Immunosuppression with drugs in renal transplant.

Let us see what we are up against once a solid organ like the kidney is transplanted into a patient after their original one has failed. Here kidney transplant will be dealt with according to a review article in the NEJM 2004.

What happens in an acute rejection reaction? Inflammatory processes are set in motion spear headed by the T lymphocytes instigated by the Antigen Presenting Cells (APCs) mainly the dendritic cells. Lets add a few details. Lymphocytes are either naive i.e. they have not encountered the antigen or be memory cells and it appears that viral antigens may resemble MHC antigens and sensitize the lymphocytes which will then react more quickly and vigorously.

What happens next is the 3 signal activation of the inflammatory reaction which primes the system to produce active T cells and alloantibody.

  1. Signal 1. These are the antigens on the dendritic cells which through the CD3 complex transduce the T cell.
  2. Signal 2. Dendritic cells provide costimulation, delivered when CD80 and CD86 on the surface of dendritic cells engage CD28 on T cells. Signals 1 and 2 activate three signal transduction pathways: the calcium–calcineurin pathway, the RAS–mitogen-activated protein (MAP) kinase pathway, and the nuclear factor-κB pathway.9 These pathways activate transcription factors that trigger the expression of many new molecules, including interleukin-2, CD154, and CD25. Interleukin-2 and other cytokines (e.g., interleukin-15)
  3. Signal 3. “Target of rapamycin” (mTOR) pathway is activated.,” This is the trigger for cell proliferation. Lymphocyte proliferation also requires nucleotide synthesis.

Proliferation and differentiation lead to the production of a large number of effector T cells.

B cells are activated when antigen engages their antigen receptors, usually in lymphoid follicles or in extrafollicular sites, such as red pulp of spleen, or possibly in the transplant, producing alloantibody against donor HLA antigens. Thus, within days the immune response generates the agents of allograft rejection, effector T cells and alloantibody.

Effector T cells that emerge from lymphoid organs infiltrate the graft and orchestrate an inflammatory response. In T-cell–mediated rejection, the graft is infiltrated by effector T cells, activated macrophages, B cells, and plasma cells and displays interferon-γ effects, increased chemokine expression, altered capillary permeability and extracellular matrix, and deterioration of parenchymal function. The diagnostic lesions of T-cell–mediated rejection reflect mononuclear cells invading the kidney tubules (tubulitis) and the intima of small arteries (arteritis). Macrophages that are activated by T cells participate through delayed-type hypersensitivity, but the injury remains antigen-specific.

Alloantibody against donor antigens that is produced systemically or locally in the graft targets capillary endothelium. Antibody-mediated rejection is diagnosed by clinical, immunologic, and histologic criteria, including a demonstration of complement factor C4d in capillaries. A failure of the graft to produce urine, a rise or failure to fall in the serum creatinine should raise a suspicion of acute rejection either immediate post -operatively or within a week of the transplant or maybe later. Ultrasound of the graft, renal scan, renal biopsy will all be required as well as a fluid and frusemide challenge and a careful follow up of the volume status and urine output.

So to sum it up the T-cell mediated response is a cellular response characterized by mononuclear cell infiltration and the antibody rejection is a vascular response damaging the endothelium of the capillaries. Both cellular and antibody responses can occur together.

How does the graft survive with immunosuppression?

Some adaptive responses take place.  Changes in the organ — a loss of donor dendritic cells and a resolution of injury — contribute to the adaptation. Regulatory T cells may also be able to control alloimmune responses, by analogy with their ability to suppress autoimmunity, although this hypothesis is unproven. The crucial element is that host T cells become less responsive to donor antigens when antigen persists and immunosuppression is maintained. 

