- Email: [email protected]
Recent Developments in Desensitization of Crossmatch-positive Kidney Transplant Recipients
Recent Developments in Desensitization of Crossmatch-positive Kidney Transplant Recipients C. Morath, G. Opelz, M. Zeier, and C. Süsal ABSTRACT Currently, there are two major options for the successful and timely transplantation of sensitized kidney transplant recipients: (1) avoidance of the sensitization barrier using special allocation programs, or (2) desensitization. In the case of broadly sensitized kidney patients, a combination of both options might be necessary. This review focuses on new advances in desensitization of crossmatch-positive kidney transplant recipients which include immunoadsorption and the administration of new substances such as the complement C5 inhibitor eculizumab. Finally, integrated algorithms that combine different measures are acknowledged. IGHLY sensitized kidney transplant recipients have two major disadvantages: (1) They have a lower chance of receiving a crossmatch-negative organ offer; therefore, their names accumulate on the waiting list. Analyzing waiting times in the United Kingdom for patients waitlisted from 1998 to 2005, Fuggle and Martin found a waiting time of 788 days for patients who possessed less than 5% panel-reactive antibodies (PRA).1 The waiting time increased to 1696 days in patients with 61% to 84% PRA and to 2232 days in highly sensitized patients with a PRA of ⱖ 85%. Some of the highly sensitized patients develop a broad range of HLA alloantibodies and will never get an acceptable organ offer without additional therapeutic or cataloguing measures. (2) If highly sensitized patients eventually are transplanted, they are at an increased risk of antibody-mediated allograft rejection, even when the crossmatch was negative at the time of transplantation.2,3 This phenomenon is attributed to a generally higher alloreactivity in these patients and/or to donor-specific antibodies (DSA) that were overlooked in the crossmatch tests or antibody screenings. Two different strategies have been proposed for addressing these problems. (1) The presence of DSA in the patient’s serum is considered a contraindication to transplantation. In this case, to avoid the crossmatch barrier, patients are given additional score points for organ allocation and enrolled into special programs, such as the Acceptable Mismatch Program of Eurotransplant, or, in the case of living-donor kidney transplantation, paired kidney donation schemes. (2) Alternatively, the HLA/crossmatch barrier is not considered a contraindication because patients are desensitized to obtain a negative pretransplant cross-
H
match constellation. In a considerable fraction of patients who possess a broad range of HLA alloantibodies, however, experience has shown that either approach alone will not be successful and that a combination of measures, such as inclusion in special allocation programs plus desensitization, will be necessary to finally allow transplantation. Currently used measures for successful desensitization and transplantation of highly sensitized kidney patients with a positive crossmatch are summarized in Table 1. In the following, we will focus on recent developments in the field of desensitization published during the last year. DESENSITIZATION OF LIVING-DONOR KIDNEY TRANSPLANT RECIPIENTS WITH A COMBINATION OF PLASMAPHERESIS AND INTRAVENOUS IMMUNOGLOBULINS
The Johns Hopkins protocol for the transplantation of sensitized living-donor kidney transplant recipients is based on a combination of plasmapheresis and low-dose intravenous immunoglobulin (IVIG) (cytomegalovirus-Ig; 100 mg/kg body weight) in combination with immunosuppression including either daclizumab or thymoglobulin induction therapy. Unfortunately, no detailed analysis on graft survival is available for a larger cohort of patients treated From the Department of Nephrology (C.M., M.Z.), and the Department of Transplantation Immunology (G.O., C.S.), University of Heidelberg, Germany. Address reprint requests to Caner Süsal, MD, Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D*69120 Heidelberg, Germany. E-mail: [email protected]
0041-1345/12/$–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.04.006
© 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1648
Transplantation Proceedings, 44, 1648 –1651 (2012)
RECENT DEVELOPMENTS Table 1. Approaches for the Transplantation of High-risk Sensitized Patients Organisatory measures Kidney paired donation Eurotransplant AM Program Desensitization Plasmapheresis ⫾ low-dose IVIG Immunoadsorption High-dose IVIG Proteasome inhibition (bortezomib) Complement inhibition (eculizumab) Integrated algorithms combining cataloguing measures and desensitization “Heidelberg Algorithm” Luminex-based algorithm (Saint-Louis Hospital, Paris, France) Abbreviations: AM, acceptable mismatch; IVIG, intravenous immunoglobulins.
