Inkidney transplant recipients, despite remarkable improvement

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1 Impact of Anemia after Renal Transplantation on Patient and Graft Survival and on Rate of Acute Rejection Darshika Chhabra,* Monica Grafals,* Anton I. Skaro,* Michele Parker, and Lorenzo Gallon* *Nephrology/Transplantation, Northwestern University, Chicago, Illinois; and Cardiology, Duke University, Durham, North Carolina Background and objectives: The impact of posttransplantation anemia on patient survival, renal allograft survival, and rate of acute rejection is not known. Design, setting, participants, & measurements: A total of 1023 patients who underwent kidney transplantation at one center from January 1992 through June 2003 were retrospectively analyzed. Posttransplantation anemia was defined as mean hemoglobin <11 g/dl after 3 mo after transplantation. Data on demographics, pretransplantation dialysis, previous transplant history, pretransplantation hemoglobin, degree of HLA mismatch, and donor characteristics were collected. Some of the posttransplantation data that were collected in addition to the hemoglobin included delayed graft function; diabetes; hypertension; induction and maintenance of immunosuppressive regimen; posttransplantation infections; and use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, statins, aspirin, and blockers. Cox regression models were used to assess the effects of posttransplantation anemia on each outcome: Mortality, graft survival, and rate of acute rejection. Median follow-up time was 4 yr. Results: During the entire follow-up period, there were 89 (9%) deaths, 143 (14%) acute rejection episodes, and 235 (23%) kidney losses. In multivariate Cox regression models, being anemic after transplantation, after the first 90 d, was associated with increased overall mortality and increased renal allograft loss. Posttransplantation anemia was also associated with increased acute rejection rates. Conclusions: This study shows that posttransplantation anemia is associated with worse patient and graft survival and higher rates of acute rejection when compared with nonanemic renal transplant recipients. Clin J Am Soc Nephrol 3: , doi: /CJN Inkidney transplant recipients, despite remarkable improvement in short-term results, long-term graft survival is still limited by death from cardiovascular events with functioning grafts and by progressive allograft dysfunction, now indicated as chronic allograft injury, which results in an annual rate of graft loss of 3 to 5% (1). With close to 5000 kidney transplants failing per year in the United States and with the recipient returning to dialysis, kidney transplant failure is a leading cause of ESRD and represents the second reason for starting renal replacement therapy (1,2). As much as 30% of kidney transplant recipients have chronic anemia, irrespective of the time from transplantation (3). In the early postoperative period, anemia is the consequence of blood loss, graft failure to generate enough erythropoietin, and drugs that inhibit bone marrow erythropoiesis (3 5). Late posttransplantation (post-tx) anemia (PTA) has been attributed to renal dysfunction, immunosuppressive drugs, antiviral agents, infections, and the use of angiotensin-converting enzyme inhibitors Received October 31, Accepted April 7, Published online ahead of print. Publication date available at Correspondence: Dr. Lorenzo Gallon, 675 N. St. Clair Galter Pavilion , Chicago, IL Phone: ; Fax: ; L-gallon@northwestern.edu (ACEI) (3,6). Despite few reports, the impact of PTA on patient survival, renal allograft survival, and the rate of acute rejection has not been extensively studied (7). Recently, it was shown that in kidney transplant recipients, anemia at baseline significantly predicted mortality and graft failure during 4 yr follow-up (8,9), raising the possibility that anemia contributes to chronic allograft injury and eventually limits longterm graft outcome. Furthermore, the presence of anemia (defined as hemoglobin [Hb] 12 g/dl) at 3 mo after