Cardiorenal Risk Stratification Pilot Study (CRiSPS)

Cardiorenal Risk Stratification Pilot Study (CRiSPS): Using FGF-23 as a Risk Stratification Biomarker in Patients With Heart Failure and Chronic Kidney Disease as a Predictor of 1-year Morbidity and Mortality Risk

This is prospective cohort study with the purpose of improving our understanding of morbidity and mortality risk in patients with heart failure and chronic kidney disease.

Study Overview

• Status: Unknown
• Conditions: Heart Failure; Chronic Kidney Diseases; Cardio-Renal Syndrome
• Intervention / Treatment: Diagnostic test: Fibroblast Growth Factor 23

Detailed Description

The CDC reports that approximately 5.7 million adults in the U.S. have heart failure (HF), and NHANES reports that 26% of individuals 60 years-of-age and older have Chronic Kidney Disease. NHANES also reports that End-Stage Kidney Disease (ESKD) accounts for $40 billion in Medicare and Non-Medicare costs in 2009; 37% of those patients had a prior episode of HF. These figures demonstrate that the treatment of patients with HF and ESKD costs Americans almost $15 billion annually. A meta-analysis of 16 studies estimates that 63% of HF patients have some kidney impairment; a serum creatinine (Cr)>1.0mg/dL or Glomerular Filtration Rate (GFR)<90 ml/min. Among HF patients with even mildly decreased GFR, mortality increases significantly; those with none, any, and at least moderate CKD experienced a 24%, 38% and 51% 1-year mortality, respectively. In 2015, 66,713 patients were seen at our hospital. About 3% of those patients had a new diagnosis of CHF and at least 30% of those patients diagnosed with CHF had a dual diagnosis of CKD. This population alone accounted for 79,835 of visits in the same year. It is evident that there are both fiscal and ethical incentives, both locally and nationally, to understand how to mitigate disease progression in this population.

Current classification schemes for patients with HF and chronic kidney disease (CKD), cardiorenal syndrome, do not significantly alter management other than managing HF or CKD independently with respect to their individual severity. In CKD, worsening renal function often leads to poor phosphate (PO4) regulation where hyperphosphatemia is significantly associated as a predictor of mortality. Further characterizations of the factors that contribute to hyperphosphatemia implicates Fibroblast Growth Factor 23 (FGF-23) as a major hormone regulator of PO4 levels in the body. FGF-23 has repeatedly demonstrated its use as an independent predictor of mortality in ESKD as well as an independent predictor of worsening renal function in non-diabetic patients with mild CKD. FGF-23 achieves PO4 level control by downregulating PO4 reabsorption via transporters in kidney's proximal tubules as well as the small intestines through an incompletely understood mechanism. This action allows the increased filtration of PO4 without proximal tubule reabsorption as well as indirectly decreased uptake of dietary PO4. In ESKD, the PO4-lowering effects of FGF-23 diminish despite rising FGF-23 levels; this indicates that pathologic hyperphosphatemia represents a decompensated state of PO4 regulation. There are studies that suggest FGF-23 is not only implicated in the worsening of CKD, but the pleiotropic effects of FGF-23 remain to be understood as a factor in cardiovascular disease. Increased FGF-23 levels have been associated with left ventricular dysfunction and atrial fibrillation as well as worsening CKD. In one study, not a single patient with Group 5 CKD had an FGF-23 level lower than 40.2ρg/dL, and more than 70% of those patients had and FGF-23 level greater than 66.1ρg/dL.14 Despite this information, it is not currently known how FGF-23 may be used as a predictor of mortality or progression of CKD in patients with cardiorenal syndrome prior to end-stage renal disease. Significant results from this study may provide a predictable classification scheme based on FGF-23 levels that may be employed in future studies to guide treatment evaluation. The prospect of treatment to reduce morbidity and mortality is supported by studies demonstrating that PO4 binders lower FGF-23 levels, even in healthy volunteers. The study proposed here is an early step in evaluating options to reduce the number of patients that progress to ESRD with a parallel step towards a reduction in significant healthcare costs. Participants in this study will only be observed after they have granted their informed consent. There are no significant potential risks posed by this study as blood collected would be from routine lab vials for the participant population. If the study has significant findings, there are immediate benefits to the population studied and the greater society.

