Division of Transplantation, Department of Surgery, University of Illinois at Chicago, Chicago, Illinois, USA
College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
Academic Editor: Haval Shirwan
Special Issue: Antibody Mediated Rejection in Organ Transplantation
Received: August 22, 2020 | Accepted: September 21, 2020 | Published: September 28, 2020
OBM Transplantation 2020, Volume 4, Issue 3, doi:10.21926/obm.transplant.2003119
Recommended citation: Di Cocco P, Fratti A, Kaylan KB, Tzvetanov IG, Benedetti E. Treatment Strategies for Antibody-mediated Rejection in Kidney Transplantation and Its Prevention. OBM Transplantation 2020;4(3):16; doi:10.21926/obm.transplant.2003119.
© 2020 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
Antibody-mediated rejection (AMR) is increasingly recognized as the leading immunological cause of graft failure after kidney transplantation [1,2], with modern immunosuppression showing little protective role [1,2,3,4]. The incidence of AMR depends on the diagnostic criteria used, recipient sensitization status, and the immunosuppressive regimen adopted, and can range from 3.1%  to 40% [6,7,8]. Approximately 30% of patients on the transplant waiting list have evidence of sensitization in the form of alloantibodies, generated from exposure to previous transplants, blood transfusions, pregnancy, or other events . The presence of a panel-reactive antibody level of at least 80% (i.e., a high level of sensitization) creates difficulty in finding matched kidneys from compatible donors, leading to low rates of transplantation in these patients [9,10]. Despite the application of various desensitization protocols and immunological risk stratification, transplantation of highly sensitized patients is linked to an increased risk of AMR [9,11]. AMR is also of significant concern in non-sensitized individuals, mostly in the setting of under-immunosuppression, with the development of de novo donor specific antibodies (DSAs) early or late after transplantation [12,13]. By 10 years after kidney transplant, 25% of 189 non-sensitized patients in one cohort study were found to have de novo DSAs . Early appearance of de novo DSAs weeks to months after transplantation may cause acute AMR and can be a significant contributor to premature graft failure. Antibody-mediated immunological injury was first hypothesized in 1971  and many studies have since confirmed the role of DSAs in AMR [8,16,17,18,19,20,21,22,23,24,25,26,27]. Furthermore, evidence of AMR in the form of DSAs is associated with a significant decrease in graft half-life and may even predict graft loss [11,14]. In one study of 219 patients with biopsy-proven AMR, Orandi et al. found a 4.73-fold higher risk of graft loss in patients with AMR and HLA-compatible deceased donor grafts.
The Banff classification, a major advancement in the field of transplantation, has been used over the past 25 years to define and categorize AMR as a clinico-pathological entity [28,29,30]. However, the heterogeneity of the clinical presentation of AMR and wide spectrum of pathologies, ranging from abrupt allograft dysfunction in the early post-transplant period to insidious or subclinical presentations later [31,32,33,34], is a key limitation toward the effective treatment of AMR . In this review, we discuss the main treatment modalities of the entire spectrum of AMR as well as emerging approaches to its prevention.
2. Treatment Modalities
The different clinical manifestations and the evolving clinico-pathological diagnosis reflect the complexity of the treatment of AMR. The current therapeutic strategy is to adopt a combination of modalities to address multiple pathophysiologic pathways . A number of different approaches have been described in the literature, including: antibody removal with plasmapheresis (PLEX) or immunoadsorption (IA), intravenous immunoglobulin (IVIg), deletion of B cells with agents such as the anti-CD20 antibody rituximab, deletion of plasma cells with the proteasomal agent bortezomib, complement inhibitors, and several other interventions as detailed below in this review. As a consequence, treatments are rarely comparable and the available evidence on treatment effect is of low quality [37,38]. Further complicating the analysis of the treatment effects is the fact that most studies are small retrospective trials of disparate patient populations . The latter is an important limitation given that numerous clinical factors are known to have significant impact on outcomes .
2.1 PLEX and IVIg
PLEX is the most common strategy for treatment of active AMR . The rationale behind its widespread use lies in its endorsement by current guidelines and conclusions from consensus workshops [41,42] despite the weakness of its efficacy and lack of Food and Drug Administration (FDA) approval [37,38].
The mechanism of action of PLEX as well as IA, an alternative extracorporeal procedure based on affinity adsorption which is less common in the United States, is to remove DSAs directly from circulation. Desensitization studies have shown PLEX in particular is the fastest method to decrease DSAs . PLEX is also the most frequent modality applied in the United States and generally involves 1.0–1.5 volume exchange using albumin or plasma as replacement. Commonly reported side effects (5-10%) include: allergic reactions that present as rigors and urticaria; symptoms of hypocalcemia such as paresthesia; and hypovolemia, which can manifest as muscle cramps and hypotension. Less frequent complications are related to the use of anticoagulants, the type of replacement fluid, and vascular access .
IVIg are derived from human plasma pooled from thousands of donors and is primarily composed of IgG with trace amounts of IgA and IgM. The dose of administration is variable with doses ranging from 100 mg/kg to 2 g/kg [35,45]. The proposed mechanisms of immunomodulation by IVIg are complex and thought to involve multiple cell types, including monocytes, macrophages, and both B and T cells as well as the complement cascade [46,47,48]. Notably, although immunoglobulins classically activate the complement cascade, IgG fragments can inhibit complement activation by binding complement factors and removing them from circulation . Additionally, high-dose IVIg delivers a lasting immunomodulatory effect on T cells and especially B cells, resulting in changes in the induction of B cell apoptosis and downstream modulation of B cell signaling [50,51,52]. According to a recent in vitro experimental study, IVIg also blocks NK cytotoxicity and antibody-dependent cellular cytotoxicity . Another potential benefit of treatment with IVIg is the replacement of antibodies lost during PLEX . In general, even high doses of IVIg are relatively safe. However, serious side effects have been reported, including acute renal dysfunction (likely related to high osmotic load), thrombotic events with rapid infusions, and aseptic meningitis .
In summary, while the combination of PLEX and IVIg is known to improve short-term outcomes, long-term results remain variable and generally less favorable [5,37,55,56,57,58,59]. In addition, there is a need to better define the duration of PLEX and dosing of IVIg, as this combination varies across different centers .
