Graft Loss and Acute Coronary Syndromes after Renal Transplantation in the United States
Kevin C. Abbott*,
Jay R. Bucci*,
David Cruess,
Allen J. Taylor and
Lawrence Y.C. Agodoa
*Nephrology Service, Walter Reed Army Medical Center (WRAMC), Washington, DC, and Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland; Preventive Medicine and Biometrics, USUHS, Bethesda, Maryland; Cardiology Service, WRAMC, Washington, DC; and Program Director, NIDDK, NIH, Bethesda, Maryland.
Correspondence to Dr. Kevin C. Abbott, LTC, MC, Nephrology Service, Walter Reed Army Medical Center, Washington, DC 20307-5001. Phone: 202-782-6462/6463/6288; Fax: 202-782-0185;
ABSTRACT. The impact of graft loss on acute coronary syndromes(ACS) after renal transplantation has not been studied in anational population. It was hypothesized that ACS might be morefrequent after graft loss, as many of the benefits of a functioningallograft on metabolism and volume regulation would be lost.Data from the 2000 United States Renal Data System (USRDS) wasused to conduct an historical cohort study of ACS in 14,237patients who received renal transplants between April 1, 1995,and June 30, 1998, (followed until April 28, 2000) with validinformation from CMS Form 2728, excluding patients with hospitalizedACS before renal transplant. Cox nonproportional regressionmodels were used to calculate the time-dependent adjusted hazardratio (AHR) of graft loss (censored for death) for time-to-firsthospitalization for ACS (International Classification of Diseases9th Modification Diagnosis Codes [ICD9] code 410.x or 411.x)occurring after transplant. The incidence of ACS was 12.1 per1000 patient-years (PY) in patients after graft loss versus6.5 per 1000 PY after transplantation (excluding patients withgraft loss). As a time-dependent variable, graft loss had anAHR of 2.54 (95% confidence interval, 1.09 to 5.96; P = 0.031by Cox regression). Other risk factors associated with ACS includeddiabetes, older recipient, and male recipient. Allograft rejectionwas NS. Renal transplant recipients share some of the risk factorsfor ACS with the general population. In addition, graft losswas identified as a unique risk factor for ACS in this population.E-mail: kevin.abbott@na.amedd.army.mil
Cardiovascular disease is a substantial health problem in renaltransplant recipients (1–3). Renal transplant recipientshave many conventional risk factors for acute cardiovasculardisease, including hypertension, hyperlipidemia, and posttransplantdiabetes mellitus. The relationship between these risk factorsand ischemic heart disease after renal transplantation has beenassessed in single-center studies (4–6). However, manyof these conventional risk factors may be influenced or mediatedby transplant immunosuppression (7). Renal transplant recipientsare also at much greater risk of deteriorating renal functionthan the general population (8). Renal insufficiency has recentlybeen identified as an independent risk factor for recurrentcoronary artery disease in the general population (9). Improvementin renal function in patients with dialysis-dependent renalfailure, such as occurs after renal transplantation in patientson the renal transplant waiting list, has been independentlyassociated with a lower risk of hospitalized acute coronarysyndromes (10).
Graft loss represents a possible intersection between the riskof immunosuppression and renal insufficiency and has been associatedwith both death(11) and hospitalized congestive heart failure(12) after renal transplantation. We hypothesized that ACS mightbe more frequent after graft loss, as many of the benefits ofa functioning allograft on metabolism and volume regulationwould be lost, and might interact with the detrimental effectsof transplant immunosuppression. Therefore, we conducted anhistorical cohort study, using a national registry (the 2000United States Renal Data System [USRDS]), of the independentassociation of graft loss after renal transplantation with time-to-hospitalizationfor acute coronary syndromes.
