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Anemia and the kidney transplant recipient

Anemia and the kidney transplant recipient
Literature review current through: Sep 2023.
This topic last updated: Mar 03, 2023.

INTRODUCTION — Anemia, usually defined as hemoglobin (Hb) <12 g/dL in females and <13 g/dL in males, is a common finding before and after kidney transplantation. It is most often related to iron deficiency, graft rejection or dysfunction, erythropoietin (EPO) deficiency, viral infection, immunosuppression, and infection prophylaxis medications.

This topic will review the epidemiology, pathogenesis, evaluation, and treatment of anemia in kidney transplant recipients. Anemia associated with chronic kidney disease (CKD) in the nontransplant setting and the benefits of the treatment of anemia in the setting of CKD are discussed elsewhere. Both topic reviews are relevant since most transplant recipients have an average estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, a level consistent with the existing definition of CKD.

(See "Treatment of anemia in patients on dialysis".)

(See "Treatment of anemia in nondialysis chronic kidney disease".)

EPIDEMIOLOGY — The prevalence of anemia after kidney transplantation varies depending upon the definition of anemia used, the time period posttransplant, immunosuppressive regimen, and frequency of treatment [1-12]. While anemia is present in almost 90 percent of patients within the first month posttransplant, the prevalence falls to 34 to 45 percent among patients more than one year posttransplant [11].

At the time of transplantation, most adult patients can be defined as anemic as target levels for hemoglobin (Hb) among United States patients on dialysis are generally 10 to 11 g/dL. Mean Hb levels rise to above 11 g/dL by three months posttransplant and to above 12 g/dL at 6 to 12 months posttransplant. Development of acute or chronic allograft dysfunction is almost invariably accompanied by worsening anemia. As examples:

At six months posttransplant, approximately one-half of patients have an Hb level that is below normal (defined here as <14 g/dL in males and <12 g/dL in females) [2,7,12].

At one year, 10 to 40 percent are anemic despite having normal graft function [2,7,12-14].

During the first five-year posttransplant period, approximately one-third of patients have Hb levels that are <12 g/dL [3,4]. More severe anemia, characterized by an Hb level <11 g/dL, occurs in 12 to 15 percent of patients [7,15].

In a registry study from 20 European countries of 3699 pediatric (<18 years old) patients transplanted between 2000 and 2012, 49.8 percent were anemic, according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) classification, which defines anemia in children as Hb below the 5th percentile for age and sex [16]. By contrast, the United Kingdom National Institute for Health and Care Excellence (NICE) guidelines for anemia in CKD suggest a target Hb of 9.5 to 11.5 g/dL in patients <2 years old, and 10 to 12 g/dL for all others. Using these criteria, just 7.8 percent of pediatric kidney transplants were anemic.

PATHOGENESIS AND RISK FACTORS — The pathogenesis of anemia posttransplant varies by time from transplant. General risk factors associated with the development of anemia in the kidney transplant patient include female sex, age, allograft dysfunction, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and choice of immunosuppressive agents [2-4,6,17,18]. Use of erythropoiesis-stimulating agent (ESA) or iron therapy can paradoxically associate with anemia due to treatment by indication bias.

Early posttransplantation — Anemia immediately posttransplant is almost universally due to lower-than-normal hemoglobin (Hb) targets in the chronic kidney disease (CKD) and end-stage kidney disease (ESKD) populations, surgical blood loss, and frequent phlebotomy. Dilutional anemia also occurs because of aggressive perioperative volume expansion. Recovery to normal adult Hb concentrations can be hindered by allograft dysfunction and other clinical events, increased donor age, and iron deficiency.

Inadequate erythropoietin (EPO) – Improvement of erythropoiesis after kidney transplantation is due to EPO production in the allograft and the loss of the uremic milieu. In general, EPO levels begin to rise on posttransplant day 2 and reach a fourfold elevation for two to three weeks, after which time restoration of negative feedback control occurs [19,20]. Early EPO surges may be inefficient in correcting anemia since the hormone seems to be inefficient in this persistent uremic setting [21,22]. Relative EPO deficiency in the setting of allograft dysfunction is likely similar to that observed with anemia in patients with nontransplant-associated CKD.

However, endocrine function of the graft may not always correlate with excretory function, perhaps because peritubular interstitial cells, which produce EPO, are selectively damaged or develop defective regulation. Anemia may also correct in some patients despite relatively low EPO levels [15,23].

