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Transplantation Reviews

Management of allosensitized cardiac transplant candidatesMauricio Velez⁎, Maryl R. Johnson

Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA

Abstract

Cardiac transplantation remains the best treatment in patients with advanced heart failure with a high risk of death. However, aninadequate supply of donor hearts decreases the likelihood of transplantation for many patients. Ventricular assist devices (VADs) are beingincreasingly used as a bridge to transplantation in patients who may not survive long enough to receive a heart. This expansion in VAD usehas been associated with increasing rates of allosensitization in cardiac transplant candidates. Anti-HLA antibodies can be detected beforetransplantation using different techniques. Complement-dependent lymphocytotoxicity assays are widely used for measurement of panel-reactive antibody (PRA) and for crossmatch purposes. Newer assays using solid-phase flow techniques feature improved specificity and offerdetailed information concerning antibody specificities, which may lead to improvements in donor-recipient matching. Allosensitizationprolongs the wait time for transplantation and increases the risk of post-transplantation complications and death; therefore, decreasing anti-HLA antibodies in sensitized transplant candidates is of vital importance. Plasmapheresis, intravenous immunoglobulin, and rituximab havebeen used to decrease the PRA before transplantation, with varying degrees of success. The most significant post-transplantationcomplications seen in allosensitized recipients are antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV). Often,AMR manifests with severe allograft dysfunction and hemodynamic compromise. The underlying pathophysiology is not fully understoodbut appears to involve complement-mediated activation of endothelial cells resulting in ischemic injury. The treatment of AMR in cardiacrecipients is largely empirical and includes high-dose corticosteroids, plasmapheresis, intravenous immunoglobulin, and rituximab. Diffuseconcentric stenosis of allograft coronary arteries due to intimal expansion is a characteristic of CAV. Its pathophysiology is unclear but mayinvolve chronic complement-mediated endothelial injury. Sirolimus and everolimus can delay the progression of CAV. In some nonsensitizedcardiac transplant recipients, the de novo formation of anti-HLA antibodies after transplantation may increase the likelihood of adverseclinical outcomes. Serial post-transplantation PRAs may be advisable in patients at high risk of de novo allosensitization.© 2009 Elsevier Inc. All rights reserved.

1. Background

Cardiac transplantation has evolved over the last severaldecades to become the best available therapy in selectpatients with advanced heart failure with a high probabilityof death. The evolution in the field has been propelled by thedevelopment of newer, more effective immunosuppressiveagents that decrease the likelihood of acute cellular rejectionand increase post-transplantation survival while havingmodest effects on the incidence of infection and malignancyafter transplantation. However, despite encouraging pro-gress, the availability of donor hearts remains rate-limiting inthe provision of transplantation to those in need [1]. An

⁎ Corresponding author. E5/582 Clinical Sciences Center, Mail Code5710, Madison, WI 53792, USA. Tel.: +1 608 263 0080; fax: +1 608 2651918.

E-mail address: [email protected] (M. Velez).

0955-470X/$ – see front matter © 2009 Elsevier Inc. All rights reserved.doi:10.1016/j.trre.2009.07.001

inadequate number of available hearts means longer wait-listtimes for many transplant candidates, with a potential forhigher wait-list mortality for the sickest patients.

Recognizing the limitations of the donor pool, pioneercardiothoracic surgeons in the late 1960s ushered in analternative for cardiac transplant candidates who would notlive long enough to obtain a new heart. This technologyinvolved mechanical circulatory support with a total artificialheart or ventricular assist devices (VADs). Mechanicalcirculatory support as a bridge to transplantation wasintroduced in 1969 when the first total artificial heart wasimplanted as a bridge to transplantation. Initially, thetechnology had major disadvantages that limited its wide-spread applicability, but for the last 40 years, tremendousprogress has been achieved. In the mid-1990s, wearableimplantable VADs began to be used widely as a bridge totransplantation [2]. By the end of the last decade, themechanical performance and clinical benefits of VADs had

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236 M. Velez, M.R. Johnson / Transplantation Reviews 23 (2009) 235–247

noticeably outweighed their drawbacks. With broaderutilization of VADs, higher rates of allosensitization wereincreasingly recognized in supported transplant candidates[3-5], complicating the ability to obtain an appropriatedonor organ.

