Current Controversies in Managing End-Stage Renal Disease Patients
Control of Hyperphosphatemia among Patients with ESRD
Joseph A. Coladonato
Carolina Kidney Associates, Greensboro, North Carolina
Address correspondence to: Dr. Joseph A. Coladonato, Carolina Kidney Associates, 309 New Street, Greensboro, NC 27405. Phone: 336-379-9708; Fax: 336-379-8714; E-mail: joeco001{at}triad.rr.com
Derangements of mineral metabolism occur during the early stagesof chronic kidney disease (CKD). Hyperphosphatemia developsin the majority of patients with ESRD and has long been associatedwith progression of secondary hyperparathyroidism and renalosteodystrophy. More recent observational data have associatedhyperphosphatemia with increased cardiovascular mortality amongdialysis patients. Adequate control of serum phosphorus remainsa cornerstone in the clinical management of patients with CKDnot only to attenuate the progression of secondary hyperparathyroidismbut also possibly to reduce the risk for vascular calcificationand cardiovascular mortality. These measures include dietaryphosphorus restriction, dialysis, and oral phosphate binders.Dietary restriction is limited in advanced stages of CKD. Phosphatebinders are necessary to limit dietary absorption of phosphorus.Aluminum hydroxide is an efficient binder; however, its usehas been nearly eliminated because of concerns of toxicity.Calcium salts are inexpensive and have been used effectivelyworldwide as an alternative to aluminum. Concerns of calciumoverload have led to the investigation of alternatives. Currently,only two Food and Drug Administration–approved noncalcium,nonaluminum binders are available. Sevelamer hydrochloride isan exchange resin and was not as effective as calcium acetatein meeting new guideline recommendations in one double-blindclinical trial. Lanthanum carbonate is a rare earth elementand has been studied less extensively. Concerns of long-termadministration and toxicity exist. Furthermore, these agentsare significantly more expensive than calcium salts, which maycontribute to patient noncompliance.
Derangements of mineral metabolism occur during the early stagesof chronic kidney disease (CKD) (1). Hyperphosphatemia occursas a consequence of diminished phosphorus filtration and excretionwith the progression of CKD. Decreased phosphorus excretioncan initially be overcome by increased secretion of parathyroidhormone (PTH), which decreases proximal phosphate reabsorption(2). Hence, phosphorus levels are usually within normal rangeuntil the GFR falls below approximately 30 ml/min, or stageIV. CKD according to the National Kidney Foundation Kidney DiseaseOutcomes Quality Initiative (NKF–K/DOQI) classification(3). In more advanced stages of CKD, the blunted urinary excretionof phosphorus can no longer keep pace with the obligatory intestinalphosphate absorption, resulting in hyperphosphatemia (4). Therefore,it is not surprising that the majority of patients with ESRDhave significant hyperphosphatemia (5).
Hyperphosphatemia has long been associated with progressionof secondary hyperparathyroidism (HPTH) and renal osteodystrophy(1). However, more recent observational data have also showna significant association of hyperphosphatemia with increasedmortality among patients who have ESRD and are on hemodialysis(5–7). Moreover, elevated serum phosphorus has been associatedwith an increased risk for cardiovascular mortality and hospitalization(all-cause, cardiovascular, and fracture) among dialysis patients(8). The exact pathogenesis is poorly understood, and researchis being developed to explore the putative role of mineral metabolismderangements and their therapies in the increased cardiovascularmortality among patients with ESRD. Nevertheless, it is generallyaccepted that adequate control of serum phosphorus remains acornerstone in the clinical management of patients with CKDnot only to attenuate the progression of secondary HPTH butalso possibly to reduce the risk for vascular calcificationand cardiovascular mortality. These measures include dietaryphosphorus restriction, dialysis, oral phosphate binders, andcontrol of HPTH.
Dietary phosphate restriction has been shown to prevent thedevelopment of HPTH early in the course of disease, as wellas increase plasma calcitriol levels and inhibit parathyroidcell proliferation (9,10). Furthermore, phosphorus restrictionmay be instrumental in preventing progressive renal failureand soft tissue calcification (11,12).
