FGF23 and Angiotensin-(1-7) in Hypophosphatemia (GAP)
Condition: Hypophosphatemia; X-linked Hypophosphatemia; Renin-angiotensin System; Left Ventricular Hypertrophy
MeSH terms: Familial Hypophosphatemic Rickets; Hypertrophy, Left Ventricular; Hypophosphatemia; Hypertrophy
Study type: Observational

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.
    

Intervention name(s): Ang II and Ang-(1-7); FGF23 and klotho
Intervention type(s): Diagnostic Test; Diagnostic Test
Intervention description(s): Measured in plasma and urine using radioimmunoassays.; Measured using ELISA's.
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.
      
Biospecimen description: 
      Plasma and urine
    
Keywords: FGF23; Angiotensin-(1-7); Hypophosphatemia