Serum Uremic Toxins and Histological Findings of the Blood Vessels in Dialysis Patients
Condition: Chronic Renal Failure
MeSH terms: Renal Insufficiency; Kidney Failure, Chronic; Renal Insufficiency, Chronic
Study type: Observational

Summary: 
      Patients treated by chronic renal replacement therapy are exposed to cardiovascular problems
      and suffer from an accelerated and sever atherosclerosis. Classical risk factors for
      atherosclerosis and cardiovascular diseases (CVD) do not explain the full risk of CVD in the
      dialysis patients. Additional risk factors are therefore likely to exist. The uremic syndrome
      is attributed to the progressive retention of a large number of compounds, which under normal
      conditions are excreted by the healthy kidneys. Uremic toxins such are parathormone (PTH),
      vitamin D and phosphates, cause development of renal osteodystrophy (ROD), i.e. disordered
      calcium and phosphate metabolism. Both conditions of hyperparathyroid and adynamic bone
      disease (ABD) lead to an elevated calcium x phosphate product and increased vascular
      calcification, which might occur in intimal and medial layer of the vessel wall. It is
      important to consider these processes separately, as the vascular consequences (occlusion
      with atheromatosis and vascular stiffening through medial calcification) are different.
      Moreover, the difference between uremic and non-uremic intimal plaque is not the size but its
      composition, with markedly increased calcium content. Hence, these observations have an
      important socio-economic impact because of the increased cardiovascular morbidity and
      mortality.

      The investigators hypothesized that uremic toxins in dialysis patients influence directly
      and/or indirectly the development of atherosclerosis, vascular calcifications and CVD.
    

Detailed description: 
      Rationale: Patients treated by chronic renal replacement therapy are exposed to
      cardiovascular problems and suffer from an accelerated and sever atherosclerosis. Classical
      risk factors for atherosclerosis and cardiovascular diseases (CVD) do not explain the full
      risk of CVD in the dialysis patients. Additional risk factors are therefore likely to exist.
      The uremic syndrome is attributed to the progressive retention of a large number of
      compounds, which under normal conditions are excreted by the healthy kidneys. Uremic toxins
      such are parathormone (PTH), vitamin D and phosphates, cause development of renal
      osteodystrophy (ROD), i.e. disordered calcium and phosphate metabolism. Both conditions of
      hyperparathyroid and adynamic bone disease (ABD) lead to an elevated calcium x phosphate
      product and increased vascular calcification, which might occur in intimal and medial layer
      of the vessel wall. It is important to consider these processes separately, as the vascular
      consequences (occlusion with atheromatosis and vascular stiffening through medial
      calcification) are different. Moreover, the difference between uremic and non-uremic intimal
      plaque is not the size but its composition, with markedly increased calcium content. Hence,
      these observations have an important socio-economic impact because of the increased
      cardiovascular morbidity and mortality.

      Hypothesis: We hypothesized that uremic toxins in dialysis patients influence directly and/or
      indirectly the development of atherosclerosis, vascular calcifications and CVD.

      Objectives:

      To asses the histology of arterial vessels in patients with end-stage renal failure and to
      evaluate its relationship with serum uremic toxins.

      To determine the biochemical and clinical risk factors that might influence the development
      of vascular calcifications and their diagnostic performance in the assessment of CVD
      morbidity and mortality.

      Methods: A cross-sectional study will be conducted at the Department of Nephrology Skopje.
      After the initial assessment patients will be followed for 2 years as the prospective part of
      the study.

      Seventy-five to ninety patients will be included, during one-year period or until proposed
      number of patients is recruited. The study cohort will be divided to 3 subgroups: 1) patients
      at the initiation of dialysis therapy, 2) patients on regular dialysis treatment for a few
      years and 3) patients undergoing renal transplantation. During the follow-up period
      cardiovascular and cerebrovascular events and the moment of their occurrence will be
      recorded, as well as the peripheral vascular diseases. Moreover, clinical, laboratory data
      and arterial vessel samples for histology will be collected at the moment of inclusion.

      Expected outcomes: We expect the determination of high correlation coefficient between
      histological parameters and various uremic toxins, which are responsible for development
      atherosclerosis and vascular calcifications, leading to an accelerated progression of CVD in
      dialysis patients. This determination could help to design new preventive therapeutic tools
      in these patients. The result of this work will impose a positive impact on quality of life
      and therapeutic costs related to atherosclerosis not only in the dialysis populations but
      also in the pre-dialysis chronic renal failure populations and kidney transplant recipients.
    

Observational model: Case-Crossover
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        CKD patients with a need for dialysis within a few months CKD patients on dialysis with
        thormbosis of AV fistula CKD patients on dialysis scheduled for kidney transplantation
      
Biospecimen description: 
      3 aliquots of 2-3 ml sera are retained for various uremic markers determination
    
Keywords: vascular calcifications; uremic toxins; renal osteodystrophy; Dialysis