calcification (n 5 27) were significantly older, had a higher frequency of DM, lower HDLcholesterol and higher alkaline phosphatase concentration

Statistical Analysis Data are shown as mean  SD, median (percentiles 25e75%) or numbers and percentages as appropriate. Student t and c2 tests were used for comparisons between

Figure 2. Severity of the vascular calcification score in the sample of HD patients. Low risk !3 points, high risk $3 points.

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Figure 3. Variables predicting the presence of vascular calcifications (from the multivariate analysis).

than those without calcification (Table 2). No other significant difference was found between these patients; however, a trend for a longer duration of ESRD, higher systolic blood pressure, higher total and LDL-cholesterol, and lower parathyroid hormone (PTH) seemed to be observed in patients with VC. Calcification was found in all the evaluated territories, being discretely higher in the radial arteries than in other sites (Table 2). In a further analysis, comparing patients with and without DM, diabetic patients had significantly ( p !0.05) older age (64 [55e67] vs. 35 [25e48] years), higher systolic (162 [146e170] vs. 133 [118e155] mmHg) and lower diastolic blood pressure (68 [60e83] vs. 74 [70e93]), higher alkaline phosphatase (233 [192e360] vs. 171 [84e505] U/L) and higher VC score (5.5 [3.0e7.0] vs. 0.0 [0.0e2.0]) than patients without DM.

Predicting Variables for Vascular Calcification In a multivariate analysis, VC in these patients was significantly predicted only by an older age; lower HDLcholesterol and higher alkaline phosphatase were marginal predictors (Table 3). It is noteworthy that DM was not a significant predictor, probably because of interaction with age. Figure 3 shows the comparison of VC according to age, HDL-cholesterol and alkaline phosphatase. Those patients 50 years or older had a higher frequency of VC, whereas those with HDL-cholesterol !40 mg/dL and alkaline phosphatase O300 U/L tended to have higher frequency of VC. Discussion To the best of our knowledge, this is the first study evaluating VC in Mexican HD patients and in a Latin American

Vascular Calcification in Hemodialysis Patients Table 2. Comparison between patients with and without vascular calcifications

Variable Age (years) Diabetes mellitus, n (%) ESRD vintage (months) BMI (kg/m2) SBP (mmHg) DBP (mmHg) TC (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) TG (mg/dL) Glucose (mg/dL) Creatinine (mg/dL) Albumin (g/dL) Phosphorus (mg/dL) Calcium (mg/dL) Calcium x phosphorus product (mg2/kg2) Alkaline phosphatase (U/L) PTH (pg/mL) VC in different arterial territories, n (%): Radial Femoral Iliac Digital

Vascular calcification (n 5 27) 50 11 96 24.4 150 70 151 90 39 116 81 8.9 4.1 5.2 9.0 46

(39e65)* (41%)* (24e132) (21.8e29.7) (124e166) (67e86) (118e171) (55e101) (26e45)* (84e153) (78e99) (5.8e11.4) (3.4e4.5) (3.5e6.3) (8.6e9.4) (31e58)

277 (176e509)* 478 (208e2568)

19 16 15 12

No vascular calcification (n 5 25) 29 1 48 23.6 133 74 142 76 45 123 84 9.3 4.1 5.5 9.0 50

(23e44) (4%) (24e120) (20.3e26.3) (118e154) (70e99) (129e176) (62e113) (34e53) (87e133) (74e96) (6.7e10.0) (3.4e4.3) (4.2e6.3) (8.6e9.4) (35e60)

160 (76e373) 517 (124e619)

(37) (31) (29) (23)

BMI, body mass index; ESRD, end-stage renal disease; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PTH, parathyroid hormone; VC, vascular calcifications. Results are shown as median (percentile 25e75%). *p!0.05 vs. no vascular calcification group.

population. Results showed a high proportion of patients with VC, with many affected vascular territories and with a high proportion of high-risk VC. Gold standards for measuring VC are electron beam computed tomography (EBCT) and multi-slice CT. Notwithstanding, plain X-ray films are inexpensive techniques that have proven to be useful in the diagnosis of VC (11), adequately correlated with more sophisticated methods (12) and that significantly predict survival for Table 3. Logistic regression of predicting variables of vascular calcification Variable Age HDL-C Alkaline phosphatase

OR (95% CI)

p

1.15 (1.01e1.31) 0.84 (0.70e1.00) 1.001 (1.00e1.01)

0.04 0.06 0.07

R2 0.60, p !0.0001. Independent variables included in this analysis: age, diabetes mellitus, LDL-cholesterol, HDL-cholesterol, alkaline phosphatase, and calcium x phosphorus product.