The average diet in North America and Europe contains approximately1000 to 1500 mg of phosphorus per day (13). Patients with ESRDabsorb approximately 50 to 60% of dietary phosphorus, and asGFR declines, urinary phosphorus excretion is inadequate tomaintain normal homeostasis, resulting in a positive phosphorusbalance (14). Vitamin D administration aggravates this problemby increasing intestinal absorption of dietary phosphorus andcalcium (15).
Aggressive dietary phosphate restriction among patients withCKD is impractical and could compromise overall nutrition, particularlyprotein intake (16). For preventing malnutrition among patientswith CKD, the NKF–K/DOQI guidelines recommend a minimumprotein intake of 1.2 g/kg per d (approximately 800 to 1000mg/d phosphorus). As renal function declines, a net positivebalance is inevitable (14,17), and thus other therapies arerequired.
The clearance of phosphorus varies among the different modalitiesof dialysis. Ideally, adequate dialysis in any form would removeadequate amounts of all uremic toxins, including phosphorus.Unfortunately, conventional, thrice-weekly hemodialysis (4 hduration) removes approximately 900 mg of phosphorus each treatment(an average of only 300 mg/d) (18). Conventional, intermittenthemodiafiltration improves phosphorus removal modestly (1030to 1700 mg/treatment) (19), but overall, conventional, intermittenthemodialysis provides inadequate removal of phosphorus. Thisseems to be due to the high postdialysis rebound from mobilizationof phosphate from the intracellular space and/or bone inducedby intradialytic removal of this solute. Moreover, the clearanceof phosphorus during peritoneal dialysis is comparable or inferiorto that of conventional hemodialysis, especially when intradialyticprotein loss is taken into consideration (20). Hence, the needfor phosphate binders for the majority of patients with ESRDis predictable.
One approach to overcome this rebound is quotidian hemodialysis.Short, daily hemodialysis utilizes blood flow rates (Qb) of450 ml/min, dialysate flow rates (Qd) of 800 ml/min, a durationof 1.5 to 2.5 h, and a frequency of six to seven treatmentsper week. Alternatively, slow nocturnal hemodialysis (NH) entailsQb of 150 to 300 ml/min, Qd of 300 ml/min, duration of 6 to8 h, and a frequency of six to seven nights per week. Duringa 4-yr observational study that compared patients who receivedconventional, intermittent hemodialysis; short, daily hemodialysis;and NH, the only modality of dialysis to show a significantreduction in the serum phosphorus levels and eliminate the needfor phosphate binders was NH (21–23). Some patients actuallyrequired phosphorus supplementation during the study (22), aswell as adjustments to dialysate calcium levels as a resultof significant reductions in serum calcium levels (23). NH hasalso been associated with improved solute clearance, qualityof life, BP control, and reduction in medication requirements.However, obstacles to its use on a larger scale include unfamiliaritywith home hemodialysis, as well as issues with reimbursementand cost of equipment and nonreusable materials.
Aluminum Hydroxide
The use of phosphate binders began in the early 1970s, whenthe importance of phosphorus control was first emphasized. Useof aluminum-containing phosphate binders was the standard ofcare among patients with ESRD. Aluminum hydroxide was a veryefficient phosphate binder (24). Unfortunately, long-term usewas associated with aluminum accumulation and toxicity, manifestingitself as encephalopathy, osteomalacia, microcytic anemia, andmyopathy (25–27). Subsequently, the use of aluminum hydroxidehas been limited to salvage, short-term therapy or abandonedentirely.
Calcium Carbonate
Calcium salts then emerged as an alternative to aluminum asa phosphate binder. It was well established that calcium saltsbound dietary phosphorus, although less efficiently than aluminum(28). Calcium carbonate has been used extensively worldwidesince the early 1980s because of its efficacy, tolerability,and affordability (29–31).