2.2 Anti-CD20: Rituximab
Rituximab is a chimeric monoclonal IgG antibody directed against the CD20 antigen expressed on the surface of both pre-B and mature B cells. Once bound to CD20, it causes B cell lysis via both complement‐dependent cytotoxicity and antibody‐dependent cell‐mediated cytotoxicity . The use of this B-cell-depleting agent in the setting of active AMR is recommended as a treatment option by Kidney Disease: Improving Global Outcomes (KDIGO) guidelines  and has been used in many institutions [56,61]. However, based on the current literature, its efficacy is limited at best. One systematic review and meta‐analysis of 10 small retrospective or non-randomized trials evaluating the use of rituximab in AMR found that use of this agent is associated with improved graft outcome . Two more recent systematic reviews and one meta-analysis was not able to show a clear benefit [38,63]. A small multi-center, double-blind randomized controlled trial of 38 patients evaluated rituximab as an addition to standard of care for treatment of active AMR . In this trial, standard of care consisted of six sessions of PLEX with IVIg at a dose of 100 mg/kg after each PLEX session, followed by 2 g/kg over 2 days at the end of the plasmapheresis cycle. At 1-year follow-up, the rituximab group did not show any difference from standard of care with respect to the primary endpoint, which was a composite of graft loss and early renal function . Rituximab has a reasonable safety profile in transplant patients .
2.3 Proteasome Inhibitor: Bortezomib
Bortezomib is a proteasome inhibitor which disrupts the normal intracellular protein degradation process  and has been shown to induce plasma cell apoptosis and block anti‐HLA antibody production . It is FDA-approved for use in multiple myeloma and mantle cell lymphoma. Studies in the transplant setting as a treatment modality for AMR have shown conflicting results. Small case series have noted beneficial effects when used in combination with plasmapheresis and IVIg or rituximab in the treatment of active AMR in kidney transplant recipients [67,68,69]. The only randomized controlled trial of bortezomib in late AMR failed to show improvement in transplant kidney function, incidence of histologic or molecular disease features, or reduction in DSAs . Other studies have shown no improvement in glomerular filtration rate after bortezomib when used as add‐on therapy with plasmapheresis and IVIg for chronic AMR . Possible explanations for its lack of efficacy are the known increase in antibody production via germinal center B cell and follicular helper T cell expansion, a process triggered by the plasma cell depletion [72,73], and the finding that bortezomib has little effect on HLA class II antibody production .
2.4 Complement Inhibitors
Over the past decade, several studies have been conducted to evaluate the ability of complement inhibitors to prevent and treat AMR.
2.4.1 C5 Inhibition
Eculizumab is a humanized monoclonal IgG antibody that binds to complement protein C5, inhibiting its cleavage to C5a and C5b and blocking the generation of the terminal complement complex C5b‐C9 . It was approved by the FDA for use in the treatment of paroxysmal nocturnal hemoglobinuria and primary atypical hemolytic uremic syndrome. Eculizumab has been used off‐label for antiphospholipid syndrome and the prevention and treatment of AMR in the kidney transplant population [7,76,77,78,79]. Following the first successful case report on the use of eculizumab to treat early active AMR in combination with plasmapheresis and low‐dose IVIg , a single-center small case series further showed that eculizumab is effective for the treatment of early active AMR occurring within the first month post-transplant . Furthermore, 2 multicenter randomized Phase II trials have suggested a protective effect for administering eculizumab prior to clinical evidence of AMR in positive crossmatch HLA-incompatible living and deceased donor populations [82,83]. However, studies with longer follow-up failed to show a statistically significant reduction in the incidence of chronic AMR [84,85], a finding likely related to the complexity of the pathophysiology of AMR.
2.4.2 C1 Inhibition
C1 inhibitor [C1-INH] is a serine protease inhibitor that inactivates both C1r and C1s, thus regulating proteases in both the classical and lectin complement pathways and resulting in major downstream effects on regulation of the coagulation and inflammation cascade [86,87]. Two C1-INH products, Berinert® (CSL Behring, Kankakee, IL, USA) and Cinryze® (Shire ViroPharma Inc., Lexington, MA, USA)  are currently approved for use by the FDA in the treatment of hereditary angioedema .
Proximal complement inhibition with C1-INH has also been studied as a therapeutic target in kidney transplant recipients with AMR [89,90]. In a single-arm pilot study, Viglietti et al. found that CI-INH (Berinert®) in combination with high-dose IVIg improved allograft function in kidney recipients with active AMR not responsive to conventional therapy . This encouraging result has been reproduced in a randomized, double-blind, placebo-controlled, multicenter Phase IIb study which evaluated the safety and efficacy of another C1-INH (Cinryze®) for the treatment of active AMR . A Phase III clinical trial is currently evaluating Cinryze® as an add-on therapy to standard-of-care PLEX and IVIg for treatment of active AMR in renal transplant recipients is ongoing (ClinicalTrials.gov identifier: NCT03221842).
2.5 Interleukin-6 Inhibitors
Tocilizumab is a humanized monoclonal antibody which binds to both soluble and membrane-bound forms of the interleukin-6 (IL-6) receptor [91,92]. It is currently FDA-approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis . IL-6 is a key cytokine that regulates inflammation and the development, maturation, and activation of T cells, B cells, and plasma cells . Based on the possible contributions of IL-6 signaling to AMR, Vo et al. conducted a small Phase I/II pilot study of tocilizumab and high-dose IVIg as a desensitization strategy in 10 patients who failed IVIg and Rituximab . This trial found significantly reduced DSAs and improved transplantation rates with tocilizumab treatment . Another study by Choi et al. was a single-center, non-randomized trial of tocilizumab as rescue therapy for chronic active AMR in 36 patients who failed IVIg plus rituximab. Patient and graft survival at 6 years was 91% and 80% respectively, which was superior to historical controls with significant reductions in DSAs and stabilization of renal function . Last, a large multi-center randomized control trial is underway to evaluate clazakizumab, an investigational anti-IL-6 monoclonal antibody for the treatment of chronic active AMR  (ClinicalTrials.gov identifier: NCT03444103).
