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

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ClinicalTrials.gov Identifier: NCT03489993
Recruitment Status : Not yet recruiting
First Posted : April 6, 2018
Last Update Posted : October 30, 2018
Sponsor:
Information provided by (Responsible Party):
Wake Forest University Health Sciences

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.


Condition or disease Intervention/treatment
Hypophosphatemia X-linked Hypophosphatemia Renin-angiotensin System Left Ventricular Hypertrophy Diagnostic Test: Ang II and Ang-(1-7) Diagnostic Test: FGF23 and klotho

Detailed Description:

Clinical data will be collected from the Electronic Medical Record, including age, sex, parent-reported race, past medical and family histories, and current medications. The investigators will calculate body mass index and define overweight/obesity as a body mass index ≥85% percentile for age and sex. The investigators will calculate the estimated glomerular filtration rate to measure renal function based on serum creatinine standardized to age, sex, and height.

Blood (less than 5 mL) and urine samples will be collected at each study visit at the same time as routine clinical labs. Ang ll and Ang-(1-7) will be measured in the plasma and urine using radioimmunoassays in a CLIA-certified laboratory within the Hypertension and Vascular Research Biomarker Analytical Core at Wake Forest School of Medicine. The investigators will calculate the ratio of the two peptides and, in the urine, standardize their values to urine creatinine. In the blood, creatinine, calcium, phosphorus, and vitamin D will be collected and in the urine, albumin, calcium, phosphorus, and creatinine will be collected all per standard of care. FGF23 and klotho will be analyzed in the Core via commercially available ELISA's.

All patients receive baseline and, if abnormal, follow-up echocardiograms to evaluate for left ventricular hypertrophy.

Blood pressure will be measured at clinic visits. Because age, sex, and height define normative pediatric values, the investigators will standardize blood pressure with z scores.


Study Type : Observational
Estimated Enrollment : 30 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Interplay of FGF23 and Angiotensin-(1-7) in Hypophosphatemia (GAP)
Estimated Study Start Date : December 2018
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2021


Group/Cohort Intervention/treatment
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)
Measured in plasma and urine using radioimmunoassays.

Diagnostic Test: FGF23 and klotho
Measured using ELISA's.




Primary Outcome Measures :
  1. Left ventricular hypertrophy [ Time Frame: 1 year ]
    Higher Ang-(1-7) levels will be associated with a decreased rate of left ventricular hypertrophy


Secondary Outcome Measures :
  1. High blood pressure [ Time Frame: 1 year ]
    Higher Ang-(1-7) levels will be associated with lower systolic blood pressure


Biospecimen Retention:   Samples Without DNA
Plasma and urine.


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Ages Eligible for Study:   2 Years to 24 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Criteria

Inclusion Criteria:

  • Confirmed diagnosis of hereditary FGF23-related hypophosphatemia

Exclusion Criteria:

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03489993


Contacts
Contact: Andrew M South, MD MS 336-716-9640 asouth@wakehealth.edu
Contact: Lauren M Vannoy, BS 336-716-7541 lvannoy@wakehealth.edu

Sponsors and Collaborators
Wake Forest University Health Sciences
Investigators
Principal Investigator: Andrew M South, MD MS Wake Forest University Health Sciences

Publications:

Responsible Party: Wake Forest University Health Sciences
ClinicalTrials.gov Identifier: NCT03489993     History of Changes
Other Study ID Numbers: IRB00049606
First Posted: April 6, 2018    Key Record Dates
Last Update Posted: October 30, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Wake Forest University Health Sciences:
FGF23
Angiotensin-(1-7)
Hypophosphatemia

Additional relevant MeSH terms:
Antihypertensive Agents
Hypertrophy
Hypertrophy, Left Ventricular
Hypophosphatemia
Familial Hypophosphatemic Rickets
Pathological Conditions, Anatomical
Cardiomegaly
Heart Diseases
Cardiovascular Diseases
Phosphorus Metabolism Disorders
Metabolic Diseases
Rickets, Hypophosphatemic
Rickets
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Hypophosphatemia, Familial
Renal Tubular Transport, Inborn Errors
Kidney Diseases
Urologic Diseases
Metal Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Calcium Metabolism Disorders
Vitamin D Deficiency
Avitaminosis
Deficiency Diseases
Malnutrition
Nutrition Disorders
Angiotensin I (1-7)