| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Renal Transplantation |
* Nephrology/Transplantation, Northwestern University, Chicago, Illinois; and Cardiology, Duke University, Durham, North Carolina
Correspondence: Dr. Lorenzo Gallon, 675 N. St. Clair Galter Pavilion 17-200, Chicago, IL 60611. Phone: 312-695-4457; Fax: 312-695-9194; E-mail: L-gallon{at}northwestern.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionConclusionsDisclosuresReferences |
|---|
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 β 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.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsDisclosuresReferences |
|---|
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 (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 long-term 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, single-center, 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 |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsDisclosuresReferences |
|---|
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 β [CREATE]) (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 β blockers; and the development of any infection after tx.
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 |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsDisclosuresReferences |
|---|
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 β blockers (Table 1). The PTA group tended to be younger (42 ± 13.1 versus 44.2 ± 12.5; P = 0.05), be more likely to be female (63 versus 37%; P < 0.0001), be nonwhite (53 versus 41%; P = 0.009), have older donors (42.6 ± 14.8 versus 37.1 ± 13.6; P < 0.0001), 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 < 0.0001), have lower eGFR (39.4 ± 17 versus 54.6 ± 17.4; P < 0.0001), have higher rates of rejection (24 versus 12%; P = 0.0002), have higher rates of allograft loss (43 versus 20%; P < 0.0001), and have higher mortality rates (15 versus 8%; P = 0.0076).
|
|
|
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsDisclosuresReferences |
|---|
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 outcome, 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, β 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 β 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 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 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 |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsDisclosuresReferences |
|---|
|
Disclosures |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsDisclosuresReferences |
|---|
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received October 31, 2007. Accepted April 7, 2008.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsDisclosuresReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  J. Wilflingseder, A. Kainz, P. Perco, R. Korbely, B. Mayer, and R. Oberbauer Molecular predictors for anaemia after kidney transplantation Nephrol. Dial. Transplant., March 1, 2009; 24(3): 1015 - 1023. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