tx was found to be an independent risk factor for being anemic at 1 yr after tx (10). In renal tx patients, cardiovascular disease (CVD) is the leading cause of death, particularly in the perioperative period (11). Anemia leads to left ventricular hypertrophy and congestive heart failure, which may contribute to increased mortality as a result of cardiovascular events in renal transplant recipients (12,13). To examine further the clinical impact of PTA on renal transplant patients, we designed the following large, singlecenter, retrospective study with the aims to evaluate (1) incidence of PTA after 3 mo and (2) association between anemia and patient survival, graft survival, and rate of acute rejection. Materials and Methods Study Design and Patients This was a single-center, retrospective study of 1023 patients who underwent kidney transplantation at our transplant center between Copyright 2008 by the American Society of Nephrology ISSN: /

2 Clin J Am Soc Nephrol 3: , 2008 Impact of Anemia on Renal Transplant Outcomes 1169 January 1992 and June The institutional review board of Northwestern University (Chicago, IL) approved the study. Patients with multiorgan transplants and those with incomplete or unavailable charts were excluded. We also excluded recipients who died or had graft loss before 90 d after tx. Mean follow-up after tx was yr with a median of 4.0 yr. Anemia Definition Because Hb levels after tx may take a few months to stabilize, we defined PTA as mean Hb 11 g/dl after 3 mo after tx. We measured post-tx Hb weekly for the first month, then at 1, 3, 6, and 12 mo and every 6 mo thereafter. We excluded the first 3 mo after tx to avoid the early post-tx fluctuation of Hb as a result of intraoperative blood loss and of significant fluid shifts that occur early after tx. Our definition of PTA was arbitrary, but we took into consideration the criteria for anemia in both men and women with chronic kidney disease (CKD) in dialysis and nondialysis patients as defined by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines, the American Society of Transplantation guidelines, and the Revised European Best Practice guidelines (14 16) and from the recent publication of two studies (Correction of Hemoglobin and Outcomes in Renal Insufficiency [CHOIR] and Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin [CRE- ATE]) (17,18) that examined the impact of anemia correction with erythropoietin on cardiovascular mortality in patients with CKD. Specifically, according to the 2007 updated National Kidney Foundation K/DOQI guidelines, in dialysis and nondialysis patients who have CKD and receive erythropoietin-stimulating agent (ESA) therapy, the selected Hb target should generally be in the range of 11.0 to 12.0 g/dl and definitely not 13 g/dl. This guideline is not gender specific (14). In the transplant population, per the American Society of Transplantation, anemia is defined as 13 g/dl in men and 12 g/dl in women (15); however, in the CKD population and as per the Revised European Best Practice guidelines for anemia in renal tx, a Hb level of 11 g/dl should trigger treatment with ESA (16). This cutoff of 11 g/dl was also used in previous studies that evaluated anemia on renal transplant outcomes, facilitating easier comparison between studies (8). Immunosuppression Maintenance immunosuppression consisted of tacrolimus or cyclosporine (CsA). Tacrolimus (Prograf, Astellas Pharma US, Inc., Deerfield, IL) was started on postoperative day 1. Target 12-h trough levels for tacrolimus were 8 to 10 ng/ml during the first 3 mo, 7 to 9 ng/ml from 4 to 6 mo after tx, and 6 to 8 ng/ml thereafter. CsA was also started on postoperative day 1. Target 12-h trough levels for CsA were 200 to 300 ng/ml during the first 3 mo, 150 to 250 ng/ml from 4 to 6 mo after tx, and 100 to 150 ng/ml thereafter. Mycophenolate mofetil (MMF; Cellcept, Roche Pharmaceuticals, Nutley, NJ) was used in 81% of the patients, and it was started on postoperative day 1 with a target dosage of 2.0 g/d. Azathioprine (Imuran, Prometheus Laboratories