**7. Therapeutic management**

### **7.1 Phases**

Immunosuppressive treatment of the transplanted patient begins with the induction phase, which begins perioperatively and continues immediately after transplantation. Maintenance therapy then continues for the life of the allograft. Induction and maintenance strategies use different medicines at specific doses or at doses adjusted to achieve target therapeutic levels to give the transplanted patient the best hope for long-term graft survival[19].

#### *Induction strategy*

The induction strategies include antibody-based therapy and aggressive early immunosuppression to avoid early acute rejection.

#### Antibody-based therapy:

This therapy uses monoclonal or polyclonal antibodies and is administered in the early posttransplant period (up to 8 wk). Antibody-based therapy allows for avoidance of or dose reduction of calcineurin inhibitors, possibly reducing the risk of nephrotoxicity. All agents are effective for preventing acute rejections, although the anti-CD25 antibodies may require concurrent administration with calcineurin inhibitors. The adverse effect profiles of polyclonal and monoclonal antibody therapies limit their use in some patients. Patients at a high risk of rejection may receive rabbit anti-thymocyte globulin (Thymoglobulin).

#### Aggressive early immunosuppression:

This therapy uses maintenance drugs at higher doses to achieve the strongest immunosuppressive effect directly following transplantation. Approximately 50% of patients do not receive antibody therapy at the time of transplantation. The highest doses of calcineurin inhibitors place patients at increased risk of nephrotoxicity and may not be the best strategy for patients at the highest risk for rejection.

#### *Maintenance strategy*

Maintenance of immunosuppression is the key for the prevention of acute and chronic rejections throughout the life of the graft.

After induction therapy, whether this involves high-dose steroids that are then tapered off or an anti-thymocyte globulin preparation, maintenance therapy involves maintaining the program of conventional immunosuppression in order to prevent graft rejection[21]. Conventional maintenance therapy has evolved over the years and now includes multiple immunosuppressive agents that are given in non-toxic doses. Historically, corticosteroids and azathioprine were used to maintain grafts after induction therapy. Cyclosporine was then added to the armamentarium for maintenance therapy. Triple-drug therapy using cyclosporine, azathioprine, and prednisone is the most common maintenance regimen for many transplant recipients. Triple-drug therapy permits lower doses of cyclosporine and azathioprine to be given, as well as enabling the use of low-dose steroids or every-other-day steroid therapy.

In stable liver transplant patients, cyclosporine can be discontinued and the recipient maintained on azathioprine or MMF and every-other-day steroids. Alternatively, patients have been maintained on cyclosporine monotherapy with complete withdrawal of MMF and steroids.

Following the clinical introduction of tacrolimus, this potent agent increased rapidly in popularity for maintenance therapy in liver transplant recipients. Tacrolimus-based therapies usually include very-low-dose prednisone, but may also utilize azathioprine or MMF. The potent activity of tacrolimus enables more rapid steroid withdrawal, and many patients can be maintained off steroids altogether with the use of tacrolimus.

#### **7.2 Anti-rejection strategies**

#### *Acute rejection*

A number of strategies are available for patients who experience an acute rejection episode. For typical patients, alteration in clinical graft function prompts a liver biopsy and pathological evaluation of the graft for rejection. The 3 agents used to treat acute rejection are (1) steroids, (2) anti-thymocyte globulin, and (3) muromonab-CD3.

dose reduction of calcineurin inhibitors, possibly reducing the risk of nephrotoxicity. All agents are effective for preventing acute rejections, although the anti-CD25 antibodies may require concurrent administration with calcineurin inhibitors. The adverse effect profiles of polyclonal and monoclonal antibody therapies limit their use in some patients. Patients at a high risk of rejection may receive rabbit anti-thymocyte globulin

This therapy uses maintenance drugs at higher doses to achieve the strongest immunosuppressive effect directly following transplantation. Approximately 50% of patients do not receive antibody therapy at the time of transplantation. The highest doses of calcineurin inhibitors place patients at increased risk of nephrotoxicity and may not be the

Maintenance of immunosuppression is the key for the prevention of acute and chronic

After induction therapy, whether this involves high-dose steroids that are then tapered off or an anti-thymocyte globulin preparation, maintenance therapy involves maintaining the program of conventional immunosuppression in order to prevent graft rejection[21]. Conventional maintenance therapy has evolved over the years and now includes multiple immunosuppressive agents that are given in non-toxic doses. Historically, corticosteroids and azathioprine were used to maintain grafts after induction therapy. Cyclosporine was then added to the armamentarium for maintenance therapy. Triple-drug therapy using cyclosporine, azathioprine, and prednisone is the most common maintenance regimen for many transplant recipients. Triple-drug therapy permits lower doses of cyclosporine and azathioprine to be given, as well as enabling the use of low-dose steroids or every-other-day

In stable liver transplant patients, cyclosporine can be discontinued and the recipient maintained on azathioprine or MMF and every-other-day steroids. Alternatively, patients have been maintained on cyclosporine monotherapy with complete withdrawal of MMF

Following the clinical introduction of tacrolimus, this potent agent increased rapidly in popularity for maintenance therapy in liver transplant recipients. Tacrolimus-based therapies usually include very-low-dose prednisone, but may also utilize azathioprine or MMF. The potent activity of tacrolimus enables more rapid steroid withdrawal, and many

A number of strategies are available for patients who experience an acute rejection episode. For typical patients, alteration in clinical graft function prompts a liver biopsy and pathological evaluation of the graft for rejection. The 3 agents used to treat acute rejection

patients can be maintained off steroids altogether with the use of tacrolimus.

are (1) steroids, (2) anti-thymocyte globulin, and (3) muromonab-CD3.

