Heart transplantation in adults: Treatment of rejection

INTRODUCTION — Despite the use of potent immunosuppressive agents both immediately after cardiac transplantation and during long-term maintenance, acute rejection is a frequent and important problem.

This topic will review the treatment of cellular and antibody-mediated rejection (AMR).

The clinical presentation and diagnosis of acute cardiac allograft rejection are discussed separately. (See "Heart transplantation in adults: Diagnosis of allograft rejection".)

Regimens for induction of immunosuppression immediately after heart transplantation and long-term regimens for the prevention of rejection are discussed separately. (See "Heart transplantation in adults: Induction and maintenance of immunosuppressive therapy".)

PRETREATMENT EVALUATION — In patients suspected of rejection or who have rejection diagnosed via surveillance or for-cause biopsy, the pretreatment evaluation consists of the following:

●History and physical examination – We assess for signs or symptoms of heart failure, arrhythmias, valve disease, and myocardial ischemia.

●Recent changes to immunosuppression – We evaluate for any changes in the dose or type of immunosuppression. In addition, we assess for adherence to the prescribed immunosuppressive regimen and for any changes in medications (eg, discontinuation of fluconazole) that may decrease immunosuppression levels.

●Recent rejection episodes – We assess for recent evidence of rejection including biopsy results and biomarker assays (eg, donor-derived cell-free deoxyribonucleic acid [DNA]). (See "Heart transplantation in adults: Diagnosis of allograft rejection", section on 'Tests for rejection'.)

●Echocardiographic assessment – If there is evidence of new or worsening heart failure, we obtain an echocardiogram.

●Hemodynamic assessment – If cardiogenic shock is suspected, we typically perform right heart catheterization to identify the presence or severity of cardiogenic shock and to help direct therapy (eg, diuretics, inotropic support). (See "Approach to diagnosis and evaluation of acute decompensated heart failure in adults", section on 'Diagnostic evaluation'.)

GENERAL MEASURES — Patients with rejection should be treated with appropriate therapies that may include:

●Dosing of oral immunosuppression to achieve or restore appropriate drug levels.

●Diuretics for volume overload. (See "Use of diuretics in patients with heart failure".)

●Treatments to address cardiogenic shock, such as inotropes and temporary mechanical support devices. (See "Treatment of acute decompensated heart failure: Specific therapies".)

●Antiarrhythmic therapy for atrial or ventricular arrhythmias. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation" and "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy".)

●Supportive measures for any end-organ dysfunction (eg, kidney dysfunction, acute liver injury). (See "Evaluation of acute kidney injury among hospitalized adult patients".)

●Antibiotic, antiviral, and antifungal prophylaxis should be given for approximately three months to any patient treated with antilymphocyte therapy. A typical regimen includes:

•An antifungal to prevent oral candidiasis and invasive fungal infection.

•Valganciclovir to prevent cytomegalovirus (CMV) infection. For patients who are at low risk for CMV infection, acyclovir may be used to prevent herpes virus infections.

•Trimethoprim-sulfamethoxazole or, in patients allergic to sulfa drugs, atovaquone, dapsone, or aerosolized pentamidine to prevent Pneumocystis jirovecii pneumonia.

Further details on management of prophylaxis can be found separately. (See "Prophylaxis of infections in solid organ transplantation", section on 'Post-transplant prophylaxis'.)

CELLULAR REJECTION

Mild to moderate asymptomatic rejection — In patients without signs or symptoms of rejection who have evidence of rejection by surveillance biopsy, the approach to treatment depends on the histologic severity of rejection:

Grade 1 R — In asymptomatic patients diagnosed with grade 1 R rejection (grades 1A, 1B, and 2 in the 1990 system) (table 1), we generally do not alter the chronic immunosuppressive regimen or provide specific treatment for rejection. However, if there is persistent low-grade rejection or recent high-grade rejection (eg, grade 2 R, grade 3 R), it is reasonable to treat such patients with an increase in oral immunosuppression (eg, increase target tacrolimus level) or with an increased dose of any chronic glucocorticoid, followed by a slow taper (eg, increase maintenance prednisone by 5 to 20 mg daily and taper [eg, by 2.5 to 5 mg] if subsequent biopsies show no evidence of rejection).