We conducted an historical cohort study of the independent associationsof time-to-ACS as a primary diagnosis at hospital dischargeoccurring before versus after incident graft loss (censoredfor death) in renal transplant recipients. Hospitalizationswere chosen because they were more accessible in the databaseand less subject to interpretation than outpatient cases ofACS, especially because the USRDS database has no informationon radiographic studies and ACS are not managed on outpatientbasis in the United States. The variables included in the USRDSdata files, as well as data collection methods and validationstudies, are listed at the USRDS website, under "Researcher’sGuide to the USRDS Database," Section E, "Contents of all theSAF’s (Standard Analysis Files)" (13), and published inthe USRDS. The demographics of the renal transplant populationhave been previously described (2001 USRDS report). SAF.TXUNOSand SAF.TXFUUNOS were selected for base and follow-up data,respectively. SAF.HOSP was used for hospitalization information,and SAF.PATIENTS was used for dates of death. Cause-of-deathdata are incomplete for renal transplant recipients. Althoughother authors have used sensitivity analyses to address thislimitation (14), this requires several assumptions. We insteadelected to use hospitalization data for our primary statisticalanalysis, because valid hospital coding is required for physicianreimbursement, and hospitalization data may provide additionalinformation on morbidity. SAF.MEDEVID was used for informationon comorbidity within 10 yr of dialysis initiation and laboratorydata at the time of dialysis initiation starting on or afterApril 1, 1995. Hospitalization data for transplant recipientsmay be unreliable 3 yr posttransplant, when hospitalizationreporting to Medicare is no longer required. In contrast todialysis patients, however, Medicare reporting starts immediatelyafter transplant. The present study limited analysis to thefirst kidney transplant occurring in an individual recipientbetween April 1, 1995, and June 30, 1998, with valid data fromCMS Form 2728, counting hospitalizations for ACS up to 3 yrposttransplant. Patients were followed until April 28, 2000.Recipients of organs other than kidneys were excluded. Hospitalizationsfor ACS occurring at any time after renal transplant, includingafter graft failure, were counted in analysis in an intentionto treat fashion.
Analytic Variables and Outcome Measures
The outcome variables were based on International Classificationof Diseases 9th Modification Diagnosis Codes (ICD9) for proceduresat hospital discharge for ACS: 410.x or 411.x, because theseconditions have similar pathogenesis and treatment (15). Toensure these were incident and not previous hospitalizations,only hospitalizations with a primary discharge procedure codefor ACS within 3 yr after the date of renal transplantationwere selected. Patients with myocardial infarction after dialysisare generally not considered suitable candidates for surgeryuntil at least 6 mo after the event (16) and were thereforeexcluded. Patient characteristics and treatment factors werethose at the date of transplant. Information on use or resultsof cardiac catheterization, treadmill testing, echocardiography,electrocardiogram, serum isoenzymes, serum albumin levels, orchest radiographs were not available. BP levels and blood lipidlevels were also not available. The USRDS information on medicationsdid not include total dose, and because almost all recipientswere on corticosteroid therapy (17), analysis of corticosteroidswas not included in the present analysis. Patient characteristicsand treatment factors were those at the date of transplant.
All analyses were performed using SPSS 9.0 TM (SPSS, Inc., Chicago,IL). Files were merged and converted to SPSS files using DBMS/Copy(Conceptual Software, Houston, TX). Statistical significancewas defined as P < 0.05. For continuous variable, valuesabove or below 3 SD from the mean were excluded from analysis.For categorical variables, missing or ambiguous values wereexcluded from analysis. Univariate analysis of factors associatedwith primary hospitalizations for ACS was performed with 2 testingfor categorical variables and t test for continuous variables,respectively. Variables with P < 0.10 in univariate analysisfor a relationship with development of a first hospitalizationfor ACS after renal transplantation in the study period wereentered into multivariate analysis as covariates. An exceptionwas made for factors thought to have a clinical reason to beassociated with ACS, in accordance with established epidemiologicprinciples (18).