Participants after this study will be equipped with more knowledge to help them understand their risk factors and help them make better decisions about their own healthcare. The investigators hope to achieve a better understanding of what levels of FGF-23 are significantly associated with morbidity and mortality in patients with CHF and CKD. This information can help us answer how current clinicians may better stratify the risks of CHF and CKD; translating theoretical disease predictions into a preventative medicine model. The answer to this question may lay the foundation for treatment and prevention option studies based on FGF-23 levels in patients that are not currently on hemodialysis.

We hypothesize (1) that in participants with congestive heart failure and chronic kidney disease who are not on hemodialysis, worsening heart disease or worsening kidney disease is associated with a significantly elevated FGF-23 serum level AND (2) participants with congestive heart failure and chronic kidney disease who are not on hemodialysis, decreased survival is associated with a significantly elevated FGF-23 serum level.

• Study Type: Observational
• Enrollment (Anticipated): 100

Contacts and Locations

• Study Contact: Name: Wesley A Romney, MD; Phone Number: 718-616-3779; Email: romneyw@nychhc.org
• Study Contact Backup: Name: Karen A Hultberg; Phone Number: 718-616-5627; Email: karen.hultberg@nychhc.org

Study Locations

• United States
  • New York
    • Brooklyn, New York, United States, 11235
      • Recruiting
      • Coney Island Hospital
      • Principal Investigator: George Juang, MD
      • Contact: Wesley A Romney, MD; Phone Number: 718-616-3779; Email: romneyw@nychhc.org
      • Contact: Karen A Hultberg; Phone Number: 718-616-5627; Email: karen.hultberg@nychhc.org
      • Sub-Investigator: Wesley A Romney, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Control Arm: People seen in the outpatient setting with congestive heart failure without renal impairment. Study Arm: People seen in the outpatient setting with congestive heart failure that have some form of renal impairment that did not start the study while on hemodialysis.

Description

Inclusion Criteria:

• Patients must have a diagnosis of congestive heart failure

Exclusion Criteria:

• Patients cannot be on hemodialysis at the study onset.
• Patients cannot have hyperphosphatemia defined as persistent serum phosphorus level>4.5mg/dL at study onset.
• Patients cannot be part of another study for the investigational treatment of heart failure or chronic kidney disease.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Heart Failure without Chronic Kidney Disease; This group has patients managed with all types of heart failure without concomitant chronic kidney disease.	Diagnostic test: Fibroblast Growth Factor 23; A sample of blood is tested for levels of fibroblast growth factor 23
Heart Failure with Chronic Kidney Disease; This group has patients managed with all types of heart failure with concomitant chronic kidney disease, without evidence of sustained hyperphosphatemia.	Diagnostic test: Fibroblast Growth Factor 23; A sample of blood is tested for levels of fibroblast growth factor 23

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	The occurrence of death	1 year from sample date
Worsening Renal Function	Significant, persistently decreased in estimated glomerular filtration rate	1 year from sample date
Worsening Cardiac Function	Decreased ejection fraction, newly documented structural abnormality	1 year from sample date
End-Stage Renal Disease Progression	Progression of patient's health condition requiring the initiation of hemodialysis	1 year from sample date

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospitalizations	Number of times the patient was hospitalized	1 year from sample date
Increased Medication Use	Number of medication changes during observation period, including for comirbidities	1 year from sample date
Worsening Control of Co-Morbidities	Progression of other co-morbid conditions including, diabetes, dyslipidemia, and hypertension.	1 year from sample date
Urgent visits	Number of times the patient visited the emergency department, urgent care, or walked into clinic.	1 year from sample date
Myocardial Infarction	Myocardial infarction diagnosed during the trial period	1 year from sample date
Coronary Artery Disease	Coronary artery disease diagnosed during the trial period	1 year from sample date
Stroke	Stroke diagnosed during the trial period	1 year from sample date
Arrhythmia	Arrhythmia diagnosed during the trial period	1 year from sample date

Collaborators and Investigators

• Sponsor: Coney Island Hospital, Brooklyn, NY
• Investigators: Principal Investigator: George Juang, MD, Coney Island Hospital

