Cardioprotective Effects of Paricalcitol Alone and in Combination With FGF23 Receptor Inhibition in Chronic Renal Failure: Experimental and Clinical Studies

Abstract

Left ventricular hypertrophy (LVH) is common in chronic kidney disease (CKD) and is associated with high cardiovascular disease mortality. 1,2 LVH in association with 3 or independent of hypertension 4 is multifactorial including suppressed vitamin D activity and elevated circulating levels of the phosphaturic hormone fibroblast growth factor (FGF) 23. [5][6][7][8] Levels of FGF23 reach extremely high concentrations with advanced stages of CKD on dialysis and strongly associate with LVH in both adults 9 and in younger pediatric patients. 10,11

Fibroblast growth factor 23 and tubular sodium handling in young patients with incipient chronic kidney disease

“…These observations raise the possibility that as a result of the renal dysfunction, FGF23 could contribute to RAAS activation [ 10 ] with subsequent increase in PRA [ 34 , 35 ], and activation of the intrarenal RAAS [ 38 ] may contribute to the progression of CKD and hypertension. Our patients with reduced GFR demonstrated significantly higher FGF23 and PRA levels, concurrent with lower concentrations of 1,25(OH) 2 D, underscoring the complex relationships between FGF23, vitamin D and the RAAS independent of overt volume changes, as observed in uremic animals [ 39 , 40 ] and in patients with genetically deficient 1,25(OH) 2 D secretion who display low or undetectable 1,25(OH) 2 D levels, elevated FGF23 and increased PRA values [ 22 ]. Whether a similar intricate cross-talk among the RAAS, vitamin D and FGF23 at the tissue level in the kidney and cardiomyocytes [ 39–41 ], may also operate at a systemic level involving the peripheral circulating RAAS and FGF23 independent of plasma volume changes in patients with CKD has been suggested [ 42 ] and will require additional investigations.…”

“…Several observations suggest alternative FGF23-dependent or -independent mechanisms that may lead to adverse cardiovascular outcomes: improved cardiac hypertrophy was observed in young dialysis patients treated with paricalcitol despite further elevations of FGF23 and persistently high BPs [ 39 ]; LVH may progress even when BP is optimally controlled in patients with moderate pre-dialysis CKD [ 49 ]; and comparable BP reduction was observed in patients with CKD Stage 1 treated with amlodipine or ramipril, although FGF23 levels declined only in those given ramipril [ 50 ]. FGF23 also suppresses renal expression of α-Klotho, and its deficiency is linked to uremic cardiomyopathy through FGF23-independent mechanisms [ 51 ] and Klotho participates in the tubular reabsorption of Na [ 13 ].…”

Fibroblast growth factor 23—Klotho and hypertension: experimental and clinical mechanisms

“…In contrast, VDR activation by paricalcitol suppresses the expression of RAAS genes in the kidney and the heart and improves kidney function, proteinuria, and cardiac hypertrophy in CKD. These effects are associated with minimal or no effects on BP [95,96]; nevertheless, BP can be inversely correlated with levels of 1,25(OH) 2 D [97]. Paricalcitol also downregulates AGT [96], and increases renal ACE2 and Ang-(1-7) expression [98] and, therefore, it appears that several mechanisms are operative in the modulation of the RAAS by FGF23 and vitamin D.…”

“…Of note, VDR agonists stimulate bone production of FGF23 and can further elevate circulating FGF23 levels in CKD [125]. However, a significant direct relationship of BP with FGF23 levels was not observed in young patients with CKD [8,96]. Furthermore, VDR agonists reduce aldosterone secretion and circulating levels [126], preserve ACE2 [98], and prevent renal Klotho reduction [127] and thus may indirectly attenuate hypertension.…”

Chronic Kidney Disease as a Risk Factor for Heart Failure With Preserved Ejection Fraction: A Focus on Microcirculatory Factors and Therapeutic Targets

“…Indeed, preliminary data of Roy et al, suggest that FGF-23 levels correlated with interstitial fibrosis in HFpEF (Roy et al, 2018). Furthermore, FGF-23 counteracted the beneficial effect of paricalcitol on left ventricular hypertrophy, by modulation of the calcineurin/nuclear factor of activated T cell (NFAT) pathway in a rat model of CKD (Czaya et al, 2019). FGF-23 inhibition with KRN23, an anti-FGF antibody, in open label phase 1/2 studies for X-linked hypophosphatemia, showed an increase in serum inorganic phosphate and active vitamin D in all subjects (Imel et al, 2015).…”