This may be a general characteristic of T-cell responses in vivo, in which antigen persistence with inadequate costimulation triggers adaptations that limit T-cell responsiveness. The resulting partial T-cell anergy (known as “adaptive tolerance” or “in vivo anergy”) is characterized by decreased tyrosine kinase activation and calcium mobilization (signal 1) and decreased response to interleukin-2 (signal 3). Adaptation in clinical transplantation resembles in vivo anergy — for example, both can occur in the presence of calcineurin inhibitors.

What is the aim of immunosuppression?

Immunosuppressive drugs appear to restrict/ reduce antigen presentation and make T cell activation less likely.

Immunosuppressive Drugs. Site of action.

Some of the sites where drugs act. As the sites are different a combination of drugs is more effective than one drug alone.

Immunosuppression can be achieved by depleting lymphocytes, diverting lymphocyte traffic, or blocking lymphocyte response pathways.

Immunosuppressive drugs have three effects:

  1. the therapeutic effect (suppressing rejection),
  2. undesired consequences of immunodeficiency (infection or cancer),
  3. nonimmune toxicity to other tissues.

Immunodeficiency leads to characteristic infections and cancers, such as post-transplantation lymphoproliferative disease, which are related more to the intensity of immunosuppression than to the specific agent used.

Immunosuppressive drugs include small-molecule drugs, depleting and nondepleting protein drugs (polyclonal and monoclonal antibodies), fusion proteins, intravenous immune globulin, and glucocorticoids


Immunosuppressive Therapies in Organ Transplantation

Natural and synthetic glucocorticoids remain at the forefront of anti-inflammatory and immunosuppressive therapies.  However, long-term use of oral glucocorticoids is associated with serious side effects, including osteoporosis, metabolic disease and increased risk of cardiovascular disease. The glucocorticoid receptor (GR) is a DNA binding protein that regulates transcription initiation and the discovery that many of the immunosuppressive actions of glucocorticoids are mediated by interference with signalling by the key inflammatory transcriptional regulators. Although categorically distinct, the innate (the relatively non-specific immediate host defence system that provides a rapid reaction to infection and tissue damage) and adaptive (the more slowly acquired, highly antigen-specific response) immune systems interact and often overlap during an inflammatory response. Foreign antigens are taken up by antigen presenting cells; particularly dendritic cells, but also macrophages, that then migrate to draining lymph nodes where they instruct the adaptive immune system (T and B lymphocytes), shaping the subsequent immune response. Glucocorticoids inhibit many of the initial events in an inflammatory response. They also promote the resolution of inflammation although the mechanisms by which they do so have received less attention than those associated with suppression of the initial response. Acutely, glucocorticoids inhibit the vasodilation and increased vascular permeability that occurs following inflammatory insult and they decrease leukocyte emigration into inflamed sites, effects that require new protein synthesis. Glucocorticoids act as agonists of glucocorticoid receptors, but at higher doses they have receptor-independent effects.

There is no consensus on the optimal dose or maintenance schedule of glucocorticoids following kidney transplantation. As part of a triple-agent immunosuppressive regimen, it is administered as methylprednisolone at 7 mg/kg (maximum of 500 mg) intravenously in the operating room, then initiate oral prednisone at a dose of 1 mg/kg per day (maximum dose of 80 mg) for the first three days posttransplant, which is then lowered to 20 mg/day for the first week. The daily dose is then tapered every week by 5 mg, resulting in 15 mg/day for one week, 10 mg/day for one week, and then 5 mg/day. In the absence of acute rejection, it is generally usual to reduce glucocorticoids to a dose of 5 mg per day by one month following kidney transplantation.

The use of long-term glucocorticoids may vary from center to center and patient to patient. In an attempt to minimize toxicity and to decrease overall immunosuppression, slow tapering and ultimate withdrawal of glucocorticoids has also been attempted.

Small molecule immunosuppressive drugs.