2.6 IgG-degrading Enzyme of Streptococcus Pyogenes (IdeS)
IgG-degrading enzyme of Streptococcus pyogenes (IdeS) is an enzyme which cleaves human IgG at a specific amino acid sequence  and can neutralize all IgG in the body within 4 hours of administration. There is a period of about 7 days during which both soluble IgG and the B cell receptor are not detectable, with a rebound and full reconstitution within 2 weeks [96,97,98]. Clinical trials in transplant patients have shown its ability to eliminate DSA and, further, it has been used safely in highly-sensitized individuals for desensitization [99,100]. Data on its use in the setting of AMR are lacking with the main obstacle being its immunogenicity: anti-IdeS antibodies usually appear after only one or two doses . An interesting area for future work would be modulation of the immunogenicity of IdeS to allow for repeated dosing without production of anti-IdeS antibodies .
There are several case series of surgical splenectomy, splenic embolization, and splenic radiation being used as a salvage procedure for severe early AMR [103,104]. These procedures must be performed rapidly after the onset of early AMR to be effective. One potential mechanistic explanation for their success is the removal of antibody‐producing plasmablasts and plasma cells that traffic to the spleen from regional lymphoid tissue. Orandi et al used this therapeutic modality as a salvage approach in the setting of early active AMR after HLA-incompatible living donor kidney transplantation . The authors found that a combination of splenectomy with eculizumab as add‐on therapy to PLEX with low-dose IVIg and rituximab resulted in the highest graft salvage rate and protection from transplant glomerulopathy when compared to splenectomy alone or eculizumab alone as an add‐on therapy. Most of the case reports or studies in the literature are in the setting of early active AMR, characterized by profound graft dysfunction and a rapid rise in DSAs, usually from an anamnestic response. The interpretation of studies of splenectomy is complicated by the fact that those patients are known to be sensitized, exhibit pre-formed antibodies, and have already undergone desensitization therapy.
3. Prevention of Antibody Mediated Rejection
AMR will always be a consideration in allogeneic transplantation . Its prevention starts with a careful assessment of the transplant candidate and immunological risk stratification. The initial assessment involves donor and recipient HLA typing, anti-HLA antibody screening, and obtaining a history of allosensitizing events, such as previous transplant, blood transfusion, or pregnancy [37,41,106]. For anti-HLA-sensitized recipients, a higher resolution of typing approaching or even reaching the allelic level, i.e., so-called “4-digit” typing, should be performed on the potential donor to match the resolution of recipient alloantibody identification assays [107,108,109]. The advantage of the 4‐digit typing in recipients with HLA antibodies is that it increases the specificity in matching, allowing for a more precise risk stratification and a theoretical reduction in immunological risk of AMR . The incidence of AMR can be greatly reduced by avoiding strong DSA . Patients with no history of allosensitizing events and with negative anti-HLA antibody testing using single-antigen or multi-antigen bead solid-phase assays are at low risk for AMR [107,109].
More than 20,000 patients awaiting kidney transplantation in the United States are sensitized to HLA class I or class II antibodies [9,111]. Until recently, a common approach to AMR prevention has been to avoid transplanting highly sensitized patients. This approach results in prolonged waiting times for suitably HLA-matched organs and may negatively impact patient health, quality of life, and healthcare costs [112,113]. With the advent of the virtual crossmatch [114,115], kidney paired donation, combined paired donation with desensitization, and the acceptable mismatch program, timely kidney transplantation has become a reality for many high-risk patients. These strategies yield reduced risk of AMR and its consequences [116,117,118,119].
There is growing evidence that non-HLA antigens are implicated in the humoral immune response to the renal allograft, substantiated by reports of AMR in HLA-identical siblings [120,121,122]. According to case reports and small case series, therapeutic success for AMR caused by non-HLA antibodies has been achieved with the treatment strategies previously described. To further complicate the picture, registry data suggest that non-HLA immunity could have a prominent role in chronic graft loss . Further studies are needed to characterize alloantibodies targeting non-HLA immunogenic antigens.
A known risk factor for the development of AMR is reduction in maintenance immunosuppression, either as a result of non-adherence or under physician direction. This form of AMR is usually associated with the development of de novo DSAs [124,125,126,127]. Given the relationship between de novo DSAs, AMR, and graft loss, transplant patients with de novo DSAs should undergo close monitoring of allograft function in order to allow for timely intervention [14,128,129].
Prevention and treatment of AMR continues to represent a key aspect of the management of kidney transplant patient. Current treatment strategies are based largely on observational studies, expert opinion, and trials with low-level evidence. While significant progress has been made toward advancing our understanding of its pathogenesis, diagnosis, treatment, and prevention, future work should focus on identifying novel therapeutic targets . The pathophysiologic complexity of AMR poses a significant challenge in the design of immunosuppressive protocols which both maximize the benefits to patients while accounting for the inherent risks of different treatment modalities.
Pierpaolo Di Cocco - Drafting the article, data collection, critical revision of the article; Alberto Fratti - Drafting the article, data collection; Kerim B. Kaylan - Drafting the article, data collection; Ivo G. Tzvetanov- Critical revision of the article; Enrico Benedetti - Conception of the work, critical revision of the article, final approval of the version to be published.
The authors have declared that no competing interests exist.
