Impact of Anemia on Survival and Rejection After Renal Transplantation

Up to 30% of kidney transplant recipients suffer from anemia at some point after transplantation, and it has been proposed that this can contribute to adverse cardiovascular events. Studies have shown that during the early postoperative period, anemia is caused by blood loss, graft failure, or erythropoiesis-inhibiting drugs, whereas late post-transplantation anemia (PTA) is caused by renal dysfunction, immunosuppressive drugs, or infection. In addition, it has been shown that anemia at baseline significantly predicts mortality and graft failure in these patients. Despite this research, extensive studies on PTA have not been published. Therefore, a recent retrospective study was undertaken to examine the impact of PTA on patient and graft survival, and the rate of acute graft rejection.

This study by Chhabra et al included 1,023 patients who underwent kidney transplantation at a single center. Of these patients, 13% were found to be anemic by the study's hemoglobin (Hb) level definition (Hb < 11 g/dL). Based on multivariate models that considered gender, race, pre-transplant Hb level, donor age, and infections after transplant as variables, the study assessed the independent association of anemia and negative outcomes. At 90 days post-transplantation, the presence of anemia was significantly and independently associated with increased overall mortality, as well as increased rejection rates. In addition, Kaplan-Meier curves for graft survival and rate of rejection were significantly worse in anemic patients compared to nonanemic patients.

The results of this study suggest a greater likelihood of negative outcomes in patients with PTA, and the authors suggest some of the possible mechanisms of this association. Because anemia can contribute to cardiovascular disease such as left ventriclular hypertrophy and congestive heart failure, it is plausible that PTA could be a similar predictor of cardiovascular morbidity. In addition, the limited oxygen delivery to tissues when anemia is present could be a key reason for poorer graft survival rates. The pathogenesis of the temporal association between PTA and rate of rejection is more difficult to understand, but statistical significance remains even after adjustment for different post-transplant periods. Although this study was limited by retrospective analysis and a lack of patient family history, the findings are consistent with other related research and need to be further explored.

Impact of anemia after renal transplantation on patient and graft survival and on rate of acute rejection. Chhabra D, Grafals M, Skaro AI, Parker M, Gallon L. Clin J Am Soc Nephrol. 2008 Jul;3(4):1168-74.

NAAC Expert Commentary:
Anemia is a common feature in patients following kidney transplantation. The pathogenesis is multifactorial, with residual chronic kidney disease, blood loss, and the effects of immunosuppressive drugs likely contributing. It has been hypothesized that the morbid impact of anemia in transplant patients is similar to that in patients with CKD or those on dialysis. That is, that anemia patients would be more likely to have cardiovascular disease, higher hospitalization rates, and poorer survival. This study confirms the high frequency of anemia in this population and does highlight some of the associated poorer outcomes, as predicted. In addition, poorer graft survival is noted in the anemic patients as well as an increased rate of graft rejection.

Because this is a retrospective study, however, it is difficult to determine mechanisms of these associations. For example, is anemia causing these adverse outcomes or merely a marker of patients who are likely to have poorer outcomes? Only prosepective trials will be able to answer this question. Of equal importance is the issue of treatment of anemia and its impact on outcomes. With the availability of ESAs, treatment is not complex. Studies to determine if such treatment will result in better outcomes are sorely needed

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DRIVE II Examines Efficacy of IV Iron in Anemic Hemodialysis Patients

Erythropoiesis-stimulating agents (ESAs), such as epoetin (EPO), and iron must be present in patients with chronic kidney disease to produce red blood cells. Although administration of both is common in clinical practice, much controversy exists on how to manage dosages properly so risks do not exceed benefits. ESAs have recently been given a boxed warning by the U.S. Food and Drug Administration concerning targeting high hemoglobin (Hb) levels in patients. Thus, recent studies have examined ways in which intravenous iron administration can help lower EPO doses while still maintaining Hb levels. The Dialysis Patients Response to IV Iron with Elevated Ferritin (DRIVE) study showed that intravenous ferric gluconate was effective in improving anemia and stabilizing Hb levels. DRIVE-II-a 6-week extension study-was recently undertaken to investigate the effects of a 1-g course of intravenous ferric gluconate on Hb, transferrin saturation (TSAT), and serum ferritin.

In the DRIVE-II study, 112 of the 129 patients who participated in DRIVE were administered either intravenous iron (control) or intravenous ferric gluconate. At the end of the study, the ferric gluconate group showed a significant decrease in EPO doses compared to their initial DRIVE dose, whereas control group levels remained unchanged. Also, 23 patients in the control group did not receive intravenous iron, and these patients showed an increase in their EPO doses and no changes in Hb levels. Furthermore, Hb, TSAT, and serum ferritin levels were higher in the ferric gluconate group, suggesting that the 1-g administration had a sustaining effect after the initial DRIVE study.

The results of this study certainly indicate that administration of ferric gluconate allows patients to receive lower doses of EPO while sustaining the clinical effects. Some researchers have expressed concerns about the use of intravenous iron in patients with elevated ferritin, such as increased risk of infection and infectious complications. But, during the course of both DRIVE studies, fewer hospitalizations and adverse events were reported in the ferric gluconate group. However, the study was not sufficiently long or large enough to fully assess cardiovascular risks, and an unblinded knowledge of the treatment group may have influenced clinician treatment decisions. Further studies will be needed to better understand ESA and iron dosing strategies.

Ferric gluconate reduces epoetin requirements in hemodialysis patients with elevated ferritin. Kapoian T, O'Mara NB, Singh AK, Moran J, Rizkala AR, Geronemus R, Kopelman RC, Dahl NV, Coyne DW. J Am Soc Nephrol. 2008 Feb;19(2):372-9.

NAAC Expert Commentary:
The purpose of the DRIVE study and its six week extension, DRIVE II, was to determine the efficacy and safety of supplemental intravenous iron in anemic hemodialysis patients receiving recombinant erythropoietin who had a transferrin saturation <25% and a serum ferritin >500ng/mL. The intravenous iron group did increase their hemoglobin levels slightly more than control patients not given intravenous iron without additional toxicity, leading the authors to conclude that intravenous iron in this situation was both safe and effective. Unfortunately, the design and power of both studies were not sufficient for the investigators to reach these conclusions.

First, the decision to increase the dose of recombinant erythropoietin in each group by 25% confuses the response to ESA and iron. In a chronic inflammatory state, such as chronic renal disease, the problem is not impaired iron availability but insufficient erythropoietin, which is required to mobilize iron and upregulate transferrin receptor expression. It is well recognized that erythropoietin trumps hepcidin in this situation and the authors merely confirmed that phenomenon.

Second, in the control groups of both DRIVE and DRIVE II, there were a disproportionate number of women, who are more likely to be iron deficient, and their response to recombinant erythropoietin proved this, reducing the effectiveness of comparisons. Third, both DRIVE and DRIVE II were open label observational studies and in addition physician discretion was also allowed with respect to erythropoietin dosing and iron administration. This discretion can introduce significant bias, weakening the conclusions of the studies.

Fourth, no attempt to estimate blood loss, iatrogenic or otherwise, was made for either experimental group. Fifth, the difference in the hemoglobin level achieved with supplemental iron was not striking and also pushed the hemoglobin level above that currently recommended for safety reasons. Finally, since the serum ferritin and transferrin saturation increased in the iron-supplemented group, a state of iron overload was achieved that was unnecessary and the 12 week observation period was certainly not long enough to exclude the possibility of iron-induced organ toxicity.

It is clear that more data derived from larger prospective trials that are conducted for longer periods are needed. Until this data becomes available, anemic hemodialysis patients not responding to conventional doses of recombinant erythropoietin, in whom the serum ferritin is >500ng/mL, should first be evaluated for a source of blood loss or infection. Then the patient should be given a higher dose of recombinant erythropoietin for a minimum of 6 weeks with serial transferrin saturation and ferritin measurements before resorting to intravenous iron supplementation.