Treating hyperphosphatemia - current and advancing drugs.

INTRODUCTION: Hyperphosphatemia is a hallmark of advanced chronic kidney disease (CKD) and associated with adverse outcomes. Preclinical and epidemiological studies strongly support a causal relationship between hyperphosphatemia and mortality as well as cardiovascular complications, especially including vascular, valvular and soft-tissue calcifications. Thus, appropriate phosphate lowering is considered to play a major role in health and longevity of CKD patients. In this respect, phosphate binders are the most powerful therapeutic option, while dietary phosphate restriction and intensified dialysis are valuable supportive approaches. AREAS COVERED: Pubmed was the primary research platform. This search focused on novel phosphate lowering compounds, including iron-containing binders and phosphate transport inhibitors, which have just become available or are in the approval process. Further, additional reports on effective strategies to counteract the adverse consequences of resistant hyperphosphatemia were also collected. EXPERT OPINION: New iron-containing drugs may offer advantages, including iron supplementation, low pill burden and high efficacy. Phosphate transport inhibitors possess a high potential as add-on compounds in patients with insufficient phosphate binder therapy. One unsolved question remains at what CKD stage to start therapeutically counteracting phosphate retention.

Use of phosphate binders in chronic kidney disease.

PURPOSE OF REVIEW: Hyperphosphatemia is a paradigmatic finding in late-stage chronic kidney disease (CKD) and consistently associated with adverse outcomes. Preclinical and epidemiological studies strongly support a causative role of hyperphosphatemia for cardiovascular complications, especially with regard to vascular, valvular and soft-tissue calcifications, and for subsequent mortality. Therefore, phosphate management is thought to play a pivotal role in health and longevity of CKD patients. In this regard, phosphate binders are considered the prime option; however, dietary phosphate restriction and intensified dialysis are also valuable supportive tools. RECENT FINDINGS: Studies on available calcium-free phosphate binders demonstrate potential to interfere with phosphate regulatory factors, such as fibroblast growth factor-23 (FGF23). Magnesium-containing phosphate binding may possess a pleiotropic potential due to its calcification inhibitory properties. Novel phosphate lowering compounds, including colestilan, iron-containing binders and nicotinamide, are underway to extend the armamentarium of phosphate-lowering strategies. An open question remains when to therapeutically counteract phosphate retention by binders. A recent prospective randomized trial in patients with moderate CKD (stages 3b-4) and phosphate levels in the upper normal range demonstrated only moderate reductions in serum phosphate levels, no effects on FGF23, but increased vascular calcification progression with active treatment versus placebo. Another small trial in patients with similar renal function given diets containing approximately 1 g of calcium and 1.4 g of phosphate per day showed neutral calcium and phosphate balances, whereas addition of calcium carbonate as a phosphate binder only caused a positive calcium, but no negative phosphate balance. SUMMARY: Adequate phosphate management in end-stage CKD remains a mainstay of our therapeutic approaches in this population, and additional promising drugs are in development and may shortly be available. The timing and indication for phosphate-lowering strategies in predialysis CKD is currently unclear.

FGF23 antagonism: the thin line between adaptation and maladaptation in chronic kidney disease.

For more than 10 years, we have been convinced by overwhelming epidemiological evidence with a high biological plausibility that hyperphosphataemia imposes one of the most sustained cardiovascular and mortality risks on patients suffering from chronic kidney disease (CKD). With the discovery of the fibroblast growth factor-23 (FGF23)/klotho axis, we not only gained a new and mechanistic understanding of phosphate handling of the body, we also felt that novel therapeutic strategies may arise counteracting the deleterious consequences of phosphate retention, dysregulation and maldistribution. Two recent experimental studies shed additional and important light on what we can expect from such new insights. Faul et al. showed us that FGF23 excess may directly induce left ventricular hypertrophy (LVH) and that FGF-receptor antagonism ameliorates CKD-induced LVH in rats. Shalhoub et al. demonstrated that FGF23 antibodies successfully ameliorated the development and progression of most features of secondary hyperparathyroidism in a rat model of CKD, however, at the expense of hyperphosphataemia, progressive vascular calcification and death. Such studies not only help to continuously improve our understanding, but also especially sharpen our perception of how thin the line may be between adaptation and maladaptation in chronic disease scenarios.

Mechanisms and treatment of extraosseous calcification in chronic kidney disease.