- Sellarés J, De Freitas DG, Mengel M, Reeve J, Einecke G, Sis B, et al. Understanding the causes of kidney transplantation failure: The dominant role of antibody-mediated rejection and nonadherence. Am J Transplant. 2012; 12: 388-399. [CrossRef]
- Meier-Kriesche HU, Ojo AO, Hanson JA, Cibrik DM, Punch JD, Leichtman AB, et al. Increased impact of acute rejection on chronic allograft failure in recent era. Transplantation. 2000; 70: 1098-1100. [CrossRef]
- El-Zoghby ZM, Stegall MD, Lager DJ, Kremers WK, Amer H, Gloor JM, et al. Identifying specific causes of kidney allograft loss. Am J Transplant. 2009; 9: 527-535. [CrossRef]
- Gaston RS, Cecka JM, Kasiske BL, Fieberg AM, Leduc R, Cosio FC, et al. Evidence for antibody- mediated injury as a major determinant of late kidney allograft failure. Transplantation. 2010; 90: 68-74. [CrossRef]
- Montgomery RA, Zachary AA, Racusen LC, Leffell MS, King KE, Burdick J, 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. Transplantation. 2000; 70: 887-895. [CrossRef]
- Vo AA, Lukovsky M, Toyoda M, Wang J, Reinsmoen L, Lai CH, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Engl J Med.2008; 359: 242-251. [CrossRef]
- Stegall MD, Diwan T, Raghavaiah S, Cornell LD, Burns J, Dean PG, et al. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant. 2011; 11: 2405-2413. [CrossRef]
- Burns JM, Cornell LD, Perry DK, Pollinger HS, Gloor JM, Kremers WK, et al. Alloantibody levels and acute humoral rejection early after positive crossmatch kidney transplantation. Am J Transplant. 2008; 8: 2684-2694. [CrossRef]
- Collins AJ, Foley RN, Chavers B, Gilbertson D, Herzog C, Ishani A, et al. 2013 USRDS annual data report: Atlas of chronic kidney disease and end-stage renal disease in the United States. Am J Kidney Dis. 2014; 63: e1-e478. [CrossRef]
- Cecka JM, Kucheryavaya AY, Reinsmoen NL, Leffell MS. Calculated PRA: Initial results show benefits for sensitized patients and a reduction in positive crossmatches. Am J Transplant. 2011; 11: 719-724. [CrossRef]
- Lefaucheur C, Loupy A, Hill GS, Andrade J, Nochy D, Antoine C, et al. Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation. J Am Soc Nephrol. 2010; 21: 1398-1406. [CrossRef]
- Chehade H, Pascual M. The challenge of acute antibody-mediated rejection in kidney transplantation. Transplantation. 2016; 100: 264-265. [CrossRef]
- Montgomery RA, Cozzi E, West LJ, Warren DS. Humoral immunity and antibody-mediated rejection in solid organ transplantation. Semin Immunol. 2011; 23: 224-234. [CrossRef]
- Everly MJ, Rebellato LM, Haisch CE, Ozawa M, Parker K, Briley KP, et al. Incidence and impact of de novo donor-specific alloantibody in primary renal allografts. Transplantation. 2013; 95: 410-417. [CrossRef]
- Rosenberg JC, Hawkins E, Rector F. Mechanisms of immunological injury during antibody-mediated hyperacute rejected of renal heterografts. Transplantation. 1971; 11: 151-157. [CrossRef]
- Strom TB, Garovoy MR. Clinical and experimental aspects of renal allograft rejection. Am J Kidney Dis. 1981; 1: 5-14. [CrossRef]
- Lefaucheur C, Suberbielle-Boissel C, Hill GS, Nochy D, Andrade J, Antoine C, et al. Clinical relevance of preformed HLA donor-specific antibodies in kidney transplantation. Am J Transplant. 2008; 8: 324-331. [CrossRef]
- Wade E, Goral S, Kearns J, Pierce E, Trofe J, Bloom R. Experience with antibody-mediated rejection in kidney allograft recipients. Clin Transpl. 2006; 439-446.
- Piazza A, Borrelli L, Monaco PI, Poggi E, Pisani F, Valeri M, et al. Post-transplant donor-specific antibody characterization and kidney graft survival. Transpl Int. 2000; 13: S439-S443. [CrossRef]
- Vasilescu ER, Ho EK, Colovai AI, Vlad G, Foca-Rodi A, Markovitz GS, et al. Alloantibodies and the outcome of cadaver kidney allografts. Hum Immunol. 2006; 67: 597-604. [CrossRef]
- Panigrahi A, Gupta N, Siddiqui JA, Margoob A, Bhowmik D, Guleria S, et al. Post-transplant development of MICA and anti-HLA antibodies is associated with acute rejection episodes and renal allograft loss. Hum Immunol. 2007; 68: 362-367. [CrossRef]
- Terasaki PI. Humoral theory of transplantation. Am J Transplantation. 2003; 3: 665-673. [CrossRef]
- Halloran PF, Schlaut J, Solez K, Srinivasa NS. The significance of the anti-class I response. II. Clinical and pathologic features of renal transplants with anti-class I-like antibody. Transplantation. 1992; 53: 550-555. [CrossRef]
- Vlad G, Ho EK, Vasilescu ER, Colovai AI, Stokes MB, Markowitz GS, et al. Relevance of different antibody detection methods for the prediction of antibody-mediated rejection and deceased-donor kidney allograft survival. Hum Immunol. 2009; 70: 589-594. [CrossRef]
- Lobo PI, Spencer CE, Stevenson WC, Pruett TL. Evidence demonstrating poor kidney graft survival when acute rejections are associated with IgG donor-specific lymphocytotoxin. Transplantation. 1995; 59: 357-360. [CrossRef]
- Martin S, Dyer PA, Mallick NP, Gokal R, Harris R, Johnson RW. Post-transplant antidonor lymphocytotoxic antibody production in relation to graft outcome. Transplantation. 1987; 44: 50-53. [CrossRef]
- Orandi BJ, Chow EH, Hsu A, Gupta N, Van Arendonk KJ, Garonzik-Wang JM, et al. Quantifying renal allograft loss following early antibody-mediated rejection. Am J Transplant. 2015; 15: 489-498. [CrossRef]
- Solez K, Axelsen RA, Benediktsson H, Burdick JF, Cohen AH, Colvin RB, et al. International standardization of criteria for the histologic diagnosis of renal allograft rejection: The Banff working classification of kidney transplant pathology. Kidney Int. 1993; 44: 411-422. [CrossRef]
- Racusen LC, Solez K, Colvin RB, Bonsib SM, Castro MC, Cavallo T, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int. 1999; 55: 713-723. [CrossRef]
- Haas M, Loupy A, Lefaucheur C, Roufosse C, Glotz G, Seron D, et al. The Banff 2017 kidney meeting report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant. 2018; 18: 293-307. [CrossRef]
