The goals of evaluating a potential recipient should be to identify potential barriers to transplantation, identify treatable conditions that would attenuate the risk of the surgery or immunosuppression, and explain the benefits and risks. Attention is given to the cause of ESRD and its tendency to recur in kidney transplants. Comorbid conditions and the effects of immunosuppression on these conditions are considered. Patient age older than 50 years,
diabetes, abnormal electrocardiogram, angina, or congestive heart failure have been demonstrated as predictors of cardiac death and nonfatal cardiac events with kidney transplantation. Noninvasive strategies such as thallium perfusion imaging and dobutamine stress echo have demonstrated the ability to predict cardiac events and may prevent high-risk patients from requiring angiography. Screening for malignancy should follow age-appropriate guidelines. In patients with malignancies, a 2- to 5-year remission may be required before transplantation depending on tumor type, invasiveness, and prior treatment. Although obesity is a risk for wound-related complications, long-term outcomes are similar to nonobese patients unless cardiovascular disease exists. Psychosocial screening is usually performed. Testing generally includes evaluation for human immunodeficiency virus (HIV) and hepatitis B and C. Imaging or functional evaluation of the kidneys and lower urinary tract may be necessary in certain patients. ABO and human leukocyte antigen (HLA) typing is performed, along with determination of serologic status for cytomegalovirus (CMV) and varicella. After a patient has been accepted as a candidate, he or she is added to the transplant waiting list, at which time initial medical screening of potential living kidney donors can take place. A patient on the waiting list for more than 1 year should be seen periodically to update his or her condition.

The candidate’s blood is screened for anti-HLA antibodies using single antigen beads (SABs) while on the transplant waiting list at various intervals depending on individual program protocols. Antibodies against another individual’s HLA antigen(s) are produced as a result of prior transfusion, pregnancy, and/or organ transplant. Anti-HLA antibodies detected as a result of this screening process are used to calculate the overall degree of HLA sensitization, or calculated panel reactive antibody (cPRA). If the antibodies are deemed clinically significant by the transplant center, the corresponding HLA antigen is listed as “unacceptable” for that recipient, and donor kidneys containing that antigen will not be offered. Thus, higher values of cPRA equate to fewer potential compatible donors, resulting in significantly longer expected waiting times for the recipient. This process is known as “virtual cross-matching.” See Section IV.A for more details regarding donor/recipient cross-matching.

Although the risks of kidney donation are small, these risks need to be carefully explained to a potential living donor. Mortality is uncommon, but has occurred in 0.02% of donors (2 per 10,000). Infection, bleeding, and other postoperative complications occur in up to 15% of patients. Progression to ESRD has occurred and may be slightly more common than in the general population, however remains an infrequent consequence. Mild blood pressure elevation and proteinuria after donation has been reported in some studies but not all, and the long-term consequences are currently unclear. After ABO compatibility and a negative cross-match are assured, the donor evaluation process can begin. If there are multiple candidates, the donor with fewer HLA mismatches is usually selected. Donors are carefully screened for kidney disease to prevent the possibility of loss of function in the remaining kidney. Hypertension, proteinuria, obesity, kidney stones, and structural
or functional kidney disease are all relative contraindications to donation depending on severity. Testing for latent diabetes mellitus with a glucose tolerance test may be performed if there is a family history or perceived risk of future diabetes. When recipients are affected by hereditary disorders such as polycystic kidney disease or hereditary nephritis, the condition must be ruled out in related donors either clinically or with genetic testing. If a donor is thought to be acceptable, imaging of the kidneys is performed with computed tomographic (CT) angiography or other modalities, allowing the team to assess for structural or vascular anomalies and suitability for laparoscopic donation.

A deceased donor must also be evaluated. The presence of metastasis, unknown cause of death, HIV, or widespread infection precludes donation. Donors with hepatitis C are sometimes accepted for hepatitis C—positive recipients. A combination of factors such as hypertension, advanced age, elevated serum creatinine, oliguria, or dependence on pressor support may exclude a donor. Preimplantation biopsies can be performed on an individual basis when there is concern about the function of a donor kidney. Standard criteria donors (SCDs) typically experienced primary brain death while cardiac and respiratory function remained intact, and do not meet expanded donor criteria. Expanded criteria donors (ECDs) are defined by any donor older than 60 years, or any donor older than 50 years with at least two of the following: terminal serum creatinine greater than 1.5, cerebrovascular accident as a cause of death, or preexisting hypertension. ECD kidneys have a 1.7 relative risk of graft failure compared with SCD kidneys but still provide survival benefit compared with dialysis in selected populations. They are commonly used in recipients with characteristics associated with poor dialysis survival such as advanced age or diabetes. In donation after cardiac death (DCD), organs are recovered from a donor who has undergone cardiac death after a period of circulatory arrest, usually in the setting of a withdrawal of care in the hospital. Although longer warm ischemia times lead to an increase in delayed graft function (DGF), DCD kidneys have similar long-term survival and function when compared with SCD kidneys.

