**8. Antirejection therapies**

Rejection is a common problem with renal allografts, and can be of cellular (lymphocyte) and/ or humoral (circulating antibody) origin. It is well known that if acute rejection is left untreated, eventually graft failure ensues. Rejection can be acute or subclinical. Acute rejection is clinically evident and often presents as a decline in kidney function associated with a rise in creatinine and classic histologic changes seen on renal biopsy. On the other hand, subclinical rejection is subtle; where histologic changes of rejection may be present in grafts that otherwise appear to have stable renal function. Immunosuppressive management for subclinical rejection has not been well delineated. [56-58] Finally, rejection may be mixed and have both cellular and humoral components.

Overall the incidence of acute rejection post-transplant has decreased. However, survival of allografts has not increased to the extent predicted, mostly due to the universal development of chronic allograft dysfunction and late graft loss. Chronic allo-immune injury has been recognized as a major contributor to late graft loss and can present early on in transplantation as demonstrated by several protocol biopsy studies. [59, 60] Compared to cell-mediated rejections, humoral rejection and chronic rejection can be challenging to treat. In addition, the optimal treatments for humoral rejection, subclinical rejection and chronic rejection have yet to be defined by the transplant community..

#### **8.1. Treatment of cellular rejection**

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

Several studies have looked at minimizing exposure to CNIs to over come nephrotoxicity. Complete calcineurin avoidance with de novo use of sirolimus has not been successful and was associated with higher incidence of rejections and graft loss. [43]. Due to this, more centers and studies have favored calcineurin minimization and withdrawal (at 3 to 6 months post transplant) as opposed to complete avoidance. The ELITE-symphony trial was a land mark trial comparing different regimens of calcineurin minimization and withdrawal demonstrat‐ ing better allograft outcomes at three years of follow up in patients on low dose tacrolimus (in addition to steroids and MMF) than standard dose cyclosporine, reduced dose cyclosporine or low dose sirolimus as primary maintenance agent. [44] A recent meta-analysis evaluating calcineurin minimization strategies concluded that calcineurin minimization decreases rates of graft failure, incidence of delayed graft function, and new onset diabetes post transplant

Rejection is a common problem with renal allografts, and can be of cellular (lymphocyte) and/ or humoral (circulating antibody) origin. It is well known that if acute rejection is left untreated, eventually graft failure ensues. Rejection can be acute or subclinical. Acute rejection is clinically evident and often presents as a decline in kidney function associated with a rise in creatinine and classic histologic changes seen on renal biopsy. On the other hand, subclinical rejection is subtle; where histologic changes of rejection may be present in grafts that otherwise appear to have stable renal function. Immunosuppressive management for subclinical rejection has not been well delineated. [56-58] Finally, rejection may be mixed and have both cellular and

Overall the incidence of acute rejection post-transplant has decreased. However, survival of allografts has not increased to the extent predicted, mostly due to the universal development of chronic allograft dysfunction and late graft loss. Chronic allo-immune injury has been recognized as a major contributor to late graft loss and can present early on in transplantation as demonstrated by several protocol biopsy studies. [59, 60] Compared to cell-mediated rejections, humoral rejection and chronic rejection can be challenging to treat. In addition, the

immunologically low risk recipients.

220 Current Issues and Future Direction in Kidney Transplantation

**8. Antirejection therapies**

humoral components.

**7.2. Calcineurin inhibitor avoidance/minimization/withdrawal**

while avoiding an increased risk of acute rejection. [55].

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