Survival of Patients on the Kidney Transplant Wait List: Relationship to Cardiac Troponin T

Transcription

1 American Journal of Transplantation 28; 8: Wiley Periodicals Inc. C 28 The Authors Journal compilation C 28 The American Society of Transplantation and the American Society of Transplant Surgeons doi: /j x Survival of Patients on the Kidney Transplant Wait List: Relationship to Cardiac Troponin T L. J. Hickson a,f.g.cosio a,b,, Z. M. El-Zoghby a, J. M. Gloor a,b,w.k.kremers b,e,m.d.stegall b,c, M. D. Griffin a,b anda.s.jaffe d a Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN b William J. Von Liebig Transplant Center, Mayo Clinic College of Medicine, Rochester, MN c Department of Surgery, Mayo Clinic College of Medicine, Rochester, MN d Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, MN e Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, MN Corresponding author: Fernando G. Cosio, Cosio.Fernando@mayo.edu Patients waiting for a kidney transplant have high mortality despite careful preselection. Herein, we assessed whether cardiac troponin T (ctnt) can help stratify risk in patients selected for kidney transplantation. ctnt levels were measured in all kidney transplant candidates but the results were not used for patient selection. Among 44 patients placed on the kidney waiting list from 9/24 to 12/2, 1% had elevated ctnt levels (>.1 ng/ml). Higherlevels relatedtodiabetes, longer time on dialysis, history of cardiovascular disease and low serum albumin. High ctnt also related to cardiac anomalies, including left ventricular hypertrophy (LVH), wall motion abnormalities and stressinducible ischemia by dobutamine echo (DSE). However, 54% of patients without these cardiac findings had elevated ctnt. Increasing ctnt levels were associated with reduced survival (HR = 129, CI ( ), p =.1) independently of low serum albumin (.449 (.24 3), p =.11) and history of stroke (3.38 ( ), p =.4). The results of the DSE and/or coronary angiography did not relate significantly to survival. However, high ctnt identified patients with abnormal echo findings and poor survival. Wait listed patients with normal ctnt have excellent survival irrespective of other factors. In contrast, high ctnt levels are strongly predictive of poor survival in the kidney transplant waiting list. Key words: Biomarker, cardiovascular, patient survival, survival, waiting list Received 2 April 28, revised 9 June 28 and accepted for publication 29 June 28 Introduction The selection of patients for kidney transplantation involves a series of evaluations intended to assess critical organ function pretransplant and thus identify those patients at risk from the transplant procedure and also more likely to achieve long-term survival after transplantation (1). A particular focus of this selection process is to assess the candidate s cardiovascular (CV) status because CV risk is high both before and after kidney transplantation (2,3). However, this assessment does not appear to be particularly effective because mortality is still high in patients awaiting transplantation in large part, although not exclusively, due to a high rate of CV events (4,5). Although some traditional CV risk factors are helpful in predicting survival in patients with advanced chronic kidney disease (CKD) (e.g. age and diabetes), metabolic variables, such as low albumin levels, low serum cholesterol levels and high calcium phosphorus product () are also related to reduced patient survival. The role of these latter variables in the selection of transplant candidates is unclear. Kidney transplantation results in relative rapid improvement in patient survival, compared to candidates remaining on dialysis (7), suggesting that although anatomical CV factors contribute to risk in dialysis patients, additional unknown variables, which appear to be correctable by restoring kidney function, are significant determinants of survival. Previous studies have shown that cardiac troponin levels, specially cardiac troponin T (ctnt), frequently are elevated in patients with CKD (8) and that levels correlate with the survival of patients on dialysis (9 11). The cardiac isoforms of troponin (I and T) are sensitive and specific markers of acute myocardial ischemia but are also elevated in response to many other forms of cardiac injury (12). Patients with