Current Controversies in Managing End-Stage Renal Disease Patients
Strategies for Improving Long-Term Survival in Patients with ESRD
Charles R. Nolan
Departments of Medicine and Surgery, Organ Transplant Section, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas
Address correspondence to: Dr. Charles R. Nolan, Organ Transplant Section, University of Texas Health Sciences Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78239-3900. Phone: 210-567-5777; Fax: 210-567-5777; E-mail: nolan{at}uthscsa.edu
In 2003, more than 320,000 people in the United States werereceiving dialysis for ESRD, with predicted increases to 650,000by 2010 and 2 million by 2030. Mortality from cardiovasculardisease (CVD) in patients with ESRD is 10 to 30 times higherthan in the general population. The exact mechanism of acceleratedCVD in patients with kidney disease is unknown. Treatment costsfor ESRD are in excess of $14 billion annually (6.4% of Medicarebudget). Strategies to improve long-term outcomes include aggressiverisk factor modification, minimization of dialysis complications,and kidney transplantation. Because abnormalities of mineralmetabolism contribute to mortality risk, phosphate binder therapyis fundamental. More expensive non–calcium-containingphosphate binders such as sevelamer have been recommended toreduce cardiovascular calcification. However, the lack of outcomedata and the $2 to $3 billion annual cost make it difficultto justify widespread utilization of newer binders as first-linetherapy. Conversely, kidney transplantation is known to improvesurvival in ESRD. Progression of atherosclerosis and CVD inpatients with renal failure is largely due to loss of renalfunction per se, and provision of a functioning kidney throughrenal transplantation halts the progression of CVD and dramaticallyreduces mortality. Despite this fact, many patients lose Medicarefunding for immunosuppressive therapy 3 yr posttransplantation.To achieve the goal of prevention of cardiovascular mortalityin patients with ESRD, it clearly would be more prudent, efficacious,and cost-effective to use Medicare prescription drug dollarsto provide full coverage for life-long immunosuppressive drugtherapy after renal transplantation.
It has been predicted that in the near future, there will bean alarming increase in the incidence and prevalence of ESRDboth in the United States and worldwide. In 2003, more than320,000 people with kidney failure were being treated with dialysisin the United States, and the prevalence is predicted to increaseto 650,000 by 2010 and 2 million by 2030 (1,2). Mortality associatedwith ESRD is primarily due to cardiovascular disease (CVD),which accounts for 50% of the deaths among dialysis patients.Upon starting dialysis, 40 to 75% of patients will already havemanifestations of CVD (3–5).
In ESRD, there are two primary mechanisms for CVD, namely vascularremodeling and vascular calcification. Vascular calcification,a marker of atherosclerosis and arterial stiffness, is commonamong dialysis patients and seems to be a significant risk factorfor cardiovascular mortality. The American Heart Associationissued a statement in 2003 that recommended patients with chronickidney disease be considered a "highest risk group" for subsequentcardiovascular disease events (1). Although traditional riskfactors for CVD are prevalent in patients with ESRD, they cannotfully explain the high mortality rate that has been reported.Other risk factors, such as electrolyte disturbances, fluidimbalance, and chronic inflammation, must also be considered.
Treatment costs associated with ESRD are in excess of $14 billionper year (3). The ESRD program consumes 6.4% of the Medicarebudget (2). Therefore, more effective treatment and preventivestrategies particularly for reducing CVD morbidity and mortalityare necessary. Methods that may be considered in improving long-termoutcomes of patients with ESRD include aggressive risk factorreduction, kidney transplantation, and minimization of dialysiscomplications. The purpose of the review is to discuss strategiesfor improvement of long-term survival related to cardiovascularcomplications in patients with ESRD.
The unique pathophysiology of patients with ESRD and its associatedtreatment result in differences in the incidence and prevalenceof CVD. Vascular calcification can lead clinically to the developmentof myocardial ischemia (6), congestive heart failure (7,8),cardiac valve insufficiency (9,10), cardiac arrhythmias (11),and ischemic episodes as a result of peripheral vascular disease(8).
