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CONNEXI 2016-08 Nephrologie

Kidney Experts Forum

Kidney Experts Forum Immunological risk assessment: the key to individualized immunosuppression after kidney transplantation Duska Dragun (Berlin); Ingeborg A Hauser (Frankfurt); Sabine Horn (Graz); Thomas Müller (Zurich); Johann Pratschke (Berlin), Peter Schemmer (Heidelberg), Friedrich Thaiss (Hamburg). Source: A Kidney Experts Forum was organized by Sanofi Genzyme on May 31, 2016, in Frankfurt, Germany, involving a panel of 20 experts in the field of kidney transplantation from Austria, Germany and Switzerland. The forum objective was to assess the contribution made by recipient, donor and transplant factors to immunological risk in kidney transplant patients. A Scientific Committee* presented highlights of each topic addressed during this meeting. Data presented were recently published in Transplantation Reviews [1]. 1.0 Following is a summary of the main background information/comments delivered. Effect of immunological risk on immunosuppression planning Prof. Ingeborg Hauser presented an overview of the impact of immunological risk on immuno-suppression choices. Incidence of acute rejection after kidney transplantation declined from 50% in the mid-1990s and has stabilized at ~10% by one year post-transplant with a similar risk in deceased- and living-donor transplants [2]. Rejection can be broken down into two major types: cell-mediated and antibody-mediated rejection. Cellular rejection occurred more commonly than antibody-mediated rejection. While cellular rejection has low impact on shortterm graft outcome, acute rejection is still associated with reduced long-term graft survival, in case of incomplete recovery of graft function [3, 4], late acute cellular rejection [5, 6], mixed cellular and antibody-mediated rejection (ABMR), in particular ABMR in the late phase [7] (Figure 1). Both conditions, mixed rejection and late ABMR, are difficult to treat and prevention is therefore essential. Education Kidney Experts Forum Probability of graft survival 0.8 0.6 0.4 0.2 0.0 Early AMR Late AMR p=0.011 0 500 1000 1500 2000 Time from rejection to graft loss (or last follow-up) (days) Figure 1: Death-censored graft survival by rejection type and time (institutional review board-approved prospective database; single-center analysis of 182 kidney transplants with a first biopsy-proven acute rejection (BPAR) episode: early (≤6 months) or late (>6 months) There is a lack of an accepted definition for at risk patients There is no global consensus as to a definition of high immunological risk. Criteria for “at-risk” patients listed in recent trial protocols are various, numerous and not well defined [8-10]. They are now often based on a combination of laboratory tests which have evolved only during recent years. For instance, the development of solid-phase single-bead antigen testing of solubilized HLA to detect HLA donor antigen specificities provided a sensitive detection of recipient HLA antibodies [11] (Figure 2). This technique is not yet universally adopted and consequently not at-risk patients are all identified. 38

Kidney Experts Forum 100 ELISA pos, SAB neg (n=3) ELISA neg, SAB neg (n=125) Death censored graft survival (%) 50 *Adjusted statistical analysis revealed a significantly increased risk for graft loss in ELISA HLA-Ab negative, but SAB-HLA-Ab positive patients. ELISA pos, SAB pos (n=43) ELISA neg, SAB pos (n=26) * 0 0 20 40 60 Months after renal transplantation Figure 2: Relevance of SAB-detected HLA-Ab in patients negative or positive for ELISA detected HLA-Ab for allograft survival. Lack of clear identification of patients at high risk of acute rejection hampers the ability to individualize immunosuppressive therapy. The immunosuppressive armamentarium currently includes various induction therapies, calcineurin inhibitors (CNIs), antiproliferative therapy (mycophenolic acid) and mammalian target of rapamycin (mTOR) inhibitors, and several dosing strategies (Table 1). In conclusion, a reliable definition of at-risk patients at the time of transplantation would refine risk stratification in tailoring immunosuppressive regimens in kidney transplant patients. Table 1: Areas of decision making when planning a post-transplant regimen Induction CNI therapy Steroid Desensitization immunologic risk status comments Low/moderate risk IL-2R antagonist [1, 24] Higher risk T cell depleting antibody [1, 25, 26] Low/moderate risk CNI avoidance generally not advised (possible with belatacept [27, 28] Low-exposure CNI + mTOR inhibitor from time of transplant is feasible [29, 30] Higher risk Low/moderate risk ABO incompatible livingdonor transplants Sensitized patients with DSA Standard CNI protocol is generally advisable Early steroid avoided (

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