Covariates used in analysis included donor and recipient age,race, gender, weight, body mass index (calculated from heightand weight), induction, maintenance, and antirejection immunosuppressivemedications, previous transplant, delayed graft function, network,state of transplant, hospitalization with a primary procedurecode for coronary revascularization before transplant (includingpercutaneous transluminal angioplasty, stenting, or coronaryartery bypass surgery), and duration of dialysis before transplantation.Because multiple episodes of rejection in the first year aftertransplant have been associated with cardiovascular events inprevious studies (4,17), we analyzed rejection separately asall cases occurring during the study period and as multiplerejection episodes occurring in the first year after transplant.Because exact dates of graft loss were known, graft loss wasanalyzed as a time-dependent variable in a nonproportional Coxregression model, coded as 1 for all events occurring aftergraft loss versus 0 for all events occurring before graft lossor in transplant recipients who did not experience graft loss.Time-dependent analysis of rejection episodes was not performedbecause the exact dates of rejection were not specified in theUSRDS database, other than those occurring within defined blocksof follow-up. Causes of end-stage renal disease were diabetes,hypertension, and glomerulonephritis. Comorbidity and laboratorydata were obtained from CMS Form 2728. Continuous variableswere also analyzed as quartiles to assess for a nonlinear relationshipbetween these values and ACS.
Graft survival time was calculated as the time from the dateof transplant until the date of graft loss after transplant.Dates of graft loss before the study period (from prior transplants)were not included in analysis. Patients were censored at death,most recent follow-up, or the end of the study. Time-to-hospitalizationfor ACS was calculated as the time of transplant until the firsthospitalization for ACS, with recipients censored (removed fromanalysis) at time of death, loss to follow-up, or the end ofthe study period. Survival time was calculated as the time formthe date of transplant until the date of death, with recipientscensored at most recent follow-up or the end of the study period.Graft loss was not censored. Multivariate analysis excludedall patients with missing values, resulting in substantiallysmaller models than the entire study population.
Hospitalizations for ACS were examined using multivariate analysiswith stepwise nonproportional hazards Cox regression (19) fortime until the first hospitalization for ACS during the studyperiod, from which adjusted hazard ratios (AHR) for each covariatewere calculated. Three additional analyses were performed becauseof potential bias. Because graft loss occurred after renal transplantationand risk of ACS might increase with time, analysis was alsoperformed limited to recipients who experienced graft loss comparedwith a cohort of patients who did not experience graft lossbut had survived at least as long as the median time to graftloss. This analysis was also performed excluding patients witha history of myocardial infarction on CMS Form 2728. Becauseof potential selection bias resulting from limiting analysisto recipients with valid data from CMS Form 2728, we also performedan analysis on the entire cohort of solitary renal transplantrecipients from April 1, 1995, to June 30, 1998, adjusted forall factors in the models above except for variables in CMSForm 2728. To assess for differences in the study populationversus the entire cohort of transplant recipients from April1, 1995, to June 30, 1998, stepwise logistic regression wasperformed for factors associated with valid information fromCMS Form 2728 (using a valid history of myocardial infarction)versus cases where this information was missing, using the samecovariates as for Cox regression above.
Of 34,977 recipients of solitary renal transplants from April1, 1995, to June 30, 1998, 32,141 had valid follow-up times.Of these, 696 were hospitalized for ACS after initiation ofdialysis and before transplant and were excluded. Of the remainingpatients, 14,237 had data available from HCFA Form 2728 includingcomorbidity and laboratory data, specifically the presence orabsence of a history of myocardial infarction before initiationof dialysis. Of 133 patients hospitalized with ACS after transplantationfrom this cohort, 83% were hospitalized once, 14% twice, 2.1%three times, and 1.3% more than three times after transplant.Table 1 shows the event rates for ACS after transplantationfor both the entire cohort and for the study population. All-causesurvival for the cohort was 96.2% at 1 yr and 89.9% at 3 yr.Death-censored graft survival was 97.2% at 1 yr and 93.8% at3 yr.
