• Cardiovascular mortality;
  • erythropoietin;
  • renal transplant recipients;
  • survival


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Cardiovascular disease (CVD) is the main cause of mortality in renal transplant recipients (RTR). Classical factors only partly explain the excess risk. We hypothesized that high EPO—a marker for inflammation, angiogenesis and hypoxia—is associated with CVD in RTR. A total of 568 RTR (51±12 years; 45% female; creatinine clearance (CrCl) 57±20 mL/min/1.73 m2) were included at median 6 [IQR 3–11] years after transplantation. Subjects on exogenous EPO and ferritin-depleted subjects were excluded. Median EPO level was 17.3 [IQR 11.9–24.2] IU/L. Gender-stratified tertiles of age-corrected EPO were positively associated with waist circumference (but not BMI), CVD history, time since transplantation, diuretics, azathioprine, CRP, mean corpuscular volume and triglyceride levels, and inversely with CrCl, RAAS-inhibition, cyclosporine, hemoglobin, total- and HDL-cholesterol. During follow-up for 7 [6–7] years, 121 RTR (21%) died, 64 of cardiovascular (CV) causes. Higher EPO (per 10 IU/L) was associated with total (HR1.16 [1.04–1.29], p = 0.01) and CV mortality (HR1.22 [1.06–1.40], p = 0.005), independent of age, gender, hemoglobin, inflammation, renal function and Framingham risk factors. Thus, EPO and mortality are linked in RTR, independent of potential confounders. This suggests that yet other mechanisms are involved. Dissecting determinants of EPO in RTR may improve understanding of mechanisms behind excess CV risk in this population.

AHT, anti-hypertensive treatment; AMI, acute myocardial infarction; ANOVA, analysis of variance; BSA, body surface area; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CI, confidence interval; CKD, chronic kidney disease; CrCl, creatinine clearance; CRP, C-reactive protein; CV, cardiovascular; CVA, cerebrovascular accident; CVD, cardiovascular disease; DBP, diastolic blood pressure; EDTA, ethylenediaminetetraacetic acid; EPO, erythropoietin; ESRD, end-stage renal disease; Hb, hemoglobin; HDL, high-density lipoprotein; hsCRP, high-sensitive C-reactive protein; ICD, International Classification of Diseases; IQR, interquartile range; LDL, low-density lipoprotein; MCV, mean corpuscular volume; MMF, mycophenolate mofetil; NT-proBNP, N-terminal probrain natriuretic peptide; PTCA, percutaneous transluminal coronary angiography; RAAS, renin angiotensin aldosterone system; rHuEPO, recombinant human erythropoietin; RTR, renal transplant recipient; SBP, systolic blood pressure; TIA, transient ischemic attack.



  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Cardiovascular disease is the most important cause of mortality among renal patients, in patients with chronic kidney disease (CKD) in native kidneys as well as in renal transplant recipients (RTR). RTR are at an increased risk for cardiovascular disease of roughly six times when compared to the general population (1). Half of the mortality in this population is attributable to cardiovascular causes (2). Identifying patients at risk has gained a lot of attention in recent decennia, yet long-term survival has not improved markedly.

One of the possible targets for improving cardiovascular risk in RTR was thought to be anemia, as it is a predictor of mortality (3) and potentially accessible to intervention, yet large interventional trials with exogenous EPO in native CKD patients, with (4) and without diabetes (5), did not show an improvement of cardiovascular morbidity or mortality after anemia correction. Rather, an increased incidence of cardiovascular events was observed in nondiabetic patients with CKD (5). Likewise, an increased incidence of cerebrovascular accidents was observed in diabetic patients with CKD receiving high doses of exogenous EPO (4).

The above studies shifted attention to EPO as a factor in cardiovascular risk. In line with this assumption, studies in heart failure and native diabetic CKD showed that endogenous EPO levels have prognostic impact for cardiovascular events (6,7). Whether endogenous EPO levels are associated with cardiovascular events in RTR is so far unknown. Considering the elevated risk for cardiovascular disease, and the specific abnormalities of EPO regulation in RTR, this would require specific investigation. Therefore, in the current study we studied the association of endogenous EPO levels with cardiovascular and all-cause mortality in a large single-center cohort of RTR.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Study population

For this prospective cohort study, all RTR who visited the outpatient clinic between August 2001 and July 2003 and who had a functioning graft for at least 1 year were included. Baseline characteristics and study setup have been published previously (8).

