Vascular Calcification's Risk Factors in Haemodialysis Patients

Cardiovascular diseases (CVD) are the main causes of death and hospitalization in patients affected by ESRD . The risk of death from CVD is already detectable in the early steps of chronic renal failure and it is from 20 to 30 times higher than in the general population. In ESRD patients the traditional risk factors for CVD do not offer a satisfactory explanation for such high mortality and morbidity rate. Among them, calcium-phosphate imbalance, inflammation, dialysis age, anaemia, hyperhomocysteinemia, oxidative stress, malnutrition, high lipoprotein levels and endothelial dysfunction have been considered (4).

Recently more attention has been paid to calcium phosphate imbalance involved either in the presence or the progression of vascular calcification (VC) in ESRD patients. Multiple factors have been noticed to contribute to VC other than mineral metabolism: the use of calcium-based phosphate binders, diabetes, aging, inflammation, cytokines and BMI.

Indeed it is now believed that arterial calcification is an active process that involves the phenotypic transformation of vascular smooth muscle cells (VSMC) into bone-forming osteoblast (ob)-like cells that are capable of expressing and/or release bone matrix proteins that are necessary to support the calcification process: OPG, RANKL, OPN, fetuin A and MGP. Several stimuli, first of all mineral changes have been shown to induce o modulate this phenotypic transformation. Indeed the expression and secretion of the above-mentioned proteins is regulated by several molecules such as TGF β, peroxisome proliferator-activated receptors (PPAR) γ, tumor necrosis factor (TNF) α.

Calcification develops at two sites in arterial wall, the intima and the media layers: 1)intimal calcification is frequent in advanced stages of atherosclerosis and is associated with plaque rupture and occlusion of the vessel;2)calcification of media layer, or Mockenberg's sclerosis, is observed in both capacitance vessels and in muscular vessels, it causes arterial stiffness and an high pulse pressure, and is an independent risk factor for mortality of ESRD patients.

Both types of calcifications have an important impact in terms of morbidity and mortality in patients with ESRD especially if the calcification pattern affects the coronary arteries.

It is often difficult to evaluate if the calcification process is mainly located in the intima, in the media or in both. New imaging techniques have recently been used in order to reliably detect and objectively measure the extent of vascular calcification. These techniques include the use of electron beam computed tomography (EBCT) and MSCT to quantify coronary artery calcification (CAC).

The degree of calcification within the coronary arteries is measured to obtain a calcium score. Recently, several studies have analyzed the correlation between VC inhibitors and promoters and both cardiovascular disease and VC . In particular, these studies have analysed the role of fetuin A, MGP, OPG, OPN. Just few studies involved uremic patients and they considered only some of these inhibitory factors individually.

The aim of our study is to evaluate in a cohort of 253 patients, the possible associations of CAC score assessed by MSCT with risk factors of VC.

We selected 253 chronic hemodialysis patients among those undergoing hemodialysis at the Nephrology Dialysis and Renal Transplantation Unit, S.Orsola University Hospital, Bologna, Italy between April 2003 and March 2008. All the patients started dialysis from at least 6 months at the beginning of the study. All the patients are considered for gender, age on starting dialysis, months of hemodialysis, length of the period starting from the chronic renal failure onset to the beginning of dialysis, BMI, blood arterial pressure, tobacco abuse.

The mean age is 62.5 ± 13.5 years, the mean dialysis age is 41.6 ± 62.8 months. For each patient a blood sample is drawn to check the basal values of hemoglobin, hematocrit, folates, vitamin B12, C reactive protein, PTH, calcium, phosphorus, albumin, alkaline phosphatase, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, uric acid, fibrinogen, homocysteine. To better understand the mineral metabolism TGFb1, fetuin A, OPG, FGF 23, OPN and MGP will be checked. The values for each patient will be the median of 4 determinations, each sample was drawn before the midweek dialysis session. The period of exposure to a calcium phosphate product major than 55 mg/dl is also evaluated in all the patients (days CaxP>55). For this measure the maximum phosphate value is considered, for those patients who assume calcium based phosphate binders the measure of calcium phosphate product is obtained considering the period of maximum oral assumption of these drugs. Furthermore the calcium phosphate product is assessed monthly, in the period of dialysis before the beginning of the study, and the times when the measure exceeded 55 mg/dl (n CaxP >55) are recorded.

In the same way is assessed the period of exposure to a phosphate concentration > 6 mg/dl and the times when the marker exceeded 6 mg/dl.

The kind of phosphate binders is recorded focusing on the different associations between the drugs commercially available. The cardiovascular status of the patient is more strictly defined with a score ranging from 0 to 2 for each patient: 0 is the absence of any cardiovascular event in the patient clinical history, 1 as one VC event, 2 as two or more cardiovascular event. As regards the cardiovascular diseases screening, it is evaluated as follows: presence or absence of ischemic cardiomyopathy, cerebral or peripheral vasculopathy. Coronary artery disease was checked by means of one of the following parameters: 1) previous documentation of acute myocardial infarction; 2) symptomatic VC events in the clinical history confirmed by a positive treadmill test; 3) coronary artery stenosis more than 50% in one of the three major coronary vessels documented by an angiographic study. Cerebrovascular disease was investigated by one of the following criteria: 1) a previous ictus cerebri; b) carotid vessel stenosis more than 50% documented by a Doppler exam. Peripheral vascular disease was assessed by the evidence of claudication intermittens, previous surgical procedure, angiographic or Doppler documentation of significative stenosis in abdominal, iliac and femoral vessels.

All the patients undergo to MSCT for the determination of coronary vascular calcification and the assessment of the calcium score. Instrumental evaluation of coronary vascular calcification and the quantification of the coronary calcium score is obtained by means of Somatom Sensation 16 Cardiac (Siemens Farcheim, Germany), the calcium score was assessed by means of a specific software (Syngo Ca-score, Siemens) according to the Agatston system (18).

Patients are also grouped by means of member of cardiovascular events and by means of serum biochemistry for bone turnover to assess if any difference might emerge. A further group of patients was obtained for BMI dividing patients with BMI < 18.5, with BMI between 18.5 and 30 and over 30 to consider any possible difference of calcium score.