Calcitriol, calcidiol, parathyroid hormone, and fibroblast growth factor-23 interactions in chronic kidney disease

Abstract

Objective: To review the inter-relationships between calcium, phosphorus, parathyroid hormone (PTH), parent and activated vitamin D metabolites (vitamin D, 25(OH)-vitamin D, 1,25(OH)2 -vitamin D, 24,25(OH)2 -vitamin D), and fibroblast growth factor-23 (FGF-23) during chronic kidney disease (CKD) in dogs and cats.

Data sources: Human and veterinary literature.

Human data synthesis: Beneficial effects of calcitriol treatment during CKD have traditionally been attributed to regulation of PTH but new perspectives emphasize direct renoprotective actions independent of PTH and calcium. It is now apparent that calcitriol exerts an important effect on renal tubular reclamation of filtered 25(OH)-vitamin D, which may be important in maintaining adequate circulating 25(OH)-vitamin D. This in turn may be vital for important pleiotropic actions in peripheral tissues through autocrine/paracrine mechanisms that impact the health of those local tissues.

Veterinary data synthesis: Limited information is available reporting the benefit of calcitriol treatment in dogs and cats with CKD.

Conclusions: A survival benefit has been shown for dogs with CKD treated with calcitriol compared to placebo. The concentrations of circulating 25(OH)-vitamin D have recently been shown to be low in people and dogs with CKD and are related to survival in people with CKD. Combination therapy for people with CKD using both parental and activated vitamin D compounds is common in human nephrology and there is a developing emphasis using combination treatment with activated vitamin D and renin-angiotensin-aldosterone-system (RAAS) inhibitors.

Figure 1

Vitamin D metabolic pathways.

Figure 2

Development of renal secondary hyperpara-thyroidism–classic theory. (Adapted from Chew DJ, DiBartola SP, Schenck PA. Canine and Feline Nephrology and Urology, Elsevier 2010.)

Figure 3

Development of renal secondary hyperpara-thyroidism–calcitriol trade-off hypothesis. (Adapted from Chew DJ, DiBartola SP, Schenck PA. Canine and Feline Nephrology and Urology, Elsevier 2010.)

Figure 4

Calcitriol's effect to genomically control the synthesis of parathyroid hormone. (Adapted from Chew DJ, DiBartola SP, Schenck PA. Canine and Feline Nephrology and Urology, Elsevier 2010.)

Figure 5

The role of fibroblast growth factor-23 (FGF-23) in the healthy animal. An increase in serum phosphorus results in an increase in expression of FGF-23. (Adapted from Schenck PA: Pathogenesis of Secondary Hyperparathyroidism–ACVIM Forum, Anaheim, California 2010.)

Figure 6

The role of FGF-23 in very early chronic kidney disease. Decreasing glomerular filtration rate (GFR) decreases the phosphate excretion by the kidney, resulting in an increase in serum phosphorus concentration. (Adapted from Schenck PA: Pathogenesis of Secondary Hyperparathyroidism–ACVIM Forum, Anaheim, California 2010.)

Figure 7

The role of FGF-23 in early chronic kidney disease. As the GFR further declines, serum phosphorus elevation becomes more severe with an increase in FGF-23 production. (Adapted from Schenck PA. Pathogenesis of Secondary Hyperparathyroidism–ACVIM Forum, Anaheim, California 2010.)

Figure 8

The role of FGF-23 in late chronic kidney disease. As more kidney function is lost, there is an absolute decrease in GFR, leading to more significant elevations of serum phosphorus concentration. (Adapted from Schenck PA: Pathogenesis of Secondary Hyperparathyroidism–ACVIM Forum, Anaheim, California 2010.)

