Kidney Transplantation and Immunosuppression

Although transplantation is a highly subspecialized field, you will provide care for kidney transplant recipients and patients receiving immunosuppressive medications. If transplantation patients are on a designated transplantation floor, you are unlikely to be directly responsible for management of immunosuppression. If transplant recipients are on the general ward, you will need to consult the transplantation team. In either case, you need a basic overview of immunosuppressive regimens, interactions with other common medications, and how to obtain accurate measurement of immunosuppressive agents.

Management

Care for transplant recipients includes:

monitoring for allograft function (and for rejection and recurrent or de novo kidney disease)
managing immunosuppressive agents
reducing risk for opportunistic infections
health maintenance, including cancer screening and vaccinations (generally done pre-transplantation with killed vaccines given as needed [e.g., flu vaccine])
monitoring for malignancies

Treatment

Management of immunosuppressive therapy varies, depending on the time since transplantation and the course.

Early (induction) therapy may involve higher doses of immunosuppressive medication and biologics. Antithymocyte globulin (most often a polyclonal antibody made in rabbits) has been used for many years, but other treatments used for induction include monoclonal antibodies (e.g., alemtuzumab and muromonab-CD3), rituximab, bortezomib, and eculizumab.
Maintenance therapy involves lower doses of glucocorticoids and immunosuppressants and may require change in medications. Patients who are admitted with rejection episodes are likely to have specific additive therapy.

Triple immunosuppression regimens: Most kidney transplant recipients receive maintenance treatment with triple immunosuppression regimens that include:

a calcineurin inhibitor (mostly tacrolimus; cyclosporine is an alternative)
an antimetabolite (usually mycophenolic acid derivative; less frequently, azathioprine)
glucocorticoids

New agents: Some newer immunosuppressive agents are being used in place of calcineurin inhibitors. These include sirolimus, everolimus, and belatacept. Some agents are still in clinical trials and not yet approved. Further, a variety of glucocorticoid-sparing or glucocorticoid-free protocols have been developed.

The following table lists common maintenance immunosuppressive drugs, mechanism of action, and potential adverse effects:

Characteristics of Immunosuppressive Drugs Used in Organ Transplantation

Drug	Description	Mechanism	Toxicity and Comments
Cyclosporine	11-amino-acid cyclic peptide from Tolypocladium inflatum	Binds to cyclophilin; complex inhibits calcineurin phosphatase and T-cell activation	Nephrotoxicity, hemolytic-uremic syndrome, hypertension, neurotoxicity, gum hyperplasia, skin changes, hirsutism, post-transplantation diabetes mellitus, hyperlipidemia Requires trough monitoring or checking levels 2 hours after administration
Tacrolimus (FK 506)	Macrolide antibiotic from Streptomyces tsukubaensis	Binds to FKBP12; complex inhibits calcineurin phosphatase and T-cell activation	Similar adverse effects as cyclosporine but with lower incidence of hypertension, hyperlipidemia, skin changes, hirsutism, and gum hyperplasia and a higher incidence of post-transplantation diabetes mellitus and neurotoxicity Requires trough monitoring
Sirolimus (rapamycin)	Triene macrolide antibiotic from S. hygroscopicus from Easter Island (Rapa Nui)	Binds to FKBP12; complex inhibits target of rapamycin and interleukin-2-driven T-cell proliferation	Hyperlipidemia, increased toxicity of calcineurin inhibitors, thrombocytopenia, delayed wound healing, delayed graft function, mouth ulcers, pneumonitis, and interstitial lung disease Requires lipid monitoring; recipients at low-to-moderate risk for rejection can stop cyclosporine treatment 2−4 months after transplantation if on sirolimus
Everolimus	Derivative of sirolimus
Mycophenolate mofetil and enteric-coated mycophenolate	Mycophenolic acid from penicillium molds	Inhibits synthesis of guanosine monophosphate nucleotides; blocks purine synthesis, prevents proliferation of T and B cells	Gastrointestinal symptoms (mainly diarrhea), neutropenia, mild anemia Blood-level monitoring not required but may improve efficacy; absorption reduced by cyclosporine
Azathioprine	Prodrug that releases 6-mercaptopurine	Converts 6-mercaptopurine to tissue inhibitor of metalloproteinase, which is converted to thioguanine nucleotides that interfere with DNA synthesis; thioguanine derivatives may inhibit purine synthesis	Leukopenia, bone-marrow depression, macrocytosis, liver toxicity (uncommon) Requires blood-count monitoring
Polyclonal anti-thymocyte globulin	Polyclonal IgG from horses or rabbits with human thymocytes; binds to unwanted antibodies	Depletes CD4 lymphocytes through acting against human T-cell surface antigens; used for induction (off-label), and used to treat rejection	Cytokine-release syndrome (fever, chills, hypotension), thrombocytopenia, leukopenia, serum sickness
Muromonab-CD3	Murine monoclonal antibody against CD3 component of T-cell-receptor signal-transduction complex	Binds to CD3 associated with T-cell receptor, leading to initial activation and cytokine release, followed by blockade of function, lysis, and T-cell depletion	Severe cytokine-release syndrome, pulmonary edema, acute renal failure, gastrointestinal disturbances, changes in central nervous system
Alemtuzumab	Humanized monoclonal antibody against CD52, a 25-to-29-kD membrane protein	Binds to CD52 on all B and T cells, most monocytes, macrophages, and natural killer cells, causing cell lysis and prolonged depletion	Mild cytokine-release syndrome, neutropenia, anemia, idiosyncratic pancytopenia, autoimmune thrombocytopenia, thyroid disease Widely used for chronic lymphocytic leukemia and multiple sclerosis (FDA-approved); used off-label in some kidney transplant regimens Alemtuzumab did not reduce calcineurin inhibitor exposure or improve transplant function or survival
Rituximab	Chimeric monoclonal antibody against membrane-spanning four-domain protein CD20	Binds to CD20 on B cells and mediates B-cell lysis	Infusion reactions, hypersensitivity reactions (uncommon)
Basiliximab	Chimeric monoclonal antibody against CD25 (interleukin-2-receptor α chain)	Binds to and blocks the interleukin-2-receptor α chain (CD25 antigen) on activated T cells, depleting them and inhibiting interleukin-2-induced T-cell activation	Hypersensitivity reactions (uncommon); two doses required No monitoring required Used with calcineurin inhibitor and glucocorticoids Used for transplant rejection prophylaxis and in induction regimens
Daclizumab	Humanized monoclonal antibody against CD25 (interleukin-2-receptor α chain)	Has similar action to basiliximab	Hypersensitivity reactions (uncommon); five doses recommended but two may suffice No monitoring required
Abatacept	Protein combining B7-binding portion of CTLA-4 with IgG Fc region	Binds to B7 on T cells, preventing CD28 signaling and signal 2	Hypersensitivity reactions, infections, malignancies
Belatacept	Monoclonal antibody	Inhibits T-cell CD28 activation and proliferation through binding to costimulatory ligands (CD80, CD86) on antigen-presenting cells	Infections, lymphoproliferative disorders, malignancy, activation of latent viral infections Used in combination with basiliximab induction, mycophenolate mofetil, and glucocorticoids for rejection prevention

Note: The dosages of cyclosporine, tacrolimus, sirolimus, and everolimus are adjusted based on a target drug level — often a trough level measured 12 hours after the last dose (typically before the morning dose). The therapeutic range is subject to variation and is often defined by patients’ immunologic risk and cumulative immunosuppression history.

Both tacrolimus and cyclosporine have hepatic and intestinal metabolism effects. A wide array of agents can interact with these effects and cause either toxicity (e.g., protease inhibitor, most macrolides, azole antifungals, non-dihydropyridine calcium-channel blockers) or low therapeutic levels (rifampin, phenytoins, barbiturates).

Find helpful tables and review of common antimicrobial interactions with immunosuppressive agents here.

Research

Landmark clinical trials and other important studies

Research

Campath, Calcineurin Inhibitor Reduction, and Chronic Allograft Nephropathy (the 3C Study)- Results of a Randomized Controlled Clinical Trial

Herrington WG et al. Am J Transplant 2018.

The randomized controlled 3C trial compared alemtuzumab and basiliximab induction and tacrolimus and sirolimus maintenance therapy at 6 months posttransplantation.

Belatacept and Long-Term Outcomes in Kidney Transplantation

Vincenti F et al. N Engl J Med 2016.

In this RCT, patient and graft survival were significantly higher with belatacept (both the more-intensive regimen and less-intensive regimens) than with cyclosporine 7 years after transplantation.

Tacrolimus Versus Ciclosporin as Primary Immunosuppression for Kidney Transplant Recipients: Meta-Analysis and Meta-Regression of Randomised Trial Data

Webster AC et al. BMJ 2005.

Systematic review and meta-analysis comparing tacrolimus with cyclosporin as the initial immunosuppressive therapy. There was a reduction in graft loss and acute rejection when using tacrolimus compared to ciclosporin.