Mechanism of CVD
The exact mechanism of accelerated CVD in patients with ESRDis unknown. Mortality from CVD in patients with ESRD is 10 to30 times higher than in the general population, even when adjustmentsare made for gender, race, and presence of diabetes (4,12).Both vascular remodeling and vascular wall calcification havebeen implicated in the pathogenesis of nonatherosclerotic vasculardisease. Vascular remodeling can occur as a result of increasedtensile stress, leading to medial wall thickening of the arterywith subsequent luminal narrowing in small-resistance arteries.This remodeling process may be mediated through endothelialcell production of growth-regulating and vasoactive factors.Coronary calcification seems to be more prevalent in patientswith renal disease compared with age- and gender-matched controlsubjects (13–15). The calcification associated with ESRDcan occur in either the intima or the media of the arterialwall. Schwarz et al. (15) has shown that coronary plaques inuremic patients are characterized by marked calcification, increasedmedia thickness, and infiltration and activation of macrophages.The primary difference in the plaques between the renal andnonrenal patients was in the composition of the plaque, notthe size. It was initially thought that vascular calcificationoccurred as a passive process that resulted from calcium-phosphoruscrystal deposition as a result of increased calcium-phosphorusion product and hyperparathyroidism. Recently, it was suggestedthat calcification is an active cell-mediated process wherebyvascular smooth muscle cells assume a bone-forming phenotype(16,17). The exact mechanisms for vascular calcification andthe relationship between arterial wall calcification and atherosclerosisare poorly understood. It is likely that the excess cardiovascularcalcification that is observed in patients with ESRD is a multifactorialprocess. Figure 1 summarizes the plethora of factors that potentiallyare involved in the pathogenesis, including hyperparathyroidism,hyperphosphatemia, hypertension, abnormal glucose metabolism,treatment with vitamin D analogs, and abnormalities in lipidmetabolism. It seems that alterations in mineral metabolismmay contribute to the development of vascular calcification(18). Vascular calcification has been associated with increasedmortality in patients with ESRD (19,20). Matsuoka et al. (21)observed that the finding of coronary calcification has prognosticsignificance in dialysis patients. The 5-yr survival of patientswith a coronary calcium score >200 was 30% lower than patientswith a score <200 (21). For a more detailed discussion ofthe mechanisms of CVD, please refer to Dr. McCullough’sarticle in this supplement issue.
Figure 1. Pathogenesis of cardiovascular disease (CVD) in chronic kidney disease. A plethora of factors may be involved in the pathogenesis of CVD in patients with ESRD, including traditional cardiac risk factors (white ovals) and kidney disease–related risk factors (gray ovals). The importance of a renal dysfunction (absence of normal renal function) cannot be overlooked when assessing mechanisms of CVD in patients with ESRD.
Risk Factors for CVD in ESRD
Patients with ESRD typically exhibit a number of risk factorsthat could translate into increased risk for mortality fromCVD. It is difficult to determine whether these factors aloneor in combination with other processes lead directly to accelerationof the atherogenic process. Further study will be necessaryto elucidate these mechanisms. The National Kidney FoundationTask Force has provided recommendations regarding the epidemiologyof CVD risk factors associated with ESRD. This statement recognizedthat the excess risk for CVD in these patients may be attributablein part to the higher prevalence of traditional risk factorsand in part to hemodynamic and metabolic factors specificallyrelated to ESRD. Therefore, risk factor identification and reductionshould focus on both classes of risk factors (22).
Traditional Risk Factors.
Traditional risk factors for CVD are those defined from thestudies of the Framingham population, including older age, diabetes,male gender, family history of coronary disease, hypertension,history of smoking, physical inactivity, high LDL levels, lowHDL levels, menopause, and psychosocial stress. Evaluation ofpatients who were on dialysis showed that white race, olderage, male gender, diabetes, and smoking were independent riskfactors for death from CVD. It is interesting that hypertensionand higher serum cholesterol were not found to be significantrisk factors for mortality in dialysis patients. This paradoxmay be an example of so-called "reverse epidemiology," whichis explained by the fact that the relationships of serum cholesterolto mortality and hypertension to mortality display a U-shapedcurve (23–26). In this regard, the reverse epidemiologymay be explained by the fact that malnutrition and cardiomyopathylead to excess mortality in dialysis patients with the lowestcholesterol levels and BP. Nonetheless, on the basis of resultsof cross-sectional studies, mortality from CVD in dialysis patientsis substantially higher than that predicted from analysis oftraditional risk factors, suggesting that additional nontraditionalrisk factors must be involved (23,27,28).