Figure 9

Megalin-mediated tubular recovery of vitamin D metabolites following glomerular filtration. (Adapted from: Dusso A, Gonzalez EA, Martin KJ. Vitamin D in chronic kidney disease. Best Pract Res Clin Endocrinol Metab 2011; 25: 647–655, and Dusso A, Arcidiacono MV, Yang J, Tokumoto M. Vitamin D inhibition of TACE and prevention of renal osteodystrophy and cardiovascular mortality. J Steroid Biochem Mol Biol 2010; 121: 193–198.)

Figure 10

Damage to tubular cells causes both apoptosis and activation of NF-κβ, which in turn has numerous effects, mediated through inflammatory and immunomodulatory cytokines acting on mononuclear cells of lymhocytic and macrophage lineages. NF-κβ also induces formation of TGF-β the major driving cytokine of fibrogenesis acting on myofibroblasts to produce extracellular matrix (ECM). The actions of calcitriol or other VDRA on the VDR have 4 main consequences illustrated. (1) Liganded VDR blocks transcription of the Renin gene commonly by over 90% thus slowing RAAS activity, (2) Liganded VDR complexes with NF-κβ disallowing its transcription factor function including numerous cytokine regulations TGF-β being an important one decreasing fibrogenesis, (3) Liganded VDR has direct effects to repress TGF-β formation by genetic regulations, and (4) Liganded VDR acts to decrease the epithelial-to-mesenchymal transition (EMT) thus decreasing formation of myofibroblasts from epithelial cells a process active in any renal injury. (Adapted from: Liu Y. Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol 2011; 7(12): 684–696.)

Figure 11

A,B. Angiotensin–II Control of TACE, TGF-α, and EGF-R in Parathyroid and Kidney (Adapted from: Dusso A, Gonzalez EA, Martin KJ. Vitamin D in chronic kidney disease. Best Pract Res Clin Endocrinol Metab 2011; 25: 647–655, and Dusso A, Arcidiacono MV, Yang J, Tokumoto M. Vitamin D inhibition of TACE and prevention of renal osteodystrophy and cardiovascular mortality. J Steroid Biochem Mol Biol 2010; 121: 193–198.) (A) Intracellular TACE (tumor necrosis factor alpha converting enzyme) translated from its mRNA in an inactive form has activation and translocation to membrane accomplished by removal of an inhibitory component. TACE in its active form is strongly stabilized by the phosphorylated EGFR (epidermal growth factor receptor) via P-ERK1/2 forming a “feed-forward” loop with TACE action via its sheddase action on Pro-TGF-α (transforming growth factor alpha [TGF-α]) generating TGF-α able to activate more EGFR and continue the cycle resulting in more generation of each participant in a “vicious cycle” with marked pathologic consequences. P-ERK ½ (extracellular signal related kinase or MAP-kinase) a general form of kinase involved in cellular effect amplifications. (B) Angiotensin II (ANG II) together with its receptor shown as the activating and translocating factor for TACE acting to generate TGF-α as the main ligand for EGFR, which when phosphorylated acts via P-ERK ½ in many pathologic roles in renal disease. P-ERK ½ diminishes the activity of calcitriol by lowering VDR levels. In parathyroids, the P-EGFR translocates to nucleus to markedly stimulate cyclin enzymes producing parathyroid hyperplasia.

Figure 12

Different stages of CKD in which calcitriol treatment can be considered A = No calcitriol supplementation. Calcitriol normalizes only at the expense of elevated PTH. B = Calcitriol treatment is started at time “x” late enough in the renal disease when calcitriol is decreased and PTH is elevated with restoration of both to normal. C = Calcitriol treatment is started at an early enough stage where calcitriol concentrations are still normal as a consequence of the increased PTH. Calcitriol supplementation remains beneficial to maintain normal calcitriol concentrations while decreasing PTH. D = Calcitriol treatment is started very early in the course of progressive nephron loss, prior to either PTH increase or calcitriol decrease as a preventative step.

Figure 13

Time sequence for PTH suppression in a cat with CKD. A standard dose of 2.5 ng/kg once daily was given orally.