Recipient factors, donor factors, and donor/recipient compatibility all influence long-term graft survival. Recipients who are younger, have low levels of PRA, have spent less time on dialysis, and who are employed or college educated have superior graft survival. Race and ethnicity may affect graft survival for both donors and recipients, with nonblack donor kidneys and nonblack, non-Hispanic recipients of grafts having the longest graft survival. Kidneys from living related or unrelated donors survive longer on average than deceased donor kidneys, as do kidneys from younger compared with older donors. As described above, deceased donor kidneys meeting ECD have a shorter expected survival versus standard criteria kidneys. Finally, factors of donor and recipient compatibility also affect outcomes: better HLA matching, negative immunologic cross-matching, CMV serologic status matching, and equivalent donor/recipient body mass index all have positive effects on long-term graft survival.

A basic review of the mechanisms of immune recognition and response to an allograft is helpful to better understand the patient who has undergone kidney transplantation as well as the pharmacologic agents used to prevent allograft rejection.

Cells in the tissues of mammals, birds, and bony fish express major histocompatibility complex (MHC) surface molecules, which are crucial for the immune system to be able to recognize and respond to a foreign antigen. In humans, these MHC molecules are located on the short arm of chromosome 6 and encode for proteins termed the HLAs. MHC molecules serve two basic functions: they identify self from nonself and coordinate the T-cell receptor (TCR) recognition of the antigen—MHC complex. The MHC molecules are divided into two groups: class I and class II. MHC class I molecules appear on the surface of all nucleated cells and are known as HLA-A, B, and C. MHC class II molecules appear on antigen-presenting cells (APCs) and are termed HLA-DR, DP, and DQ. One MHC haplotype is inherited from each parent as a locus containing each of the six genetically linked HLA molecules. In kidney transplantation, only the HLA-A, -B, and -DR are determined due to their immunogenicity. A “zero-antigen mismatched kidney” has no mismatches in either locus for HLA-A, -B, and -DR, although mismatches may be present at HLA-C, -DP, -DQ, or at other minor antigens. Although advances in immunosuppression have narrowed advantages for well-matched transplants, a two-haplotype identical transplant from a family member or a zero-antigen mismatched deceased donor transplant confers a graft survival benefit compared with transplants with lesser degrees of matching.

APCs are distributed in a ubiquitous manner in body tissues and allow T cells to recognize foreign antigens. Monocytes, macrophages, dendritic cells, and activated B cells can all serve as APCs. Either by phagocytosis or through surface immunoglobulin (Ig) (B cells), APCs capture foreign antigens, degrade and process them into peptides, and express these foreign peptides on MHC class II surface molecules. Through TCR interactions and various downstream events, the T cell is then able to coordinate an immune response to this foreign antigen.

T cells are processed in the thymus and are central to cellular immunity and allograft recognition and rejection. These properties make them a common target of drugs designed to prevent rejection. Central to the immune response is the ability of the T cell to recognize foreign antigens through a surface TCR. These receptors recognize antigens through either indirect or direct pathways. The indirect pathway involves TCR recognition of a foreign (nonself) MHC antigen that has been shed from the graft and is presented by a self-MHC molecule located on an APC surface. The direct pathway involves TCR recognition of an intact foreign MHC antigen present on the surface of a donor APC that has been shed from the
graft. This latter phenomenon occurs only in alloimmune responses and is responsible for the majority of TCR recognition in acute graft rejection at a frequency of 100:1 compared with indirect recognition.

There are two major classes of T cells: T-helper cells which express CD4 surface molecules (CD4⁺), and cytotoxic T cells which express CD8 (CD8⁺). CD4⁺ cells recognize MHC class II molecules on the surface of APCs, whereas CD8⁺ cells are restricted to recognition of MHC class I. CD4⁺ cells are activated after recognition of a foreign antigen (e.g., foreign MHC from a kidney transplant). They then initiate an immune response to foreign peptides by secreting cytokines important in B-cell proliferation and activation and cytotoxic T-cell activation. CD8⁺ T cells kill cells bearing foreign antigen through the use of cytotoxic molecules such as perforins, granzymes, and Fas, which triggers apoptosis in the targeted cell. Regulatory T cells (Treg) are a recently described T-helper cell subset that suppress the activation and proliferation of CD4⁺ and CD8⁺ T cells and have been implicated in allograft tolerance.