Iron deficiency – Iron deficiency plays a major role in persistent anemia in the immediate posttransplant period. Despite the recognition of iron requirements for effective ESA therapy, iron deficiency remains common among patients presenting for kidney transplantation. Iron stores may be rapidly depleted posttransplant due to surgical blood loss, frequent phlebotomy, and utilization of stores for enhanced erythropoiesis [8]. Return of regular menses resulting in iron losses may further contribute to iron deficiency in females. Chronic use of proton pump inhibitors (PPIs) in kidney transplant recipients is also associated with iron deficiency [24]. This may be due to PPIs impairing iron absorption by enterocytes.

Regulation of iron absorption and mobilization from iron stores to support erythropoiesis is impaired in the initial posttransplant period and during most acute rejection episodes. Serum hepcidin is the regulator of intestinal iron absorption and release of iron from reticuloendothelial stores. Hepcidin is cleared by the kidney, and therefore its levels increase as kidney function declines. Consequently, hepcidin levels are elevated in most patients on dialysis, leading to poor iron absorption and mobilization for erythropoiesis. Elevated hepcidin levels are seen in many kidney transplant patients and correlate with poor transplant function, higher ferritin, and other inflammatory markers [25,26]. Interleukin (IL)-6, a major regulator of hepcidin production, has been shown to be elevated immediately posttransplant and in the setting of acute rejection [27,28].

The accurate assessment of iron stores posttransplant is difficult because ferritin is a positive acute-phase reactant while transferrin saturation (TSAT) varies inversely with acute-phase reactants. A high ferritin may reflect adequate iron stores, inflammation, or both, while low TSAT may be due to low iron stores, inflammation, or both. This combination of high ferritin and low TSAT is characteristic of the anemia of chronic disease and reflects the actions of IL-6, hepcidin, and other inflammatory signals mentioned above. Acute or chronic rejection, progressive decline in kidney function, and inflammation or infection may lead to elevated ferritin. Conversely, ferritin levels fall with iron utilization but also rise with increased gastrointestinal iron absorption following transplantation. Thus, ferritin measurements have inconsistently reflected iron stores among kidney transplant recipients and do not always correlate with anemia [7,15]. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Iron studies (list of available tests)'.)

Donor kidney characteristics – Cold and warm ischemia times do not correlate with EPO levels [29,30]. Patients with delayed graft function have a slower rise in EPO levels, which increase with improvement in graft function. Interstitial fibrosis and tubular atrophy in the donor kidney at the time of transplant associate independently with anemia at 12 months posttransplant [31].

Later (>3 months) posttransplantation

Immunosuppressive agents – The antimetabolites mycophenolate mofetil (MMF), enteric-coated mycophenolate sodium (EC-MPS), and azathioprine cause marrow suppression and can also result in anemia [2,17,32]. However, the mean relative decrease in Hb concentration with these drugs may only be 0.2 to 0.3 g/dL, respectively [2]. More severe anemia is sometimes seen with these agents and responds to a reduction in dose.

Sirolimus also causes marrow suppression and anemia, particularly early after initiation, but the effect may lessen over time [33-37]. In general, the calcineurin inhibitors do not cause marrow suppression directly and do not typically cause anemia. However, sirolimus and the calcineurin inhibitors (tacrolimus and cyclosporine) may cause thrombotic microangiopathy and hemolytic anemia [23,38]. (See "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors", section on 'Hematologic effects'.)

Other medications – The use of ACE inhibitors and ARBs has correlated with anemia in a dose-related fashion in kidney transplant patients [17,18]. Based upon these effects, these medications may be used to treat posttransplant erythrocytosis [2,38]. Other medications commonly used in kidney transplant patients that may cause anemia include ganciclovir, valganciclovir, and trimethoprim-sulfamethoxazole (TMP-SMX). Use of dapsone for Pneumocystis jirovecii pneumonia prophylaxis has been associated with a higher risk of anemia than atovaquone [39]. (See "Kidney transplantation in adults: Posttransplant erythrocytosis".)

Graft dysfunction and rejection – In kidney transplant recipients, serum creatinine levels that are >2 mg/dL (177 micromol/L) correlate strongly with anemia [32]. In addition, episodes of acute rejection also have correlated with an average decrease of 0.5 g/dL in the Hb concentration, which may be due to decreased EPO levels [20,30].