with this protocol. In a review article, 1- and 3-year graft survival rates in 62 living donor kidney recipients transplanted against a positive flow cytometric or anti-human globulin complement-dependent lymphocytoxicity (CDC) crossmatch were reported to be not different from the graft survival rates in non-sensitized recipients of live donors.4 A more detailed analysis on patient survival of livingdonor kidney transplant recipients from the same center who were desensitized because of a positive crossmatch result or Luminex-detectable DSA was published recently.5 As many as 98% of 215 desensitized patients could be transplanted. Four patients had a persisting positive CDC crossmatch with a titer of ⱖ1:8 despite treatment and were therefore not transplanted. Seventy-four patients with an initially positive CDC crossmatch, 95 patients with an initially negative CDC but positive flow cytometric crossmatch, and 42 patients with negative crossmatch results but Luminex-detectable DSA were analyzed. One thousand fifty matched “dialysis-only” patients and 1040 matched patients on “dialysis-or-transplantation therapy” served as controls. Independent of the degree of sensitization (positive or negative crossmatch results), patients had a survival benefit when they were desensitized for incompatible livingdonor kidney transplantation as compared to waiting for a compatible deceased-donor organ without further desensitization. Although the 1-year patient survival rate of 90.6% was rather low in the living-donor kidney transplant cohort and not different from survival in patients that were waitlisted, desensitized patients clearly had a survival benefit in the long-term: 80.6% patient survival at 8 years compared to 30.5% for patients in the dialysis-only group; and 49.1% in the dialysis-or-transplantation group (P ⬍ .001 for both). PERITRANSPLANT IMMUNOADSORPTION FOR DESENSITIZATION OF DECEASED-DONOR KIDNEY TRANSPLANT RECIPIENTS
To remove HLA alloantibodies during a short period immediately before transplantation, measures such as the administration of IVIG alone may not be sufficient. HLA
1649
alloantibodies can be eliminated from the patient’s circulation by plasmapheresis or immunoadsorption. First reports on the use of immunoadsorption date back to the 1990s. However, success rates were rather low because of insufficient protocols that used immunoadsorption only once before transplantation.6 At the end of the 1990s, the Vienna group started a program for the desensitization of sensitized deceased-donor kidney transplant recipients which consisted of peritransplant immunoadsorption in combination with powerful immunosuppression including antilymphocyte antibody therapy. The long-term data were published recently. Between 1999 and 2008, a total of 68 patients with a CDC-PRA of ⱖ40% were transplanted,7 of which 21 patients had a positive CDC crossmatch before pretransplant immunoadsorption and an additional 30 patients had DSA detectable by Luminex technology only. Seventeen patients were sensitized but had no positive crossmatch results or Luminex-detected DSA. In contrast to earlier studies, immunoadsorption was continued after transplantation until stabilization of graft function was achieved. The overall 5-year graft survival rate was 63%, death-censored graft survival was 76%, and patient survival was 87%. There was a trend towards a lower death-censored graft survival rate early after transplantation but no significant difference in long-term deathcensored graft survival between crossmatch- and DSApositive and -negative groups. Antibody-mediated rejection episodes occurred in 24% to 30% of the patients. COMPARISON OF IMMUNOADSORPTION AND PLASMAPHERESIS IN RECIPIENT DESENSITIZATION