One prospective, randomized, open-label trial suggested thathigh-dose calcium carbonate was effective as monotherapy tocontrol mild to moderate secondary HPTH (PTH 150 to 600 pg/ml)among hemodialysis patients (32). Indridason et al. (32) randomlyassigned 52 patients to receive escalating doses of calciumcarbonate alone, daily oral calcitriol, or intermittent intravenous(IV) calcitriol. The calcitriol groups received calcium carbonatein fixed doses. The mean serum phosphorus was significantlylower in the calcium carbonate group throughout the study andwas 3.5 mg/dl at the treatment end of 36 wk. However, this requireda mean dose of 7 g/d elemental calcium. The oral and IV calcitriolgroups required aluminum hydroxide to help control hyperphosphatemia.PTH levels were significantly decreased in all groups but mostnotable in the IV calcitriol group (240 ± 37.7 to 65± 10 pg/ml). Although not statistically significant,there was a trend toward fewer hypercalcemic episodes in thecalcium carbonate group. No adverse effect on surrogate markersof bone metabolism was noted with the administration of calciumcarbonate.
Overall, calcium carbonate adequately controls phosphorus; however,its effectiveness may be limited by hypercalcemia. Calcium carbonatecontains a high proportion of elemental calcium (40%), and hypercalcemiacan occur when given at escalating doses (33), when administeredconcomitantly with vitamin D (which increases gastrointestinal[GI] absorption of calcium), or with use of higher dialysatecalcium concentrations (31,34). Furthermore, the proportionof calcium absorbed from phosphate-binder intake dramaticallyincreases when there is unsynchronized administration in relationto meals. Significantly more elemental calcium is absorbed whencalcium carbonate is given on an empty stomach or 2 h aftermeals compared with administration before or directly aftermeals (35).
Calcium Acetate
Calcium acetate (PhosLo, Nabi Pharmaceuticals, Boca Raton, FL)is an alternative to calcium carbonate as a phosphate binderand contains less elemental calcium (25%) than calcium carbonate.GI washout studies have shown that the amount of phosphorusbound per amount of calcium absorbed was almost twice as greatwith calcium acetate compared with calcium carbonate (36). Moreover,Mai et al. (37) showed that phosphorus absorption decreasedto 40% of the ingested load with calcium carbonate comparedwith 21.7% with an equivalent amount of calcium acetate. Thus,among patients with ESRD, calcium acetate binds approximatelytwice the amount of phosphorus per amount of calcium absorbed(38,39). This is believed to be attributable to the increasedsolubility of calcium acetate in both acid and alkaline solutionsin vitro.
Calcium acetate is well tolerated and has been shown to significantlyreduce and maintain serum phosphorus and calcium x phosphorusproduct levels during a long-term clinical trial (40). Thisprospective, randomized, controlled trial was undertaken toprove that sevelamer hydrochloride was more effective in loweringthe Ca x PO4 product compared with calcium-containing phosphatebinders. During the 52-wk treatment phase, study patients experiencedsignificant reductions in serum phosphorus and Ca x PO4 product,and no significant difference was noted between treatment arms.
Hypercalcemia, however, has been associated with both calciumcarbonate and calcium acetate ingestion. Growing concerns havebeen voiced regarding calcium loading and its putative rolein the progression of cardiovascular calcifications and theincreased cardiovascular mortality among patients with ESRD.Although associations have been drawn from cross-sectional observationalstudies and one prospective, randomized trial (40), the burdenof proof for causation remains unmet given the limitations ofstudy design, failure to account for confounders such as establishedrisk factors for cardiovascular disease (dyslipidemia, smoking,oxidative stress, hyperhomocysteinemia, inflammation [C-reactiveprotein]), and a flawed causal pathway linking calcium ingestionin the form of phosphate binders with coronary calcification(41). Nonetheless, alternatives to calcium-containing bindersare necessary and wisely have been explored in greater magnitude.