Patients returning to hemodialysis following failure of their kidney transplant suffer from a chronic inflammatory state that is associated with resistance to ESAs [40]. A transplant nephrectomy in symptomatic patients ameliorates markers of chronic inflammation and leads to recovery of sensitivity to ESAs.

Donor and recipient characteristics – Donor age >50 to 60 years has been associated with a decrease in EPO levels and an increased incidence of anemia [2,30,32]. Female recipients are more likely to have posttransplant Hb levels <12 g/dL at 6 and 12 months. This may be due to increased iron loss with menses and androgen deficiency relative to males [4].

Infections – Infections, including those due to parvovirus B19, Epstein-Barr virus (EBV), cytomegalovirus (CMV), BK polyomavirus, varicella-zoster virus, tuberculosis, herpesviruses, and staphylococci, have also been associated with an increased risk of anemia [23,41]. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Transient aplastic crisis' and "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Other manifestations'.)

Other causes – Other causes of anemia in the later posttransplantation setting include certain comorbid conditions (new diagnoses of heart failure, gastritis, peripheral vascular disease, and cerebrovascular accident) [2], secondary hyperparathyroidism [1-6], and folate and vitamin B12 deficiency [42].

The passenger leukocyte syndrome is a very rare cause of hemolytic anemia in solid organ transplant recipients that occurs in the setting of ABO-compatible or Rh-compatible, but nonidentical, donor and recipient mismatches [43-48]. Passenger leukocyte syndrome most commonly occurs following transplantation of an organ from a donor with ABO-O blood type into a recipient with ABO-A or -B blood type or from an Rh-negative donor into an Rh-positive recipient. The donor organ contains B cells and plasma cells (so-called passenger leukocytes) that produce anti-isoagglutinin or anti-Rh antibodies that lead to the syndrome. Passenger leukocyte syndrome typically presents as a mild hemolytic anemia with an acute onset within the first few weeks posttransplantation. The diagnosis is made by the direct antiglobulin (Coombs) test. Treatment is usually supportive, although plasmapheresis and cytolytic therapy have been used. The clinical course is typically self-limiting, although antibodies may persist at detectable levels for 12 to 851 days posttransplantation [49]. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Associated conditions'.)

SURVEILLANCE — Kidney transplant recipients should undergo regular surveillance for anemia after transplantation with a complete blood count (CBC). At most transplant centers, a CBC is obtained at least weekly for the first three months and then every two to four weeks for a year and then monthly to every three months thereafter. (See "Kidney transplantation in adults: Overview of care of the adult kidney transplant recipient", section on 'Routine follow-up and laboratory monitoring'.)

Most transplant recipients are anemic at the time of transplant and during the early posttransplant period, but hemoglobin (Hb) levels are expected to gradually increase over the first three months posttransplant if the allograft is functioning (see 'Epidemiology' above). Thus, our approach to patients who are found to be anemic on routine screening is as follows:

All patients should have an assessment of iron stores (serum iron, total iron-binding capacity, percent transferrin saturation [TSAT], serum ferritin).

In patients who are less than three months posttransplant, we generally do not perform a further diagnostic evaluation for anemia unless the Hb level decreases to below the level at the time of transplant.

In patients whose Hb levels fail to normalize after three months posttransplant, we perform a diagnostic evaluation for anemia. (See 'Diagnostic evaluation' below.)

In patients whose Hb levels normalize by three months posttransplant, we continue to monitor for recurrent anemia and perform a diagnostic evaluation if anemia is observed. (See 'Diagnostic evaluation' below.)

DIAGNOSTIC EVALUATION — Kidney transplant recipients are evaluated for anemia and iron deficiency at the time of transplantation. In addition, kidney transplant recipients with persistent anemia at three months posttransplant or new-onset anemia after three months posttransplant (see 'Surveillance' above) should undergo further diagnostic evaluation. This evaluation should include an assessment for causes of anemia shared with nontransplant patients, as well as for more specific causes that may be unique to kidney transplant recipients (see "Diagnostic approach to anemia in adults" and "Diagnosis of hemolytic anemia in adults"):

Assessment for history of blood loss

Assessment for symptoms and/or signs of infection (eg, fever, malaise)

