Table 1.

FGF23-targeted therapeutic strategies to improve hypertension in CKD

Intervention	FGF23-Klotho-linked effects
Thiazide diuretics and sodium restriction	↓NCC, ↓sodium reabsorption ↑natriuresis, ↓volume expansion, vasodilation → ↓ BP
Dietary phosphate restriction and phosphate binders	↓FGF23, ↓sympatoadrenergic activity, ↓vascular mineralization → ↓ BP and cardioprotection
Oral blocking agent of tubular phosphate reabsorption (preclinical phase)	↓NaPi 2a activity, ↑phosphaturia, ↓serum phosphate → ↓FGF23
RAAS inhibition (ACEI, ARB)	↓Sodium reabsorption, ↑ACE2/Ang-(1-7) (relative to ACE/Ang II) interferes with FGF23 effects, ↓bone FGF23 secretion, ↑Klotho, ↑cardio-kidney protection → ↓BP
Mineralocorticoid receptor blockers in obesity	↓Leptin, ↓aldosterone, ↓FGF23 → ↓BP
Dietary vitamin D and VDR activators	↓Renin and ACE/Ang II, ↑ACE2/Ang-(1-7), ↑Klotho, ↑cardio-kidney-protection → ↓BP (indirectly)
Calcimimetics	↓PTH, ↓FGF23 (long-term salutary effects?)
Humanized anti-FGF23 monoclonal antibody (burosumab)	Blocks FGF23 activation on receptor. Improves hypophosphatemia, bone, and growth derangements in XLH. Unknown effects on BP and cardiac hypertrophy in CKD
Recombinant ACE2 (preclinical and early clinical)	↑Serum ACE2, ↑degradation of Ang II ↑Ang-(1-7) → ↓systemic BP, ↓pulmonary BP. Attenuates kidney damage
Exogenous Klotho administration	↓Ang II levels, ↑Klotho kidney expression, ↑kidney perfusion, ↓BP

FGF23, fibroblast growth factor 23; BP, blood pressure; NCC, sodium chloride cotransporter; NaPi 2a, sodium phosphate cotransporter; RAAS, renin-angiotensin-aldosterone system; ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; ACEI, ACE inhibitor; ARB, angiotensin receptor blocker; Ang II, angiotensin II; Ang-(1-7), angiotensin-(1-7); XLH, X-linked hypophosphatemia. For corresponding references, see text