Clinical trial NCT03489993: FGF23 and Angiotensin-(1-7) in Hypophosphatemia (GAP)
Official title: Interplay of FGF23 and Angiotensin-(1-7) in Hypophosphatemia (GAP)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Hypophosphatemia
X-linked Hypophosphatemia
Renin-angiotensin System
Left Ventricular Hypertrophy
Keywords: FGF23
Angiotensin-(1-7)
Hypophosphatemia
Lead sponsor: Wake Forest University Health Sciences
Sponsor class: OTHER
First posted: 2018-04-06
Enrollment: 8
Sex: ALL
Minimum age (years): 2
Maximum age (years): 24
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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

Primary outcomes:
measure: Left ventricular hypertrophy
timeFrame: 1 year
Secondary outcomes:
measure: High blood pressure
timeFrame: 1 year
Other outcomes:
Locations:
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
Study officials:
affiliation: Wake Forest University Health Sciences
name: Andrew M South, MD MS
role: PRINCIPAL_INVESTIGATOR
References:
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