Assessment of dietary intake

Assessment of medication history for potentially causative medications (eg, mycophenolate mofetil [MMF], enteric-coated mycophenolate sodium [EC-MPS], azathioprine, mammalian [mechanistic] target of rapamycin [mTOR] inhibitors, angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], ganciclovir, trimethoprim-sulfamethoxazole [TMP-SMX])

Assessment of kidney allograft function (serum creatinine, spot urine protein-to-creatinine ratio)

Red blood cell (RBC) indices

Reticulocyte count

Iron studies (serum iron, total iron-binding capacity, percent transferrin saturation [TSAT], serum ferritin)

Testing for presence of hemolysis (eg, indirect bilirubin, lactate dehydrogenase, haptoglobin)

Testing for folate and vitamin B12 deficiency

We do not routinely evaluate all anemic transplant recipients for infection with parvovirus B19 or other viruses. However, if the initial diagnostic evaluation as detailed above does not identify a clear cause of anemia, we perform testing for parvovirus B19 infection by means of nucleic acid amplification testing (NAAT). (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Nucleic acid detection'.)

An accurate assessment of iron stores in kidney transplant recipients can be challenging. While low levels of ferritin and TSAT indicate true deficiency, inflammation may suppress TSAT and increase ferritin, obscuring the diagnostic utility of these tests. In addition, since no prospective studies have defined specific ferritin and TSAT levels for transplant recipients, criteria from the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Anemia in Chronic Kidney Disease are used to define iron deficiency [50]. (See 'Early posttransplantation' above and "Inflammation in patients with kidney function impairment" and "Diagnosis of iron deficiency in chronic kidney disease".)

The concurrent presence of leukopenia, thrombocytopenia, and/or acute kidney allograft dysfunction suggests the following potential causes of anemia:

Global myelosuppression is commonly caused by immunosuppression, nutritional deficiency, and prophylactic medications but can also be seen in the setting of viral infections. (See 'Later (>3 months) posttransplantation' above.)

Hemolytic uremic syndrome should be suspected when anemia is associated with kidney dysfunction, thrombocytopenia, and evidence of microangiopathic hemolytic anemia. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)" and "Thrombotic microangiopathy after kidney transplantation".)

By comparison, the presence of anemia alone, without leukopenia or thrombocytopenia, along with a low reticulocyte count and no nutritional deficiencies suggest parvovirus B19 infection or, very rarely, anti-erythropoietin (EPO) antibodies [51]. (See "Clinical manifestations and diagnosis of parvovirus B19 infection" and "Pure red cell aplasia (PRCA) due to anti-erythropoiesis-stimulating agent antibodies".)

TREATMENT

General principles — The general principles of anemia management in patients with chronic kidney disease (CKD) or end-stage kidney disease (ESKD) also apply to the treatment of anemia in kidney transplant recipients. These include treatment of the underlying cause of anemia (if identified), treatment of iron deficiency (if present), and the use of erythropoiesis-stimulating agents (ESAs) to reduce the need for red blood cell (RBC) transfusions. The selection of individual therapy depends upon the severity of anemia and the presence of iron deficiency. As treatment of iron deficiency may resolve the anemia, it should be treated before the administration of ESAs.

(See "Treatment of anemia in nondialysis chronic kidney disease".)

(See "Treatment of anemia in patients on dialysis".)

(See "Treatment of iron deficiency in patients with nondialysis chronic kidney disease (CKD)".)

(See "Treatment of iron deficiency in patients on dialysis".)

Special considerations in the treatment of anemia in kidney transplant recipients include the following:

Target hemoglobin levels – The optimal target hemoglobin (Hb) level for kidney transplant recipients is not well defined and may differ depending upon kidney allograft function and patient functional status.

Management of immunosuppression and other medications – Immunosuppressive agents (mycophenolate mofetil [MMF], enteric-coated mycophenolate sodium [EC-MPS], azathioprine, sirolimus) and other medications (eg, angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], ganciclovir, trimethoprim-sulfamethoxazole [TMP-SMX]) are common causes of posttransplant anemia. Dose reduction or discontinuation of these agents may be indicated depending upon the time from transplant and status of the kidney allograft. (See 'Later (>3 months) posttransplantation' above.)

