Cardiovascular Effects of Sevelamer in Stage 3 CKD

Abstract

Serum phosphate independently predicts cardiovascular mortality in the general population and CKD, even when levels are in the normal range. Associations between serum phosphate, arterial stiffness, and left ventricular (LV) mass suggest a possible pathophysiological mechanism, potentially mediated by the phosphaturic hormone fibroblast growth factor-23 . To what extent the phosphate binder sevelamer modulates these effects is not well understood. In this single-center, randomized, double-blind, placebo-controlled trial, we enrolled 120 patients with stage 3 nondiabetic CKD. After a 4-week openlabel run-in period, during which time all patients received sevelamer carbonate, we randomly assigned 109 patients to sevelamer (n=55) or placebo (n=54) for an additional 36 weeks. We assessed LV mass and systolic and diastolic function with cardiovascular magnetic resonance imaging and echocardiography, and we assessed arterial stiffness by carotid-femoral pulse wave velocity. The mean age was 55 years, and the mean eGFR was 50 ml/min per 1.73 m 2 . After 40 weeks, we found no statistically significant differences between sevelamer and placebo with regard to LV mass, systolic and diastolic function, or pulse wave velocity. Only 56% of subjects took $80% of prescribed therapy; in this compliant subgroup, treatment with sevelamer associated with lower urinary phosphate excretion and serum FGF-23 but not serum phosphate, klotho, vitamin D, or cardiovascular-related outcomes of interest. In conclusion, this study does not provide evidence that sevelamer carbonate improves LV mass, LV function, or arterial stiffness in stage 3 nondiabetic CKD. Over the last decade, phosphate has emerged as an important cardiovascular risk factor. 1 Serum phosphate within the normal range independently predicted mortality in the Framingham Offspring Study. 2 CKD is the most common cause of abnormal phosphate handling, and the relationship between phosphate and adverse cardiovascular outcome was first identified in hemodialysis patients. 3,4 Additional studies have shown this relationship in early stage CKD, 5,6 type 2 diabetes mellitus, 7 and patients with coronary artery disease and normal renal function. 8 The strong association between serum phosphate and increased arterial stiffness 9 as well as increased left ventricular (LV) mass [10][11][12] suggests a potential mechanism, although the cellular processes remain unclear. The ability of the kidneys to excrete phosphate is reduced at a GFR below 60 ml/min per 1.73 m 2 . Serum phosphate, however, remains within the normal range until the GFR falls below 30 ml/min per 1.73 m 2 because of increased production of the phosphatonins parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23), which promote urinary phosphate excretion. 13,14 Recent data have linked

Associations of FGF-23 and sKlotho with Cardiovascular Outcomes among Patients with CKD Stages 2–4

“…Earlier experimental and epidemiologic studies suggested hyperphosphatemia, hyperparathyroidism, and hypovitaminosis D as emerging cardiovascular risk factors (14)(15)(16). Surprisingly, in interventional trials, intake of phosphate binders, cinacalcet, or active vitamin D did not exert a consistently beneficial effect on surrogate markers of CVD (8)(9)(10)(11) or reduce cardiovascular event rates (12).…”

“…CKDmineral and bone disorders (CKD-MBD) may substantially contribute to this high cardiovascular morbidity. Thus, clinical interest traditionally focused on identification (2-4) and treatment (5-7) of hyperphosphatemia, hyperparathyroidism, and hypovitaminosis D. Nonetheless, several interventional trials targeting these traditional CKD-MBD components failed to provide consistent evidence for a beneficial cardiovascular effect (8)(9)(10)(11)(12).…”

Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD

“…Large doses of these binders are required as a direct consequence of their limited efficiency. The vast majority 12 as a result of the number and size of tablets required (recommended doses for Renvela and Fosrenol are 0.8-1.6 g per meal 22 and 0.5-1 g per meal, respectively), 23 the three times daily dosing regimen, and the requirement for additional fluid taken with the bulky tablets in patients who were fluid restricted. The pharmacologic activity of tenapanor was evaluated in the NPX rat, an animal model of CKD that features pronounced vascular calcification.…”

“…FGF-23 increases very early in the course of CKD and is strongly associated with death and cardiovascular disease, including left ventricular hypertrophy and vascular calcification. 2,30,31 Several studies have shown that reducing FGF-23 by means of treatment with P binders improves cardiovascular disease in patients who are normophosphatemic independent of serum P. 12,26,27 Although the link between elevated FGF-23 levels and disease outcomes is becoming clearer, evidence of a direct role for FGF-23 in pathogenesis remains elusive. However, recently, a group has shown that FGF-23 enhances P-induced calcification in the aortas of CKD rats and Klotho-overexpressing vascular smooth muscle cells by promoting osteoblastic differentiation.…”

“…[9][10][11] All have a high pill burden, and efficacy is limited by poor compliance associated with inconvenient administration and a high prevalence of gastrointestinal side effects. 8,11,12 Ca-based binders can lead to hypercalcemia and vascular calcification. 9 An alternative strategy for limiting systemic uptake of dietary P involves the inhibition of gastrointestinal tract P transporters.…”