In patients with fever or other signs of infection (e.g. complaints of upper respiratory tract infection or urinary tract infection), baseline visits were postponed until symptoms had resolved. Patients with overt congestive heart failure and patients diagnosed with cancer other than cured skin cancer were not considered eligible for the study. Smoking status and cardiovascular history were evaluated by questionnaire. Items scored for coronary artery disease were acute myocardial infarction (AMI), percutaneous transluminal coronary angiography (PTCA) and coronary artery bypass grafting (CABG). Other items scored were cerebrovascular accidents (CVA) and transient ischemic attacks (TIA). Data on age, gender, transplantation date, time on dialysis, diabetes and medication use were obtained from the Groningen Renal Transplant Database, a database containing information on all renal transplant recipients in Groningen since 1968.

From the 847 eligible subjects, 606 subjects signed informed consent forms and were included in the study. Included subjects did not differ from not included subjects in either age, gender, body dimensions or renal function. From the 606 subjects included, EPO levels were available in 592 subjects. Subjects on erythropoiesis stimulating agents were excluded (13 subjects), as well as ferritin-depleted [ferritin < 15 μg/L (9)] subjects (11 subjects), which left 568 subjects for analysis.

Standard immunosuppressive treatment consisted of the following: from 1968 to 1989, prednisolone and azathioprine (100 mg/day); from January 1989 to February 1993, cyclosporine standard formulation (Sandimmune, Novartis Pharma B.V., Arnhem, The Netherlands; 10 mg/kg; trough levels of 175 to 200 μg/L in first 3 months, 150 μg/L between 3 and 12 months posttransplant, and 100 μg/L thereafter) and prednisolone (starting with 20 mg/day, rapidly tapered to 10 mg/day); from March 1993 to May 1997, cyclosporine microemulsion (Neoral, Novartis Pharma B.V., Arnhem, The Netherlands; 10 mg/kg, trough levels idem) and prednisolone; from May 1997 till date, mycophenolate mofetil (Cellcept, Roche B.V., Woerden, The Netherlands; 2 g/day) was added.

Clinical measurements

Further measurements included morning blood pressure measurements (before antihypertensive medication was taken) and the anthropometric parameters length, weight, waist and hip circumference (all after shoes and heavy clothing were removed). BMI calculated as weight in kilograms divided by length in meters squared. BSA calculated as Weight 0.425* Height 0.725) * 0.007 184.

Patients collected 24-h urine the day before the outpatient clinic visit, allowing for renal function assessment and measurement of sodium and creatinine excretion.

Laboratory measurements

All laboratory measurements were performed from EDTA-plasma after an 8- to 12-h fasting period. Plasma creatinine, total cholesterol, LDL, HDL-cholesterol, triglycerides, hsCRP and proteinuria assessed as previously described (10). EPO levels were measured on the Immulite 2000 assay (DPC, Los Angeles, CA, USA), ferritine levels on the Roche Modular E170 (F. Hoffmann-La Roche Ltd., Basel, Switzerland), NT-proBNP levels by immunoassay on the ELECSYS2010 instrument (ELECSYS proBNP, Roche Diagnostics, Germany).


The endpoints of the study were total and cardiovascular mortality. Adequate collection of up-to-date data on events and mortality is ensured by the continuous surveillance system of the outpatient clinic and the collaboration with peripheral hospitals, which were contacted in case the current status of a patient was unknown. Causes of death were coded according to the International Classification of Diseases, ninth revision (ICD-9). Cardiovascular death was defined as deaths in which the principal cause of death was cardiovascular in nature, using ICD-9 codes 410–447. Follow-up was completed until May 19, 2009. There was no loss to follow-up.

Statistical analysis

Data were analyzed with SPSS 16.0 (SPSS Inc. Chicago, IL, USA). Normally distributed variables given as mean ± standard deviation or as median [interquartile range (IQR)] when skewed. Hazard ratios (HRs) reported with (95% confidence interval).

Associations and differences between variables tested with Pearson's correlations test, Spearman rank test, Student's t-tests, Mann–Whitney U-tests or χ-square tests, whichever appropriate.

