FGF23 and Angiotensin-(1-7) in Hypophosphatemia (GAP)

NCT03489993 | Completed

• 1 other identifier: IRB00049606
• Study Type: observational
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

Hereditary hypophosphatemia encompasses rare genetic conditions characterized by renal phosphate wasting. Increased circulating levels of fibroblast growth factor 23 (FGF23), a key regulator of phosphorus metabolism, are critical to the pathophysiology of these diseases, most notably in X-linked hypophosphatemia (XLH). Increased FGF23 induces hypertrophy and scarring in the heart in part via stimulating the traditional renin-angiotensin system (RAS) pathway, angiotensin-converting enzyme (ACE)/angiotensin (Ang ll), particularly in patients with chronic kidney disease, but the effect of FGF23 on the heart in patients with FGF23-related hypophosphatemic diseases is unknown. In addition, the relationship between FGF23 and the angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) (Ang-(1-7) pathway of the RAS is unknown. The objective of this study is to describe the relationship between FGF23, which causes low phosphorus levels, and components of the RAS in the blood and urine to help the investigators understand why the disease occurs and how to better treat it. Subjects will be identified by querying the Electronic Medical Record according to medical diagnosis. Thirty subjects, 2-24 years of age, will be recruited from the tertiary care Pediatric Endocrinology and Pediatric Nephrology clinics at Brenner Children's Hospital. Inclusion criteria include a confirmed diagnosis of hereditary FGF23-related hypophosphatemia. Clinical data will be obtained from the Electronic Medical Record. Each subject will undergo study assessments at baseline, 6 months and 1 year that include blood work, an echocardiogram, and blood pressure measurements. The primary hypothesis is that subjects with higher Ang-(1-7) levels have lower rates of cardiac hypertrophy and thus are protected against high FGF23 levels. The secondary hypothesis is that subjects with higher Ang-(1-7) levels have lower systolic blood pressure.

Conditions

Hypophosphatemia; X-linked Hypophosphatemia; Renin-angiotensin System; Left Ventricular Hypertrophy

Keywords

FGF23; Angiotensin-(1-7); Hypophosphatemia

Outcome Measures

Primary Outcomes (1)

• Left ventricular hypertrophy

  Higher Ang-(1-7) levels will be associated with a decreased rate of left ventricular hypertrophy

  1 year

Secondary Outcomes (1)

• High blood pressure

  1 year

Study Arms (1)

FGF23-Related Hypophosphatemic Diseases

The diagnostic tests Ang II, Ang-(1-7), FGF23, and klotho will be measured in the cohort. Patients in the cohort will have the diseases X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets type 1 (ARHR1), autosomal recessive hypophosphatemic rickets type 2 (ARHR2), osteoglophonic dysplasia, Jansen-type metaphyseal chondrodysplasia, Raine syndrome, McCune-Alright syndrome, and epidermal nevus syndrome (ENS).

Diagnostic Test: Ang II and Ang-(1-7); Diagnostic Test: FGF23 and klotho

Interventions

Ang II and Ang-(1-7) DIAGNOSTIC_TEST

Measured in plasma and urine using radioimmunoassays.

FGF23-Related Hypophosphatemic Diseases

FGF23 and klotho DIAGNOSTIC_TEST

Measured using ELISA's.

FGF23-Related Hypophosphatemic Diseases

Eligibility Criteria

• Age: 2 Years - 24 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Subjects with hereditary FGF23-related hypophosphatemia will be recruited from the tertiary care Pediatric Endocrinology and Pediatric Nephrology clinics at Brenner Children's Hospital.

You may qualify if:

• Confirmed diagnosis of hereditary FGF23-related hypophosphatemia

You may not qualify if:

• Acquired FGF23-related hypophosphatemia
• Age less than 2 years
• Age more than 24 years
• Inability to provide urine sample

Sponsors & Collaborators

• Wake Forest University Health Sciences: lead

Study Sites (1)

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

Related Publications (9)

• Dalton GD, Xie J, An SW, Huang CL. New Insights into the Mechanism of Action of Soluble Klotho. Front Endocrinol (Lausanne). 2017 Nov 17;8:323. doi: 10.3389/fendo.2017.00323. eCollection 2017.