In view of the inadequate supply of donor hearts and thegrowing prevalence of heart failure in developed countries, itis expected that the number of patients with advanced heartfailure requiring bridging to transplantation with VADs willincrease. Recently published data show that the meansurvival of United Network for Organ Sharing status 2patients on the cardiac transplant waiting list has improvedsince 1990 and currently matches mean post-transplantationsurvival at 1 year. This observation suggests that the risk-benefit ratio may not favor transplantation in patients listedas status 2 [6]. In the coming years, primarily those patientswho are eligible for status 1 will be likely to receive a hearttransplant. Currently, the status 1 category on the hearttransplant wait-list is largely populated by VAD-supportedpatients, and this phenomenon is expected to grow in thefuture. Understanding this trend in cardiac “transplantabil-ity” is fundamental in recognizing the increasing challengethat allosensitization represents for the ever-growing numberof cardiac transplant candidates that are bridged totransplantation with VADs. Pretransplantation and post-transplantation allosensitization has been associated withoutcomes that impact allograft survival negatively; therefore,effective strategies to prevent and decrease allosensitizationin this population are necessary.

This review will focus on the clinical aspects ofallosensitized cardiac transplant recipients. We will discussmethods for determining allosensitization, risk factors forallosensitization, the impact of allosensitization before andafter cardiac transplantation, and available strategies todecrease sensitization in patients awaiting heart transplan-tation and to treat antibody-mediated rejection (AMR)after transplantation.

2. Detection of anti-HLA antibodies

Histocompatibility testing identifies appropriate donor-recipient pairs to achieve successful transplantation. Pre-transplantation crossmatching identifies recipient serumantibodies that react with donor antigens, a condition that

Table 1Currently used anti-HLA antibody detection techniques in candidates awaiting he

Characteristic Cell-based techniques

Sensitivity CDC b CDC + DTTHLA antigens Natural configuration on cell surface,

unable to detect specificitiesFalse-positive reactions Non-HLA specific antibodiesFalse-negative reactions Antibody levels below detection threshold

DTT indicates dithiothreitol; ELISA, enzyme-linked immunosorbent assay. Wit2006;36:255-264, Zeevi A, Girnita A, Duquesnoy R.

defines the concept of allosensitization. It is criticallyimportant to determine whether these antibodies mayincrease the risk of post-transplantation adverse outcomes,as is the case with anti-HLA immunoglobulins [7].

Screening for allosensitization through the detection ofanti-HLA antibodies is at the core of compatible donorselection in solid organ transplantation. One of the majorlimitations of our current understanding of histocompat-ibility testing is the lack of complete knowledge regardingwhich antibody specificities are likely to increase the riskof post-transplantation complications. The limited specifi-city of certain crossmatch techniques has confounded thisissue further.

Anti-HLA antibodies are directed to donor majorhistocompatibility complex class I and II HLA antigensthat are expressed on allograft endothelial cells. The risk ofearly graft failure after transplantation is higher in thepresence of a positive crossmatch with donor HLA antigensdue to circulating recipient antidonor antibodies. To detectallosensitization, transplant candidates undergo testing thatexposes HLA antigens from random individuals to therecipient's serum through a variety of different techniques,collectively referred to as a panel-reactive antibody (PRA)test [8,9]. The rationale for PRA testing in cardiac transplantcandidates comes from previous experience in kidneytransplantation, showing an inverse relationship betweenPRA level and allograft survival [10-12]. Most early studiesidentified HLA class I and II antibodies with complement-dependent lymphocytotoxic techniques; however, progressover the years has made other analytical methods available,including flow cytometry and solid-phase flow methods.Over the last 4 decades, technological progress has led to theintroduction of different methods for antibody detection [13].Table 1 includes a summary of the characteristics of currentlyused antibody-detection techniques in recipients awaitingheart transplantation.

2.1. Clinical relevance of detected antibodies

The histocompatibility testing techniques used varyamong centers. The complement-dependent lymphocyto-toxicity assay (CDC) continues to be broadly used in allcardiac transplant candidates as an initial screening methodto rule out an increased PRA and as a rapid crossmatchtechnique. Considering the limited specificity of this

art transplantation

Solid-phase techniques

ELISA b flowIsolated proteins bound to artificial surface,may detect specificities if single antigens are usedReactions with cryptic epitopes on denatured HLA moleculesLoss of epitope expression on isolated molecules

h kind permission from Springer Science+Business Media: Immunol Res

237M. Velez, M.R. Johnson / Transplantation Reviews 23 (2009) 235–247

technique, patients who have a PRA of 10% or higherundergo further testing with more specific methods, typicallyflow cytometry or antibody detection using single antigenbeads in a Luminex template. These tests can identify high-risk class I or class II anti-HLA antibodies and commonlyoffer perspective regarding the likelihood that a particularcandidate will receive a new heart within a reasonable timeframe. Unacceptable donor antigens can also be identified,making possible the use of virtual crossmatching in somecases [14].

