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Editorials |
* Department of Medicine and the Transplantation Service, University Hospitals Case Medical Center, Cleveland, Ohio
Address correspondence to: Dr. Donald E. Hricik, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, Ohio 44106. Phone: 216-844-8060; Fax: 216-844-5204; E-mail: dhricik{at}aol.com
Improvements in early outcomes of kidney transplant recipients have shifted attention to long-term outcomes, specifically prompting attention to metabolic factors that are linked to cardiovascular disease, the most common cause of death after transplantation. One of those factors, posttransplant anemia (PTA), has been the subject of several recent studies and editorials (1–6). In the general population, chronic anemia is known to lead to left ventricular hypertrophy, which, in turn, is a well-recognized risk factor for cardiovascular mortality (7,8). It is logical, but largely unproven, that similar associations between anemia and cardiovascular disease are present in the kidney transplant population. Collectively, the recent studies of kidney transplant recipients show that late PTA (i.e., anemia occurring 
12 mo after transplantation) is common, with cited prevalence rates ranging from 20 to 57%. Of the many variables associated with late PTA, impairment of renal function, not surprisingly, plays a preeminent role. Because renal impairment per se is strongly associated with cardiovascular disease both in the general population (9,10) and in kidney transplant recipients (11), it has been difficult to demonstrate an effect of anemia on posttransplant cardiovascular mortality that is independent of impaired renal function.
Transplant recipients differ from other patients with chronic kidney disease because they bear the additional burden of therapy with immunosuppressive drugs that may directly exacerbate anemia. Indeed, the wide variation in the reported prevalence of PTA likely reflects differences in the use of antiproliferative immunosuppressive agents (e.g., azathioprine, mycophenolate mofetil, and sirolimus) that may directly but variably inhibit erythropoeisis (3,4). Other factors commonly associated with PTA include recipient age and female gender, donor age, and the use of angiotensin converting-enzyme inhibitors or angiotensin receptor blockers, the latter likely related to the influence of these drugs on angiotensin II type I receptors that are increased on erythroid progenitors in patients with PTA (12). In understanding the pathophysiology of cardiovascular disease after kidney transplantation, it is important to recognize that other immunosuppressants also may play a role by directly impairing renal function (e.g., calcineurin inhibitors) or by exacerbating risk factors such as hypertension, hyperlipidemia, and glucose intolerance (e.g., corticosteroids and calcineurin inhibitors). Clearly, the pathophysiology of both anemia and cardiovascular disease after kidney transplantation reflects an intricate interplay between renal function, immunosuppression, and many other factors.
In this issue of JASN, Imoagene-Oyedeji et al. describe their single center experience with late PTA (13). The 20.3% prevalence of anemia 12 mo after transplantation is similar to that described in previous reports. An effect of antiproliferative agents could not be ascertained from this study because patients were treated uniformly with mycophenolate mofetil. Aside from the notable absence of an association between use of angiotensin antagonists and anemia, the other risk factors for anemia (gender, recipient age, donor age) in this study confirm those described in other recent studies. The study is the first of its kind, however, to demonstrate that the presence of anemia one year after transplantation is directly associated with subsequent cardiovascular mortality independent of many other known risk factors. Most importantly, the authors demonstrate convincingly that this association was independent of impaired renal function. Interestingly, PTA at 12 mo was associated with both cardiovascular and all-cause mortality.
The observations of Imoagene-Oyedeji et al. also confirm those of other recent studies in another important regard: Transplant physicians have been notoriously deficient in their evaluation and treatment of PTA. The authors acknowledge that, during the period of their study, "a workup for anemia was not performed routinely, and neither iron supplementation nor recombinant human erythropoeitin typically was implemented". The results of their study suggest that we need no further data on the prevalence of PTA or its associated risk factors. What we need is the development of algorithms and guidelines for the diagnostic evaluation and treatment of PTA. We also need additional research to explore some unanswered questions: How common is iron deficiency as a cause of anemia? Do transplant patients respond to oral iron therapy? Are patients receiving antiproliferative immunosuppressive agents resistant to iron therapy or to therapy with exogenous erythropoeitin? Can changes in immunosuppression correct PTA? Is preservation of renal function more important than correction of anemia in preventing posttransplant cardiovascular disease? Are the putative cardiovascular and renoprotective benefits of angiotensin inhibitors outweighed by their tendency to cause PTA?
Whether treatment and reversal of anemia can prevent cardiovascular disease, either in kidney transplant recipients or in patients with chronic kidney diseases, looms as an important question that can be answered only with large prospective studies. In the meantime, sufficient data has now accumulated to suggest that transplant physicians should adopt a rigorous approach to the evaluation and treatment of anemia complicating kidney transplantation.
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Footnotes |
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See the related article, "Posttransplantion Anemia at 12 Months in Kidney Transplant Recipients Treated with Mycophenolate Mofetil: Risk Factors and Implications for Mortality," on pages 3240–3247.
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