- Kissmeyer-Nielsen F, Olsen S, Petersen VP, Fjeldborg O. Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells. Lancet. 1966; 2: 662-665. [CrossRef]
- Williams GM, Hume DM, Hudson Jr RP. Morris PJ, Kano K, Milgrom F. “Hyperacute” renal- homograft rejection in man. N Engl J Med. 1968; 279: 611-618. [CrossRef]
- Gloor JM, Cosio FG, Rea DJ, Wadei HM, Winters JL, Moore SB, et al. Histologic findings one year after positive crossmatch or ABO blood group incompatible living donor kidney transplantation. Am J Transplant. 2006; 6: 1841-1847. [CrossRef]
- Rafiq MA, De Boccardo G, Schroppel B, Bromberg JS, Sehgal V, Dinavahi R, et al. Differential outcomes in 3 types of acute antibody-mediated rejection. Clin Transplant. 2009; 23: 951-957. [CrossRef]
- Montgomery RA, Loupy A, Segev DL. Antibody‐mediated rejection: New approaches in prevention and management. Am J Transplant. 2018; 18: 3-17. [CrossRef]
- Schinstock CA, Mannon RB, Budde K, Chong AS, Haas M, Knechtle S, et al. Recommended treatment for antibody-mediated rejection after kidney transplantation: The 2019 expert consensus from the transplantation society working group. Transplantation. 2020; 104: 911-922. [CrossRef]
- Roberts DM, Jiang SH, Chadban SJ. The treatment of acute antibody-mediated rejection in kidney transplant recipients-a systematic review. Transplantation. 2012; 94: 775-783. [CrossRef]
- Wan SS, Ying TD, Wyburn K, Roberts DM, Wyld M, Chadban SJ. The treatment of antibody-mediated rejection in kidney transplantation: An updated systematic review and meta-analysis. Transplantation. 2018; 102: 557-568. [CrossRef]
- Loupy A, Lefaucheur C. Antibody-mediated rejection of solid-organ allografts. N Engl J Med. 2018; 379: 1150-1160. [CrossRef]
- Burton SA, Amir N, Asbury A, Lange A, Hardinger KL. Treatment of antibody-mediated rejection in renal transplant patients: A clinical practice survey. Clin Transplant. 2015; 29: 118-123. [CrossRef]
- Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009; 9: S1-S155. [CrossRef]
- Velidedeoglu E, Cavaillé-Coll MW, Bala S, Belen OA, Wang Y, Albrecht R. Summary of 2017 FDA public workshop: Antibody-mediated rejection in kidney transplantation. Transplantation. 2018; 102: e257-e264. [CrossRef]
- Stegall MD, Gloor J, Winters JL, Moore SB, Degoey S. A comparison of plasmapheresis versus high-dose IVIG desensitization in renal allograft recipients with high levels of donor specific alloantibody. Am J Transplant. 2006; 6: 346-351. [CrossRef]
- Okafor C, Ward DM, Mokrzycki MH, Weinstein R, Clark P, Balogun RA. Introduction and overview of therapeutic apheresis. J Clin Apher. 2010; 25: 240-249. [CrossRef]
- Levine MH, Abt PL. Treatment options and strategies for antibody mediated rejection after renal transplantation. Semin Immunol. 2012; 24: 136-142. [CrossRef]
- Jordan SC, Toyoda M, Vo AA. Intravenous immunoglobulin a natural regulator of immunity and inflammation. Transplantation. 2009; 88: 1-6. [CrossRef]
- Tyan DB, Li VA, Czer L, Trento A, Jordan SC. Intravenous immunoglobulin suppression of HLA alloantibody in highly sensitized transplant candidates and transplantation with a histoincompatible organ. Transplantation. 1994; 57: 553-562. [CrossRef]
- Glotz D, Haymann JP, Sansonetti N, Francois A, Menoyo-Calonge V, Bariety J, et al. Suppression of HLA-specific alloantibodies by high-dose intravenous immunoglobulins (IVIg). A potential tool for transplantation of immunized patients. Transplantation. 1993; 56: 335-337. [CrossRef]
- Basta M. Ambivalent effect of immunoglobulins on the complement system: Activation versus inhibition. Mol Immunol. 2008; 45: 4073-4079. [CrossRef]
- Bayry J, Lacroix-Desmazes S, Carbonneil C, Misra N, Donkova V, Pashov A, et al. Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin. Blood. 2003; 101: 758-765. [CrossRef]
- Tha-In T, Metselaar HJ, Tilanus HW, Boor PP, Mancham S, Kuipers EJ et al. Superior immunomodulatory effects of intravenous immunoglobulins on human T-cells and dendritic cells: Comparison to calcineurin inhibitors. Transplantation. 2006; 81: 1725-1734. [CrossRef]
- Toyoda M, Pao A, Petrosian A, Jordan SC. Pooled human gammaglobulin modulates surface molecule expression and induces apoptosis in human B cells. Am J Transplant. 2003; 3: 156-166. [CrossRef]
- Pradier A, Papaserafeim M, Li N, Rietveld A, Kaestel C, Gruaz L, et al. Small-molecule immunosuppressive drugs and therapeutic immunoglobulins differentially inhibit NK cell effector functions in vitro. Front Immunol. 2019; 10: 556. [CrossRef]
- Rault R, Piraino B, Johnston JR, Oral A. Pulmonary and renal toxicity of intravenous immunoglobulin. Clin Nephrol. 1991; 36: 83-86.
- Rocha PN, Butterly DW, Greenberg A, Reddan DN, Tuttle-Newhall J, Collins BH, et al. Beneficial effect of plasmapheresis and intravenous immunoglobulin on renal allograft survival of patients with acute humoral rejection. Transplantation. 2003; 75: 1490-1495. [CrossRef]
- Lefaucheur C, Nochy D, Andrade J, Verine J, Gautreau C, Charron D, et al. Comparison of combination plasmapheresis/IVIG/anti-CD20 versus high-dose IVIG in the treatment of antibody-mediated rejection. Am J Transplant. 2009; 9: 1099-1107. [CrossRef]
- Böhmig GA, Wahrmann M, Regele H, Exner M, Robl B, Derfler K, et al. Immunoadsorption in severe c4d-positive acute kidney allograft rejection: A randomized controlled trial. Am J Transplant. 2007; 7: 117-121. [CrossRef]
- Yamada C, Ramon DS, Cascalho M, Sung RS, Leichtman AB, Samaniego M, et al. Efficacy of plasmapheresis on donor‐specific antibody reduction by HLA specificity in post-kidney transplant recipients. Transfusion. 2015; 55: 727-735. [CrossRef]
- Allen NH, Dyer P, Geoghegan T, Harris K, Lee HA, Slapak M. Plasma exchange in acute renal allograft rejection. A controlled trial. Transplantation. 1983; 35: 425-428. [CrossRef]
- Rituxan [package insert]. South San Francisco, CA: Genentech; 2016.
- Oblak T, Lindič J, Gubenšek J, Kveder R, Rigler AA, Škoberne A, et al. Treatment of antibody‐mediated rejection of kidney grafts with bortezomib and/or rituximab compared to standard regimen: Experience of Slovene National Center. Clin Nephrol. 2017; 88: 91‐96. [CrossRef]
- Hychko G, Mirhosseini A, Parhizgar A, Ghahramani N. A systematic review and meta‐analysis of rituximab in antibody‐mediated renal allograft rejection. Int J Organ Transplant Med. 2011; 2: 51‐56.
- Macklin PS, Morris PJ, Knight SR. A systematic review of the use of rituximab for the treatment of antibody-mediated renal transplant rejection. Transplant Rev (Orlando). 2017; 31: 87-95. [CrossRef]
- Sautenet B, Blancho G, Büchler M, Morelon E, Toupance O, Barrou B, et al. One‐year results of the effects of rituximab on acute antibody‐mediated rejection in renal transplantation: RITUX ERAH, a multicenter double‐blind randomized placebo‐controlled trial. Transplantation. 2016; 100: 391‐399. [CrossRef]
- Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc.; 2015.
- Perry DK, Burns JM, Pollinger HS, Amiot BP, Gloor JM, Gores GJ, et al. Proteasome inhibition causes apoptosis of normal human plasma cells preventing alloantibody production. Am J Transplant. 2009; 1: 201-209. [CrossRef]
- Everly MJ, Everly JJ, Susskind B, Brailey P, Arend LJ, Alloway RR, et al. Bortezomib provides effective therapy for antibody‐ and cell‐mediated acute rejection. Transplantation. 2008; 86: 1754‐1761. [CrossRef]
- Waiser J, Budde K, Schütz M, Liefeldt L, Rudolph B, Shonemann C, et al. Comparison between bortezomib and rituximab in the treatment of antibody‐mediated renal allograft rejection. Nephrol Dial Transplant. 2012; 27: 1246‐1251. [CrossRef]
- Kim M, Martin ST, Townsend KR, Gabardi S. Antibody‐mediated rejection in kidney transplantation: A review of the pathology, diagnosis, and treatment options. Pharmacotherapy. 2014; 34: 733‐744. [CrossRef]
- Eskandary F, Regele H, Baumann L, Bond G, Kozakowski N, Wahrmann M, et al. A randomized trial of bortezomib in late antibody-mediated kidney transplant rejection. J Am Soc Nephrol. 2018; 29: 591-605. [CrossRef]
- Gupta G, Jawdeh BG, Racusen LC, Bhasin B, Arend LJ, Trollinger B, et al. Late antibody‐mediated rejection in renal allografts: Outcome after conventional and novel therapies. Transplantation. 2014; 97: 1240‐1246. [CrossRef]
- Kwun J, Burghuber C, Manook M, Iwakoshi N, Gibby A, Hong JJ, et al. Humoral compensation after bortezomib treatment of allosensitized recipients. J Am Soc Nephrol. 2017; 28: 1991‐1996. [CrossRef]
- Gonzales MA, Gandhi MJ, Schinstock CA, Moore NA, Smith BH, Braaten NY, et al. 32 doses of bortezomib for desensitization is not well tolerated and is associated with only modest reductions in anti‐HLA antibody. Transplantation. 2017; 101: 1222‐1227. [CrossRef]
- Philogene MC, Sikorski P, Montgomery RA, Leffell MS, Zachary AA. Differential effect of bortezomib on HLA class I and class II antibody. Transplantation. 2014; 98: 660‐665. [CrossRef]
- Soliris [package insert]. New Haven, CT: Alexion Pharmaceuticals, Inc.; 2016.
- Zuber J, Le Quintrec M, Krid S, Bertoye C, Gueutin V, Lahoche A, et al. Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation. Am J Transplant. 2012; 12: 3337‐3354. [CrossRef]
- Lonze BE, Singer AL, Montgomery RA. Eculizumab and renal transplantation in a patient with CAPS. N Engl J Med. 2010; 362: 1744‐1745. [CrossRef]
- Lonze BE, Zachary AA, Magro CM, Desai NM, Orandi BJ, Dagher NN, et al. Eculizumab prevents recurrent antiphospholipid antibody syndrome and enables successful renal transplantation. Am J Transplant. 2014; 14: 459‐465. [CrossRef]
- Matar D, Naqvi F, Racusen LC, Carter‐Monroe N, Montgomery RA, Alachkar N. Atypical hemolytic uremic syndrome recurrence after kidney transplantation. Transplantation. 2014; 98: 1205‐1212. [CrossRef]
- Locke JE, Magro CM, Singer AL, Segev DL, Haas M, Hillel AT, et al. The use of antibody to complement protein C5 for salvage treatment of severe antibody‐mediated rejection. Am J Transplant. 2009; 9: 231‐235. [CrossRef]
- Tan EK, Bentall A, Dean PG, Shaheen MF, Stegall MD, Shintock CA. Use of eculizumab for active antibody-mediated rejection that occurs early post-kidney trans-plantation: A consecutive series of 15 cases. Transplantation. 2019; 103: 2397-2404. [CrossRef]
- Marks WH, Mamode N, Montgomery RA, Stegall MD, Ratner LE, Cornell LD, et al. Safety and efficacy of eculizumab in the prevention of antibody-mediated rejection in living-donor kidney transplant recipients requiring desensitization therapy: A randomized trial. Am J Transplant. 2019; 19: 2876-2888. [CrossRef]
- Glotz D, Russ G, Rostaing L, Legendre C, Tufveson G, Chadban S, et al. Safety and efficacy of eculizumab for the prevention of antibody-mediated rejection after deceased-donor kidney transplantation in patients with preformed donor-specific antibodies. Am J Transplant. 2019; 19: 2865-2875. [CrossRef]
- Cornell LD, Schinstock CA, Gandhi MJ, Kremers WK, Stegall MD. Positive crossmatch kidney transplant recipients treated with eculizumab: Outcomes beyond 1 year. Am J Transplant. 2015; 15: 1293‐1302. [CrossRef]
- Schinstock CA, Bentall AJ, Smith BH, Cornell LD, Everly M, Gandhi MJ, et al. Long-term outcomes of eculizumab-treated positive crossmatch recipients: Allograft survival, histologic findings, and natural history of the donor-specific antibodies. Am J Transplant. 2019; 19: 1671-1683. [CrossRef]
- Berinert [package insert]. Kankakee, IL: CSL Behring LLC; 2015.