CKD frequently have persistent elevations in troponin which may be related in part to myocardial ischemia but are also likely related to additional factors such as left ventricular hypertrophy (LVH) and myocardial strain due to hypertension and/or volume overload which may particularly relevant to this population (12). In this study we assessed the potential use of ctnt to predict the survival of patients waiting for a kidney transplant. It should be noted that kidney transplant candidates represent a subset of the general dialysis population selected, based on the results of noninvasive and invasive tests, to have relatively low CV risk. These analyses showed that 2352

2 Survival of Patients on the Kidney Transplant Wait List independent of traditional tests of CV risk assessment, ctnt levels accurately stratify risk of death in kidney transplant candidates. Methods Patient population The study cohort included 44 patients with advanced CKD referred to Mayo Clinic Rochester, Minnesota, for evaluation for kidney transplantation and placed on the transplant waiting list between September 24 and December 2. During this period of time, we measured ctnt in all transplant candidates but did not consider this result in the final decision on whether or not the patient was an appropriate candidate for transplantation. Demographic and clinical information was retrieved from electronic databases. The study was approved by the IRB. The characteristics of this patient population are summarized in Table 1. Pretransplant evaluation At our institution, all candidates undergo a complete physical examination, laboratory panel, chest X-ray and electrocardiography (EKG) during their first visit. Additional CV evaluation is done according to the candidate s perceived risk. Thus, patients with diabetes, older than 59 years and/or on dialysis for more than 1 year have a dobutamine stress echo (DSE). In addition, patients who do not meet the above criteria but who are considered to have a high CV risk by the evaluating physicians also have a DSE. A cardiology consult is sought in all patients with a positive DSE. DSE was performed in 427 of the 44 patients (7%) in this cohort with standard images at baseline and during stepwise infusion of dobutamine up to 4 lg/kg/min followed by atropine in patients achieving suboptimal heart rate. Target heart rate was 85% of the maximum predicted heart rate for the patient s age. A positive DSE, that is stress-inducible ischemia, was defined as new evidence of regional dysfunction from the baseline echo. It is our routine clinical practice to repeat the DSE test yearly in patients with high CV risk who remain on the kidney transplant wait list. The following echocardiographic parameters were analyzed: left ventricular ejection fraction% (EF); LVH defined as left ventricular mass index greater than 125 Table 1: Patient characteristics Patient characteristics Value Number of patients 44 Age (years) 51 ± 13 Sex (% females) 44% Race (% Caucasian) 98% Diabetes 3% Primary renal diagnosis Glomerular 132 (2%) Diabetes 118 (18%) Polycystic kidney disease 9 (11%) Hypertension/vascular 52 (8%) Retransplantation 119 (19%) Other 113 (18%) Unknown 41 (%) Dialysis at evaluation 2% CV disease pretransplant All 192 (34%) Cardiac 172 (29%) Stroke 34 (5%) Peripheral vascular disease 9 (11%) Follow-up months, mean and median (range) 11,.17 (1 7) g/m 2 in men or 11 g/m 2 in women; regional wall motion score indexes, at both rest and after dobutamine infusion, calculated as the sum of wall motion scores divided by the number of segments visualized. Wall motion at rest and after stress were scored as normal (1.), moderately abnormal ( ), and severely abnormal ( 1). Based on the results of the DSE and the cardiologist s evaluation coronary angiography was performed in 134 patients. Coronary arteries were scored based on the highest degree of stenosis of single major epicardial arteries: normal; mild <5% stenosis; moderate 5% 7%; and severe >7%. For this study, ctnt levels were measured in all patients during the initial evaluation for kidney transplant candidacy and during annual follow up if the candidate remained on the waiting list. In patients with multiple ctnt levels, the results of the latest level was used in these analyses. During the time of this study, the evaluating