Kidney Disease–Related Cardiovascular Risk Factors.
Kidney disease–related risk factors include albuminuria,proteinuria, extracellular fluid volume overload, disordersof calcium and phosphorus metabolism, electrolyte imbalance,hypertriglyceridemia, hyperhomocysteinemia, chronic inflammationor infection, elevated lipoprotein (a), increased thrombogenicfactors, malnutrition, anemia, increased oxidative stress, andother uremic toxins (3). As renal function declines, most patientswill have abnormal serum phosphorus and calcium concentrations,decreasing vitamin D levels, and increased levels of parathyroidhormone (PTH). Abnormalities of phosphorus and calcium metabolism,particularly hyperphosphatemia, seem to contribute to cardiovascularcalcification (9,14,18,29). Increased serum phosphorus concentrations(29,30) and elevated calcium-phosphorus ion product are independentpredictors for death in patients with ESRD (29–31). Ganeshet al. (30) reported that patients with serum phosphorus >6.5mg/dl had a relative risk of 1.41 for cardiac death and 1.20for sudden death. A weak association between PTH levels between496 and 9476 pg/ml and mortality was also reported. In a morerecent analysis, after adjustment for case mix and laboratoryvalues, serum phosphorus concentrations >5.0 mg/dl were associatedwith increased relative risk for death (32). Higher adjustedserum calcium concentrations were also associated with increasedrisk for death. Moderate to severe hyperparathyroidism (PTHconcentrations >600 pg/ml) likewise were associated withincreased relative risk for death. When examined collectively,the population-attributable mortality risk percentage for disordersof mineral metabolism was 17.5%, owing largely to the high prevalenceof hyperphosphatemia (32). Unfortunately, these observationalstudies provide correlations but do not elucidate the mechanismor prove causality. Giachelli et al. (33) proposed that phosphorusmay have a direct effect on vascular smooth muscle cells thatpredisposes these cells to behave like osteoblasts and depositcalcium in the arterial walls of patients with ESRD. For instance,when vascular smooth muscle cells are cultured in high-phosphatemedium, there is upregulation of the transcription of osteocalcin,a bone-specific protein (34). Overall, these data suggest thatdisorders of mineral metabolism and, most important, hyperphosphatemiaplay an important role in the development of cardiovascularcalcification in patients who have chronic kidney disease andare on maintenance dialysis.
Uremia is also a proinflammatory state associated with markersof chronic inflammation such as C-reactive protein and increasedlevels of proinflammatory cytokines, both of which correlatewith increased mortality (35). These cytokines and inflammatorystimuli are thought to play a role in the progression of atheroscleroticdisease (36). Oh et al. (37) found that coronary calcium scoresin young patients who were on dialysis correlate significantlywith elevated C-reactive protein levels. Vascular inflammationmay trigger calcification in dialysis patients at the end oftheir dialysis session, when the plasma is maximally alkalinized(38). Some authors have suggested that oxidative stress andchronic inflammation may be the primary mechanisms underlyingthe excess CVD reported in patients with ESRD (39,40).
Dialysis-Related Risk Factors.
In addition to all of the risk factors mentioned above, theremay be risk factors that are attributable to the dialysis procedureper se. These risk factors include hemodynamic stress causedby intra- and interdialytic changes in cardiac filling pressuresand wide fluctuations in BP, bioincompatibility of dialyzermembranes, dialysate impurities, and rapid changes in serumelectrolyte concentrations (41).