The protein A (Immunosorba, Fresenius Medical Care, Bad Homburg, Germany; Ig-Therasorb: Miltenyi Biotec, Bergisch Gladbach, Germany) as well as the Ig-Therasorb immunoadsorption device consist of two parallel, regenerable columns that bind IgG subclasses 1, 2, and 4 with high affinity, and IgG 3, IgA, and IgM with variable affinity. With the treatment of 2.5 plasma volumes, immunoadsorption is capable of removing 87% of IgG, whereas albumin or antithrombin III remain almost unaffected and thus do not require replacement.8,9 With multiple immunoadsorption treatments, more than 98% of IgG or a specific antibody such as donor-specific HLA alloantibody may be eliminated from the systemic circulation. Potential advantages of immunoadsorption-based desensitization over plasmapheresis are listed in Table 2. Especially in the context of rapid crossmatch conversion immediately before kidney transplantation, immunoadsorption offers the opportunity for selective depletion of immunoglobulins without a need for substitution with fresh frozen plasma or albumin. Moreover, compared to plasmapheresis, immunoadsorption is associated with better tolerability and a lower likelihood of allergic reactions, and therefore allows the treatment of larger plasma volumes with higher antibody reduction rates. In the study of Bartel et al, a median of 9 L and 8 L of plasma were processed during pretransplant immunoadsorption treatment in CDC crossmatch-positive and CDC crossmatch-negative
1650
MORATH, OPELZ, ZEIER ET AL Table 2. Potential Advantages of Immunoadsorption Over Plasmapheresis Plasmapheresis
Unselective Necessity for substitution of plasma proteins (albumin, donor plasma including, ie, complement, ADAMTS-13) Limited plasma exchange rates Variable reduction of immunoglobulins Allergic reactions frequent Single use device Variable cost Limited evidence
Immunoadsorption
Selective No substitution of plasma components
High plasma exchange rates Strong reduction of immunoglobulin G Allergic reactions infrequent Mostly multiple use device High cost, which decreases with the number of treatments Limited evidence
Abbreviation: ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13.
kidney recipients, respectively.7 These volumes would most likely not have been achieved with the use of plasmapheresis. PERITRANSPLANT TREATMENT WITH A COMPLEMENT C5-INHIBITOR
A recently introduced concept in the prevention of antibody-mediated allograft injury is based not solely on recipient desensitization but includes the abrogation of alloantibody-mediated end-organ damage by the blockage of complement activation. The monoclonal antibody eculizumab binds to complement factor C5 and prevents generation of the proinflammatory peptide C5a and assembly of the cytotoxic membrane-attack complex C5b-9. Stegall et al recently reported on their results obtained in a first series of sensitized living-donor kidney transplant recipients in whom the use of eculizumab was tested for the prevention of antibody-mediated allograft rejection.10 Twenty-six CDC crossmatch-negative, but flow cytometric crossmatch-positive kidney transplantations realized with the pre- and posttransplant usage of eculizumab were compared to a historical control group of 51 transplantations in which desensitization had been performed without the administration of eculizumab. In both groups, pretransplant plasma exchange was performed when T- and B-flow crossmatch channel shifts were ⱖ 300 (69% of patients in both groups). Acute humoral rejection was observed in only 7.7% of patients treated with eculizumab, as compared to a 41.2% rate in the historical control group. Similarly, 1-year protocol biopsy specimens revealed transplant glomerulopathy in 6.7% of eculizumab-treated patients compared to 35.7% in control patients. None of the patients in the eculizumab group had a positive anti-human globulin enhanced T-cell cytotoxicity crossmatch before transplantation as compared to 8 patients in the historical control group. Even in the absence of patients with a very high immunological risk, chronic allograft injury occurred in a significant number of patients. Nevertheless, it seems that complement inhibition, in addition to recipient desensitization, represents a new powerful tool for
accomplishing kidney transplantation in immunological highrisk patients. Studies are underway to further evaluate the potential of this promising substance also in high-risk patients with positive CDC crossmatch results. ALGORITHMS FOR TRANSPLANTATION OF HIGHLY SENSITIZED PATIENTS