nephrologists did not consider ctnt levels in deciding whom to evaluate with additional testing nor as a selection criteria for specific management. ctnt determinations were done using an electrochemiluminescent immunoassay (Roche Diagnostics, Indianapolis, IN). For this study, ctnt levels were grouped as follows: <.1 ng/ml; >.1 <.3;.3.9; and.1 based on previous analyses (9). In our current clinical practice at Mayo Clinic a ctnt value <.1 ng/ml (the 99th percentile value) is considered to be the upper limit of the reference range. Data analyses Means of two data sets were compared by Student s t-test or a nonparametric test (Wilcoxon test) if the data were not normally distributed. Comparisons between more than two sets of data were done by ANOVA or Kruskall Wallis if not normally distributed. Proportions were compared by chi-square. The relationships between ctnt levels and other variables were done by linear regression after log transformation of ctnt values because these values were not normally distributed. The primary endpoint of the analysis was death. Patient followed up was censored at the time of kidney transplantation, at death or on December, 27. Survival and variables related to survival were analyzed by Kaplan Meier estimation and Cox regression. The cause of patient death was determined by review of our medical records if the patient expired in our institution or by review of external death certificates when available. Results ctnt levels in kidney transplant candidates The distribution of ctnt levels in the 44 study patients was a follows: 253 patients (39%) had ctnt <.1 ng/ml that is within the normal range; 184 (29%) had ctnt between.1 and.3 ng/ml; 12 (2%) had ctnt between.4 and.9; and 81 (13%) had ctnt levels equal or higher than.1 ng/ml. In 242 patients ctnt levels were measured more than once since the initial evaluation and listing. In patients whose initial ctnt levels were normal (<.1 ng/ml), 71% continued to have normal levels on repeated determinations but 29% developed elevated ctnt. In patients whose initial ctnt levels were elevated (>.1 ng/ml), 83% continued to have elevated levels on repeated determinations and in a small minority (17%) subsequent ctnt determinations became normal. The latest ctnt level available was included in this analysis. The incidence of an abnormal ctnt level varied with the patient s primary renal diagnosis (Figure 1). Specifically, patients with diabetes and those with hypertensive/vascular American Journal of Transplantation 28; 8:

3 Hickson et al. causes for CKD had a higher incidence of elevated ctnt than patients with glomerulonephritis and those with polycystic kidney disease (PKD). Furthermore, ctnt levels were quantitatively higher in patients with diabetes than in the other three groups (p<.1, Kruskall Wallis). Higher ctnt levels were also related to a longer time on dialysis (r =.254, p<.1, by linear regression using log transformed ctnt levels); lower serum albumin (r =.182, p<.1); male sex (r =.19, p<.1); older age (r =.11, p =.3); and history of CV disease (r =.218, p =.1). By multiple linear regression analysis longer time on dialysis, lower serum albumin, male sex and history of CV, but not age, were significantly related to an elevated ctnt level (data not shown). Figure 2 displays the relationship between ctnt levels and time on dialysis in patients with or without diabetes mellitus. Increasing time on dialysis was associated with progressive increases in the percent of patients with abnormal ctnt in both groups of patients. However, the prevalence of elevated ctnt was higher in diabetics than in nondiabetics not on dialysis or on dialysis for less than 1year. Results of cardiac evaluation and relationship to ctnt One hundred and ninety two patients (34%) had a history of symptomatic CV disease prior to their transplant evaluation (Table 1). Among the 44 patients in the study, 427 (7%) had a DSE, 132 (2%) had coronary angiography and 4 (.2%) had a coronary artery intervention prior to listing (28 angioplasties/stents and 12 bypass surgeries) (Table 2). Pateint with elevated ctnt (%) Glomerular Diabetes PKD Hypertension Figure 1: Prevalence of elevated ctnt levels (>.1 ng/ml) in patients with several pretransplant kidney diagnoses. Chisquare p <.1 indicating a higher prevalence of elevated ctnt in