Most small-molecule immunosuppressive agents are derived from microbial products and target proteins that have been highly conserved in evolution. Small-molecule immunosuppressive drugs at clinically tolerated concentrations probably do not saturate their targets. For example, cyclosporine acts by inhibiting calcineurin but only partially inhibits calcineurin as used clinically. Without target saturation, the drug’s effects are proportional to the concentration of the drug, which makes dosing and monitoring critical. Cyclosporine acts by inhibiting calcineurin but only partially inhibits calcineurin as used clinically. Without target saturation, the drug’s effects are proportional to the concentration of the drug, which makes dosing and monitoring critical.

Depleting protein immunosuppressive agents

Depleting protein immunosuppressive agents are antibodies that destroy T cells, B cells, or both. T-cell depletion is often accompanied by the release of cytokines, which produces severe systemic symptoms, especially after the first dose. The use of depleting antibodies reduces early rejection but increases the risks of infection and post-transplantation lymphoproliferative disease and can be followed by late rejection as the immune system recovers. Recovery from immune depletion takes months to years and may never be complete in older adults. 

Nondepleting protein drugs

These are monoclonal antibodies or fusion proteins that reduce responsiveness without compromising lymphocyte populations. They typically target a semi redundant mechanism such as CD25, which explains their limited efficacy but the absence of immunodeficiency complications. These drugs have low nonimmune toxicity because they target proteins that are expressed only in immune cells and trigger little release of cytokines.

Small Molecule Drugs.

Characteristics of Small-Molecule Immunosuppressive Drugs Used in Organ Transplantation or in Phase 2–3 Trials.

Azathioprine, is derived from 6-mercaptopurine, was the first immunosuppressive agent to achieve widespread use in organ transplantation. The developers of azathioprine, Gertrude Elion and George Hitchings, were acknowledged by a share of the 1988 Nobel Prize. Azathioprine is thought to act by releasing 6-mercaptopurine, which interferes with DNA synthesis. Other possible mechanisms include converting costimulation into an apoptotic signal. After cyclosporine was introduced, azathioprine became a second-line drug and largely replaced by mycophenolate mophetil.

Initial therapy following transplant: IV, Oral: 2 to 5 mg/kg once (Cristelli 2013; manufacturer labeling).

Maintenance: Oral: 1 to 3 mg/kg (usual dose: 50 to 150 mg/day) once daily or 100 mg once daily (for patients <75 kg) or 150 mg (for patients ≥75 kg) once daily (Remuzzi 2007) or 2 mg/kg/day with dose adjusted based on safety/tolerability (Cristelli 2013).

Pregnant patients: ≤2 mg/kg/day.

Most transplant centers administer mycophenolate (MMF or EC-MPS) as an antimetabolic agent to kidney transplant recipients rather than azathioprine. This practice is based upon multiple large trials and meta-analyses showing lower acute rejection rates, and possibly improved graft survival, with MMF as compared with azathioprine.

Calcineurin Inhibitors.

Cyclosporine and tacrolimus selectively inhibit calcineurin, thereby impairing the transcription of interleukin (IL)-2 and several other cytokines in T lymphocytes. Calcineurin inhibitors have been mainstays of immunosuppression in solid organ transplantation for over three decades.

Cyclosporine and tacrolimus are occasionally used in the treatment of various immune-mediated diseases. However, concerns about their long-term toxicity (especially kidney dysfunction and hypertension) and the availability of newer biologic agents have restricted the use of cyclosporine and tacrolimus to patients who have not responded to conventional treatment.

Cyclosporine, a cornerstone of immunosuppression in transplantation, is in effect a prodrug that engages cyclophilin, an intracellular protein of the immunophilin family, forming a complex that then engages calcineurin. Cyclosporine is a lipophilic cyclic peptide of 11 amino acids derived from a fungus.

Cyclosporine and tacrolimus act primarily on T helper cells, although some inhibition of T suppressor and T cytotoxic cells may also occur. Cyclosporine also increases the expression of transforming growth factor (TGF)-beta, which may be an important mechanism by which it causes renal fibrosis. Unlike some other immunosuppressive agents, such as azathioprine and the alkylating agents, cyclosporine and tacrolimus lack clinically significant myelosuppressive activity.

The adverse effects of cyclosporine, which are related to the concentration of the drug, include nephrotoxicity, hypertension, hyperlipidemia, gingival hyperplasia, hirsutism, and tremor. Cyclosporine can also induce the hemolytic–uremic syndrome and post-transplantation diabetes mellitus. Recent developments include monitoring of the peak cyclosporine levels two hours after administration to better reflect exposure to the drug. A chemically modified cyclosporine, ISA(TX)247, is under development.

Most centers start calcineurin inhibitor therapy just before transplantation or within the first 24 hours of transplantation. Some centers delay the introduction of a calcineurin inhibitor until the serum creatinine has decreased by 50 percent from the pretransplant value or the patient has significant urine output. However, there is little evidence that delayed, rather than immediate, initiation of a calcineurin inhibitor results in lower rates of delayed graft function.

Liquid cyclosporine is available in capsules, oral solution, and concentrate for injection:

●Liquid-filled capsules of 25 mg and 100 mg are stored at less than 86°F (30°C) but not frozen.

●The oral solution of 100 mg/mL in 50 mL bottles remains stable for two months after opening if stored in the original container at less than 86°F (30°C) but does not require refrigeration and should not be frozen.

●Concentrate for injection of 50 mg/mL in 5 mL ampules should be stored at less than 86°F (30°C) and protected from light and freezing. Dilutions in 5 percent glucose or normal saline are stable for 24 hours. Substantial amounts of cyclosporine may be lost during intravenous administration through plastic tubing. Polyoxyethylated castor oil that is contained in the concentration for intravenous cyclosporine infusion can cause phthalate stripping from polyvinyl chloride (PVC)-containing intravenous tubing. Thus, when intravenous nonmodified cyclosporine is administered, PVC-free intravenous fluid containers and tubing should be used.

Modified — Capsules and solution are for oral use; no parenteral formulation is available. Patients who need an intravenous formulation should be prescribed cyclosporine nonmodified concentrate for injection. Cyclosporine modified capsules or the equivalent generic product are preferred due to superior pharmacokinetic profile compared with the nonmodified formulation:

●Capsules of 25 mg and 100 mg should be stored at 68 to 77°F (20 to 25°C); some generic formulations are available in a 50 mg capsule.

●The oral solution of 100 mg/mL is available in 50 mL bottles, which remains stable for two months after opening if stored in the original container at 68 to 77°F (20 to 25°C).

Cyclosporine modified – For nonautoimmune disease, cyclosporine modified is initially dosed at 4 to 10 mg/kg/day orally in two divided doses. Most clinicians start at the lower end of the dosing range and make adjustments based upon drug concentrations. The first dose may be administered within 24 hours of transplantation. In newly transplanted patients, the initial dose of cyclosporine modified is the same as the initial dose of cyclosporine nonmodified, although cyclosporine modified is preferred.

Tacrolimus engages another immunophilin, FK506-binding protein 12 (FKBP12), to create a complex that inhibits calcineurin with greater molar potency than does cyclosporine and is a macrolide antibiotic. Initial trials indicated that there was less rejection with tacrolimus than with cyclosporine, but recent analyses suggest that in the current dosing strategies, the efficacy of cyclosporine is similar to that of tacrolimus. Tacrolimus resembles cyclosporine in that it can result in nephrotoxicity and the hemolytic–uremic syndrome, but it is less likely to cause hyperlipidemia, hypertension, and cosmetic problems and more likely to induce post-transplantation diabetes. Tacrolimus has been suspected of inducing more BK-related polyomavirus nephropathy than has cyclosporine in patients who have undergone kidney transplantation, especially when used with mycophenolate mofetil, but renal function may be better with tacrolimus. New developments include a preparation of modified-release tacrolimus to permit once-daily dosing.

The use of tacrolimus has increased steadily, and the drug is now the dominant calcineurin inhibitor, but most transplantation programs exploit the strengths of both tacrolimus and cyclosporine, depending on the risks in individual patients. Hypertension, hyperlipidemia, and the risk of rejection argue for tacrolimus, whereas a high risk of diabetes (e.g., older age or obesity) argues for cyclosporine.

Tacrolimus– Tacrolimus is typically dosed at 0.1 to 0.2 mg/kg/day orally in two divided doses. Most clinicians start at the lower end of the dosing range and make adjustments based upon drug concentrations. The product information recommends the following for tacrolimus initiation [16]:

•At 0.1 mg/kg/day in kidney transplant recipients who also receive mycophenolate mofetil plus an interleukin (IL)-2 receptor antagonist

•At 0.2 mg/kg/day in kidney transplant recipients treated with azathioprine rather than mycophenolate mofetil

•At 0.1 to 0.15 mg/kg/day in adult liver transplant recipients

•At 0.075 mg/kg/day in adult heart transplant recipients

Extended-release tacrolimus products – In patients receiving mycophenolate mofetil, glucocorticoids, and basiliximab induction, extended-release tacrolimus capsules (Astagraf XL) should be given at a dose of 0.15 to 0.2 mg/kg/day prior to reperfusion or within 48 hours of the completion of the transplant procedure. In patients treated with mycophenolate mofetil and glucocorticoids without basiliximab induction, extended-release tacrolimus capsules should be given as a single dose of 0.1 mg/kg within 12 hours prior to reperfusion, then 0.2 mg/kg at least 4 hours after the preoperative dose, and within 12 hours after reperfusion, then 0.2 mg/kg daily [13]. The recommended starting dose of extended-release tacrolimus tablets (Envarsus) in de novo kidney transplant patients is 0.14 mg/kg/day with antibody induction [20].

Drug monitoring — Therapeutic monitoring of cyclosporine and tacrolimus is complicated by the narrow margin between adequate immunosuppression and toxicity. Whole blood should be used as a sample for both drugs. A variety of assays are available, and clinicians should become familiar with the one used in their local laboratory.

Cyclosporine should be monitored using 12-hour trough (C0), two-hour post-dose (C2), or abbreviated area under the time concentration curve (AUC) . Although monitoring of C0 is common practice, there is a poor correlation with safety, efficacy, and drug exposure using this strategy. Some centers use C2 monitoring among kidney transplant recipients since these concentrations may correlate more closely with exposure, and higher C2 concentrations have been associated with decreased acute rejection rates in the first year. In one study of liver transplant patients, C2 was more closely associated with the first four-hour post-dose cyclosporine exposure (AUC0-4) than C0. C2 monitoring may be more accurate but is often more difficult and less convenient for the patient. Most centers monitor either C0 or C2 concentrations but not both. In rare circumstances, assessing both may be beneficial in a patient with absorption issues.

Tacrolimus should be monitored using 12- and 24-hour trough (C0) concentrations for the immediate-release and extended-release preparations, respectively.

Blood concentrations should be checked two to three days after starting cyclosporine or tacrolimus and after any dose change. Typically, after transplant, concentrations are measured every one or two days while hospitalized. After discharge, levels should be measured once or twice weekly for the first month, then weekly until three months posttransplantation, then every two weeks until six months posttransplant, and then monthly. Some stable, low-risk patients may have concentrations monitored every two to three months. However, if drugs that affect cyclosporine or tacrolimus metabolism are added or withdrawn, more frequent measurement of trough concentrations will be required. Tacrolimus and cyclosporine reach steady-state concentrations after four to six doses.

Inosine Monophosphate Dehydrogenase Inhibitors: mycophenolate mofetil.

 Mycophenolic acid inhibits inosine monophosphate dehydrogenase, a key enzyme in purine synthesis. Mycophenolate mofetil is a prodrug that releases mycophenolic acid, and in large-scale trials with cyclosporine, it was superior to azathioprine in preventing rejection of kidney transplants.  Protocols using mycophenolate mofetil and calcineurin inhibitors improved patient survival and graft survival and reduced early and late allograft rejection.

Renal transplantation:


CellCept: Initial: 1 g twice daily. Maintenance dose may vary based on concomitant immunosuppression. Doses >2 g/day have been associated with an increased incidence of adverse effects but may be necessary in some patients (EMMC study group 1999; TMMRT study group 1996).

Myfortic: Oral: Initial: 720 mg twice daily. Maintenance doses may vary based on concomitant immunosuppression.

IV: CellCept: See oral dosing for CellCept; IV and oral doses (of mycophenolate mofetil) are equivalent. If converting from Myfortic to IV CellCept, convert Myfortic to equivalent CellCept oral dose first. Transition to oral therapy as soon as tolerated.

Target-of-Rapamycin Inhibitors (mTOR)

Sirolimus, everolimus and temsirolimus engage FKBP12 to create complexes that engage and inhibit the target of rapamycin but cannot inhibit calcineurin. Inhibition of the target of rapamycin blocks signal 3 by preventing cytokine receptors from activating the cell cycle.

Sirolimus (rapamycin) is a macrocyclic triene antibiotic that is produced by fermentation of Streptomyces hygroscopicus. Sirolimus was discovered from a soil sample collected in Rapa Nui, which is also known as Easter Island [1]. Although it was originally developed as an antifungal agent, it was later found to have immunosuppressive (US FDA approval in 2003 for prevention of acute rejection in kidney transplantation) and antiproliferative properties that may be useful to treat or prevent proliferative diseases such as tuberous sclerosis, psoriasis, and malignancy. Temsirolimus and everolimus are both analogs of sirolimus approved for the treatment of renal cell carcinoma. In April 2010, everolimus was approved by the US FDA for prevention of acute rejection in kidney transplantation.

Sirolimus is available in a 1 mg/mL oral solution (60 mL) and a 0.5, 1, and 2 mg triangular-shaped tablet. Although the oral solution and tablet are not bioequivalent, clinical equivalence has been demonstrated [3].

Everolimus is available as a 0.25, 0.5, and 0.75 mg round, flat tablet.



Sirolimus – Sirolimus is typically administered as a tablet, although a solution is available for those who are not able to swallow.

Sirolimus oral solution should be taken in the following manner:

•Empty the medication from the amber syringe into a glass or plastic container.

•Then, it should be vigorously stirred with 2 ounces of water or orange juice.

•After immediately drinking the mixture, the container should again be filled with an equal amount of fluid and consumed immediately.

Sirolimus should not be mixed with grapefruit juice.

•The oral solution should be protected from light and stored under refrigeration at all times to prevent degradation.

Everolimus – Everolimus is administered as a tablet.

Dose — Clinical trials of initial immunosuppressive regimens after kidney transplant have included sirolimus as a component of a regimen that includes cyclosporine and glucocorticoids. In these trials, a one-time loading dose of 6 or 15 mg (three times the maintenance dose), followed by a maintenance dose of either 2 or 5 mg/day, was utilized.

An initial everolimus dose of 0.75 mg given orally twice daily is recommended for adult kidney transplant patients in combination with reduced-dose cyclosporine.

Sirolimus and everolimus were developed for use with cyclosporine, but the combination increased nephrotoxicity, the hemolytic–uremic syndrome, and hypertension. Sirolimus has been combined with tacrolimus (e.g., the Edmonton protocol for pancreatic islet transplantation) to avoid the toxicity of sirolimus–cyclosporine combinations. However, a controlled trial in renal transplantation showed that sirolimus plus tacrolimus produced more renal dysfunction and hypertension than did mycophenolate mofetil plus tacrolimus, which indicates that sirolimus potentiates tacrolimus nephrotoxicity.