- Cinryze [package insert]. Lexington, MA: Shire ViroPharma Inc.; 2014.
- Levy JH, O’Donnell PS. The therapeutic potential of a kallikrein inhibitor for treating hereditary angioedema. Expert Opin Investig Drugs. 2006; 15: 1077-1090. [CrossRef]
- Viglietti D, Gosset C, Loupy A, Deville L, Verine J, Zeevi A, et al. C1 inhibitor in acute antibody-mediated rejection nonresponsive to conventional therapy in kidney transplant recipients: A pilot study. Am J Transplant. 2016; 16: 1596-1603. [CrossRef]
- Montgomery RA, Orandi BJ, Racusen L, Jackson AM, Garonzik-Wang JM, Shah T, et al. Plasma-derived C1 esterase inhibitor for acute antibody-mediated rejection following kidney transplantation: Results of a randomized double-blind placebo-controlled pilot study. Am J Transplant. 2016; 16: 3468-3478. [CrossRef]
- Tanaka T, Kishimoto T. The biology and medical implications of interleukin‐6. Cancer Immunol Res. 2014; 2: 288-294. [CrossRef]
- Kim I, Wu G, Chai NN, Klein AS, Jordan S. Anti‐interleukin 6 receptor antibodies attenuate antibody recall responses in a mouse model of allosensitization. Transplantation. 2014; 98: 1262-1270. [CrossRef]
- Vo AA, Choi J, Kim I, Louie S, Cisneros K, Kahwahji J, et al. A phase I/II trial of the interleukin‐6 receptor‐specific humanized monoclonal (tocilizumab) + intravenous immunoglobulin in difficult to desensitize patients. Transplantation. 2015; 99: 2356-2363. [CrossRef]
- Choi J, Aubert O, Vo A, Loupy A, Haas M, Puliyanda D, et al. Assessment of tocilizumab (anti- interleukin-6 receptor monoclonal) as a potential treatment for chronic antibody-mediated rejection and transplant glomerulopathy in HLA-sensitized renal allograft recipients. Am J Transplant. 2017; 17: 2381-2389. [CrossRef]
- Eskandary F, Dürr M, Budde K, Doberer K, Reindl-Schwaighofer R, Waiser J, et al. Clazakizumab in late antibody- mediated rejection: Study protocol of a randomized controlled pilot trial. Trials. 2019; 20: 37. [CrossRef]
- Von Pawel-Rammingen U, Björck L. IdeS and SpeB: Immunoglobulin-degrading cysteine proteinases of Streptococcus pyogenes. Curr Opin Microbiol. 2003; 6: 50-55. [CrossRef]
- Wenig K, Chatwell L, Von Pawel-Rammingen U, Björck L, Huber R, Sondermann P. Structure of the streptococcal endopeptidase IdeS, a cysteine proteinase with strict specificity for IgG. Proc Natl Acad Sci U S A. 2004; 101: 17371-17376. [CrossRef]
- Järnum S, Bockermann R, Runström A, Winstedt L, Kjellman C. The bacterial enzyme ideS cleaves the IgG-type of B cell receptor (BCR), abolishes BCR-mediated cell signaling, and inhibits memory B cell activation. J Immunol. 2015; 195: 5592-5601. [CrossRef]
- Jordan SC, Lorant T, Choi J, Kjellman C, Winstedt L, Bengtsson M, et al. IgG endopeptidase in highly sensitized patients undergoing transplantation. N Engl J Med. 2017; 377: 442-453. [CrossRef]
- Lonze BE, Tatapudi VS, Weldon EP, Min ES, Ali NM, Deterville CM, et al. Ides (imlifidase): A novel agent that cleaves human IgG and permits successful kidney transplantation across high-strength donor-specific antibody. Ann Surg. 2018; 268: 488-496. [CrossRef]
- Winstedt L, Järnum S, Nordahl EA, Olsson A, Runström A, Bockermann R, et al. Complete removal of extracellular IgG antibodies in a randomized dose‐escalation phase I study with the bacterial enzyme IdeS - a novel therapeutic opportunity. PLOS ONE. 2015; 10: e0132011. [CrossRef]
- Lorant T, Bengtsson M, Eich T, Eriksson B, Winstedt L, Järnum S, et al. Safety, immunogenicity, pharmacokinetics, and efficacy of degradation of anti‐HLA antibodies by IdeS (imlifidase) in chronic kidney disease patients. Am J Transplant. 2018; 18: 2752-2762. [CrossRef]
- Locke JE, Zachary AA, Haas M, Melancon JK, Warren DS, Simpkins CE, et al. The utility of splenectomy as rescue treatment for severe acute antibody mediated rejection. Am J Transplant. 2007; 7: 842-846. [CrossRef]
- Kaplan B, Gangemi A, Thielke J, Oberholzer J, Sankary H, Benedetti E. Successful rescue of refractory, severe antibody mediated rejection with splenectomy. Transplantation. 2007; 83: 99-100. [CrossRef]
- Orandi BJ, Zachary AA, Dagher NN, Bagnasco SM, Garonzik-Wang JM, Van Arendonk KJ, et al. Eculizumab and splenectomy as salvage therapy for severe antibody-mediated rejection after HLA-incompatible kidney transplantation. Transplantation. 2014; 98: 857-863. [CrossRef]
- Uhlig K, Macleod A, Craig J, Lau L, Levey AS, Levin A, et al. Grading evidence and recommendations for clinical practice guidelines in nephrology. A position statement from kidney disease: Improving global outcomes (KDIGO). Kidney Int. 2006; 70: 2058-2065. [CrossRef]
- Reed EF, Rao P, Zhang Z, Gebel H, Bray RA, Guleria I, et al. Comprehensive assessment and standardization of solid phase multiplex-bead arrays for the detection of antibodies to HLA. Am J Transplant. 2013; 13: 1859-1870. [CrossRef]
