Immunosuppression Drugs In Renal Transplant

Definition Of Organ Transplant

An organ transplant is a surgical operation in which a failing or damaged organ in the human body is removed and replaced with a functioning one. The donated organ may be from a deceased donor, a living donor, or an animal. The immune systems of two people are different so that is why there is a chance of rejection. That is why renal transplants, or any other transplant was not that possible. But with the advent of immunosuppressive drugs which suppresses the immune system, transplant is a reality now.

Immunosuppression Agents

• The immunosuppressive agents can be either chemical agents or biological agents.

But the better way of classifying the immunosuppressive drugs is into the Induction agents and Maintenance agents. Drugs that are used as an induction just before the transplants, or within the first 10 to 15 days of the transplant. These particular immunosuppressive agents are very strong.  Other type of drugs are maintenance agents. Once the body has accepted the donor organ, the immunosuppressive agents are still needed to prolong the stay of that particular organ in the recipient. These come under the category of the maintenance immunosuppressants.

This is the timeline where the various immunosuppressive agents were invented:

Protocols In Use

• Immunosuppressive agents are given before and after renal transplant to manage and treat patients. Pre-transplant immunosuppressive agents include steroids, micromophetol, and Tacrolimus, which are given just before and during the transplant. For the first three days prednisolone 100 milligrams is given. Then MMF is given from 500 to 1000 milligrams. But if the DLC count is not that great or the particular patient is more susceptible to the infection, then MMF is reduced. The induction agent, either depleting (ATG) or non-depleting (Basiliximab), is given 1 hour before the transplant, depending on the cross-match and rejection factors. The post-transplant maintenance regimen involves three main drugs: Tacrolimus, MMF, and prednisone (or cyclosporine if there is neurotoxicity). The levels of Tacrolimus need to be monitored and maintained within a specific range as they fluctuate significantly. The three-drug regimen is the most common and followed protocol for maintenance of renal transplant patients. Side effects of these drugs include neurotoxicity, infection susceptibility, and fluctuating levels of Tacrolimus.

Steroids

• Glucocorticoids-they are potent immunosuppressants. The upregulation of the gene encoding 1k-β. This protein binds to and inhibits the function of NF-κB. Steroids inhibit the cytokine secretion of IL-1,6 and TNF.  Function of macrophages is blocked. Phospholipase A2, and arachidonic acid cascade is inhibited High-dose IV steroids used as induction therapy. It is tapered to the maintenance dose of 5 to 15 mg/d over 3 to 6 months.

Side Effects

• Steroids have several side effects including  Hypertension,  Hypoglycemia(diabetes),  Weight gain,  Peptic ulcers d, Pancreatitis,  Osteoporosis with avascular necrosis of the femoral head, Susceptibility to pyogenic and opportunistic infections. Steroids increase the chances of opportunistic or biogenic infection. The inhibition of NFkB ultimately causes the down regulation of cytokines and hampers DNA replication. Steroids are tapered gradually from a high dose to a maintenance dose and then brought down to 5-50 milligrams per day.

Cyclosporine

• They were discovered from the fungus Tolypocladium inflatum. They engage cyclophilin, forming a complex that inhibits calcineurin phosphatase and T-cell activation. NEORAL: Oral formulation - it immediately forms a micro emulsion in an aqueous environment improved bioavailability. The oral dose is 10 mg/kg per day. It has a narrow therapeutic window.  Close monitoring is required. The 2-hour past dose level (C2) is significantly more accurate than C0 and shows a better correlation with calcineurin inhibition activity and short-term graft survival.

Tacrolimus (Pangraf)

• Tacrolimus is a commonly used immunosuppressant drug in renal transplantation, also known as Prograf or Pangraf. It is isolated from Fungus Streptomyces tsukubaensis. It engages immunophilin FK506-binding protein 12 (FKBP12) to create a complex that inhibits calcineurin. The efficacy is similar to cyclosporine. It has less Nephrotoxicity and Hemolytic-uremic syndrome, Hirsutism, Gingival hyperplasia, and gout. It is most likely to induce post transplantation diabetes and neurotoxicity. Its use has increased steadily. Regular Monitoring of Levels is required. Usual target level is = 5-15 mg/L. The target level depends on -  Level of adjunctive immunosuppressive therapy, risk of acute rejection, higher levels have been used for 1-2 days to fight rejection. Level should not be allowed to exceed 20 mg/L. Both Tacrolimus and cyclosporine inhibit the calcium urine, leading to reduced DNA replication.