Inc., San Diego, CA) was used in 23% of the patients, and it was started on postoperative day 1 with a target dosage of 150 mg/d. Dosages of both drugs were adjusted as indicated for leukopenia. Sirolimus (Rapamycin, Wyeth Pharmaceuticals Inc., Madison, NJ) was used only in 4% of the patients. Induction therapy for all patients consisted of perioperative intravenous corticosteroid therapy with methylprednisolone 500 mg on day 0, 250 mg on day 1, and 125 mg on day 2. From 1992 through 1999, patients were maintained on long-term prednisone (dosage between 5.0 and 7.5 mg/d) throughout the post-tx period. From 1999 through 2003, patients were maintained without the use of long-term prednisone. Furthermore, induction therapy also consisted of one of the following: Anti IL-2 receptor antagonist Basiliximab at day 0 and day 2 at the dosage of 20 mg intravenously; rabbit antithymocyte -globulin (Thymoglobulin, Genzyme Corp., Cambridge, MA) at a dosage of 1.0 to 1.5 mg/kg intravenously starting intraoperatively and infused daily for 3 to 7 d; anti-cd3 mab (OKT3, Ortho Biotech Products LP, Bridgewater, NJ) given as a 5-mg intravenous push as initial dose, followed by 2.5 mg/d intravenously for 5 to 7 d; or anti-cd52 (Alemtuzumab, Bayer HealthCare Pharmaceuticals, Wayne, NJ), given as a 30-mg intravenous push intraoperatively as a single dose. Outcomes Outcomes of the study were patient and graft survival and incidence of acute renal allograft rejection during the post-tx period. All rejection episodes were biopsy proven. Graft loss was defined as return to dialysis. Rejection Monitoring and Treatment Acute cellular rejections were suspected by unexplained serum creatinine elevation. Whenever possible, suspected acute rejection was confirmed by percutaneous renal transplant biopsy before starting antirejection therapy. A total of 95% of our patients underwent renal allograft biopsy to make the diagnosis of acute rejection. Rejections were treated with methylprednisolone 500 mg intravenously for 3 d followed by a 1-wk course of prednisone taper for mild acute rejection or with an antilymphocyte antibody therapy (Thymoglobulin or OKT3) for 7 to 10 d for more severe grades. No specific immunosuppressive therapy or modification of the immunosuppressive regimen was offered to patients with biopsy-proven chronic rejection. Renal Allograft Function Measurement GFR was estimated (egfr) at different time points after tx (weekly for the first month, then at 1, 3, 6, and 12 mo and every 6 mo thereafter), using the abbreviated Modification of Diet in Renal Disease (MDRD) equation (19). Antibiotic Prophylaxis Cytomegalovirus (CMV) prophylaxis for patients who underwent tx from 1992 through 1997 consisted of 12 wk of acyclovir. From 1997 through 2002, CMV prophylaxis for seronegative and seropositive patients who received a kidney from a CMV-positive donor consisted of oral ganciclovir 1000 mg orally three times daily for 6 mo after tx. After 2002, all CMV-seronegative and -seropositive patients who received a kidney from a CMV-positive donor were treated with CMV prophylaxis with valganciclovir 900 mg orally once daily for 6 mo. Seronegative recipients of a kidney from a CMV-negative donor did not receive CMV prophylaxis. Prophylactic therapy for Pneumocystis carinii pneumonia was administered to all patients for up to 1 yr after tx. For fungal prophylaxis, patients were given oral clotrimazole or nystatin for 3 mo after tx. Covariates We collected data on recipient age, gender, race (white, black, Asian, Hispanic, or other), modality and duration of pre-tx dialysis, previous tx history, pre-tx Hb and hematocrit, degree of HLA mismatch, and donor characteristics such as donor age and type of tx (living or deceased). Some of the post-tx data that we collected in addition to the Hb, hematocrit, and egfr included delayed graft function (DGF); diabetes; hypertension; induction and maintenance immunosuppressive regimen; use of ACE/angiotensin receptor blocker (ARB), statins, aspirin, and blockers; and the development of any infection after tx.

3 1170 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: , 2008 Statistical Analysis Two-sample t test was used to compare differences in continuous variables between the two groups (with and without PTA). 2 test was used to compare differences in discrete variables. Cox regression models were used to assess the effects of PTA on each outcome: Patient survival, graft survival, and rate of acute rejection. Factors that were significantly different between the groups and that are likely to affect outcome were adjusted for in the multivariate model. P 0.05 was considered significant. Times from transplantation to each outcome were modeled using Kaplan-Meier analyses, and a Kaplan- Meier curve was generated. Results A total of 1023 renal transplant recipients were included in the analysis. Median follow-up time was 4 yr. Mean pre-tx Hb was 11.6 g/dl, with 361 (35%) being anemic. Mean Hb after 90 d after tx ranged from 7.3 to 18.5, with a mean Hb of 12.8 g/dl. Of the 1023 patients, 136 (13%) were found to be anemic after tx by our definition of anemia (Hb 11g/dl). During the period after 90 d after tx, there were 89 (9%) deaths, with 143 (14%) acute rejection episodes and 235 (23%) kidney losses. Patient Characteristics There were no significant differences in patients with and without PTA in regard to pre-tx dialysis; duration and type of dialysis; donor type; degree of HLA mismatch; percentage of patients with diabetes; percentage of patients with hypertension; type of maintenance immunosuppression (except for MMF and prednisone); type of induction therapy; and use of ACE/ARB, statins, aspirin, and blockers (Table 1). The PTA group tended to be younger ( versus ; P 0.05), be more likely to be female (63 versus 37%; P ), be nonwhite (53 versus 41%; P 0.009), have older donors ( versus ; P ), be anemic before tx (46 versus 34%; P 0.003), have DGF (32 versus 23%; P 0.027), be less likely to be on MMF (71 versus 83%; P 0.001), be more likely to be on prednisone (77 versus 65%; P 0.005), have higher rates of infection (57 versus 37%; P ), have lower egfr ( versus ; P ), have higher rates of rejection (24 versus 12%; P ), have higher rates of allograft loss (43 versus 20%; P ), and have higher mortality rates (15 versus 8%; P ). Multivariate Analyses To assess the independent association of anemia and negative outcomes, we built multivariate models. All variables that showed significant association with the outcome measures in the univariate Cox models were considered for inclusion in the multivariate models. Accordingly, male gender, race, pre-tx Hb, DGF, donor age, MMF use, prednisone use, mean egfr, and infections after tx were the covariables entered into the multivariate Cox proportional hazards models in addition to the presence of anemia. On the basis of these models, we found that the presence of anemia in the period 90 d after tx was significantly and independently associated with increased overall mortality (hazard ratio [HR] 3.18; 95% confidence interval [CI] 1.74 to 5.82; P ) and increased renal allograft loss (HR 2.67; 95% CI 1.85 to 3.85; P ). PTA was also associated with increased acute rejection rates (HR 1.78; 95% CI 1.11 to 2.84; P ; Table 2). Patient and Graft Survival According to Post-tx Hb Level Kaplan-Meier patient and graft survival curves, covariate adjusted, were statistically different and significantly worse in the anemic group than among the nonanemic group. Mortality occurred in 15% of the anemic group versus 8% of the nonanemic group (P ; Figure 1). Renal allograft loss occurred in 43% of the anemic group versus 20% of the nonanemic group (P ; Figure 2). Acute Rejection Rate Kaplan-Meier curve, covariate adjusted, for rate of rejection during the post-tx period was significantly worse in the anemic group compared with the nonanemic group (24 versus 12%, respectively; P ; Figure 3). Discussion This study shows that PTA (mean Hb 11 g/dl in the period after 3 mo after tx) is associated with worse patient and graft survival and higher rates of acute rejection when compared with nonanemic renal transplant recipients. After controlling for several covariables, renal transplant patients with PTA had 3.18 times higher chance of dying, 2.67 times higher chance to lose their renal allograft, and 1.78 times higher chance to develop acute rejection compared with patients with no anemia after tx. Our findings are consistent with a recent report by Molnar et al. (8), who, in a prospective cohort study, found that anemia at baseline significantly predicted mortality and graft failure over 4 yr follow-up and with two retrospective studies that demonstrated that PTA at 12 mo (defined as Hb 12 g/dl) was associated with decreased patient and graft survival (10) and that lower Hb was associated with adverse outcomes, including mortality and graft loss in renal tx patients (20). We also identified direct associations between PTA and older donor age and DGF, as well as an inverse relationship with male gender, as described previously (21,22). Contrary to other studies, we did not find an association between PTA and the use of MMF (10) and the use of ACE or ARB (22). Possible explanations for this discrepancy in our study are that the majority of our patients were on MMF and that only 25% were taking ACE or ARB. The use of ACE/ARB was scattered throughout the cohort, and there was no significant difference in the proportion of patients in the anemic and nonanemic group on ACE/ARB in our study (Table 1). In our study, a greater proportion of patients in the anemic group were on prednisone compared with the nonanemic group. Previous studies observed increased anemia in the steroid-free group early after tx; however, this usually normalizes later on in the post-tx period, probably as a result of an increase in ESA use. Similarly, confounding by increased ESA use in the MMF group may account for the lack of the association between PTA and the use of MMF in our study. In our study, we collected all of the information on many of the key issues that are known to be predictive of post-tx out-

4 Clin J Am Soc Nephrol 3: , 2008 Impact of Anemia on Renal Transplant Outcomes 1171 Table 1. Comparison of patients with and without PTA (Hb 11 g/dl) a Parameter Hb 11 (n 887) Hb 11 (n 136) P Hb after tx (g/dl; mean SD) Age (yr; mean SD) Male gender (n % ) 555 (63) 50 (37) White race (n % ) 523 (59) 64 (47) Pre-tx dialysis (n % ) 719 (83) 113 (88) Duration on dialysis (yr; mean SD) Dialysis type (HD; n % ) 562 (78) 85 (75) Donor type (living; n % ) 709 (80) 117 (86) Donor age (yr; mean SD) HLA mismatch (mean SD) Hb pre-tx (mean SD) Anemia pre-tx (n % ) 298 (34) 63 (46) DGF (n % ) 178 (23) 39 (32) Induction IL-2-RA (n % ) 266 (30) 38 (28) Induction (Thymoglobulin or OKT3; n % ) 487 (55) 71 (52) Induction (Alemtuzumab; n % ) 133 (15) 27 (20) MMF prescription (n % ) 735 (83) 97 (71) Tacrolimus prescription (n % ) 538 (61) 89 (65) Tacrolimus (trough levels; ng/ml; mean SD) Sirolimus prescription (n % ) 38 (4) 10 (7) Sirolimus (trough levels; ng/ml; mean SD) CsA prescription (n % ) 333 (38) 48 (35) CsA (trough levels; ng/ml; mean SD) Azathioprine prescription (n % ) 211 (24) 27 (20) Prednisone prescription (n % ) 558 (65) 103 (77) ACE/ARB prescription (n % ) 212 (24) 34 (25) Statin prescription (n % ) 264 (33) 33 (26) Aspirin prescription (n % ) 229 (26) 34 (25) blocker prescription (n % ) 463 (53) 74 (55) Any infection (n % ) 302 (37) 72 (57) Diabetes (n % ) 167 (19) 23 (17) Hypertension (n % ) 487 (55) 73 (54) egfr (MDRD) (mean SD) Acute rejection (n % ) 110 (12) 33 (24) Renal allograft loss (n % ) 177 (20) 58 (43) Death (n % ) 69 (8) 20 (15) a ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CsA, cyclosporine; DGF, delayed graft function; egfr, estimated GFR; Hb, hemoglobin; MDRD, Modification of Diet in Renal Disease; MMF, mycophenolate mofetil; PTA, posttransplantation anemia. come, including HLA mismatch; incidence of DGF; years on dialysis before tx; donor characteristics; percentage of patients with diabetes; hypertension; rate of infections; rate of acute rejections; and use of medications that can potentially have a positive impact on post-tx outcome such as aspirin, blockers, ACEI, and statins. It is important to point out that some of this information such as race; dialysis modality before tx; donor characteristics; degree of HLA mismatch; development of DGF; induction and maintenance immunosuppression; and use of medications such as ACE/ARB, statins, aspirin, or blockers was not collected in the study by Molnar et al. (8), and this was one of the limitations of their observation. Multiple possible explanations can account for the association among anemia, increased mortality, increased rate of renal allograft loss, and increased rate of acute rejection. In renal tx patients, similar to dialyzed patients, CVD is the leading cause of death (11,12). In the National Kidney Foundation K/DOQI clinical guidelines for anemia in CKD, anemia is recognized as being associated with increased cardiovascular morbidity, impaired cognitive ability, and reduced quality of life in patients with ESRD (14). In predialysis patients, anemia has been identified as an independent risk factor for progression to kidney failure (23), and the treatment of anemia with erythropoietin has been associated with slower decline of kidney function (24). Anemia leads to left ventricular hypertrophy and congestive heart failure, which contributes to increased

5 1172 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: , 2008 Table 2. Covariate adjusted analysis of association of PTA and mortality, graft loss, and acute rejection a Variable Mortality Graft loss Acute Rejection P HR 95% CI P HR 95% CI P HR 95% CI Mean Hb 11 ( 90 d after tx) to to to 2.84 Male gender to to to 2.24 White Race to to to 0.76 Donor age to to to 1.01 Hb Pre-Tx to to to 1.12 DGF to to to 1.41 MMF prescription to to to 2.76 Prednisone prescription to to to 1.94 Mean GFR ( 90 d after tx) to to to 0.97 Infections to to to 1.85 a CI, confidence interval; HR, hazard ratio. Figure 1. Cumulative patient survival in anemic versus nonanemic group up to 9 yr after transplantation (tx). The Kaplan- Meier curves, covariate adjusted, are statistically different (P ). Hgb, hemoglobin. Figure 2. Cumulative renal allograft survival in anemic nonanemic group up to 9 yr after tx. The Kaplan-Meier curves, covariate adjusted, are statistically different (P ). mortality as a result of cardiovascular events (11 13). It is therefore reasonable that the presence of anemia is a predictor of negative outcome in renal transplant recipients. In our study, mean egfr after tx was not significantly associated with increased mortality (Table 2). It is possible that the subset of patients with the most severe degree of renal allograft dysfunction (and thus at greatest risk for developing CVD) returned to dialysis, did not have follow-up in the transplant clinic, and thus were not included in our final analysis. Anemia in chronic allograft injury may accelerate the decline in renal function by limiting oxygen delivery to tissues, particularly to the tubulointerstitium (25). In turn, hypoxia contributes to the formation of reactive oxygen species, which adds further insult to renal tissues and induces the release of proinflammatory molecules that recruit inflammatory cells into the interstitium (25). It is also notable that chronic hypoxia and oxidative stress are profibrogenic stimuli for tubular cells and interstitial fibroblasts (26), eventually representing a common pathway to the progression to ESRD (25). In transplant recipients, the hypoxic damage may be potentiated by the use of immunosuppressive agents, particularly calcineurin inhibitors, and by the concomitant presence of congestive heart failure, which reduces renal blood flow (27). The possibility that anemia may accelerate kidney allograft damage by limiting oxygen delivery was recently tested by correcting anemia with erythropoietin in a rat model of chronic renal allograft injury (Gallon et al., manuscript submitted). In this study, we demonstrated that long-term administration of erythropoietin, at a dosage that fully corrected PTA, preserved proximal tubular cell structure, promoted tubular cell survival, and limited tubulointerstitial and glomerular damage. As a result of the retrospective design of our study, it is difficult to establish a temporal relationship between anemia and acute rejection rates. In an attempt to address this, we analyzed patients who experienced rejection more than 90 d after tx, and instead of looking at the mean Hb for the entire

