Left Ventricular Hypertrophy: Is Hyperphosphatemia among Dialysis Patients a Risk Factor?
Steven G. Achinger and
Juan Carlos Ayus
Texas Diabetes Institute, Bexar County Hospital District, San Antonio, Texas
Address correspondence to: Dr. Juan Carlos Ayus, Medical Director, Dialysis Service, Texas Diabetes Institute, University Dialysis West, 701 S. Zarzamora, San Antonio, TX 78201. Phone: 713-795-9333; Fax: 713-942-9342; E-mail: carlosayus{at}yahoo.com
Cardiovascular disease occurs in ESRD patients at rates thatare far higher than is seen in the general population, and cardiovasculardeaths account for the majority of deaths among dialysis patients.Abnormal mineral metabolism is a novel cardiovascular risk factoramong dialysis patients. Recently published results demonstratedthat even with good control of BP and anemia, conventional hemodialysisis associated with significant left ventricular hypertrophy(LVH); however, daily hemodialysis was associated with a significantreduction in LV mass index (LVMI). Furthermore, it was shownthat control of serum phosphorus correlates with the reductionin LVMI. These data suggest a novel mechanism for the deleteriouseffect of elevated serum phosphorus on cardiovascular outcomesamong hemodialysis patients: LVH. Other investigators have notedan association of hyperphosphatemia and LVH; however, this studywas the first to demonstrate that improvement in serum phosphorusis associated with reduction in LVM. In addition, it is shownthat daily hemodialysis is an effective modality in improvingserum phosphorus through significantly improved phosphorus removal.Elevated serum phosphorus leads to vascular calcification, whichcan lead to LVH by decreasing vascular compliance. However,our study showed an improvement in LVMI during a 12-mo period.Because vascular calcification is unlikely to remit over thistime period, it is proposed that serum phosphorus has a reversible,cardiotoxic effect that leads to LVH that can be reversed successfullywith good control of serum phosphorus.
Mortality among hemodialysis patients remains unacceptably highwith the prognosis of patients with newly diagnosed ESRD inthe United States approximating that of lung cancer patients(1). Cardiovascular disease is present in patients with ESRDat rates that far exceed the general population and accountsfor the majority of deaths among patients with ESRD (2). However,cardiovascular disease in the ESRD population has unique aspects.This is exemplified best by the results of the 4-D trial, inwhich control of hypercholesterolemia failed to improve mortalityamong dialysis patients (3). Approaches to preventing cardiovasculardeath among dialysis patients requires an approach that is tailoredto the particular aspects of cardiac disease in uremia. Thereis a high prevalence of echocardiographic abnormalities amongdialysis patients (Figure 1); only 16% of prevalent dialysispatients have normal anatomic and functional findings (4), andthese abnormalities predict mortality among dialysis patients(5,6). Hyperphosphatemia is a widely recognized risk factorfor cardiovascular mortality in the ESRD population (7,8). Currently,the mechanistic link between hyperphosphatemia and cardiovascularmortality in dialysis patients is not known; however, recentdata suggest that the deleterious effects of hyperphosphatemiamay be related to left ventricular hypertrophy (LVH) (9–11).Furthermore, our group recently published data that suggestthat correction of hyperphosphatemia is associated with reductionin left ventricular mass index (LVMI) (11). This review focuseson the new evidence that suggests that hyperphosphatemia leadsto LVH and highlights effective treatment options.
Hyperphosphatemia is a consequence of altered divalent ion balancethat is caused by the decline in GFR in renal failure. Unlikeserum calcium, which is not a good indicator of total body calciumstores (12), elevations in serum phosphorus in ESRD are indicativeof total body phosphorus excess. Hyperphosphatemia is the underlyingabnormality that leads to many of the mineral metabolism complicationsof ESRD, such as secondary hyperparathyroidism and resultantbone disease (13) and vascular calcification (14). It now isrecognized that the metabolic complications of ESRD have a significantimpact on mortality through increases in cardiovascular disease;therefore, understanding of these complications and efficacioustherapies is critical to improving outcomes.