Table 1.Table 1. Event rates for acute coronary syndromes after renal transplantation, April 1, 1995, to June 30, 1998a
Rates of ACS are shown in Table 1. Unadjusted rates of ACS werehigher after graft loss than before or in patients who did notexperience graft loss. As shown, unadjusted rates of ACS weregreater in the cohort of recipients transplanted between April1, 1995, and June 30, 1998, than in the study population, whichmay be due to differences in the study population (Table 2).
Table 2.Table 2. Factors associated with Acute Coronary Syndromes (ACS) after renal transplantation, renal transplant recipients presenting to ESRD April 1, 1995, to June 30, 1998
Characteristics of the study population and univariate associationswith ACS are shown in Table 2. Compared with all patients transplantedbetween April 1, 1995, amd June 30, 1998, the study populationincluded fewer recipients of cadaver kidneys, fewer AfricanAmericans, and fewer patients with delayed graft function, allograftrejection, and graft loss, whereas more patients had diabetes,younger age, more recent year of first ESRD treatment and transplant,and more repeat transplant recipients. Of patients with graftloss, 48% had previous rejection, and 18% of patients with rejectionlater developed graft loss. Factors significantly associatedwith ACS in univariate analysis included increased risk of ACSin recipients who were male, diabetic, older, who weighed more(but not those with higher BMI), history of coronary revascularization,longer cold ischemic time, graft loss, cadaveric donor, delayedgraft function, history of cardiovascular disease, lower albumin,chronic lung disease, and Medicare eligibility.
Table 3 shows factors associated with ACS in Cox regression.As shown, graft loss was independently associated with ACS,along with older year of transplant and increasing durationof follow-up after transplant. Neither the year of first ESRDservice nor the duration of waiting time before transplant wassignificant. Neither rejection occurring at any time duringthe study period nor multiple episodes of rejection in the firstyear were associated with ACS in either univariate or multivariateanalysis. Among demographic factors, increased age and diabeteswere significant. No prior comorbidities were significant afterall other factors were assessed. The interaction between diabetesand female gender was statistically significant, but there wereno other significant interactions, specifically between diabetesand graft loss or gender and graft loss.
Table 3.Table 3. Cox regression analysis of factors associated with acute coronary syndromes after renal transplantationa
Results of stratified models, performed to assess for possiblebias in our model, are shown in Table 4. Graft loss was stillsignificant when all the above analyses were performed, excludingpatients with a history of myocardial infarction on CMS Form2728 (n = 13,936).
Table 4.Table 4. Cox regression analysis of factors associated with acute coronary syndromes after renal transplantation, stratified modelsa
Figure 1 shows a Kaplan-Meier plot of the unadjusted time-to-hospitalizationfor ACS for the study population, comparing time-to-ACS aftergraft loss versus time-to-ACS after transplant excluding patientswho eventually developed graft loss. Figure 2 shows a similarplot adjusted for age, race, gender, diabetes, history of myocardialinfarction, year of first dialysis, and time since transplantation.Figures 3 and 4 show similar plots for the entire cohort. Figure 5shows unadjusted mortality after ACS stratified by graft lossfor the study population, which did not differ significantlyin Cox regression. In analysis performed on the entire cohortof solitary renal transplant recipients from April 1, 1995,to June 30, 1998 (n = 32,141), graft loss was similarly associatedwith ACS as a time-dependent variable (AHR, 2.99; 95% CI, 2.18to 4.10; P < 0.0001). In the larger cohort, other factorsindependently associated with ACS were diabetes, older recipientage, male gender, elevated body mass index, earlier year ofdialysis, and maintenance rapamycin use.