Because EPO differed between sexes, we first generated gender-stratified tertiles of EPO to allow for gender independent presentation of data. To account for the known association between age and EPO (11), we then calculated age-adjusted values for all baseline characteristics presented. The ANOVA test was used to test differences in gender-stratified tertiles of age-corrected EPO levels, thus allowing for age- and gender-independent comparison of baseline variables. Backward linear regression analysis was constructed including all variables with p < 0.1 upon ANOVA to determine independent continuous contributions of variables on EPO levels. In the case of heteroscedasticity, variables were log transformed to obtain equally distributed residuals.

To analyze the association of EPO with mortality, age- and gender-adjusted tertiles of EPO were plotted in Kaplan–Meier analyses with log rank test to assess significance of difference between groups. Additionally, univariate Cox regression was used to assess hazard ratios of tertiles. Finally, Cox regression analyses were built for EPO levels with all variables with p < 0.1 upon linear regression analysis and factors known to influence EPO levels or cardiovascular risk, including Framingham risk factors, creatinine clearance and urinary protein excretion. As a sensitivity analysis, backward and forward Cox regression analyses were performed for both total and cardiovascular mortality with all variables under consideration.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Of all study subjects, 55% were male. Median EPO levels were 17.3 [IQR 11.9–24.2] IU/L.

Age-adjusted baseline characteristics according to gender-stratified tertiles of EPO are given in Table 1. From this table, it becomes apparent that EPO levels are associated with waist circumference (but not BMI), prior history of CVD, use of azathioprine, use of diuretics, high-sensitive CRP (hsCRP) levels, mean corpuscular volume (MCV), triglycerides and proteinuria and inversely with hemoglobin (Hb), ferritin levels, use of renin–angiotensin–aldosterone System (RAAS) inhibiting medication, use of cyclosporine, total-, and HDL-cholesterol and renal function.

Table 1.  Baseline table for gender-stratified tertiles of age-adjusted EPO levels (N = 568)
  Tertiles of EPOp-Value
  1. EPO = erythropoietin; MCV = mean corpuscular volume; CAD = coronary artery disease; CVA = cerebrovascular accident; TIA = transient ischemic attack; BMI = body mass index; SBP = systolic blood pressure; DBP = diastolic blood pressure; AHT = antihypertensives; RAASi = renin–angiotensin–aldosterone system inhibitors; hsCRP = high sensitive C-reactive protein; Hb = hemoglobin; HDL = high-density lipoprotein.

Demographics N = 189N = 190N = 189 
 Malen (%)108 (55%)109 (55%)108 (55%)NA
 Age(years)47 ± 1252 ± 1254 ± 10<0.001
 EPO(U/L)10.2 [9.5–10.8]17.4 [16.9–18.0]35.1 [34.6–35.6]<0.001
 Hemoglobin(g/dL)14.1 ± 1.513.9 ± 1.513.6 ± 1.60.008
 Anemian (%)32 (17%)25 (13%)41 (23%)0.002
 MCV(fl)90 [89–90]91 [91–92]92 [91–92]0.01
 Ferritin(μg/L)157 [144–170]158 [146–171]121 [111–131]0.07
CVD history
 CADn (%)9 (5%)20 (10%)18 (9%)0.05
 CVA / TIAn (%)7 (4%)8 (4%)19 (10%)0.04
 Time on transplant(years)4.9 [2.3–9.6]6.4 [3.4–11.6]6.7 [3.0–13.7]0.001
 Time on dialysis(months)27 [16–45]27 [12–48]29 [14–51]0.89
Immunosuppression    <0.001
 Cyclosporinen (%)143 (73%)117 (60%)115 (59%) 
 Tacrolimusn (%)28 (14%)30 (15%)24 (12%) 
Proliferation inhibitor    0.003
 Azathioprinen (%)34 (18%)65 (33%)93 (48%) 
 Mycophenolic acidn (%)96 (49%)80 (41%)63 (32%) 
Body composition
 Length(m)1.72 ± 0.101.72 ± 0.091.72 ± 0.090.97
 BMI(kg /m2)25.9 ± 4.325.9 ± 4.226.3 ± 4.30.57
 Waist(cm)95.2 ± 13.196.3 ± 12.999.6 ± 13.10.006
Smoking    0.32
 Current smokingn (%)47 (24%)33 (17%)50 (25%) 
 Previous smokingn (%)82 (42%)84 (42%)83 (42%) 
Blood pressure
 SBP(mmHg)153 ± 22152 ± 22155 ± 220.42
 DBP(mmHg)90 ± 1091 ± 1090 ± 100.64
 Number of AHT(n)2 [1–3]2 [1–3]2 [1–3]0.12
 Use of RAASin (%)86 (44%)58 (29%)59 (30%)0.002
 Use of diureticsn (%)76 (39%)78 (40%)101 (53%)0.007
hsCRP(mg /L)1.6 [1.5–1.8]1.9 [1.7–2.1]2.7 [2.4–3.0]0.001
 Glycolized Hb(%)6.5 [6.4–6.6]6.3 [6.3–6.4]6.5 [6.4–6.6]0.22
 Diabetesn (%)36 (18%)29 (15%)39 (20%)0.33
 Duration of diabetes(years)5 [3–7]5 [3–6]4 [3–5]0.64
 Glucose(mmol/L)4.9 ± 0.24.6 ± 0.24.9 ± 0.1<0.001
 Triglycerides(mmol/L)2.05 [1.99–2.09]2.14 [2.11–2.18]2.37 [2.33–2.41]<0.001
 Total cholesterol(mmol /L)5.67 ± 0.115.66 ± 0.105.54 ± 0.09<0.001
 HDL – cholesterol(mmol /L)1.14 ± 0.051.13 ± 0.041.07 ± 0.04<0.001
Renal function
 Creatinine clearance(mL /min /1.73 m2)59 ± 2058 ± 2053 ± 200.02
 Urine protein excretion(g /day)0.3 [0.3–0.3]0.4 [0.3–0.4]0.4 [0.3–0.4]0.16

