Long-term Outcomes of Kidney Transplant Patients with Anemia

Anemia is commonly associated with patients who have received kidney transplants, although few patients in this population with anemia receive erythropoietin treatment. Some studies have claimed that such under-treatment may lead to adverse outcomes such as mortality and cardiovascular problems. However, no current evidence points to such risks in kidney transplant recipients (KTR). Recently, two well-studied cohorts of KTR were merged together to examine the association of anemia and patient outcome, as well as assess the presence of anemia as a main study exposure.

The patient population included one cohort of 438 stable KTR from a 1995 study examining anemia and iron status and another cohort of 733 KTR from a 1996-98 study that explored the prevalence and correlates of homocysteine in KTR. All patients involved in these studies received a comprehensive baseline assessment, which included participants age, gender, underlying kidney disease, and number of procedures since transplantation. After merging the cohorts, a total of 825 KTR were examined. The presence of anemia was assessed using the hemoglobin concentration definition recommended by the American Society of Transplantation (less than or equal to 12 g/dL for women, less than or equal to 13 g/dL for men). Statistical analyses examined baseline characteristics compared to KTR with or without anemia. Univariate and multivariate hazard models described relationships between the outcomes of interest, which were all-cause mortality and kidney allograft loss.

The cohorts were followed longitudinally for a median of 8.2 years; 251 patients died and 401 kidney allografts were lost. In an analysis of increasing hemoglobin relationships (less than or equal to 10 g/dL was used as a reference group), multivariate models found no association between hemoglobin concentrations and all-cause mortality. In contrast, an examination of increasing hemoglobin concentrations revealed lower rates of allograft loss in patients with higher hemoglobin concentrations, even after multivariate adjustment.

This study confirms the results of some recent studies in which anemia was not associated with all-cause mortality. The current study used the largest cohort to date to examine this association, containing nearly twice as many patients with even longer follow-up. The study raises some interesting questions regarding an association between increased kidney allograft loss and lower hemoglobin. More studies need to be done, though, to determine if this association is affected by underlying inflammatory responses or other unmeasured factors. Furthermore, more rigorous testing is required to assess new potential erythropoietin therapies and their effects on anemic patients.

Please reference the source article:
A prospective study of anaemia and long-term outcomes in kidney transplant recipients. Winkelmayer WC, Chandraker A, Alan Brookhart M, Kramar R, Sunder-Plassmann G. Nephrol Dial Trans. 21(12):3559-66, 2006 Dec.

NAAC Expert Commentary:
The authors present us with evidence that anemia in kidney transplant recipients is not associated with increased mortality. This runs counter to the multitude of observational studies performed in end stage renal disease (ESRD) patients showing increased mortality with decreasing hemoglobin. Approximately 14,000 kidney transplants are performed each year in the United States and remain the preferred method of treatment for ESRD. Concern in the general nephrology subspecialty about treatment end points of anemia has raised awareness as to which guidelines to pursue.

This study accurately represents the renal transplant population as it pertains to anemia. In the prospective cohort of 825 kidney transplant recipients, 41.1% of recipients were anemic, which is comparable to current published data. Analysis of the outcomes of these patients stratified by hemoglobin level, using both multivariant and univariant analysis, showed no increased mortality with decreasing hemoglobin. Of interest was the increasing probability of graft loss with decreasing renal function. This association suggests that subclinical or clinical rejection, unknown inflammatory processes, or both, may be responsible for anemia in these patients.

Clinical Guidelines and Evidence-based Management of Anemia in Cancer Patients

The use of erythropoiesis stimulating agents (ESAs) has provided significant therapeutic benefits to patients suffering from cancer-related anemia. Though ESAs have been shown to effectively restore hemoglobin levels and improve patient quality of life, some variable treatment outcomes have spurred organizations such as the European Society for Research and Treatment of Cancer (EORTC) to propose evidence-based guidelines to improve clinician diagnosis and treatment. An emerging method to match clinical practice with established guidelines is to design computerized systems based on patient data. The RESPOND system, a web-based clinical guidance system, is the focus of a recent study analyzing the impact of evidence-based guidelines on patient care.

To test whether the RESPOND system produced effective, evidence-based guidelines, a two-step validation process was undertaken. First, a panel of physicians and nurses with significant clinical and scientific experience in cancer-related anemia rated the accuracy of the EORTC-based algorithms developed for the RESPOND system. If an algorithm was judged to be accurate, it will indicate a reliable analysis model, as well as an adequate guideline. Second, a cohort of adult cancer patients with anemia will be examined in a clinical trial. The trial will compare clinician practice patterns with EORTC guidelines in groups that used RESPOND versus groups that did not use RESPOND. For each patient, a congruence score will be given which quantifies anemia assessment, management, and outcome according to EORTC guidelines.

Currently, the first step of the RESPOND validation trial has been completed. After one round of review, all but 5 algorithms were approved by the review panel, and after a follow-up revision, a consensus was reached unanimously on all algorithmic definitions. Step 2, the assessment of the congruence of clinical practice patterns with EORTC guidelines, is still in progress. Obviously, exploring the clinical value of the RESPOND system with an observational study or a cluster randomized controlled trial is an essential next step. However, many ethical questions need to be addressed before subjecting patients to clinical care based on the guidance of a decision-support tool that is not yet fully tested. More studies need to be done in regards to ESA dosing, as well as how accurately a computer system like RESPOND reflects the complexities of clinical treatment decisions. Furthermore, patient preferences in planning care must be considered, especially in the area of informed consent in evidence-based studies.

Please reference the source article:
Promoting evidence-based management of anemia in cancer patients: Background, development, and scientific validation of RESPOND, a web-based clinical guidance system based on the EORTC guidelines. Aapro M, Man Erps J, Macdonald K, Soubeyran P, Turner M, Muenzberg M, Dunlop R, Warrinnier H, Abraham I. Crit Rev Oncol Hematol. 2007 Jun 12.

NAAC Expert Commentary:
The administration of erythropoietic stimulating agents (ESAs) in patients with cancer and chemotherapy-related anemia may present some risks, including deep vein thrombosis, pulmonary embolism and possibly enhanced tumor growth. To minimize these potential complications, it is important to administer ESAs within the restriction of professional guidelines. The assessment of guidelines adherence is a formidable challenge. Aapro and other investigators of the EORTC have generated a computer system that may guide the use of ESAs according to the EORTC guidelines. This article describes research to develop the program, called RESPOND.

This approach is undoubtedly very interesting for the treatment of anemia in neoplastic and also non-neoplastic diseases (such as renal failure); if successful, it might be extended to the application of virtually all forms of treatment guidelines. However, until the program has been validated – the process of validation is ongoing – and the results are available, no definite statement on the value of RESPOND may be issued. Nonetheless, this approach is certainly meritorious and the results of the ongoing research are anxiously awaited since RESPOND has the potential to simplify and render more effective the practice of medicine.

Hypochromic erythrocytes as marker and predictor in myeloma and lymphoma patients

Anemia of chronic disease (ACD) has been associated with the occurrence of anemia in patients with myeloma and lymphoma, and is characterized by an insufficient production of erythropoietin that can lead to iron-restricted erythropoiesis (IRE). Although administration of recombinant human erythropoietin (rHuEPO) has shown to be an effective means of treating anemia, a significant frequency of unresponsive patients has led to questions about the value of predictive models and their ability to predict rHuEPO responsiveness. However, a recent study has shown that hypochromic erythrocytes (HYPO%) are promising predictors of functional iron deficiency (FID) and erythrocyte hemoglobinization (EH). This study examined the effectiveness of biochemical and hematological markers in recognizing IRE and FID, as well as predicting rHuEPO responses and recognizing patients who could benefit from IV iron coadministration.

In the study, 41 patients (20 men and 21 women) were subcutaneously administered rHuEPO-beta at 10,000 IU or 30,000 IU once weekly for 6 weeks. If patients responded, rHuEPO was discontinued. Patients who did not respond received 200 mg of IV iron sucrose in addition to rHuEPO once weekly for 4 weeks. HYPO% levels, as well as an array of other markers were measured at baseline and after 1, 2, and 6 weeks of rHuEPO administration. Parameters were also measured for non-responders on weeks 7, 8, 9, and 10.

Of the 41 patients enrolled in the study, 27 (65.8%) responded to rHuEPO, while 10 of 12 (83.3%) non-responders responded after 4 weeks of IV iron sucrose; of the original 14 non-responders, 2 patients did not comply. Univariate analysis indicated that HYPO% is an independent predictive marker of response to rHuEPO in those who initially responded to rHuEPO, as well as those who responded after 4 weeks of IV iron sucrose administration. In addition, HYPO% showed a clear superiority to traditional IRE markers such as serum ferritin and TSAT% in regards to sensitivity, specificity, and accuracy.

These results could be a useful basis for recognizing IRE and FID in patients with myeloma and lymphoma, and could help optimize rHuEPO treatment plans by adding IV iron in a rational manner. Further studies are required to assess how early recognition of IRE before or during the course of rHuEPO treatments can help patients overcome rHuEPO resistance and optimize anemia treatments.

Please reference the source article:
Hypochromic erythrocytes (%): a reliable marker for recognizing iron-restricted erythropoiesis and predicting response to erythropoietin in anemic patients with myeloma and lymphoma. Katodritou E, Terpos E, Zervas K, Speletas M, Kapetanos D, Kartsios C, Verrou E, Banti A, Effraimidou S, Christakis J. Annals of Hematology. 2007 May;86(5):369-76. Epub 2007 Feb 14.

NAAC Expert Commentary:
An adequate supply of iron is essential for erythropoiesis. Under circumstances of increased demand for red blood cells, such as with moderate degrees of anemia, the amount of iron available from reticuloendothelial iron stores is sufficient to increase the rate of erythropoiesis at least 3-fold. In this circumstance, the addition of oral iron increases the rate of erythropoiesis by about 25%. However, if the serum iron can be increased to greater than 200 µg %, as is the case in hemochromatosis, the rate of erythropoiesis can be increased 6-fold. Erythropoietin is the hormone responsible for regulating blood production in accordance with long term tissue oxygen needs. If stimulation of the marrow by erythropoietin is sufficiently prolonged, a shift in iron stores from the marrow to the circulating red cell mass can induce a state of relative iron deficiency. This is seen most commonly in the disease polycythemia vera.

However, following the development of recombinant erythropoietin for pharmacologic enhancement of red cell production, impairment of erythropoiesis due to insufficient iron stores has become a more pervasive clinical problem. This is especially true of patients with end stage renal disease who are not iron-overloaded or suffering from an inflammatory or infectious disorder, since they have an otherwise functionally normal bone marrow. By contrast, patients with cancer have impaired erythropoiesis, generally not due to iron lack, but due to impaired erythropoietin production as well as impaired red cell production, both of which are due to inhibition by inflammatory cytokines. At the same time, inflammatory cytokines such as hepcidin cause a redistribution of body iron, making it difficult to determine by classical iron indices whether a patient is truly iron deficient or merely sequestering iron due to lack of an appropriate erythropoietic stimulus. This has led to attempts to develop other measures of iron availability and iron-deficient erythropoiesis; unfortunately, often without consideration of the context in which they are used. That is to say, what is true in end stage renal disease may not be applicable to anemias associated with cancer or infection, since the reasons for marrow failure may be different.

In this article the authors have investigated the hypochromic erythrocyte both as a marker for iron-restricted erythropoiesis and as a predictive marker for erythropoietin-responsiveness in a group of anemic patients with a hematologic malignancy being treated with recombinant erythropoietin. They also compared this marker with several other markers that have been used to predict the efficacy of recombinant erythropoietin. They found that the percentage of hypochromic red cells had a better predictive value than the serum ferritin (less than 100 ng/mL) or transferrin saturation (less than 20%) as a marker of iron deficiency and that a low baseline percentage of hypochromic red cells alone or together with the reticulocyte count was more effective in predicting erythropoietin-responsiveness than other proposed predictors.

There are a number of problems with this study. First, the initial rate of erythropoietin-responsiveness (~66%) was equivalent to what has generally been observed in virtually every clinical trial of recombinant erythropoietin in anemic cancer patients undergoing chemotherapy. When the additional 10 of 12 patients receiving intravenous iron are included, the response rate rises to a phenomenal 90%. Unfortunately, we are not given any specific data on individual patients to permit any judgment as to the actual presence of iron deficiency as identified by the percentage of hypochromic erythrocytes, and the fact that absent bone marrow iron stores was an exclusion criterion for this study suggests that no patients were actually iron deficient. In this regard, some anemic cancer patients do take longer than others to respond to recombinant erythropoietin and that possibility was not excluded here because this was not a randomized clinical trial. Also, the article does not provide data regarding change in the percentage of hypochromic red cells with iron replacement. Additionally, hypochromic red cells were compared individually to the serum ferritin and percent transferrin saturation and not with both together as is traditionally the case. Using only a univariate analysis, prevented the identification of potential confounders, possible through multivariate analysis. Also analytically invalid was the comparison of other predictive algorithms previously employed in patients with other types of cancer. Truly necessary to make these types of conclusions is a prospective study comparing these markers in the same type of patients using a randomized design.

From the data presented, one could also argue that the reticulocyte count alone was a more valid predictor of responsiveness than the percentage of hypochromic erythrocytes. One must question the validity of the hypochromic erythrocyte as an early marker of iron-restricted erythropoiesis for the simple reason that microcytosis occurs before hypochromia, when the supply of iron is restricted. In summary, the authors have not adequately proven what they have concluded in their discussion.