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Post-liver-transplant anemia: Etiology and management
Article first published online: 30 JAN 2004
Copyright © 2004 American Association for the Study of Liver Diseases
Volume 10, Issue 2, pages 165–173, February 2004
How to Cite
Maheshwari, A., Mishra, R. and Thuluvath, P. J. (2004), Post-liver-transplant anemia: Etiology and management. Liver Transpl, 10: 165–173. doi: 10.1002/lt.20031
- Issue published online: 30 JAN 2004
- Article first published online: 30 JAN 2004
Anemia is common after liver transplantation, with the incidence ranging from 4.3% to 28.2% depending on the criteria used to define anemia. The cause of anemia is unidentified in the majority of patients, and it is likely to be multifactorial. Immunosuppressive-medication-induced bone marrow suppression is perhaps the most common cause of unexplained anemia. Chronic blood loss, iron deficiency, hemolysis, and renal insufficiency are other potential causes of chronic anemia. Rare causes, somewhat unique to transplantation, include aplastic anemia, graft-versus-host disease (GVHD), and lymphoproliferative disease. Anemia due to immunosuppressive medication is challenging, since almost all drugs currently used for this purpose cause anemia, but the renal-sparing property of sirolimus may benefit the subgroup in which renal insufficiency is contributing to anemia. Aplastic anemia is seen in young patients transplanted for non-A, non-B, non-C, fulminant hepatic failure. It is thought to be immunologically mediated, secondary to an unknown viral infection, and is associated with a grave prognosis. GVHD is another infrequent (approximately 1% of transplant recipients) but serious cause of severe anemia that carries a dismal prognosis. Lymphoproliferative disorder, too may rarely rare cause anemia and it may respond to reduction of immunosuppression. Recipients of solid-organ transplants do not mount a significant increase in erythropoietin in response to anemia. In conclusion, though there are no data on the response of anemia to erythropoietin in liver transplant recipients, it appears to benefit other solid-organ-transplant recipients with anemia. (Liver Transpl 2004;10:165–173.)
Anemia is common in patients with chronic liver disease.1–3 A high prevalence of anemia has been reported in recipients of kidney, heart, and lung transplantation.4–7 Although the prevalence of anemia remains stable in children (approximately 26% at 5 years) after renal transplantation, the prevalence increases with time in adult renal transplant recipients.6, 7 However, there is only minimal information on the prevalence, natural history, and management of anemia following liver transplantation (LT). In this review, our objective is to critically appraise our current knowledge of anemia in liver transplant recipients.
Prevalence of Anemia
The reported prevalence of anemia in liver transplant recipient ranges from 4.3% to 28.2%.8, 9 In a retrospective review, 23 (4.3%) of 533 adults were found to have hemoglobin (Hb) less than 9 g/dL when studied 1 to 86 months after liver transplantation.8 In another retrospective cross-sectional review, 62 (28.2%) of 175 children were found to have anemia (Hb < 10.5 g/dL) when Hb was determined at least 6 months after liver transplantation; in this study anemia was defined as Hb less than 2 SD below age and gender-adjusted mean Hb levels.9 In prospective trials that evaluated different immunosuppressive regimens, the incidence of anemia ranged from 1% to 53%.10, 11 The discrepancies in the reported incidence or prevalence may be a reflection of the differences in the definition of anemia, the patient's age, the immunosuppressive regimen, and the differences in time interval after transplantation.
Causes of Anemia
Immediate postoperative anemia could be secondary to blood loss, renal insufficiency, infections, and medications. In this review, we will focus on the causes, natural history, and treatment of anemia that occur 30 days or more after LT. The causes of anemia in liver transplant recipients are listed in Table 1; it is likely that more than one factor is responsible for anemia in the majority of liver transplant recipients. Moreover, in a significant number of patients no obvious cause is identified in spite of exhaustive diagnostic tests. In one study,8 only 47% of adult patients had an identifiable etiology for their anemia, and in another study, 84% of children had no identifiable cause for anemia.9 It is probable that multiple etiologies or hitherto unrecognized causes may explain anemia in these patients after LT. In the following section, we will discuss the commonly recognized causes of anemia in liver transplant recipients.
|Aplastic anemia||28%–31% of children & 5% of adults transplanted for FHF;||Unknown viral infection, possibly immune mediated|
|0.007% in all patients post-LT|
|Tacrolimus||5%–47%||Myelosuppression, hemolysis, red cell aplasia, PTLD|
|Cyclosporine A||1%–38%||Myelosuppression, hemolysis, microangiopathic anemia|
|NSAIDs||Rarely prescribed after LT, uncommon||UGI & LGI ulceration|
|Parvovirus B19||1.8%||Lysis of erythroid precursor cells|
|CMV||Although common, anemia is infrequent||Destruction of marrow stromal cells, hemolysis|
|EBV||Rare complication of infectious mononucleosis||Infection of marrow progenitor cells|
|HBV||Rare||Inhibition of marrow progenitor cells (in vitro)|
|HCV||Rare||Bone marrow depression (in vitro)|
|Nutritional||Predominantly children (7.1%)||Poor intake or absorption|
|GI blood loss||Predominantly adult (10.1%)||Ulceration due to NSAIDs or corticosteroids, colon cancer|
|Tacrolimus||Incidence of anemia unknown, risk of severe renal insufficiency: 6.25%–8% at 7 years, up to 18.1% at 13 years||Suspect decreased EPO production|
|PTLD||2%–3.6% lifetime risk||Bone marrow suppression|
|GVHD||1% or less||Bone marrow suppression|
|Hemolysis||Infrequent||ABO incompatibility, medications, PTLD, hypersplenism|
|Multifactorial or unknown||47%–57%||More than one mechanism|
Aplastic anemia is a rare but serious cause of anemia in liver transplant recipients. Hepatitis-associated aplastic anemia (AA) was first described in 1955, and over the next 20 years, more than 200 cases were reported in the literature. Aplastic anemia complicating LT was first described in 1987 in a 7-year-old child who underwent LT for fulminant hepatic failure (FHF) due to acute non-A, non-B hepatitis.12 Subsequent reports have shown a high incidence (5–33%) of AA in patients who were transplanted for FHF secondary to non-A, non-B, non-C hepatitis.13 In one study, Tzakis et al.,14 reported AA in 9 (28%; 8 children, 1 adult) of 32 patients who underwent LT for FHF due to acute non-A, non-B hepatitis. In another study, 33% of children and 5% of adults who underwent LT for FHF presumably due to acute non-A, non-B, non-C hepatitis developed aplastic anemia.13 In contrast to the recipients who had LT for acute hepatitis, the incidence of AA is only 1 to 2 per 1,000 patients with acute “viral” hepatitis who did not undergo LT.15 In addition, the overall incidence of AA was only 7 per 100,000 in a large unselected group of patients (all etiologies) who had LT.16 Moreover, the reported incidence of AA in general population in the posttransplant setting may have an “unidentified” viral etiology, and the immunosuppression was perhaps responsible for the higher incidence of AA in patients who undergo LT for presumed, unidentified viral hepatitis and FHF.
Parvovirus B19 is known to preferentially infect the globoside-containing erythroid precursor cells causing anemia by lysis of the infected cells. Initial reports had suggested that parvovirus B19 might have a potential role in the development of AA, especially in those who present with FHF.17 Solid-organ transplant recipients are also susceptible to parvovirus B19 reactivation, infections, or reinfection either from donor organs or blood products.18 In one study, 32% of liver transplant recipients had evidence of parvovirus B19 viremia, but there was no clear association between the presence of infection and anemia.8 Similarly, in children, only 1.8% of patients showed an association between anemia and parvovirus B19 infection.9 The current evidence indicates that the association between parvovirus B19 infection and post-LT anemia is weak.
Cytomegalovirus(CMV) and Epstein-Barr virus (EBV) have been implicated as causes of anemia in transplant recipients. EBV genome and antigens have been identified in the bone marrow of patients with AA. In a prospective report, 5 patients with AA, 3 with a previous history of infectious mononucleosis, had evidence of EBV infection in the marrow cells.19 The same study also reported the presence of EBV DNA in the marrow cells of 1 (5%) of 40 patients with AA who were evaluated retrospectively. Unlike EBV, CMV lacks the ability to infect bone marrow progenitor cells but instead infects the marrow stromal cells, as shown in an in vitro study. The cytopathic effect of CMV on the marrow fibroblasts and adipocytes may cause physical changes in the microenvironment and thereby reduce the ability of the stromal layers to support the proliferation of the primitive myeloid progenitor cells.20
Other flaviviral infections, including hepatitis C virus (HCV), have also been shown to replicate in the bone marrow and possibly suppress bone marrow, resulting in anemia.21 However, there is no evidence to suggest that HCV causes AA.22 There is experimental evidence to show inhibition of erythroid progenitor cells by HBV infection in vitro, which may explain the bone marrow depression observed occasionally in acute HBV infection.23 In addition, there are isolated case reports of aplastic anemia associated with acute HBV hepatitis.24, 25 It has also been suggested that occult or undiagnosed HBV infection may be a cause of marrow failure in some cases of FHF from presumed non-A, non-B hepatitis.26
Aplastic anemia, associated with “viral” hepatitis or after LT for FHF, is seen predominantly in children and young adults, and it is believed to result from a presumed viral pathogen that operates through immune-mediated mechanisms. There is no direct relationship between aplastic anemia and the severity of hepatitis. The vast majority of patients develop AA as the liver enzymes demonstrate a downward trend, and this may support the hypothesis that it is probably “immune mediated.” In a literature review of 31 patients who developed AA after they had LT for non-A, non-B, non-C induced FHF,27 there was a male preponderance, with a mean age of 10 years (range, 1.2–29 years). The average interval between the onset of hepatitis and the development of AA was 47.6 days (range, 7–154 days); 22% of the patients developed AA before LT and 78% after LT. In those who had LT, AA developed after a mean interval of 10.3 days after LT and ranged between 21 days pre- and 49 days post-LT. There was a considerable geographical variation among patients who developed AA after LT for FHF, with the majority of reports originating from North America. This geographical difference may reflect a reporting bias or, less likely, the epidemiological characteristics of the etiologic agent involved.
The clinical presentation and the outcome of AA in these patients are determined to some extent by their age and the nature of the liver disease. Despite the absence of any previous hematological disorders, the diagnosis of AA in transplant recipients requires a high index of clinical suspicion. The differential diagnosis of pancytopenia in these patients is very broad and includes graft-versus-host disease (GVHD), CMV infection, immunosuppressive or other medications, and acute parvovirus B19 infection. The outcome of AA is dependent on the age of the patient, with a higher mortality in older patients; it ranges from approximately 50% for patients less than 18 years old to approximately 100% in elderly patients.
Immunosuppressive medications have long been implicated in the pathogenesis of anemia after transplantation due to their bone-marrow-depressive effects. The controlled trials comparing immunosuppressive regimens have shown an incidence of anemia that ranges from 1% to 53%. In the European FK506 liver study10 that compared cyclosporine and tacrolimus, the incidence of anemia was 1% in the cylcosporine (CsA) group (n = 265) and 5% in the tacrolimus (n = 264). In sharp contrast, a much higher incidence was reported by the US FK506 liver study group,28 where anemia was noted in 38% of patients in the CsA group (n = 266) and 47 % in the tacrolimus group (n = 263). Similar discrepancies have been reported with other immunosuppressive agents. When mycophenolate mofetil (MMF) was compared with placebo in combination with CsA and corticosteroids in renal transplant recipients,29 the incidence of anemia was 1.8% in the placebo group (n = 166), 4.2% in the MMF 2 g/day group (n = 165), and 6.8% in the MMF 3 g/day group (n = 160). However, another study that compared MMF and azathioprine in combination with CsA and corticosteroids in liver transplant recipients11 reported anemia as an adverse event in 43% of patients in the MMF group (n = 277) and 53% in the azathioprine group (n = 287). In addition to bone marrow suppression, there may be other mechanisms by which these drugs cause anemia. Tacrolimus and CsA are both known to cause microangiopathic hemolytic anemia and hemolytic uremic syndrome.30–32 Drug-induced hemolysis is usually immunologically mediated; however, drugs such as dapsone may also cause direct toxic effects on red blood cells. Tacrolimus has also been implicated in the development of pure red-cell aplasia in children and adults.33 Although the authors of these studies did not describe their “criteria” for the diagnosis of anemia in their papers, it is likely that the differences in their definitions may explain the major disparities in the incidence of anemia. Other commonly used drugs in liver transplant recipients may also cause anemia by different mechanisms. Trimethoprim-sulfamethoxazole and interferon-alfa may cause myelosuppression, and dapsone and furosemide may cause hemolytic anemia.
Hemolytic anemia is immunologically mediated in most instances and may be the result of medications, GVHD, hypersplenism, or ABO incompatibility. GVHD is an infrequent but important cause of anemia after LT. Donor T cells in liver allografts may provoke GVHD in some patients, and this may also result in bone marrow depression. The incidence of GVHD is 1% or less,34 but it is associated with a very high mortality rate. The typical clinical presentation of GVHD includes fever, skin rash, diarrhea, and pancytopenia, beginning 2 to 6 weeks after. Unlike AA, GVHD seems to occur more frequently in older patients (age > 65 years) with younger donors (age difference of > 40 years), and those with close donor/recipient human leukocyte antigen (HLA) matching. The diagnosis is made by demonstration of chimerism with the presence of both donor and recipient lymphocytes in peripheral blood and bone marrow. The mortality from GVHD exceeds 75%, primarily due to infectious complications. Treatment is usually ineffective and involves either increased or decreased immunosuppression along with supportive treatment. It has been suggested that prophylactic treatment of donor livers in high-risk subjects may reduce the risk of GVHD; however, there are no studies to support this hypothesis in LT, although a similar strategy has been employed in small-bowel transplantation.35
Immunologically mediated hemolysis is also an important cause of post-LT anemia. ABO incompatibility may cause significant hemolysis. Hemolysis following ABO-incompatible liver transplantation results from a type of graft-versus-host reaction in which the B-lymphocytes in the donor liver produce antibodies to the ABO antigens of the recipient. ABO antibodies, typically immunoglobulin G, appear 7 to10 days after transplantation and last for about a month. Hemolysis is seen more frequently in recipients with blood group type A. Treatment aimed at the removal of circulating antibodies such as plasmapheresis, and transfusions to maintain adequate hematocrit are usually adequate for this self-limited process. However, there have been case reports of severe hemolysis causing acute renal failure that required dialysis and retransplantation. Patients with ABO-unmatched liver transplantation that demonstrate early evidence of hemolysis have also been noted to have reduced graft survival.36
Hypersplenism may persist after liver transplantation, and this may possibly contribute to anemia after LT. Previous studies have shown improved platelet counts beginning at 2 weeks, reaching a peak at 4 weeks, and persistence at those levels at 1 year after transplantation.37, 38 Similar effects were seen on white blood cell counts as well. To our knowledge, there are no studies that evaluated the role of hypersplenism on red cells, but it is reasonable to assume that the effects of hypersplenism on red blood cell counts may resolve within a few weeks after transplantation.
Other Causes of anemia
Iron deficiency is a frequent cause of anemia in liver transplant recipients, especially children.9 In adults, occult gastrointestinal blood loss is frequently the underlying cause of iron deficiency anemia. Increased colorectal adenoma and carcinoma have been reported in liver transplant recipients.39 We have recently shown that anemia is common in patients with end-stage liver disease, and this may be partly related to renal insufficiency.40 Severe renal insufficiency is seen in 6% to 8% of patients at 7 years41, 42 and about 18% at 13 years43 after transplantation. Although renal insufficiency may be an important cause of anemia, there is a paucity of data on the relationship between anemia and renal insufficiency in LT recipients.
Posttransplant lymphoproliferative disorder (PTLD) may present with anemia as an initial manifestation. PTLD occurs in 2% of all recipients of LT44 and carries a poor prognosis with a median survival of 14 months.45 Autoimmune hemolytic anemia may be an initial manifestation of PTLD, and diagnosis of PTLD may be delayed since drugs, including tacrolimus, may initially be considered as potential culprits of hemolytic anemia.46
Management of Anemia
The diagnostic workup of post-LT anemia is similar to that of any other patient with chronic anemia (Table 2). The only exception is that conditions unique to LT, such AA, GVHD, and PTLD, should be considered in the differential diagnosis. In addition, a diagnostic bone marrow biopsy is required more frequently in patients with chronic anemia after LT.
|Interval After LT||Etiology||Diagnostic Tests|
|0–14 days||Bleeding||Blood counts, imaging studies, endoscopy|
|Sepsis||Blood and body fluid cultures, imaging for occult infections|
|Medications||Consider change of medications (avoid myelosuppressive drugs, decrease immunosuppression)|
|Hemolysis||Coomb's test, haptoglobin, LDH, unconjugated bilirubin|
|2–6 weeks||Medications||Consider alternative medications|
|Aplastic anemia||Bone marrow biopsy|
|GVHD||Demonstration of chimerism|
|Parvovirus B19||IgM antibody titers, B19 DNA|
|> 6 weeks||Medications||Consider alternative immunosuppressive regimens|
|Iron deficiency||Iron indices, workup for occult GI blood loss|
|Renal insufficiency||Trial of renal-sparing immunosuppressive agents or EPO|
|PTLD||Indices of hemolysis such as haptoglobin, bilirubin and Coomb's test, bone marrow biopsy|
|Multifactorial/unknown||Trial of EPO|
The measurement of erythropoietin (EPO) levels has been a topic of considerable interest. A study of cirrhotic patients47 showed inappropriate EPO response to anemia. Although it has been suggested that EPO response may improve after transplantation,48, 49 low-to-normal EPO levels were seen uniformly in anemic patients after heart, heart-lung, or lung transplantation in the absence of renal insufficiency. Interestingly, patients with iron deficiency were the only subset of pediatric post-LT recipients that was able to increase EPO levels appropriately in response to anemia.9 These observations suggest that the monitoring of EPO levels is not a useful diagnostic tool.
Treatment options for Aplastic anemia (AA) include increased or decreased immunosuppression, use of antithymocyte globulin (ATG), or allogenic bone marrow transplantation. Management of AA can be difficult in transplant recipients, since these patients are already receiving immunosuppressive drugs such as prednisone and CsA, both of which have been shown to be effective in some nontransplant patients with AA. Intensive antiinfective prophylaxis and supportive treatment with transfusions of blood products remain the mainstay of therapy while awaiting spontaneous bone marrow recovery. In addition, medications with potential marrow toxicity should be discontinued. Pentamidine is substituted for cotrimoxazole, and baseline CsA- or tacrolimus-based immunosuppression is either discontinued or reduced. ATG may be effective in the treatment of hepatitis-associated AA that has been treated conservatively or with LT. Usually the effect of ATG is delayed, and repeated administrations are necessary.27 However, the exact role of ATG is unclear, since spontaneous recovery may also occur with maintenance immunosuppression after LT without the use of ATG.13, 14 In a controlled trial of ATG versus placebo, patients with AA from variety of causes showed a response rate of 52% at 3 months and 62% at 2 years in the ATG group. In comparison, there was no response to placebo at 3 months when patients on placebo arm were switched to ATG. The switchover made it difficult to interpret the long-term results, but these observations appear to support the role of ATG.50 It has been postulated that the role of ATG may be to prevent the development of a graft-versus-host reaction from the stem cells in the donor liver. Patients with AA should be appropriately tested for CMV, EBV, HBV, HCV, and parvovirus B19 as a part of diagnostic workup. While antiviral agents such as ganciclovir are routinely employed in the care of the aplastic patient, treatments with intravenous immunoglobulin G (IVIG) for parvovirus B19 cannot be justified without a firm diagnosis.
The reported a mortality rate of AA after LT approaches 50% and is higher in the adult population and in patients undergoing LT for indications other than FHF.16 The cause of death is usually sepsis from overwhelming fungal or bacterial infection, or intracranial hemorrhage from the bleeding diathesis. Therefore, intensive antimicrobial and antifungal therapy is critical in preventing or treating sepsis while awaiting marrow recovery. Leukocyte-depleted blood products should be used to avoid HLA sensitization, and prophylactic irradiation of blood products has been recommended to reduce the risk of transfusion-related GVHD.27
Previous reports have recommended the use of hemopoietic growth factors such as granulocyte colony stimulating factor (G-CSF); however growth factors are ineffective once patients develop complete aplasia.16 In a review of 32 cases of AA, four of the five patients who received as G-CSF monotherapy without other immunosuppressants died due to septic or bleeding complications.27 The use of growth factors has therefore proven unsuccessful and may indeed delay the diagnosis of AA.
Although spontaneous recovery of AA has been reported, the time to recovery may be very prolonged, leaving the patient transfusion-dependent for months, risking exposure to multiple donors and potentially increasing the risk of GVHD. There are case reports of long-term success with allogenic bone marrow transplantation in patients, especially children, with post-LT AA.51–53 The option of bone marrow transplantation is especially beneficial in those unresponsive to ATG treatment who have HLA matched siblings.
Drug-induced anemia frequently responds to withdrawal of the offending agent, but in cases of CsA- or tacrolimus-induced hemolysis or microangiopathic anemia, plasmapheresis and hemodialysis are frequently required to remove the immune complexes that cause renal failure and other vascular thrombotic complications.54 Although both CsA and tacrolimus cause hemolytic anemia, presumably autoimmune in nature, there are no reports of cross-reaction between these drugs, and therefore these drugs could be safely interchanged.
Graft Versus Host Disease
GVHD can be either acute or chronic in nature, causing anemia accompanied by pancytopenia. There is a single report of Evans's syndrome (autoimmune hemolytic anemia and thrombocytopenia) complicating chronic GVHD, and this should be considered as a potential differential diagnosis.55 The diagnosis of GVHD is often made by bone marrow biopsy and the demonstration of chimerism between donor and recipient lymphocytes. GVHD is associated with a mortality close to 90%.34 Conventional treatment involves increased levels of immunosuppression by corticosteroids or calcineurin inhibitors, although there have been reports of withdrawal of immunosuppression with improvement in GVHD without concomitant rejection.56 In a recent report, it was suggested that infusion of basiliximab (2 infusions 4 days apart) may improve GVHD, but this observation was based on 2 patients who were treated before they developed pancytopenia.57 This interesting observation merits further attention, since the outcome of GVHD is almost always fatal with conventional treatment.
Renal dysfunction is a recognized complication of the calcineurin inhibitors, and renal function may improve when these drugs are switched to renal-sparing immunosuppressants such as sirolimus.58–60 A multicenter, randomized trial is in progress to examine the benefit of sirolimus conversion in patients with renal insufficiency after LT. EPO may be beneficial in patients with renal insufficiency and anemia, but the current data are limited to renal transplant recipients, and there is no information on liver transplant recipients.61, 62
The treatment of iron-deficiency anemia frequently involves identification of the underlying cause, such as occult blood loss from the gastrointestinal tract in adults or nutritional deficiencies in children. Some authors5, 9 have recommended against the routine empirical use of oral iron supplementation in patients with posttransplant anemia who demonstrate normal indices. The administration of EPO has been shown to improve hemoglobin in solid-organ recipients.4, 45 This is an attractive option, since the majority of patients after LT has unexplained anemia. However, to date there are no controlled trials that have examined the efficacy, both in terms of increased hemoglobin and quality of life, or the cost-benefit analysis of EPO in LT recipients. If EPO were used, concomitant iron therapy would be recommended, as EPO can exacerbate microcytic anemia in those with low iron stores.
Anemia is common after LT, with the incidence ranging from 4.3% to 28.2%, depending on the criteria used to define anemia. The cause of anemia is unidentified in majority of patients and it is likely that it is multifactorial. Immunosuppressive-medication-induced bone marrow suppression is perhaps the most common cause of unexplained anemia. Chronic blood loss, iron deficiency, hemolysis, and renal insufficiency are other potential causes of chronic anemia. Rare causes, somewhat unique to transplantation, include aplastic anemia, GVHD, and lymphoproliferative disorder. Anemia due to immunosuppressive medication is challenging, since almost all drugs currently used for this purpose cause anemia, but the renal-sparing property of sirolimus may benefit the subgroup in which renal insufficiency is contributing to anemia. AA is seen in young patients transplanted for non-A, non-B, non-C, FHF. It is thought to be immunologically mediated, secondary to an unknown viral infection, and is associated with a grave prognosis. GVHD is another infrequent (approximately 1% of transplant recipients) but serious cause of severe anemia that carries a dismal prognosis. Lymphoproliferative disorder too may rarely cause anemia, and this may respond to the reduction of immunosuppression. Recipients of solid-organ transplants do not mount a significant increase in EPO in response to anemia. There are no data on the response of anemia to EPO in liver transplant recipients, but it appears to benefit other solid-organ transplant recipients with anemia. Future studies should focus on identifying the incidence of symptomatic anemia and the role of specific host and iatrogenic risk factors in the pathogenesis of anemia. The efficacy and cost-effectiveness of EPO and its impact on quality of life should be assessed prospectively in liver transplant recipients with chronic anemia.
- 28The US multicenter FK506 liver study group. A comparison of Tacrolimus (FK506) and Cyclosporine for immunosuppression in liver transplantation. N Eng J Med 1994; 331: 1110–1115
- 29European mycophenolate mofetil cooperative study group. Placebo-controlled study of mycophenolate mofetil combined with Cyclosporine and corticosteroids for prevention of acute rejection. Lancet 1995; 345: 1321–1325
- 58Rapamune Maintenance Regimen Study Group. Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study. Transplantation 2003; 76: 364–370, , , , , , , et al.