Figure 1. Time to hospitalizations for acute coronary syndromes (ACS) in years, occurring after graft loss censored for death (GL) versus occurring after transplant excluding patients who developed graft loss (Tx) respectively. United States renal transplant recipients between April 1, 1995, and June 30, 1998, with valid data from CMS Form 2728 (n = 14,237). ACS developed much more rapidly after graft loss than after transplant (P = 0.004 by log rank test). Graft loss was also independently associated with a higher rate of ACS as a time-dependent variable in Cox regression analysis (Table 5). Table 5.Table 5. Patients at risk, Figure 1
Figure 2. Time-to-hospitalizations for ACS in years, occurring after graft loss censored for death (GL) versus occurring after transplant censoring events after graft loss (Tx), adjusted for age, race, gender, diabetes, history of myocardial infarction or ischemic heart disease, year of first dialysis, and follow-up time after transplant. United States renal transplant recipients between April 1, 1995, and June 30, 1998, with valid data from CMS Form 2728 (n = 14,237). ACS developed much more rapidly after graft loss than after transplant (P = 0.004 by log rank test). Graft loss was also independently associated with a higher rate of ACS as a time-dependent variable in Cox regression analysis.
Figure 3. Time-to-hospitalizations for ACS in years, occurring after graft loss censored for death (GL) versus occurring after transplant censoring events after graft loss (Tx). All United States renal transplant recipients between April 1, 1995, and June 30, 1998 (n = 32,141). ACS developed much more rapidly after graft loss than after transplant (P < 0.001 by log rank test) (Table 6). Table 6.Table 6. Patients at risk, Figure 3
Figure 5. Mortality after hospitalizations for ACS in years, occurring after graft loss censored for death (GL) and after transplant excluding patients with graft loss (Tx). United States renal transplant recipients between April 1, 1995, and June 30, 1998, with valid data from CMS Form 2728 (n = 14,237). Patients with GL died after ACS at a higher rate than Tx, but was not statistically significant (P = 0.42 by log rank test) (Table 7). Table 7.Table 7. Patients at risk, Figure 5
Figure 4. Time to hospitalizations for acute coronary syndromes (ACS) in years, occurring after graft loss censored for death (GL) versus occurring after transplant excluding patients who developed graft loss (Tx), adjusted for age, race, gender, diabetes, year of first dialysis, and follow-up time after transplant. United States renal transplant recipients between April 1, 1995, and June 30, 1998 (n = 32,141). ACS developed much more rapidly after graft loss than after transplant (P < 0.001 by Cox regression). Graft loss was also independently associated with a higher rate of ACS as a time-dependent variable in Cox regression analysis.
Because allograft rejection was not associated with ACS, thevalidity of its measurement in this study was tested by itspotential associations with graft loss and all-cause mortality.As expected, allograft rejection (both as measured as all eventsoccurring in the study and as multiple events in the first posttransplantyear) was independently associated with both graft loss andall-cause mortality.
Mortality after ACS was 10.7% at 30 d and 38% at 2 yr in thestudy population. Mortality after ACS was higher in recipientswho eventually experienced graft loss but was not statisticallysignificant (Figure 2). Graft loss was also independently associatedwith all-cause mortality as a time-dependent variable (AHR,6.39; 95% CI, 5.47 to 7.46). Graft loss was not significantlyassociated with specific causes of ACS, either acute myocardialinfarction (ICD9 410.x) or unstable coronary syndromes (ICD9411.x).
Specific causes of death were missing or unknown for 55% ofrecipients. However, factors associated with cardiac death weresimilar to those associated with ACS; specifically, graft losswas significantly associated with cardiac death (AHR, 3.94;95% CI, 2.02 to 7.75; P = 0.0001).
This historical cohort study of an essentially complete nationalpopulation of renal transplant recipients demonstrated thathospitalized acute coronary syndromes were significantly morecommon after graft loss (AHR, 2.54) than either before graftloss or in transplant recipients who did not experience graftloss. Mortality after myocardial infarction (3) and demographicfactors in the study population were similar to previous USRDSreports except for a lower proportion of cadaveric donors, asdocumented in Table 2. This may represent living donor recipientsbeing overrepresented in our study due to their shorter waitingtimes for transplant and greater likelihood of having CMS Form2728 completed before transplant within the time frame of thecurrent study. It is possible this introduced bias in the study,because recipients of living donor have lower rates of graftloss and better survival than recipients of cadaver kidneys(2). Although previous studies have associated graft loss withincreased all-cause mortality, none had found that graft losshad an independent association with acute coronary heart diseaseafter renal transplantation. Graft loss was the only transplant-specificrisk factor other than year of transplant and duration of follow-upafter transplantation that persisted in multivariate analysis(Table 3). The significant negative association between durationof follow-up after transplantation and ACS can be explainedby the increased mortality associated with ACS (Figure 5). Thus,patients who survived longer were much less likely to have ACS.This should not be interpreted to mean that ACS was less likelyto occur with longer durations after transplant, as is clearfrom Figures 1 to 4.