Use of iron – Both oral and intravenous (IV) iron have been found to be safe and effective in kidney transplant recipients [52]. Due to the already high pill burden of transplant patients, we prefer IV iron therapy over oral iron therapy whenever known or suspected iron deficiency anemia is present [53]. Several IV iron formulations are available, including ferric gluconate, iron sucrose, ferumoxytol, ferric carboxymaltose, ferric derisomaltose, and iron dextran. All of these products are comparably effective in treating iron deficiency. The selection of an IV iron formulation may vary by institutional preference. (See "Treatment of iron deficiency anemia in adults", section on 'Choice of IV formulation' and "Treatment of iron deficiency in patients with nondialysis chronic kidney disease (CKD)", section on 'Intravenous iron'.)

In our experience, oral iron has been inadequate to replace or maintain adequate iron stores and may bind with immunosuppressant medications, such as MMF/MPS. The phosphate binder ferric citrate is approved for the treatment of iron deficiency anemia in CKD but has not been studied in the kidney transplant population. Like other oral iron preparations, this agent may bind to immunosuppressants.

Posttransplant erythrocytosis may develop in patients receiving oral iron supplementation. Hb often decreases four weeks after iron discontinuation in this setting [4,12].

Use of ESAs – The use of ESAs in kidney transplant recipients varies depending upon the time from transplantation. As an example, we do not use ESAs in the immediate transplant period. With anemia of CKD occurring more than three months posttransplant in the iron-replete patient, we may initiate an ESA. Patients receiving an ESA should be apprised of the risks of stroke, thrombotic events, and possibly increased risk of recurrent cancer prior to ESA use. (See "Treatment of anemia in nondialysis chronic kidney disease".)

Use of blood transfusions – We avoid the use of blood transfusions whenever possible to minimize the risk of allosensitization and rejection. However, if a blood transfusion is necessary in a kidney transplant recipient, cytomegalovirus (CMV)-seronegative and/or filtered blood products are preferable to leukocyte-reduced products as CMV and other viruses may be transmitted in plasma [54]. Irradiation of blood products is probably unnecessary [55].

Approach based on time from transplantation — Our approach to the management of anemia in kidney transplant recipients differs depending upon the time from transplant and the cause of anemia. (See 'Diagnostic evaluation' above.)

Patients awaiting transplantation — Anemia in patients who are awaiting a kidney transplant should be managed with the same approach used to treat anemia in the general CKD or ESKD population. Whenever possible, the use of RBC transfusions should be avoided to minimize the risk of immunologic sensitization, which may delay or reduce the possibility of receiving a transplant [56]. This is consistent with the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for the treatment of anemia in patients eligible for solid organ transplantation [50].

(See "Treatment of anemia in nondialysis chronic kidney disease".)

(See "Treatment of anemia in patients on dialysis".)

Patients perioperative and early posttransplantation — Our approach in patients who are in the perioperative and immediately posttransplant period is as follows:

Perioperatively, we target Hb levels of >10 g/dL as these levels appear safe and may reduce cardiovascular events in the early posttransplant period [57]. The pretransplant use of ESAs and iron in patients with dialysis and nondialysis CKD should maintain Hb levels in the range of 10 to 11.5 g/dL, therefore minimizing the need for peritransplant RBC transfusions. We limit RBC transfusions to patients with an Hb <7 g/dL or <8 g/dL in those with preexisting cardiovascular disease (CVD). This is consistent with the 2016 Clinical Practice Guidelines of the American Association of Blood Banks [58].

In patients with an Hb <10 g/dL and evidence of iron deficiency (ie, transferrin saturation [TSAT] ≤20 percent and serum ferritin level ≤200 ng/mL) at the time of transplantation, we administer 1 g of IV iron (typically as iron sucrose) in anticipation of iron losses with phlebotomy during the early posttransplant period. This approach is based on our clinical experience and is not supported by high-quality evidence.

In patients who were previously receiving ESA therapy, we stop the ESA at the time of transplant because of hyporesponsiveness to ESAs in the early posttransplant period, the thrombotic and cardiovascular risks of these drugs, and the expectation that endogenous erythropoietin (EPO) production will occur posttransplant. We do not give ESAs to patients with delayed graft function, as use of ESA therapy in this population is controversial and responsiveness to ESAs may be poor.

