The future of phosphate binders: a perspective on novel therapeutics

Abstract

Chronic kidney disease-mineral bone disorder (CKD-MBD) is a common complication of CKD. The therapeutic strategies for the treatment of CKD-MBD include phosphate binders, active vitamin D analogs and calcimimetics. The first class of drugs provided nephrologists with a range of phosphate binders that are able to decrease circulating phosphate and parathyroid hormone but involve some tolerability and safety issues. In the past 2 years, new phosphate binders have been launched and others are still under development. Serum phosphate increases only in the late stages of CKD but clinical abnormalities begin to occur earlier when multiple mechanisms try to compensate for the progressive reduced ability of the kidney to eliminate phosphorus with urine. Accordingly, starting phosphate binders when phosphatemia reaches values higher than normal may represent a late therapeutic approach. Serum phosphorus is not the ideal biomarker for the diagnosis and treatment of phosphate imbalance. This role could be better played by fibroblast growth factor 23, whose serum concentrations rise earlier in CKD. A more detailed knowledge of the mechanisms underlying CKD-MBD development will provide new therapeutic targets and then new perspectives for the treatment of phosphate imbalance in the future.

Keywords::

• chronic kidney disease-mineral bone disorder
• fibroblast growth factor 23
• phosphate
• phosphate binders
• vascular calcifications

1. Introduction

Chronic kidney disease-mineral bone disorder (CKD-MBD) increasingly affects CKD patients as they undergo progressive renal impairment. It is defined as ‘a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following: abnormalities of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D metabolism; abnormalities in bone turnover, mineralization, volume, linear growth, or strength; vascular or other soft tissue calcification’ [1]. CKD-MBD pathophysiology is shown in Figure 1.

Figure 1. Illustration of the pathophysiology of CKD-MBD according to GFR value and CKD stage. The more recent data from literature suggest the first abnormality to be a decrease in klotho expression. This determines a progressive peripheral resistance to FGF23 and an increase in its serum levels. By inhibiting 1α-hydroxylase, FGF23 reduces 1,25-dihydroxyvitamin D3 [1,25(OH)₂D3] production with consequent secondary hyperparathyroidism, enhanced bone remodeling, increased serum phosphorus and calcium levels, vascular smooth muscle cell calcifications and further increase in FGF23 expression.

KDIGO Guidelines [2] suggest that monitoring of serum levels of calcium, phosphorus, PTH and alkaline phosphatase should start in CKD stage 3 (Guideline 3.1.1.) and that therapeutic approach should be decided based on trends rather than on a single laboratory value (Guideline 3.1.4.). The purpose is to prevent or at least reduce secondary hyperparathyroidism and vascular calcifications, the latter ultimately being responsible for adverse cardiovascular outcomes and increased overall mortality [3].

The therapeutic options for the treatment of CKD-MBD include phosphate binders, active vitamin D analogs and calcimimetics. The physiological role played by vitamin D in calcium/phosphate balance justifies the use of vitamin D sterols, active vitamin D analogs and calcimimetics in CKD (Figure 2).

Figure 2. Illustration of vitamin D metabolism. In the skin, 7-dehydrocholesterol is converted to cholecalciferol (vitamin D3) by ultraviolet B (UVB) rays. Then, a 25-hydroxylase present in the liver transforms cutaneous cholecalciferol and the one deriving from diet and supplements in 25-hydroxyvitamin D3, which in turn is converted to 1,25-dihydroxyvitamin D3 by the renal 1α-hydroxylase. 1,25-dihydroxyvitamin D3 is the active form of vitamin D and, by binding to its related receptor (vitamin D receptor [VDR]), exerts the hormone effects on different target tissues. The physiological role played by vitamin D in calcium/phosphate balance justifies the use of the drugs listed in the table at the top right of the picture in CKD patients.

