Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation.

The clinical importance of preexisting HLA antibodies at the time of transplantation, identified by contemporary techniques, is not well understood. We conducted an observational study analyzing the association between preexisting donor-specific HLA antibodies (HLA-DSA) and incidence of acute antibody-mediated rejection (AMR) and survival of patients and grafts among 402 consecutive deceased-donor kidney transplant recipients. We detected HLA-DSA using Luminex single-antigen assays on the peak reactive and current sera. All patients had a negative lymphocytotoxic cross-match test on the day of transplantation. We found that 8-year graft survival was significantly worse (61%) among patients with preexisting HLA-DSA compared with both sensitized patients without HLA-DSA (93%) and nonsensitized patients (84%). Peak HLA-DSA Luminex mean fluorescence intensity (MFI) predicted AMR better than current HLA-DSA MFI (P = 0.028). As MFI of the highest ranked HLA-DSA detected on peak serum increased, graft survival decreased and the relative risk for AMR increased: Patients with MFI >6000 had >100-fold higher risk for AMR than patients with MFI <465 (relative risk 113; 95% confidence interval 31 to 414). The presence of HLA-DSA did not associate with patient survival. In conclusion, the risk for both AMR and graft loss directly correlates with peak HLA-DSA strength. Quantification of HLA antibodies allows stratification of immunologic risk, which should help guide selection of acceptable grafts for sensitized patients.

[1]  E. Thervet,et al.  Outcome of Subclinical Antibody‐Mediated Rejection in Kidney Transplant Recipients with Preformed Donor‐Specific Antibodies , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[2]  J. Bromberg,et al.  Intravenous immunoglobulin and thymoglobulin induction treatment in immunologically high-risk kidney transplant recipients. , 2005, Transplantation.

[3]  S. Mulgaonkar,et al.  Renal Transplantation in Patients With Pre‐Transplant Donor‐Specific Antibodies and Negative Flow Cytometry Crossmatches , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[4]  P. Kerr,et al.  A Single Low-Fixed Dose of Rituximab to Salvage Renal Transplants From Refractory Antibody-Mediated Rejection , 2009, Transplantation.

[5]  S. Jordan,et al.  Acceptable Donor-Specific Antibody Levels Allowing for Successful Deceased and Living Donor Kidney Transplantation After Desensitization Therapy , 2008, Transplantation.

[6]  P. Terasaki,et al.  Significance of the positive crossmatch test in kidney transplantation. , 1969, The New England journal of medicine.

[7]  Markus Exner,et al.  Capillary deposition of complement split product C4d in renal allografts is associated with basement membrane injury in peritubular and glomerular capillaries: a contribution of humoral immunity to chronic allograft rejection. , 2002, Journal of the American Society of Nephrology : JASN.

[8]  J. Bromberg,et al.  Addition of plasmapheresis decreases the incidence of acute antibody-mediated rejection in sensitized patients with strong donor-specific antibodies. , 2008, American Society of Nephrology. Clinical Journal.

[9]  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.

[10]  K. Mussatto,et al.  The virtual crossmatch – A screening tool for sensitized pediatric heart transplant recipients , 2006, Pediatric transplantation.

[11]  L. Rostaing,et al.  Rituximab therapy for acute humoral rejection after kidney transplantation. , 2007, Transplantation.

[12]  T. Larson,et al.  Transplant Glomerulopathy: Subclinical Incidence and Association with Alloantibody , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[13]  M. Stegall,et al.  The Spectrum of Antibody‐Mediated Renal Allograft Injury: Implications for Treatment , 2008, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[14]  E. Thervet,et al.  Posttransplant Prophylactic Intravenous Immunoglobulin in Kidney Transplant Patients at High Immunological Risk: A Pilot Study , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[15]  D. Nochy,et al.  Comparison of Combination Plasmapheresis/IVIg/Anti‐CD20 Versus High‐Dose IVIg in the Treatment of Antibody‐Mediated Rejection , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[16]  P. Sinnott,et al.  Pretransplant Donor-Specific Antibodies in Cytotoxic Negative Crossmatch Kidney Transplants: Are They Relevant? , 2008, Transplantation.