A considerable fraction of highly sensitized patients on the waiting list are broadly sensitized and have a chance of successful kidney transplantation only when different options are combined. For living-donor kidney transplantations, options such as kidney-paired donation are available for increasing the chance of receiving a compatible allograft.11 Kidney-paired donation can be combined with recipient desensitization to optimize the number of successful transplants. Special programs for deceased-donor kidney transplantations have been implemented by Eurotransplant (Eurotransplant Acceptable Mismatch Program) and more recently also in France.12 An integrated algorithm that combines several measures for the successful transplantation of high-risk sensitized patients was recently published by our group (Table 3).13 This algorithm contains seven independent measures: (1) a risk categorization based on enzyme-linked immunosorbent assay (ELISA) screenTable 3. “Heidelberg Algorithm” 1. Pretransplant identification of high-risk patients Donor-independent CDC-PRA-DTT ⱖ 85% (current or historical) HLA class I and II antibody positivity in ELISA HLA class I positivity in ELISA (retransplant) Donor-dependent Positive CDC B-cell crossmatch in retransplant recipients with HLA class II antibody positivity in ELISA Positive CDC T-cell crossmatch DSA with more than 1000 MFI in Luminex (living donor) 2. Good HLA match in patients with HLA class I and class II antibody positivity in ELISA (deceased donor) CDC-PRA-DTT ⱖ 10%: 0–1 HLA-A, -B, -DR mismatches CDC-PRA-DTT ⬍ 10%: 0–2 HLA-A, -B, -DR mismatches 3. Acceptable Mismatch Program of Eurotransplant (deceased donor) CDC-PRA-DTT ⱖ 85% (current or historical) 4. Pretransplant treatment Single plasmapheresis (deceased donor) Repeated immunoadsorption (living donor) Rituximab 375 mg/m2 (when all crossmatches are negative) 5. Posttransplant treatment Repeated plasmapheresis (deceased donor) Repeated immunoadsorption (living donor) 6. Protocol biopsies On days 7 and 90 7. Posttransplant monitoring of donor-specific antibodies On days 0, 7, 30, 180, and every 6 months thereafter by CDC, ELISA, Luminex Adapted from Morath et al.13 Abbreviations: CDC, complement-dependent lymphocytotoxicity; PRA, panel-reactive antibodies; DTT, dithiothreitol; ELISA, enzyme-linked immunosorbent assay; DSA, donor-specific antibodies; MFI, mean fluorescence intensity.
RECENT DEVELOPMENTS
ing and CDC crossmatch results in deceased-donor kidney recipients, and on Luminex testing in living-donor kidney transplant recipient; (2) a good HLA match in the case of deceased-donor kidney transplantation; (3) inclusion of eligible patients in the Eurotransplant Acceptable Mismatch Program; (4) pretransplant desensitization; (5) posttransplant apheresis; (6) protocol biopsies on days 7 and 90; and (7) posttransplant HLA alloantibody monitoring. Until November 2011, 79 patients have been transplanted according to this algorithm with good short to intermediate-term outcomes. CONCLUSIONS
New developments for the desensitization of crossmatchpositive kidney transplantations are: (1) The introduction of more specific antibody elimination methodologies, such as immunoadsorption which allows the rapid elimination of alloantibodies within a short period, especially in the context of rapid crossmatch conversion after a deceased-donor organ offer; (2) The advent of drugs that follow new concepts such as the recently introduced complement inhibitor eculizumab. Eculizumab, in addition to recipient desensitization, may significantly reduce antibody-mediated rejection rates after crossmatch-positive kidney transplantation; and (3) The implementation of algorithms that combine different measures for this difficult to transplant cohort, such as the “Heidelberg Algorithm.” Meanwhile, other important measures such as improved HLA matching at the epitope level for prevention of sensitization after a failed transplant are increasingly acknowledged. REFERENCES 1. Fuggle SV, Martin S: Tools for human leukocyte antigen antibody detection and their application to transplanting sensitized patients. Transplantation 86:384, 2008