The best known cardiovascular consequence of hyperphosphatemiais vascular calcification, which is a common complication ofESRD and diabetes (15–17). Vascular calcification, atthe cellular level, is an active process that can be inducedby hyperphosphatemia (14). In vitro studies have demonstratedthat uremic serum induces vascular smooth muscle cells to increaseproduction of osteopontin and alkaline phosphatase and subsequentlyincrease calcification (18). High levels of phosphate in cellculture can induce phenotypic changes in vascular smooth musclecells, upregulating genes that are associated with bone formation(osteocalcin, osteopontin, and Runx2) and leading to apatitedeposition in the matrix surrounding the cells (14,19,20). Elevatedextracellular phosphate levels leads to increased cellular uptakeof phosphate via pit-1, a type III sodium-phosphate co-transporter(14). The ensuing elevated intracellular phosphate levels inducethe cellular transformation that ultimately leads to the releaseof pro-calcifying factors (including calcium-binding proteinsand alkaline phosphatase) (19). In human studies, increasedexpression of Osf2/Cbfa1 (a transcription factor that is involvedin osteoblast differentiation and bone formation) has been demonstratedin the epigastric arteries of uremic patients (21). These findingsshow that vascular calcification that is induced by hyperphosphatemiais a regulated process with similarities to bone mineralizationand not a passive phenomenon.
Other factors that play a role in vascular calcification includeage, dialysis vintage, and the use of calcium-containing phosphorusbinders (15) as well as the presence of diabetes (22). Theseother factors create a substrate on which vascular calcificationcan occur, and poor mineral metabolism (especially elevatedserum phosphorus) over time accelerates this underlying process.Therefore, poor metabolic control (once ESRD is established)as well as calcium loading through calcium-containing phosphatebinders are major modifiable risk factors for this condition(Figure 2). The goal of therapy is to prevent the progressionof vascular calcification in those with established manifestationsand to prevent the development in those who do not have establishedcalcification.
LVH is a powerful predictor of cardiovascular outcomes in hemodialysispatients and is a multifactorial process with many causes inESRD, such as anemia, pressure loading through hypertension,and reduced vascular compliance (5,23). Our group recently publishedresults that demonstrate that even with aggressive therapy forBP control (average systolic BP of 145 mmHg) and anemia, conventionalhemodialysis is associated with significant LVH (mean LVMI of155 g/m2) (11), whereas short daily dialysis is associated witha significant reduction in LVMI (154 to 108 g/m2) and controlof serum phosphorus (mean serum phosphorus of 4.2 mg/dl) correlateswith this reduction in LVMI. There findings suggest a novelmechanism for the deleterious effect of hyperphosphatemia oncardiovascular outcomes among hemodialysis patients (11). Previousinvestigators have noted the association of hyperphosphatemiaand LVH (9,10), although our study is the first that we areaware of to show that improvement in serum phosphorus is associatedwith improvement in LVH. Several studies now have noted an associationof altered mineral metabolism and LVH and cardiac dysfunction.Marchais et al. (24) noted increased diastolic and mean arterialpressures, higher cardiac index, higher heart rate, and increasedstroke index in hyperphosphatemic versus normophosphatemic patients.Strozecki et al. (9) showed that poor control of serum phosphorusand calcium-phosphorus product is associated with increasedLVM. A recent report by Galetta et al. (10), using echocardiographyand tissue Doppler imaging, showed that higher plasma phosphateand calcium-phosphate products are associated with signs ofdiastolic dysfunction in a cross-sectional study. Hayashi etal. (25) performed echocardiography before and after hemodialysisin 13 conventional hemodialysis patients and demonstrated thatelevated serum phosphorus and calcium-phosphorus product areassociated with decreased isovolumetric contraction velocityand peak systolic velocities, suggesting that poor mineral metabolismcan affect systolic function. Furthermore, they showed thatafter a single hemodialysis session, these indices improved.These recent studies suggest that poor mineral metabolism hasadverse consequences on LV geometry and function and that dialysisimproves LV function, particularly in those with poor controlof mineral metabolism. In support of these findings, a recentanimal study showed that isolated hyperphosphatemia (inducedby five-sixths nephrectomy, parathyroidectomy, parathyroid hormonereplacement, and high-phosphorus diet) (26), in a model of chronicrenal failure, leads to increased LVM. It is interesting that,in this study, vascular calcification was not demonstrated inthe experimental animals (26). These studies suggest that poorcontrol of mineral metabolism plays a role in the pathogenesisof LVH among dialysis patients.
