REVIEW URRENT C OPINION
Phosphate management in chronic kidney disease Ishir Bhan
Purpose of review The review focuses on the rationale and evidence behind management strategies for hyperphosphatemia in patients with chronic kidney disease (CKD). Recent findings Optimal management of phosphate in CKD remains an area of uncertainty, but multiple studies now point to a clinical benefit from the use of phosphate binders. Evidence of improved survival is particularly strong with sevelamer, though it remains unclear whether the absence of calcium or other properties of sevelamer are responsible for this relationship. Newer agents, such as iron-based binders or niacin compounds to inhibit phosphorus absorption, may have additional benefits which will be better defined with additional experience. A reduced pill count may be a particularly beneficial characteristic of newer agents, and has been associated with improved response to therapy. Increased use of frequent, nocturnal hemodialysis is an additional tool to help ameliorate phosphate control. Data on the reduction of fibroblast growth factor 23 through use of phosphate binders remain weak. Summary An improved understanding of phosphate regulation and the development of new therapeutic agents have reinvigorated a once stagnant field, but significant changes to practice cannot yet be justified. There is increasing support for using sevelamer in place of calcium-based binders, though economic practicability remains challenging. Keywords chronic kidney disease, hyperphosphatemia, mineral and bone disease, phosphate binders
INTRODUCTION Hyperphosphatemia develops in chronic kidney disease (CKD) as a result of a reduced ability to excrete the ingested load. Early in CKD, proximal tubular reabsorption of phosphorus can be suppressed by rising levels of fibroblast growth factor 23 (FGF-23). As kidney disease progresses and glomerular filtration rate (GFR) falls below 20–30 ml/min, this rise in FGF-23 can no longer adequately augment phosphate excretion, and phosphate levels begin to rise [1]. As these levels increase, so does the risk of inappropriate deposition of calcium and phosphorus, potentially leading to vascular calcification and an associated increase in mortality. The high levels of parathyroid hormone (PTH) commonly seen in advanced CKD augment bone turnover, releasing calcium and phosphorus into the circulation, and bringing calcium levels closer to normal. However, in the setting of limited phosphate excretion, this secondary hyperparathyroidism can worsen the underlying hyperphosphatemia, which itself can stimulate PTH release. Thus, control of phosphorus has the potential to interrupt a www.co-nephrolhypertens.com
deleterious cycle. Interest in phosphate control has increased in recent years by the discovery that high levels of FGF-23 have been strongly linked to mortality in end-stage renal disease (ESRD), predialysis CKD, and even the general population. This review will address strategies to manage hyperphosphatemia in CKD and review potential advantages and disadvantages of the available options.
PHOSPHATE TARGETS In addition to its effects on the hormonal balance and bone, hyperphosphatemia could play a direct role in morbidity and mortality by promoting the deposition of calcium and phosphorus in the Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA Correspondence to Ishir Bhan, MD, MPH, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. Tel: +1 617 726 3934; fax: +1 617 726 8481 Curr Opin Nephrol Hypertens 2014, 23:174–179 DOI:10.1097/01.mnh.0000441155.47696.41 Volume 23 Number 2 March 2014
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Phosphate management Bhan
KEY POINTS Processed foods with phosphate additives should be avoided in patients with CKD and hyperphosphatemia. Phosphate binders are an effective tool to reduce phosphate, and factors such as cost, pill burden, and calcium should be weighed as part of binder selection. Increasing support for sevelamer as a potential mediator of improved survival should prompt its consideration as a first choice for phosphate reduction.
vasculature and other nonbone tissues, although this relationship has not been consistently observed [2]. Regardless of the mechanism, a body of observational data has linked hyperphosphatemia to increased mortality in ESRD and advanced CKD. However, it is important to recognize that, despite studies associating hyperphosphatemia with adverse outcomes, a cause-and-effect relationship between control of phosphate and improved outcomes has not been definitively established. Despite this, current Kidney Disease Improving Global Outcomes (KDIGO) guidelines advocate maintenance of serum phosphate within the normal range for predialysis (stage 3–5) CKD and ‘toward the normal range’ for patients with ESRD on dialysis [3].
DIETARY PHOSPHATE CONTROL The American diet is rich in phosphorous, with daily phosphorus intake reaching 1500 mg or greater. Thus, dietary restriction of phosphorus would seem to be a logical first step in treating hyperphosphatemia. However, many high-phosphorus foods are also rich in protein, so a potential risk of dietary phosphate restriction is a compromise of protein intake, which may be particularly detrimental in patients with ESRD. Whereas short-term studies have suggested some benefit of dietary restriction, convincing real-world data are lacking. One recent study of prescribed phosphorus restriction demonstrated no survival benefit in hemodialysis, and in fact suggested an increase in mortality with phosphate restriction in some subgroups [4]. Typical assessments of dietary phosphate have focused on the natural phosphorous content, targeting daily phosphorus intake below 900 mg. True phosphorus content of foods, can, however, be difficult to determine accurately. Processed foods often contain phosphate additives, and these additional sources of phosphorus may increase the daily intake by over 1 g per day without offering any additional nutritional benefit [5]. Additionally, not
all phosphate content is equally bioavailable; plantbased phosphorus is generally poorly absorbed, whereas phosphate additives exhibit near-complete absorption. Avoidance of processed foods containing phosphate additives is particularly beneficial in ESRD, where limiting dietary phosphorus without compromising protein intake is ideal. Current food labeling does explicitly list phosphate content, so vigilance toward ingredients lists and avoidance of processed foods are of greatest benefit when targeting dietary changes. One clinical trial aimed at educating patients to identify foods rich in phosphate additives demonstrated modest, though statistically significant, improvements in phosphorus control [6].