patients with diabetes and in patients with hypertension, compared with the other two groups. Figure 2: Association between ctnt levels, diabetes and time on dialysis. Y-axis represents the percent of patients in each subgroup with ctnt level >.1. Patient without DM (N = 412) (hatched bars); patients with DM (N = 232) (black bars). Elevated ctnt levels were related to the presence of LVH diagnosed by either EKG or echo; reduced left ventricular EF; stress-induced ischemia; and the presence of ventricular wall motion abnormalities at rest. Among patients who had coronary arteriography the severity of the coronary artery disease was not related significantly to ctnt levels (Table 2). As expected by these relationships, elevated ctnt levels were more common in patients classified as Table 2: Results of cardiac evaluation and relationship with ctnt levels Tests Relationship Parameter done (N) N (%) to ctnt a EKG 557 LVH 12 (29%).22 (<.1) Echocardiography 427 LVH 111 (41%).177 (.3) LV ejection fraction 131 (28%).98 (.34) <55% Adequacy of the 214 (8%) DSE b Ischemia on DSE 18 (25%).135 () Resting wall motion 91 (25%).15 (.2) abnormalities c Stress wall motion 11 (35%) (.15) abnormalities c Coronary angiography 132 No CAD d 13 (9%) (.237) Mild CAD 31 (25%) Moderate CAD 11 (1%) Severe CAD 77 (5%) Coronary artery 4 interventions Stent 28 (%) Surgery 12 (%) a Linear regression analysis using log transformed ctnt values. Results represent correlation coefficient (r) and (p-values). b Defined as achievement of target heart rate. c Regional wall motion score >1.. d CAD = coronary artery disease American Journal of Transplantation 28; 8:

4 Survival of Patients on the Kidney Transplant Wait List 1. 95% 1. Figure 3: Left: Patient survival while waiting for a kidney transplant. Cumulative patient survival at 12, 24 and 3 months is indicated. Right: survival of patients in the waiting list classified according to their ctnt level at the time of evaluation: ( -) ctnt<.1; (o - o) ctnt.1.3; ( ) ctnt.3 and.9; (...) ctnt.1. Log rank p =.4. Patient Survival. 89% 83%. 3 3 having high CV risk (defined by the presence of ischemia on DSE and/or LVH and/or reduced EF and/or wall motion abnormalities) than in those with lower CV risk (defined by the absence of any of these variables) (72% versus 54% respectively, p <.1). However, it is remarkable that 54% of patients considered to have lower CV risk based on cardiac testing had elevated ctnt levels and that 9% of those had ctnt levels >.1 ng/ml. Patient survival on the kidney transplant waiting list After a mean of 11± 11 months of follow up (median.2, range 1 7) 35 patients died (5.4%) and 37 (58%) were transplanted. The cause of death was known in 27 patients (77%) and included cardiovascular (33.3%), infections (7%) and other causes (5%). Figure 3 displays patient survival for the entire population (left) and the association between ctnt levels and patient survival (right). Approximately % of patients on the waiting list died every year. Increasing ctnt levels related to progressively reduced survival. The survival of patients with ctnt levels between.1 and.3 ng/ml did not differ significantly from that of patients with levels <.1 (p = 41). In contrast, ctnt levels between.3 and.9 ng/ml were associated with significantly increased mortality (Hazard Ratio, HR = 3.11; confidence interval, CI (1 8.1), p =.4) and mortality was further increased in patients with ctnt levels.1 ng/ml (HR = 45, CI ( ), p =.9). During the course of the study, 2% of patients with ctnt levels <.1 ng/ml died compared to 3% of those with ctnt.1.3, 1% of those with ctnt.4.9 and 15% of those with ctnt.1. Of interest, the relationship between ctnt and survival on the waiting list was significant for patients not on dialysis at the time of evaluation (HR = 2 (1 4.3), p<.1) and for those on dialysis (HR = 1 ( ), p =.3). When the cutoff for ctnt was set at.3 ng/ml the sensitivity of the test was 7% and the specificity 9%. Twelve percent of patients with elevated ctnt died (positive predictive value) while 98% of patients with normal ctnt survived (negative predictive value). Table 3 displays results of analyses of clinical variables related to patient survival. By univariate analysis reduced patient survival was significantly associated with: elevated ctnt levels, lower serum albumin and