(Thymoglobulin).

*Maintenance strategy* 

steroid therapy.

and steroids.

*Acute rejection* 

**7.2 Anti-rejection strategies** 

Aggressive early immunosuppression:

rejections throughout the life of the graft.

best strategy for patients at the highest risk for rejection.

Steroids are the first-line treatment for rejection. These agents are the mainstay of therapy for acute rejection episodes, preventing macrophage IL-1 release and blocking T cell synthesis of IL-2. Steroids also have anti-inflammatory properties. The typical dosage is 10 mg/kg/d for 3-5 days, which is then tapered down to a maintenance dose. Steroids reverse 60-75% of rejection episodes.

Anti-thymocyte globulin: This agent binds all circulating T and B lymphocytes, which are then lysed or phagocytosed by macrophages and neutrophils. The efficacy of anti-thymocyte globulin is similar to muromonab-CD3. Anti-thymocyte globulin treatment is generally reserved for steroid-resistant acute rejection because of its cost, toxicity, and the development of anti-drug antibodies.

Muromonab-CD3: This agent displaces the T3 molecule from antigen receptors, binds all mature T cells, and prevents alloantigen recognition. The reversal rate of first acute rejection episodes is 94% for patients treated with muromonab-CD3. Muromonab-CD3 is sometimes used as the first-line agent for severe vascular rejections. The development of human antimurine antibodies allows for the reappearance of CD3 T cells, which may decrease muromonab-CD3 efficacy and necessitate higher doses, possibly increasing the risk of infection. A second course of muromonab-CD3 treatment may be given for recurrent rejection, although repeated treatments can be associated with complications from the development of anti-murine antibodies. The success rate in recurrent episodes is approximately 40-50%.

#### *Chronic rejection*

For patients with chronic rejection, newer agents may be on the horizon to slow or reverse the rejection process. Unless inadequate immunosuppression is the cause of rejection, changes in immunosuppressive therapy are generally not effective in reversing chronic rejection. In liver transplant recipients whose organs have significant regenerative abilities, the use of high-dose tacrolimus appears to have some effect in reversing chronic rejection; however patients must be treated early in the course of chronic rejection. The addition of sirolimus to MMF is currently being studied to determine efficacy. Long-term data on transplanted patients treated with sirolimus demonstrated that the chronic rejection rates are much lower compared to rates traditionally reported for cyclosporine-based regimens. Blood pressure management, treatment of hyperlipidemia, and diabetes management are the current mainstays of treatment for graft preservation[20].

#### **7.3 Primary immunosuppressive agents**

Calcineurin inhibitors combine with binding proteins to inhibit calcineurin activity. This works to inhibit IL-2, which is critical for T helper cell proliferation. Calcineurin normally exerts phosphatase activity on the nuclear factor of activated T cells. This factor then migrates to the nucleus to initiate IL-2 transcription. Although studies have shown that cyclosporine and tacrolimus were associated with similar rates of graft survival, several studies have shown lower rates of rejection episodes with tacrolimus.

Levels of both cyclosporine and tacrolimus must be carefully monitored. Trough levels appear to correlate well with drug exposure in patients receiving tacrolimus. Initially, levels can be kept in the range of 10-20 ng/mL; however, after 3 months, levels are kept lower (5-10 ng/mL) to reduce the risk of nephrotoxicity. Controversy continues regarding the best method to monitor cyclosporine levels.

### **7.4 Adjuvant agents**

These agents are usually combined with a calcineurin inhibitor and include steroids, azathioprine, MMF, and sirolimus. Currently, most protocols use a calcineurin inhibitor and steroids with or without MMF. The use of adjuvant agents allows clinicians to achieve adequate immunosuppression while decreasing the dose and toxicity of individual agents.

In kidney transplant recipients, mycophenolate mofetil has assumed an important role in immunosuppression after several clinical trials reported a marked decrease in the prevalence of acute cellular rejection compared to azathioprine; furthermore, a reduction in 1-year treatment failures was also reported for MMF. Ongoing long-term studies suggest MMF also reduces the prevalence of chronic rejection.

Sirolimus has shown great promise for its potential to combat acute cellular rejection and to provide rescue immunosuppression. Current work shows that sirolimus causes a significant decrease in acute rejection and improvement in patient and graft survival compared to azathioprine[21, 22].