1651 2. Süsal C, Döhler B, Opelz G: Presensitized kidney graft recipients with HLA class I and II antibodies are at increased risk for graft failure: a Collaborative Transplant Study report. Hum Immunol 70:569, 2009 3. Collaborative Transplant Study, University of Heidelberg, Germany: Available at: www.ctstransplant.org. Accessed December 29, 2010 4. Montgomery RA, Zachary AA: Transplanting patients with a positive donor-specific crossmatch: a single center’s perspective. Pediatr Transplant 8:535, 2004 5. Montgomery RA, Lonze BE, King KE, et al: Desensitization in HLA-incompatible kidney recipients and survival. N Engl J Med 365:318, 2011 6. Higgins RM, Bevan DJ, Carey BS, et al: Prevention of hyperacute rejection by removal of antibodies to HLA immediately before renal transplantation. Lancet 348:1208, 1996 7. Bartel G, Wahrmann M, Regele H, et al: Peritransplant immunoadsorption for positive crossmatch deceased donor kidney transplantation. Am J Transplant 10:2033, 2010 8. Belak M, Borberg H, Jimenez C, et al: Technical and clinical experience with protein A immunoadsorption columns. Transfus Sci 15:419, 1994 9. Gjorstrup P, Berntorp E, Larsson L, et al: Kinetic aspects of the removal of IgG and inhibitors in hemophiliacs using protein A immunoadsorption. Vox Sang 61:244, 1991 10. Stegall MD, Diwan T, Raghavaiah S, et al: Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant 11:2405, 2011 11. Montgomery RA: Renal transplantation across HLA and ABO antibody barriers: integrating paired donation into desensitization protocols. Am J Transplant 10:449, 2010 12. Doxiadis, II, Smits JM, Persijn GG, et al: It takes six to boogie: allocating cadaver kidneys in Eurotransplant. Transplantation 77:615, 2004 13. Morath C, Beimler J, Opelz G, et al: An integrative approach for the transplantation of high-risk sensitized patients. Transplantation 90:645, 2010
H
match constellation. In a considerable fraction of patients who possess a broad range of HLA alloantibodies, however, experience has shown that either approach alone will not be successful and that a combination of measures, such as inclusion in special allocation programs plus desensitization, will be necessary to finally allow transplantation. Currently used measures for successful desensitization and transplantation of highly sensitized kidney patients with a positive crossmatch are summarized in Table 1. In the following, we will focus on recent developments in the field of desensitization published during the last year. DESENSITIZATION OF LIVING-DONOR KIDNEY TRANSPLANT RECIPIENTS WITH A COMBINATION OF PLASMAPHERESIS AND INTRAVENOUS IMMUNOGLOBULINS
The Johns Hopkins protocol for the transplantation of sensitized living-donor kidney transplant recipients is based on a combination of plasmapheresis and low-dose intravenous immunoglobulin (IVIG) (cytomegalovirus-Ig; 100 mg/kg body weight) in combination with immunosuppression including either daclizumab or thymoglobulin induction therapy. Unfortunately, no detailed analysis on graft survival is available for a larger cohort of patients treated From the Department of Nephrology (C.M., M.Z.), and the Department of Transplantation Immunology (G.O., C.S.), University of Heidelberg, Germany. Address reprint requests to Caner Süsal, MD, Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D*69120 Heidelberg, Germany. E-mail: [email protected]
0041-1345/12/$–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.04.006
© 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1648
Transplantation Proceedings, 44, 1648 –1651 (2012)
RECENT DEVELOPMENTS Table 1. Approaches for the Transplantation of High-risk Sensitized Patients Organisatory measures Kidney paired donation Eurotransplant AM Program Desensitization Plasmapheresis ⫾ low-dose IVIG Immunoadsorption High-dose IVIG Proteasome inhibition (bortezomib) Complement inhibition (eculizumab) Integrated algorithms combining cataloguing measures and desensitization “Heidelberg Algorithm” Luminex-based algorithm (Saint-Louis Hospital, Paris, France) Abbreviations: AM, acceptable mismatch; IVIG, intravenous immunoglobulins.
