Chronic kidney disease (CKD) has become a major worldwide healthcare problem, affecting an estimated 5%-10% of the world's population (Hamer and El Nahas 2006). Progression to end stage renal disease (ERSD), the need for renal replacement therapy, and the high annual death rate of dialysis patients are the most noticeable outcomes of CKD. Most patients with CKD in fact die mainly from cardiovascular disease, rather than from ERSD.
Coronary artery calcification (CAC), a surrogate marker of atherosclerosis, is a common finding in CKD. Extensive calcification has been documented in dialysis patients by computed tomography, but cardiovascular calcification (CVC) affects patients not undergoing dialysis as well, developing early in the progression of CKD, and progressively worsening with the decline of the glo¬merular filtration rate (GFR), particularly in diabetics progressing to ERSD (Qunibi 2007). Presence of proteinuria, reduced renal function, diabetic nephropathy, and the progression rate to ERSD are the classical main uremia-related factors that increase the risk of calcification in CKD. Several observational studies have now identified the altered mineral metabolism, and particularly hyperphosphatemia, as a key player in CVC and not exclusively in musculoskeletal health. Hyperphosphatemia associated with surrogate clinical events such as CAC, aortic calcification, valvular calcifica¬tion, aortic stiffness, pulse pressure, as well as with hard clinical outcomes such as hospitalization, and all-cause and cardiovascular mortality (Ybung et al 2005; Vbung 2007; Toussaint and Kerr 2007).
Elevated serum phosphorus (P) level is highly prevalent in uremic patients, despite diet restriction and dialysis. It is associated with an increased mortality risk in hemodialysis (HD) patients. Block et al (1998), through a multivariate analysis of data from the United States Renal Data System (URDS), identified elevated serum P level as an independent predictor of mortality. The overall mortality risk associated with serum P above 6.5 mg/dL was 27% greater than that of patients with serum P between 2.4 and 6.5 mg/dL. Moreover, CaxP product greater than 72 mg2/dL2 was also associated with increased mortality risk. Altered mineral metabolism could aggravate the effects of coronary atherosclerosis. An increased intracellular P intake via Pit-1, a sodium-dependent P co-transporter, stimulates the phenotypic conversion of smooth muscle cell to osteoblatic cell lineage, thus leading to an increased extracellular matrix deposition favoring CaxP product precipitation, with the proposed final outcome of vascular stiffiiess (Giachelli 2003; Li et al 2006).
In primary cultures of vascular smooth muscle cells derived from ath¬erosclerotic human aortas, activation of osteoblast specific transcriptional programs related to skeletal morphogenesis did not lead to matrix mineralization until the P concentration of the tunica media was increased, an event occurring only after the onset of renal dysfunction and hyperphosphatemia (Mathew et al 2008). Indeed, using high-resolution B-mode ultrasonography, Kawagishi etal(l 995) found that elevated serum P level was strongly associated with changes in intima¬media thickness of the carotid artery, an effect independent of several other commonly measured coronary risk factors. It was therefore hypothesized that the increased mortality risk associated with elevated P level in HD patients was primarily due to cardiac rather than non-cardiac causes of death. In a chronic HD patient with serum P > 6.5 mg/dL, Ganesh et al (2001) demonstrated a 41% greater risk of death resulting from coronary artery disease (CAD) and a 20% greater risk of death resulting from sudden death compared with patients with serum P level between 2.4 and 6.5 mg/dL.