Magnesium Salts
Magnesium hydroxide and carbonate have been studied as adjunctsor alternatives to calcium-based binders over the years. However,these agents are not particularly effective as phosphate binders,and adjustments in dialysate magnesium are necessary (42). Giventhe lower efficacy of phosphorus binding of magnesium salts,larger doses are required and adverse GI effects such as diarrhea,hyperkalemia, and hypermagnesemia are often treatment limiting(43–45). MagneBind (Nephro-Tech Inc., Shawnee, KS) isa commercially available binding agent that contains varyingamounts of magnesium carbonate and calcium carbonate. It isconsidered a dietary supplement; therefore, the safety and efficacyof this agent as a phosphate binder has not been evaluated bythe Food and Drug Administration (FDA).
Sevelamer Hydrochloride
Sevelamer hydrochloride (RenaGel, Genzyme Corp., Cambridge,MA) is a novel nonaluminum, noncalcium phosphate-binding polymer.Sevelamer is a hydrogel of cross-linked poly(allylamine) andis completely resistant to digestive degradation and, therefore,not absorbed from the GI tract. It is an exchange resin thatbinds dietary phosphorus and releases chloride (46). Multipleclinical studies have demonstrated that sevelamer lowers serumphosphorus levels among patients with ESRD and is generallywell tolerated (40,47,48). Furthermore, sevelamer binds bileacids and thereby reduces fecal bile acid excretion and lowersLDL cholesterol (49).
Use of sevelamer has gained support in light of growing concernsof calcium loading and hypercalcemia. In fact, sevelamer therapyhas been associated with hypocalcemia, and study subjects oftenrequired the administration of 1 g of elemental calcium at bedtimeduring clinical studies (40,47–50).
Several open-label studies that compared sevelamer and calciumsalts have suggested similar abilities to lower and maintainserum phosphorus levels (40,46–50). However, sevelamerhas not consistently reduced serum phosphorus levels to thenewly recommended NKF–K/DOQI targets in these previousstudies.
To date, one prospective, double-blind, randomized, controlledtrial has determined whether calcium acetate or sevelamer hydrochloridebest achieves recently recommended treatment goals of phosphorusand Ca x PO4 product (51). During the 8-wk study, patients wererandomly assigned to either calcium acetate or sevelamer. Initialdoses were determined by postwashout phosphorus levels consistentwith package inserts of both agents. After 3 wk of therapy,the calcium acetate recipients reached the NKF–K/DOQItarget serum phosphorus level of 5.5 mg/dl; however, this goalwas never achieved in the sevelamer group. Serum calcium levelwas significantly higher in the calcium acetate group; the goalCa x PO4 product was achieved within 2 wk and was maintainedthroughout the study period. This study was the first to showthat calcium acetate more effectively lowered serum phosphorusand Ca x PO4 product compared with sevelamer hydrochloride.
These results conflict with a previous, open-label clinicaltrial that compared sevelamer with calcium salts (both carbonateand acetate) (40). In that study, there was no difference inthe primary end point, control of Ca x PO4 product, but therewas an attenuation of coronary and aortic calcification as measuredby electron-beam computed tomography. The exact mechanism(s)and implication(s) remain uncertain given the current stateof scientific evidence. Some would argue that sevelamer wasunderdosed during the CARE Study (51). However, the achieveddose of sevelamer (17.2 capsules, or 6.9 g/d) was higher thanthose administered in the Treat-to-Goal Study (6 g/d). One reasonfor the discrepancy may be the bias associated with open-labeltrials. Alternatively, the investigators postulated that bettercontrol of phosphorus in the calcium acetate group was relatedto a decreased phosphorus release from bone as a result of bettercorrection of metabolic acidosis (52).
Aside from efficacy, other concerns regarding the use of sevelamerexist. Because phosphate is bound in exchange for hydrochloricacid, lower levels of serum bicarbonate have been noted withlong-term administration compared with calcium salts (40,51).In at least one clinical trial, the serum bicarbonate levelsfell below the NKF–K/DOQI targets (52), and further investigationon the effects of metabolic acidosis may be necessary. Also,sevelamer remains one of the most expensive phosphate binderscurrently available. Nevertheless, sevelamer remains an importanttherapy in the control of hyperphosphatemia among patients withESRD.