with this protocol. In a review article, 1- and 3-year graft survival rates in 62 living donor kidney recipients transplanted against a positive flow cytometric or anti-human globulin complement-dependent lymphocytoxicity (CDC) crossmatch were reported to be not different from the graft survival rates in non-sensitized recipients of live donors.4 A more detailed analysis on patient survival of livingdonor kidney transplant recipients from the same center who were desensitized because of a positive crossmatch result or Luminex-detectable DSA was published recently.5 As many as 98% of 215 desensitized patients could be transplanted. Four patients had a persisting positive CDC crossmatch with a titer of ⱖ1:8 despite treatment and were therefore not transplanted. Seventy-four patients with an initially positive CDC crossmatch, 95 patients with an initially negative CDC but positive flow cytometric crossmatch, and 42 patients with negative crossmatch results but Luminex-detectable DSA were analyzed. One thousand fifty matched “dialysis-only” patients and 1040 matched patients on “dialysis-or-transplantation therapy” served as controls. Independent of the degree of sensitization (positive or negative crossmatch results), patients had a survival benefit when they were desensitized for incompatible livingdonor kidney transplantation as compared to waiting for a compatible deceased-donor organ without further desensitization. Although the 1-year patient survival rate of 90.6% was rather low in the living-donor kidney transplant cohort and not different from survival in patients that were waitlisted, desensitized patients clearly had a survival benefit in the long-term: 80.6% patient survival at 8 years compared to 30.5% for patients in the dialysis-only group; and 49.1% in the dialysis-or-transplantation group (P ⬍ .001 for both). PERITRANSPLANT IMMUNOADSORPTION FOR DESENSITIZATION OF DECEASED-DONOR KIDNEY TRANSPLANT RECIPIENTS
To remove HLA alloantibodies during a short period immediately before transplantation, measures such as the administration of IVIG alone may not be sufficient. HLA
1649
alloantibodies can be eliminated from the patient’s circulation by plasmapheresis or immunoadsorption. First reports on the use of immunoadsorption date back to the 1990s. However, success rates were rather low because of insufficient protocols that used immunoadsorption only once before transplantation.6 At the end of the 1990s, the Vienna group started a program for the desensitization of sensitized deceased-donor kidney transplant recipients which consisted of peritransplant immunoadsorption in combination with powerful immunosuppression including antilymphocyte antibody therapy. The long-term data were published recently. Between 1999 and 2008, a total of 68 patients with a CDC-PRA of ⱖ40% were transplanted,7 of which 21 patients had a positive CDC crossmatch before pretransplant immunoadsorption and an additional 30 patients had DSA detectable by Luminex technology only. Seventeen patients were sensitized but had no positive crossmatch results or Luminex-detected DSA. In contrast to earlier studies, immunoadsorption was continued after transplantation until stabilization of graft function was achieved. The overall 5-year graft survival rate was 63%, death-censored graft survival was 76%, and patient survival was 87%. There was a trend towards a lower death-censored graft survival rate early after transplantation but no significant difference in long-term deathcensored graft survival between crossmatch- and DSApositive and -negative groups. Antibody-mediated rejection episodes occurred in 24% to 30% of the patients. COMPARISON OF IMMUNOADSORPTION AND PLASMAPHERESIS IN RECIPIENT DESENSITIZATION
The protein A (Immunosorba, Fresenius Medical Care, Bad Homburg, Germany; Ig-Therasorb: Miltenyi Biotec, Bergisch Gladbach, Germany) as well as the Ig-Therasorb immunoadsorption device consist of two parallel, regenerable columns that bind IgG subclasses 1, 2, and 4 with high affinity, and IgG 3, IgA, and IgM with variable affinity. With the treatment of 2.5 plasma volumes, immunoadsorption is capable of removing 87% of IgG, whereas albumin or antithrombin III remain almost unaffected and thus do not require replacement.8,9 With multiple immunoadsorption treatments, more than 98% of IgG or a specific antibody such as donor-specific HLA alloantibody may be eliminated from the systemic circulation. Potential advantages of immunoadsorption-based desensitization over plasmapheresis are listed in Table 2. Especially in the context of rapid crossmatch conversion immediately before kidney transplantation, immunoadsorption offers the opportunity for selective depletion of immunoglobulins without a need for substitution with fresh frozen plasma or albumin. Moreover, compared to plasmapheresis, immunoadsorption is associated with better tolerability and a lower likelihood of allergic reactions, and therefore allows the treatment of larger plasma volumes with higher antibody reduction rates. In the study of Bartel et al, a median of 9 L and 8 L of plasma were processed during pretransplant immunoadsorption treatment in CDC crossmatch-positive and CDC crossmatch-negative
1650
MORATH, OPELZ, ZEIER ET AL Table 2. Potential Advantages of Immunoadsorption Over Plasmapheresis Plasmapheresis
Unselective Necessity for substitution of plasma proteins (albumin, donor plasma including, ie, complement, ADAMTS-13) Limited plasma exchange rates Variable reduction of immunoglobulins Allergic reactions frequent Single use device Variable cost Limited evidence
Immunoadsorption
Selective No substitution of plasma components
High plasma exchange rates Strong reduction of immunoglobulin G Allergic reactions infrequent Mostly multiple use device High cost, which decreases with the number of treatments Limited evidence
Abbreviation: ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13.
