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

Study Overview
=================
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.

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.

Official Title
-----------------
Interplay of FGF23 and Angiotensin-(1-7) in Hypophosphatemia (GAP)

Conditions
-----------------
Hypophosphatemia, X-linked Hypophosphatemia, Renin-angiotensin System, Left Ventricular Hypertrophy

Intervention / Treatment
-----------------
* Diagnostic Test: Ang II and Ang-(1-7)
* Diagnostic Test: FGF23 and klotho


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed diagnosis of hereditary FGF23-related hypophosphatemia Exclusion Criteria: Acquired FGF23-related hypophosphatemia Age less than 2 years Age more than 24 years Inability to provide urine sample

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 24 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| FGF23-Related Hypophosphatemic Diseases<br>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)<br>* Measured in plasma and urine using radioimmunoassays.<br>Diagnostic Test: FGF23 and klotho<br>* Measured using ELISA's.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left ventricular hypertrophy | Higher Ang-(1-7) levels will be associated with a decreased rate of left ventricular hypertrophy | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| High blood pressure | Higher Ang-(1-7) levels will be associated with lower systolic blood pressure | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Angiotensin-(1-7), FGF23, Hypophosphatemia