Typically, the patient can remain on their usual schedule of rejection surveillance. If the patient has factors that increase the likelihood of acute rejection (eg, persistent grade 1 R rejection, recent changes in immunosuppression), additional testing for rejection within two to four weeks may be appropriate.

Our approach is primarily based on our experience and that of other centers; there are no reliable large-scale data to guide practice. In our experience, patients who do not undergo specific treatment for grade 1 R rejection have a low risk of developing worse rejection in the short-term. There are weak data to suggest that patients with recurrent acute cellular rejection, even if mild, may have an increased risk for adverse long-term outcomes, such as development of cardiac allograft vasculopathy [1,2].

Grade 2 R — Our approach to the management of asymptomatic grade 2 R rejection is as follows:

●Acute treatment – In patients with asymptomatic grade 2 R rejection (table 1), we suggest treatment with glucocorticoids rather than no treatment. A typical regimen is oral prednisone (1 to 3 mg/kg for three to five days) [3]; an alternative regimen is intravenous methylprednisolone 250 to 1000 mg/day for three days [4].

Antimicrobial and antiviral prophylaxis should be implemented in patients who receive high-dose steroids. (See 'General measures' above.)

●Short-term changes to chronic immunosuppressive regimen – After acute treatment of grade 2 R rejection, short-term changes to chronic immunosuppression are based on:

•Circumstances of the episode of rejection (eg, immunosuppression levels, adherence).

•History of rejection (eg, isolated versus persistent).

•Severity of other recent rejection episodes (eg, recent grade 3 R rejection, history of hemodynamic compromise).

•Findings on subsequent biopsy (eg, resolution, persistence).

Further immunosuppressive therapy depends on the presence of the risk factors noted above:

•Patients without risk factors – In patients who underwent acute therapy for grade 2 R rejection who have none of the risk factors noted above, we generally resume the patient's chronic immunosuppression regimen without changes to doses, agents, or target levels. We taper the dose of prednisone if there is evidence or high suspicion of adrenal insufficiency, while some experts may taper glucocorticoid doses to provide additional immunosuppression or to reduce the risk of adrenal insufficiency. (See "Glucocorticoid withdrawal", section on 'Tapering regimens'.)

•Patients with risk factors – In patients who have one or more of the risk factors noted above, we typically increase the patient's immunosuppression in the short-term. The approach to temporary increases in immunosuppression is individualized but may include an increase in or addition of low-dose glucocorticoids (eg, prednisone 5 to 20 mg daily), an increase in target levels of calcineurin inhibitors or mammalian target of rapamycin (mTOR) inhibitors, or a change in regimen (eg, discontinuation of mycophenolate mofetil and addition of sirolimus). The duration of such changes is typically determined by the patient's history of rejection and the results of ongoing testing.

●Subsequent testing and management – Repeat endomyocardial biopsies are typically obtained approximately two weeks after completion of acute treatment of grade 2 R rejection to verify histologic resolution. Resolution of rejection is defined as a subsequent biopsy of grade 1 R or less. Subsequent therapy is tailored to the findings on repeat biopsy.

If repeat endomyocardial biopsy shows persistent grade 2 R rejection, the options for therapy include antithymocyte globulin (0.75 to 1.5 mg/kg/day for three to five days), switching calcineurin or mTOR inhibitors (eg, change cyclosporine to tacrolimus), or adding or replacing mycophenolate or azathioprine with an mTOR inhibitor (sirolimus or everolimus).

●Recommendations of others and rationale – Our approach to the management of grade 2 R rejection is similar to professional guidelines and is largely based on our experience [5]. There are no high-quality studies to guide practice; the available studies of grade 2 R rejection are retrospective and were conducted prior to widespread use of the revised biopsy grading system [6,7]:

•In one study of patients with grade 2 rejection (1990 system (table 1)), resolution of rejection occurred in 85 percent of patients treated with glucocorticoids compared with 87 percent of those who were not treated with glucocorticoids [6].

