Fibroblast Growth Factor 23 and Risk of Cardiac Arrhythmias in Hemodialysis Patients

Fibroblast Growth Factor 23 and Risk of Cardiac Arrhythmias in Hemodialysis Patients: a Proof-of-concept Study (FibCa-HD)

Despite recent progress in the field of hemodialysis (HD), mortality remains unacceptably high, particularly due to cardiac arrhythmias. Recent evidence suggests that fibroblast growth factor 23 (FGF23) is implicated in the pathogenesis of cardiac arrhythmias and sudden death. However, several aspects of both the pathogenetic mechanism(s) as well as the actual association in individuals with Chronic Kidney Disease (CKD) and the effect of dialysis clearance of FGF23 need to be elucidated.

The investigators aim at testing the independent association of FGF23 changes due to dialysis removal and electrocardiographic (ECG) abnormalities (namely QTc prolongation) in a well characterized sample of patients undergoing maintenance HD. The study will be developed in the Division of Nephrology, Ente Ospedaliero Cantonale.

This is an exploratory, observational, prospective, mono-center study that aims to elucidate the pathogenesis of cardiac repolarization and arrhythmias in subjects with CKD receiving maintenance dialysis.

This exploratory research project aims to confirm the link between FGF23 and ECG abnormalities (QTc as a proxy for cardiac arrhythmias) in a well-characterized sample of HD patients and expand our understanding of the molecular mechanisms by which FGF23 may trigger arrhythmias.

Previous works suggest that FGF23 cardiac toxicity may be mediated by the activation of FGFR4 and that modulation of FGF23-FGFR4 signaling through monoclonal antibodies can attenuate the toxic effects of FGF23 on the CM. Although these preliminary data warrant clinical and molecular confirmation, they also suggest FGF23-FGFR4 modulation as a novel potential therapeutic target in CKD to improve morbidity and mortality.

During a standard dialysis session, FGF23 is acutely removed while Ca2+ is provided to the patients. However, shortly after the HD session completion, it was documented that FGF23 serum levels rebound. The investigators hypothesize that acute reduction and subsequent rebound of circulatory levels of FGF23 coupled with calcium loading induced by HD may favour a Ca 2+ influx in the CM and trigger cardiac arrhythmias.

This exploratory study aims to determine the independent association between variations in serum levels of FGF23 and QTc (msec) during and after dialysis. In particular, the primary endpoint of the study is defined as the association between QTc variations (msec) defined as the difference between QTc pre-dialysis and QTc 1 hour after dialysis session completion and variations of serum levels of FGF23 defined as the difference between serum levels of FGF23 at dialysis session completion and after 1-hour form dialysis session completion. The investigators hypothesize that these time points should maximize the chance of detecting a significant association between the exposure variable (FGF23) and the outcome of interest (QTc).

All study procedures are non-invasive, and they will be carried out between the beginning of the last HD of the week and the beginning of the first HD of the following week (long interdialytic interval) to allow for the maximum variation of serum levels of FGF23 between dialysis sessions.

All study-related procedures are performed on top of standard clinical practice, and guidelines are performed non-invasively. Study participants will undergo the following procedures:

• ECG: A standard 12-leads ECG will be recorded at the beginning, at the end as well as 60 minutes after the end of the last HD session of the week and at the beginning of the first HD session of the following week. All readings will be performed will be centralized and read by a single investigator blinded to clinical information at EOC.
• Laboratory assessment: a blood sample will be taken at the beginning, at the end, and 60 minutes after the end of the last HD session of the week and at the beginning of the first HD session of the following week. Laboratory investigations will check the serum values of cardiovascular biomarkers (including FGF23) associated with QTc and volume expansion (OH: overhydration). Venous blood samples for measurement of cardiovascular biomarkers will be drawn at each time point and stored in the biobank at Ente Ospedaliero Cantonale (EOC) according to the standard procedures. These aliquotes will be used to assess FGF23 and for subsequent in-vitro evaluation of the cardiac arrhythmogenicity of patients' sera in relation to the homeostasis variation induced by HD.
• Volume assessment: total body weight will be measured at dialysis session, to calculate the net body weight increase during the long interval. Overhydration (OH) will be quantitatively assessed with a portable whole-body bioimpedance spectroscopy device (Fresenius Medical Care GmbH, Bad Homburg, Germany). The total body water (TBW), the extracellular water (ECW), the intracellular water (ICW), and the OH are calculated as previously defined
• Applanation tonometry: Central blood pressure (BP) values and aortic pressure waveforms will be obtained non-invasively directly from the common carotid artery using a validated high fidelity PulsePen tonometer (DiaTecne, San Donato Milanese, Italy). In particular, the subendocardial viability ratio (SEVR) will be calculated during the first HD session of the week according to the central BP wave form as previously reported
• Echocardiogram: If no echocardiogram exam within 12 months from study inception is available in the patient's chart, a two-dimensional echocardiographic study will be performed before the first HD session of the week utilizing a standard equipment as per standard clinical practice. Digital images will be acquired in the long axis and short axis parasternal views and the apical four and two chamber views and three-cycle clips will be stored on magnetic optical disks for future review. The presence of valvular calcification (aortic and mitral valve) as well as systolic and diastolic function assessment will be performed.

Adverse event: The occurrence of any adverse events (AE) will be recorded for the occurrence of any event from study inception until the end of the following week This exploratory study will be carried out at the Division of Nephrology, Ente Ospedaliero Cantonale (EOC), Ticino, Switzerland.

The study envisages the enrolment of:

• Adult subjects (>18 years of age) who can sign an informed consent.
• on maintenance HD (for at least 3 months)

Exclusion Criteria:

• history of cardiac arrhythmias at study recruitment define as atrial fibrillation or pace-maker assisted cardiac rhythm