In a backward linear regression analysis, use of azathioprine, age, hsCRP, MCV, triglycerides and diuretics remained as significant positive independent determinants of continuous EPO levels, while use of RAAS inhibiting medication, Hb, total cholesterol, ferritin and cyclosporine remained as significant negative independent determinants of continuous EPO levels (Table 2). R2 of the final model was 0.25.

Table 2.  Backward linear regression model for determinants of log transformed EPO levels
Multivariate determinants of log transformed EPO levels
 β95% CIStandardized betap-Value
  1. Excluded in backward regression analysis: gender, time since transplantation, history of CVD, smoking status, number of antihypertensives used, serum glucose levels, HDL-cholesterol, creatinine clearance, urinary protein excretion and body mass index.

Use of azathioprine0.110.06; 0.150.21<0.001
Age0.0040.002; 0.0050.190.002
Use of RAAS inhibition−0.08−0.12; −0.04−0.16<0.001
Hemoglobin−0.04−0.06; −0.02−0.16<0.001
hsCRP (log)0.060.03;
Total cholesterol (log)−0.41−0.64; −0.19−0.14<0.001
Ferritin (log)−0.08−0.13; −0.04−0.14<0.001
MCV0.0040.001; 0.0070.100.007
Triglycerides (log)0.100.01;
Use of cyclosporine−0.05−0.08; −0.01−0.090.024
Use of diuretics0.040.00;

Of the 568 subjects in the study, 121 (21%) died during the follow-up of 3647 person-years. A total of 64 (11%) of these deaths were of cardiovascular origin. Subsequently, we performed univariate Cox-regression analyses corresponding to the Kaplan–Meier curves presented in Figure 1. For mortality, HRs for the second and third age- and gender adjusted tertiles versus the first tertile were 1.18 (95% CI 0.72–1.94, p = 0.52) and 1.66 (1.03–2.67, p = 0.04) respectively. For cardiovascular mortality, HR for second tertile was 1.31 (0.63–2.76, p = 0.47) and 2.23 (1.12–4.47, p = 0.02 for the third tertile).


Figure 1. Total (121 events) and cardiovascular (64 events) mortality according to Kaplan–Meier analyses for age-adjusted, gender-stratified tertiles of EPO.*Significance tested with log rank test. Cut-off levels for tertiles of EPO were: tertile 1: EPO < 13.9 IU/L; tertile 2: EPO 13.4–22.4 IU/L; tertile 3: EPO 21.0–182.0 IU/L.

