Phosphate binders in chronic kidney disease. When should we start, what should we prescribe?

Abstract

It has been more than 2000 years since Hippocrates described renal disease and observed its progressive nature. Decreased survival and deteriorated health status of these patients' being is attributed to cardiovascular disease. There is increasing interest regarding the impact of non-traditional risk factors, including hyperphosphatemia, elevated calcium-phosphate (CaxPO₄) product, elevated parathyroid hormone levels and extensive use of calcium-containing phosphate binders on vascular calcification. There is a mounting body of evidence implying that a holistic and methodic approach should clearly suggest starting the battle against vascular calcification early in the course of chronic kidney disease. Type of phosphate binder used should be carefully selected, especially in the presence of vascular calcification.

Keywords::

• chronic kidney disease
• hyperphosphatemia
• lanthanum carbonate
• phosphate binders
• vascular calcification

It has been more than 2000 years since Hippocrates described renal disease. Moreover, he stated that disease generally evolves gradually! He made various treatment suggestions regarding kidney disease. Impressively, he also observed that when renal disease signs appear at or after the fifth decade of life, there is little possibility of complete regression [1]. It is then an ancient observation that chronic kidney disease (CKD) is a progressive entity. Even though we seem to have forgotten the old scripts, our understanding of renal disease has improved significantly during the past century.

The article by Cozzolino et al. comes to verify and improve our knowledge in a skeptic and methodic way regarding homeostasis and management of phosphate discrepancies in CKD patients [2]. This way, the authors set a new corner stone in CKD treatment, mainly regarding timely prescription of phosphate binders, and possible prevention of complications attributed to phosphate metabolism discrepancies.

Why do we care much about mineral homeostasis in CKD patients? Reduced survival and increased morbidity of CKD and end-stage renal disease patients is a common secret; deteriorated health status of these patients being mainly attributed to cardiovascular disease [3]. Almost half a century ago, Lindner initially observed that there was an increased mortality in CKD patients due to atherosclerotic complications [4]. Factors traditionally implicated in cardiovascular disease, like age, hypertension, diabetes, left ventricular hypertrophy and smoking, are also seen in CKD patients [5,6]. Nevertheless, these factors alone could not explain the accelerated vascular calcification seen in CKD patients. Truth is that this entity was initially described by Vichow two centuries ago as metastatic calcification [7]. Scientists did not pay much attention to his remarks though. Now, there is increasing interest regarding the impact of non-traditional risk factors, including hyperphosphatemia, elevated calcium-phosphate (CaxPO₄) product, elevated parathyroid hormone levels and extensive use of calcium-containing phosphate binders. It has been shown that increased vascular calcification seen in CKD patients might be influenced by elevated phosphate levels and elevated CaxPO₄ product [8,9]. Typical western diet is rich in phosphate content. Unfortunately, as renal function declines, so does phosphate excretion by the kidneys. Even though decreased consumption of phosphate-rich food is generally prescribed in CKD patients, complete restriction is not a feasible task. Inevitably, this leads to the necessity of phosphate binders' use. Phosphate binders known today are calcium-containing binders and calcium-free binders. A recent data analysis did not prove the superiority of any phosphate binder on cardiovascular end points or survival [10]. In a recent small double-blind placebo-control study, Block et al. compared the effect of sevelamer carbonate, lanthanum carbonate, calcium acetate or placebo on vascular calcification of the coronary arteries and abdominal aorta. Interestingly, their results showed that active therapy significantly increased calcification of coronary arteries and abdominal aorta. They made an appealing hypothesis, that phosphate binders might upregulate expression of intestinal sodium-phosphorus cotransporter type 2b, leading in increased paracellular transport, thus limiting their efficacy, especially after missed doses [11]. Inevitably, their results are translated with skepticism regarding safety and efficacy of phosphate binders. On the other hand, it has been shown by others that increased doses of calcium-containing phosphate binders might have a detrimental effect on vasculature [12]. Furthermore, KDIGO guidelines generally suggest to prefer calcium-free phosphate binders in the presence of vascular calcification [13]. Recently, INDENDENT study results has shown a significant reduction of all-cause mortality and dialysis inception in CKD patients receiving non-calcium phosphate binder sevelamer [14]. A newer phosphate binder, lanthanum carbonate, additionally to its non-calcium-containing nature, has the most potent phosphate-binding capacity among the phosphate binders available for prescription [15]. This characteristic is particularly useful in everyday clinical practice, since adherence to treatment depends greatly to the daily number of prescribed tablets.

All things considered, there is a mounting body of evidence implying that a holistic and methodic approach should clearly suggest starting the battle against vascular calcification early in the course of CKD. Additional research is needed to reveal those patients who will benefit the most from treatment. Type of phosphate binder used should be carefully selected especially in the presence of vascular calcification, since safety and efficacy of phosphate binders in CKD remains uncertain.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.