Complement-dependent lymphocytotoxicity has beenstudied specifically in the context of heart transplantationoutcomes. In the early 1990s, Lavee and colleagues [8]described how a CDC PRA of 10% or higher was associatedwith an increased incidence of acute cellular rejection andcardiac allograft vasculopathy (CAV) in the early post-transplantation period. Smith and colleagues [15] alsoshowed that heart transplant candidates transplanted againsta positive crossmatch had drastically reduced allograftsurvival during the first year when compared with patientswith a negative crossmatch. In a retrospective study of hearttransplant recipients, Kobashigawa and colleagues [16]found that transplant candidates with a PRA of 11% orhigher detected by CDC had higher post-transplantationmortality when compared with those with a lower PRA.Eighty-eight percent of deaths in allosensitized patientsoccurred within 3 months after transplantation and weremostly due to immune-related causes (allograft rejection andCAV) [16].

Although flow PRA results correlate well with post-transplantation clinical outcomes [17], data are lacking onthe clinical use of newer solid-phase assays such as antibodydetection using single antigen beads in a Luminex templateto estimate the likelihood of AMR, CAV, or allograftsurvival. In addition, contemporary solid-phase techniquesbased on the Luminex template use recombinant HLAantigens, which may not be identical in shape to the HLAantigens found on donor cell surfaces. This fact may raisequestions concerning the validity of the informationobtained. It is also clear that besides offering informationon known specificities, more specific techniques offer awealth of data concerning less known antibodies, which haveuncertain clinical significance. While transplantation centersthat use contemporary antibody-detection technologies relyon their results to make clinical decisions, evidence-baseddata on the clinical utility and prognostic significance ofnewer methods for histocompatibility testing are limited.

Post-transplantation outcomes in VAD recipients are alsoaffected by allosensitization, as evidenced by slightly higherrates of allograft rejection. However, overall allograftsurvival seems to be unaffected [18,19]. Recent smallstudies of heart transplant candidates supported with VADshave offered limited evidence into the relevance ofpretransplantation allosensitization in this specific group inthe contemporary era. Schmid and colleagues [20] followed41 patients bridged with VADs and found that post-

transplantation survival and the incidence of allograftrejection were comparable with those of controls withoutVAD support. Pamboukian and colleagues [21] studied 98patients with and without VAD support and reported on theirrates of allosensitization and post-transplantation outcomes.Even though VAD patients had a higher likelihood of havinga PRA of 10% or higher (19% vs 2%), this was notassociated with higher rates of allograft rejection orvasculopathy. Post-transplantation survival was unaffectedin VAD-supported patients. Other studies have found similarrates of allosensitization in VAD recipients; however, thisfactor does not seem to affect the likelihood of unfavorableimmune outcomes or allograft survival [22,23].

The apparent lack of impact of allosensitization on post-transplantation outcomes in VAD recipients may be relatedto more aggressive immunosuppression used in this group.Because of their higher PRAs, VAD-supported hearttransplant candidates are more likely to receive desensitiza-tion therapies before transplantation, and allograft rejectionepisodes may be treated more aggressively. Post-transplanta-tion survival rate in patients supported with VADs is similarto that of nonsupported patients, yet the causes of death aredifferent. Up to 75% of post-transplantation mortality inVAD-supported heart recipients is related to infectiouscomplications, perhaps related to the more aggressiveimmunosuppression they receive, or direct effects of someVADs on the immune system, whereas rejection may accountfor 20%. Nonsupported transplant recipients commonly dieof rejection (38%), ischemic complications (31%), andrespiratory failure (23%) [24].

3. Mechanisms of allosensitization

3.1. Allosensitization by exposure to foreign antigens

Commonly recognized risk factors for allosensitization inall transplant candidates include previous allografts, bloodproduct transfusions, and pregnancy [5]. As explainedabove, the use of VADs as a bridge to transplantation hasalso been recognized as a risk factor for allosensitizationresulting in an increased PRA [25,26]. The most frequentcause of allosensitization before cardiac transplantation isprevious blood transfusions. With the increasing number ofolder patients who have undergone previous cardiac surgerybeing listed for transplantation, the number of sensitizedcandidates is likely to increase. Although cardiac retrans-plantation represents less than 3% of all cardiac transplants[1], patients with prior allografts are also more likely to besensitized. Finally, women with a history of pregnancy mayhave become sensitized to paternal antigens [27,28].