a history of stroke. Of interest, age, diabetes and history of heart disease and/or peripheral vascular disease were not significantly associated with survival in the univariate analysis, perhaps a consequence of the selection process and the short followup time. In a multivariate analysis high ctnt, low serum albumin and history of stroke were independently associated with reduced patient survival (Table 3). Additional variables considered in these analyses but not significantly related to survival included: sex, race, BMI, smoking, creatinine at evaluation, the use of dialysis at the time of evaluation, time on dialysis, serum cholesterol, hemoglobin and history of previous transplants. None of the results of additional cardiac testing related significantly to survival, including LVH (p =.428), ejection fraction (p =.35), stress-induced ischemia (p = 25), wall motion abnormalities at either rest (p =.33) or after stress (p = 14) and the severity of coronary artery disease by angiography (p =.183). However, ctnt levels considered together with the results of cardiac studies were significantly related to survival (Figure 4). Thus, ctnt elevations related to the survival of patients who had a DSE, that is those considered clinically to have high CV risk (N = 427) (Figure 4A); patients with an EF<55% (N = 129) (Figure 4B); patients with stress-induced ischemia (N = 113) (Figure 4C); and patients who had a coronary angiogram (N = 132) (Figure 4D). Also of interest, among patients considered to be at lower CV risk Table 3: Analyses of variables related to patient survival on the kidney transplant waiting list Univariate Multivariate Variables HR (CI) p HR (CI) p ctnt 129 ( ) (1.7 21).22 level a Serum.449 (.24 3) (.27 8).43 albumin History 3.38 ( ).4 22 (1.2 5).13 of stroke a ctnt levels were analyzed after grouping values at four levels: <.1;.1.3,.4.9 and.1. American Journal of Transplantation 28; 8:

5 Hickson et al. (defined as: no ischemia on DSE, no LVH, normal EF and no LV wall motion abnormalities) elevated ctnt also related to survival (N = 422) (HR = 17 ( ), p =.39). In these analyses ctnt levels were classified into three rather than four groups because of the relative low numbers of patients in each subgroup. The range of ctnt levels in each subgroup is indicated in Figure 4 legend. Discussion These studies focused on the potential role of ctnt levels in predicting the survival of patients in the kidney transplant waiting list. The findings of these studies are in general agreement with previous studies showing a strong relationship between ctnt and survival of the general population of dialysis patients (9 11). However, this observation is in fact somewhat surprising and it would be expected that aggressive evaluation and treatment of CV disease would have resulted in a reduction in the number of patients with high ctnt and high risk. This prediction is not confirmed by these results leading to the inescapable conclusion that current pretransplant evaluation protocols do not discriminate adequately those patients who, as indicated by their elevated ctnt levels, are at heightened CV risk. Results of previous studies, assessing ctnt levels in wait listed patients are consistent with the observations made here (13). These analyses identify the group of kidney transplant candidates with high ctnt as having high mortality while waiting for a graft. There was a gradient of risk with those with higher ctnt suffering higher event rates. Conversely, a normal ctnt was highly predictive of excellent survival (2% mortality over the period of observation) even in patients considered clinically to be at high risk including DM, older A Patient survival in patients who had a DSE C Patient survival with inducible ischemia B 1. Patient survival with EF<55% D 1. Survival of patients with coronary angiograms Figure 4: Relationship between ctnt and the survival of patients who had noninvasive or invasive cardiac studies. (A) Patients considered clinically to have high CV risk and thus having a DSE (N = 427, HR = 2.1 ( ), p =.4); (B) patients with EF < 55% (N = 129, HR = 35 (1.3 8), p =.7); (C) patients with ischemia during DSE (N = 113, HR = 4.23 ( ), p =.34); (D) patients undergoing a coronary angiogram (N = 132, HR = 247 (1.19 3), p =.19). In these analyses ctnt levels were divided into three groups: <.3 ( );.4.9 (o o) and.1 ng/ml ( ). 235 American Journal of Transplantation 28; 8:

6 Survival of Patients on the Kidney Transplant Wait List age and those with additional cardiac testing, those with stress-induced myocardial ischemia, those with low ejection fraction and those considered to have such high CV risk that they required a coronary arteriography. The concept that ctnt helps further define CV risk in patients already at high risk is not new. For example, ctnt levels stratify the risk of patients with acute coronary syndromes with or without renal disease (14,15), patients with congestive heart failure (1) and that of patients on dialysis (9 11). In our laboratory, a ctnt level <.1 is considered to be normal in accord with guidelines from both cardiology and laboratory medicine groups. However, in this study survival was not significantly different between patients with ctnt levels <.1 and those with levels between.1 and.3 ng/ml perhaps a reflection of a relatively small sample size. The association between ctnt and survival was independent of two other variables, low serum albumin and history of stroke. A low serum albumin has been associated with reduced survival in dialysis patients (). Our results suggest that this parameter should be considered in the evaluation of candidates for kidney transplantation. It is of interest to speculate that low serum albumin is related to higher ctnt levels perhaps because both parameters may be related to inflammation in dialysis patients. Unfortunately we did not have CRP values in this cohort given the potential importance of this analyte in predicting events (1,17). We noted previously (18) and in this study that history of stroke is a powerful and independent predictor of patient survival, statistically stronger than history of heart disease and/or peripheral vascular disease. These results suggest that stroke should also be considered, independently of other CV risk factors, in the selection of patients for kidney transplantation. It is of interest and of concern that our current assessment of high CV risk does not match particularly well with the strongest parameter predictive of survival, namely ctnt levels. It should be noted that in this study ctnt levels were studied prospectively and that these results were not used in deciding on patient evaluation or management. Using our current practice protocols 2% of patients with ctnt <.3 ng/ml, that is levels associated with low CV risk, undergo perhaps unnecessary noninvasive cardiac evaluation in our program. Perhaps more concerning, 29% of patients with high ctnt do not undergo further cardiac scrutiny in our program since they are considered clinically to be at low risk. Other transplant programs apply more aggressive protocols for evaluation of high risk kidney transplant candidates (19). However, those investigations are costly, often fruitless in low risk patients and likely are not particularly helpful in defining risk, as shown here. Consistent with these results recent studies involving a large number of patients showed that results of stress imaging and coronary arteriography did not predict survival but that reduced EF is strongly associated with survival (2). The results of this study suggest a new paradigm in the assessment of CV risk: ctnt levels may be used as the first step in the identification of patients at high risk of dying while waiting for a transplant who, independently of all other risk factors, perhaps should undergo cardiac evaluation. Clearly, the presence of coronary artery disease may not be all that should be taken into account as part of such an evaluation. In fact, volume overload, poorly controlled hypertension and LVH are likely contributing factors to the elevations in ctnt in dialysis patients (12). In fact, consistent with previous studies (21) we find no association between ctnt levels and severity of coronary artery disease in our CKD patients. Furthermore, recent imaging studies found no evidence of myocardial infarction in dialysis patients with elevated ctnt (22). ctnt was noted to be elevated in 1% of patients placed on the kidney transplant waiting list. These results also suggest that ctnt levels should be monitored periodically while patients wait for their transplant as those levels may increase with longer