Lanthanum Carbonate
Lanthanum carbonate (Fosrenol, Shire US Inc., Wayne, PA) isa rare earth element that was approved recently by the FDA forthe treatment of hyperphosphatemia among patients with ESRD.Lanthanum belongs to a group known as the "lanthanides" andhas a low solubility. In the acid environment of the stomachand upper small intestine, lanthanum dissociates sufficientlyto become available for phosphate binding. In laboratory experiments,lanthanum was found to be as effective as aluminum hydroxideand more effective than calcium carbonate or sevelamer hydrochlorideat binding dietary phosphate at equivalent doses (53). Severalclinical trials have shown that lanthanum is effective and welltolerated among healthy volunteers as well as hemodialysis patients(54,55). In short-term studies, lanthanum significantly reducedserum phosphorus levels and Ca x PO4 product compared with placeboamong patients with ESRD (56–59). Lanthanum carbonatetherapy in doses ranging from 1500 to 3000 mg/d, however, wasunable to lower the serum phosphorus below 5.5 mg/dl in anyof these trials.
Lanthanum is not metabolized and has a low GI absorption. Itsmain route of elimination is biliary. However, in long-termclinical studies, patients who were administered lanthanum carbonateat various doses developed increased serum levels (60). In lightof past experiences with chronic aluminum ingestion and toxicity,long-term safety with lanthanum carbonate remains a great concern.In two different rat models of CKD, the oral administrationof lanthanum led to more than a 10-fold increase of tissue contentin the liver, lung, and kidney (61). Furthermore, rats thatwere administered large doses of lanthanum for 12 wk showeda dose-dependent decrease in bone formation rate and osteomalacia(62). However, this may have been related to phosphorus depletionrather than lanthanum toxicity (63).
Given the toxic effects of mineral and metal accumulation reportedin the past, the long-term effects of lanthanum on bone havebeen an area of speculation. Before FDA approval, long-termoutcomes on bone morphology were required. In a prospective,randomized, parallel study, 197 patients were randomly assignedto receive either lanthanum carbonate or the standard phosphatebinder. Bone biopsies were obtained at either 1 or 2 yr of treatment(64,65). During these trials, treatment with lanthanum carbonatewas not associated with any significant shift on the classificationof bone disease, and there was no incidence of osteomalaciaas seen on bone biopsies in either group. Moreover, 11 patientswho had been receiving lanthanum for >4 yr underwent bonebiopsies, which did not reveal any evidence of aluminum-likeeffects (66).
Overall, lanthanum carbonate was well tolerated, and the mostcommon adverse events were GI, such as nausea and vomiting,which abated over time. Lanthanum was supplied as a chewabletablet in two dosage strengths, 250 and 500 mg. The total dailydose ranged between 1500 and 3000 mg. Despite encouraging resultsand need for alternative phosphate binders, the widespread useof lanthanum may be limited by concerns of long-term exposureand cost.
Polynuclear Iron Preparations
The use of trivalent iron has increased since the observationthat the solubility product of these agents and phosphate isextremely low. Several animal studies and small-scale humantrials have suggested their efficacy and tolerability (67–69).Although these agents are promising and potentially will becomea low-cost alternative to current therapies, they remain inthe early stages of clinical development at this time.