3.2. Ventricular assist devices as risk factors forallosensitization in cardiac transplant candidates

Ventricular assist devices consist of a combination ofnonbiological and bioprosthetic materials, in continuous


contact with circulating blood (Fig. 1). Before VADintroduction, it was known that common inert materialstrigger host responses that include inflammation, fibrosis,

Fig. 1. Mechanisms of action of VADs. The volume displacement VAD (A) consistsprovides electrical power to a motor that moves a pusher plate up and down repeatThe backward regurgitation of blood flow is prevented by inflow and outflow valproliferation and may be responsible for immune activation and allosensitization. Thblood flow from the left ventricle into the ascending aorta. A percutaneous drivellevitating inside the pump with the use of electromagnetism. This mechanism ppermission from Baughman KL, Jarcho JA. N Engl J Med. 2007;357:846-849. Co

and coagulation, and, not unexpectedly, similar responseswere seen in VAD recipients [9,29]. These responsescontribute to the pathogenesis of complications seen in

of a chamber or sac that fills and empties cyclically. A percutaneous drivelineedly, compressing the volume chamber and resulting in pulsatile blood flow.ves. Some of these VADs feature a textured lining that promotes neointimale axial flow VAD (B) is smaller in size and features a helical rotor that drivesine provides electrical power to a motor that makes the impeller spin whilerovides continuous, nonpulsatile blood flow. Adapted and reprinted withpyright ©2007 Massachussetts Medical Society. All rights reserved.

able 2lements with presumed involvement in the immune system dysfunctionen in LVAD recipients

ellsActivated macrophages/monocytes (CD14+,CD68+, NFκB+)

Found on LVAD surface; stimulateT-lymphocyte activation via IL-2receptor pathways

CD95(Fas)+ T lymphocytes Found in circulation, on LVAD surface;in heightened activation state, prone toapoptosis, poor response toTCR-mediated activation

Hyperreactive B lymphocytes Found in circulation; release anti-HLAclass I and II IgG,antiphospholipid antibody

ytokinesIL-2 Promotes T-cell activation, down-

regulated by selective loss of TH1 T-cellsIFN-γ Promotes T-cell activation, down-

regulated by selective loss of TH1 T-cellsIL-10 Stimulates B-cell hyperreactivitysCD40L Stimulates B-cell hyperreactivity

N indicates interferon; sCD40L, soluble CD40 ligand; TCR, T-cellceptor.


VAD recipients, such as thromboembolism and systemicinfection. The incidence of thromboembolism has decreasedsignificantly in VADs that feature a textured interior surfacethat promotes the growth of a neointimal layer. However, thedevelopment of a neointima is associated with the depositionof cytokine-releasing macrophages and activated helper Tlymphocytes on the VAD surface [9]. These helper Tlymphocytes show a heightened level of activation whencompared with those of controls with advanced heart failure.Their activation profile is marked by enhanced spontaneousproliferation after interleukin-2 (IL-2) stimulation butcontrasted by a susceptibility to premature cell death, asevidenced by surface expression of CD95, a marker ofactivation-induced apoptosis. In addition to a susceptibilityto early cell death, T lymphocytes of VAD recipients exhibitimpaired proliferative responses to T-cell receptor–mediatedactivation [30]. The combination of these observations mayresult in an impairment of cellular immunity in VADrecipients, with vulnerability to systemic Candida infections[30]. Activated T lymphocytes in VAD patients selectivelyexpress TH2-type cytokines, such as IL-4 and transformationgrowth factor β. It has been postulated that an excessive loadof circulating apoptotic waste and the predominant expres-sion of TH2-type cytokines are responsible for B-lymphocytehyperreactivity, evolution into plasma cells, and autoanti-body production in VAD recipients. These patients show a 3-to 4-fold frequency of anti-HLA class I and II immunoglo-bulin G (IgG) levels (Fig. 2) and also significantly higherlevels of antiphospholipid antibody when compared withcontrols with advanced heart failure [9]. Although anti-HLAIgM antibodies that may cause a positive crossmatch are alsoproduced under these circumstances, there is no definiteassociation between their presence and deleterious effectsafter cardiac transplantation (Table 2) [15,31].

Polyclonal expansion of B lymphocytes and theirsubsequent hyperreactivity may also be associated withincreased levels of CD40 ligand (CD40L) derived from

Fig. 2. PRA levels in VAD-supported vs unsupported cardiac transplantcandidates. Patients who underwent VAD support before transplantationdemonstrate an increase in 90th percentile (taller bar) and mean (thehorizontal line within each bar) PRA levels when compared with non-VADcontrols (P b .0001). Reprinted from J Heart Lung Transplant, volume 25,Joyce et al, Impact of left ventricular assist device (LVAD)–mediatedhumoral sensitization on post-transplant outcomes, pages 2054-9, copyright2005, with permission from Elsevier.