[17]  J. Steiger,et al.  Clinical Relevance of Pretransplant Donor-Specific HLA Antibodies Detected by Single-Antigen Flow-Beads , 2009, Transplantation.

[18]  D. Nochy,et al.  Clinical relevance of preformed HLA donor-specific antibodies in kidney transplantation. , 2008, Contributions to nephrology.

[19]  Cecka Jm,et al.  Crossmatch tests--an analysis of UNOS data from 1991-2000. , 2001 .

[20]  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.

[21]  J. Cecka,et al.  Crossmatch tests--an analysis of UNOS data from 1991-2000. , 2001, Clinical transplants.

[22]  V. Sánchez Rituximab and Intravenous Immune Globulin for Desensitization during Renal Transplantation , 2010 .

[23]  S. Jordan Management of the Highly HLA‐ Sensitized Patient. A Novel Role for Intravenous Gammaglobulin , 2002, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[24]  D. Segev,et al.  Subclinical Acute Antibody‐Mediated Rejection in Positive Crossmatch Renal Allografts , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[25]  S. Berger,et al.  Practical application of the virtual crossmatch , 2007, Pediatric transplantation.

[26]  J. Friedewald,et al.  Perception Versus Reality?: Virtual Crossmatch—How to Overcome Some of the Technical and Logistic Limitations , 2009 .

[27]  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.

[28]  R. Alloway,et al.  Reducing De Novo Donor‐Specific Antibody Levels during Acute Rejection Diminishes Renal Allograft Loss , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[29]  D. Nochy,et al.  Determinants of Poor Graft Outcome in Patients with Antibody‐Mediated Acute Rejection , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[30]  P. Terasaki,et al.  The Importance of Anti‐HLA‐Specific Antibody Strength in Monitoring Kidney Transplant Patients , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[31]  M. Stegall,et al.  Histologic Findings One Year After Positive Crossmatch or ABO Blood Group Incompatible Living Donor Kidney Transplantation , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[32]  J. Bariéty,et al.  Desensitization and Subsequent Kidney Transplantation of Patients Using Intravenous Immunoglobulins (IVIg) , 2002, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[33]  Jeffrey T. Sholander,et al.  Using real data for a virtual crossmatch. , 2009, Human immunology.

[34]  I. Doxiadis,et al.  Extending options for highly sensitized patients to receive a suitable kidney graft. , 2005, Current opinion in immunology.

[35]  I. Doxiadis,et al.  The acceptable mismatch program as a fast tool for highly sensitized patients awaiting a cadaveric kidney transplantation: short waiting time and excellent graft outcome. , 2004, Transplantation.

[36]  J. Bromberg,et al.  Intravenous immunoglobulin induction treatment in flow cytometry cross-match-positive kidney transplant recipients. , 2005, Human immunology.

[37]  M. A. Head,et al.  Organ Procurement and Transplantation Network/United Network for Organ Sharing Histocompatibility Committee Collaborative Study to Evaluate Prediction of Crossmatch Results in Highly Sensitized Patients , 2009, Transplantation.

[38]  M. Stegall,et al.  Alloantibody Levels and Acute Humoral Rejection Early After Positive Crossmatch Kidney Transplantation , 2008, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[39]  K. Kokko,et al.  Transplanting the Highly Sensitized Patient: The Emory Algorithm , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[40]  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.

[41]  G. Einecked,et al.  Banff 07 Classification of Renal Allograft Pathology : Updates and Future Directions , 2008 .

[42]  R. Colvin,et al.  Chronic humoral rejection: identification of antibody-mediated chronic renal allograft rejection by C4d deposits in peritubular capillaries. , 2001, Journal of the American Society of Nephrology : JASN.

[43]  S. Kaveri,et al.  Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. , 2001, The New England journal of medicine.