ESA therapy in the immediate posttransplant setting shortens the time to improved Hb [59] but has not been shown to improve clinical outcomes [60]. In a randomized trial of 104 patients that examined the efficacy of high-dose epoetin beta before transplant and during the first two weeks posttransplant, there was no difference in the frequency of delayed graft function between patients who received and did not receive epoetin [61]. Similarly, a retrospective study found no difference in three-month Hb levels or delayed graft function between patients who received and did not receive EPO during the first six months posttransplant [62].

Two studies have examined the effect of high-dose EPO on delayed or slow graft function [63,64]. In one study, 72 patients were randomly assigned to receive an intra-arterial injection of epoetin (40,000 units) or placebo at the time of reperfusion of the transplanted kidney. There was no difference between groups in the need for dialysis within the first week or in the percentage of patients with slow graft function (defined as ≤40 percent decrease in serum creatinine by postoperative day 3). The second trial randomly assigned 92 patients to IV epoetin (33,000 units) daily for three doses, beginning three to four hours before transplantation. Epoetin treatment had no effect on the incidence or duration of delayed graft function but did increase the risk of thrombotic events at one month and one year [63].

Patients later (>3 months) posttransplantation — Anemia in the immediate posttransplant setting typically improves within two to three months with endogenous EPO production from the allograft. However, several factors, including immunosuppressive agents, other medications (such as ACE inhibitors and ARBs), graft dysfunction, and infections, may contribute to the persistence or new onset of anemia after the early posttransplant period. Such potentially correctable factors should be identified and treated as appropriate prior to the initiation of ESA therapy. In addition, the approach to the treatment of anemia in transplant recipients who are >3 months posttransplant depends upon the functional status of the kidney allograft. (See 'Diagnostic evaluation' above.)

Patients with stable graft function — In kidney transplant patients with stable graft function (estimated glomerular filtration rate [eGFR] ≥45 mL/min/1.73 m2), our approach is as follows:

In patients with evidence of folate and/or vitamin B12 deficiency, we treat as appropriate to correct the deficiency, as discussed elsewhere. (See "Treatment of vitamin B12 and folate deficiencies".)

In patients with evidence of iron deficiency, we treat with IV iron. Dosing and administration of IV iron is presented elsewhere. (See "Treatment of iron deficiency in patients with nondialysis chronic kidney disease (CKD)", section on 'Intravenous iron'.)

In patients who do not have a clearly identifiable cause of anemia and are taking an ACE inhibitor or ARB, we weigh the potential risks and benefits of continuing these medications. If the patient does not require the ACE inhibitor or ARB for management of another comorbidity (eg, heart failure), then it is reasonable to discontinue the ACE inhibitor or ARB and monitor for improvement of anemia. If the anemia improves, the ACE inhibitor or ARB can be reintroduced at a later time (eg, after one year), if indicated, with monitoring for worsening of the anemia.

In patients who are receiving higher doses of an antimetabolite (eg, MMF 1000 mg twice daily or EC-MPS 720 mg twice daily) as part of their maintenance immunosuppression regimen, if anemia is severe and dose reduction is possible given the patient's immunologic risk of rejection, we reduce the dose of the antimetabolite by 50 percent. As an example, if the patient is on EC-MPS 720 mg twice daily, we decrease the dose to 360 mg twice daily. Similarly, if the patient is on MMF 1000 mg twice daily, we decrease the dose to 500 mg twice daily.

In patients who are receiving ganciclovir and/or TMP-SMX, we make sure that these agents are appropriately dosed for the level of kidney allograft function. We do not routinely dose reduce or discontinue these agents to treat anemia.

If anemia persists in spite of treatment of the above potentially reversible causes, we initiate an ESA in patients with an Hb <9 g/dL and target Hb levels of 10 to 11.5 g/dL, which are similar to those suggested for most patients with nondialysis and dialysis CKD. During routine management, patients may exceed 11 g/dL, and the dose of ESA should be temporarily stopped or reduced 25 percent monthly until the target is achieved. (See "Treatment of anemia in nondialysis chronic kidney disease", section on 'Target hemoglobin value' and "Treatment of anemia in patients on dialysis", section on 'Target Hb levels'.)

The optimum target Hb level for transplant recipients with stable graft function is not known. Observational studies in kidney transplant recipients have suggested that mortality may be increased with Hb levels >12.5 g/dL [65,66].