- Visentin J, Vigata M, Daburon S, Contin-Bordes C, Fremeaux-Bacchi V, Dromer C, et al. Deciphering complement interference in anti-human leukocyte antigen antibody detection with flow beads assays. Transplantation. 2014; 98: 625-631. [CrossRef]
- Tambur AR, Campbell P, Claas FH, Feng S, Gebel HM, Jackson AM, et al. Sensitization in transplantation: Assessment of risk (STAR) 2017 working group meeting report. Am J Transplant. 2018; 18: 1604-1614. [CrossRef]
- McCaughan J, Xu Q, Tinckam K. Detecting donor-specific antibodies: The importance of sorting the wheat from the chaff. Hepatobiliary Surg Nutr. 2019; 8: 37-52. [CrossRef]
- Blume OR, Yost SE, Kaplan B. Antibody-mediated rejection: Pathogenesis, prevention, treatment, and outcomes. J Transplant. 2012; 2012: 201754. [CrossRef]
- Montgomery RA, Lonze BE, King KE, Kraus ES, Kucirka LM, Locke JE, et al. Desensitization in HLA-incompatible kidney recipients and survival. N Engl J Med. 2011; 365: 318-326. [CrossRef]
- Vo AA, Petrozzino J, Yeung K, Sinha A, Kahwaji J, Peng A, et al. Efficacy, outcomes, and cost- effectiveness of desensitization using IVIG and rituximab. Transplantation. 2013; 95: 852-858. [CrossRef]
- Amico P, Hönger G, Steiger J, Schaub S. Utility of the virtual crossmatch in solid organ transplantation. Curr Opin Organ Transplant. 2009; 14: 656-661. [CrossRef]
- Bingaman AW, Murphey CL, Palma-Vargas J, Wright F. A virtual crossmatch protocol significantly increases access of highly sensitized patients to deceased donor kidney transplantation. Transplantation. 2008; 86: 1864-1868. [CrossRef]
- Montgomery RA, Zachary AA, Ratner LE, Segev DL, Hiller JM, Houp J, et al. Clinical results from transplanting incompatible live kidney donor/recipient pairs using kidney paired donation. JAMA. 2005; 294: 1655-1663. [CrossRef]
- Segev DL, Gentry SE, Warren DS, Reeb B, Montgomery RA. Kidney paired donation and optimizing the use of live donor organs. JAMA. 2005; 293: 1883-1890. [CrossRef]
- Montgomery RA. Renal transplantation across HLA and ABO antibody barriers: Integrating paired donation into desensitization protocols. Am J Transplant. 2010; 10: 449-457. [CrossRef]
- Claas FH, Witvliet MD, Duquesnoy RJ, Persijn GG, Doxiadis II. The acceptable mismatch program as a fast tool for highly sensitized patients awaiting a cadaveric kidney transplantation: Short waiting time and excellent graft outcome. Transplantation. 2004; 78: 190-193. [CrossRef]
- Grafft CA, Cornell LD, Gloor JM, Cosio FG, Gandhi MJ, Dean PG, et al. Antibody-mediated rejection following transplantation from an HLA-identical sibling. Nephrol Dial Transplant. 2010; 25: 307-310. [CrossRef]
- Kalil J, Guilherme L, Neumann J, Rosales C, Marin M, Saldanha L, et al. Humoral rejection in two HLA identical living related donor kidney transplants. Transplant Proc. 1989; 21: 711-713.
- Montoliu J, Cheigh JS, Mouradian JA, Suthanthiran M, Riggio RR, Rubin AL, et al. Delayed hyperacute rejection in recipients of kidney transplants from HLA identical sibling donors. Am J Med. 1979; 67: 590-596. [CrossRef]
- Opelz G. Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet. 2005; 365: 1570-1576. [CrossRef]
- Wiebe C, Gibson IW, Blydt-Hansen TD, Karpinski M, Ho J, Storsley LJ, et al. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant. 2012; 12: 1157-1167. [CrossRef]
- Schinstock CA, Cosio F, Cheungpasitporn W, Dadhania DM, Everly MJ, Samaniedo-Picota MD, et al. The value of protocol biopsies to identify patients with de novo donor-specific antibody at high risk for allograft loss. Am J Transplant. 2017; 17: 1574-1584. [CrossRef]
- Schinstock CA, Dadhania DM, Everly MJ, Smith B, Gandhi M, Farkash E, et al. Factors at de novo donor-specific antibody initial detection associated with allograft loss: A multicenter study. Transpl Int. 2019; 32: 502-515. [CrossRef]
- Aubert O, Loupy A, Hidalgo L, Van Huyen JP, Higgins S, Viglietti D, et al. Antibody-mediated rejection due to preexisting versus de novo donor-specific antibodies in kidney allograft recipients. J Am Soc Nephrol. 2017; 28: 1912-1923. [CrossRef]
- Wiebe C, Gibson IW, Blydt-Hansen TD, Pochinco D, Birk PE, Ho J, et al. Rates and determinants of progression to graft failure in kidney allograft recipients with de novo donor-specific antibody. Am J Transplant. 2015; 15: 2921-2930. [CrossRef]
- Archdeacon P, Chan M, Neuland C, Velidedeoglu E, Meyer J, Tracy L, et al. Summary of FDA antibody-mediated rejection workshop. Am J Transplant. 2011; 11: 896-906. [CrossRef]
- OʼConnell PJ, Kuypers DR, Mannon RB, Abecassis M, Chadban SJ, Gill JS, et al. Clinical trials for immunosuppression in transplantation: The case for reform and change in direction. Transplantation. 2017; 101: 1527-1534. [CrossRef]