•Another report suggested that even late after transplantation, the outcome of grade 2 rejection (1990 system) was not necessarily benign [7]. In a multivariable analysis, grade 2 rejection (grade 1 R in the 2004 system (table 1) was the strongest predictor of the development grade 3A (now grade 2 R) or higher rejection on a subsequent biopsy (odds ratio 2.4) [7].

Symptomatic or grade 3 R rejection — Patients with new cardiac symptoms (eg, new signs or symptoms of heart failure, new atrial flutter) with confirmed or suspected cellular rejection and those with grade 3 R rejection require empiric treatment for rejection. The approach is follows:

●Acute treatment – For most patients, we suggest initial treatment with antithymocyte globulin (ATG; 0.75 to 1.5 mg/kg/day for three to five days) in combination with three days of intravenous (IV) glucocorticoids (250 to 1000 mg/day for three days). In addition, we implement therapies appropriate for heart failure, cardiogenic shock, and arrhythmias as appropriate. (See 'General measures' above.)

After acute treatment, we assess for resolution of signs and symptoms of rejection. If signs or symptoms of rejection persist, additional treatments are individualized and often include an additional course of high-dose IV glucocorticoids and ATG.

In our experience, this regimen reverses more than 80 percent of rejection episodes. There are no data to guide practice.

●Changes to chronic immunosuppression – After acute treatment of severe rejection, calcineurin inhibitors and other maintenance immunosuppressive agents (eg, mycophenolate mofetil) are either continued at their pretreatment doses or at higher doses.

●Subsequent monitoring and management – Endomyocardial biopsies are obtained approximately two weeks after the initial diagnosis to assess for resolution. If resolution occurs, we typically increase the frequency of surveillance testing for one to two months. The management of persistent rejection is discussed below.

Recurrent cellular rejection — The treatment of recurrent rejection depends on the grade of rejection and the severity of any allograft dysfunction:

●Asymptomatic grade 1 R rejection – If grade 1 R rejection persists either with or without treatment, an augmentation or change in immunosuppression is reasonable. For example, cyclosporine may be switched to tacrolimus, target tacrolimus levels may be increased, or the dose of maintenance glucocorticoids may be increased.

●Asymptomatic grade 2 R rejection – In patients with persistent 2 R rejection, we typically treat with intravenous glucocorticoids at a high dose (500 to 1000 mg/day for three days) and ATG.

●Grade 3 R or symptomatic rejection – Patients with refractory grade 3 R rejection or symptomatic rejection should be treated with high-dose intravenous glucocorticoids and ATG until the grade of histologic rejection has improved and there is evidence of improved cardiac function.

These approaches are based on our experience and the notion that ongoing rejection may lead to graft dysfunction; there are no data to guide practice.

Refractory rejection — If rejection persists despite repeated doses of high-dose glucocorticoids and ATG, options for therapy include:

●Photophoresis – Photopheresis, also called photochemotherapy, involves ex vivo separation of leukocytes from erythrocytes and exposure of the leukocytes to 8-methoxypsoralen and ultraviolet light. The leukocytes that are rapidly proliferating (such as T cells responding to alloantigens) are preferentially damaged. The damaged cells are returned to the patient and presumably induce counterimmune responses such as T-cell vaccination.

Photopheresis is a treatment option for patients who have persistent rejection despite increases in their long-term immunosuppressive regimen or who do not acutely respond to intravenous glucocorticoids or other immunosuppressants (eg, ATG). Photopheresis is usually performed twice per week for four weeks, followed by monthly sessions for five additional months.

The use of photopheresis in this population is based on our experience; the evidence describing photopheresis for the treatment of cardiac allograft rejection is limited to older studies that included small numbers of patients [8,9].

●Total lymphoid irradiation – Total lymphoid irradiation (at a dose of 8 Gy) has been used to treat resistant cardiac or renal allograft rejection [10,11]. It is an option for patients who have exhausted all other therapeutic options. Side effects include leukopenia and nausea. This technique is also limited by being costly, time consuming, and slow.

●Retransplantation – In patients in whom rejection cannot be controlled or in whom rejection causes severe and refractory heart failure symptoms, retransplantation may be an option. The evaluation for retransplantation is discussed separately. (See "Heart transplantation in adults: Indications and contraindications" and "Heart transplantation in adults: Indications and contraindications", section on 'Indications for retransplantation'.)

ANTIBODY-MEDIATED REJECTION

Hyperacute rejection — Patients with primary graft dysfunction who have elevated donor-specific antibodies (DSA) evident on the retrospective crossmatch, known as preformed antibody to donor antigen, or donor-recipient ABO incompatibility require treatment for hyperacute rejection. In such patients, we suggest combination therapy that includes acute plasmapheresis, high-dose intravenous (IV) glucocorticoids, and IV immunoglobulin (IVIG). In addition, patients may require supportive measures for cardiac dysfunction (eg, inotropes, temporary mechanical circulatory support).

Professional guidelines do not describe a specific regimen of therapy [5]. Our approach is based on our experience and is intended to rapidly reduce circulating antibodies and prevent further antibody production. Terminal complement inhibition (ie, eculizumab) or an interleukin-6 receptor blocker (ie, tocilizumab) may be used to treat hyperacute rejection, but experience with these agents is limited [12,13].

Elevated donor-specific antibodies — In patients with evidence of high circulating DSA but without pathologic evidence (ie, immune deposition in myocardial structures) of antibody-mediated rejection (pAMR) or cardiac dysfunction, the need for treatment is unclear. Some experts offer no treatment, while others treat with the goal of reducing DSA levels, especially among patients with particularly high DSA levels or past evidence of cardiac dysfunction. Since the quantification of DSA and C1q binding are highly variable between centers, local expertise is required to determine absolute thresholds for treatment. However, newly identified DSA and rising DSA represent high-risk scenarios that often prompt treatment.

The approach to treatment is individualized. Treatment options include a change in long-term immunosuppression (eg, mycophenolate mofetil, sirolimus, higher target levels or doses of existing agents), intensive inpatient treatment with plasmapheresis and IVIG, immune therapies such as rituximab and bortezomib, or a combination of therapies.

In the presence of elevated DSA, surveillance for changes in DSA should occur periodically. In general, more frequent surveillance is performed if DSA levels are high by local standards, DSA levels are increasing, new DSA was detected, or an interval sensitizing event occurred (eg, blood transfusion).

Professional guidelines do not comment on a specific approach to patients with asymptomatic DSA elevation or AMR, and there are few studies to guide practice [5].

Biopsy-proven AMR — Patients with pAMR grade 1 and higher grades of AMR generally undergo dedicated treatment for AMR. However, the intensity of treatment varies according to the patient’s characteristics including:

●Recent history of AMR and any ongoing treatments for AMR

●Clinical evidence of acute or chronic graft dysfunction (eg, reduced left ventricular systolic dysfunction)

●Severity of rejection by biopsy (ie, pAMR 1 to 3)

●Recent trends in DSAs including new or increasing DSA levels

●Elevated donor-derived cell-free DNA levels

The management of AMR consists of the following:

●Supportive treatments for cardiac dysfunction – In patients with AMR and cardiac dysfunction, we provide appropriate treatment for cardiac complications such as cardiogenic shock and arrhythmias.

●Initial immunomodulatory therapy – A typical initial treatment regimen for acute AMR consists of combination therapy with IV glucocorticoids (250 to 1000 mg daily for three days), plasmapheresis (three to seven sessions), and IVIG (1 to 2 g/kg given in two divided doses). Some centers also treat with antithymocyte globulin (0.75 to 1.5 mg/kg for three to five days). However, the agents, doses, and duration of therapy are typically individualized to the degree of AMR and severity of cardiac dysfunction.

●Additional immune therapy – Upon completion of initial therapy, practice varies, but may include follow-up therapy with rituximab, bortezomib, or other immunomodulating agents. Treatment typically continues until signs and symptoms of cardiac dysfunction improve. However, the AMR process may resolve before the signs and symptoms of cardiac dysfunction, which may be permanent.

Changes to long-term immunosuppression may include the addition of oral glucocorticoids, high-dose antimetabolite (eg, mycophenolate mofetil), or transition to a regimen that contains sirolimus or everolimus.

●Subsequent testing – Repeat hemodynamic assessment, cardiac biopsies, echocardiography, and DSA level testing should be performed as needed. DSA levels are typically monitored periodically (eg, monthly to every three months for 6 to 12 months after treatment has been administered). However, the timing of such studies is unclear, and DSA levels obtained during treatment may not fully reflect the effects of treatment.

There are no prospective studies to guide the approach to therapy for patients with biopsy evidence of AMR. The available data suggest worse prognosis among patients who develop AMR, and there are single-center reports that describe the response to therapy:

●A small study suggested that the outcome in patients with AMR severe enough to produce hemodynamic compromise may be improved by plasmapheresis in combination with pulse IV glucocorticoids (250 to 1000 mg/day for three days) and antithymocyte globulin (0.75 to 1.5 mg/kg/day for three to five days) [14].

Refractory AMR — In patients with evidence of ongoing AMR, therapy is individualized based on the past response to specific therapies and severity of cardiac dysfunction. Therapy may include repeat plasmapheresis along with other immunomodulatory therapies such as IVIG, rituximab, alemtuzumab, bortezomib, eculizumab, tocilizumab, photopheresis, or total lymphoid irradiation.

Long-term regimens may include oral glucocorticoids, sirolimus, everolimus, or cyclophosphamide [15]. Some centers administer IVIG monthly in patients who have completed initial therapy for refractory or severe AMR. However, there are no data to guide the duration of therapy or that describe the efficacy of this approach.

There are no high-quality studies to direct therapy for refractory AMR.

Prognosis — AMR is associated with a poor prognosis, with reduced survival and increased incidence of allograft failure and development of cardiac allograft vasculopathy. However, the data are not reliable enough to provide more accurate prognostic information [15].

MIXED REJECTION — In patients with evidence of cellular and antibody-mediated rejection (AMR), therapy is individualized. In general, we provide therapies targeted at both mechanisms of rejection, and often treat with the full course of AMR therapy, including pulse glucocorticoids, antithymocyte globulin, plasmapheresis, IVIG, and other adjunctive agents, based on the severity of rejection and presence of graft dysfunction. (See 'Cellular rejection' above and 'Antibody-mediated rejection' above.)

NON-HLA ANTIBODY-MEDIATED REJECTION — In patients without detectable donor-specific antibodies but who have compliment deposition on cardiac biopsy, non-human leukocyte antigen (non-HLA) antibody-mediated rejection (AMR) may be present. The approach to diagnosis of non-HLA AMR is discussed separately. (See "Heart transplantation in adults: Diagnosis of allograft rejection", section on 'Acute antibody-mediated (humoral) rejection'.)

Therapy for non-HLA AMR is poorly defined, but typically includes therapies appropriate for AMR, as noted above.

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: Heart transplant (The Basics)")

●Beyond the Basics topics (see "Patient education: Heart transplantation (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Pretreatment evaluation – In patients suspected of rejection or who have biopsy evidence of rejection, the pretreatment evaluation consists of a history with a focus on recent changes to immunosuppression and recent rejection episodes, physical examination, echocardiographic assessment, and, if cardiogenic shock is suspected, hemodynamic assessment. (See 'Pretreatment evaluation' above.)

●General measures – Patients with rejection should be treated with therapies appropriate for any cardiac complications of rejection (eg, heart failure, arrhythmias), immunosuppression appropriate for the severity of rejection, antibiotics and antiviral agents for prophylaxis in those who receive high-dose immunosuppressants, and therapy for any end-organ dysfunction. (See 'General measures' above.)

