Effects of a Reduction in Renal Function on Cardiovascular Structure and Function (CRIB-DONOR II)

Effects of a Reduction in Renal Function on Cardiovascular Structure and Function: A 5 Year Study of Kidney Donors.

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.

Study Overview

• Status: Completed
• Conditions: Hypertension; Chronic Kidney Disease; Hypertrophy, Left Ventricular
• Intervention / Treatment: Procedure: Nephrectomy

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.

• Study Type: Observational
• Enrollment (Actual): 95

Contacts and Locations

Study Locations

• United Kingdom
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B15 2TH
      • Queen Elizabeth Hospital Birmingham

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Living donors and healthy controls

Description

Inclusion Criteria:

All patients who took part in the original CRIB-Donor study.

Exclusion Criteria:

Pregnant women

Patients will have previously met nationally set criteria for living donation which excludes those with:

Diabetes mellitus Atrial fibrillation Left ventricular dysfunction (ejection fraction <40% on transthoracic echocardiography) History of cardiovascular or pulmonary disease Evidence of hypertensive end-organ damage.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Donors; Patients who donated a kidney and took part in the original CRIB-DONOR study.	Procedure: Nephrectomy; This is observational in design.
Controls; Healthy subjects who took part in the original CRIB-DONOR study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left ventricular mass and interstitial fibrosis	Measured by CMR (part 1 of study).	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aortic compliance	Measured by CMR (part 1 of study).	3 years
Cardiovascular age	Measured by telomere length and studies of DNA damage (part 1 and 2 of study).	3 years
Oxidative stress, inflammation and collagen turnover	Measured by assay and bioassay (part 1 of study).	3 years
Blood pressure	Measured by ambulatory blood pressure monitoring (part 1 of study).	3 years

Collaborators and Investigators

• Sponsor: University Hospital Birmingham NHS Foundation Trust
• Investigators: Principal Investigator: Professor John Townend, MbChB, University Hospital Birmingham NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 23, 2017
• Primary Completion (ACTUAL): March 20, 2020
• Study Completion (ACTUAL): July 31, 2020

Study Registration Dates

• First Submitted: November 22, 2016
• First Submitted That Met QC Criteria: November 22, 2016
• First Posted (ESTIMATE): November 25, 2016

Study Record Updates

• Last Update Posted (ACTUAL): October 5, 2020
• Last Update Submitted That Met QC Criteria: October 2, 2020
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Urologic Diseases; Renal Insufficiency; Pathological Conditions, Anatomical; Cardiomegaly; Kidney Diseases; Renal Insufficiency, Chronic; Hypertrophy; Hypertrophy, Left Ventricular
• Other Study ID Numbers: RRK5913

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO