Overcoming Immunologic Incompatibility: Transplanting the Difficult to Transplant Patient

Immunologic incompatibilities between donor and recipient have limited the access to renal transplantation for many patients. Previously the presence of donor‐specific alloantibodies directed against donor major histocompatibility complex (MHC) antigens or natural antibodies directed against donor ABO blood group antigens was considered an absolute contraindication to renal transplantation. However, with the current understanding of humoral immune responses, superior immunosuppressive agents, and improved diagnosis and treatment of antibody‐mediated rejection, renal transplantation can be safely performed with outstanding results despite the presence of donor‐specific antibody. In this review we discuss the biology of antibody‐mediated rejection and sensitization. We discuss the diagnostic tests necessary to characterize the type, affinity, and avidity of the donor‐directed antibodies. Current methods for performing renal transplants across ABO and human leukocyte antigen (HLA)‐sensitized barriers are covered, including the potential morbidities. The rest of the review focuses on advances in managing these antibodies to increase the likelihood of receiving a deceased donor kidney or allow transplantation from a living donor against whom one has a prohibitive antibody.

[1]  C. Nast,et al.  Post‐transplant therapy with high‐dose intravenous gammaglobulin: Applications to treatment of antibody‐mediated rejection , 2005, Pediatric transplantation.

[2]  G. Danovitch,et al.  Current status of kidney and pancreas transplantation in the United States, 1994–2003 , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[3]  H. Genberg,et al.  ABO Incompatible Kidney Transplantations Without Splenectomy, Using Antigen‐Specific Immunoadsorption and Rituximab , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[4]  D. Stablein,et al.  Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial. , 2004, Journal of the American Society of Nephrology : JASN.

[5]  U. Galili Immune response, accommodation, and tolerance to transplantation carbohydrate antigens. , 2004, Transplantation.

[6]  Jonathan Himmelfarb,et al.  Donor Kidney Exchanges , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[7]  Stefanos Zenios,et al.  Practical and Ethical Challenges to Paired Exchange Programs , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[8]  M. Stegall,et al.  ABO-Incompatible Kidney Transplantation , 2004, Transplantation.

[9]  S. Greenstein,et al.  Successful Rescue Therapy with Plasmapheresis and Intravenous Immunoglobulin for Acute Humoral Renal Transplant Rejection , 2004, Transplantation.

[10]  S. Zenios,et al.  Restricting Living-Donor–Cadaver-Donor Exchanges to Ensure that Standard Blood Type O Wait-List Candidates Benefit , 2004, Transplantation.

[11]  R. Montgomery,et al.  Plasmapheresis, CMV Hyperimmune Globulin, and Anti‐CD20 Allow ABO‐Incompatible Renal Transplantation Without Splenectomy , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[12]  Akira Hasegawa,et al.  Excellent Long‐term Outcome of ABO‐Incompatible Living Donor Kidney Transplantation in Japan , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[13]  Y. Becker,et al.  Rituximab as Treatment for Refractory Kidney Transplant Rejection , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[14]  M. Zand,et al.  TREATMENT OF C4D-POSITIVE ACUTE HUMORAL REJECTION WITH PLASMAPHERESIS AND RABBIT POLYCLONAL ANTITHYMOCYTE GLOBULIN , 2004, Transplantation.

[15]  R. Montgomery,et al.  Successful Renal Transplantation across Simultaneous ABO Incompatible and Positive Crossmatch Barriers , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[16]  W. Land,et al.  Plasmapheresis in C4d‐positive Acute Humoral Rejection Following Kidney Transplantation: A Review of 4 Cases , 2003, Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy.

[17]  P. Nickerson,et al.  Pre‐Transplant Assessment of Donor‐Reactive, HLA‐Specific Antibodies in Renal Transplantation: Contraindication vs. Risk , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[18]  R. Montgomery,et al.  Specific and durable elimination of antibody to donor HLA antigens in renal-transplant patients , 2003, Transplantation.

[19]  M. Mihatsch,et al.  Kidney transplants, antibodies and rejection: is C4d a magic marker? , 2003, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[20]  E. Kamil,et al.  Intravenous immune globulin treatment inhibits crossmatch positivity and allows for successful transplantation of incompatible organs in living-donor and cadaver recipients1 , 2003, Transplantation.

[21]  G. Tydén,et al.  Successful ABO-incompatible kidney transplantations without splenectomy using antigen-specific immunoadsorption and rituximab , 2003, Transplantation.

[22]  T. Larson,et al.  Overcoming a Positive Crossmatch in Living‐Donor Kidney Transplantation , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[23]  M. Fishbein,et al.  Antibody‐Mediated Rejection Criteria – an Addition to the Banff ′97 Classification of Renal Allograft Rejection , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[24]  C. Cunningham-Rundles,et al.  Utility of Intravenous Immune Globulin in Kidney Transplantation: Efficacy, Safety, and Cost Implications , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[25]  J. Tuttle-Newhall,et al.  Beneficial effect of plasmapheresis and intravenous immunoglobulin on renal allograft survival of patients with acute humoral rejection1 , 2003, Transplantation.

[26]  T. Larson,et al.  ABO-incompatible kidney transplantation using both A2 and non-A2 living donors , 2003, Transplantation.

[27]  R. Colvin,et al.  Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology, and pathologic classification. , 2002, Journal of the American Society of Nephrology : JASN.

[28]  C. Bryan,et al.  Increased Access to Transplantation for Blood Group B Cadaveric Waiting List Candidates by Using A2 Kidneys: Time for a New National System? , 2002, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[29]  P. Nickerson,et al.  Flow cytometric crossmatching in primary renal transplant recipients with a negative anti-human globulin enhanced cytotoxicity crossmatch. , 2001, Journal of the American Society of Nephrology : JASN.

[30]  W. Hörl,et al.  C4d-positive acute humoral renal allograft rejection: effective treatment by immunoadsorption. , 2001, Journal of the American Society of Nephrology : JASN.

[31]  R. Howard,et al.  OUTCOME OF KIDNEY TRANSPLANTS IN PATIENTS KNOWN TO BE FLOW CYTOMETRY CROSSMATCH POSITIVE1 , 2001, Transplantation.

[32]  Francis L. Delmonico,et al.  ACUTE HUMORAL REJECTION IN RENAL ALLOGRAFT RECIPIENTS: I. INCIDENCE, SEROLOGY AND CLINICAL CHARACTERISTICS1 , 2001, Transplantation.

[33]  P. Randhawa,et al.  IVIG rescue therapy in renal transplantation. , 2001, Transplantation proceedings.

[34]  G. Opelz,et al.  A RANDOMIZED AND PROSPECTIVE STUDY COMPARING TREATMENT WITH HIGH-DOSE INTRAVENOUS IMMUNOGLOBULIN WITH MONOCLONAL ANTIBODIES FOR RESCUE OF KIDNEY GRAFTS WITH STEROID-RESISTANT REJECTION , 2001, Transplantation.

[35]  M. Fernandez-Vina,et al.  A HIGH PANEL-REACTIVE ANTIBODY RESCUE PROTOCOL FOR CROSS-MATCH-POSITIVE LIVE DONOR KIDNEY TRANSPLANTS1 , 2000, Transplantation.

[36]  R. Montgomery,et al.  PLASMAPHERESIS AND INTRAVENOUS IMMUNE GLOBULIN PROVIDES EFFECTIVE RESCUE THERAPY FOR REFRACTORY HUMORAL REJECTION AND ALLOWS KIDNEYS TO BE SUCCESSFULLY TRANSPLANTED INTO CROSS-MATCH-POSITIVE RECIPIENTS , 2000, Transplantation.

[37]  F. Port,et al.  Effect of waiting time on renal transplant outcome. , 2000, Kidney international.

[38]  S. Gruber,et al.  Flow cytometry-detected IgG is not a contraindication to renal transplantation: IgM may be beneficial to outcome. , 1999, Transplantation.

[39]  R. Colvin,et al.  Plasma exchange and tacrolimus-mycophenolate rescue for acute humoral rejection in kidney transplantation. , 1998, Transplantation.

[40]  M. Fishbein,et al.  Posttransplant therapy using high-dose human immunoglobulin (intravenous gammaglobulin) to control acute humoral rejection in renal and cardiac allograft recipients and potential mechanism of action. , 1998, Transplantation.

[41]  P. Schnuelle,et al.  Should A2 kidneys be transplanted into B or O recipients? , 1998, The Lancet.

[42]  P I Terasaki,et al.  Paired kidney exchange is not a solution to ABO incompatibility. , 1998, Transplantation.

[43]  T. Fuller,et al.  HLA alloantibodies and the mechanism of the antiglobulin-augmented lymphocytotoxicity procedure. , 1997, Human immunology.

[44]  A. Steinberg,et al.  The frequencies of HLA alleles and haplotypes and their distribution among donors and renal patients in the UNOS registry. , 1996, Transplantation.

[45]  T. Pruett,et al.  EVIDENCE DEMONSTRATING POOR KIDNEY GRAFT SURVIVAL WHEN ACUTE REJECTIONS ARE ASSOCIATED WITH IgG DONOR‐SPECIFIC LYMPHOCYTOTOXIN , 1995, Transplantation.

[46]  L. Czer,et al.  Intravenous immunoglobulin suppression of HLA alloantibody in highly sensitized transplant candidates and transplantation with a histoincompatible organ. , 1994, Transplantation.

[47]  G. Riethmüller,et al.  Capillary deposition of C4d complement fragment and early renal graft loss. , 1993, Kidney international.

[48]  J. Squifflet,et al.  Present experiences in a series of 26 ABO-incompatible living donor renal allografts. , 1987, Transplantation proceedings.

[49]  M. R. Mickey,et al.  Serotyping for homotransplantation. XX. Selection of recipients for cadaver donor transplants. , 1968, The New England journal of medicine.

[50]  M. R. Mickey,et al.  Serotyping for Homotransplantation , 1968 .

[51]  M. Gnant,et al.  Risk factors for development of panel reactive antibodies and their impact on kidney transplantation outcome. , 1992, Transplant international : official journal of the European Society for Organ Transplantation.

[52]  C. V. van Buren,et al.  Improved graft survival for flow cytometry and antihuman globulin crossmatch-negative retransplant recipients. , 1990, Transplantation.