However, one study has suggested that graft survival may be better among patients treated to higher Hb values [67]. This two-year, open-label trial (Correction of Anemia and Progression of Renal Insufficiency in Transplant Patients [CAPRIT]) of 125 kidney transplant recipients with an estimated creatinine clearance <50 mL/min/1.73 m2 randomly assigned patients to receive epoetin with a target of 13 to 15 g/dL (complete correction group) or 10.5 to 11.5 g/dL (partial correction group) [67]. Compared with the partial correction group, the complete correction group had a smaller decrease in estimated creatinine clearance (5.9 versus 2.4 mL/min/1.73 m2), lower rate of ESKD (21 versus 4.8 percent), and higher death-censored graft survival (80 versus 95 percent). The CAPRIT trial is limited by its short duration, open-label design, and small size [68].

These results are strikingly different from those observed in the much larger Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) and Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) trials, which randomly assigned patients with nontransplant CKD [69,70]. The CHOIR and TREAT trials found an increased risk of cardiovascular events and no delay in progressive kidney failure by targeting normalization of Hb with ESA therapy. The Cardiovascular Reduction Early Anemia Treatment Epoetin beta (CREATE) trial employed anemia management similar to CAPRIT and found that randomization to a higher Hb target significantly increased the likelihood of initiating chronic dialysis [71]. We find it difficult to conceive of mechanisms by which somewhat higher Hb and/or more ESA could protect a transplant kidney but not native kidneys.

Much larger trials comparing ESA treatment with placebo are needed to define the risks and benefits of anemia management in transplant recipients.

The administration of darbepoetin alfa is also generally effective in kidney transplant recipients. In a retrospective, 12-week study of 36 patients, 81 percent achieved the target Hb level of >12 g/dL (mean time to response of 4.4 weeks) [72]. A longer duration of therapy was required in those with longstanding anemia and/or exposure to concurrent ACE inhibitor therapy.

Daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, has been approved for treatment of anemia in patients with ESKD on dialysis but is not approved for use in patients with nondialysis CKD. Further study of the safety of this class of agents in kidney transplant recipients is needed before its use can be considered.

Patients with a failing graft — Patients with failing transplants in stage 4 to 5 CKD frequently become anemic, and ESA therapy may be required to alleviate symptoms and reduce the risk of transfusions. The management of anemia in this patient population is similar to that in the general CKD or ESKD population, except that higher doses of ESAs may be required due to chronic inflammation. As discussed above for patients with stable graft function, we address any potential reversible causes (eg, nutritional deficiency, iron deficiency, immunosuppression, other medications) (see 'Patients with stable graft function' above). We generally initiate ESA therapy when the Hg is 9 to 10 g/dL and the iron stores appear adequate. We assess the risks from ESA therapy, which are higher in those with CVD, prior thrombotic events, stroke, or cancer. In patients with higher risks from ESA therapy, we generally avoid ESAs until anemia is more severe (ie, Hb <9 g/dL). (See "Treatment of anemia in nondialysis chronic kidney disease" and "Treatment of anemia in patients on dialysis" and "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease", section on 'Infection or inflammation'.)

Kidney transplant recipients restarting dialysis have lower Hb levels when compared with patients with nontransplant CKD (Hb levels of 8.9 versus 10.2 g/dL, respectively), which correlate with increased hospitalizations and higher mortality [5]. Use of ESAs such as epoetin may reduce the frequency and severity of anemia in patients with failing transplants but have not been shown to reduce mortality [73].

Patients who have returned to dialysis and are resistant to ESAs may benefit from allograft nephrectomy. (See 'Later (>3 months) posttransplantation' above.)

Special populations

Patients with parvovirus B19 infection — Anemia caused by parvovirus B19 infection has been corrected by treatment with IV immune globulin (IVIG) and by lowering immunosuppression to facilitate viral clearance [51]. (See "Treatment and prevention of parvovirus B19 infection".)

Patients with thrombotic microangiopathy — The treatment of thrombotic microangiopathy in kidney transplant recipients is discussed in more detail elsewhere. (See "Thrombotic microangiopathy after kidney transplantation".)

PROGNOSIS — Conflicting results have been found relating to the prognosis of kidney transplant recipients with anemia [74-76]. To better define this relationship, the correlation between anemia (defined as <12 g/dL in females and <13 g/dL in males) and patient and allograft survival was evaluated in a prospective cohort study of 938 kidney transplant recipients [66]. At four years, multivariate analysis revealed that anemia was associated with an increased risk of mortality (hazard ratio [HR] 1.69, 95% CI 1.15-2.5) and allograft failure (HR 2.56, 95% CI 1.48-4.1). Similar results were observed when anemia was defined as <11 g/dL.

