Integral pharmacological management of bone mineral disorders in chronic kidney disease (part I): from treatment of phosphate imbalance to control of PTH and prevention of progression of cardiovascular calcification

ABSTRACT

Introduction: Chronic kidney disease-mineral and bone disorders (CKD-MBD), involving a triad of laboratory and bone abnormalities, and tissue calcifications, are associated with dismal hard-outcomes.

Areas covered: In two comprehensive articles, we review contemporary and future pharmacological options for treatment of phosphate (P) imbalance (this part 1) and hyperparathyroidism (part 2), taking into account CKD-accelerated atheromatosis/atherosclerosis and/or cardiovascular calcification (CVC) processes.

Expert opinion: Improvements in CKD-MBD require an integral approach, addressing all three components of the CKD-MBD triad. Individualization of treatment with P-binders and combinations of anti-parathyroid agents may improve biochemical control with lower incidence of undesirable effects. Isolated biochemical parameters do not accurately reflect calcium or P load or bone activity and do not stratify high cardiovascular risk patients with CKD. Initial guidance is provided on reasonable therapeutic strategies which consider the presence of CVC. This part reflects that although there is not an absolute evidence, many studies point to the need to improve P imbalance while trying to, at least, avoid progression of CVC by restriction of Ca-based P-binders if economically feasible. The availability of new drugs (i.e. inhibitors of intestinal transporters), and studies including early CKD should ultimately lead to clearer and more cost/effective clinical targets for CKD-MBD.

KEYWORDS:

• Chronic kidney disease
• CKD-MBD
• phosphate
• phosphate binders
• iron
• hyperparathyroidism
• vascular calcification
• calcium receptor
• vitamin D

Article highlights

• CKD is linked to an extremely important and independent increase in morbidity and mortality

• Mineral and bone disorders (MBD) explain part of this disproportionate risk

• The term CKD-MBD was coined to define a triad of laboratory and bone abnormalities and tissue calcifications (including vascular and cardiac valvular), all of which are linked to poor hard-outcomes

• Treatment of CKD-MBD requires an integral approach, addressing all 3 components of the CKD-MBD triad (including potential consideration of CVC by X-rays)

• Serum P and FGF23 are strongly associated with cardiovascular morbidity and mortality

• Avoidance of P overload and serum P control, ideally towards normophosphatemia, is one of the key issues for management of CKD-MBD

• Management of P is achieved by careful dietary P restriction, the individualized prescription of P-binders, reasonable combinations with antiparathyroid-agents, and adequate dialysis

• We favor limiting the use of Ca-based P-binders as much as possible and depending on the available resources, especially in patients with ABD or low PTH, the elderly, diabetics, patients with CVC, and those on active vitamin D or coumadin treatment

• Combination of P-binders is plausible

• Targeting alternative mechanisms such as inhibition of intestinal or renal transporters may improve clinical results

• Primary prevention of hyperphosphatemia is still not widely substantiated

• RCTs including patients with early CKD should ultimately lead to the definition of clearer and more cost-effective biochemical and clinical targets for CKD-MBD

• It is not 1A-evidence level proven whether any of these approaches helps to improve hard-outcomes in affected patients, but these regimens seem prudent to avoid iatrogenic progression of CVC whereas multi-interventional independent RCTs and earlier stage prevention of arterial lesions appear distant possibilities.

This box summarizes key points contained in the article

CKD: chronic kidney disease; MBD: mineral and bone disorders; CKD-MBD: chronic kidney disease-mineral and bone disorder; CVC: cardiovascular calcification; P: phosphate; FGF23: fibroblast growth factor 23; Ca: calcium; PTH: parathyroid hormone; RCT: randomized clinical trial

Acknowledgment

We want to thank Ricardo Pellejero for his invaluable bibliographic assistance. J Bover belongs to the Spanish National Network of Kidney Research RedinRen (RD06/0016/0001 and RD12/0021/0033) and the Spanish National Biobank network RD09/0076/00064. J Bover also belongs to the Catalan Nephrology Research Group AGAUR 2009 SGR-1116. J Bover and M.M. Diaz-Encarnacion collaborate with the Spanish ‘Fundación Iñigo Alvarez de Toledo’ (FRIAT).

Declaration of interests

J Bover has received speaking honoraria from Abbvie, Amgen, Genzyme, and Shire; fees as a consultant for Abbvie, Amgen, Vifor/Fresenius-Pharma, Chugai, Medice and Genzyme/Sanofi. M.M. Diaz-Encarnacion and J Bover received a research grant from Abbvie. P Ureña reports personal fees and grants from Amgen, Abbvie, Genzyme-Sanofi, Medice, Hemotech, and Fresenius. E Fernández has received speaking honoraria from Abbvie, Amgen, Genzyme, and Shire; fees as a consultant for Abbvie, Amgen, Vifor/Fresenius-Pharma. EF received a research grant from Abbvie