Effects of a Reduction in Renal Function on Cardiovascular Structure and Function
Condition: Chronic Kidney Disease; Hypertrophy, Left Ventricular; Hypertension
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Hypertrophy, Left Ventricular; Hypertrophy
Study type: Observational

Summary: 
      Chronic kidney disease (CKD) is present in 1 in 7 of the population and confers a high risk
      of cardiovascular disease. The pathophysiology of cardiovascular disease in CKD is poorly
      understood because CKD is always accompanied by confounding factors including the underlying
      disease process (e.g. diabetes mellitus, systemic vasculitis) and the consequences of CKD
      including hypertension, anaemia and inflammation.

      Nephrectomy in kidney donors causes a 30% reduction in renal function providing an ideal
      study population to measure prospectively the effects of reduced kidney function on the
      cardiovascular system.

      The CRIB-Donor study (ClinicalTrials.gov Identifier:NCT01028703) demonstrated adverse effects
      on cardiovascular structure and function at 12 months compared to controls including an
      increase in left ventricular mass. This proposal will measure the changes in cardiovascular
      structure and function, cardiovascular age and biochemical changes at 5 years providing
      information on the long term effects of reduced renal function.
    

Detailed description: 
      A reduction in renal function at one year in kidney donors is associated with adverse
      cardiovascular structural and functional changes. Increases in LV mass and perhaps fibrosis
      along with increased arterial stiffness are associated with adverse changes in prognostic
      imaging biomarkers and may in the long term contribute to the development of clinical disease
      such as heart failure and arrhythmia.

      It is important to follow this valuable and well characterised cohort of subjects to
      investigate the further natural history of these cardiovascular effects and determine whether
      such changes tend to regress, stabilise or worsen over time.

      Hypotheses:

      The reduction in GFR occurring after surgical uni-nephrectomy in donors is associated with
      long term adverse cardiac and vascular effects which include:

        1. A sustained increased in left ventricular mass, impaired left ventricular systolic and
           diastolic function and increased left ventricular interstitial fibrosis.

        2. Reduced aortic distensibility.

        3. Increased systolic but not diastolic blood pressure.

        4. Increases in oxidative stress, inflammation and collagen turnover

        5. Cardiovascular ageing as evidenced by adverse effects on telomere length and DNA damage.

      Study design:

      We aim to follow up all 124 patients who originally took part in the CRIB-DONOR study at 5
      years and eventually 10 years post nephrectomy.

      Statistics and sample size:

      Using the effect sizes and variances from our previous work (change in LV mass 7g, SD of
      change 10g) we calculate that by studying 50 subjects in each group we will have 93% power to
      detect a difference in LV mass of 7g with an alpha value of 0.05. Due to the nature of a
      follow up study some drop out can be expected. A minimum of 34 patients is required in each
      group in order to achieve an 80% power. This effect is clinically important; a fall in LV
      mass index of one SD has been shown to be associated with a 38% reduction in cardiovascular
      mortality.

      With respect to telomere shortening, assuming mean and SD of base pair length of 5500 and 530
      the study will be able to detect a difference of 0.612 SD, i.e. 324 base pairs. A sample size
      of 50 patients per group would provide a 85% power to detect a difference.
    

Intervention name(s): Nephrectomy
Intervention type(s): Procedure
Intervention description(s): This is observational in design.
Observational model: Cohort
Time perspective: Other
Sampling method: Non-Probability Sample
Study population: 
        Living donors and healthy controls
      
Biospecimen description: 
      Serum, plasma, acellular urine and DNA (for telomere length).