Our findings show that in patients in whom phosphorus is improved,LVH improves (11). Decreased vascular compliance through vascularcalcification that is induced by poor mineral metabolism isa very likely mechanism for the association of poor mineralmetabolism and cardiovascular disease. However, our study suggeststhat other mechanisms may contribute. Vascular calcificationis a long-term process that is not likely to be reversed ina 12-mo study of daily hemodialysis, such as ours (11), especiallybecause the most efficacious dialytic intervention at achievingphosphorus control, nocturnal hemodialysis, does not inducea remission of vascular calcification (27). Therefore, it wouldbe unlikely that control of serum phosphorus would contributeto improvement in LVMI if vascular calcification is necessaryfor hyperphosphatemia to induce LVH. If reduction in serum phosphoruscan contribute to reduction in LVM, then a different mechanismis likely. Previous in vitro studies showed that elevated phosphoruscan induce cellular changes and cellular phenotype (14,19).This leaves open the possibility that hyperphosphatemia canfacilitate LVH through changes in systemic vascular resistanceby altering vascular reactivity or endothelial function by inducingendothelial or vascular smooth muscle phenotype. Therefore,our results, for the first time, suggest that the effects ofhyperphosphatemia on LVM, noted by several other groups independentfrom us (9,10), is a reversible process (Figure 3). We proposethat there is a pathway, independent of overt vascular calcification,that mediates the development of LVH in dialysis patients. Whetherthis is an effect on vascular reactivity or a direct myocardialeffect is purely speculative at this point, and future studyin this area is needed.
Given the known associations of elevated serum phosphorus andmortality on dialysis, control of serum phosphorus is one ofthe key elements in risk factor reduction and is recognizedby the Kidney Disease Outcomes Quality Initiative (K/DOQI) asan important area of intervention (28). K/DOQI goals are basedon observational studies that showed higher mortality associatedwith hyperphosphatemia (7,8). However, these and other, morerecently published studies challenge the current K/DOQI goalfor serum phosphorus. Block et al. (8) reported that the lowestmultivariable adjusted relative risk for death occurred forserum phosphorus of 4.0 to 5.0 mg/dl with an adjusted 10% relativeincrease for 5.0 to 5.5 mg/dl. In Dialysis Outcomes and PracticePatterns Study (DOPPS), a serum phosphorus of 4.5 to 5.0 mg/dlhad the lowest multivariable adjusted relative risk for death,with a 12% relative increase for 5.0 to 5.5 mg/dl (29). Theseand other findings from a European dialysis population (30)suggest that current K/DOQI goals may be too permissive of hyperphosphatemia>5.0 mg/dl (8,29,30).
As currently written, the K/DOQI guidelines do not mandate reducingphosphorus to the levels that are known to be associated withthe lowest risk for mortality (Figure 4). Daily hemodialysiswith session length of 3 h is a modality that has been shownto reduce effectively serum phosphorus levels (11,31); increasingdialysis frequency currently is recommended only when the relativerisk for death is increased by 43% (28). In addition, theseguidelines suggest changing only the variable of dialysis frequency,without explicitly stating that total dialysis time also mustbe increased, because just altering frequency has not been shownto reduce effectively serum phosphorus levels (32–34).We believe that the best interpretation of the available literaturesuggests that to mitigate the effects of hyperphosphatemia,serum phosphorus goals should be <5.0 mg/dl and that themost efficacious approach to achieving this is to use eithernocturnal hemodialysis (which is the modality with the greatestphosphorus removal) or daily hemodialysis six times a week witha session length of 3 h. Some patients may be able to achievecontrol of serum phosphorus with more modest increases in totaltime, but it must be emphasized that simply changing dialysisfrequency while keeping total time constant will not improvemetabolic control.