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Subsequently, Cox regression models were built for EPO levels as a continuous variable, with the determinants of EPO levels on univariate linear regression analysis and factors known to influence EPO levels or cardiovascular risk included to test whether inclusion of the factors in the model might alter the association between EPO and cardiovascular and total mortality (Table 3). The first was crude and in a second model, age and gender were added. The third model additionally contained hemoglobin, MCV and ferritin levels, while the fourth added instead significant determinants of inflammation; hsCRP and use of azathioprine and cyclosporine, in the fifth renal parameters were included, as known determinants of both mortality and EPO levels. The sixth model contained age, gender, waist circumference, triglyceride levels and classical Framingham risk factors (Table 3). Neither of the adjustments did materially change the significant association of EPO with outcome.

Table 3.  Cox regression analyses in cardiovascular and total mortality for EPO levels (per 10 IU/L increase)
 All-cause mortalityCardiovascular mortality
(121 events)(64 events)
  1. Model 1: Crude.

  2. Model 2: Adjustment for age and gender.

  3. Model 3: Model 2 plus adjustment for hemoglobin levels, MCV and log ferritin.

  4. Model 4: Model 2 plus adjustment for log hsCRP, use of azathioprine and cyclosporine.

  5. Model 5: Model 2 plus adjustment for creatinine clearance, proteinuria, use of diuretics and RAAS inhibition.

  6. Model 6: Model 2 plus adjustment for waist circumference, triglycerides and Framingham risk factors (smoking, diabetes, total cholesterol, HDL cholesterol and systolic blood pressure).

Model 11.13 [1.05–1.22]<0.0011.16 [1.05–1.27]<0.001
Model 21.15 [1.04–1.28]0.0051.20 [1.06–1.36]0.003
Model 31.16 [1.05–1.28]0.0031.21 [1.06–1.38]0.005
Model 41.13 [1.02–1.27]0.031.20 [1.05–1.37]0.006
Model 51.11 [1.01–1.23]0.051.15 [1.01–1.31]0.03
Model 61.16 [1.04–1.29]0.011.22 [1.06–1.40]0.005

Finally, EPO was a consistent determinant of both total and cardiovascular mortality in the forward and backward Cox regression analyses, independent of CRP, age, creatinine clearance, urinary protein excretion, presence of diabetes, use of MMF and smoking status (Table 4). The associated hazard ratio was comparable to that of CRP.

Table 4.  Forward and backward regression analysis, including all variables
 All-cause mortalityCardiovascular mortality
(121 events)(64 events)
HR (95% CI)p-ValueHR (95% CI)p-Value
Age (per year)1.07 (1.05–1.09)<0.0011.08 (1.05–1.11)<0.0001
Creatinine clearance (per mL/min/1.73 m2)0.97 (0.96–0.98)<0.0010.96 (0.94–0.98)<0.001
Protein excretion (per g/24 h)1.25 (1.08–1.43)0.003….…..
Diabetes (yes/no)1.74 (1.15–2.62)0.0082.17 (1.27–3.73)0.005
Use of MMF (yes/no)1.65 (1.09–2.49)0.022.84 (1.53–5.28)0.001
Smoking at any time (yes/no)1.70 (1.11–2.61)0.022.12 (1.17–3.87)0.01
EPO (per 10 IU/L)1.13 (1.02–1.25)0.031.17 (1.02–1.35)0.02
CRP (per doubling)1.11 (1.01–1.24)0.031.18 (1.02–1.37)0.02


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

In this study in 568 RTR we showed endogenous EPO levels to be associated with total and cardiovascular mortality. To our knowledge, this is the first study in renal patients to show that endogenous EPO levels are linked to worse outcome. Even after correction for hematopoietic, renal and inflammatory markers, EPO was significantly associated with mortality in this renal transplant population.

The role of EPO has been well established in both chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients, where substantial evidence from large cohort studies (4,5) has shown that correcting anemia, unless severe, with recombinant EPO (rHuEPO) is not beneficial and may in fact have strong adverse effects, which include increased risk for cardiovascular morbidity and mortality. The highest risk was seen in patients requiring the highest rHuEPo dosage, most likely reflecting resistance to EPO through inflammation (5). In line with these findings, we found increased risk for mortality in subjects with higher EPO levels. This may suggest EPO resistance plays a role in the increased risk for cardiovascular mortality in these subjects; however EPO levels predicted mortality independent of C-reactive protein, renal function, hematological parameters and classical cardiovascular risk factors, suggesting involvement of either EPO as such, or other pathways in the association between EPO and cardiovascular risk.