●Cellular rejection

•Mild to moderate asymptomatic rejection – In patients without signs or symptoms of rejection who have evidence of rejection by surveillance biopsy, the approach to treatment depends on the histologic severity of rejection:

-Grade 1 R – Asymptomatic patients diagnosed with grade 1 R rejection (grades 1A, 1B, and 2 in the 1990 system) (table 1) do not generally require changes to their chronic immunosuppressive regimen or specific treatment for rejection. However, if rejection occurs in a background of sustained rejection or graft dysfunction, it is reasonable to treat grade 1 R rejection. (See 'Grade 1 R' above.)

-Grade 2 R – In patients with asymptomatic grade 2 R rejection (table 1), we suggest initial treatment with glucocorticoids rather than no treatment (Grade 2C). A typical regimen is oral prednisone (1 to 3 mg/kg for three to five days); an alternative regimen is intravenous (IV) methylprednisolone 250 to 1000 mg/day for three days.

After acute treatment of grade 2 R rejection, short-term changes to chronic immunosuppression and rejection surveillance are based on patient characteristics (eg, circumstances of the episode of rejection, severity of other recent rejection episodes). (See 'Grade 2 R' above.)

•Symptomatic or grade 3 R rejection – Patients with new symptoms of cardiac dysfunction (eg, heart failure, atrial flutter) with confirmed or suspected cellular rejection and those with grade 3 R rejection require empiric treatment for rejection. For most patients, we suggest initial treatment with antithymocyte globulin (ATG; 0.75 to 1.5 mg/kg/day for three to five days) in combination with three days of IV glucocorticoids (250 to 1000 mg/day for three days) rather than other regimens (Grade 2C). If ATG is unavailable, it is reasonable to treat with glucocorticoids alone until ATG can be obtained.

The approach to changes to long-term immunosuppression and the subsequent approach to rejection monitoring are individualized. (See 'Symptomatic or grade 3 R rejection' above.)

●Antibody-mediated rejection

•Hyperacute rejection – Patients with primary graft dysfunction who have elevated donor-specific antibodies (DSA) evident on the retrospective crossmatch, known either as preformed antibody to donor antigen or donor-recipient ABO incompatibility, require treatment for hyperacute rejection. For such patients, we suggest combination therapy that includes acute plasmapheresis, high-dose IV glucocorticoids, and IV immunoglobulin (IVIG). Patients may require supportive measures for cardiac dysfunction (eg, inotropes, temporary mechanical circulatory support). (See 'Hyperacute rejection' above.)

•Elevated donor-specific antibodies – In patients with evidence of high circulating DSA but without evidence of immune deposition in myocardial structures or cardiac dysfunction (ie, pathologic antibody-mediated rejection [pAMR] 0), the approach is individualized and varies by center. Some experts offer no treatment, while others treat with the goal of reducing DSA levels, especially among patients with particularly high DSA levels or past evidence of cardiac dysfunction.

Treatment options include ongoing observation without a change in therapy, a change in long-term immunosuppression (eg, mycophenolate mofetil, sirolimus, higher target levels or doses of existing agents), intensive inpatient treatment with plasmapheresis and IVIG, immune therapies such as rituximab and bortezomib, or a combination of therapies. (See 'Elevated donor-specific antibodies' above.)

•Biopsy-proven AMR – In patients with pAMR grade 1 or higher, we suggest treatment with combination therapy that includes IV glucocorticoids (250 to 1000 mg daily for three days), plasmapheresis (three to seven sessions), and IVIG (1 to 2 g/kg given in two divided doses). Some centers also treat with ATG (0.75 to 1.5 mg/kg for three to five days). However, the agents, doses, and duration of therapy are typically individualized to the degree of AMR and severity of cardiac dysfunction. (See 'Biopsy-proven AMR' above.)

●Mixed rejection and non-HLA-mediated rejection – In patients with evidence of cellular and AMR or non-human leukocyte antigen (non-HLA) AMR, therapy is individualized. (See 'Mixed rejection' above and 'Non-HLA antibody-mediated rejection' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Mariell Jessup, MD, who contributed to earlier versions of this topic review.