Vascular Calcification's Risk Factors in Haemodialysis Patients
Condition: Chronic Kidney Failure; Inflammation; Vascular Calcification
MeSH terms: Renal Insufficiency; Kidney Failure, Chronic; Calcinosis; Vascular Calcification; Inflammation
Study type: Observational

Summary: 
      A not randomized , cross sectional study will be done to determine the possible association
      of coronary artery calcification (CAC) score assessed by multirow spiral computed tomography
      (MSCT) with specific and non specific uremic factor of vascular calcification.
    

Detailed description: 
      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.
    

Observational model: Cohort
Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        253 chronic hemodialysis patients were selected 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 have started dialysis from at
        least 6 months at the beginning of the study.
      
Biospecimen description: 
      For each patient a blood sample was 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 methabolism 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.
    
Keywords: Coronary artery calcification; calcium score; (TGF) b1,; fetuin A; osteoprotegerin (OPG); fibroblast growth factor (FGF) 23,; matrix gla protein (MGP); hemodialysis patients