T cells and APCs have a number of important interactions central to allograft recognition and rejection. Signal 1 is the term for initial binding of the T cell to the APC through interactions between the TCR/CD3 complex and foreign peptide expressed in MHC. Signal 1 is a calciumdependent process and results in calcineurin activation. Although signal 1 alone will cause anergy, the addition of signal 2, also known as costimulation, will lead to an immune response. The best understood costimulation signal is between CD28 on the T-cell surface and B7 on the APC surface. CD28/B7 activation leads to intracellular signaling, interleukin 2 (IL-2) production, and T-cell activation. While CD28 is expressed on resting T cells, the T-cell surface molecule cytotoxic T lymphocyte antigen-4 (CTLA-4) Ig is expressed only on activated T cells. CTLA-4 binds preferentially to B7 and eventually inactivates the immune response, thereby providing potent negative feedback. Another costimulatory molecule, CD40, is found on APCs and activated B cells, and binds to CD40 ligand (CD40L) on T cells. The CD40/CD40L pathway is important in Ig production and class switching by B cells.

B cells develop at multiple sites of the body, including the liver, spleen, and lymph nodes. In response to T-cell allorecognition-induced activation and proliferation signaling, B cells produce antibodies that are specific to foreign MHC antigens. When these antibodies are specific to donor antigens they are termed donor-specific antibodies (DSA). Antibody-mediated cellular cytotoxicity occurs via complement fixation and subsequent cell lysis. B cells and antibodies are important in allograft rejection, with the potential to cause hyperacute rejection (immediate allograft destruction due to preformed antibodies), as well as acute and chronic antibodymediated rejection (due to either preformed or de novo DSA).

In the 1960s and 1970s the first transplant immunosuppressive agents consisted of steroids and azathioprine. Since that time the number of available
immunosuppressive agents has increased greatly. Agents can be used for desensitization therapy prior to transplant, induction therapy at the time of transplant, maintenance therapy to prevent rejection of the allograft, or the treatment of acute rejection. There is a large degree of overlap between indications, and many agents are used “off-label.” Commonly used agents, their mechanism of action, and common toxicities appear in Table 13-1. Desensitization is discussed separately (see Section IV.A).

a. Basiliximab: Chimeric murine/human monoclonal antibody that binds to the IL-2 receptor on activated T cells, inhibiting IL-2-induced T-cell activation and proliferation without depleting T-cell populations. It is given as 20 mg intravenous (IV) infusions at the time of transplant and 4 days later, and is 75% humanized with minimal side effects.

b. Antithymocyte Globulin (ATG, thymoglobulin): Polyclonal Ig preparations developed by injecting human thymic extracts into rabbits (rATG) or, less commonly, horses (Atgam) and purifying the antibodies produced. These preparations neutralize lymphocytes by multiple antibody-mediated mechanisms, with a sustained effect on proliferation, and are more effective than basiliximab in preventing acute rejection. Toxicities are related to immunosuppression, heterogeneity of preparations, allergic or anaphylactoid responses to nonhuman preparations, and cytopenias. Dosing schedules are commonly 1.5 mg/kg IV daily for 3 to 5 days but vary by center.

c. Alemtuzumab (Campath): Humanized monoclonal anti-CD-52 antibody that depletes both B and T cells. Due to its potent immunosuppressive properties it is often used with steroid avoidance and immunosuppression-reduction protocols; however, it is also associated with profound lymphopenia, susceptibility to infection, and autoimmune syndromes. Furthermore, a change in type and timing of rejection may be seen, including monocyte-induced and humoral rejections occurring past the early posttransplant months. It is used off-label for kidney transplant induction and standard dosing has not been defined; however, 30 mg IV at the time of transplant is common.

a. Calcineurin Inhibitors: Cyclosporine A (CsA) and tacrolimus (FK506) are the mainstay of maintenance immunosuppression. Both agents bind intracellular calcineurin, inhibiting translocation of transcription factor nuclear factor of activated T-cells (NFAT) to the nucleus and subsequent cytokine-induced cell proliferation. Cyclosporine and tacrolimus have similar side effects, but hyperlipidemia, hypertension, hirsutism, and gingival hyperplasia are more common with cyclosporine, and posttransplant diabetes mellitus (PTDM) and neurotoxicity may be more common with tacrolimus. They both have potential to cause nephrotoxicity. Dosing is adjusted according to trough or peak blood levels and varies depending on immunosuppressive regimen (see Section V.C.1).

b. Mammalian Target of Rapamycin Inhibitors (mTOR-Is): Sirolimus and everolimus downregulate mTOR, inhibiting IL-2-mediated signal transduction and cell proliferation. Important toxicities include

hypertriglyceridemia, hypercholesterolemia, cytopenias, pneumonitis, delayed wound healing, lymphoceles, diarrhea, and proteinuria, as well as potentiation of calcineurin inhibitor toxicity. As with calcineurin inhibitors, dosing is adjusted according to trough or peak blood levels and varies depending on immunosuppressive regimen (see Section V.C.1).