Mortality Benefit Associated with Selected ESRD Interventions
Phosphate Binders
Hyperphosphatemia has been identified as an independent riskfactor for increased cardiovascular mortality in patients withESRD (30,32). The multifaceted therapeutic approach to controlof serum phosphorus includes dietary phosphorus restriction,adequate dialysis, and usually treatment with dietary phosphatebinders. Phosphate binders that are currently used in clinicalpractice include calcium-based agents such as calcium acetateand calcium carbonate and the non–calcium-based agentssevelamer and lanthanum carbonate. Data from observational studieshave suggested that coronary artery calcium scores and large-vesselcalcification correlate with the daily dose of calcium-basedphosphate binder (8,18). The Treat-to-Goal study demonstratedthat dialysis patients who received sevelamer hydrochloride(Renagel, Genzyme, Cambridge, MA) had slower progression ofcoronary and aortic calcification than patients who receivedcalcium-based phosphate binders (42). In a post hoc analysisof this study, oral calcium loading was identified as the keyfactor associated with progressive coronary artery and aorticcalcification (43). However, deficiencies in the design of thisstudy make it difficult to assess the validity of the calciumloading hypothesis. Unfortunately, the study was not designedsuch that non–phosphate binder exposure to calcium waskept similar between the two groups. In this regard, patientsin the sevelamer treatment group received supplemental calciumin at least three forms: (1) Nighttime supplementation of calciumcarbonate on an empty stomach to treat hypocalcemia; (2) adjustmentof dialysate calcium concentration during the study to maintainnormal serum calcium concentrations; and (3) sevelamer-treatedpatients received larger doses of vitamin D analogues, whichwould be likely to enhance dietary calcium absorption. It isentirely possible that sevelamer-treated patients who were givencalcium supplementation on an empty stomach were actually exposedto a greater oral calcium load than were patients who receivedcalcium acetate as a phosphate binder. Another post hoc analysisof this study reported no difference in the rates of progressionof coronary and aortic calcification in patients who were treatedwith calcium acetate compared with those who were treated withcalcium carbonate even though predicted oral calcium loadingwould have been significantly greater in patients who were treatedwith calcium carbonate (44). Overall, the results of this studyand deficiencies in study design suggest that some mechanismother than calcium loading may be responsible for the findingthat sevelamer-treated patients have slower progression of cardiovascularcalcification.
Another important critique of the Treat-to-Goal study is thefailure to achieve equivalent control of LDL and total cholesterolin the two treatment groups. Because sevelamer is a bile acidsequestrant, sevelamer-treated patients had significantly lowerlevels of total cholesterol and LDL cholesterol compared withpatients who received calcium-based phosphate binders. BecauseLDL may play a significant role in the progression of coronaryartery calcification, the investigators should have controlledLDL in both groups. In fact, previous studies in the generalpopulation have shown that administration of a HMG-CoA reductaseinhibitor ameliorates or reverses coronary artery calcification(45,46). Preliminary results of a recent study also suggestedthat administration of colestimide (bile acid sequestrant) incombination with atorvastatin slowed the progression of aorticcalcification in dialysis patients (47). These investigatorsspeculated that the decrease in aortic calcification resultedfrom control of serum phosphorus and LDL cholesterol levels.Thus, dramatic reductions in cholesterol levels may providean explanation for the reduced rate of cardiovascular calcificationthat was reported in the sevelamer-treated patients in the Treat-to-Goalstudy.
Kidney Transplantation
Patients with chronic renal failure have dramatically higherrates of cardiovascular morbidity and mortality than the generalpopulation (Figure 2). Cardiovascular mortality increases 10-foldin patients with ESRD, even after adjustments for the effectsof age, gender, race, and the presence of diabetes (48). Ischemicheart disease and congestive heart failure each are presentin approximately 50% of patients who start dialysis, and thecase fatality rate of these diseases in patients with ESRD isextremely high. Moreover, patients who are on dialysis experiencedramatically rapid progression of atherosclerosis (49). It wasrecognized recently that chronic renal insufficiency per seseems to be a risk factor for cardiovascular mortality (50).Shulman et al. (51) showed that in the general population, elevatedserum creatinine is one of the strongest predictors of mortality.Furthermore, the level of renal function attained after renaltransplantation is strongly associated with increased risk forcardiovascular death (52). A serum creatinine >1.5 mg/dlwas found to be a significant risk factor for cardiovasculardeath. Moreover, cardiovascular death risk increased progressivelywith higher levels of serum creatinine.
Figure 2. Cardiovascular mortality in patients with ESRD. This figure displays the cardiovascular mortality in the general population compared with patients who have renal failure and are treated with either dialysis or renal transplantation. The data presented are stratified by age, gender, and race. NCHS, National Center for Health Statistics multiple cause of mortality data files International Classification of Diseases codes 402, 404, 410 to 414, and 425 to 429; USRDS, United States Renal Data System. Reprinted from reference (4), with permission.