time on dialysis (23). These analyses show that several variables are related to an elevated ctnt and of interest those variables are also related to survival after transplantation. For example, the increase in ctnt associated with increasing time on dialysis is consistent with two previous observations: first, increased posttransplant mortality is noted when patients are on dialysis for more than 1 year (24,25) and we show here that the proportion of patients with elevated ctnt increases sharply after 1 year on dialysis. Second, in patients with diabetes the survival risk associated with dialysis is noted after brief periods of time (18,2) and we show here that diabetes is associated with higher ctnt levels even before dialysis is initiated. In contrast to these findings, a previous study found no association between dialysis time and ctnt levels (13). The data available is insufficient in that publication for us to try to explain this negative finding. It is interesting that some causes of CKD, notably PKD and glomerulonephritis, are associated with significantly lower risk of having an elevated ctnt. We interpret these results to indicate that reduced kidney function is not sufficient to cause an increase in ctnt and that other variables, such as DM and hypertension, contribute to the elevation in ctnt and thus to the high CV risk of CKD patients. Identifying these additional variables may suggest new therapies to prevent CKD-associated CV risk. Those studies will be greatly facilitated by having a marker for CV risk such as ctnt. It is important to note that autopsy studies have shown that an elevated ctnt are invariable associated with pathologic evidence of myocardial injury in patients with or without CKD (27). These results should be interpreted within the confines of the population studied. For example, this cohort was selected for transplantation based on our current practice criteria. Thus, they are a lower risk group than the general dialysis population. Furthermore, this cohort although representative of this geographic region was racially quite uniform. Based on our current protocols not all patients referred for transplantation have an extensive cardiac American Journal of Transplantation 28; 8:

7 Hickson et al. evaluation. Thus, these results may be influenced by the clinical preclassification of patients according to their perceived CV risk that as noted may not be accurate. Finally, these results were based on an analysis of survival after rather short period of follow up. The selection of patients for kidney transplantation continues to be challenging and current protocols are clearly imprecise. This study suggests that ctnt can be very helpful stratifying patients CV risk, perhaps identifying patients who do or do not additional CV work up and also helping in the interpretation of the results of cardiac studies. Based on these results we would suggest more intense cardiac evaluation in patients with high ctnt recognizing that coronary artery disease and elevations of ctnt are not synonymous. Treatment of factors that may contribute to high ctnt in dialysis patients, such as coronary artery stenosis, uncontrolled hypertension and volume overload (12) may lead to normalization of ctnt levels. However, whether changes in ctnt levels are associated with improved survival is presently unknown and needs to be evaluated. Acknowledgments This work was supported by grants from the Mayo Clinic Transplant Center and from the Division of Nephrology and Hypertension. We thank the kidney pancreas transplant coordinators for their dedication to the care of transplant candidates and recipients and their help in the collection of data from these patients. We also thank Ms. Cynthia Handberg for her excellent secretarial assistance. References 1. Kasiske BL, Ramos EL, Gaston RS et al. The evaluation of renal transplant candidates: Clinical practice guidelines. J Am Soc Nephrol 1995; : Levey AS, Beto JA, Coronado BE et al. Controlling the epidemic of cardiovascular disease in chronic renal disease: What do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis 1998; 32: Kasiske BL. Cardiovascular disease after renal transplantation. Semin Nephrol 2; 2: Danovitch GM, Hariharan S, Pirsch JD et al. Management of the waiting list for cadaveric kidney transplants: Report of a