  PMID: 29250031 BACKGROUND

• Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, Gutierrez OM, Aguillon-Prada R, Lincoln J, Hare JM, Mundel P, Morales A, Scialla J, Fischer M, Soliman EZ, Chen J, Go AS, Rosas SE, Nessel L, Townsend RR, Feldman HI, St John Sutton M, Ojo A, Gadegbeku C, Di Marco GS, Reuter S, Kentrup D, Tiemann K, Brand M, Hill JA, Moe OW, Kuro-O M, Kusek JW, Keane MG, Wolf M. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011 Nov;121(11):4393-408. doi: 10.1172/JCI46122. Epub 2011 Oct 10.

  PMID: 21985788 BACKGROUND

• Gutierrez OM, Wolf M, Taylor EN. Fibroblast growth factor 23, cardiovascular disease risk factors, and phosphorus intake in the health professionals follow-up study. Clin J Am Soc Nephrol. 2011 Dec;6(12):2871-8. doi: 10.2215/CJN.02740311. Epub 2011 Oct 27.

  PMID: 22034506 BACKGROUND

• Isakova T, Xie H, Yang W, Xie D, Anderson AH, Scialla J, Wahl P, Gutierrez OM, Steigerwalt S, He J, Schwartz S, Lo J, Ojo A, Sondheimer J, Hsu CY, Lash J, Leonard M, Kusek JW, Feldman HI, Wolf M; Chronic Renal Insufficiency Cohort (CRIC) Study Group. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA. 2011 Jun 15;305(23):2432-9. doi: 10.1001/jama.2011.826.

  PMID: 21673295 BACKGROUND

• Kinoshita Y, Fukumoto S. X-Linked Hypophosphatemia and FGF23-Related Hypophosphatemic Diseases: Prospect for New Treatment. Endocr Rev. 2018 Jun 1;39(3):274-291. doi: 10.1210/er.2017-00220.

  PMID: 29381780 BACKGROUND

• Mitsnefes MM, Betoko A, Schneider MF, Salusky IB, Wolf MS, Juppner H, Warady BA, Furth SL, Portale AA. FGF23 and Left Ventricular Hypertrophy in Children with CKD. Clin J Am Soc Nephrol. 2018 Jan 6;13(1):45-52. doi: 10.2215/CJN.02110217. Epub 2017 Oct 12.

  PMID: 29025789 BACKGROUND

• Akimoto T, Yoshizawa H, Watanabe Y, Numata A, Yamazaki T, Takeshima E, Iwazu K, Komada T, Otani N, Morishita Y, Ito C, Shiizaki K, Ando Y, Muto S, Kuro-o M, Kusano E. Characteristics of urinary and serum soluble Klotho protein in patients with different degrees of chronic kidney disease. BMC Nephrol. 2012 Nov 23;13:155. doi: 10.1186/1471-2369-13-155.

  PMID: 23176706 BACKGROUND

• de Borst MH, Vervloet MG, ter Wee PM, Navis G. Cross talk between the renin-angiotensin-aldosterone system and vitamin D-FGF-23-klotho in chronic kidney disease. J Am Soc Nephrol. 2011 Sep;22(9):1603-9. doi: 10.1681/ASN.2010121251. Epub 2011 Aug 18.

  PMID: 21852584 BACKGROUND

• Drew DA, Katz R, Kritchevsky S, Ix J, Shlipak M, Gutierrez OM, Newman A, Hoofnagle A, Fried L, Semba RD, Sarnak M. Association between Soluble Klotho and Change in Kidney Function: The Health Aging and Body Composition Study. J Am Soc Nephrol. 2017 Jun;28(6):1859-1866. doi: 10.1681/ASN.2016080828. Epub 2017 Jan 19.

  PMID: 28104822 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Plasma and urine

MeSH Terms

Conditions

Hypophosphatemia; Familial Hypophosphatemic Rickets; Hypertrophy, Left Ventricular

Condition Hierarchy (Ancestors)

Phosphorus Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Rickets, Hypophosphatemic; Rickets; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Hypophosphatemia, Familial; Renal Tubular Transport, Inborn Errors; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Metal Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Calcium Metabolism Disorders; Vitamin D Deficiency; Avitaminosis; Deficiency Diseases; Malnutrition; Nutrition Disorders; Cardiomegaly; Heart Diseases; Cardiovascular Diseases; Hypertrophy; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms

Study Officials

• Andrew M South, MD MS

  Wake Forest University Health Sciences

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 29, 2018
• First Posted: April 6, 2018
• Study Start: December 6, 2018
• Primary Completion: December 23, 2020
• Study Completion: December 23, 2020
• Last Updated: August 5, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)