Chapter 25

Renal Transplantation

Ali Naji, MD, PhD; Somnath Chattopadhyay, MD

Indications

Renal transplantation is now regarded as the treatment of choice for a spectrum of pathology leading to end-stage renal disease (ESRD). The three most common indications for renal replacement are insulin-dependent diabetes mellitus, glomerulonephritis, and hypertensive glomerulosclerosis. Other causes of renal failure include polycystic kidney disease, systemic lupus erythematosus, Alport disease, Immunoglobulin A (IgA), nephropathy, obstructive nephropathy, recurrent pyelonephritis, nephrosclerosis, interstitial nephritis, and chronic calcineurin inhibitor-induced nephrotoxicity.

Patients may be placed on the waiting list either upon initiation of chronic maintenance dialysis (defined as dialysis that is regularly furnished to an ESRD candidate) or when the creatinine clearance or glomerular filtration rate (GFR) is less than approximately 20 mL/min.

Preemptive transplantation, which predominantly is indicated for recipients who have a living kidney donor, has been shown in large studies to have significant patient and graft survival. These results are postulated to be due to long-term cardiovascular effects of hemodialysis, lower rates of delayed graft function (DGF) and rejection seen in preemptive transplantation, and better socioeconomic and demographic features of the patient population able to opt for preemptive transplantation. However, preemptive transplants are still a small percentage of the total number of transplants, owing to a limited donor pool.

Although renal transplantation improves survival and quality of life for ESRD patients, a shortage of donor organs is the major limiting factor. Currently 97,503 are on a waiting list for a kidney; in 2012 only 16,485 patients received a kidney transplant.

Immunological barriers to renal transplant

Major histocompatibility antigens

The major histocompatibility antigen complex (MHC) includes genes encoding the human leukocyte antigens (HLA) on chromosome 6. The MHC molecules are transmembrane proteins that present peptide antigens to T lymphocytes and induce immune recognition.

Class I MHC is expressed on all cell types including lymphocytes and presents small peptide antigens derived from intracellular proteins. MHC Class I presentation is restricted to CD8-bearing T lymphocytes. MHC Class II expression is restricted to immune cells with antigen-presenting cell (APC) capacity (macrophages, dendritic cells, B lymphocytes), vascular endothelial cells, and some parenchymal cell types (enterocytes), and presents larger peptide antigens that are derived from the breakdown of exogenous peptides. MHC Class II presentation is restricted to CD4-bearing T lymphocytes.

MHC genes are expressed codominantly (a paternal and maternal allele of all MHC genes is equally expressed). Any two siblings have a 25% chance of being HLA identical and a 50% chance of sharing one haplotype. The importance of HLA matching on graft survival is well established, although even totally mismatched living donor transplants have a better outcome than deceased donor transplants.

Allograft rejection

The clinical manifestations of allograft rejection fall under three major categories: hyperacute, acute, and chronic.

1. Hyperacute rejection
Hyperacute rejection is caused by preformed antibodies against ABO or MHC antigens present on the endothelial cells. This in turn leads to activation of the classic complement pathway. Complement components C3a and C5a attract inflammatory cells and platelets to the target sites, and component C5b-9 forms the membrane attack complex and damages the endothelium. Injury to the endothelial cells exposes the underlying matrix, and tissue factor is released which activates the extrinsic coagulation pathway. This leads to intravascular thrombosis, hemorrhage, and graft loss. Hyperacute rejection can be prevented by using ABO-compatible grafts and crossmatch testing for preformed anti-HLA antibodies.

2. Acute cellular rejection (ACR)
ACR is a T cell-mediated process. T cells are activated via two different pathways: In the direct pathway, the donor MHC molecules on the donor APCs are recognized as “non self” by the recipient T cells, leading to an alloimmune response. In the indirect pathway, the alloimmune response is elicited by the recipient APCs presenting donor MHC antigens to recipient T cells. Histologically, ACR manifests as endotheliitis, tubulitis, and glomerulopathy and is usually reversible with intensification of immunosuppression.

3. Chronic rejection
Chronic rejection is the major cause of late renal allograft loss. The biology of chronic rejection is not fully understood. It has been suggested that, in contrast to acute rejection, the indirect pathway, and alloantibodies and complement, may play dominate roles in chronic rejection. Chronic rejection is not reversible by intensification of immunosuppression.

Immunosuppression

Immunosuppression after renal transplantation is divided into two phases: (1) induction, which is a period of high-dose immunosuppression in the perioperative period and (2) maintenance, which occurs posttransplant at lower doses for the life of the renal transplant.

The immunosuppressant drugs commonly used include:

1. Anti-T-cell antibodies (Thymoglobulin)
Thymoglobulin is a polyclonal rabbit antihuman thymocyte antibody preparation. The purified IgG fraction contains antibodies directed against cell-surface molecules expressed on T lymphocytes, B cells, NK cells, and macrophages. Additionally, polyclonal antibodies cross-link the TCR, causing partial T-cell activation and blockade of T-cell proliferation. After administration, these antibodies cause rapid lymphopenia secondary to complement-mediated cell lysis and opsonization. A massive release of cytokines may occur, known as cytokine release syndrome, characterized by fevers, chills, dyspnea, bronchospasm, flash pulmonary edema, and central nervous system complications. Pretreatment with corticosteroids is recommended to reduce the incidence of this “cytokine storm.”

2. Anti-IL2 receptor antibody (basiliximab)
Basiliximab is a chimeric murine/human monoclonal antibody that binds to the IL-2 receptor alpha chain known as CD25, which expresses preferentially on activated T lymphocytes. It is used as an induction immunosuppression and is generally reserved for recipients who are at low risk of rejection (e.g., HLA identical donor).

3. Corticosteroids (prednisone)
Corticosteroids are used as induction agents and in maintenance regimens. Corticosteroids in the form of prednisone are also the most common agents used for treatment of acute allograft rejection. Corticosteroids have a variety of antiinflammatory and immunomodulatory effects. Corticosteroids also impair monocyte and macrophage function and decrease the number of circulating CD4 + T cells. Adverse effects include diabetes, muscle loss, psychosis, cataracts, peptic ulceration, osteoporosis, and impaired wound healing. In renal transplantation, early withdrawal (within 3 months) is associated with an increased incidence of acute rejection; delayed withdrawal increases the risk of late acute rejection.

4. Calcineurin inhibitors (CNI) (cyclosporine and tacrolimus)
Calcineurin is a calcium/calmodulin-dependent phosphatase which, when activated, leads to T-cell proliferation. Cyclosporine binds to cyclophilin, and tacrolimus to an intracellular binding protein named FK506-binding protein (FKBP-12). These CNI-immunophilin complexes inhibit calcineurin activity, preventing cytokine gene transcription. The net result is a blockade in the production of cytokines such as IL-2 and inhibition of T-cell activation and proliferation. Both tacrolimus and cyclosporine provide optimal immunosuppression and result in equivalent graft and patient survival. However, incidence of acute rejection episodes may be lower with a tacrolimus-only regimen when compared to a cyclosporine-only regimen.
Many side effects of CNIs are dose related and include nephrotoxicity (which presents in the long term as interstitial fibrosis and fibrous intimal thickening), hypertension, neurotoxicity presenting as headache (more common with tacrolimus), tremors, agitations, psychosis and hallucinations, diabetes (more common with tacrolimus), hyperkalemia, hyperlipidemia, gingival hyperplasia, and hypertrichosis (specific for cyclosporine). Additionally, drugs that interact with CYP3A4 (e.g., antifungals) also affect the concentration of CNIs, which are metabolized by the cytochrome P450 3A4 enzyme in the gut and liver.

5. Mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)
MMF and MPS are rapidly converted in the liver to mycophenolic acid (MPA), which is the active compound. MPA preferentially blocks proliferation of activated lymphocytes. The main dose-related side effects of MPA are diarrhea, nausea, vomiting, and myelosuppression. Azathioprine is used by most centers in patients intolerant of MMF.

6. Mammalian target of rapamycin (mTOR) inhibitors (sirolimus)
Sirolimus inhibits mTOR, which in turn blocks T-cell activation. It is not used in the perioperative period because of its profound inhibition of fibroblast activity, preventing wound healing. Important side effects of sirolimus include hypercholesterolemia, myelosuppression, mouth ulcers, interstitial pneumonitis, and poor wound healing. Sirolimus is metabolized by the cytochrome P450 3A4 enzyme and therefore has similar drug-drug interactions as CNIs.