PHOSPHATE BINDERS: OPTIONS Given the challenges of dietary phosphate restriction, phosphate binders have become the mainstay of therapy in CKD-associated hyperphosphatemia. Aluminum binders are no longer used as chronic therapy due to bone and nervous system toxicities. Calcium-based binders, which include calcium carbonate and calcium acetate, avoid aluminum’s adverse effects. Calcium carbonate is widely available without prescription. It binds phosphorus weakly in an acidic environment, yet solubility is poor in an alkaline environment. Calcium acetate (PhosLo) is considerably more water soluble and overall appears superior as a phosphate-binding agent at equivalent doses of elemental calcium, with a lower risk of hypercalcemia [7–9]. Other binders based on calcium are not commonly used. Calcium citrate, used commonly to treat or prevent osteoporosis, is generally avoided in the CKD population due to its poor performance and risk of citrate promoting aluminum absorption. A combination of calcium acetate and magnesium carbonate appears to be effective, though carries a small risk of hypermagnesemia [10]. It remains poorly studied and its role in the therapeutic armamentarium has yet to be defined. Whereas calcium-based binders were used to avoid the toxicities of aluminum, there has been increasing concern that chronic exposure to a high calcium load could promote vascular calcification and lead to premature morbidity and mortality. Sevelamer, a synthetic polymer, effectively binds phosphate, but is not absorbed. The initially available hydrochloride preparation (Renagel) increased the risk of metabolic acidosis, even in patients on dialysis [11]. However, the newer carbonate formulation (Renvela) avoids this risk. Lanthanum carbonate (Fosrenol) is an alternative, metal-based phosphate binder that is generally well tolerated and as effective as other binders at controlling phosphorus [12,13]. Whereas there has
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Clinical nephrology
been concern about the potential long-term effects of lanthanum accumulation in the liver and other tissues, these effects have not been clinically evident, nor has there been evidence linking lanthanum to nephrogenic systemic fibrosis, which has been associated with exposure to gadolinium, another lanthanide [14]. Low pill burden may be a particular advantage of lanthanum [15]. Iron-based binders are another emerging therapy. A recent open-label randomized trial compared the iron-based binder PA21 to sevelamer [16 ]. Both efficacy and frequency of adverse effects were similar between the two agents, although the study was not specifically designed to compare efficacy. At higher doses, discontinuation was more common in PA21, though the most common reason for discontinuation was hypophosphatemia. No effect on iron metabolism, including serum iron, transferrin, or ferritin was observed. Ferric citrate is another promising iron-based agent, though additional clinical data are needed before the role of iron-based binders becomes clear [17]. &
PHOSPHATE BINDERS AND CLINICAL OUTCOMES Phosphate binders have demonstrated efficacy in reducing serum phosphorus levels; but does this therapy result in improved clinical outcomes? An analysis of over 6000 incident hemodialysis patients demonstrated improved 1-year mortality in patients treated with phosphate binders, with hazard ratios ranging between 0.58 and 0.82, depending on the analysis [18]. Whereas retrospective studies cannot prove cause-and-effect relationships, the authors performed an analysis matched by baseline phosphorus level and propensity score (to control for factors that influenced the decision to start binders). The effect was consistent across a wide range of demographic and laboratory-defined subgroups. A historical cohort study of over 1188 men with predialysis CKD at a single Veterans Affairs medical center similarly found an adjusted hazard ratio for death of 0.61 for patients treated with phosphate binders, with most exposed to both calcium acetate and sevelamer [19]. The effect was more evident in patients with higher baseline phosphorus levels, though serum phosphorous actually increased over time in patients treated with binders. These results, along with the comparatively weaker associations of serum phosphorus with mortality, raise the question of whether phosphate binders might have a beneficial effect independent from that measured by their influence on serum phosphorus. Indeed, an analysis from the United Kingdom examining the effect of achieving Kidney Disease Outcomes 176
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Quality Initiative (KDOQI) targets for phosphorus failed to show a statistically significant benefit despite a study population of 7076 patients [20]. The data linking binder use to improved outcomes, however, remain contradictory, particularly in predialysis CKD. A prospective study attempted to address this by randomly assigning 148 patients with an estimated GFR (eGFR) of 20–45 ml/min to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo [21 ]. There was greater decrease in phosphorus in the binder arm, with a 22% reduction in mean 24-h urine phosphorus, suggesting effective binding. While PTH was stable in the binder arm, it increased in the placebo group, suggesting an additional benefit of this therapy consistent with its known actions. Enthusiasm was tempered, however, by a significant increase in both coronary artery and aortic calcification in the phosphate-binder arms. These effects were strongest among those receiving calcium acetate, but did not appear to be restricted to this arm. Moreover, a reduction in FGF-23 (which has been linked to increased mortality) – an effect many had hoped phosphate binders would be able to achieve – was not apparent in this study, although more recent studies contradict this [22,23]. A prospective trial focused on outcomes of morbidity and mortality rather than surrogate endpoints would be central in providing clarity, but is not currently available. &
ARE SOME BINDERS BETTER THAN OTHERS? Concerns about calcium load and effects on vascular calcification have led to several comparative studies between binders. The Treat to Goal trial compared sevelamer hydrochloride to either calcium acetate or calcium carbonate in 200 incident dialysis patients [24]. Despite equivalent phosphorus control, the calcium binders were associated with more hypercalcemia, and higher coronary artery and aortic calcium scores. The Renagel in New Dialysis (RIND) study randomized 129 incident hemodialysis patients to sevelamer hydrochloride or calcium [25]. Here again, calcium-based binders were associated with a greater increase in coronary artery calcium score over 18 months. However, it is notable that one-third of the patients had no coronary calcification detected at baseline, and none of these patients progressed regardless of treatment assignment. Therefore, it may be that patients with established disease are at a particular risk of progressive calcification. A subsequent analysis of these data demonstrated a significant mortality advantage to sevelamer, with a hazard ratio of 3.1 [26]. Although it may be presumed that the calcium itself Volume 23 Number 2 March 2014
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Phosphate management Bhan
