Immunosuppressants in Kidney Transplantation

Immunosuppressants Use in Kidney Transplantation

• Recipient recognition of the transplanted graft is based on the recipient's reaction to histocompatibility antigens.
• Grafts can be recognized as 'self' or 'foreign'.
• Immunosuppressive therapy is crucial for preventing rejection.

Histocompatibility Antigens

• HLA Class I and HLA Class II are vital cellular components involved in the immune response in the body
• HLA Class I antigens are found on virtually all nucleated cells and play a crucial role in displaying peptides derived from intracellular pathogens and in recognizing self-MHC-associated peptides.
• HLA Class II antigens are primarily expressed on antigen-presenting cells (APCs), including macrophages, dendritic cells, and B cells.

The Immune Response to Grafts

• In a kidney transplant, T cells play a vital role in the process.

• After transplantation, the recipient's immune system can recognize the donated kidney as foreign tissue and initiate an attack.

• To reduce the risk of rejection or prevent rejection, immunosuppressive drugs, like the ones mentioned in later sections, are prescribed.

Panel-Reactive Antibody (PRA)

• This test assesses the recipient's serum against HLA specificities of potential donors.
• The percentage of cell reactions determines the recipient's PRA.
• A higher PRA (>20%-50%) indicates greater risk of rejection.

Lymphocyte Cross-Match

• Cytotoxic and/or flow cytometry cross-matches the recipient's serum to assess preformed antibodies against donor lymphocytes.
• A positive cross-match, where recipient cytotoxic IgG antibodies are present, may need to be considered a contraindication for kidney transplantation.

ABO Blood Typing

• ABO blood typing is an essential evaluation for organ transplantation, especially for kidneys.
• Transplantation with ABO incompatibility usually results in hyperacute rejection of the graft.

Desensitization Strategies

• Desensitization strategies aim to reduce HLA antibodies in potential recipients, lessening the risk of a positive crossmatch.
• This involves methods like plasmapheresis and rituximab to address existing antibodies.
• Such protocols increase the chance of successful transplantations.

Immunosuppressives

• Many drugs are used, categorized based on their mechanism of action e.g., antireceptor antibodies, calcineurin inhibitors, and mTOR inhibitors.
• These drugs prevent the immune system from rejecting the transplanted kidney.

Drugs that Inhibit T-cell Activation

• Several drugs are used to inhibit T-cell activation, preventing the rejection of the transplanted kidney, including Cyclosporine Tacrolimus, Belatacept, Basiliximab, Daclizumab.
• These drugs target specific components of the T-cell activation pathway.

T-cell Depleting Drugs

• T-cell depleting drugs, such as Muromonab-CD3 and Anti-thymocyte globulin, directly target and eliminate T cells, minimizing the risk of rejection.

Rejection

• Rejection episodes can be acute or chronic.
• Acute rejection commonly occurs within the first 60 days post transplant
• Chronic rejection is a slower process, often spanning several years.
• Cellular or antibody-mediated rejection are two major types of rejection.

Hyperacute Rejection

• This type of rejection happens within minutes to hours after transplantation.
• Improved HLA typing and ABO matching have reduced its occurrence.

Accelerated Rejection

• Accelerated rejections can occur primarily in recipients who have undergone prior kidney transplants, multiple pregnancies, or blood transfusions.
• This type is often resistant to standard rejection therapies.

Acute Rejection

• Acute rejection often arises within the initial week or months after transplantation.
• It's often linked to patient noncompliance with medications and monitoring.

Chronic Rejection

• Chronic rejection occurs gradually, typically over several years.
• It usually leads to gradual decline in renal function and kidney failure.
• It can be either cellular- or antibody-mediated.

Chronic Allograft Injury (CAI)

• CAI is a diagnosis of exclusion.
• It points to a progressive decline in renal function.
• It typically involves several factors including previous infection, immunosuppression therapy and nonimmunological factors like hypertension or recipient comorbidities.

Immunosuppressive Therapy

• Induction and maintenance therapies are crucial post-transplantation.
• Common induction therapies include ATG and Basiliximab.
• Common maintenance therapies include calcineurin inhibitors, antimetabolites, and corticosteroids.

Antibody-Mediated Rejection

• Plasma exchange, IVIG, Rituximab, and Bortezomib are some of the therapies used for antibody-mediated rejection.
• These treatments aim to remove antibodies that target the donor kidney.

T-cell-Mediated Rejection

• Methylprednisone is used to treat these cases.
• Rabbit antithymocyte globulin is also helpful along certain maintenance therapies.

Chronic Rejection Therapy

• Chronic antibody-mediated rejection is treated using therapies that have been used in other antibody-mediated rejection cases.
• However, these measures aren't consistently effective.

Therapeutic Use of ATG

• ATG is used for induction immunosuppression to reduce transplant rejection risk.
• It's highly effective for cases where recipients have a high risk, including repeat transplants.

Basiliximab: Therapeutic Use

• Basiliximab is used as prophylaxis post transplant especially in cases where the risk is 'low' and 'intermediate'.

Mycophenolic Acids

• Mycophenolic acids are immunosuppressants used in combination with other medications to assist in preventing the rejection of transplanted organs.

Azathioprine: Therapeutic Use

• Azathioprine is used in conjunction with other immunomodulatory agents to reduce the risk of rejection in patients with unsuitable mycophenolic acid therapies or pregnancies.

Cyclosporine

• Approved for prevention and treatment of solid organ transplant rejection.
• Can be used alone or in combination with other immunosuppressants.

Tacrolimus

• Tacrolimus immediate-release formulations are widely used for prophylaxis and treatment post-transplant in various solid organ cases when paired with other immunosuppressants.

Sirolimus

• Sirolimus has side effects like delayed wound healing and affecting the lipid profile.

Prednisone

• Prednisone is used with other immunosuppressive drugs for transplant rejection.

Special Outpatient Medications

• Many medications are used to maintain a healthy transplant function and to avoid rejection.
• Erythropoiesis stimulating agents, and anti-viral agents are crucial components.

Screening and Graft Monitoring

• Routine screening and monitoring is needed after transplantation to detect any signs of dysfunction, and optimize graft health.
• This includes various tests that assess kidney function and other relevant factors.

Management of Comorbidities

• Managing comorbidities is crucial for kidney transplant recipients.
• Special focus on bone disease, hyperuricemia, and infection management to help prevent, monitor, and adjust treatment for potential issues.

Management of Infection

• Appropriate treatment methods, such as antiviral drugs and antifungal agents.
• Close monitoring for infections is crucial as they could negatively impact the health condition of the patient.