Clinical trial NCT06668831: Fibroblast Growth Factor 23 and Risk of Cardiac Arrhythmias in Hemodialysis Patients
Official title: Fibroblast Growth Factor 23 and Risk of Cardiac Arrhythmias in Hemodialysis Patients: a Proof-of-concept Study (FibCa-HD)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Hemodialysis
Keywords: fgf23
cardiac arrhythmia
QTc
cardiovascular risk
Lead sponsor: Ente Ospedaliero Cantonale, Bellinzona
Sponsor class: OTHER
First posted: 2024-10-31
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Adult subjects on maintenance hemodialysis

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Associations of QTc and FGF23 changes
timeFrame: the primary endpoint will be assessed one hour after dialysis cessation
Secondary outcomes:
measure: To gauge the dynamic association between FGF23 and QTc we will also explore
timeFrame: these endpoints will be assessed between dialysis session initiation and 1 hour after dialysis session cessation
measure: To gauge the dynamic association between FGF23 and QTc we will also explore
timeFrame: These endpoints will be assessed bewteen the beginning of the last dialysis of the week and the beginning of the first dialysis of the following week (72 hours)
Other outcomes:
Locations:
city: Lugano
country: Switzerland
facility: Servizio di Nefrologia, Ospedale Regionale di Lugano, Civico
Study officials:
affiliation: Ente Ospedaliero Cantonale, Bellinzona
name: Antonio Bellasi, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Arrigo M, Von Moos S, Gerritsen K, Sadoune M, Tangvoraphonkchai K, Davenport A, Mebazaa A, Segerer S, Cippa PE. Soluble CD146 and B-type natriuretic peptide dissect overhydration into functional components of prognostic relevance in haemodialysis patients. Nephrol Dial Transplant. 2018 Nov 1;33(11):2035-2042. doi: 10.1093/ndt/gfy113.
citation: Tiong MK, Krishnasamy R, Smith ER, Hutchison CA, Ryan EG, Pascoe EM, Hawley CM, Hewitson TD, Jardine MJ, Roberts MA, Cho Y, Wong MG, Heath A, Nelson CL, Sen S, Mount PF, Vergara LA, Paul-Brent PA, Johnson DW, Toussaint ND. Effect of a medium cut-off dialyzer on protein-bound uremic toxins and mineral metabolism markers in patients on hemodialysis. Hemodial Int. 2021 Mar 28. doi: 10.1111/hdi.12924. Online ahead of print.
citation: Fu X, Cui QQ, Ning JP, Fu SS, Liao XH. High-Flux Hemodialysis Benefits Hemodialysis Patients by Reducing Serum FGF-23 Levels and Reducing Vascular Calcification. Med Sci Monit. 2015 Nov 11;21:3467-73. doi: 10.12659/msm.894894.
citation: Sikaneta T, Ho N, Bellasi A, Mahdavi S, Taskapan H, Svendrovski A, Makanjee B, Roberts J, Wu G, Nathoo B, Tam P. QTc Interval Prolongation Is Independently Associated with FGF23 and Predicts Mortality in Predialysis Chronic Kidney Disease. Cardiorenal Med. 2024;14(1):45-57. doi: 10.1159/000535133. Epub 2024 Jan 8.
citation: Graves JM, Vallejo JA, Hamill CS, Wang D, Ahuja R, Patel S, Faul C, Wacker MJ. Fibroblast growth factor 23 (FGF23) induces ventricular arrhythmias and prolongs QTc interval in mice in an FGF receptor 4-dependent manner. Am J Physiol Heart Circ Physiol. 2021 Jun 1;320(6):H2283-H2294. doi: 10.1152/ajpheart.00798.2020. Epub 2021 Apr 30.
citation: Di Iorio B, Bellasi A. QT interval in CKD and haemodialysis patients. Clin Kidney J. 2013 Apr;6(2):137-43. doi: 10.1093/ckj/sfs183. Epub 2013 Jan 17.
citation: Vazquez-Sanchez S, Poveda J, Navarro-Garcia JA, Gonzalez-Lafuente L, Rodriguez-Sanchez E, Ruilope LM, Ruiz-Hurtado G. An Overview of FGF-23 as a Novel Candidate Biomarker of Cardiovascular Risk. Front Physiol. 2021 Mar 9;12:632260. doi: 10.3389/fphys.2021.632260. eCollection 2021.
citation: Niu J, Shah MK, Perez JJ, Airy M, Navaneethan SD, Turakhia MP, Chang TI, Winkelmayer WC. Dialysis Modality and Incident Atrial Fibrillation in Older Patients With ESRD. Am J Kidney Dis. 2019 Mar;73(3):324-331. doi: 10.1053/j.ajkd.2018.09.011. Epub 2018 Nov 16.
citation: Rantanen JM, Riahi S, Schmidt EB, Johansen MB, Sogaard P, Christensen JH. Arrhythmias in Patients on Maintenance Dialysis: A Cross-sectional Study. Am J Kidney Dis. 2020 Feb;75(2):214-224. doi: 10.1053/j.ajkd.2019.06.012. Epub 2019 Sep 18.
citation: Di Lullo L, Rivera R, Barbera V, Bellasi A, Cozzolino M, Russo D, De Pascalis A, Banerjee D, Floccari F, Ronco C. Sudden cardiac death and chronic kidney disease: From pathophysiology to treatment strategies. Int J Cardiol. 2016 Aug 15;217:16-27. doi: 10.1016/j.ijcard.2016.04.170. Epub 2016 May 3.