Although not indicated for the treatment of hyperphosphatemia,calcimimetics are a new class of agents in the armamentariumavailable to treat secondary HPTH and may have a significantimpact on the choice of phosphate binders in the future (70).Cinacalcet (Sensipar, Amgen, Thousand Oaks, CA) is a first-in-classagent that binds to and allosterically modifies the calcium-sensingreceptor (CSR), increasing its sensitivity to extracellularcalcium (71). The CSR located on the chief cell of the parathyroidgland is the principal regulator of PTH secretion, and activationby serum calcium leads to the activation of secondary messengerpathways and a cascade of intracellular events resulting indecreased PTH secretion (72). Cinacalcet is the only FDA-approvedcalcimimetic for use in the United States for the treatmentof HPTH. In three large, prospective, randomized, double-blind,controlled trials, cinacalcet significantly reduced PTH levelscompared with placebo (73–75). Moreover, cinacalcet significantlyreduced serum phosphorus, calcium, and intuitively the Ca xPO4 product in all three studies over the 26-wk study period.The exact mechanism by which cinacalcet lowers calcium, phosphorus,and Ca x PO4 product is unclear but may be related to the attenuatedrelease of PTH and subsequent mineralization of bone similarto that seen in the period after surgical parathyroidectomy(i.e., hungry bone syndrome). Alternatively, cinacalcet hasalso been shown to downregulate mRNA expression levels encodingproteins that are involved in active transcellular calcium reabsorptionin the intestine (76).
Cinacalcet was well tolerated but did have a higher incidenceof GI intolerance (nausea and vomiting) compared with placebo.These symptoms were reduced when the drug was administered withfood. Cinacalcet was also associated with a 5 to 8% incidenceof hypocalcemia as defined by a serum calcium <7.5 mg/dlthat necessitated modification of calcium-containing phosphatebinders, vitamin D sterols, or both (73,74). Despite the absenceof a significant difference in the dose of either phosphatebinders or vitamin D sterols between the groups during the relativelyshort study period, the incidence of hypocalcemia cannot beoverlooked because it has also been associated with increasedmortality among patients with ESRD (77). These findings warrantfurther investigation; however, the chain of logic suggeststhe potential need for calcium supplementation of some formby increasing dialysate calcium concentration, nightly calciumsalt ingestion, or calcium-containing phosphate binders. Thepotential benefit of the last is apparent.
Despite the growing diversity of therapeutic options available,achievement and maintenance of the NKF–K/DOQI targetsfor hyperphosphatemia and HPTH remain poor. Fewer than 50% ofprevalent dialysis patients met guideline recommendations forphosphorus control during the first 6 mo of the Dialysis Outcomesand Practice Patterns Study and fell to 25% for the entire 12mo of the study (78). Several reasons may account for failureto adequately treat hyperphosphatemia, such as compliance, costof therapies, binder inefficiency as a result of inappropriateadministration or prescription, and refractory disease statesat time of initiation of renal replacement therapy.
Compliance
Unfortunately, poor compliance with diet and phosphate bindersis common among adult chronic hemodialysis patients (79,80).It is believed that aggressive patient education programs andpositive reinforcement by the nursing staff, renal dieticians,and nephrologists may be beneficial (81). Effective dietarycounseling requires a team effort, and restricted diets shouldbe personalized. Patients also need to be instructed on howto read food labels so that they can identify products withphosphate additives. Although the most common reason given bypatients is that they forgot to take their binders, it is importantto note that noncompliance is often multifactorial. A web-basedsurvey revealed that 64% of patients did not comply with regularlyprescribed drugs because they "forgot." It is interesting that35% did not take their medications because they wanted to savemoney.
Cost
Financial limitations rather than psychologic/cultural issuesmay play an even bigger role among patients with ESRD. Moreaffordable fare including processed meats and cheeses, driedfruits and beans, peanut butter, and eggs are foodstuffs thatare very high in phosphorus. These are often the only sourcesof protein available to dialysis patients with limited resources(82).