The principal nonimmune toxic effects of sirolimus and everolimus include hyperlipidemia, thrombocytopenia, and impaired wound healing. Other reported effects include delayed recovery from acute tubular necrosis in kidney transplants, reduced testosterone concentrations, aggravation of proteinuria, mouth ulcers, skin lesions, and pneumonitis. However, sirolimus and everolimus may reduce cytomegalovirus disease. 

Practitioners can reduce the toxicity of the combination of a target-of-rapamycin inhibitor and a calcineurin inhibitor by withdrawing one of the drugs. For example, withdrawing cyclosporine in patients in stable condition who are receiving the sirolimus–cyclosporine combination reduces renal dysfunction and hypertension, with a small increase in rejection episodes, which suggests a strategy for avoiding the toxic effects of calcineurin inhibitors.

Dihydroorotate Dehydrogenase Inhibitors

Leflunomide is a dihydroorotate dehydrogenase inhibitor that is approved for rheumatoid arthritis. Dihydroorotate dehydrogenase is a key enzyme in pyrimidine synthesis. Its active metabolite, A77 1726, was modified to create FK778. Leflunomide is not in widespread use as an immunosuppressant in renal transplant but may be substituted for mycophenolate in the presence of BK viremia or nephropathy. FK778 may have activity against BK-related polyomavirus and have a lower incidence of gastrointestinal effects than does mycophenolate mofetil, but its nonimmune toxic effects such as anemia must be evaluated.

Non depleting and fusion antibodies

Daxiliximab and Basiliximab

The anti-CD25 monoclonal antibodies daclizumab and basiliximab are widely used in transplantation for induction in patients who have a low-to-moderate risk of rejection.

Depleting antibodies.

Polyclonal antithymocyte globulin is produced by immunizing horses or rabbits with human lymphoid cells, harvesting the IgG, and absorbing out toxic antibodies (e.g., those against platelets and erythrocytes). As an induction agent, polyclonal antithymocyte globulin is usually used for 3 to 10 days to produce “profound and durable” lymphopenia that lasts beyond one year. 

In addition to immunodeficiency complications, toxic effects of polyclonal antithymocyte globulin include thrombocytopenia, the cytokine-release syndrome, and occasional serum sickness or allergic reactions. Rabbit preparations of polyclonal antithymocyte globulin (such as Thymoglobulin and ATG-Fresenius) are favored over horse polyclonal antithymocyte globulin because of greater potency.

Muromonab-CD3, a mouse monoclonal antibody against CD3, has been used for 20 years to treat rejection and for induction. Muromonab-CD3 binds to T-cell-receptor–associated CD3 complex and triggers a massive cytokine-release syndrome before both depleting and functionally altering T cells. Humans can make neutralizing antibodies against muromonab-CD3 that terminate its effect and limit its reuse. Prolonged courses of muromonab-CD3 increase the risk of post-transplantation lymphoproliferative disease. The use of muromonab-CD3 declined when newer small-molecule immunosuppressive drugs reduced rejection episodes. A trial of a humanized anti-CD3 monoclonal antibody in kidney transplantation was stopped.

Alemtuzumab, a humanized monoclonal antibody against CD52, massively depletes lymphocyte populations. It is approved for treating refractory B-cell chronic lymphocytic leukemia but is not approved for immunosuppression in transplantation.

Rituximab (anti-CD20 monoclonal antibody) eliminates most B cells and is approved for treating refractory non-Hodgkin’s B-cell lymphomas, including some post-transplantation lymphoproliferative disease in organ-transplant recipients. Rituximab is used off-label in combination with maintenance immunosuppressive drugs, plasmapheresis, and intravenous immune globulin to suppress deleterious alloantibody responses in transplant recipients.

Renal transplant is a complex problem to deal with. New drugs are developing. Non-glucocorticoid therapies are being used. results have got better. Most patients survive at least 5 years and more if their doctor gets it right. I hope you learnt something useful.

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I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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