1. What is the goal of immunosuppression?

The central goal of immunosuppression is to prevent rejection of the renal allograft. The intensity of immunosuppression must be weighed against the undesired consequences of immunodeficiency, such as infection or cancer. Close monitoring, knowledge, and expertise are required to balance the efficacy and toxicity of kidney transplantation immunosuppression.

2. What are the classes of immunosuppressive therapies used in kidney transplantation?

See Table 57.1 .

3. What are the different phases of immunosuppression?

Induction involves the use of powerful immunosuppressive agents to provide a high degree of immunosuppression immediately post-transplant. This prevents acute rejection and allows time for maintenance immunosuppression to be titrated to appropriate levels.

Maintenance immunosuppression’s objectives are to prevent rejection and safely preserve the function of the kidney allograft. These agents are used for the life of the transplant.

4. What are desensitization protocols?

Desensitization for the highly sensitized patients involves decreasing preformed antibody levels. This occurs prior to induction. There are several different methods that include various medications, including rituximab, bortezomib, intravenous immunoglobulin, plasmapheresis, and early initiation of maintenance immunosuppression weeks before transplantation. The outcomes have been equivocal. In addition, there is a significant financial cost as well as increased malignancy and infectious risk for the patient.

5. What are the methods of induction therapy?

Induction strategies can be classified according to the mechanism of the agent used. The two mechanisms that define these agents are lymphocyte-depleting and non-lymphocyte-depleting agents. The lymphocyte-depleting agents used today are rabbit or equine anti-thymocyte globulin (thymoglobulin) and alemtuzumab (humanized anti-CD52 monoclonal antibody, Campath-1H, approved to treat chronic lymphocytic leukemia). Neither agent is approved for induction by the US Food and Drug Administration, despite their widespread use. The non-lymphocyte-depleting agent used is basiliximab (interleukin-2 receptor antibody, anti-CD25). Large pulse doses of steroids are also commonly used at the time of induction in addition to the lymphocyte- or non-lymphocyte-depleting agent. Overall, 85% of transplant programs use induction therapy, most commonly thymoglobulin followed by campath-1H and then basiliximab. Basiliximab is used in those individuals at lower immunologic risk (e.g., Caucasian race, first transplant, older patient, low panel reactive antibody. The benefit is a better safety profile than lymphocyte-depleting agents—in other words, less risk of infection and cancer. Those patients who are at higher risk for rejection should receive induction with a lymphocyte-depleting agent. The most common lymphocyte-depleting agent used today is thymoglobulin. Campath-H1 was the formulation of alemtuzumab sold up until 2012. It is no longer produced, and the remaining supply is used by certain transplant centers until there is no more available. The new formulation of alemtuzumab now in production is called Lemtrada.

6. What is the three-signal model of T cell-mediated rejection?

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  Signal 1: Antigen triggers T-cell receptors and synapse formation occurs.

  
  
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  Signal 2: Signal 1 allows co-stimulation of antigen-presenting cells to occur.

  
  
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  Signal 3: Signal 1 and signal 2 stimulate a cascade of intracellular events culminating in the initiation of the T-cell cycle; stimulation of the T-cell cycle allows T cells to infiltrate the graft.

  
  
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  Summary effect is to inhibit T-cell receptor activation, cytokine production, and subsequent lymphocyte proliferation to prevent rejection.

7. What are the main drugs used for maintenance therapy?

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  Calcineurin inhibitors (CNI): tacrolimus, cyclosporine

  
  
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  Anti-metabolites: azathioprine, mycophenolate mofetil (MMF), and mycophenolic acid (MPA)

  
  
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  mTOR (mammalian target of rapamycin) inhibitors: rapamycin and everolimus

  
  
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  Corticosteroids

  
  
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  Selective co-stimulation blockade: belatacept

The most frequently used combination today is tacrolimus, anti-metabolite (MMF or MPA), and prednisone.

8. What are CNIs?

CNIs remain a cornerstone of immunosuppressive regiments in kidney transplantation. This class of drugs works by blocking calcineurin, an intricate protein in the signal transduction pathway that activates signal 3. The two prototypes of the class are tacrolimus and cyclosporine, with tacrolimus being the primary drug of choice today.

The side effects of the CNIs include:

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  Nephrotoxicity (discussed in next question)

  
  
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  Thrombotic microangiopathy (TMA)

  
  
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  New onset diabetes after transplant

  
  
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  Hypertension

  
  
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  Tremor

  
  
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  Hypercalciuria, hyperkalemia, and hypomagnesemia

  
  
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  Alopecia (Tacrolimus,)

  
  
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  Hirsutism, gingival hyperplasia, hyperuricemia, metabolic acidosis, hypophosphatemia (Cyclosporine)

9. Discuss CNI nephrotoxicity.

CNI nephrotoxicity can be divided into acute and chronic forms.

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  Acute nephrotoxicity usually involves afferent vascular constriction and lower kidney blood flow, leading to kidney ischemia and damage. This resolves with either removal of the drug or lower drug levels. TMA secondary to CNIs can present acutely as well. TMA can also be seen in antibody-mediated rejection.

  
  
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  Chronic CNI nephrotoxicity is seen histologically by global and focal glomerulosclerosis, arteriolar hyaline thickening, isometric tubular vacuolization, and focal areas of tubular atrophy and interstitial fibrosis. The fibrosis is classically seen in bands on biopsy and is called stripped fibrosis.