**7. Alternative maintenance regimens**

Different immunosuppressive strategies and protocols have evolved over time to address several major concerns with maintenance regimens. Major concerns include the long term side effects of chronic steroid use, as well as long term calcineurin nephrotoxicity which contribute to decreased long-term graft survival. Protocols that have been studied and published include steroid withdrawal and avoidance, as well as studies where calcineurin use is avoided, minimized or replaced with other agents.

#### **7.1. Steroid withdrawal/avoidance (SAW)**

Steroid withdrawal typically involves discontinuing steroids several months post transplan‐ tation whereas steroid avoidance involves no corticosteroid maintenance at all and only a brief exposure to steroids in the immediate post operative period. Studies demonstrate that early steroid withdrawal is safer than late withdrawal as late withdrawal was associated with increased risk of acute rejections. [52, 53] A recent meta-analysis of 34 randomized controlled studies using SAW regimens published by Knight et al concluded that SAW is associated with increased risk of acute rejection, however this did not impact long term patient or graft survival. [54] There is a more favorable cardiovascular profile with SAW most likely secondary to decreased incidence of hypertension, new onset diabetes and dyslipidemia. As many studies have shown increased risk of acute rejections with SAW it is generally implemented with caution in high immunologic risk recipients (high PRA, repeat transplants, young African American recipients, patients with prior rejections and/or unstable graft function). With use of more potent induction regimens more US centers are currently implementing SAW in immunologically low risk recipients.

optimal treatments for humoral rejection, subclinical rejection and chronic rejection have yet

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Acute cellular rejection is a T-cell–mediated process, is usually easy to treat, and responds well to therapy. T-cell directed induction therapies, and calcineurin maintenance has substantially decreased the overall incidence of cell-mediated acute rejections. Low grade cellular rejection with out vascular involvement is treated with high dose, intravenous steroids. The dose and duration of treatment with corticosteroids has not been well defined by studies, and is often left to physician discretion. Thymoglobulin in combination with steroids is used to treat severe and high grade acute cellular rejections with a vascular component. Although Thymoglobulin is most widely used for high grade cellular rejections, there are small case series and small

Humoral rejection mediated by alloreactive B-cells, alloantibodies and complement are more challenging to treat. Humoral rejection is often refractory to treatment and continues to be a significant problem in transplantation due to difficulties in establishing a consensus for safe optimal treatments directed against allosensitization and alloantibody production. Humoral responses also greatly contribute to late acute graft losses and the development of chronic rejection. [62] Humoral rejection has been linked to the presence of donor specific antibody and activation of complement resulting in C4d deposits in renal tissue. Therapeutic strategies have been aimed both at removing alloantibodies as well as decreasing alloantibody produc‐

The best known treatment algorithms to treat antibody mediated rejection include combina‐ tions of plasma exchange to remove donor-specific antibody, and/or intravenous immuno‐ globulins and the anti-CD20 monoclonal antibody (rituximab) to suppress donor-specific antibody production. [65, 66] There are no randomized controlled trials powered to show efficacy or safety of potential different combinations of these different therapeutic strategies. Some side effects of plasmapheresis include hypotension, citrate induced hypocalcemia, complications with access placement, and infections due to removal of immunoglobulins. Adverse reactions of IVIG include anaphylactoid reactions, fevers, chills, flushing, myalgias, malaise, headache, nausea, vomiting, dilutional hyponatremia, pseudohyponatremia, hemol‐

Bortezomib continues to be a promising agent for acute humoral rejection because of its ability to target multiple pathways involved in B-cell activation and antibody production and its direct activity against CD138+ long lived plasma cells that exist in survival niches such as the bone marrow and spleen. [67] These cells, primarily responsible for producing high affinity alloantibody, are not targeted by Rituximab, the current mainstay treatment for humoral rejection. [68, 69] Initial reports on Bortezomib were in patients with AMR that were refractory to traditional anti-humoral therapies, but recent reports show that Bortezomib can be used as

ysis and neutropenia. See previous section on Rituximab for side effects.

studies that favor the use of alemtuzumab for treatment of cellular rejections. [61]

to be defined by the transplant community..

**8.1. Treatment of cellular rejection**

**8.2. Treatment of humoral rejection**

tion by impairing and/or depleting B-cells. [63, 64]