Azathioprine

•  AZA is a derivative of 6-mercaptopurine, the active agent. It inhibits DNA synthesis - alkylate DNA precursors and interferes with DNA repair. An adjunctive component of immunosuppressive drug regimens. The use of AZA has decreased. It interferes with DNA synthesis suppressing proliferation of activated B and T lymphocytes. The adverse effects include bone marrow suppression, hepatotoxicity, nausea, vomiting, pancreatitis, and alopecia. 1-3 mg/kg per day for maintenance. Chemo capture purine reduces purine synthesis.

Also Read: Complications of Renal Transplant

Mycophenolate Mofetil (Cellcept)

• It is isolated from Penicillium stoloniferum. It inhibits inosine monophosphate dehydrogenase, a key enzyme in purine synthesis. It blocks the proliferative response of both T and B cells, inhibits antibody formation, and prevents the clonal expansion of cytotoxic T cells. It is superior to Azathioprine in preventing rejection of kidney transplants. Enteric-coated mycophenolic acid (Myfortic) has been introduced as an alternative to mycophenolate mofetil. DOSE:1 -2g/day PO in 2 divided doses. The dose may be reduced if the patient has an infection. The dose may be reduced if the TLC count is less than four.

Mycophenolate Mofetil (Cellcept)

• It is not nephrotoxic. It causes bone marrow inhibition and GIT upset. 50% patients having diarrhea - the resolution of symptoms occurs without any dose ad Over - immunosuppression causes higher CMV infection. Maintenance agents include Stacys, mycophenolate, and vitaline. Vitaline is reduced to 5-10 milligrams per day. Mycophenolate is commonly used as a maintenance agent.

Mmf (Cellcept) Vs Azathioprine

• It has replaced Azathioprine. It is effective in combination with many other agents. There is 27% decreased relative rate for chronic allograft rejection. It is simple to use without monitoring. It is free from organ toxicity and cardiovascular risk. Side effects are few: gastrointestinal (mainly diarrhea) and hematologic (anaemia, leukopenia).

Sirolimus (Rapaimmune)  

• It binds FKBP-12 to create complexes that inhibit the target of rapamycin (mTOR). It prevents cytokine (IL-2) receptors from activating the cell cycle. Hyperlipidemia, Thrombocytopenia, and impaired wound healing. It allows early withdrawal of steroids and decreased Calcineurin doses. 2-5 mg/d -  adjusted to trough drug levels.

• It is used in cases of high risk of post transplant malignancy or who develop de novo malignancy after transplant. Steroids are used as an induction and maintenance agent, and act by inhibiting the synthesis of CDNs through NSKB beta. Calcineurin inhibitors are commonly used in maintenance therapy, with tacrolimus being preferred for renal transplant patients due to its lower hepatotoxicity. Tactile limits can cause neurotoxicity and cyclosporine can cause gingival hypersensitivity. Mycophenolate is a commonly used maintenance agent that reduces purine synthesis and is more effective than azathioprine. Diarrhea and leukopenia are common side effects of mycophenolate.

High Risk Immunosuppression

• The Kidney Disease Improving Global Outcome (KIDGO) clinical practice guidelines include one or more acute rejection of the following: One or more human leukocyte antigen (HLA) mismatches , younger recipient and older donor age, African-American ethnicity (in the United States), panel reactive antibody (PRA) greater than 0 percent, presence of a donor-specific antibody (DSA), blood group incompatibility, delayed onset of graft function, Cold ischemia time greater than 24 hours. The condition leading to higher risk of acute rejection is Rabbit antithymocyte globulin (ATG) superior to interleukin-2 (IL-2) receptor antagonist. The condition leading to lower risk of acute rejection is IL-2 receptor antagonists have similar rate w.r.t ATG-Thymoglobulin of Acute Rejection, Patient and graft survival, infection. In general, the risk of acute kidney rejection should be carefully considered in the pre-operative period, and appropriate immunosuppressive therapy should be initiated based on the patient's individual risk factors. Depleting agents act by depleting lymphocytes, which can increase the risk of infection, inflammatory complications, and malignancy.  Non-depleting agents prevent tissue proliferation and have a low risk of malignancy. Syllables are used for patients with a high risk of malignancy or who have developed malignancy. Maintenance therapy includes steroids, calcium inhibitors such as tacrolimus or cyclosporine, and mycophenolate to reduce DNA replication. Tacrolimus is commonly used but has a unique side effect of neurotoxicity. Cyclosporin is associated with gingival hypertrophy. Mycophenolate is better than azathioprine in terms of efficacy but can cause diarrhoea as a side effect.

Also Read: Prune Belly Syndrome (Eagle Belly Syndrome)

Induction Immuno-Suppression

• It prevents acute rejection during the early post transplantation period by providing a high degree of immuno-suppression at the time of transplantation. It is initiated intraoperatively or immediately post-operatively; concluded within the first 3-14 days after transplantation.

Anti-thymocyte Globulins (ATG)

• These are produced by immunizing horses or rabbits with human lymphoid cells, harvesting the IgG. These induce T-cell depletion and modulation through multiple mechanisms -Fc-receptor-mediated complement-dependent lysis, -Opsonization and phagocytosis by macrophages, -Immuno-modulation - apoptosis and antibody-dependent T-cell mediated cytotoxicity. They are associated with an expansion of suppressor T cells - long-term immunosuppression. ATG causes lysis of T cell.

Dosing

• DOSE: 1-4 mg/kg/day for 3-10 days after transplantation. The most common dosage strategy is 1.5 mg/kg/day for 3-5 days. Dose adjustments: Doses may be halved or administered at less frequent intervals if:- Platelet count drops to 50,000-75,000 platelets/mm3. White blood cell count drops to 2,000-3,000 cells/mm3. Discontinuation of the drug should be considered if these values drop below: 50,000 platelets/mm3, 2,000 white blood cells/mm. They are used for 3 to 10 days to produce "profound and durable" lymphopenia. They are used for re-transplant, high PRA, African Americans.

Adverse effects

1. Fever (63% and 63%), 2. Chills (57% and 43%), 3. Headache (40% and 35%), 4. Nausea (37% and 28%),- 5. Diarrhea (37% and 32%). 6. Malaise (13% and 4%), 7. Dizziness (9% and 25%, 8. Pain (46% and 43%)

Muromonab

• OKT3 is a murine monoclonal antibody directed against the CD3 receptor. It causes internalization of the TCR complex. DOSE: 5 mg/day for a duration of 3-14 days. Adequate dosing: There should be - Flow cytometry and staining for CD3+ T cells in recipients' blood samples. Depletion to less than 10% of baseline. Prolonged courses - increase the risk of post-transplantation lymphoproliferative disease. The formation of neutralizing antibodies against the monoclonal murine antibody reduces its efficacy, and “anti-OKT3 response." It was discontinued in 2009.

Alemtuzemab (campath 1h)

• Alemtuzumab is a humanized monoclonal antibody that recognizes CD52 and is used in the treatment of chronic lymphocytic leukemia (CLL). CD52 is present on virtually all B cells and T cells, as well as macrophages, NK cells, and some granulocytes. Advantages: CD52 is not expressed on granulocytes, RBC and hematopoietic stem cells. It is clinically well tolerated with less infusion related side-effects like fever, chills. It has a simple administration (DO and D1-4). It triggers antibody-dependent lysis of these cells. It has a profound depletion effect - Long term minimization of immunosuppression [ 99% T-cells and 75% B-cells]. DOSE: Doses of 20 mg-30 mg on the day of transplant and then again on postoperative day 1 or 4.

Adverse effects include:

• Neutropenia (70%), thrombocytopenia (52%), anemia (47%), Nausea (54%), vomiting (41%), diarrhea (22%), Headache (24%), dysesthesias (15%), dizziness (12%), Autoimmune hemolytic anemia (<5%)

Rituximab (Anti CD 20)

• It eliminates most B cells. This is more used for treating acute dissection rather than kind of preventing it. Rituximab is used off-label in combination with maintenance immunosuppressive drugs, as induction therapy and treatment of antibody-mediated rejection.

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