Renal transplantation has been shown to confer a significantsurvival advantage over maintenance dialysis (Figure 3) (53).It is likely that most of the survival advantage is relatedto decreases in both progression of CVD and cardiovascular mortalityafter successful kidney transplantation (54). The CVD ratespeaked during the first 3 mo after transplantation and thereafterprogressively decreased with time posttransplantation (Figure 4).This improved survival was evident in both living and deceaseddonor transplants, even in patients with ESRD caused by diabetes.In contrast, the CVD rates in dialysis patients who were onthe transplant waiting list increased sharply and progressivelyin association with waiting list vintage (Figure 4). This survivaladvantage conferred by successful renal transplantation is particularlystriking in view of the fact that immunosuppressive medicationshave many potentially deleterious effects on standard cardiovascularrisk factors. The immunosuppressive regimens can cause or worsenhypertension, hyperlipidemia, and diabetes. Furthermore, thereare abnormalities of mineral metabolism after transplantationsuch as hypercalcemia as a result of residual hyperparathyroidismand increased gastrointestinal calcium absorption and hypophosphatemiaas a result of PTH-induced phosphaturia. Thus, it is apparentthat the predominant theme underlying the rapid progressionof atherosclerosis and CVD in patients with renal failure isthe loss of renal function per se and that provision of a functioningkidney through renal transplantation halts the progression ofCVD and dramatically reduces cardiovascular mortality risk (54).
Figure 3. Adjusted relative risk for death after cadaveric kidney transplantation. The transplant group was 23,275 recipients of a first cadaveric transplant. The reference group was 46,164 dialysis patients on the transplant waiting list (relative risk 1.0). Patients in both groups had equal length of follow-up since placement on the waiting list. Values were adjusted for age, gender, race, cause of ESRD, and time from first dialysis treatment to placement on the waiting list. The points at which the risk for death and the likelihood of survival were equal in the two groups are indicated. A log scale was used. Reprinted from reference (53), with permission.
Figure 4. Kidney transplantation halts cardiovascular disease progression in patients with ESRD. Overall death rates () and cardiovascular death rates () for deceased donor kidney transplants according to transplant vintage (A) and dialysis patients awaiting transplant according to vintage on transplant waiting list (B). The overall and CVD death rates peaked during the first 3 mo after transplantation and then decreased subsequently by transplant vintage when censoring for graft loss. In contrast, the overall and CVD death rates for dialysis patients on the transplant waiting list increased sharply and progressively according to time on transplant waiting list. Adapted from reference (54), with permission.
The majority of interventions that are made in the health caresetting increase the per-patient lifetime health care costs.If our overall goal in clinical practice were to minimize totalhealth care costs, then providing no treatment would be thepreferred alternative. Clearly, this is not our goal, and amore appropriate therapeutic goal should be maximization ofthe health gain received from any particular therapy. Becausehealth care resources have become more limited in recent years,pharmacoeconomic assessment of therapeutic interventions hasbecome common practice. The cost of therapy is clearly an importantconsideration in patients with ESRD. The annual direct costsfor ESRD are $23 billion (55). Compared with maintenance dialysis,renal transplantation has been shown to reduce overall lifetimehealth care cost along with increasing patient benefit. Thebenefit of renal transplantation was first described in 1968,when it was shown to increase patient survival and quality oflife (56). Studies since that time have validated these resultsand have shown increases in quality of life in addition to increasedemployment rate (53,57–59). Renal transplantation is morecost-effective even in patients who are nonadherent with medicaltherapy posttransplantation (60). However, dialysis is one ofthe most expensive health interventions for which reimbursementis provided. Although the initial cost of renal transplantationmay be higher, after 2 to 3 postoperative years, it becomesa cost-saving intervention when compared with dialysis, evenconsidering the cost of maintenance immunosuppression (61,62).Thus, it seems logical that an intervention that has be provedto reduce mortality and is cost-effective should be promotedto reduce the economic burden of dialysis while increasing patientquality of life.
