BOne Dysfunction in Donor NEphrectomieS
Condition: Renal Failure; Kidney Donors
MeSH terms: Renal Insufficiency
Study type: Observational

Summary: 
      Most dialysis patients die from vascular disease, which is statistically associated with
      changes related to chronic kidney disease associated mineral bone disorder (CKD-MBD)3-9.
      Understanding the mechanisms behind this high death rate is crucial to improving the length
      and quality of life for patients with all grades of kidney disease, including those on
      dialysis. This is a priority for patients and clinicians alike.

      Most humans with early CKD are asymptomatic and unaware that they have a problem with their
      kidneys. Therefore they are unlikely to consult a doctor and early CKD is often unrecognised.
      Patients who are aware of early CKD often have other co-morbidities including diabetes,
      hypertension and vascular disease which, in the setting of a clinical study, complicate the
      identification of changes solely resulting from CKD. However over the past decade living
      kidney donation has become increasingly common and is now the source of organs for more than
      120 patients annually at Manchester's renal transplant centre. Prospective donors are
      carefully examined and known to have normal kidney function without other co-morbidities.
      They then undergo a planned unilateral nephrectomy and lose approximately 50% of their kidney
      mass, creating an immediate state of moderate CKD. Over subsequent months the remaining
      kidney will hypertrophy and partially correct this, although the mechanisms are unknown. In
      the immediate post-operative period donors are inpatients on the kidney transplant ward and
      have regular blood and urine tests meaning that careful study of metabolic processes during
      their recovery is relatively easy by analysis of serial plasma and urine samples. Sequential
      changes in the plasma and urine levels of different bone turnover markers and metabolites can
      be analysed and will provide valuable new information to increase our understanding of the
      initial stage of CKD-MBD development.
    

Detailed description: 
      The likelihood of five year survival for a 60 year old dialysis patient (50%) is
      significantly worse than for breast (88%), prostate (90%) or colon cancer sufferers (56%)1,
      but robust information about the contributory risk-factors to inform clinician-patient
      discussions is lacking2. Most dialysis patients die from vascular disease, which is
      statistically associated with changes related to chronic kidney disease associated mineral
      bone disorder (CKD-MBD)3-9. Understanding the mechanisms behind this high death rate is
      crucial to improving the length and quality of life for patients with all grades of kidney
      disease, including those on dialysis. This is a priority for patients and clinicians alike.

      A recent Kidney Disease Improving Global Outcomes (KDIGO) statement highlighted the poor
      level of understanding of the mechanisms of CKD-MBD in early and late kidney disease which
      inhibits the development of targeted therapies to either halt the process or at least improve
      outcomes10-12.

      CKD confers certain atypical risk factors for mortality, most notably a state of disordered
      mineral metabolism which is implicated in the development of hyperphosphataemia,
      hyperparathyroidism and vascular calcification. Despite the variety of biological
      malfunctions attributed to CKD-MBD, the pathophysiology is not understood, partly because
      there is no animal model of progressive CKD. Rodent models do not survive long enough for the
      all changes of CKD-MBD to develop. Therefore current therapy is inadequate, and usually
      deployed late in the course of CKD when the patient has progressed to end-stage renal
      disease. Furthermore there is no reliable evidence that current therapies improve patient
      outcome in terms of length or quality of life. The progression of CKD is not always linear
      and less than 5% of patients proceed to end-stage renal disease. While aetiology of renal
      impairment determines progression to some extent, there is no reliable means of determining
      who will progress and who will not so that targeted study of early CKD-MBD pathogenesis is
      not possible.

      Most humans with early CKD are asymptomatic and unaware that they have a problem with their
      kidneys. Therefore they are unlikely to consult a doctor and early CKD is often unrecognised.
      Patients who are aware of early CKD often have other co-morbidities including diabetes,
      hypertension and vascular disease which, in the setting of a clinical study, complicate the
      identification of changes solely resulting from CKD. However over the past decade living
      kidney donation has become increasingly common and is now the source of organs for more than
      120 patients annually at Manchester's renal transplant centre. Prospective donors are
      carefully examined and known to have normal kidney function without other co-morbidities.
      They then undergo a planned unilateral nephrectomy and lose approximately 50% of their kidney
      mass, creating an immediate state of moderate CKD. Over subsequent months the remaining
      kidney will hypertrophy and partially correct this, although the mechanisms are unknown. In
      the immediate post-operative period donors are inpatients on the kidney transplant ward and
      have regular blood and urine tests meaning that careful study of metabolic processes during
      their recovery is relatively easy by analysis of serial plasma and urine samples. Sequential
      changes in the plasma and urine levels of different bone turnover markers and metabolites can
      be analysed and will provide valuable new information to increase our understanding of the
      initial stage of CKD-MBD development.
    

Intervention name(s): Radioisotope GFR test
Intervention type(s): Radiation
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        living kidney donors
      
Biospecimen description: 
      Serum, Urine and DNA samples
    
Keywords: Donor; CKD-MBD; FGF23