promoted calcification, change in calcium score in this study did not correlate with the development of hypercalcemia nor did the degree of progression depend on the calcium load, raising the question of whether sevelamer might have an independent effect to retard calcification. The larger Dialysis Clinical Outcomes Revisited (DCOR) study included over 2000 prevalent hemodialysis patients as part of a randomized trial, again comparing sevelamer to calcium-based binders [27]. Unlike the Treat to Goal and RIND trials, the authors did not find an advantage to sevelamer use, this time using either all-cause or cardiovascular mortality as the endpoint of choice, though some measures of hospitalization were lower with sevelamer. The recent INDEPENDENT trial randomized 466 incident hemodialysis patients to sevelamer or calcium carbonate over 24 months and found lower all-cause and cardiovascular mortality in the sevelamer arm, but better phosphate control was achieved in the sevelamer arm as well, making it unclear if these results would extend to a calcium-based regimen that was more efficacious (e.g. calcium acetate or alternative dosing) [28 ]. All these trials have been somewhat limited by loss to follow-up. Sevelamer use is known to influence cholesterol levels, which may have driven the effects on vascular calcification and possibly other outcomes. Significant reductions in both total and low-density lipoprotein (LDL) cholesterol associated with sevelamer use were seen in both the Treat to Goal and RIND trials. To address this, the Calcium Acetate Renagel Evaluation 2 (CARE-2) study compared calcium acetate to sevelamer in a 12-month study of 203 prevalent hemodialysis patients with hyperphosphatemia and detectable baseline coronary artery calcification. In addition to phosphate binders, however, all patients were prescribed atorvastatin to control LDL cholesterol to less than 70 mg/dl. As a result, cholesterol profiles were similar in both arms at the end of the study. Increases in coronary artery calcification did not differ between the groups, suggesting that the cholesterol changes, rather than calcium, may have mediated differences between these treatments in other studies. A recent meta-analysis concluded that, overall, noncalcium-based binders appeared to be associated with decreased all-cause mortality, but this was based largely on studies of sevelamer [29 ]. Given the significant cost associated with sevelamer [30], and continuing uncertainty about its effects on clinical endpoints and the mechanisms by which these changes may be achieved, sevelamer cannot be unequivocally advocated over calcium acetate at this time. The data for lanthanum are considerably weaker. &
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OTHER APPROACHES Other approaches may also have an influence on phosphate management. Although there is some debate about the relative effects of different vitamin D compounds on phosphate absorption, active vitamin D formulations have the potential to increase gastrointestinal absorption and should be avoided in patients with severe hyperphosphatemia [3,31]. While hemodialysis is effective at clearing phosphorus with a typical 4-h dialysis removing approximately 1 g of phosphorus, this is inadequate to maintain phosphorus control in most individuals [32]. Therefore, adjustments in hemodialysis prescription would not be expected to significantly alter serum phosphate. Nocturnal hemodialysis offered at home 6 days a week can clear twice as much phosphorus compared to a conventional regimen, and an in-center program was associated with modestly lower serum phosphorus levels: this approach may be beneficial in appropriate patients [33,34]. Continuous renal replacement therapy can remove 1 g or more of phosphorus daily, but is not feasible in the outpatient setting [35]. Cinacalcet can be used to treat hyperparathyroidism in place of or in addition to active vitamin D analogs, and in theory might be expected to reduce phosphorus in ESRD (due to both a lower requirement for vitamin D and because of suppression of PTH-induced phosphate release from bone). However, the recent EValuation of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) randomized trial comparing cinacalcet with placebo failed to demonstrate superior control of phosphate in a hemodialysis population [36 ]. Newer pharmacologic agents to specifically address phosphorus absorption may offer additional options. Derivatives of niacin may act via blocking the sodium–phosphate co-transporter in the gut. A prolonged release formulation of nicotinic acid was demonstrated to control phosphorus without affecting calcium levels when given in lieu of calciumbased binders [37]. An alternative formulation, niacinamide, was studied alongside phosphate binders in a double-blind trial and demonstrated effective phosphorus reduction [38]. The potential risks of niacin-based therapies include effects on glucose, flushing, diarrhea, thrombocytopenia, and myopathy. Further studies are needed to more clearly define the role of niacin-based therapies and evaluate potential risks in the CKD population. However, these agents may offer promise as adjuncts or alternatives in patients to reduce pill burden, which has been linked to poor control of phosphorus [39 ]. A summary of treatment approaches is presented in Table 1.
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Clinical nephrology Table 1. Treatment options for phosphate control in CKD Treatment
Mechanism
Comments
Dietary control
Reduced intake of phosphorus
Challenging to implement. Phosphate content in food can be difficult to determine. Phosphate additives are particularly bioavailable.
Calcium acetate/carbonate
Intestinal phosphate binding
Concern for high calcium burden promoting vascular calcification.
Sevelamer hydrochloride/carbonate
Intestinal phosphate binding
High cost, but strongest association with improved survival. Mechanism of benefit may include effects other than phosphate reduction.
Lanthanum carbonate
Intestinal phosphate binding
Low pill burden, less well studied compared with calcium and sevelamer.
Iron-based binders
Intestinal phosphate binding
Limited data available.
Niacin-based compounds
Inhibits phosphate absorption
Limited data available.
Nocturnal hemodialysis
Increased clearance of phosphate
Not practical in all patients, limited availability.
CKD, chronic kidney disease.
CONCLUSION Phosphate management in CKD remains a therapeutic challenge. While the control of dietary phosphate intake is important, it can be challenging due to the limitation of food labeling. Avoidance of processed foods with phosphate additives may be most beneficial, avoiding the potential protein restriction that accompanies the avoidance of naturally phosphate-rich foods. Phosphate binders should be used in many cases of advanced CKD, and calcium acetate, sevelamer, and lanthanum all appear to be effective. Recent data, though not definitive, point to a possible survival advantage associated with sevelamer use when compared with calcium-based binders. Despite the limitations of the data, sevelamer carbonate should be considered as a first choice for treating hyperphosphatemia when economically practical, particularly in patients with higher calcium levels. Data on newer agents such as iron-based binders and niacin appear promising, but are too limited to guide specific recommendations. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Levin A, Bakris GL, Molitch M, et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int 2006; 71:31–38.