kidney recipients, respectively.7 These volumes would most likely not have been achieved with the use of plasmapheresis. PERITRANSPLANT TREATMENT WITH A COMPLEMENT C5-INHIBITOR
A recently introduced concept in the prevention of antibody-mediated allograft injury is based not solely on recipient desensitization but includes the abrogation of alloantibody-mediated end-organ damage by the blockage of complement activation. The monoclonal antibody eculizumab binds to complement factor C5 and prevents generation of the proinflammatory peptide C5a and assembly of the cytotoxic membrane-attack complex C5b-9. Stegall et al recently reported on their results obtained in a first series of sensitized living-donor kidney transplant recipients in whom the use of eculizumab was tested for the prevention of antibody-mediated allograft rejection.10 Twenty-six CDC crossmatch-negative, but flow cytometric crossmatch-positive kidney transplantations realized with the pre- and posttransplant usage of eculizumab were compared to a historical control group of 51 transplantations in which desensitization had been performed without the administration of eculizumab. In both groups, pretransplant plasma exchange was performed when T- and B-flow crossmatch channel shifts were ⱖ 300 (69% of patients in both groups). Acute humoral rejection was observed in only 7.7% of patients treated with eculizumab, as compared to a 41.2% rate in the historical control group. Similarly, 1-year protocol biopsy specimens revealed transplant glomerulopathy in 6.7% of eculizumab-treated patients compared to 35.7% in control patients. None of the patients in the eculizumab group had a positive anti-human globulin enhanced T-cell cytotoxicity crossmatch before transplantation as compared to 8 patients in the historical control group. Even in the absence of patients with a very high immunological risk, chronic allograft injury occurred in a significant number of patients. Nevertheless, it seems that complement inhibition, in addition to recipient desensitization, represents a new powerful tool for
accomplishing kidney transplantation in immunological highrisk patients. Studies are underway to further evaluate the potential of this promising substance also in high-risk patients with positive CDC crossmatch results. ALGORITHMS FOR TRANSPLANTATION OF HIGHLY SENSITIZED PATIENTS
A considerable fraction of highly sensitized patients on the waiting list are broadly sensitized and have a chance of successful kidney transplantation only when different options are combined. For living-donor kidney transplantations, options such as kidney-paired donation are available for increasing the chance of receiving a compatible allograft.11 Kidney-paired donation can be combined with recipient desensitization to optimize the number of successful transplants. Special programs for deceased-donor kidney transplantations have been implemented by Eurotransplant (Eurotransplant Acceptable Mismatch Program) and more recently also in France.12 An integrated algorithm that combines several measures for the successful transplantation of high-risk sensitized patients was recently published by our group (Table 3).13 This algorithm contains seven independent measures: (1) a risk categorization based on enzyme-linked immunosorbent assay (ELISA) screenTable 3. “Heidelberg Algorithm” 1. Pretransplant identification of high-risk patients Donor-independent CDC-PRA-DTT ⱖ 85% (current or historical) HLA class I and II antibody positivity in ELISA HLA class I positivity in ELISA (retransplant) Donor-dependent Positive CDC B-cell crossmatch in retransplant recipients with HLA class II antibody positivity in ELISA Positive CDC T-cell crossmatch DSA with more than 1000 MFI in Luminex (living donor) 2. Good HLA match in patients with HLA class I and class II antibody positivity in ELISA (deceased donor) CDC-PRA-DTT ⱖ 10%: 0–1 HLA-A, -B, -DR mismatches CDC-PRA-DTT ⬍ 10%: 0–2 HLA-A, -B, -DR mismatches 3. Acceptable Mismatch Program of Eurotransplant (deceased donor) CDC-PRA-DTT ⱖ 85% (current or historical) 4. Pretransplant treatment Single plasmapheresis (deceased donor) Repeated immunoadsorption (living donor) Rituximab 375 mg/m2 (when all crossmatches are negative) 5. Posttransplant treatment Repeated plasmapheresis (deceased donor) Repeated immunoadsorption (living donor) 6. Protocol biopsies On days 7 and 90 7. Posttransplant monitoring of donor-specific antibodies On days 0, 7, 30, 180, and every 6 months thereafter by CDC, ELISA, Luminex Adapted from Morath et al.13 Abbreviations: CDC, complement-dependent lymphocytotoxicity; PRA, panel-reactive antibodies; DTT, dithiothreitol; ELISA, enzyme-linked immunosorbent assay; DSA, donor-specific antibodies; MFI, mean fluorescence intensity.
