Left Ventricular Fibrosis in Chronic Kidney Disease (FibroCKD)

Onset and Functional Consequences of Left Ventricular (LV) Fibrosis in Chronic Kidney

This study aims to understand the onset an functional consequences of left ventricular interstitial fibrosis in patients with chronic kidney disease (stage 2 to 5), as well as assess whether transplantation results in a regression of cardiac fibrosis.Thus all patients will undergo: 1) a cardiac magnetic resonance imaging (MRI) scan to assess cardiac function and measure left ventricular interstitial fibrosis; 2) a cardiopulmonary stress echocardiogram to understand the functional consequences of fibrosis and rule out any underlying ischaemic heart disease; 3) a 24 hour holter monitor and electrocardiogram (ECG) to assess whether these patients are at higher risk of arrhythmia.

Study Overview

• Status: Unknown
• Conditions: Myocardial Fibrosis; Chronic Kidney Diseases; Cardio-Renal Syndrome; Uraemic Cardiomyopathy
• Intervention / Treatment: Diagnostic test: cardiac magnetic resonance scan; Diagnostic test: Cardiopulmonary exercise test with stress echocardiogram; Diagnostic test: 24-hour ECG holter monitor; Diagnostic test: 12-lead ECG; Biological: Blood test; Diagnostic test: Cardiopulmonary exercise test

Detailed Description

Aim and objectives:

The primary objective of this study is to test the following hypotheses:

i) Patients with early stage chronic kidney disease (CKD) exhibit diffuse LV fibrosis manifest by prolonged native myocardial T1 times and expansion of the extracellular volume (ECV) measured on MRI with a graded relationship to eGFR (stage of CKD), independent of blood pressure and arterial stiffness.

The secondary research objectives are to test the following hypotheses:

i) Prolonged native myocardial T1 times are associated with impaired diastolic function, altered arterial-ventricular interaction and impaired effort tolerance.

ii) Prolonged T1 times correlate with increases in serum biomarkers of collagen turnover associated with myocardial fibrosis that could be used to risk stratify individuals and enable targeted, personalized clinical care.

iii) Renal transplantation results in a regression of myocardial fibrosis as measured by T1 mapping.

DESIGN:

A cross-sectional analysis of 40 patients in each stage 2-5 CKD will be undertaken. These individuals will only be studied once (at baseline). In addition to this, at least 20 patients will be studied who are about to undergo a kidney transplant. These individuals will be studied at baseline (around the time of surgery), at 6 weeks post-operatively, and then 1 year post-operatively to assess the effect on renal transplantation on myocardial fibrosis.

SUBJECTS:

Patients will be recruited from the clinics run by University Hospitals Birmingham NHS Foundation Trust (UHB) with stages 2, 3, 4 and 5 CKD defined using eGFR calculated with the 4-variable 'Modification of Diet in Renal Disease' (MDRD) equation, with a minimum of two consecutive tests at least 90 days apart. Forty patients will be recruited per group of CKD. All study subjects will undergo a cardiac MRI scan, a cardiopulmonary exercise tests with stress echocardiogram, a 24-hour ECG holter monitor, and blood tests.

CONTROLS:

Forty healthy control subjects and forty hypertensive control subjects will be studied. All patients will undergo the identical research protocol to the CKD subjects, except they will not have a stress echocardiogram or an ECG holter monitor.

• Study Type: Observational
• Enrollment (Anticipated): 260

Contacts and Locations

• Study Contact: Name: Manvir K Hayer, MBChB; Phone Number: 07812732857; Email: manvir.hayer@uhb.nhs.uk
• Study Contact Backup: Name: Jonathan N Townend, MD; Phone Number: 01213712000

Study Locations

• United Kingdom
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B15 2QT
      • Recruiting
      • University Hospital Birmingham
      • Contact: Jonathan N Townend, MD; Phone Number: 01213712000
      • Contact: Manvir K Hayer, MBChB; Phone Number: 01213712000

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Stable CKD from early to severe late stage (stage 2 to 5). Patients expected to undergo live-donor kidney transplantation. Healthy controls. Hypertensive controls (stable, well controlled hypertension).