However, an analysis of 825 kidney transplant recipients over 8.2 years found no relationship of anemia to mortality in multivariate analyses [74].

In the Assessment of Lescol in Renal Transplantation (ALERT) study of 2102 kidney transplant recipients, in which 29 percent of females and 30 percent of males were anemic, hemoglobin (Hb) levels were not associated with any effect on cardiovascular morbidity and mortality (HR 0.97, 95% CI 0.90-1.05 per g/dL) or all-cause death (HR 0.96, 95% CI 0.90-1.03 per g/dL) after extensive multivariate adjustments for clinical and demographic factors [77]. Hb levels, however, were negatively associated with graft loss (HR 0.86, 95% CI 0.80-0.92 per g/dL).

Left ventricular hypertrophy (LVH), an important risk factor for cardiovascular mortality among patients with CKD, may be in part a consequence of untreated anemia. Since cardiovascular disease (CVD) is the leading cause of death in diabetic kidney transplant recipients, the adverse effects of anemia may be more evident in diabetic kidney transplant recipients in the United States, when compared with other nationalities, as the United States transplant population has a relatively higher cardiovascular risk profile, with a higher percentage of patients with diabetes. Unfortunately, existing trials have not demonstrated that aggressive treatment of anemia regresses or retards progression of LVH, and any benefit of ESA therapy may be outweighed by the risks of these drugs [69,70,78]. (See "Cardiovascular and renal effects of anemia in chronic kidney disease", section on 'Left ventricular hypertrophy' and "Treatment of anemia in patients on dialysis", section on 'Adverse effects of ESAs'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)

SUMMARY AND RECOMMENDATIONS

Overview – Anemia, usually defined as hemoglobin (Hb) <12 g/dL in females and <13 g/dL in males, is a common finding before and after kidney transplantation. It is most often related to iron deficiency, graft rejection or dysfunction, erythropoietin (EPO) deficiency, viral infection, immunosuppression, and infection prophylaxis medications. (See 'Introduction' above.)

Epidemiology – While anemia is present in almost 90 percent of patients in the first month posttransplant, the prevalence falls to 34 to 45 percent among patients more than one year posttransplant depending upon the definition of anemia used, time period posttransplant, and immunosuppressive regimen. Anemia early posttransplantation generally corrects without intervention. (See 'Epidemiology' above.)

Pathogenesis – The pathogenesis of anemia posttransplant varies by time from transplant and by patient characteristics. Anemia immediately posttransplant is almost universally due to lower-than-normal Hb targets in the chronic kidney disease (CKD) and end-stage kidney disease (ESKD) populations, surgical blood loss, frequent phlebotomy, and iron deficiency. Persistence or new onset of anemia after the early posttransplant period may be caused by several factors including immunosuppressive agents, other medications (such as angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers [ARBs]), graft dysfunction, and infections. (See 'Pathogenesis and risk factors' above.)

Surveillance – Kidney transplant recipients should be regularly screened for anemia after transplantation with a complete blood count (CBC). At most transplant centers, a CBC is obtained weekly for the first three months, then every two to four weeks out to one year and then monthly to every three months thereafter. (See 'Surveillance' above.)

Diagnostic evaluation – Kidney transplant recipients who are found to have persistent (ie, Hb levels that fail to normalize at three months posttransplant) or new-onset anemia should undergo a diagnostic evaluation to determine the cause of anemia. Such an evaluation should include an assessment for causes of anemia shared with nontransplant patients, as well as for more specific causes that may be unique to kidney transplant recipients. (See 'Diagnostic evaluation' above.)

Treatment – The general principles of anemia management in patients with CKD or ESKD also apply to the treatment of anemia in kidney transplant recipients. These include treatment of the underlying cause of anemia (if identified), treatment of iron deficiency (if present), and the use of erythropoiesis-stimulating agents (ESAs) to reduce the need for red blood cell (RBC) transfusions. As in nontransplant patients with CKD or ESKD, the selection of individual therapy depends upon the severity of anemia and the presence of iron deficiency. Anemic patients who are iron deficient should be treated with iron before the administration of ESAs. (See 'Treatment' above.)

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Topic 7330 Version 31.0

References

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