The fact that EPO was associated with mortality independent of CRP does not exclude a role for inflammation in the association between EPO and cardiovascular risk. There are several inflammatory pathways that do not necessarily include CRP (12). A link between EPO and cardiovascular risk can, however, also lie outside pathways involving chronic low grade inflammation. One of the most obvious of these potential pathways may be stimulation of aberrant angiogenesis with associated plaque rupture (13).

It is known that rHuEPO promotes angiogenesis (14). Angiogenesis may lead to unstable plaques via intraplaque hemorrhages, which in turn causes plaque instability (13) and may as such lead to thrombotic and hemorrhagic events. Remarkably, we also found a negative association between EPO levels and cholesterol levels in this study. Exogenous EPO is known to improve lipid abnormalities (15); how this may affect the process of plaque formation should be investigated.

Another potential pathway involved in the cascade between EPO, anemia, inflammation and mortality may be renal hypoxia. Both renal vascular dysfunction and decreased ejection fraction may cause renal hypoperfusion, leading to compensatory increased EPO production along with RAAS and sympathic nervous system activation with subsequent sodium and fluid retention, known as the cardiorenal axis, but angiotensin II activity may also upregulate EPO levels (16), which explains why EPO levels were negatively associated with use of RAAS inhibiting medication (17). As increased RAAS activity has been shown to be associated with cardiovascular risk (18), it remains unclear to what extent EPO plays a role in this cascade. In combination with RAAS inhibiting medication in native CKD, diuretics may lower EPO levels (17), possibly due to reduced oxygen demand via reduced sodium reabsorption. In variance, in the current RTR population diuretics were more often used by subjects with the highest EPO levels. This may partly be due to less use of RAAS inhibiting medication, whereby increased aldosterone levels stimulate oxygen consumption. Furthermore, it has been shown that in hypoxic kidney with reduced blood flow, diuretics do not decrease oxygen demand (19). Although information on renal blood flow was not available, GFR was reduced in subjects with highest EPO levels.

EPO levels were also associated with use of azathioprine and negatively with use of cyclosporine and hemoglobin levels. This may suggest the mild bone marrow suppression, caused by azathioprine, due to its antiproliferative effect, may give rise to a compensatory increase in EPO levels. A change in immunosuppressants to cyclosporine may reduce this bone marrow suppression and allow for restoration of EPO levels to normal values. Whether this indicates that EPO levels may be indicative of the extent of bone marrow suppression should be further investigated.

Furthermore, EPO levels were negatively associated with ferritin levels. Although ferritin depleted subjects were excluded from the analysis, ferritin was thus still a determinant of EPO levels, suggesting that the inhibiting effect of ferritin on erythropoiesis is still there, even when an absolute deficiency is not present. The association between MCV and EPO levels, however, suggests there may well be folate and vitamin B12 deficiencies, unfortunately data on folate and B12 were not available. The compensatory increased endogenous EPO levels may lead to thrombocytosis and thus to increased risk of thrombotic events.

Higher EPO levels may also affect cardiovascular risk through nonhematopoietic effects. rHuEPO may give rise to hypertension (20); in our study EPO levels were however not related to mean arterial pressure or the number of antihypertensives prescribed.

Thus, there is much unclear still about the mechanisms behind the association between EPO levels and cardiovascular disease. Nevertheless, EPO was independently associated with cardiovascular disease in RTR. Endogenous EPO levels may be helpful in identifying resistance to exogenous EPO, precluding inadvert use of exogenous EPO. Prospective interventional studies could help to address the possible underlying mechanisms, such as hypoxia, inflammation and angiogenesis.

The lack of data on baseline cardiac status, other than clinical assessment, is one of the main limitations of our study. Furthermore, data are observational and EPO levels were only measured at baseline. Repeated measurements could have improved power of our findings and could have elucidated the mechanisms behind the association between cardiovascular risk and EPO levels. Thus, this study looks at only a small part of the relationship between CVD, EPO and survival in RTR and would require more thorough prospective studies to support its major findings.

In conclusion, EPO levels were associated with overall and cardiovascular mortality in renal transplant recipients. Further research to elucidate underlying mechanisms in the association between EPO and mortality may help improve our understanding of the pathophysiology that explains the excess cardiovascular risk in this population.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. Part of the data from this study have been presented at the American Society of Nephrology Week 2011 in Denver, Colorado. No part of these data have been published previously in any paper or journal.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References