Figure 4. Algorithm for treatment of hyperphosphatemia according to the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines (28). *Relative risk for death reported by Block et al. (8).
Hemodialysis does not remove significant amounts of phosphorus,mainly because of the pooling of phosphate in the intracellularcompartment, which causes much of the phosphorus not to be readilyaccessible during a treatment. During either high-flux or low-fluxhemodialysis, serum phosphorus rapidly decreases, reaching ahypophosphatemic nadir at approximately 120 min (35,36). Afterthis, there is an immediate postdialysis phosphate rebound inwhich the serum phosphorus level rises and even can surpassthe predialysis level (35–38). Therefore, a point at whichredistribution is complete is not clearly identified. It isinteresting that this rebound in serum phosphorus levels hasbeen noted to begin even before the end of hemodialysis. Therefore,phosphate kinetics in dialysis patients is complicated and notcompletely understood at this point.
Phosphate efflux into the dialysate is greatest during the firsthour of the treatment, corresponding to the time during whichserum phosphorus levels are highest (35). Phosphate efflux thenfalls off, but remains at roughly half the initial value atthe end of the treatment despite stable serum phosphorus levels.Recently, we directly measured serum phosphorus removal in agroup of conventional and short daily hemodialysis patientswith good control of serum phosphorus (predialysis phosphorus4.2 to 4.5 mg/dl), and we found that daily dialysis removessignificantly more phosphorus than conventional and that conventionaldialysis removes only 1573 mg of phosphorus, when predialysisphosphorus levels are well controlled (39). What is clear isthat conventional dialysis does not remove sufficient phosphorusto achieve good control of serum phosphorus in the majorityof dialysis patients.
The National Kidney Foundation’s K/DOQI provides for thenephrology community a set of standardized target ranges formetabolic control. Recent data, however, suggest that thesegoals often are not met (29,40) with conventional hemodialysis.Newer vitamin D analogues (41), calcimimetics (42), and non–calcium-basedphosphate binders (43–45) all are welcome developmentsin the effort to improve metabolic control; however, failureto achieve mineral metabolism goals remains a significant problem(46). A consensus on how best to improve achievement of K/DOQIgoals for mineral metabolism has not yet been reached in thecontext of conventional hemodialysis.
Recently, intensive hemodialysis therapies (nocturnal and dailyhemodialysis) have shown some promise in the area of mineralmetabolism. Nocturnal hemodialysis, which increases both dialysisfrequency and total weekly dialysis time, will induce negativephosphorus balance, to the point that phosphorus supplementationbecomes necessary. This modality has been shown to achieve excellentcontrol of serum phosphorus without the use of phosphate-bindingmedications (47). However, daily hemodialysis had mixed effectson serum phosphorus in previous studies (32–34). Our groupwas the first to report good control of serum phosphorus ina controlled study of daily in-center hemodialysis with reductionin use of phosphate binders (11). The prescription of more frequentdialysis sessions, using the same weekly total time, would bepredicted to enhance phosphorus removal by maximizing the first-hourremoval, which is greatest during the first hour of hemodialysis(48). What this does not account for is the increased proteinintake that also is seen in the setting of short daily hemodialysis(31,49–51), so the net effect is no major change in phosphorusbalance, which has been shown consistently with short dailyhemodialysis. In a single small study, Lugon et al. (33) reportedimprovement of serum phosphorus; however, this occurred withpredialysis phosphorus of 7 mg/dl, because dialytic phosphorusremoval is much more efficient at this high of a predialysisphosphorus (Figure 5, Table 1). Yuen et al. (31) also showedthat frequent hemodialysis, prescribed for longer weekly durations,is associated with improved control of hyperphosphatemia. Therefore,the current literature does not support the use of "short" (1.5to 2.5 h) daily hemodialysis as a modality to improve controlof mineral metabolism; however, daily hemodialysis (six timesper week, 3 h per session) has been shown to be effective.