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2. Giachelli CM. Vascular calcification mechanisms. J Am Soc Nephrol 2004; 15:2959–2964. 3. Kidney Disease Improving Global Outcomes KDIGO CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 2009; (113):S1–S130. 4. Lynch KE, Lynch R, Curhan GC, Brunelli SM. Prescribed dietary phosphate restriction and survival among hemodialysis patients. Clin J Am Soc Nephrol 2011; 6:620–629. 5. Uribarri J, Calvo MS. Hidden sources of phosphorus in the typical American diet: does it matter in nephrology? Semin Dial 2003; 16:186–188. 6. Sullivan C, Sayre SS, Leon JB, et al. Effect of food additives on hyperphosphatemia among patients with end-stage renal disease: a randomized controlled trial. J Am Med Assoc 2009; 301:629–635. 7. Ben Hamida F, Esper el I, Compagnon M, et al. Long-term (6 months) crossover comparison of calcium acetate with calcium carbonate as phosphate binder. Nephron 1993; 63:258–262. 8. Caravaca F, Santos I, Cubero JJ, et al. Calcium acetate versus calcium carbonate as phosphate binders in hemodialysis patients. Nephron 1992; 60:423–427. 9. Schaefer K, Scheer J, Asmus G, et al. The treatment of uraemic hyperphosphataemia with calcium acetate and calcium carbonate: a comparative study. Nephrol Dial Transplant 1991; 6:170–175. 10. de Francisco ALM, Leidig M, Covic AC, et al. Evaluation of calcium acetate/ magnesium carbonate as a phosphate binder compared with sevelamer hydrochloride in haemodialysis patients: a controlled randomized study (CALMAG study) assessing efficacy and tolerability. Nephrol Dial Transplant 2010; 25:3707–3717. 11. Thet Z, Win AK, Pedagogos E, et al. Differential effects of phosphate binders on predialysis serum bicarbonate in end-stage kidney disease patients on maintenance haemodialysis. BMC Nephrol 2013; 14:205. 12. Persy VP, Behets GJ, Bervoets AR, et al. Lanthanum: a safe phosphate binder. Semin Dial 2006; 19:195–199. 13. Finn WF. SPD 405-307 Lanthanum Study Group. Lanthanum carbonate versus standard therapy for the treatment of hyperphosphatemia: safety and efficacy in chronic maintenance hemodialysis patients. Clin Nephrol 2006; 65:191–202. 14. De Broe ME. Can the risk of gadolinium be extrapolated to lanthanum? Semin Dial 2008; 21:142–144. 15. Ishizu T, Ishizu T, Hong Z, et al. Efficacy of continuous oral administration of lanthanum carbonate over 24 months. Ther Apher Dial 2013; 17 (S1):22– 28. 16. Wu¨thrich RP, Chonchol M, Covic A, et al. Randomized clinical trial of the iron& based phosphate binder PA21 in hemodialysis patients. Clin J Am Soc Nephrol 2013; 8:280–289. Randomized trial of novel, iron-based, phosphate-binding agents. Iron-based binders are likely to become increasingly common in the near future. 17. Dwyer JP, Sika M, Schulman G, et al. Dose-response and efficacy of ferric citrate to treat hyperphosphatemia in hemodialysis patients: a short-term randomized trial. Am J Kidney Dis 2013; 61:759–766. 18. Isakova T, Gutie´rrez OM, Chang Y, et al. Phosphorus binders and survival on hemodialysis. J Am Soc Nephrol 2009; 20:388–396. 19. Kovesdy CP, Kuchmak O, Lu JL, Kalantar-Zadeh K. Outcomes associated with phosphorus binders in men with nondialysis-dependent CKD. Am J Kidney Dis 2010; 56:842–851.
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Phosphate management Bhan 20. Tangri N, Wagner M, Griffith JL, et al. Effect of bone mineral guideline target achievement on mortality in incident dialysis patients: an analysis of the United Kingdom Renal Registry. Am J Kidney Dis 2011; 57:415– 421. 21. Block GA, Wheeler DC, Persky MS, et al. Effects of phosphate binders in & moderate CKD. J Am Soc Nephrol 2012; 23:1407–1415. Randomized trial studying the effects of calcium-based binders, lanthanum, and sevelamer vs. placebo. It demonstrated increased vascular calcification with all agents, though no mortality data presented. 22. Isakova T, Barchi-Chung A, Enfield G, et al. Effects of dietary phosphate restriction and phosphate binders on FGF23 levels in CKD. Clin J Am Soc Nephrol 2013; 8:1009–1018. 23. Covic A, Passlick-Deetjen J, Kroczak M, et al. A comparison of calcium acetate/magnesium carbonate and sevelamer-hydrochloride effects on fibroblast growth factor-23 and bone markers: post hoc evaluation from a controlled, randomized study. Nephrol Dial Transpl 2013; 28:2383– 2392. 24. Chertow GM, Burke SK, Raggi P. Treat to Goal Working Group. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 2002; 62:245–252. 25. Block GA, Spiegel DM, Ehrlich J, et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int 2005; 68:1815–1824. 26. Block GA, Raggi P, Bellasi A, et al. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int 2007; 71:438–441. 27. St Peter WL, Liu J, Weinhandl E, Fan Q. A comparison of sevelamer and calcium-based phosphate binders on mortality, hospitalization, and morbidity in hemodialysis: a secondary analysis of the Dialysis Clinical Outcomes Revisited (DCOR) randomized trial using claims data. Am J Kidney Dis 2008; 51:445–454. 28. Di Iorio B, Molony D, Bell C, et al. Sevelamer versus calcium carbonate in & incident hemodialysis patients: results of an open-label 24-month randomized clinical trial. Am J Kidney Dis 2013; 62:771–778. A recent randomized trial of sevelamer vs. calcium binders demonstrating improved survival in the sevelamer arm, although this arm also achieved better phosphorus control.
29. Jamal SA, Vandermeer B, Raggi P, et al. Effect of calcium-based versus noncalcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet 2013; 382:1268–1277. A large meta-analysis of comparative phosphate binder studies providing the strongest evidence to date for a survival advantage associated with noncalcium binder use compared with calcium-based binders. This relationship was predominantly driven by sevelamer. 30. Manns B, Klarenbach S, Lee H, et al. Economic evaluation of sevelamer in patients with end-stage renal disease. Nephrol Dial Transplant 2007; 22: 2867–2878. 31. Ramirez JA, Emmett M, White MG, et al. The absorption of dietary phosphorus and calcium in hemodialysis patients. Kidney Int 1986; 30:753–759. 32. Hou SH, Zhao J, Ellman CF, et al. Calcium and phosphorus fluxes during hemodialysis with low calcium dialysate. Am J Kidney Dis 1991; 18:217–224. 33. Mucsi I, Hercz G, Uldall R, et al. Control of serum phosphate without any phosphate binders in patients treated with nocturnal hemodialysis. Kidney Int 1998; 53:1399–1404. 34. FHN Trial Group. In-center hemodialysis six times per week versus three times per week. N Engl J Med 2010; 363:2287–2300. 35. Sharma S, Waikar SS. Phosphate balance in continuous venovenous hemofiltration. Am J Kidney Dis 2013; 61:1043–1045. 36. Chertow GM, Block GA, Correa-Rotter R, et al., EVOLVE Trial Investigators. & Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 2012; 367:2482–2494. A randomized trial of cinacalcet in ESRD demonstrating no mortality benefit. Also demonstrated no improvement in phosphorus control. 37. Mu¨ller D, Mehling H, Otto B, et al. Niacin lowers serum phosphate and increases HDL cholesterol in dialysis patients. Clin J Am Soc Nephrol 2007; 2:1249–1254. 38. Cheng SC, Young DO, Huang Y, et al. A randomized, double-blind, placebocontrolled trial of niacinamide for reduction of phosphorus in hemodialysis patients. Clin J Am Soc Nephrol 2008; 3:1131–1138. 39. Wang S, Alfieri T, Ramakrishnan K, et al. Serum phosphorus levels and pill & burden are inversely associated with adherence in patients on hemodialysis. Nephrol Dial Transplant 2013. [Epub ahead of print] A study of phosphate binder adherence, highlighting the importance of considering pill burden in the prescription of a phosphate-binding regimen.