Strong and unidirectional associations exist between the severity of cardiovascular calcifications and mortality in patients with advanced chronic kidney disease. In the past 10 years, a wealth of experimental and clinical information has been published on the key pathophysiological events that contribute to the development and progression of vascular and soft-tissue calcifications. These processes involve a sensitive balance of calcification inhibition, induction and removal. The traditional view of regarding secondary hyperparathyroidism and elevated calcium × phosphate product as the pivotal risk factors for calcification has been challenged by data demonstrating a role for other, more subtle and complex pathomechanisms. These mechanisms include the loss of endogenous calcification inhibitors, deficient clearance of calcified debris, effects of vitamin K and vitamin D, and the action of calcification inducers as in osteogenic transdifferentiation. In this Review, we describe our current knowledge of the factors involved in the passive and active regulation of extraosseous calcification processes, with an assessment of their importance as targets for future diagnostic and therapeutic interventions.

Vitamin D, chronic kidney disease and survival: a pluripotent hormone or just another bone drug?

It is now about 40 years ago that the mechanism of renal 1-α-hydroxylation of vitamin D was discovered and characterized. After this seminal observation, the key role of the active vitamin D derivative 1, 25-(OH)2-vitamin D (calcitriol) in calcium homeostasis and bone mineralization, and its specific role in the course of chronic kidney disease (CKD) and renal osteopathy, was unraveled step by step, while the precursor 25-OH-vitamin D (calcidiol) was gradually ignored. Calcitriol and its synthetic analogue alfa-calcidol became the first-line standard drug to tackle secondary hyperparathyroidism (sHPT) in CKD. Potential side-effects, including hypercalcemia, hyperphosphatemia, and vascular calcification, were partly abrogated by developing less calcemic substances such as paricalcitol or maxacalcitol. Thus, TIME Magazine surprised when nominating vitamin D, with regard to its newly discovered pleiotropic actions, as one of the "top medical breakthroughs" in the December issue of 2007. This vote was driven by novel and spectacular insights into the pivotal regulatory role of vitamin D with regard to autoimmune diseases, immune defense, cancer development and progression, and cardiovascular function and disease. More than 30 cell types express the vitamin D receptor (VDR), and more than ten organs in addition to the kidney are capable of paracrine 1-α-hydroxylation. More than 200 genes are under the control of calcitriol. A MEDLINE search performed in December 2009 focusing on the keywords "vitamin D-and-kidney-and-2009" yielded 523 hits. This review intends to give a subjective and CKD-related update on novel biological and clinical insights with relevance to the steroid hormone vitamin D.

Review article: Getting the balance right: assessing causes and extent of vascular calcification in chronic kidney disease.

Vascular calcification is part of the definition of chronic kidney disease-mineral and bone disorder (CKD-MBD). It is also a surrogate parameter of cardiovascular and all-cause mortality risk in the CKD population. However, vascular calcification is not a homogenous entity, but a rather complex manifestation influenced by derangements of calcium and phosphate homeostasis, by dysregulated calcification inhibitors and promoters, and by the type of arterial disease (atherosclerosis vs arteriosclerosis). Despite the clear-cut risk association between the presence of vascular calcification and mortality, it is currently not well defined, how this knowledge about calcification should be translated into active clinical management. Further, the choice of the appropriate imaging test is a matter of debate. This article attempts to provide an update on insights into the pathophysiology of vascular calcification processes and a subjective view of the clinical consequences of management of CKD patients at risk.

Dietary and pharmacological control of calcium and phosphate metabolism in predialysis stages of chronic kidney disease.

Data on calcium and phosphate metabolism in the predialysis stages of chronic kidney disease (CKD) are scarce when compared with the available information on patients on dialysis. Visible derangements of calcium and phosphate levels start to become apparent when GFR falls below 40 ml/min. In some but not all patients, hyperphosphatemia may be a mortality risk predictor in CKD stages 4-5. There are only few treatment studies targeting hyperphosphatemia in these CKD stages. However, the RIND study, evaluating progression of coronary artery calcification in incident hemodialysis patients, demonstrated that vascular calcification processes manifest in predialysis stages in the majority of patients, which may well be linked to deranged calcium and phosphate homeostasis. Novel insights into the pathophysiology of calcium and phosphate handling, especially the discovery of the phosphatonin FGF23, suggest that a more complex assessment of phosphate balance is warranted. This assessment should include measurements of fractional phosphate excretion and phosphatonin levels to objectively judge and effectively correct phosphate overload.