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these kinds of patients (7). Some Clinical Practice Guidelines suggest the use of X-ray studies as a reasonable alternative to diagnose VC and predict cardiovascular outcome in patients on dialysis or with CKD stages 3e5 (13). X-rays as used in the present study are internationally accepted and used (14), particularly in countries where the availability of EBCT or multi-slice CT scanners is limited. Prevalence of VC using plain-X ray films is high and has been reported in 60e75% of HD patients (11) and in other ESRD populations (6,15). In our study, half of the patients had some degree of VC. Moreover, VC was found in a rather similar frequency in all the arterial territories evaluated in this study (slightly higher frequency in radial arteries). This finding was different from that observed by Adragao et al. (6) who reported iliac and femoral calcification with higher frequency. It is not clear whether this VC distribution would be associated with specific outcomes in our population; however, iliac localization of VC could be an important predictor for leg amputation and severity of peripheral arterial disease in patients with chronic kidney disease (16). It is also interesting that almost a quarter of our patients had a high-risk calcification score. This score has been associated with poor cardiovascular outcome in other studies (7). The mechanism by which the process of VC is produced is complex. It does not consist of a simple precipitation of calcium and phosphate into the vessel wall but rather is an active and modifiable process (17). Moreover, several modifiable factors (such as serum calcium and phosphorus, hyperparathyroidism, dyslipidemia, and hypertension, among others) and non-modifiable factors (such as age, time on dialysis, race or diabetes) promoting VC are extremely frequent in patients with chronic kidney disease (18). In the current study, only age was a significant predictor for the presence of VC, with HDL-cholesterol and alkaline phosphatase as marginal predicting variables. In one study performed in Spanish subjects, age was the strongest predictor of VC (19). It has been repeatedly shown that age is a main factor for VC in both general and ESRD populations (17,19). Age has an independent effect on vascular function. In fact, there is a term called ‘‘vascular aging’’ (20,21) that is associated with VC (22). Several agerelated mechanisms affect vascular flow and elasticity including calcium deposition (23). HDL-cholesterol is inversely associated with cardiovascular disease and death (24). High levels of HDL-cholesterol are protective for cardiovascular mortality. In our study, a nonsignificant trend to lower HDL-cholesterol and VC was found. Additionally, alkaline phosphatase is associated with glucose metabolism and with the most important components of metabolic syndrome, although the link between alkaline phosphatase and VC is not completely understood (25). Prevalence of VC has been reported to be higher in diabetic than in non-diabetic patients (26), probably due to the presence of more risk factors in such a population (19,26).

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In concordance, in our study a higher frequency of VC in those patients with DM was observed; however, in the multivariate analysis, DM was no longer a predictor for VC, probably because of an important interaction with age (patients with DM were significantly older than patients without diabetes). In Mexico, HD is less frequently used compared to PD as renal replacement therapy (8); therefore, it would be necessary to evaluate prevalence of VC in PD patients because they may have particular risk factors for VC (e.g., prolonged exposure for high calcium concentration in dialysis fluids) (27). It is also necessary to evaluate the effect of VC on survival of ESRD patients and other clinical outcomes such as HD technique failure in our population. In conclusion, 1/2 of our patients on HD had VC. Territories of radial, iliac, femoral and digital arteries were roughly equally affected, and 25% of patients had a calcification considered as severe ($3 points). Older age was the only significant predicting variable for VC, with low HDLcholesterol and high alkaline phosphatase as marginal predictors. Conflict of Interest The authors declare no conflict of interest.

Acknowledgments We appreciate the kind help of Adolfo Cota in processing laboratory samples.