Graft loss uniquely represents a possible convergence of thecardiovascular risks associated with both transplant immunosuppressionand dialysis-dependent renal failure. Previous studies havefound that over 50% of causes of death after graft loss wereattributed to cardiovascular disease, just as in the entirerenal transplant population, arguing against a predominant rolefor infectious death (11). Only one other study has shown anassociation of graft loss with cardiovascular outcomes (congestiveheart failure) (12). Because prospective studies may not beavailable in renal transplant recipients who experience graftloss, registry data may be needed to suggest the mechanism ofincreased mortality in this population. The reasons why renalfailure may be associated with increased rates of cardiovascularevents have been the subject of a previous review (20). Authorsof another review were "convinced that currently identifiedrisk factors do not fully explain the abysmal cardiovascularrisk of the uremic patient." (21) The relative risk of graftloss for ACS of 2.54 in the present study is similar to therelative risk of renal transplantation in comparison with diabeticpatients on maintenance dialysis on the renal transplant waitinglist (0.38, the reciprocal of which is 2.63) (10). Because thepresent study was weighted toward recipients of living donortransplants, the impact of graft loss on ACS may be underestimatedin the present study despite its use of comorbidity data.
The increased risks of older age, male gender, diabetes, andits interaction with female gender were also consistent withprevious studies (4). Because BP and lipid levels were not measured,the Framingham prediction model could not be used, althoughthe limitations of the Framingham model should be considered(22). Outcomes in this study were less sensitive and more specificin comparison with the Framingham model to maximize the specificityof risk factor analysis, mainly to avoid finding an associationbetween graft loss and ACS when none existed.
In contrast, allograft rejection was not significantly associatedwith ACS, despite its potential association with all-cause mortalityand graft loss. It has been postulated that allograft rejection(through renal insufficiency and possible volume overload) and/orits treatment with high-dose corticosteroids may raise BP andalter lipid levels (23), both risk factors for cardiovascularevents. Kasiske et al. (4) found that two or more rejectionepisodes in the first post transplant year were associated withincreased risk of ischemic heart disease outcomes, Rigatto etal. (5) also found that rejection was also associated with ischemicheart disease after renal transplantation. However, the nationalincidence of allograft rejection has declined considerably (8)since the time frame of both those studies, which included considerablenumbers of patients transplanted before 1995. The lack of significanceof rejection in the present analysis may also reflect heterogeneityin the way allograft rejection is diagnosed and treated in anational registry versus single-center studies (24), differencesin endpoints between studies, or differences in the populationsstudied and the ways in which they react to rejection and itstreatment. Neither study assessed the association between graftloss and coronary heart disease events after transplantation.Other factors independently associated with graft rejection,such as donor age and race (25), and use of antirejection antibodieswere also NS in analysis of ACS, suggesting that either renalinsufficiency itself or unidentified risk factors co-segregatingwith graft rejection are responsible for the increased riskof ACS.
The lack of significance of hematocrit, albumin and other laboratoryvalues in the present analysis may be related to the inabilityof the present study to measure these values after the startof dialysis. This is significant considering the considerablewaiting time from initiation of dialysis to receipt of a renaltransplant, or changes from increased levels of erythropoietin.
