Left Ventricular Fibrosis in Chronic Kidney Disease

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.

• cardiac magnetic resonance scan (Diagnostic test): An MRI scan of the heart
• Cardiopulmonary exercise test with stress echocardiogram (Diagnostic test): An exercise bicycle test with echocardiogram done during the exercise.
• 24-hour ECG holter monitor (Diagnostic test): 3 stickers attached to a small monitor are worn for 24 hours.
• 12-lead ECG (Diagnostic test): Can be done immediately by the bedside.
• Cardiopulmonary exercise test (Diagnostic test): An exercise bicycle test. No stress echocardiogram.
• Blood test (Biological): 20 mls of blood will be taken to measure routine laboratory tests and biomarkers of fibrosis.

Primary outcomes

• The effect of eGFR on heart muscle scarring (measured from cardiac MRI using T1 times). [One baseline visit only]: 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.

Secondary outcomes

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

Sex: All, ages: 18 Years to 100 Years, accepts healthy volunteers

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

• Results publication: 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. PMID 32682713

• Nicola C Edwards, PhD, Principal investigator, University Hospital Birmingham NHS Foundation Trust