Focusing on phosphate binders, they act by binding dietary phosphate in the gastrointestinal tract in order to reduce its absorption and so interfere with CKD-MBD progression. Nephrologists are currently provided with a range of phosphate binders that are able to decrease circulating phosphate and PTH but imply some tolerability and safety issues. These medications can be schematically classified into two groups according to the presence or absence of calcium. Calcium-based binders (calcium acetate, calcium carbonate) are effective in lowering phosphatemia; however, their use has been associated with hypercalcemia, positive calcium balance and cardiovascular calcifications [4]. Calcium-free phosphate binders, including sevelamer, lanthanum carbonate and others, should not entail an increase in serum calcium levels, owing to the absence of calcium in their chemical composition. A meta-analysis demonstrated that they seem not to be superior in lowering phosphorus levels compared with calcium-based binders and, in direct comparisons, calcium salts are even more effective [5]. The difference in the effects of the two classes of drugs on calcium and phosphorus levels reasons out the reduced ability of calcium-free phosphate binders to suppress serum PTH compared to calcium-based drugs [6]. Additionally, sevelamer carbonate can induce gastrointestinal symptoms (nausea, vomiting, abdominal pain, constipation, diarrhea, dyspepsia) and, on the other hand, lanthanum carbonate may accumulate in the tissues, particularly in bone, with still poorly known potential long-term consequences [4]. Some authors [7] demonstrated that 1-year lanthanum treatment in dialysis patients is associated with an increase in bone content of the element that remains stable for 2 years after discontinuation. Large trials with adequate follow-up periods are lacking, so we cannot exclude that lanthanum bone deposition could be significantly detrimental [8].

2. New phosphate binders

Recently, Wu-Wong and Mizobuchi [9] evaluated currently available drugs and new phosphate binders by reviewing literature and searching on ClinicalTrials.gov website [10] for completed trials and clinical studies. They discussed advantages and adverse effects of drugs that have been launched in the past 2 years and new still-developing phosphate binders.

Within the first group is bixalomer, an amine functional polymer that has been marketed in Japan recently. It is able to bind phosphate and correct hyperphosphatemia through a still unknown mechanism and its use seems to be associated with fewer gastrointestinal symptoms, if compared with sevelamer hydrochloride [11,12], although other authors observed no significant differences in gastrointestinal adverse effects between the two drugs [13]. Another recently launched phosphate binder is RenaGum™. It is a chewing gum containing chitosan, a natural linear polysaccharide that binds salivary phosphate in the mouth and in the gastrointestinal tract and eliminates it through feces [14]. It has been observed that chitosan, mainly added to a basic standard therapy rather than administered as a single drug, significantly contributes to reduction of phosphatemia in hemodialysis patients as well as in CKD patients not on dialysis [15]. Also Velphoro® (PA21) has recently received US FDA approval for the treatment of hyperphosphatemia in hemodialysis patients. It is a chewable phosphate binder including polynuclear iron (III)-oxyhydroxide in its chemical structure and seems not to be inferior to sevelamer in lowering serum phosphate [16]. Nevertheless, patients affected by significant gastric or hepatic disorders, a history of hemochromatosis or other diseases with iron accumulation have been excluded from the clinical studies made so far because of the risk of iron overload.

Wu-Wong and Mizobuchi [9] also examined new phosphate binders still under development. Most of them are iron-based compounds and this is related to the known ability of chemicals containing iron to bind dietary phosphate. Those tested in human trials include: fermagate (iron-magnesium hydroxycarbonate), PT20 (ferric hydroxide adipate), SBR759 (polymeric complex composed of iron [III] and starch) and Zerenex™ (ferric citrate coordination complex, also named KRX-0502). Moreover, preclinical studies have been performed to evaluate the effectiveness of crosslinking chitosan–Fe(III), iron–dextran, iron hydroxide and iron saccharide. As regard non-iron-based compounds, Genz-644470 has been evaluated in humans, whereas only preclinical data are available for the poly(allylamine) polymer TRK-390.

In conclusion, the therapeutic armamentarium for the treatment of CKD-MBD is going to be enriched with new phosphate binders that are expected to be more tolerated than and at least as effective as the already-available drugs.