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8. Cueto-Manzano AM, Rojas-Campos E. Status of renal replacement therapy and peritoneal dialysis in Mexico. Perit Dial Int 2007;27: 142e148. 9. Paniagua R, Amato D, Vonesh E, et al. Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial. J Am Soc Nephrol 2002;13: 1307e1320. 10. Salusky IB, Goodman WG. Cardiovascular calcification in end-stage renal disease. Nephrol Dial Transplant 2002;17:336e339. 11. Rodriguez-Garcia M, Gomez-Alonso C, Naves-Diaz M, et al. Vascular calcifications, vertebral fractures and mortality in haemodialysis patients. Nephrol Dial Transplant 2009;24:239e246. 12. Bellasi A, Ferramosca E, Muntner P, et al. Correlation of simple imaging tests and coronary artery calcium measured by computed tomography in hemodialysis patients. Kidney Int 2006;70:1623e1628. 13. Improving Global Outcomes (KDIGO) CKDeMBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease—mineral and bone disorder (CKDeMBD). Kidney Int 2009;76(suppl 113):S1eS130. 14. Bellasi A, Raggi P. Techniques and technologies to assess vascular calcification. Semin Dial 2007;20:129e133. 15. Wang AY, Wang M, Woo J, et al. Cardiac valve calcification as an important predictor for all-cause mortality and cardiovascular mortality in long-term peritoneal dialysis patients: a prospective study. J Am Soc Nephrol 2003;14:159e168. 16. An WS, Son YK, Kim SE, et al. Vascular calcification score on plain radiographs of the feet as a predictor of peripheral arterial disease in patients with chronic kidney disease. Int Urol Nephrol 2010;42: 773e780. 17. Moe SM, Chen NX. Mechanisms of vascular calcification in chronic kidney disease. J Am Soc Nephrol 2008;19:213e216. 18. Cannata-Andıa JB, Rodrıguez-Garcıa M, Carrillo-Lopez N, et al. Vascular calcifications: pathogenesis, management, and impact on clinical outcomes. J Am Soc Nephrol 2006;17(suppl 3):S267eS273. 19. Rodriguez-Garcia M, Naves Diaz M, Cannata Andıa JB. Bone metabolism, vascular calcifications and mortality: associations beyond mere coincidence. J Nephrol 2005;18:458e463. 20. O’Rourke MF. Arterial aging: pathophysiological principles. Vasc Med 2007;12:329. 21. Benetos A, Laurent S, Hoeks AP, et al. Arterial alterations with aging and high blood pressure. A noninvasive study of carotid and femoral arteries. Arterioscler Thromb Vasc Biol 1993;13:90e97. 22. London GM, Pannier B, Marchais SJ. Vascular calcifications, arterial aging and arterial remodeling in ESRD. Blood Purif 2013;35:16e21. 23. Tejwani V, Qian Q. Calcium regulation and bone mineral metabolism in elderly patients with chronic kidney disease. Nutrients 2013;5: 1913e1936. 24. Lewis GF, Rader DJ. New insights into regulation of HDL metabolism and reverse cholesterol transport. Circ Res 2005;96:1221e1232. 25. Ching-Lung C, Tan KCB, Lam KSL, et al. The relationship between glucose metabolism, metabolic syndrome, and bone specific alkaline phosphatase: a structural equation modeling approach. J Clin Endocrinol Metab 2013 (in press). 26. Garcia-Canton C, Bosch E, Ramirez A, et al. Vascular calcification and 25-hydroxyvitamin D levels in non-dialysis patients with chronic kidney disease stages 4 and 5. Nephrol Dial Transplant 2011;26: 2250e2256. 27. Weinreich T, Ritz E, Passlick-Deetjen J. Long-term dialysis with lowcalcium solution (1.0 mmol/L) in CAPD: effects on bone mineral metabolism. Collaborators of the Multicenter Study Group. Perit Dial Int 1996;16:260e268.

Vascular calcification in Mexican hemodialysis patients.

Vascular calcification (VC) is a predictor of poor survival and cardiovascular outcome in end-stage renal disease (ESRD) patients; however, there is s...
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