New therapies: calcimimetics, phosphate binders and vitamin D receptor activators
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- Cannata-Andía, J.B., Rodriguez-García, M., Román-García, P. et al. Pediatr Nephrol (2010) 25: 609. doi:10.1007/s00467-010-1462-9
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At present, new compounds are available to treat secondary hyperparathyroidism, namely calcimimetics, novel phosphorus binders and also novel vitamin D receptor activators. Calcimimetics increase the sensitivity of the parathyroid gland to calcium through spatial configurational changes of the calcium-sensing receptor. In addition, experimental studies have demonstrated that calcimimetics also upregulate both the calcium-sensing receptor and the vitamin D receptor. They are efficacious in children, though the experience in paediatric chronic kidney disease is still limited. Sevelamer, lanthanum carbonate and magnesium iron hydroxycarbonate are novel phosphorus binders available on the market. Several studies have demonstrated their efficacy and safety up to 6 years, though costs are the main limitation for a wider use. Since almost all the experience available on the new phosphorus binders comes from its use in adults, studies on children are needed in order to confirm the efficacy and safety of these products. Other new salts and polymers are also being developed. New vitamin D receptor activators, such as paricalcitol, are as effective at suppressing parathyroid hormone (PTH) as the traditional vitamin D receptor activators used for the past two decades, but they have a better and safer profile, showing fewer calcaemic and phosphoraemic effects while preserving the desirable effects of the vitamin D receptor activators on the cardiovascular system, hypertension, inflammation and fibrosis. Their use in children with chronic kidney disease has revealed similar responses to those of adults. The novel compounds discussed in this review should facilitate and improve the management of mineral and bone disorders in children with chronic kidney disease.
KeywordsCalcimimeticsVitamin D receptor activator (VDRA)Phosphorus binderChronic kidney disease-related mineral and bone disorders (CKD-MBDs)Children
Secondary hyperparathyroidism (SHPT) is a complication of chronic kidney disease (CKD). The regulatory mechanisms of parathyroid hormone (PTH) synthesis are complex, involving calcium, the calcium-sensing receptor (CaSR), phosphorus, calcitriol and the vitamin D receptor (VDR) [1, 2].
In CKD the ability of the kidneys to remove phosphorus from circulating plasma is reduced, leading to the accumulation of phosphorus. In addition, calcitriol synthesis decreases in direct response to the decline in kidney function, triggering a cascade of events that include decreased calcium absorption and an increase in PTH production. Elevations in serum PTH concentration are observed early in the development of CKD [3, 4]. Prevention and treatment of SHPT are critical, because mineral metabolism imbalances are associated with increased morbidity and mortality rates in CKD patients [5, 6].
Fortunately, several new compounds are now available that can slow down and/or prevent the progression of SHPT, namely calcimimetics, phosphorus binders and vitamin D receptor activators (VDRAs).
Serum calcium, the calcium-sensing receptor and calcimimetics
Extracellular calcium is the main parathyroid regulator; low levels of calcium stimulate PTH secretion, while elevated levels inhibit hormone release and favour degradation within the parathyroid gland [7–10]. The parathyroid gland’s response is sigmoidal; thus, small changes in extracellular calcium cause large PTH variations. The effects of calcium on PTH are mediated by its specific receptor, the CaSR, which belongs to the G-protein-coupled receptor family and is present in the membrane of the parathyroid cells . Any increments in extracellular calcium are sensed by the CaSR, which triggers a cascade of intracellular signalling that results in the inhibition of PTH synthesis and secretion.
It has been demonstrated that, in CKD, there is a significant reduction in CaSR expression. As a result, the parathyroid gland is less able to sense the increments of calcium; hence, PTH synthesis and release increase inadequately [1, 2, 12]. The response of the parathyroid gland depends on the rapidity and duration of the hypocalcaemic stress; PTH release in response to calcium occurs within seconds to minutes after signalling through the CaSR . Chronic hypocalcaemia and hyperphosphataemia stimulate PTH gene expression and subsequent PTH synthesis within hours to days , and proliferation of parathyroid cells occurs over days to weeks . The continuous stimulation of the parathyroid gland results in gland enlargement and uncontrolled excess of PTH. Until now, in order to control this situation, calcium supplements and high doses of VDRAs have been used, inducing unwelcome increases of serum calcium (Ca) which, in turn, have been consistently associated with an increased risk of death [5, 6]. Fortunately, calcimimetics are already available in several countries and offer a great opportunity for us to avoid this situation by improving the management of SHPT in patients with stage 5 CKD.
Calcimimetics interact with CaSR at different sites of the molecule, not where calcium binds the CaSR. Calcimimetics change the spatial configuration of CaSR, and, as a result, the sensitivity of CaSR to calcium is increased. In addition, experimental studies have demonstrated that calcimimetics upregulate CaSR and VDR; hence, thanks to this process, they may prevent or attenuate parathyroid hyperplasia [16–18]. Calcimimetics produce persistent long-term suppression of PTH release; however, due to is half-life, they also induce short-term suppression of PTH synthesis, allowing circadian fluctuations of the circulating PTH with potential anabolic effects on bone, as has been experimentally demonstrated in low-bone turnover states and in ovariectomized rats [19, 20].
Several studies of patients with stage 5 CKD have demonstrated a sustained effect of calcimimetics on the parathyroid gland control, with concomitant and useful reductions in serum phosphorus and serum calcium [21–23]. In addition, large trials are in progress to evaluate the effect of calcimimetics on relevant clinical and hard outcomes, such as vascular calcifications, myocardial events and deaths .
By contrast, in patients with stages 3 and 4 CKD, calcimimetics should not be used, since they can induce undesirable increments in serum phosphorus by mechanisms not fully understood [25, 26]. On the other hand, cinacalcet can be beneficial to patients with stages 3 and 4 CKD who have received kidney transplants, for whom the calcimimetic-induced reduction in the ‘PTH-induced phosphaturia’ and the consequent retention of phosphorus may counterbalance the frequently observed PTH-dependent reduction in serum phosphorus due to the persisting parathyroid gland hyperplasia.
Calcimimetics are efficacious in children at stage 5 CKD, though the experience is quite limited due to the reduced number of patients studied [27, 28]. Experimental studies have demonstrated that calcimimetics do not affect growth or promote weight gain in chronic kidney failure . However, a reduction of median testosterone levels has been recently reported . Thus, the long-term safety of calcimimetics on the skeleton remains to be defined, and large long-term randomized controlled trials should be conducted in this area.
Impact of high levels of serum phosphorus; experience with novel phosphorus binders
High serum phosphorus levels, a highly prevalent condition in CKD patients, have been associated with the pathogenesis of secondary hyperparathyroidism [5, 6, 31], the development of vascular calcification , vascular stiffness , left ventricular hypertrophy , and death [5, 6]. A high level of serum phosphorus has become an extremely important pathogenetic factor in the constellation of chronic kidney disease-related mineral and bone disorders (CKD-MBDs). Furthermore, the reduction of serum phosphorus caused by the use of phosphorus binders has been recently associated with better survival rates [34, 35]. Even though high serum phosphorus levels may play a key harmful role in the above-mentioned clinical outcomes, some of its effects can also be partly due to a new phosphorus-related player: fibroblast growth factor 23 (FGF 23), a phosphatonin that may carry out actions that are dependent upon and independent of phosphorus .
The kidneys and the bones are the main regulators of phosphorus homoeostasis in day-to-day life. While kidneys remove phosphorus from circulating plasma, bone acts as a reservoir of phosphorus. As mentioned, the ability of the kidneys to remove phosphorus in patients with CKD is reduced (stages 3–5), or absent (stage 5D), resulting in high serum phosphorus levels which, in combination with low serum calcium and low calcitriol levels, stimulate PTH synthesis and secretion. In fact, the most well-known and most studied consequences of high levels of serum phosphorus are the effects on the parathyroid glands, which, in turn, affect bone metabolism. High serum phosphorus levels impair calcitriol synthesis, increase skeletal resistance to PTH and also directly increase PTH synthesis. In addition, several studies have shown that high serum phosphorus levels increase parathyroid cell proliferation and that they can reduce CaSR expression [37, 38].
The three most important factors in the management of high levels of serum phosphorus are dietary restriction, the use of phosphorus binders, and adequate dialysis. In this review we concentrate only on the effect of phosphorus binders. All currently available oral phosphorus binders, the so-called old and new phosphorus binders, have limitations.