6 Clin J Am Soc Nephrol 3: , 2008 Impact of Anemia on Renal Transplant Outcomes 1173 Figure 3. Acute rejection episodes in anemic versus nonanemic group up to 9 yr after tx. The Kaplan-Meier curves, covariate adjusted, are statistically different (P ). period after 90 d after tx, we used the mean Hb level for the period before each rejection episode. For the patients who did not experience rejection, the mean Hb for the entire period 90 d after tx was used. Using this method, although the rejection rate in the anemic group was slightly lower than in the original analysis, the difference still remained statistically significant. Mean Hb in the period before the acute rejection episode was associated with 21% acute rejection episodes compared with 13% in the nonanemic group (P 0.009). Our study has several limitations, and the results should be interpreted with caution. One important limitation is in the intrinsic design of the study. Our data, in fact, were collected retrospectively, as has been the case with other studies in this area. A second important limitation is that, although we collected and examined most of the traditional risk factors for CVD, we lacked information regarding family history of CVD, tobacco use, and pre- and post-tx body mass index. At the same time, our findings are consistent with recently published data, and further investigation on this subject is needed with appropriate clinical trials to establish a uniform consensus for the definition of PTA and evaluate whether treatment of PTA can improve renal transplant patient outcomes. Conclusions Our study shows that PTA (mean Hb 11 g/dl in the period after 3 mo after tx) is associated with worse patient and graft survival and higher rates of acute rejection when compared with nonanemic renal transplant recipients. Acknowledgments Part of this study was supported by a generous donation from D. Gray and B. Gray. Disclosures None. References 1. Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, Birk PE, Campbell PM, Cascalho M, Collins AB, Demetris AJ, Drachenberg CB, Gibson IW, Grimm PC, Haas M, Lerut E, Liapis H, Mannon RB, Marcus PB, Mengel M, Mihatsch MJ, Nankivell BJ, Nickeleit V, Papadimitriou JC, Platt JL, Randhawa P, Roberts I, Salinas-Madriga L, Salomon DR, Seron D, Sheaff M, Weening JJ: Banff 05 Meeting Report: Differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy ( CAN ). Am J Transplant 7: , Halloran PF, Langone AJ, Helderman JH, Kaplan B: Assessing long-term nephron loss: Is it time to kick the CAN grading system? Am J Transplant 4: , Shah N, Al-Khoury S, Afzali B, Covic A, Roche A, Marsh J, Macdougall IC, Goldsmith DJ: Posttransplantation anemia in adult renal allograft recipients: Prevalence and predictors. Transplantation 81: , Kessler M: Erythropoietin and erythropoiesis in renal transplantation. Nephrol Dial Transplant 10: , Goch J, Birgegard G, Wikstrom B, Tufveson G, Danielson BG: Serum erythropoietin levels in the immediate kidneyposttransplant period. Nephron 60: 30 34, Afzali B, Al-Khoury S, Shah N, Mikhail A, Covic A, Goldsmith D: Anemia after transplantation. Am J Kidney Dis 48: , Yorgin PD, Scandling JD, Belson A, Sanchez J, Alexander SR, Andreoni KA: Late post-transplant anemia in adult renal transplant recipients: An under recognized problem? Am J Transplant 2: , Molnar MZ, Czira M, Ambrus C, Szeifert L, Szentkiralyi A, Beko G, Rosivall L, Remport A, Novak M, Mucsi I: Anemia is associated with mortality in kidney transplanted patients: A prospective cohort study. Am J Transplant 7: , Locatelli F, Pisoni RL, Combe C, Bommer J, Andreucci VE, Piera L, Greenwood R, Feldman HI, Port FK, Held PJ: Anemia in hemodialysis patients on five European countries: Association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 19: , Imoagene-Oyedeji AE, Rosas SE, Doyle AM, Goral S, Bloom RD: Posttransplantation anemia at 12 months in kidney recipients treated with mycophenolate mofetil: Risk factors and implications for mortality. J Am Soc Nephrol 17: , Ponticelli C, Villa M: Role of anaemia in cardiovascular mortality and morbidity in transplant patients. Nephrol Dial Transplant 17: 41 46, Rigatto C, Parfrey P, Foley R, Negrijn C, Tribula C, Jeffery J: Congestive heart failure in renal transplant recipients: Risk factors, outcomes, and relationship with ischemic heart disease. J Am Soc Nephrol 13: , Rigatto C, Foley R, Jeffery J, Negrijn C, Tribula C, Parfrey P: Electrocardiographic left ventricular hypertrophy in renal transplant recipients: Prognostic value and impact of blood pressure and anemia. J Am Soc Nephrol 14: , National Kidney Foundation-KDOQI clinical practice guideline and clinical practice recommendations for ane-

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