Social workers are also vital team members to help identifyand enroll patients into pharmaceutically sponsored patient-assistanceprograms, because newer noncalcium, nonaluminum phosphate bindersare expensive. For example, RenaGel costs approximately $1.48/pill(83). Assuming the mean RenaGel dose required in long-term clinicaltrials (8 tablets/d), the yearly cost would be roughly $4200for this medication alone. In contrast, PhosLo costs approximately$0.20/pill, with a yearly cost of approximately $500/yr (basedon 7 tablets/d per the Treat-to-Goal Study). This substantialdiscrepancy in cost could have even farther reaching consequenceswith the implementation of the NKF–K/DOQI guidelines forthe use of RenaGel (84). Manns et al. (85) performed a systematicreview to analyze the potential economic impact of RenaGel prescriptionon the basis of these guidelines. According to their data, 51%of Canadian and 64% of American cohorts would respectively meetthe NKF–K/DOQI criteria for use of RenaGel. For the UShemodialysis population, this would result in expenditures ofapproximately $781 million for RenaGel alone. This is a substantialburden to assume without the benefit of any outcomes data tosupport these recommendations. Moreover, Fosrenol, the otheralternative to calcium salts, costs approximately $2/pill (83).According to current studies, the yearly cost would range fromapproximately $2400/yr (using the minimum dose of 1500 mg/d)to $4800/yr (using 3000 mg/d). These figures are disconcertingin light of the current budgetary concerns and rising cost ofmedical care.
Binder Performance
Calcium carbonate dissolves best in an acidic environment; however,its binding to phosphorus is best at higher pH and falls significantlyat a pH below 5, which may be one reason that it is less effectivethan aluminum for phosphorus reduction (36). Furthermore, variabilityin dissolution rates exists among different manufacturers ofcalcium carbonate (86), mainly because the FDA does not viewit as a drug. Therefore, calcium carbonate is not subjectedto the rigorous standards of the FDA, similar to other "nutritionalsupplements."
Prescription Error
Dietary habits of our patients are variable in not only thenumber of meals per day but also in the proportion of phosphorusin each meal and/or snack. Therefore, a careful dietary historyis essential to prescribe phosphate binders properly to matchquantity of phosphorus ingestion with appropriate binder dosage.Moreover, the temporal relationship with meals is crucial tobind dietary phosphate adequately. It is well established thatunsynchronized administration of binders significantly increasesthe proportion of dietary phosphorus absorbed compared withconcomitant administration of binder with meals (24,35,36,46,87).
Refractory Disease State
Control of serum phosphorus becomes more difficult with theworsening severity of secondary HPTH over time. The reasonsare multifactorial and include increased circulating PTH (whichstimulates further release of phosphorus and calcium from bone),reduced production of active vitamin D metabolites, vitaminD receptor downregulation, and decreased CSR expression andautonomous parathyroid cell proliferation (88,89). Vitamin Dand its analogs suppress PTH; however, with increased parathyroidtissue, the required doses are higher and subsequently increaseintestinal absorption of calcium and phosphorus (90). This canfurther exacerbate the problem by worsening hyperphosphatemiaand also limit further use of vitamin D and its analogs as aresult of elevations of Ca x PO4 product. The resultant metabolicabnormalities, as well as parathyroid hyperplasia, are not easilyreversed; therefore, early interventions to prevent the developmentand/or progression of secondary HPTH and its sequelae are crucial.
Major advances in the understanding of mineral metabolism disturbancesin CKD have been made in recent years. However, there remainsa need for prospective, randomized, controlled trials to evaluatethe effects of phosphorus control via various modalities onhard clinical outcomes such as cardiovascular events. Thesewill need to account for other processes that are known to contributeto intimal injury and propagate atherosclerosis such as dyslipidemia,inflammation, and hyperhomocysteinemia. Subsequently, cost-effectiveanalyses for different therapies are necessary given the considerablefinancial burden for as of yet unproved therapies. Likewise,outcomes related to the implementation of these therapies duringearlier stages of CKD require further exploration.
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Top
Abstract
Introduction
5.5 mg/dl; however, this goal was never achieved in the sevelamer group. Serum calcium level was significantly higher in the calcium acetate group; the goal Ca x PO4 product was achieved within 2 wk and was maintained throughout the study period. This study was the first to show that calcium acetate more effectively lowered serum phosphorus and Ca x PO4 product compared with sevelamer hydrochloride. 
