Kidney Sodium Content in Cardiorenal Patients

Evaluation of Kidney Medullary Sodium Content Using 23Na MRI to Understand and Predict Diuretic Resistance

Diuretic therapy is the cornerstone of the management of fluid overload in heart failure. Resistance to diuretic therapy is the most common reason for treatment failure in patients affected by the combination of heart failure and kidney disease. Currently, there is no way of predicting whether heart failure patients will develop resistance to diuretic therapy and what dose of diuretic is necessary to overcome diuretic resistance. Answering these questions would allow doctors to be able to prescribe an accurate dose of diuretic therapy to prevent diuretic resistance and potential side effects of an excessive diuretic dose. With magnetic resonance imaging, it is possible to measure the kidney sodium (salt) content and observe the diuretic response in patients with heart failure and kidney disease. The investigators speculate that measuring kidney sodium content will allow to predict diuretic response in these patients. The aim of this study is to compare the kidney sodium content in patients with chronic cardiorenal syndrome with and without diuretic resistance. Secondly, in a sample of patients with diagnosed diuretic resistance,the aim will be to observe the changes in kidney sodium content induced by an additional dose of diuretic therapy and to observe whether these changes are associated with a response to diuretic therapy.

This is a prospective, interventional, pilot study involving patients recruited from the Heart Failure outpatient clinic at St. Joseph's Hospital in London, Ontario. Depending on scanner availability, the study visits may also take place at Robarts Research Institute, University of Western Ontario. All eligible patients who consent to take part in the study will undergo one study visit. During this visit, all study participants will undergo a combined proton (1H) and 23Na MRI scan of their kidneys to measure kidney sodium content. Prior to the scan, all participants will be asked to complete a questionnaire, will have their fluid volume measured using bioimpedance spectroscopy, will have their heart failure classified using the NYHA system, will have their weight taken using a clinical scale, and will have their sitting blood pressure and heart rate measured three times consecutively using a standard automatic blood pressure monitor. In addition to this, all participants will undergo a research focused echocardiogram, provide a spot urine sample and have blood work collected. All participants will be responsible to complete a 24-hour urine volume test the day before the study visit and bring the special container to the team on the visit day. Study participants who meet the criteria for diuretic resistance will undergo a second study visit within one week of the first one. During this visit, participants will receive an additional intravenous dose of diuretic (furosemide) and they will subsequently undergo a second proton and 23Na MRI scan of their kidneys. Prior to the scan participants will undergo the same study procedures as in visit one excluding the questionnaire. In addition to this, participants will be responsible to record their weight at home the morning before the visit and bring their weight to the study team. After the scan, all participants will have their blood pressure, heart, rate, and weight measured again, and will be asked to complete a 24-hour urine collection. Furthermore, participants will be asked to take their weight using a home scale the morning after the scan and a member of the research team will phone the participants to collect this information.

Patients with diuretic resistance: The presence of diuretic resistance, defined as having clinical signs of fluid overload despite diuretic therapy (this information is routinely collected at each clinical visit). "Fluid overload" is defined as the presence of at least two of the following clinical features: Peripheral or sacral oedema Jugular venous distension ≥ 7 cm Radiographic pulmonary oedema or pleural effusion Enlarged liver or ascites Pulmonary rales, paroxysmal nocturnal dyspnoea, or orthopnoea Point of Care UltraSound (POCUS) evidence of congestion. Inferior Vena Cava diameter >2.5 cm and/or failure to collapse at least 50% with sharp inspiration

We will measure kidney sodium content in patient with cardiorenal syndrome. we will inject within the week of this first measurement furosemide only in patient who will be resistant to diuretics (Based on these parameters, diuretic response will be defined as: A reduction in fractional spot urinary sodium An increase in urinary volume A >1 kg reduction in body weight within 24 hours from diuretic administration (extrapolation of guidance on management of acute HF) and we will do another measurement of kidney sodium content after furosemide injection.

To demonstrate a statistically significant difference in medullary sodium concentration of at least 100 mmol/L between patients with chronic cardiorenal syndrome who are responsive versus patients who are resistant to their current diuretic therapy.

To demonstrate a difference in corticomedullary sodium gradient between patients with chronic cardiorenal syndrome who are responsive versus patients who are resistant to their current diuretic therapy.

To demonstrate a change in medullary sodium concentration compared to baseline in patients with chronic cardiorenal syndrome and diuretic resistance who show a clinical response to an additional diuretic dose, assessed by the lost of weight.

To demonstrate a change in corticomedullary sodium gradient compared to baseline in patients with chronic cardiorenal syndrome and diuretic resistance who show a clinical response to an additional diuretic dose

To investigate the correlation between kidney sodium content and renal function assessed by GFR measurement (mL/min/1.73m2)

To investigate the correlation between kidney sodium content and cardiac biomarkers assessed by NT-ProBNP

To investigate the correlation between kidney sodium content and inflammation biomarkers assessed by CRP (mg/dL)

To investigate the correlation between kidney sodium content and NYHA class (no unit, scale from 0 to 4)

To investigate the correlation between kidney sodium content and extra cellular volume content (in liters) measured by bioimpedance spectroscopy.

Inclusion Criteria for Visit 1 Clinico-pathological diagnosis of heart failure Age ≥ 18 years Estimated GFR ≥ 15 mL/min/1.73m2 Receiving loop diuretics for at least a week at ≥ 40 mg/day (furosemide) or 2 mg/day (bumetanide), either orally or intravenously Willing and able to provide consent Inclusion Criteria for Visit 2 · Patients from visit 1 with diuretic resistance Exclusion Criteria for Visit 1 Direct contraindications to MR scanning (implanted materials etc.) Additional diuretic types other than spironolactone/epleronone/metolazone/finerenone Liver disease with hepato-renal syndrome Pregnant, breastfeeding or intending pregnancy Kidney malformation leading to chronic kidney disease (for example polycystic kidney) Unable to provide consent Exclusion criteria for Visit 2 · Hypokalemia (serum potassium <3.5 mmol/l)

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