survey and recommendations by the Clinical Practice Guidelines Committee of the American Society of Transplantation. J Am Soc Nephrol 22; 13: Gill JS, Rose C, Pereira BJ, Tonelli M. The importance of transitions between dialysis and transplantation in the care of end-stage renal disease patients. Kidney Int 27; 71: Hocher B, Ziebig R, Altermann C et al. Different impact of biomarkers as mortality predictors among diabetic and nondiabetic patients undergoing hemodialysis. J Am Soc Nephrol 23; 14: Wolfe RA, Ashby VB, Milford EL et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant [see comments]. N Engl J Med 1999; 341: Lamb EJ, Kenny C, Abbas NA et al. Cardiac troponin I concentration is commonly increased in nondialysis patients with CKD: Experience with a sensitive assay. Am J Kidney Dis 27; 49: Apple FS, Murakami MM, Pearce LA, Herzog CA. Predictive value of cardiac troponin I and T for subsequent death in end-stage renal disease. Circulation 22; 1: defilippi C, Wasserman S, Rosanio S et al. Cardiac troponin T and C-reactive protein for predicting prognosis, coronary atherosclerosis, and cardiomyopathy in patients undergoing long-term hemodialysis. JAMA 23; 29: Deegan PB, Lafferty ME, Blumsohn A, Henderson IS, McGregor E. Prognostic value of troponin T in hemodialysis patients is independent of comorbidity. Kidney Int 21; : Jaffe AS, Babuin L, Apple FS. Biomarkers in acute cardiac disease: The present and the future. J Am Coll Cardiol 2; 48: Roberts MA, MacMillan N, Hare DL et al. Cardiac troponin levels in asymptomatic patients on the renal transplant waiting list. Nephrology (Carlton) 2; 11: Aviles RJ, Askari AT, Lindahl B et al. Troponin T levels in patients with acute coronary syndromes, with or without renal dysfunction. N Engl J Med 22; 34: Heidenreich PA, Alloggiamento T, Melsop K, MCDonald KM, Go AS, Hlatky MA. The prognostic value of troponin in patients with non-st elevation acute coronary syndromes: A meta-analysis. J Am Coll Cardiol 21; 38: Peacock WF, De MT, Fonarow GC et al. Cardiac troponin and outcome in acute heart failure. N Engl J Med 28; 358: Apple FS, Murakami MM, Pearce LA, Herzog CA. Multi-biomarker risk stratification of N-terminal pro-b-type natriuretic peptide, highsensitivity C-reactive protein, and cardiac troponin T and I in endstage renal disease for all-cause death. Clin Chem 24; 5: Cosio FG, Hickson LJ, Griffin MD, Stegall MD, Kudva YC. Patient survival and cardiovascular risk after kidney transplantation: The challenge of diabetes. Am J Transplant 28; 8: Witczak BJ, Hartmann A, Jenssen T, Foss A, Endresen K. Routine coronary angiography in diabetic nephropathy patients before transplantation. Am J Transplant 2; : Hage FG, Smalheiser S, Zoghbi GJ et al. Predictors of survival in patients with end-stage renal disease evaluated for kidney transplantation. Am J Cardiol 27; 1: Sharma R, Pellerin D, Gaze DC et al. Dobutamine stress echocardiography and cardiac troponin T for the detection of significant coronary artery disease and predicting outcome in renal transplant candidates. Eur J Echocardiogr 25; : defilippi CR, Thorn EM, Aggarwal M et al. Frequency and cause of cardiac troponin T elevation in chronic hemodialysis patients from study of cardiovascular magnetic resonance. Am J Cardiol 27; 1: Wu AH, Jaffe AS, Apple FS et al. National academy of clinical biochemistry laboratory medicine practice guidelines: Use of cardiac troponin and B-type natriuretic peptide or N-terminal prob-type natriuretic peptide for etiologies other than acute coronary syndromes and heart failure. Clin Chem 27; 41: Cosio FG, Alamir A, Yim S et al. Patient survival after renal transplantation. Part I. The impact of dialysis pre-transplant. Kidney Int 1998; 53: American Journal of Transplantation 28; 8:

8 Survival of Patients on the Kidney Transplant Wait List 25. Meier-Kriesche HU, Kaplan B. Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outcomes: A paired donor kidney analysis. Transplantation 22; 74: Becker BN, Rush SH, Dykstra DM, Becker YT, Port FK. Preemptive transplantation for patients with diabetes-related kidney disease. Arch Int Med 2; 1: Ooi DS, Isotalo PA, Veinot JP. Correlation of antemortem serum creatine kinase, creatine kinase-mb, troponin I, and troponin T with cardiac pathology. Clin Chem 2; 4: American Journal of Transplantation 28; 8: