Fibroblast growth factor 23 is likely to be the most important regulator of phosphate homeostasis, which mediates its functions through fibroblast growth factor receptors and the coreceptor Klotho. In addition to reducing expression of the sodium-phosphate cotransporters NPT2a and NPT2c in the proximal tubules, fibroblast growth factor 23 inhibits renal 1α-hydroxylase and stimulates 24-hydroxylase and appears to reduce parathyroid hormone secretion in short-term studies. Fibroblast growth factor 23 synthesis and secretion by osteocytes and osteoblasts are upregulated through 1,25-dihydroxyvitamin D3 and through an increased dietary phosphate intake. Recent studies have indicated that a low-protein diet and calcium deficiency reduce circulating fibroblast growth factor 23 levels, but magnesium deficiency increases fibroblast growth factor levels. Drugs such as phosphate binders, bisphosphonate, and estrogens have various effects on circulating fibroblast growth factor 23 levels. The high cardiovascular disease event rates and mortality associated with elevated levels of this hormone may be due to various effects on the cardiovascular system, including left ventricular hypertrophy, arterial stiffness, vascular calcifications, endothelial dysfunction, and increased levels of inflammatory markers. In addition, elevated levels of this hormone may contribute to mineral bone metabolism disorders and to patient and allograft survival after renal transplant. Here, we discuss the effects of fibroblast growth factor 23 on adverse renal, bone, and cardiovascular outcomes after kidney transplant.

Key words : Cardiovascular disease, FGF23, Kidney transplant, Mineral bone disorders

Introduction

Fibroblast growth factors (FGFs) are humoral factors originally identified by their ability to stimulate cell proliferation. Twenty-two FGF family members are found in humans, which are grouped into 7 subfamilies based on differences in sequences and phylogeny, and these family members play diverse biologic roles in the regulation of cell proliferation, differentiation, and function.¹

Fibroblast growth factor 23 (FGF23) seems to target the kidney, parathyroid gland, and possibly the pituitary gland and choroid plexus, and Klotho is an essential cofactor of FGF23 for receptor activation.² Fibroblast growth factor 23 stimulates phosphaturia, inhibits parathyroid hormone (PTH) secretion, and lowers circulating levels of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] by inhibiting renal 1α-hydroxylase and stimulating catabolic 24-hydroxylase. Levels of FGF23 decrease drama­tically after successful renal transplant and remain within normal limits when graft function is good. Recent studies have suggested that high levels of FGF23 encountered in terminal renal failure had persisted after kidney transplant and may have contributed to early posttransplant hypophos­phatemia.³

Study methods
For this study, we conducted a systematic literature search via PubMed and Google Scholar from inception to January 2016, using FGF23 as the obligated term, combined with the terms kidney transplant or transplantation and renal transplant or transplantation and other medical subject headings. This search was supplemented with the authors’ working knowledge and reference lists of review articles and textbooks, with relevant references in articles also included.

Structure and function of fibroblast growth factor 23
Fibroblast growth factors are classically considered to be paracrine factors and are known for their roles in tissue patterning and organogenesis during embryogenesis. However, recent studies have indicated that FGF19 subfamily members FGF19, FGF21, and FGF23 work as endocrine factors to regulate bile acid, carbohydrate, and phosphate metabolism. Fibroblast growth factor 23 was identified in 2000, and it was initially shown to be preferentially expressed by the ventrolateral thalamic nucleus. The identified gene of FGF23 was found to be mutated in patients with hyperphosphatemic rickets. Since then, studies have revealed that FGF23 is a key humoral regulator of phosphate homeo­stasis.⁴ The protein FGF23 has a molecular weight of 32 kDa and belongs to the FGF22 family. The protein consists of a signal peptide with 251 amino acids in the amino-terminal domain, an FGF homology region shared by the other 22 fibroblast growth factor family members, and a novel 71-amino acid carboxyl terminus.

Between the latter two domains, there is a cleavage site that contains an RXXR motif. This motif is characteristic of cleavage sites for enzymes of the proconvertase type of the subtilisin/kexin member of the serine protease family. It is probable that the proconvertases are the enzymes responsible for the degradation of FGF23. Fibroblast growth factor 23 is primarily produced by osteocytes in bones⁵ in response to 1,25(OH)₂D₃, which increases the mRNA levels encoding this phosphaturic hormone. Fibroblast growth factor 23 mediates its action in the kidney through an FGF receptor (FGFR)/Klotho complex to downregulate expression of the NPT2a and NPT2c sodium-phosphate cotransporters in the proximal tubules. There are 4 FGFR genes (FGFR1, FGFR2, FGFR3, FGFR4) that encode receptors consisting of 3 extracellular immunoglobulin domains (D₁, D₂, D₃), a single-pass transmembrane domain, and a cytoplasmic tyrosine kinase domain. A hallmark of FGFRs is the presence of an acidic, serine-rich sequence in the linker between D1 and D2, termed the acid box. The D2-D3 fragment of the FGFR ectodomain is necessary and sufficient for ligand binding and specificity, whereas the D1 domain and the acid box are proposed to have a role in receptor autoinhibition. However, it is uncertain whether FGF23 signals initially through receptors in the distal convoluted tubule cells in which extracellular regulated kinase phosphorylation occurs in response to FGF23. These cells are adjacent to NPT2a-expressing proximal tubular cells; therefore, speculation exists that a paracrine signal from the distal to the proximal tubule is required for decreasing NPT2a expression.

Even small changes in plasma FGF23 levels are associated with significant changes in urinary phosphate excretion. In addition to its effect on tubular phosphate handling, FGF23 reduces PTH secretion and inhibits 1α-hydroxylase, leading to a decrease in 1,25(OH)₂D₃ production, which contributes to the development of hypocalcemia and leads to an increase in PTH production. The 1,25(OH)₂D₃ itself increases FGF23 production (Figure 1). After unilateral nephrectomy in healthy kidney donors, this is associated with increased urinary phosphate excretion.⁶

Klotho and fibroblast growth factor 23
Since the discovery of Klotho in 1997, another 2 related paralogs (β-Klotho, which is involved in bile acid and energy metabolism, and γ-Klotho, with a yet to be defined function) have been described, leading to the revised naming of Klotho as α-Klotho. Full-length Klotho is a single-pass transmembrane protein that functions as a coreceptor for FGF23, which promotes negative phosphate balance by inhibiting 1,25(OH)₂D₃ synthesis and inducing phosphaturia. The soluble ectodomain of Klotho, usually called soluble Klotho, possesses glycosidase activity that trims sugar chains on ion channels and transporters on the cell surface, regulating their activity and/or cell surface retention time. It has been shown that this is one of the major mechanisms whereby soluble Klotho modulates calcium channels, sodium phosphate cotransporter-2a (NaPi-2a), and the potassium channel.⁷

Another shorter length Klotho protein only encompassing the Klotho 1 domain in blood circulation is the secreted Klotho protein encoded by an alternative spliced transcript at Klotho gene exon 3. However, its biologic function is poorly known. Renal Klotho transcript is markedly decreased in chronic kidney disease (CKD) patients with diverse causes such as obstructive nephropathy rejected transplanted kidneys, diabetic nephropathy, minimal-change nephritic syndrome, immunoglobulin nephropathy, and chronic glomerulonephritis. By using a recently developed enzyme-linked immunosorbent assay kit, Yamazaki and associates examined plasma-soluble Klotho in healthy participants and found a correlation between plasma Klotho level and serum creatinine, serum urea nitrogen, and FGF23, suggesting that plasma-soluble Klotho levels may be associated with renal function, although true or surrogate glomerular filtration rate was not measured.⁸

Effects of diet and drugs on fibroblast growth factor 23 levels
In patients with CKD, FGF23 levels are thought to increase as a compensatory response to maintain normal phosphorus balance because the capacity for renal phosphorus excretion declines. A vegetarian diet allows a minor absorption of dietary phosphate contained in vegetables compared with meat, resulting in a reduced intestinal absorption. In a study by Di Iorio and associates,⁹ low-protein intake led to an important reduction of dietary phosphorus levels and phosphorus renal filtration, with these effects of a low-protein diet on phosphorus determining a reduction of FGF23 levels without using phosphate binders.⁹

In study by Rodriguez-Ortiz and associates, Wistar rats with normal renal function were fed a diet low in both calcium and vitamin D. The resulting hypocalcemia was associated with low FGF23 despite high PTH and high calcitriol levels. Fibroblast growth factor 23 was positively correlated with calcium and negatively with PTH. Together, these results suggested that hypocalcemia reduces the circulating concentrations of FGF23.¹⁰ A magnesium-deficient diet results in decreased serum phosphorus levels and increased urinary phosphorus excretion. Fibroblast growth factor 23 is a potent regulator of phosphorus hemostasis, and it also stimulates renal inorganic phosphate excretion by decreasing NaPi-IIa expression. Thumfardt and associates11 examined the effects of alterations in dietary magnesium intake on renal inorganic phosphate handling. Urinary inorganic phosphate excretion and renal expression of NaPi-IIa and NaPi-IIc were measured in rats fed a normal (0.2%) or high magnesium (2.5%) diet, with high magnesium resulting in decreased renal inorganic phosphate excretion and increased protein expression of NaPi-IIa and NaPi-IIc. Serum FGF23 levels were unchanged in rats fed the high-magnesium diet.¹¹

Recent evidence has suggested phosphate binders not only reduce phosphorus and PTH but also FGF23. This may offer additional benefits beyond simply treating secondary hyperparathyroidism and renal bone disease, including improvements in FGF23-related patient outcomes, especially during earlier stages of CKD.¹² In addition, it is possible that increases in serum phosphate levels stimulated by 1,25(OH)₂D₃ treatment may exacerbate phosphate retention and elevate FGF23 levels; these effects are potentially associated with poor patient outcomes. Concomitant therapy with phosphate binders may therefore be required.

Bisphosphonates may modify bone turnover. Fibroblast growth factor 23 is produced by bone cells, and it has been correlated with bone turnover markers in patients with fibrous dysplasia of bone and in healthy young men. Data on the effects of bisphosphonate administration on the serum levels of FGF23 are scarce. In another study, Samadfam and associates showed that bone remodeling (and specifically the rate of bone formation) is a potent stimulus for modulating the production and release of FGF23 into the circulation. This may explain differences in serum FGF23 levels that occur with altered circulating levels of hormones or minerals or with locally active factors such as bisphosphonates or modulators of receptor-activated nuclear factor-κB ligand that modify bone turnover.¹³ Carrillo-Lopez and associates reported that estrogens significantly increased FGF23 mRNA and serum levels and that estrogens led to transcriptional and translational upregulation of FGF23 in osteoblast-like cells in a time- and concentration-dependent manner. These results suggest that estrogens regulate PTH indirectly, possibly through FGF23.¹⁴

FGF23 and cardiovascular mortality in postrenal transplant
Cardiovascular disease is the leading cause of mortality in adult renal transplant recipients.¹⁵ Deregulation of calcium and phosphate metabolism is common in patients with CKD and in kidney transplant recipients with impaired renal function. In a prospective study by Baia and associates, plasma FGF23 levels were shown to be independently associated with cardiovascular and all-cause mortality after kidney transplant. Although patients with the highest FGF23 levels were characterized by an overall high cardiovascular risk profile, the associations between FGF23 and mortality (cardio­vascular and all-cause) remained significant after adjustment for several major cardiovascular risk factors, including Framingham risk factors, suggesting that FGF23 is a strong and independent risk marker.¹⁶ In addition, Dominguez and associates reported associations between FGF23 and mortality, with events related to cardiovascular disease more likely in individuals with lower fractional excretion of phosphate independent of PTH and kidney function. In such individuals, the renal tubular response to FGF23 may be suboptimal.¹⁷ Prior studies have shown that higher FGF23 concentrations are strongly associated with mortality and cardiovascular disease events. With even very modest decrements in kidney function, FGF23 concentrations are frequently elevated. High phosphorus intake could lead to increased mortality by stimulating higher concentrations of FGF23, which may lead to left ventricular hypertrophy, congestive heart failure, and mortality.¹⁸

One possible explanation of the association between FGF23 levels and cardiovascular adverse events was shown in a study of chronic renal insufficiency. Faul and associates showed that elevated FGF23 levels are associated with left ventricular hypertrophy, as assessed by echo­cardiography in 3070 participants. In addition, the group also showed that FGF23 induced hypertrophic genes in neonatal rat ventricular cardiomyocytes.¹⁹ Because Klotho was not detected in cardiomyocytes, this effect was considered to be Klotho independent.

A signal transduction pathway study indicated that FGF23 induced hypertrophic genes through calcineurin. Furthermore, intramyocardial and intravenous injection of FGF23 in mice resulted in left ventricular hypertrophy, with left ventricular hypertrophy being inhibited in the animal model of CKD by the FGF receptor 1 (FGFR1)-selective inhibitor PD173074. Collectively, the investigators postulated that FGF23 induces cardiac hypertrophy through an FGFR-phospholipase Cγ-calcineurin pathway in a Klotho-independent manner.²⁰ The FGF23 renal coreceptor Klotho has been shown to be an early biomarker for CKD in humans and mice, and Klotho deficiency contributes to soft tissue calcification in CKD.²¹ Depletion of FGF23 causes hyperphosphatemia, upregulation of 1,25(OH)₂D₃, ectopic calcification, and early death.²²

In the recent study from Gutiérrez and associates, multivariate analyses showed that an increase in serum phosphate levels higher than 5.5 mg/dL and an increase of FGF23 were associated with a 20% increase in mortality risk, suggesting hyper­phosphatemia and increased FGF23 as sensitive biomarkers to assess risk of death.²³ However, with the increasing number of publications demonstrating the involvement of FGF23 in left ventricular dysfunction, atrial fibrillation, and left ventricular hypertrophy, it appears feasible that under pathologic conditions secondary sources of FGF23 exist. Oncostatin M was shown to potently induce expression and secretion of FGF23. Oncostatin M belongs to the interleukin 6 class of cytokines, which also comprises leukemia inhibitory factor and cardiotrophin. Oncostatin M exerts its effects in humans via the type 1 receptor, which is a heteromer of glycoprotein 130, leukemia inhibitory factor receptor-α and type 2 receptor complex, consisting of glycoprotein 130 and oncostatin M receptor-β. In addition, inflammatory processes, apart from those affecting the heart, may create some secondary oncostatin M responsive sources, such as the liver, and contribute to increased circulating levels of FGF23. The presence of FGF23 in the myocardium of patients with different types of heart failure and in mice with inflammatory heart failure suggests that macrophages are responsible for the FGF23 ex­pression in cardiomyocytes via oncostatin M.²⁴ Elevated circulating FGF23 concentrations have been associated with left ventricular hypertrophy, and it has been suggested that FGF23 exerts a direct effect on the myocardium. Although it is possible that “off target” effects of FGF23 present in very high concentrations could induce left ventricular hypertrophy, this possibility is controversial, since α-Klotho is not expressed in the myocardium. Another possibility is that the effects of FGF23 on the heart are mediated indirectly via “on target” activation of other humoral pathways.²⁵ The high rates of cardiovascular disease and mortality associated with elevated FGF23 levels may be due to various effects on the cardiovascular system, including left ventricular hypertrophy, arterial stiffness, vascular calcifications, endothelial dysfunction, and increased levels of inflammatory markers (Figure 2). With the bone recognized as an endocrine organ, a direct effect on the cardiovascular system by bone-derived hormones could be construed as “osteocardiac syndrome.” Additional indirect effects through the action of FGF23 on the kidney would create “osteorenocardiac syndrome.”²⁶

Fibroblast growth factor 23 and mineral metabolism parameters after kidney transplant
Successful transplant can reverse many com­plications of end-stage kidney disease; however, disturbances of bone and mineral metabolism, also referred to as mineral and bone disorders, may persist, and new bone disorders may also emerge as a result of transplant-related medications. Although bone disease has been recognized as a common complication in kidney transplant recipients, the routine application of adequate diagnostic tools and preventive or treatment strategies to correct bone loss or mineral disarrays may often be suboptimal. The hallmark of mineral and bone disorders is renal dystrophy, also known as kidney bone disease, which is classified into 4 major groups: high turnover bone disease, adynamic or low turnover bone disease, mixed renal osteodystrophy, and osteo­malacia (Figure 3). Recent evidence suggests that renal osteodystrophy and its primary causes including disordered parathyroid function and disarrays in vitamin D and FGF23 are related to cardiovascular disease and mortality.²⁷ The extreme elevations of FGF23 in dialysis patients, who can manifest 100- to 1000-fold elevations above normal ranges, sets the stage for tertiary FGF23 excess in the event of a kidney transplant. After transplant, there are some mineral alterations that could be related to FGF23 effects. Both FGF23 and PTH levels decreased substantially during the first week after transplant, but FGF23 levels still remained 10 times above normal. Currently, persistent excess of FGF23 after transplant has been suggested as the main contributing factor to posttransplant hypophos­phatemia and calcitriol deficiency despite a functioning allograft and the presence of persistent hyperparathyroidism. Data collectively suggest that, although FGF23 levels decline to a range that is comparable to patients with CKD, ongoing elevations above the normal range contribute to early posttransplant hypophosphatemia, loss of bone mineral density (BMD), and survival and allograft outcomes.²⁸

Hypophosphatemia
Kidney transplant recovers many kidney functions, thereby providing lessened rates of morbidity and mortality than a state of end-stage renal disease. Acute or chronic posttransplant hypophosphatemia may cause detrimental effects. In the early post­transplant period, when serum phosphate is the lowest, muscle weakness may appear, whereas effects of chronic hypophosphatemia are less clear. However, posttransplant bone disease is becoming a well-recognized entity, and partial involvement of hypophosphatemia has been suggested to occur after bone mineralization. Hypophosphatemia is reported to be present in as many as 90% of posttransplant patients. Although hypophosphatemia is usually seen early after transplant, phosphate levels remain low for a long time compared with that shown in CKD patients matched for glomerular filtration rate. Persistent hyperparathyroidism has long been suggested to be the cause of hypophosphatemia. However, inappropriate urinary phosphate wasting has been reported to occur despite low levels of PTH. Because FGF23 levels at 12 months posttransplant were relatively low and intact PTH levels were comparably high relative to glomerular filtration rate, pathogenesis of hypophosphatemia at 12 months may be due largely to persistent hyper­parathyroidism rather than due to high FGF23 levels. It could also be interpreted that FGF23 remains inappropriately elevated especially in light of the low serum phosphorus and decreased urinary phosphate reabsorption. Thus, dysregulation of the FGF23 inorganic phosphate and PTH axis may be present. Risk factors for hypophosphatemia in kidney trans­plant recipients early after transplant therefore may include disorders in regulation of tubular reabsorption of phosphate as a consequence of increased PTH level and activity, increased levels of FGF23, and adverse effects from immuno­suppressive drugs (tacrolimus, high steroid dose).²⁹ Several groups have published observational studies about FGF23 excess and posttransplant hypopho­sphatemia (Table 1).

A prospective observational cohort study by Kawarazaki and associates examined 39 consecutive living donor kidney transplant recipients and parameters of bone and mineral metabolism, including intact PTH and FGF23 levels. The group showed that FGF23 decreased to comparable levels for renal function, whereas hyperparathyroidism persisted at 12 months after transplant. Multivariate linear regression analyses revealed that pretransplant intact PTH correlated with hypercalcemia at 12 months and pretransplant FGF23 was the best pretransplant predictor of persistent hypophos­phatemia at 12 months.³⁰

A prospective, longitudinal study by Bhan and associates investigated 27 living donor transplant recipients and reported that hypophosphatemia at < 2.5 mg/dL developed in 85% of patients, including 1 patient who had previously undergone para­thyroid­ectomy. In addition, 37% of patients showed phosphate levels of < 1.5 mg/dL. Within the first week after transplant, mean FGF23 levels decreased to 557 ± 7579 relative units (RU)/mL, which were still above reference ranges. High FGF23 levels in the early posttransplant period appear to be more strongly associated with posttransplant hypophos­phatemia than PTH.31 In a prospective observational study by Evenepoel and associates, mineral metabolism (including PTH and FGF23) levels were measured in 50 renal transplant recipients at the time of transplant, at month 3, and at month 12. Fibroblast growth factor 23 levels and fractional phosphorus excretion significantly declined over time after renal transplant. The group demonstrated that hyperphos­phatemia and renal phosphorus wasting regress by1 year after successful renal transplant.32 In a cross-sectional study, Rao and associates investigated 106 kidney transplant patients, with hypophosphatemia rate of 34%, hypercalcemia rate of 3%, and rate of elevated PTH of 66%, at median of 12.8 months after transplant. Serum PTH levels were not associated with estimated glomerular filtration rate, corrected calcium levels, or serum phosphate. Fibroblast growth factor 23 levels were above the reference limits in 7% of patients; higher levels were associated with higher serum phosphate and PTH levels after adjustment for transplant kidney function.

Fibroblast growth factor 23 is an important driver of mineral metabolism in prevalent transplant patients. Its modulatory role in mineral metabolism homeostasis may be heightened as feedback suppression of PTH is disturbed.33 In a prospective observational study, Evenepoel and associates examined 41 recipients of deceased donor kidneys and elucidated the natural history of full-length FGF23 and the complex interactions of FGF23 with phosphate, calcium, PTH, and vitamin D early after transplant. They concluded that persistence of FGF23 contributes to hypophosphatemia and suboptimal calcitriol levels in renal transplant recipients.³⁴ Economidou and associates found that FGF23 levels decreased dramatically after successful renal transplant. Pretransplant FGF23 levels correlate with phosphorus levels 3 months after transplant.³⁵ Sirilak and associates investigated mineral levels in 229 kidney transplant recipients at least 1 year after their procedure. Despite reduced graft function, most kidney transplant recipients had lower serum phosphate levels than nontransplant patients accompanied by renal phosphate loss. Fibroblast growth factor 23 was mostly lower than or comparable with nontransplanted individuals, whereas parathyroid hormone was elevated in most transplant recipients. Relatively low serum phosphate from renal phosphate leak continued to be present in recipients in long-term kidney transplant follow-up.³⁶

Hypercalcemia
Hypercalcemic secondary hyperparathyroidism after kidney transplant occurs in approximately 30% to 50% of kidney transplant recipients early after transplant. The enlarged parathyroid gland involutes subsequently, and hypercalcemia resolves in most patients. Patients without improvement of hyper­parathyroidism and hypercalcemia are defined as having persistent, hypercalcemic, secondary hyper­parathyroidism or tertiary hyperparathyroidism. Increased serum calcium could result from high bone turnover, which, in turn, leads to a brittle bone with increased fracture risk. Borchhardt and associates found that hypercalcemia of posttransplant hyper­parathyroidism was associated with high or low turnover bone disease. Decreased calcium excretion suggests an additive tubular effect on hyper­calcemia.³⁷ Hypercalcemia can be severe enough to cause calciphylaxis, leading to renal failure, as has been reported, eventually requiring parathy­roidectomy. High PTH concentrations stimulate renal production of calcitriol, which, in turn, increases intestinal absorption and improves the skeletal mobilization of calcium.

Another potential factor causing hypercalcemia after kidney transplant is recovered circulating levels of calcitriol, secondary to its increased renal tubular synthesis, further stimulated by the inappropriately high PTH and low phosphorus levels. The recovered calcitriol levels may also induce hypercalcemia both by its intestinal and bone effects.^38,39 Evenepoel and associates in a single center observational study demonstrated that microscopic nephrocalcinosis is highly prevalent in the early posttransplant period and suggested disordered mineral metabolism as its pathogenesis.⁴⁰

The best way to avoid hypercalcemia after kidney transplant is to optimally treat secondary hyper­parathyroidism before kidney transplant. Some authors reported an absolute indication to para­thyroidectomy for patients on kidney transplant wait lists in the presence of a severe secondary hyperparathyroidism, defined by high PTH levels (intact PTH > 800 pg/mL) and hypercalcemia (total serum calcium > 10.4 mg/dL), which cannot be controlled by available medical therapy. A strong, although not absolute, further indication to the surgical intervention before renal transplant might also be the presence of secondary hyper­parathyroidism controlled only by maximal medication doses. In hypercalcemic kidney trans­plant recipients, cinacalcet lowered serum calcium and raised serum phosphate levels. By minimizing PTH-mediated phosphaturia and modestly reducing FGF23, cinacalcet might be an option in certain kidney transplant recipients. However, cinacalcet should be reserved for some specific cases such as kidney transplant patients with posttransplant hyperparathyroidism associated with overt hypercalcemia (serum calcium > 12 mg/dL) and those who have already have had a previous parathyroidectomy and/or have clinical conditions that make the intervention a risk procedure and/or refuse the intervention for any reason.⁴¹

Other investigators have proposed beginning treatment with cinacalcet in all patients with corrected serum calcium > 11 mg/dL and in those with corrected serum calcium between 10.5 and11 mg/dL for more than 6 months, in all cases with PTH > 120 pg/mL. The starting dose should be30 mg/day of cinacalcet, which should be maintained for 6 months. In the event that the patient responds to the initial dose of 30 mg/day (corrected serum calcium < 10.2 mg/dL at 6 months after treatment), they proposed maintaining the same dose for another 6 months (1 year total) and, if there is good control, discontinuing the medication, with a new test after 6 months. If calcium levels increased again above 10.2 mg/dL, treatment has been recom­mended again with cinacalcet. However, if levels remain high with an initial dose of 30 mg/day (corrected serum calcium > 10.2 mg/dL after 6 months), the dose should be increased to 60 mg/dL. If by increasing the dose we are able to control calcemia, we could consider decreasing the dose again to 30 mg/day after 6 months and maintaining this regimen for at least another 6 months. If calcemia is controlled in this way, we could consider withdrawing the drug. If the patient has corrected serum calcium > 10.5 mg/dL for more than 12 months despite an increased dose of cinacalcet, the most suitable course of action would be to consider parathyroidectomy.⁴² Others believe cinacalcet provides an alternative to parathyroidectomy for the treatment of posttransplant hyperparathyroidism.⁴³

Calcitriol deficiency after renal transplant
Calcitriol deficiency persists in patients with a functioning allograft for several months after transplant despite excessive PTH, a healthy allograft, and hypophosphatemia, each of which should stimulate its production. Mazzaferro and associates investigated the effects of reduced 25-hydroxy­vitamin D on circulating 1,25(OH)₂D₃ in 111 patients with chronic renal failure compared with 136 transplant recipients. This study showed that, in patients with CKD, circulating levels of calcitriol are influenced by glomerular filtration rate, vitamin D status, and, importantly, hydroxylase efficiency. Compared with patients with chronic renal failure, transplant recipients with increased hydroxylation efficiency can better tolerate vitamin D insuf­ficiency.⁴⁴ Renal transplant recipients have a high prevalence of vitamin D deficiency versus healthy individuals. This arises for several reasons, including the mild-to-moderate degree of renal functional impairment that characterizes most allografts (causing loss of renal tubular 1α-hydroxylase, also known as cytochrome P450 family 27 subfamily B member 1 or CYP27B1), the raised serum concentrations of FGF23, immunosuppressive drugs inducing vitamin D catabolism, and medically advised sun-avoidance behavior. Fibroblast growth factor 23 actively inhibits vitamin D through suppression of 1α-hydroxylase, reducing 1α-hyd­roxylation of 25-hydroxyvitamin D and induction of CYP24A1, which enhances calcitriol and 25-hydroxy­vitamin D degradation. The skeletal, renal, and gastrointestinal effects of vitamin D on calcium and phosphate homeostasis are well known, with vitamin D deficiency linked to increased risk of postrenal transplant bone mineral loss and fractures. Vitamin D is also recognized to exert effects on both the innate and adaptive immune systems. In so doing, vitamin D status in renal transplant recipients can affect immunologically driven posttransplant outcomes, notably allograft rejection, transplant function, and development of de novo posttransplant malignancies.⁴⁵ The active vitamin D hormone, 1,25(OH)₂D₃, can be produced in endothelial cells through activity of a specific endothelial α-hydroxylase on circulating 25-hydroxyvitamin D. There is now an abundance of data that demonstrate the beneficial effects of 1,25(OH)₂D₃ on mediators of inflammation through the modulation of macrophage/monocytes and T and B lymphocytes. It also affects the differentiation of active CD4-positive T cells, enhances the inhibitory function of T cells, and promotes differentiation of monocytes into mature macrophages. Endothelial dysfunction can be detected at early stages of CKD. Although endothelial functions improve after successful renal transplant, renal transplant recipients still have worse endothelial function than healthy individuals.46 Vitamin D deficiency and high FGF23 levels may have a role in endothelial dysfunction in patients with CKD. Furthermore, vitamin D deficiency is associated with endothelial dysfunction in renal transplant recipients. In a study of 109 renal transplant recipients who underwent brachial flow-mediated dilatation, serum 25-hydroxyvitamin D and FGF23 levels were measured, with vitamin D levels significantly lower in patients with endothelial dysfunction than in patients with normal endothelial functions and FGF23 levels without different between the 2 groups. 25-Hydroxyvitamin D levels had a significant positive correlation with amount of flow-mediated dilatation, but FGF23 levels were not predictive of flow-mediated dilatation in this model.

Bone mineral loss after renal transplant
Accelerated BMD loss is an almost universal complication in transplant recipients. The accelerated BMD loss in organ transplant recipients is mainly considered as an adverse effect of immuno­suppressive drugs, especially glucocorticoids. It is, however, well established that fracture risk is higher in renal transplant recipients than in recipients of other organs. Specific risk factors such as preexisting renal osteodystrophy, hypogonadism, and metabolic acidosis undoubtedly play important roles. Post­transplant disturbances in phosphate homeostasis should be accounted for as well. Hypophosphatemia is a frequent finding early after transplant, and renal phosphate wasting is the main mechanism contributing to this complication. It is recognized that both hypophosphatemia and renal phosphate wasting may have detrimental effects on bone mineralization. Kanaan and associates performed a two-center observational retrospective cohort study in 127 renal transplant recipients and found that patients with high serum FGF23 levels and/or low PTH levels at time of transplant are at risk for increased BMD loss during the first year post­transplant.⁴⁷ Fernandez and associates explored circulating FGF23 in association with fatness and insulin sensitivity, atherosclerosis, and BMD in 2 cohort studies and concluded that the associations between circulating FGF23 concentrations and glucose metabolism, BMD, and atherosclerosis are dependent on iron and obesity status-associated insulin resistance.⁴⁸

Fibroblast growth factor 23 and allograft outcomes
Allograft and patient survival rates have improved steadily over the past decades as a result of advances in surgical techniques, immunosuppressive regi­mens, and prophylaxis against opportunistic infections. As a result, death and disability caused by cardiovascular disease and late graft loss caused by chronic allograft nephropathy have surpassed infection and early allograft loss caused by rejection as the primary threats to the health of kidney transplant recipients. Many kidney transplant recipients develop hypophosphatemia and hyper­calcemia because of persistent elevations of FGF23 and PTH in the early period after a successful transplant. Although these overt changes in serum phosphate and calcium usually resolve without intervention within weeks to months, the effects of increased FGF23 and PTH levels on long-term patient and allograft survival rates are unknown. Wolf and associates tested increased FGF23 as an independent risk factor for all-cause mortality and allograft loss in a prospective cohort of 984 stable kidney transplant recipients. Higher FGF23 levels were independently associated with increased risk of the composite outcome of all-cause mortality and allograft loss.⁴⁹ Fibroblast growth factor 23 modulates the metabolism of minerals and vitamin D. In CKD, this process is disturbed owing to decreased parathyroid expression of the FGF23 receptor complex Klotho-FGF1. Krajisnik and associates demonstrated that similar alterations occur in parathyroid glands from kidney transplant recipients in association with a decline in allograft function. The group demonstrated similar phenotypic alterations in the expression of the parathyroid Klotho-FGFR1 complex among patients who received kidney transplants.^50,51

Conclusions

Cardiovascular disease is the leading cause of mortality in adult renal transplant recipients. Fibroblast growth factor 23 is an independent risk factor for cardiovascular mortality; moreover, it seems that excess FGF23 is an important factor in pathogenesis of bone disease, altered mineral metabolism, and allograft survival after renal transplant. Although it may be relevant to consider therapies that reduce FGF23 levels to improve cardiovascular outcomes, it should be kept in mind that high FGF23 levels may serve an important physiologic goal, namely, to keep phosphate balance.

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