Another important consideration in the cost of ESRD treatmentis adjunctive therapy with phosphate binders. On the basis ofresults from the Calcium Acetate Renagel Evaluation study (63)and average wholesale prices, the doses that are necessary totreat hyperphosphatemia with PhosLo (Nabi Pharmaceuticals, BocaRaton, FL) and Renagel would result in projected annual costsper patient of $732 and $4283, respectively. In this regard,it should be note that if concerns over calcium loading withcalcium-based phosphate binders lead to the widespread adoptionof sevelamer as the first-line phosphate binder, then the costfor treatment of the 300,000 patients who are on dialysis inthe United States would increased by >$1.0 billion annually.Because doses of sevelamer two to three times higher than thoseused in the Calcium Acetate Renagel Evaluation study are nowused routinely to treat hyperphosphatemia, the actual costsmay well exceed $2 to $3 billion annually. Although the lipid-loweringproperties of sevelamer may play a beneficial role in slowingthe progression of cardiovascular calcification (42), cost-benefitanalysis suggests that a combination of an HMG-CoA reductaseinhibitor and a calcium-based phosphate binder might be a morecost-effective alternative (63).
The Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelineshave recommended the use of non–calcium phosphate–bindingagents for several common clinical situations (64). However,these treatment guidelines were developed without considerationof the economic impact. Given the enormous financial burdenof caring for dialysis patients, it is imperative that beforewidespread implementation, costly new therapeutic agents mustbe shown to have similar efficacy in achieving K/DOQI guidelinesfor phosphorus and calcium-phosphorus ion product. The additionalcosts should also be justified by validation of the beneficialeffects of the higher priced drugs on rates of hospitalizationand mortality. To date, phosphate-binder therapy with sevelamerhas not been shown to meet either of these criteria. Manns etal. (65) recommended that the hypothesized benefits of sevelameron cardiovascular mortality be tested in well-designed, randomizedintervention trials before embarking on national programs toexpand Medicare coverage to cover the cost of sevelamer. Itwas estimated that sevelamer would have to show a 45% reductionin hospitalizations to offset its substantially increased cost.Moreover, because the actual doses of sevelamer that are necessaryto achieve control of serum phosphorus may be higher than thoseused in previously published studies, the true economic impactof widespread implementation of the K/DOQI Bone Metabolism guidelinefor phosphate binder therapy may well be greater than the currentprojected costs.
These cardiovascular mortality and economic data raise an importantquestion: Is it wise to accept the unproved calcium-loadinghypothesis regarding cardiovascular calcification and spendan additional $3 billion per year for newer phosphate bindertherapy when we already have an ESRD therapy, in the form ofrenal transplantation, that has been proved to halt progressionof CVD and significantly improve mortality? This is not a trivialissue. Although immunosuppressive therapy to maintain functioningrenal allografts has been shown to reduce cardiovascular mortalityin patients with ESRD, many patients lose their Medicare fundingfor immunosuppressive therapy a mere 3 yr after transplantation.With regard to our goal of prevention of cardiovascular mortalityin patients with ESRD, it would clearly be more prudent, efficacious,and cost-effective to use the soon-to-be-available Medicareprescription drug dollars instead to provide coverage for life-longimmunosuppressive drug therapy after renal transplantation.
The role of CVD as a cause of mortality in ESRD patients hasreceived recent attention, and a focal point of the discussionis the process of vascular calcification. The precise mechanismof CVD in these patients remains unknown, but it is likely thata plethora of different factors contribute to the process. Thus,it is probably overly simplistic to implicate and target a singlefactor as the most important pathogenic mechanism in the developmentof cardiovascular calcification. Detection of risk factors forCVD (both traditional and kidney disease related) in the earlystages of renal impairment may be necessary to have a significantimpact on outcome. Additional studies with mortality end pointsare urgently needed to determine whether therapeutic measuresaimed at prevention of cardiovascular calcification will translateinto an improvement in long-term cardiovascular mortality. Asour knowledge of the mechanisms of CVD in chronic kidney diseasecontinues to expand, additional targets for intervention willbe identified, and it is likely that a multifaceted therapeuticapproach will be required to achieve a substantial reductionin cardiovascular mortality in dialysis patients.
Currently, only one therapy has been shown to reduce cardiovascularmortality in patients with ESRD. This therapy is renal transplantation.It is apparent from the available literature that with regardto prolonging life and reducing cardiovascular mortality, dialysisis not a good substitute for provision of a well-functioningkidney with transplantation. On the basis of efficacy and pharmacoeconomicsanalyses, serious consideration should be given to revisionof the Medicare Modernization Act such that all kidney transplantrecipients are eligible for life-long full prescription drugcoverage for immunosuppressive medications.
Acknowledgments
C.R.N. receives grant support and honoraria from Nabi Biopharmaceuticals.
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Abstract
Introduction
) and cardiovascular death rates (