Publications and helpful links

General Publications

• Gutierrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, Smith K, Lee H, Thadhani R, Juppner H, Wolf M. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008 Aug 7;359(6):584-92. doi: 10.1056/NEJMoa0706130.
• Writing Group Members; Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jimenez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB; American Heart Association Statistics Committee; Stroke Statistics Subcommittee. Executive Summary: Heart Disease and Stroke Statistics--2016 Update: A Report From the American Heart Association. Circulation. 2016 Jan 26;133(4):447-54. doi: 10.1161/CIR.0000000000000366. No abstract available.
• Fliser D, Kollerits B, Neyer U, Ankerst DP, Lhotta K, Lingenhel A, Ritz E, Kronenberg F; MMKD Study Group; Kuen E, Konig P, Kraatz G, Mann JF, Muller GA, Kohler H, Riegler P. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol. 2007 Sep;18(9):2600-8. doi: 10.1681/ASN.2006080936. Epub 2007 Jul 26.
• Smith GL, Lichtman JH, Bracken MB, Shlipak MG, Phillips CO, DiCapua P, Krumholz HM. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol. 2006 May 16;47(10):1987-96. doi: 10.1016/j.jacc.2005.11.084. Epub 2006 Apr 24.
• Prie D, Friedlander G. Genetic disorders of renal phosphate transport. N Engl J Med. 2010 Jun 24;362(25):2399-409. doi: 10.1056/NEJMra0904186. No abstract available.
• Prie D, Urena Torres P, Friedlander G. Latest findings in phosphate homeostasis. Kidney Int. 2009 May;75(9):882-9. doi: 10.1038/ki.2008.643. Epub 2009 Feb 4.
• Ferrari SL, Bonjour JP, Rizzoli R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab. 2005 Mar;90(3):1519-24. doi: 10.1210/jc.2004-1039. Epub 2004 Dec 21.
• Bogadel'nikov IV. [State of the kallikrein-kinin system in bacterial poisoning]. Zh Mikrobiol Epidemiol Immunobiol. 1978 Nov;(11):20-5. No abstract available. Russian.
• Ikee R, Tsunoda M, Sasaki N, Sato N, Hashimoto N. Emerging effects of sevelamer in chronic kidney disease. Kidney Blood Press Res. 2013;37(1):24-32. doi: 10.1159/000343397. Epub 2013 Mar 6.
• Liu S, Quarles LD. How fibroblast growth factor 23 works. J Am Soc Nephrol. 2007 Jun;18(6):1637-47. doi: 10.1681/ASN.2007010068. Epub 2007 May 9.
• Larsson T, Nisbeth U, Ljunggren O, Juppner H, Jonsson KB. Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int. 2003 Dec;64(6):2272-9. doi: 10.1046/j.1523-1755.2003.00328.x.
• Seiler S, Cremers B, Rebling NM, Hornof F, Jeken J, Kersting S, Steimle C, Ege P, Fehrenz M, Rogacev KS, Scheller B, Bohm M, Fliser D, Heine GH. The phosphatonin fibroblast growth factor 23 links calcium-phosphate metabolism with left-ventricular dysfunction and atrial fibrillation. Eur Heart J. 2011 Nov;32(21):2688-96. doi: 10.1093/eurheartj/ehr215. Epub 2011 Jul 6.
• Tanaka S, Fujita S, Kizawa S, Morita H, Ishizaka N. Association between FGF23, alpha-Klotho, and Cardiac Abnormalities among Patients with Various Chronic Kidney Disease Stages. PLoS One. 2016 Jul 11;11(7):e0156860. doi: 10.1371/journal.pone.0156860. eCollection 2016.

Helpful Links

• United States Renal Data System 2017 Annual Data Report
• Kidney Disease Statistics for the United States

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2018
• Primary Completion (Anticipated): October 31, 2019
• Study Completion (Anticipated): December 31, 2019

Study Registration Dates

• First Submitted: August 9, 2018
• First Submitted That Met QC Criteria: August 9, 2018
• First Posted (Actual): August 14, 2018

Study Record Updates

• Last Update Posted (Actual): October 16, 2018
• Last Update Submitted That Met QC Criteria: October 12, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: Coronary Artery Disease; Atherosclerosis; CKD; Dialysis; FGF23; HFrEF; HFpEF
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Urologic Diseases; Renal Insufficiency; Heart Failure; Kidney Diseases; Renal Insufficiency, Chronic; Cardio-Renal Syndrome; Molecular Mechanisms of Pharmacological Action; Mitosis Modulators; Mitogens
• Other Study ID Numbers: 18-08-172-378(HHC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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