The ‘old phosphorus binders’
Aluminium hydroxide was the first phosphorus binder, and it has been widely used for many years. It is the most potent phosphorus binder, but also the most toxic one . For this reason, in the 1980s, it was progressively replaced by the calcium-containing phosphorus binder. The use of the latter also became widespread, but, later on, several disadvantages became apparent. It has been proven that the use of calcium salts, especially if exceeding 1.5 g of calcium daily, increases the risk of vascular calcification, even in children and young adults , and that it can also lead to greater vascular stiffness . Magnesium-containing phosphorus binders have also been used as an alternative, but they are generally less effective. The adverse events have limited the use of the calcium-containing phosphorus-binders and stimulated the synthesis of a new generation of phosphorus binders, including salts and polymers, some of them already available in the market, such as sevelamer and lanthanum carbonate, while others are still being developed .
The ‘new phosphorus binders’
Sevelamer hydrochloride was the first non-aluminium, non-calcium-based phosphorus binder commercially available. Several studies have demonstrated that sevelamer is effective in lowering serum phosphorus levels without inducing increments in serum calcium and may attenuate coronary and aortic calcification, in comparison with calcium-containing phosphorus binders . Other additional beneficial pleiotropic effects of sevelamer have been reported, but they need further confirmation [44, 45]. Despite the fact that sevelamer hydrochloride offers several advantages, gastrointestinal disturbances and metabolic acidosis have been limiting factors for the widespread use of this phosphorus binder. However, the formulation as sevelamer carbonate has been recently introduced; this new formulation would be an advantage in the use of this compound.
Lanthanum carbonate became available in 2005 in the United States of America and in 2006 in the European Union. Preclinical animal studies demonstrated that lanthanum carbonate, a non-aluminium, non-calcium-based binder, featured a phosphorus binding capacity closer to that of aluminium with a better safety profile and a low systemic uptake. A minor fraction of the oral dose is absorbed (<0.0013%), circulates bound to serum proteins, and is mainly cleared through biliar excretion after transition through the liver within lysosomes . Clinical trials using calcium carbonate as comparator demonstrated that lanthanum carbonate was as effective as calcium carbonate, but that it induced significantly less hypercalcaemia . The relative potency of lanthanum carbonate as a binder allows a reduced pill burden . Despite concerns being raised about potential liver and bone toxicity related to its long-term use , recent publications have shown a satisfactory long-term safety profile (up to 6 years of use) . However, another recent study demonstrated that, 1 year after discontinuation of lanthanum therapy, bone lanthanum content remains elevated in dialysis patients . The long-term effects of lanthanum carbonate on the skeleton are unknown, so more studies, specifically on children with CKD, are needed in order to confirm its efficacy and safety.
Magnesium iron hydroxycarbonate is another new oral phosphorus binder that has shown promising preliminary results ; its use is associated with increased serum magnesium levels. Even though the long-term effects of high serum magnesium levels has not been specifically assessed, hypermagnesaemia has been associated with a reduction of vascular calcification  and adynamic bone .
A matter of great concern common to all the new phosphorus binders is their cost in comparison with that of previous phosphorus binders. The aim is to replace low-cost phosphorus binders, such as calcium salts; however, the high cost will be an important limiting factor in the widespread use of the new phosphorus binders.
In summary, there are a few novel phosphorus binders available and others being researched. In addition, there is already abundant experience of the use of sevelamer hydrochloride in children with stage 5 CKD, which has shown a similar pattern of response to that observed in adults . Generally speaking, the safety profile of the new phosphorus binders available on the market is safer than that of the old phosphorus binders, although their cost is higher.
The vitamin D system and the new VDR activators
Vitamin D is a steroid hormone system that has long been known for its key role in the regulation of calcium and phosphorus and the mineralization of bone. Calcitriol, the physiological VDRA, is the natural parathyroid gland regulator and exerts its effect on PTH secretion by inhibiting mRNA synthesis through its action on the VDR, a highly specific receptor that acts as a transcription factor . When calcitriol binds the receptor, it induces the translocation of the calcitriol–VDR complex to the cell nucleus, forming a heterodimer with the retinoid X receptor (RXR). Then, the calcitriol–VDR–RXR complex binds the vitamin D-responsive elements present in the PTH gene promoter, blocking its transcription . In addition, calcitriol is able of inhibiting PTH secretion by increasing calcium absorption in the intestine, while also increasing bone resorption and, consequently, calcium release from bone. In contrast to what occurs with calcium and the CaSR, calcitriol regulates the expression of its own receptor (VDR), stimulating its synthesis. The deficit of calcitriol observed in CKD patients is associated with a decrease in VDR levels in the parathyroid gland. Besides its effect on VDR, calcitriol can also regulate the CaSR .
Until now, VDRAs have been used mainly in the treatment of SHPT. However, there is new evidence suggesting that the use of VDRAs might have other relevant consequences for CKD patients. One of the seminal contributions in this area was the study performed by Teng et al. , who showed a better survival rate in patients treated with paricalcitol than in those treated with calcitriol, supporting the hypothesis that the less calcaemic and phosphoraemic VDRAs may be advantageous for CKD patients. Since then, several papers have dealt with the likely effects of VDRAs on survival beyond calcium and phosphorus metabolism [58–61]. However, it is important to stress that, so far, all the current favourable experience with different VDRAs comes from epidemiological association studies; thus, randomised clinical trials in this area should be performed.
There is evidence linking VDRAs with improvement in left ventricular function. Animals lacking the VDR show cardiovascular abnormalities, such as hypertension and left ventricular hypertrophy, and cardiomyocytes develop contractile abnormalities [62, 63]. Vitamin D may also influence growth, hypertrophy, collagen deposition, and differentiation of cardiomyocytes [64–66]. Moreover, lower levels of calcidiol have been associated with a higher risk of hypertension, a greater rate of progression to CKD, and death [67, 68]. In addition, differential effects between VDRAs has been demonstrated: in fact, hypertensive rats treated with paricalcitol showed better left ventricular function  and significant renin suppression with a less calcaemic effect than those treated with calcitriol .
The presence of VDR on the vascular wall suggests that some of the differential effects of VDRA on the cardiovascular system might be driven by its effects on the vasculature. In fact, high doses of paricalcitol induced almost no vascular calcification, whereas calcitriol induced massive aortic calcifications in experimental animals . The negative effect of calcitriol on the vasculature has also been recently observed in children on dialysis, in whom calcitriol use has been associated with increased vascular calcification .
Other beneficial effect of VDRAs on CKD patients may be related to their effects on inflammation and fibrosis. Low vitamin D levels are associated with high C-reactive protein levels  and cardiovascular disease . Similarly, recent studies have suggested that paricalcitol might reduce fibrosis, inflammation and proteinuria independently of glomerular filtration rate and blood pressure or angiotensin-converting enzyme inhibitors, though the concomitant use of the latter may improve its performance [75–78].
In summary, new VDRAs, such as doxercalciferol , maxicaltriol, and paricalcitol, which is the most extensively VDRA studied [56, 57], have a better and safer profile than those of classic VDRAs such as calcitriol and alphacalcidol, showing less calcaemic and phosphoraemic effects and a comparable PTH lowering action while preserving the desirable effects of the VDRAs on the cardiovascular system, hypertension, inflammation and fibrosis. So far, the available experience of its use in children with CKD presents responses and characteristics similar to those of adults [80, 81].
Finally, a few words about 25(OH)D3 (calcidiol): several studies carried out mainly in adults have shown a widespread calcidiol deficiency/insufficiency in healthy populations and in patients with different degrees of CKD [82–84]. The normal range of 25(OH)D3 serum concentrations has been redefined, and levels >30 ng/ml are recommended . A few studies published about children have also demonstrated a high prevalence of calcidiol deficiency in CKD stages 2–4 [79, 86–88]. In addition, in both adults and children with CKD, a significant inverse relationship between circulating 25(OH)D3 and PTH has been found. Thus, even though native vitamin D or calcidiol supplements are not ‘new therapies’, their important role in the management of CKD-MBDs has been recently emphasized. Hence, it is important that we look for vitamin D deficiency and treat it appropriately as early as possible, as well as in advanced CKD.
In recent years we have made important advances in the knowledge and understanding of the pathogenic roles calcium, CaSR, phosphorus, VDR and VDRAs play in the regulation of parathyroid function and bone metabolism, but also in other aspects beyond them. All these advances should allow the better management of CKD-MBDs, based on a threefold approach targeting simultaneously, whenever possible, VDR, CaSR and phosphorus, looking for responses not only in the classic bone and mineral parameters, but also in other components of the revisited CKD-MBD constellation . Nevertheless, more studies specifically conducted in paediatric patients with CKD are necessary.
The studies on CKD-MBDs were supported by Fondo de Investigaciones Sanitarias (FIS 06/0646, FIS 07/0893, FIS 08/90136), Fundación Renal Íñigo Álvarez de Toledo and ISCIII-Retic-RD06, REDinREN (16/06). P.R.G. was supported by COF-08-FICYT and D.T.P. by BP08-016, Severo Ochoa, FICYT. The authors thank Marino Santirso for the language review.