Figure 5. Four-hour dialytic phosphorus removal versus predialysis phosphorus. Studies from Table 1 were included in Figure 5 when treatment times were reported as 4 h and predialysis phosphorus levels were stated.
Table 1. Previous studies that quantified dialysis phosphorus removal
To our knowledge, conventional hemodialysis with currently acceptedphosphate-binding therapy has never achieved mean serum phosphorusof <5.0 mg/dl in a large, controlled study. There is no questionof the efficacy of phosphate-binding medications when the predialysisserum phosphorus is poorly controlled; however, as serum phosphoruslevels begin to decline, the efficacy of conventional hemodialysisat removing serum phosphorus decreases significantly (Figure 5,Table 1). This occurs because removal of phosphorus with hemodialysisis much more effective when predialysis phosphorus levels arehigh (36–38,52–57). Dietary phosphorus restrictionand phosphate-binding efficiency that maintains phosphorus balancewhen the serum phosphorus is 6.5 mg/dl will not be enough ifthe serum phosphorus drops to 5.5 mg/dl. Stated another way,the more effectively one reduces phosphorus levels by decreasingintake, the less effective dialysis is at removing phosphorus.Therefore, a veritable wall is erected, below which the phosphoruslevel cannot drop without increasing dialytic removal, unlessthe patient risks malnutrition. We provide evidence that conventionalhemodialysis removes only 1572 mg/wk when the serum phosphorusis well controlled, whereas with similar predialysis phosphoruslevels, short daily hemodialysis removes approximately 2452mg of phosphorus in a week (39). Therefore, at lower levelsof predialysis serum phosphorus, conventional hemodialysis hasvery limited phosphorus removal. For this reason, phosphorusbinders alone, in the presence of adequate protein intake, willnot be able to achieve excellent control of serum phosphorus(4.0 to 4.5 mg/dl) in the majority of patients.
In this context, we propose the following algorithm in the approachto hyperphosphatemia (Figure 6). It is important first to achievegood control with the use of either phosphate binders or phosphatebinders in conjunction with daily dialysis. Once serum phosphorusgoal is reached, we believe that it is prudent to attempt towithdraw phosphate-binding medications, slowly, while maintainingserum phosphorus below 5.0 mg/dl to limit exposure to potentialadverse effects.
Epidemiologic studies have shown clear associations of increasedserum phosphorus and mortality among dialysis patients (7,8).Poor control of mineral metabolism also has been associatedwith functional and structural cardiac abnormalities (9,10,24).We recently provided evidence, for the first time, that improvementof serum phosphorus during the period of 1 yr is associatedwith reduction in LVMI in hemodialysis patients (11). Hyperphosphatemiahas been linked to vascular calcification, and it currentlyis hypothesized that this is the mechanism of cardiac damagewith hyperphosphatemia. Our data suggest a reversible natureof the cardiotoxic insult of hyperphosphatemia, and cardiovascularcalcification would not explain these findings because it isdoubtful that established vascular calcification could be reversedthrough daily hemodialysis. We therefore hypothesize that anindependent pathway leads to a reversible insult that leadsto LVH. Our data, however, cannot tell us whether phosphorusper se or another covariate (e.g., another uremic toxin) leadsto the cardiotoxicity. Further study in this area is needed.However, current practices do not lead to adequate control ofserum phosphorus, and we propose a treatment algorithm thatcalls for increasing dialysis frequency and total weekly dialysistime to achieve adequate control of serum phosphorus (Figure 6).We encourage the nephrology community to support increased dialysistreatments as an effective tool to achieve optimal control ofserum phosphorus to improve cardiovascular risk among dialysispatients.
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Abstract
Introduction