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Phosphate management in chronic kidney disease Ishir Bhan
Purpose of review The review focuses on the rationale and evidence behind management strategies for hyperphosphatemia in patients with chronic kidney disease (CKD). Recent findings Optimal management of phosphate in CKD remains an area of uncertainty, but multiple studies now point to a clinical benefit from the use of phosphate binders. Evidence of improved survival is particularly strong with sevelamer, though it remains unclear whether the absence of calcium or other properties of sevelamer are responsible for this relationship. Newer agents, such as iron-based binders or niacin compounds to inhibit phosphorus absorption, may have additional benefits which will be better defined with additional experience. A reduced pill count may be a particularly beneficial characteristic of newer agents, and has been associated with improved response to therapy. Increased use of frequent, nocturnal hemodialysis is an additional tool to help ameliorate phosphate control. Data on the reduction of fibroblast growth factor 23 through use of phosphate binders remain weak. Summary An improved understanding of phosphate regulation and the development of new therapeutic agents have reinvigorated a once stagnant field, but significant changes to practice cannot yet be justified. There is increasing support for using sevelamer in place of calcium-based binders, though economic practicability remains challenging. Keywords chronic kidney disease, hyperphosphatemia, mineral and bone disease, phosphate binders
INTRODUCTION Hyperphosphatemia develops in chronic kidney disease (CKD) as a result of a reduced ability to excrete the ingested load. Early in CKD, proximal tubular reabsorption of phosphorus can be suppressed by rising levels of fibroblast growth factor 23 (FGF-23). As kidney disease progresses and glomerular filtration rate (GFR) falls below 20–30 ml/min, this rise in FGF-23 can no longer adequately augment phosphate excretion, and phosphate levels begin to rise [1]. As these levels increase, so does the risk of inappropriate deposition of calcium and phosphorus, potentially leading to vascular calcification and an associated increase in mortality. The high levels of parathyroid hormone (PTH) commonly seen in advanced CKD augment bone turnover, releasing calcium and phosphorus into the circulation, and bringing calcium levels closer to normal. However, in the setting of limited phosphate excretion, this secondary hyperparathyroidism can worsen the underlying hyperphosphatemia, which itself can stimulate PTH release. Thus, control of phosphorus has the potential to interrupt a www.co-nephrolhypertens.com
deleterious cycle. Interest in phosphate control has increased in recent years by the discovery that high levels of FGF-23 have been strongly linked to mortality in end-stage renal disease (ESRD), predialysis CKD, and even the general population. This review will address strategies to manage hyperphosphatemia in CKD and review potential advantages and disadvantages of the available options.
PHOSPHATE TARGETS In addition to its effects on the hormonal balance and bone, hyperphosphatemia could play a direct role in morbidity and mortality by promoting the deposition of calcium and phosphorus in the Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA Correspondence to Ishir Bhan, MD, MPH, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. Tel: +1 617 726 3934; fax: +1 617 726 8481 Curr Opin Nephrol Hypertens 2014, 23:174–179 DOI:10.1097/01.mnh.0000441155.47696.41 Volume 23 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Phosphate management Bhan
KEY POINTS Processed foods with phosphate additives should be avoided in patients with CKD and hyperphosphatemia. Phosphate binders are an effective tool to reduce phosphate, and factors such as cost, pill burden, and calcium should be weighed as part of binder selection. Increasing support for sevelamer as a potential mediator of improved survival should prompt its consideration as a first choice for phosphate reduction.
vasculature and other nonbone tissues, although this relationship has not been consistently observed [2]. Regardless of the mechanism, a body of observational data has linked hyperphosphatemia to increased mortality in ESRD and advanced CKD. However, it is important to recognize that, despite studies associating hyperphosphatemia with adverse outcomes, a cause-and-effect relationship between control of phosphate and improved outcomes has not been definitively established. Despite this, current Kidney Disease Improving Global Outcomes (KDIGO) guidelines advocate maintenance of serum phosphate within the normal range for predialysis (stage 3–5) CKD and ‘toward the normal range’ for patients with ESRD on dialysis [3].
DIETARY PHOSPHATE CONTROL The American diet is rich in phosphorous, with daily phosphorus intake reaching 1500 mg or greater. Thus, dietary restriction of phosphorus would seem to be a logical first step in treating hyperphosphatemia. However, many high-phosphorus foods are also rich in protein, so a potential risk of dietary phosphate restriction is a compromise of protein intake, which may be particularly detrimental in patients with ESRD. Whereas short-term studies have suggested some benefit of dietary restriction, convincing real-world data are lacking. One recent study of prescribed phosphorus restriction demonstrated no survival benefit in hemodialysis, and in fact suggested an increase in mortality with phosphate restriction in some subgroups [4]. Typical assessments of dietary phosphate have focused on the natural phosphorous content, targeting daily phosphorus intake below 900 mg. True phosphorus content of foods, can, however, be difficult to determine accurately. Processed foods often contain phosphate additives, and these additional sources of phosphorus may increase the daily intake by over 1 g per day without offering any additional nutritional benefit [5]. Additionally, not
all phosphate content is equally bioavailable; plantbased phosphorus is generally poorly absorbed, whereas phosphate additives exhibit near-complete absorption. Avoidance of processed foods containing phosphate additives is particularly beneficial in ESRD, where limiting dietary phosphorus without compromising protein intake is ideal. Current food labeling does explicitly list phosphate content, so vigilance toward ingredients lists and avoidance of processed foods are of greatest benefit when targeting dietary changes. One clinical trial aimed at educating patients to identify foods rich in phosphate additives demonstrated modest, though statistically significant, improvements in phosphorus control [6].
PHOSPHATE BINDERS: OPTIONS Given the challenges of dietary phosphate restriction, phosphate binders have become the mainstay of therapy in CKD-associated hyperphosphatemia. Aluminum binders are no longer used as chronic therapy due to bone and nervous system toxicities. Calcium-based binders, which include calcium carbonate and calcium acetate, avoid aluminum’s adverse effects. Calcium carbonate is widely available without prescription. It binds phosphorus weakly in an acidic environment, yet solubility is poor in an alkaline environment. Calcium acetate (PhosLo) is considerably more water soluble and overall appears superior as a phosphate-binding agent at equivalent doses of elemental calcium, with a lower risk of hypercalcemia [7–9]. Other binders based on calcium are not commonly used. Calcium citrate, used commonly to treat or prevent osteoporosis, is generally avoided in the CKD population due to its poor performance and risk of citrate promoting aluminum absorption. A combination of calcium acetate and magnesium carbonate appears to be effective, though carries a small risk of hypermagnesemia [10]. It remains poorly studied and its role in the therapeutic armamentarium has yet to be defined. Whereas calcium-based binders were used to avoid the toxicities of aluminum, there has been increasing concern that chronic exposure to a high calcium load could promote vascular calcification and lead to premature morbidity and mortality. Sevelamer, a synthetic polymer, effectively binds phosphate, but is not absorbed. The initially available hydrochloride preparation (Renagel) increased the risk of metabolic acidosis, even in patients on dialysis [11]. However, the newer carbonate formulation (Renvela) avoids this risk. Lanthanum carbonate (Fosrenol) is an alternative, metal-based phosphate binder that is generally well tolerated and as effective as other binders at controlling phosphorus [12,13]. Whereas there has
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Clinical nephrology
been concern about the potential long-term effects of lanthanum accumulation in the liver and other tissues, these effects have not been clinically evident, nor has there been evidence linking lanthanum to nephrogenic systemic fibrosis, which has been associated with exposure to gadolinium, another lanthanide [14]. Low pill burden may be a particular advantage of lanthanum [15]. Iron-based binders are another emerging therapy. A recent open-label randomized trial compared the iron-based binder PA21 to sevelamer [16 ]. Both efficacy and frequency of adverse effects were similar between the two agents, although the study was not specifically designed to compare efficacy. At higher doses, discontinuation was more common in PA21, though the most common reason for discontinuation was hypophosphatemia. No effect on iron metabolism, including serum iron, transferrin, or ferritin was observed. Ferric citrate is another promising iron-based agent, though additional clinical data are needed before the role of iron-based binders becomes clear [17]. &
PHOSPHATE BINDERS AND CLINICAL OUTCOMES Phosphate binders have demonstrated efficacy in reducing serum phosphorus levels; but does this therapy result in improved clinical outcomes? An analysis of over 6000 incident hemodialysis patients demonstrated improved 1-year mortality in patients treated with phosphate binders, with hazard ratios ranging between 0.58 and 0.82, depending on the analysis [18]. Whereas retrospective studies cannot prove cause-and-effect relationships, the authors performed an analysis matched by baseline phosphorus level and propensity score (to control for factors that influenced the decision to start binders). The effect was consistent across a wide range of demographic and laboratory-defined subgroups. A historical cohort study of over 1188 men with predialysis CKD at a single Veterans Affairs medical center similarly found an adjusted hazard ratio for death of 0.61 for patients treated with phosphate binders, with most exposed to both calcium acetate and sevelamer [19]. The effect was more evident in patients with higher baseline phosphorus levels, though serum phosphorous actually increased over time in patients treated with binders. These results, along with the comparatively weaker associations of serum phosphorus with mortality, raise the question of whether phosphate binders might have a beneficial effect independent from that measured by their influence on serum phosphorus. Indeed, an analysis from the United Kingdom examining the effect of achieving Kidney Disease Outcomes 176
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Quality Initiative (KDOQI) targets for phosphorus failed to show a statistically significant benefit despite a study population of 7076 patients [20]. The data linking binder use to improved outcomes, however, remain contradictory, particularly in predialysis CKD. A prospective study attempted to address this by randomly assigning 148 patients with an estimated GFR (eGFR) of 20–45 ml/min to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo [21 ]. There was greater decrease in phosphorus in the binder arm, with a 22% reduction in mean 24-h urine phosphorus, suggesting effective binding. While PTH was stable in the binder arm, it increased in the placebo group, suggesting an additional benefit of this therapy consistent with its known actions. Enthusiasm was tempered, however, by a significant increase in both coronary artery and aortic calcification in the phosphate-binder arms. These effects were strongest among those receiving calcium acetate, but did not appear to be restricted to this arm. Moreover, a reduction in FGF-23 (which has been linked to increased mortality) – an effect many had hoped phosphate binders would be able to achieve – was not apparent in this study, although more recent studies contradict this [22,23]. A prospective trial focused on outcomes of morbidity and mortality rather than surrogate endpoints would be central in providing clarity, but is not currently available. &
ARE SOME BINDERS BETTER THAN OTHERS? Concerns about calcium load and effects on vascular calcification have led to several comparative studies between binders. The Treat to Goal trial compared sevelamer hydrochloride to either calcium acetate or calcium carbonate in 200 incident dialysis patients [24]. Despite equivalent phosphorus control, the calcium binders were associated with more hypercalcemia, and higher coronary artery and aortic calcium scores. The Renagel in New Dialysis (RIND) study randomized 129 incident hemodialysis patients to sevelamer hydrochloride or calcium [25]. Here again, calcium-based binders were associated with a greater increase in coronary artery calcium score over 18 months. However, it is notable that one-third of the patients had no coronary calcification detected at baseline, and none of these patients progressed regardless of treatment assignment. Therefore, it may be that patients with established disease are at a particular risk of progressive calcification. A subsequent analysis of these data demonstrated a significant mortality advantage to sevelamer, with a hazard ratio of 3.1 [26]. Although it may be presumed that the calcium itself Volume 23 Number 2 March 2014
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Phosphate management Bhan
promoted calcification, change in calcium score in this study did not correlate with the development of hypercalcemia nor did the degree of progression depend on the calcium load, raising the question of whether sevelamer might have an independent effect to retard calcification. The larger Dialysis Clinical Outcomes Revisited (DCOR) study included over 2000 prevalent hemodialysis patients as part of a randomized trial, again comparing sevelamer to calcium-based binders [27]. Unlike the Treat to Goal and RIND trials, the authors did not find an advantage to sevelamer use, this time using either all-cause or cardiovascular mortality as the endpoint of choice, though some measures of hospitalization were lower with sevelamer. The recent INDEPENDENT trial randomized 466 incident hemodialysis patients to sevelamer or calcium carbonate over 24 months and found lower all-cause and cardiovascular mortality in the sevelamer arm, but better phosphate control was achieved in the sevelamer arm as well, making it unclear if these results would extend to a calcium-based regimen that was more efficacious (e.g. calcium acetate or alternative dosing) [28 ]. All these trials have been somewhat limited by loss to follow-up. Sevelamer use is known to influence cholesterol levels, which may have driven the effects on vascular calcification and possibly other outcomes. Significant reductions in both total and low-density lipoprotein (LDL) cholesterol associated with sevelamer use were seen in both the Treat to Goal and RIND trials. To address this, the Calcium Acetate Renagel Evaluation 2 (CARE-2) study compared calcium acetate to sevelamer in a 12-month study of 203 prevalent hemodialysis patients with hyperphosphatemia and detectable baseline coronary artery calcification. In addition to phosphate binders, however, all patients were prescribed atorvastatin to control LDL cholesterol to less than 70 mg/dl. As a result, cholesterol profiles were similar in both arms at the end of the study. Increases in coronary artery calcification did not differ between the groups, suggesting that the cholesterol changes, rather than calcium, may have mediated differences between these treatments in other studies. A recent meta-analysis concluded that, overall, noncalcium-based binders appeared to be associated with decreased all-cause mortality, but this was based largely on studies of sevelamer [29 ]. Given the significant cost associated with sevelamer [30], and continuing uncertainty about its effects on clinical endpoints and the mechanisms by which these changes may be achieved, sevelamer cannot be unequivocally advocated over calcium acetate at this time. The data for lanthanum are considerably weaker. &
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OTHER APPROACHES Other approaches may also have an influence on phosphate management. Although there is some debate about the relative effects of different vitamin D compounds on phosphate absorption, active vitamin D formulations have the potential to increase gastrointestinal absorption and should be avoided in patients with severe hyperphosphatemia [3,31]. While hemodialysis is effective at clearing phosphorus with a typical 4-h dialysis removing approximately 1 g of phosphorus, this is inadequate to maintain phosphorus control in most individuals [32]. Therefore, adjustments in hemodialysis prescription would not be expected to significantly alter serum phosphate. Nocturnal hemodialysis offered at home 6 days a week can clear twice as much phosphorus compared to a conventional regimen, and an in-center program was associated with modestly lower serum phosphorus levels: this approach may be beneficial in appropriate patients [33,34]. Continuous renal replacement therapy can remove 1 g or more of phosphorus daily, but is not feasible in the outpatient setting [35]. Cinacalcet can be used to treat hyperparathyroidism in place of or in addition to active vitamin D analogs, and in theory might be expected to reduce phosphorus in ESRD (due to both a lower requirement for vitamin D and because of suppression of PTH-induced phosphate release from bone). However, the recent EValuation of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) randomized trial comparing cinacalcet with placebo failed to demonstrate superior control of phosphate in a hemodialysis population [36 ]. Newer pharmacologic agents to specifically address phosphorus absorption may offer additional options. Derivatives of niacin may act via blocking the sodium–phosphate co-transporter in the gut. A prolonged release formulation of nicotinic acid was demonstrated to control phosphorus without affecting calcium levels when given in lieu of calciumbased binders [37]. An alternative formulation, niacinamide, was studied alongside phosphate binders in a double-blind trial and demonstrated effective phosphorus reduction [38]. The potential risks of niacin-based therapies include effects on glucose, flushing, diarrhea, thrombocytopenia, and myopathy. Further studies are needed to more clearly define the role of niacin-based therapies and evaluate potential risks in the CKD population. However, these agents may offer promise as adjuncts or alternatives in patients to reduce pill burden, which has been linked to poor control of phosphorus [39 ]. A summary of treatment approaches is presented in Table 1.
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Clinical nephrology Table 1. Treatment options for phosphate control in CKD Treatment
Mechanism
Comments
Dietary control
Reduced intake of phosphorus
Challenging to implement. Phosphate content in food can be difficult to determine. Phosphate additives are particularly bioavailable.
Calcium acetate/carbonate
Intestinal phosphate binding
Concern for high calcium burden promoting vascular calcification.
Sevelamer hydrochloride/carbonate
Intestinal phosphate binding
High cost, but strongest association with improved survival. Mechanism of benefit may include effects other than phosphate reduction.
Lanthanum carbonate
Intestinal phosphate binding
Low pill burden, less well studied compared with calcium and sevelamer.
Iron-based binders
Intestinal phosphate binding
Limited data available.
Niacin-based compounds
Inhibits phosphate absorption
Limited data available.
Nocturnal hemodialysis
Increased clearance of phosphate
Not practical in all patients, limited availability.
CKD, chronic kidney disease.
CONCLUSION Phosphate management in CKD remains a therapeutic challenge. While the control of dietary phosphate intake is important, it can be challenging due to the limitation of food labeling. Avoidance of processed foods with phosphate additives may be most beneficial, avoiding the potential protein restriction that accompanies the avoidance of naturally phosphate-rich foods. Phosphate binders should be used in many cases of advanced CKD, and calcium acetate, sevelamer, and lanthanum all appear to be effective. Recent data, though not definitive, point to a possible survival advantage associated with sevelamer use when compared with calcium-based binders. Despite the limitations of the data, sevelamer carbonate should be considered as a first choice for treating hyperphosphatemia when economically practical, particularly in patients with higher calcium levels. Data on newer agents such as iron-based binders and niacin appear promising, but are too limited to guide specific recommendations. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Levin A, Bakris GL, Molitch M, et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int 2006; 71:31–38.
