Kidney allocation to highly sensitized patients Focus on acceptable mismatches Sebastiaan Heidt Eurotransplant Reference Laboratory EFI 12-05-2016

HLA matching in kidney transplantation HLA matching improves graft survival rate Many transplants are performed with some degree of HLA mismatch Collaborative Transplant Study 2010 Kidney allocation to highly sensitized patients 10-Nov-18

Sensitization to HLA Prior organ transplants Blood transfusion Pregnancies Kidney allocation to highly sensitized patients 10-Nov-18

Hyperacute rejection The presence of pre-transplant donor-reactive antibodies can lead to hyperacute rejection Pre-transplant crossmatching prevents transplantation into recipients with pre-existing donor-reactive antibodies Patients with antibodies against many specificities rarely get transplanted Kissmeyer-Nielsen et al., Lancet 1966 Kidney allocation to highly sensitized patients 10-Nov-18

Highly sensitized patients Highly sensitized patients awaiting a renal transplant are accumulating on the waiting list (many unacceptable antigens) Definition highly sensitized: At least 85% PRA in two different sera excluding irrelevant antibodies Virtual PRA of at least 85% (specificities of the HLA antibodies in context of the frequencies of the HLA antigens in the donor population) Kidney allocation to highly sensitized patients 10-Nov-18

Options for highly sensitized patients Transplant with HLA identical or compatible donor (taking into account unacceptable antigens) Do not accept that the patient is sensitized and try to remove antibodies Accept that the patient is sensitized and and try to stimulate the allocation of crossmatch negative donor kidneys to these patients Kidney allocation to highly sensitized patients 10-Nov-18

Low chance for highly sensitized patients to be transplanted through regular allocation Kidney allocation to highly sensitized patients 10-Nov-18

Poor patient survival rate for patients on dialysis Adapted from Montgomery et al., N Engl J Med 2011 Kidney allocation to highly sensitized patients 10-Nov-18

Desensitization protocols Two main desensitization protocols have been used: Plasmapheresis with low dose IVIg (living donor transplant recipients) high dose IVIg combined with rituximab Many patients have early acute ABMR due to antibody rebound Plasma cells are not depleted Side effects due to high levels of immunosuppression Success of desensitization is highly dependent on initial antibody levels Kidney allocation to highly sensitized patients 10-Nov-18

The ET acceptable mismatch (AM) program Basis: definition of those HLA antigens toward which the patient did never form antibodies and use this knowledge for donor selection These antigens are called acceptable antigens and help to predict a negative crossmatch Acceptable antigens are added to the HLA phenotype of the patient to increase chance of an organ offer Mandatory shipment of compatible organ to AM patient Kidney allocation to highly sensitized patients 10-Nov-18

AM program inclusion criteria Inclusion criteria evaluated for each patient: Minimum of 2 years on ET-KAS waiting list (defined by date of first dialysis) At least 85% PRA tested by CDC in two different sera excluding irrelevant antibodies Virtual PRA of at least 85% (antibodies detectable only by solid phase assays are only considered if explainable by immunizing event) Kidney allocation to highly sensitized patients 10-Nov-18

How acceptable antigens are defined Original method: Consider the HLA type of negative panel donors in screening Extensive antibody screening against a patient specific panel (donors with a single HLA-A or -B mismatch), from a pool of 20,000 HLA typed blood donors Testing serum of patients against cells expressing only one HLA type (SAL) Use of solid phase assays Use of computer algorithms for determining acceptable antigens (HLAMatchmaker) Kidney allocation to highly sensitized patients 10-Nov-18

Selection of acceptable antigens by CDC A1 is an acceptable antigen A32 and A2 are unacceptable antigens Kidney allocation to highly sensitized patients 10-Nov-18

Combination of patient HLA and AM: negative crossmatch Simplified example: HLA-C and HLA-DQ are also considered Kidney allocation to highly sensitized patients 10-Nov-18

Increased chance to be transplanted Kidney allocation to highly sensitized patients 10-Nov-18

Are acceptable mismatches truly acceptable? ET-KAS AM Pairwise log-rank, Bonferroni corrected P-values. Broad mismatches Heidt et al., Transplant Immunol 2015 Kidney allocation to highly sensitized patients 10-Nov-18

10-year graft survival ET-KAS vs. AM Selection: ≥ 1996 Renal only Deceased donor ≥ 1 HLA antigen mm Pairwise log-rank, Bonferroni corrected P-values. AM vs 0-5%: 0.062, AM vs. 6-85%: 1.000 ET-KAS % AM P-value First Tx 42227 85.1% 250 28.8% <0.000001 Re-Tx 7377 14.9% 619 71.2%

10-year graft survival re-transplant recipients Selection: ≥ 1996 Renal only Deceased donor ≥ 1 HLA antigen mm Re-transplant Pairwise log-rank, Bonferroni corrected P-values Kidney allocation to highly sensitized patients 10-Nov-18

10-year graft survival re-transplant recipients Selection: ≥ 1996 Renal only Deceased donor ≥ 1 HLA antigen mm Re-transplant  Multivariate analysis Pairwise log-rank, Bonferroni corrected P-values Kidney allocation to highly sensitized patients 10-Nov-18

Highly sensitized patients benefit from transplantation via AM program Multivariate analysis (Cox regression) 95% C.I. HR Lower Upper P-Value A-B-DR mm 1,2,3 (ref) 4,5,6 1.27 1.001 1.618 0.049 Tx Period 1996-2005 (ref) 2006-2015 0.62 0.506 0.771 <0.001 Donor sex Female (ref) Male 0.82 0.677 0.985 0.034 Recipient age ≤ 50 (ref) > 50 0.77 0.620 0.949 0.014 Donor age 1.80 1.489 2.174 Tx via AM No (ref) Yes 0.71 0.564 0.891 0.003 Not significant: recipient sex, blood group donor, CIP, waiting time Kidney allocation to highly sensitized patients 10-Nov-18

However, not all AM patients can be transplanted Still some AM patients with ‘exotic’ HLA types within the ET donor population remain on the waiting list Kidney allocation to highly sensitized patients 10-Nov-18

EUROSTAM project: a Europe-wide AM program Solution: look into donor populations where the ‘exotic’ phenotype is more common Exchange between allocation programs The EUROSTAM project (FP7, 2012-2015): Simulation studies on basis of the HLA phenotypes in different European populations Feasibility study which lead to an advice to the European Union on how to achieve exchange between allocation organizations http://eurostam.eu Kidney allocation to highly sensitized patients 10-Nov-18

Conclusions The AM program increased the chance for a highly sensitized patient to be transplanted The AM program has been highly successful, with over 1000 highly sensitized patients transplanted Acceptable mismatches are truly acceptable: no match-effect Excellent ten-year graft survival of AM patients Second option for those that still do not receive an organ: allocation outside geographical area (EUROSTAM) Last option for highly sensitized patients: desensitization Kidney allocation to highly sensitized patients 10-Nov-18

Kidney allocation to highly sensitized patients Focus on acceptable mismatches The ETRL team: Thanks to: Marian Witvliet - Screening and tissue typing Yvonne Zoet laboratory Leiden Geert Haasnoot - ETRL immunologists Petra van der Kroef - EUROSTAM consortium Anouk de Jong Sebastiaan Heidt Frans Claas Kidney allocation to highly sensitized patients 10-Nov-18