RECENT DEVELOPMENTS
ing and CDC crossmatch results in deceased-donor kidney recipients, and on Luminex testing in living-donor kidney transplant recipient; (2) a good HLA match in the case of deceased-donor kidney transplantation; (3) inclusion of eligible patients in the Eurotransplant Acceptable Mismatch Program; (4) pretransplant desensitization; (5) posttransplant apheresis; (6) protocol biopsies on days 7 and 90; and (7) posttransplant HLA alloantibody monitoring. Until November 2011, 79 patients have been transplanted according to this algorithm with good short to intermediate-term outcomes. CONCLUSIONS
New developments for the desensitization of crossmatchpositive kidney transplantations are: (1) The introduction of more specific antibody elimination methodologies, such as immunoadsorption which allows the rapid elimination of alloantibodies within a short period, especially in the context of rapid crossmatch conversion after a deceased-donor organ offer; (2) The advent of drugs that follow new concepts such as the recently introduced complement inhibitor eculizumab. Eculizumab, in addition to recipient desensitization, may significantly reduce antibody-mediated rejection rates after crossmatch-positive kidney transplantation; and (3) The implementation of algorithms that combine different measures for this difficult to transplant cohort, such as the “Heidelberg Algorithm.” Meanwhile, other important measures such as improved HLA matching at the epitope level for prevention of sensitization after a failed transplant are increasingly acknowledged. REFERENCES 1. Fuggle SV, Martin S: Tools for human leukocyte antigen antibody detection and their application to transplanting sensitized patients. Transplantation 86:384, 2008
1651 2. Süsal C, Döhler B, Opelz G: Presensitized kidney graft recipients with HLA class I and II antibodies are at increased risk for graft failure: a Collaborative Transplant Study report. Hum Immunol 70:569, 2009 3. Collaborative Transplant Study, University of Heidelberg, Germany: Available at: www.ctstransplant.org. Accessed December 29, 2010 4. Montgomery RA, Zachary AA: Transplanting patients with a positive donor-specific crossmatch: a single center’s perspective. Pediatr Transplant 8:535, 2004 5. Montgomery RA, Lonze BE, King KE, et al: Desensitization in HLA-incompatible kidney recipients and survival. N Engl J Med 365:318, 2011 6. Higgins RM, Bevan DJ, Carey BS, et al: Prevention of hyperacute rejection by removal of antibodies to HLA immediately before renal transplantation. Lancet 348:1208, 1996 7. Bartel G, Wahrmann M, Regele H, et al: Peritransplant immunoadsorption for positive crossmatch deceased donor kidney transplantation. Am J Transplant 10:2033, 2010 8. Belak M, Borberg H, Jimenez C, et al: Technical and clinical experience with protein A immunoadsorption columns. Transfus Sci 15:419, 1994 9. Gjorstrup P, Berntorp E, Larsson L, et al: Kinetic aspects of the removal of IgG and inhibitors in hemophiliacs using protein A immunoadsorption. Vox Sang 61:244, 1991 10. Stegall MD, Diwan T, Raghavaiah S, et al: Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant 11:2405, 2011 11. Montgomery RA: Renal transplantation across HLA and ABO antibody barriers: integrating paired donation into desensitization protocols. Am J Transplant 10:449, 2010 12. Doxiadis, II, Smits JM, Persijn GG, et al: It takes six to boogie: allocating cadaver kidneys in Eurotransplant. Transplantation 77:615, 2004 13. Morath C, Beimler J, Opelz G, et al: An integrative approach for the transplantation of high-risk sensitized patients. Transplantation 90:645, 2010