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2. Giachelli CM. Vascular calcification mechanisms. J Am Soc Nephrol 2004; 15:2959–2964. 3. Kidney Disease Improving Global Outcomes KDIGO CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 2009; (113):S1–S130. 4. Lynch KE, Lynch R, Curhan GC, Brunelli SM. Prescribed dietary phosphate restriction and survival among hemodialysis patients. Clin J Am Soc Nephrol 2011; 6:620–629. 5. Uribarri J, Calvo MS. Hidden sources of phosphorus in the typical American diet: does it matter in nephrology? Semin Dial 2003; 16:186–188. 6. Sullivan C, Sayre SS, Leon JB, et al. Effect of food additives on hyperphosphatemia among patients with end-stage renal disease: a randomized controlled trial. J Am Med Assoc 2009; 301:629–635. 7. Ben Hamida F, Esper el I, Compagnon M, et al. Long-term (6 months) crossover comparison of calcium acetate with calcium carbonate as phosphate binder. Nephron 1993; 63:258–262. 8. Caravaca F, Santos I, Cubero JJ, et al. Calcium acetate versus calcium carbonate as phosphate binders in hemodialysis patients. Nephron 1992; 60:423–427. 9. Schaefer K, Scheer J, Asmus G, et al. The treatment of uraemic hyperphosphataemia with calcium acetate and calcium carbonate: a comparative study. Nephrol Dial Transplant 1991; 6:170–175. 10. de Francisco ALM, Leidig M, Covic AC, et al. Evaluation of calcium acetate/ magnesium carbonate as a phosphate binder compared with sevelamer hydrochloride in haemodialysis patients: a controlled randomized study (CALMAG study) assessing efficacy and tolerability. Nephrol Dial Transplant 2010; 25:3707–3717. 11. Thet Z, Win AK, Pedagogos E, et al. Differential effects of phosphate binders on predialysis serum bicarbonate in end-stage kidney disease patients on maintenance haemodialysis. BMC Nephrol 2013; 14:205. 12. Persy VP, Behets GJ, Bervoets AR, et al. Lanthanum: a safe phosphate binder. Semin Dial 2006; 19:195–199. 13. Finn WF. SPD 405-307 Lanthanum Study Group. Lanthanum carbonate versus standard therapy for the treatment of hyperphosphatemia: safety and efficacy in chronic maintenance hemodialysis patients. Clin Nephrol 2006; 65:191–202. 14. De Broe ME. Can the risk of gadolinium be extrapolated to lanthanum? Semin Dial 2008; 21:142–144. 15. Ishizu T, Ishizu T, Hong Z, et al. Efficacy of continuous oral administration of lanthanum carbonate over 24 months. Ther Apher Dial 2013; 17 (S1):22– 28. 16. Wu¨thrich RP, Chonchol M, Covic A, et al. Randomized clinical trial of the iron& based phosphate binder PA21 in hemodialysis patients. Clin J Am Soc Nephrol 2013; 8:280–289. Randomized trial of novel, iron-based, phosphate-binding agents. Iron-based binders are likely to become increasingly common in the near future. 17. Dwyer JP, Sika M, Schulman G, et al. Dose-response and efficacy of ferric citrate to treat hyperphosphatemia in hemodialysis patients: a short-term randomized trial. Am J Kidney Dis 2013; 61:759–766. 18. Isakova T, Gutie´rrez OM, Chang Y, et al. Phosphorus binders and survival on hemodialysis. J Am Soc Nephrol 2009; 20:388–396. 19. Kovesdy CP, Kuchmak O, Lu JL, Kalantar-Zadeh K. Outcomes associated with phosphorus binders in men with nondialysis-dependent CKD. Am J Kidney Dis 2010; 56:842–851.
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Phosphate management Bhan 20. Tangri N, Wagner M, Griffith JL, et al. Effect of bone mineral guideline target achievement on mortality in incident dialysis patients: an analysis of the United Kingdom Renal Registry. Am J Kidney Dis 2011; 57:415– 421. 21. Block GA, Wheeler DC, Persky MS, et al. Effects of phosphate binders in & moderate CKD. J Am Soc Nephrol 2012; 23:1407–1415. Randomized trial studying the effects of calcium-based binders, lanthanum, and sevelamer vs. placebo. It demonstrated increased vascular calcification with all agents, though no mortality data presented. 22. Isakova T, Barchi-Chung A, Enfield G, et al. Effects of dietary phosphate restriction and phosphate binders on FGF23 levels in CKD. Clin J Am Soc Nephrol 2013; 8:1009–1018. 23. Covic A, Passlick-Deetjen J, Kroczak M, et al. A comparison of calcium acetate/magnesium carbonate and sevelamer-hydrochloride effects on fibroblast growth factor-23 and bone markers: post hoc evaluation from a controlled, randomized study. Nephrol Dial Transpl 2013; 28:2383– 2392. 24. Chertow GM, Burke SK, Raggi P. Treat to Goal Working Group. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 2002; 62:245–252. 25. Block GA, Spiegel DM, Ehrlich J, et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int 2005; 68:1815–1824. 26. Block GA, Raggi P, Bellasi A, et al. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int 2007; 71:438–441. 27. St Peter WL, Liu J, Weinhandl E, Fan Q. A comparison of sevelamer and calcium-based phosphate binders on mortality, hospitalization, and morbidity in hemodialysis: a secondary analysis of the Dialysis Clinical Outcomes Revisited (DCOR) randomized trial using claims data. Am J Kidney Dis 2008; 51:445–454. 28. Di Iorio B, Molony D, Bell C, et al. Sevelamer versus calcium carbonate in & incident hemodialysis patients: results of an open-label 24-month randomized clinical trial. Am J Kidney Dis 2013; 62:771–778. A recent randomized trial of sevelamer vs. calcium binders demonstrating improved survival in the sevelamer arm, although this arm also achieved better phosphorus control.
29. Jamal SA, Vandermeer B, Raggi P, et al. Effect of calcium-based versus noncalcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet 2013; 382:1268–1277. A large meta-analysis of comparative phosphate binder studies providing the strongest evidence to date for a survival advantage associated with noncalcium binder use compared with calcium-based binders. This relationship was predominantly driven by sevelamer. 30. Manns B, Klarenbach S, Lee H, et al. Economic evaluation of sevelamer in patients with end-stage renal disease. Nephrol Dial Transplant 2007; 22: 2867–2878. 31. Ramirez JA, Emmett M, White MG, et al. The absorption of dietary phosphorus and calcium in hemodialysis patients. Kidney Int 1986; 30:753–759. 32. Hou SH, Zhao J, Ellman CF, et al. Calcium and phosphorus fluxes during hemodialysis with low calcium dialysate. Am J Kidney Dis 1991; 18:217–224. 33. Mucsi I, Hercz G, Uldall R, et al. Control of serum phosphate without any phosphate binders in patients treated with nocturnal hemodialysis. Kidney Int 1998; 53:1399–1404. 34. FHN Trial Group. In-center hemodialysis six times per week versus three times per week. N Engl J Med 2010; 363:2287–2300. 35. Sharma S, Waikar SS. Phosphate balance in continuous venovenous hemofiltration. Am J Kidney Dis 2013; 61:1043–1045. 36. Chertow GM, Block GA, Correa-Rotter R, et al., EVOLVE Trial Investigators. & Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 2012; 367:2482–2494. A randomized trial of cinacalcet in ESRD demonstrating no mortality benefit. Also demonstrated no improvement in phosphorus control. 37. Mu¨ller D, Mehling H, Otto B, et al. Niacin lowers serum phosphate and increases HDL cholesterol in dialysis patients. Clin J Am Soc Nephrol 2007; 2:1249–1254. 38. Cheng SC, Young DO, Huang Y, et al. A randomized, double-blind, placebocontrolled trial of niacinamide for reduction of phosphorus in hemodialysis patients. Clin J Am Soc Nephrol 2008; 3:1131–1138. 39. Wang S, Alfieri T, Ramakrishnan K, et al. Serum phosphorus levels and pill & burden are inversely associated with adherence in patients on hemodialysis. Nephrol Dial Transplant 2013. [Epub ahead of print] A study of phosphate binder adherence, highlighting the importance of considering pill burden in the prescription of a phosphate-binding regimen.
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