Comparing death risk between CAD and non-CAD causes of death in HD patients, he showed that elevated serum P level in HD patients significantly and preferentially predisposes to CAD deaths, thus supporting the concept of hyperphosphatemia as a cardiotoxin. The author suggested a role for elevated serum P either in the development, progression, or rupture of atheromatous plaques in the coronary arteries of preva¬lent ERSD patients. All the previous analysis involved HD populations with serum P > 6.5 mg/dL, which means a P value at least 1 mg/dL higher than the National Kidney Foundation (K/DOQI) recommended upper limit of 5.5 mg/ dL fbr chronic HD patients. Interestingly, both in CKD patients with serum P within the K/DOQI recommended serum P level range (>2.7 and <4.5 mg/dL), as in the case of stage 3 CKD patients (Kestenbaum et al 2005), and in stage 4 CKD patients with elevated serum P but not yet in dialy¬sis, arterial stiffness and mortality risk from cardiovascular events are significantly increased (Sigrist et al 2007).
Hyperphosphatemia and phosphate binders
The evidence that links mortality with altered mineral metabolism, and particularly the association of mortality with elevated serum P and CaxP levels, is well documented. Therefore, mineral metabolism provides a new perspective fbr improving mortality in patients with kidney disease. Hyperphosphatemia requires strict management through dietary restriction, dialysis, and use of phosphate binders. Phosphate binder therapy is a critical factor in the manage¬ment of hyperphosphatemia in advanced kidney disease. The aim is to achieve serum P m 5.5 mg/dL in HD patients, and possibly even lower. Phosphate binders mainly act in reduc¬ing the amount ofbioavailable PO4 generated by food intake into gastrointestinal fluids, through precipitation and/or entrapment, and potentiating its excretion by the fecal route. Several options are commercially available, namely: calcium carbonate and calcium acetate, magnesium hydroxide and magnesium carbonate, aluminium hydroxide, lanthanum carbonate, the non-calcium and metal-free sevelamer hydrochloride (for review: Almirall and Valenzuela 2006; Cozzolino et al 2008), and sevelamer carbonate (Renvela® which obtained FDA approval in October 2007, but is not approved yet in EU). Others substances are cur¬rently under development (McIntyre 2007). It is beyond the aim of this review to provide details on all the above-listed phosphate binders.
Nevertheless, it is worth noting that each of those listed, although to various degrees effective in serum P reduction, is not devoid of concern (for review: Almirall and Valenzuela 2006). Systemic toxicity, observed as liver, lung, and kidney deposition, and neurotoxicity, has been reported for lanthanum carbonate at the experimental level (Lacour et al 2005, 2007; Slatopolsky etal 2005), but not yet in the clinical setting (Cozzolino et al 2008), and some criticism remains because of past experience with another metal-based P binder, aluminium hydroxide (Driieke 2007). An increase in vascular calcification, suggestive of a possibly increased mortality risk, has been advocated for calcium-basedP04 binders. Intolerance to sevelamer in 9%-34% of HD patients because of gastrointestinal complaints (Almirall and Valenzuela 2006), worsening of metabolic acidosis (De Santo et al 2006), reports of stercoral ulceration (Madan et al 2008) , and peritonitis (EMEA 2007) have been highlighted for sevelamer hydrochloride. The Dialysis Outcomes and Practice Patterns Study (DOPPS) revealed considerable varia¬tion in the use of phosphate binders among the seven different countries participating in the study, although calcium-based binders were the preferred option (Young et al 2005). At that time, the use of non-calcium and metal-free polymers such as sevelamer was clearly underestimated because of the very recent approval of the pharmaceutical.
Nowadays, unexpect¬edly, most patients are still prescribed calcium-based agents, despite evidence of increased vascular calcification, arterial stiffiiess, and coronary calcification both in HD and predialy¬sis patients (Block et al 2007; Russo et al 2007; Sigrist et al 2007). The widespread use of calcium-based binders could have several explanations. Some authors have reported that calcium-based salts in HD patients showed good phosphate- binding capability, cost affordability, and lack of compel¬ling evidence for a significantly reduced outcome in overall mortality compared with sevelamer (St. Peter et al 2008; Suki 2008). Others, however, have interpreted the reduced calcification in sevelamer-treated patients by its lipid-lower¬ing properties more than its phosphate-binding properties (Winkelmayer and Tonelli 2008).