3. Expert opinion

CKD-MBD is a common complication of chronic renal failure. Serum phosphate rises only in the late stages of CKD but clinical abnormalities begin to occur early when multiple mechanisms, including the increase in the blood levels of the phosphaturic hormones fibroblast growth factor 23 (FGF23) and PTH, try to compensate for the progressive reduced ability of the kidney to eliminate phosphorus through urine. Accordingly, starting phosphate binders when phosphatemia reaches values higher than normal may represent a late therapeutic approach: this, at least in part, reasons out the still unsuccessful attempt to reduce vascular calcifications and the consequent increased incidence of cardiovascular events and mortality in CKD patients as compared to general population. The development of new phosphate binders is undoubtedly welcome and needed, especially due to the safety and tolerability concerns existing in the current available drugs, but we should go back to the physiology of mineral metabolism and the pathophysiology of CKD-MBD starting from the early stages of renal impairment in order to identify novel potential therapeutic targets.

It is known that FGF23 is secreted by osteoblasts and osteocytes; in healthy young men, it is involved in the regulation of inorganic phosphate homeostasis and its levels are directly related to dietary phosphate intake [17].

FGF23 increases precociously in the course of CKD as a compensatory mechanism to prevent the onset of hyperphosphatemia and secondary hyperparathyroidism. However, FGF23 becomes crucial in CKD-MBD pathogenesis and progression (Figure 1). The rise in FGF23 levels is associated with the reduction of renal function and is mainly caused by hyperphosphatemia, hypercalcemia, secondary hyperparathyroidism and deficiency of the FGF23 tissue co-receptor klotho, the latter mechanism inducing a progressive peripheral resistance to FGF23 [18].

Many other factors might have a role in renal osteodystrophy due to their documented involvement in the regulation of bone remodeling. They include, for example, the osteoprotegerin/receptor activator of NF-κB and its ligand (OPG/RANK/RANKL) system [19], the hormone relaxin-2 [20] or the guidance protein semaphorin 3A [21].

Hence, the pathogenesis of CKD-MBD is potentially very complex and is still poorly understood and, as already suggested [9], probably serum phosphorus is neither the ideal biomarker nor the unique parameter to be considered for the diagnosis and treatment of phosphate imbalance. The role of biomarker could be better played by FGF23, whose serum concentrations rise earlier in CKD. However, we still lack standardized assay methods and validated reference values to use FGF23 in clinical practice.

Moreover, a recent work by Block et al. [22] demonstrated that the administration of phosphate binders (calcium acetate or lanthanum carbonate or sevelamer carbonate versus placebo) to patients with moderate-to-advanced CKD and normal or almost normal phosphatemia is able to reduce serum and urinary phosphorus and slow down the progression of secondary hyperparathyroidism but it does not determine noteworthy changes in neither plasma C-terminal FGF23 nor intact FGF23 levels. Actually, the latter observation is true only if we consider globally the phosphate binders tested: indeed, in this study, sevelamer carbonate significantly reduced intact FGF23, but calcium acetate increased it, whereas patients receiving lanthanum carbonate did not show any difference compared with the placebo group. These results are confirmed by Ureña-Torres et al. who reported no sustained decrease in intact FGF23 concentrations in normophosphatemic patients with stage 3 CKD treated with lanthanum carbonate [23]. Moreover, Nagano et al. have previously demonstrated that sevelamer hydrochloride reduced serum phosphorus and subsequently FGF23 levels in rats with chronic renal failure [24].

Block et al. also observed that the use of phosphate binders significantly increased vascular calcifications in the coronary arteries and abdominal aorta [22].

According to these unexpected data, we wonder whether phosphorus is the real enemy to fight or it would be rather necessary to interfere directly with the increased FGF23 levels or the reduced expression of klotho, in order to halt CKD-MBD onset or progression at the very beginning and in such a way reduce adverse cardiovascular outcomes. In this context, preliminary data on animal models suggest that klotho delivery may be advantageous in CKD [25], whereas FGF23 neutralization by monoclonal FGF23 antibodies seems to improve secondary hyperparathyroidism but increases phosphatemia, aortic calcification and mortality [26].

The new phosphate binders under development or recently launched should demonstrate to be noninferior and better tolerated than established drugs. Additionally, a more detailed knowledge of the mechanisms underlying CKD-MBD and vascular calcification development will provide new therapeutic targets and new perspectives for the treatment of phosphate imbalance in the future.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents, received or pending, or royalties.

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