Description

Inclusion Criteria:

• >18 years old
• CKD stage 2, 3, 4 and 5

Exclusion Criteria:

• Pregnancy
• Ischaemic heart disease (angina, ACS)
• Cerebral vascular disease
• Peripheral vascular disease
• Renovascular disease
• Diabetes mellitus
• Valvular heart disease (more than mild)
• Established diagnosis of heart failure
• Cannot have an MRI scan

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
CKD; 40 patients per group of CKD from stage 2 to stage 5.	Diagnostic test: cardiac magnetic resonance scan; An MRI scan of the heart; Diagnostic test: Cardiopulmonary exercise test with stress echocardiogram; An exercise bicycle test with echocardiogram done during the exercise.; Diagnostic test: 24-hour ECG holter monitor; 3 stickers attached to a small monitor are worn for 24 hours.; Diagnostic test: 12-lead ECG; Can be done immediately by the bedside.; Biological: Blood test; 20 mls of blood will be taken to measure routine laboratory tests and biomarkers of fibrosis.
Kidney transplant recipients; 20 live-donor recipients will be studied pre-operatively and then followed up at 6 weeks and 1 years post-operatively.	Diagnostic test: cardiac magnetic resonance scan; An MRI scan of the heart; Diagnostic test: 24-hour ECG holter monitor; 3 stickers attached to a small monitor are worn for 24 hours.; Diagnostic test: 12-lead ECG; Can be done immediately by the bedside.; Biological: Blood test; 20 mls of blood will be taken to measure routine laboratory tests and biomarkers of fibrosis.; Diagnostic test: Cardiopulmonary exercise test; An exercise bicycle test. No stress echocardiogram.
Controls; 40 healthy controls and 40 hypertensive controls.	Diagnostic test: cardiac magnetic resonance scan; An MRI scan of the heart; Diagnostic test: Cardiopulmonary exercise test with stress echocardiogram; An exercise bicycle test with echocardiogram done during the exercise.; Diagnostic test: 12-lead ECG; Can be done immediately by the bedside.; Biological: Blood test; 20 mls of blood will be taken to measure routine laboratory tests and biomarkers of fibrosis.; Diagnostic test: Cardiopulmonary exercise test; An exercise bicycle test. No stress echocardiogram.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The effect of eGFR on heart muscle scarring (measured from cardiac MRI using T1 times).	eGFR is a measurement of kidney function. Heart muscle scarring levels can be derived from cardiac MRI using a technique called T1 mapping. T1 maps of the heart will be acquired using cardiac MRI. eGFR will be measured from a blood tests, using the MDRD equation. The relationship between the measured T1 times and eGFR will be analysed using statistical tests.	One baseline visit only

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The relationship between prolonged myocardial T1 and diastolic function.	The following diastolic function parameters will be measured on echocardiography: E/A, deceleration time and E/e'.	One baseline visit only
The relationship between prolonged myocardial T1 and effort tolerance.	The percent predicted peak oxygen uptake during exercise testing will be used as a surrogate marker of effort tolerance.	One baseline visit only
The effect of renal transplantation on myocardial fibrosis.	Myocardial T1 times (cardiac MRI) and eGFR (blood testing) will best measured.	Baseline visit (pre-operation), then follow up at 6 weeks and 1 year.

Collaborators and Investigators

• Sponsor: Dr Manvir Kaur Hayer
• Collaborators: British Heart Foundation
• Investigators: Principal Investigator: Nicola C Edwards, PhD, University Hospital Birmingham NHS Foundation Trust

Publications and helpful links

General Publications

• Hayer MK, Radhakrishnan A, Price AM, Liu B, Baig S, Weston CJ, Biasiolli L, Ferro CJ, Townend JN, Steeds RP, Edwards NC; Birmingham Cardio-Renal Group. Defining Myocardial Abnormalities Across the Stages of Chronic Kidney Disease: A Cardiac Magnetic Resonance Imaging Study. JACC Cardiovasc Imaging. 2020 Nov;13(11):2357-2367. doi: 10.1016/j.jcmg.2020.04.021. Epub 2020 Jul 15.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2015
• Primary Completion (ANTICIPATED): July 1, 2018
• Study Completion (ANTICIPATED): August 1, 2018

Study Registration Dates

• First Submitted: May 18, 2017
• First Submitted That Met QC Criteria: June 5, 2017
• First Posted (ACTUAL): June 6, 2017

Study Record Updates

• Last Update Posted (ACTUAL): June 6, 2017
• Last Update Submitted That Met QC Criteria: June 5, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Urologic Diseases; Renal Insufficiency; Heart Failure; Fibrosis; Kidney Diseases; Renal Insufficiency, Chronic; Cardiomyopathies; Cardio-Renal Syndrome
• Other Study ID Numbers: UHB

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No