This study has several limitations. Findings are associative,not causative. Laboratory, invasive, and radiologic studiescould not be independently verified. Although ICD-9 codes aresubject to errors in miscoding and duplication, their use providedthe only means of assessing the frequency of acute coronarysyndromes in the USRDS. Unfortunately, use of primary dischargecodes for ACS might miss ACS occurring in the perioperativeor immediate posttransplant phase, but use of non-primary diagnosescould have introduced historical, not active, diagnoses intothe study. This is therefore one potential limitation that couldhave underestimated the early occurrence of ACS after transplant.ICD-9 codes have been used for determining rates of medicalconditions in other studies (3) and are likely to be at leastas reliable as outcomes used in recent studies (14,26,27). Regardless,use of hospitalizations and, as a result, ICD-9 codes to determinethe frequency of acute coronary syndromes in the ESRD populationis likely to produce an underestimate of disease prevalence,because both mild cases and pre-hospital fatalities are underrepresented.We specifically could not assess the frequency of sudden cardiacdeath, which may be a major presentation of unstable coronarysyndromes. However, analysis based on causes of death in renaltransplant recipients may be limited not only because of thelarge percentage of missing causes, but also because, in theabsence of autopsy verification, sudden death cannot necessarilybe distinguished between coronary artery plaque rupture andthrombosis versus other causes of sudden death common in renaltransplant recipients (28–31).
Reliance on CMS Form 2728 for comorbidity data could have ledto selection bias as shown in Table 2, although we also validatedour findings in a larger cohort of renal transplant recipients.Limitations of Form 2728 have been addressed in other studies;however, the form’s accuracy is highest for cardiovasculardiseases (32). We were unable to assess dialysis adequacy ordialysis modality after graft loss, although the utility ofsuch information in comparison with patients with functioningrenal allografts is unproven. We could not assess the impactof BP or lipid levels, which are important limitations. Theshort follow-up of the study disproportionately impacted patientswho experienced graft loss. As a result, the beneficial effectsof renal transplantation may be weakened in this study, andpatients with early graft loss more frequently have acute complicationsand comorbidities not taken into account in this study thatmight have influenced the occurrence of ACS. Despite these limitations,our analysis is strengthened by the completeness and large sizeof the database, its population-based character, and its relativelycomplete follow-up. Because patients were at increased riskof all-cause mortality after graft loss, survival bias is anunlikely explanation for their higher rate of ACS.
In conclusion, analysis of the national renal transplant populationconfirms that while renal transplant recipients share some ofthe risk factors for ACS with the general population, the occurrenceof dialysis-dependent renal failure after transplantation, asdetermined by graft loss, is a major risk factor for ACS inthis population. This association may be accounted for by ahigher rate of traditional risk factors, such as hypertensionand hyperlipidemia after graft loss, as well as new risk factors,such as inflammation that may be increased by chronic immunosuppression,or as yet unidentified mechanisms. Because graft loss is socommon after renal transplantation, it should also be consideredan endpoint of interest in future studies of cardiovasculardisease in renal transplant recipients.
Footnotes
The opinions are solely those of the authors and do not representan endorsement by the Department of Defense or the NationalInstitutes of Health. This is a U.S. Government work. Thereare no restrictions on its use.
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Received for publication April 5, 2002.
Accepted for publication June 18, 2002.
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Abstract
Introduction
3 yr posttransplant, when hospitalization reporting to Medicare is no longer required. In contrast to dialysis patients, however, Medicare reporting starts immediately after transplant. The present study limited analysis to the first kidney transplant occurring in an individual recipient between April 1, 1995, and June 30, 1998, with valid data from CMS Form 2728, counting hospitalizations for ACS up to 3 yr posttransplant. Patients were followed until April 28, 2000. Recipients of organs other than kidneys were excluded. Hospitalizations for ACS occurring at any time after renal transplant, including after graft failure, were counted in analysis in an intention to treat fashion. 
2 testing for categorical variables and t test for continuous variables, respectively. Variables with P < 0.10 in univariate analysis for a relationship with development of a first hospitalization for ACS after renal transplantation in the study period were entered into multivariate analysis as covariates. An exception was made for factors thought to have a clinical reason to be associated with ACS, in accordance with established epidemiologic principles (18). 