TEse

C

C

IFre

inappropriately activated T lymphocytes. CD40 is a memberof the TNF receptor superfamily that is expressed in Blymphocytes and has an important role in stimulatorypathways resulting in B-cell survival and proliferation. Itsligand, CD40L, is expressed by activated T lymphocytes. Itscirculating form in serum has been found to be biologicallyactive in terms of B-lymphocyte activation and is predictiveof autoantibody formation and autoimmune disease activity[32]. In a study of 111 patients supported with texturedpulsatile left VADs (LVADs) as bridge to transplantation,Schuster and colleagues [32] showed that increased serum

ig. 3. Increased levels of soluble CD40L in the circulation of allosensitizedVAD recipients. Sensitized LVAD recipients had more than 8-fold highervels of serum CD40L when compared with either nonsensitized LVADcipients, heart failure controls, or healthy volunteers. Results are expresseds the mean ± SEM of experiments using sera from 12 sensitized LVADcipients, 10 nonsensitized LVAD recipients, 8 New York Heart Associa-on class IV heart failure controls, and 6 healthy volunteers. Reprinted fromum Immunol volume 63, Schuster et al, B-cell activation andllosensitization after left ventricular assist device implantation is due to-cell activation and CD40 ligand expression, pages 211-20, copyright002, with permission from Elsevier.

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ig. 4. Effect of IgG anti-HLA class I antibodies on waiting time to cardiacansplantation. In 37 allosensitized VAD recipients (Δ), the presence ofnti-HLA class I IgG increased waiting time to cardiac transplantationompared with 18 nonsensitized VAD recipients (□) (P b .001). Reprintedith permission from John et al [45].


levels of CD40L are associated with clinical allosensitizationdetected with a CDC in VAD recipients (Fig. 3).

Perioperative platelet transfusions also result in thedevelopment of anti-HLA class I antibodies in VADrecipients [4,33]. Red blood cell transfusions seem to havea less significant impact on the level of circulating anti-HLAantibodies, especially when leukocyte-reduced products areused [34,35]. Anti-HLA class II antibody levels do not seemto be affected by blood product transfusions. HLA-DR3 maybe associated with a higher likelihood of developing anti-HLA class II antibodies in VAD recipients [9].

There is some evidence to suggest that the degree ofsensitization may vary between different VAD types, beinglower for devices without a textured interior surface andaxial flow devices owing to a smaller area of contact betweenthe device and bloodstream, with a lesser degree of immuneactivation [36,37]. Some early data on patients with axialflow devices (MicroMed DeBakey LVAD) showed increasedproduction of C5a and IL-6 during the first 12 weeks afterimplantation when compared with patients who received anontextured pulsatile device (Novacor LVAD). This findingcreated concern for the possibility of increased B-cellactivation and subsequent sensitization mediated by IL-6[38]. However, investigators in that study did not look atanti-HLA antibodies or post-transplantation outcomes inthose patients.

More recent data have shown that the initial immunesystem abnormalities noted after the implantation of axialflow pumps, including CD95-mediated T-lymphocyte acti-vation and apoptosis, seem to resolve after 7 weeks [39].This improvement in immune activation is thought toaccount for the lower degree of sensitization morecommonly seen in patients with axial flow devices. Asmall study in patients supported with an axial flow pumpwho had no anti-HLA antibodies before implantation foundthat there were no detectable levels of anti-HLA class I orclass II IgG after a mean follow-up period of 87 days afterimplantation. Furthermore, acute cellular rejection episodesand post-transplantation survival within the first year werecomparable to published statistics in patients withoutmechanical circulatory support [40].

4. Management of allosensitized cardiactransplant candidates

The management of allosensitized cardiac transplantcandidates presents steep challenges for transplantationcardiologists and surgeons. The differences in specificityof different antibody-detection techniques, the uncertaintyabout which antibody specificities are relevant, and theincomplete understanding of B-cell immunity in allotrans-plantation make solid progress in this area difficult. There islimited available literature on strategies to treat allosensiti-zation in cardiac transplant candidates, and much of thecurrent therapeutic practices are derived from experience

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with the transplantation of other solid organs. It is clear,however, that allosensitized patients experience delays totransplantation because of the relatively limited acceptabledonor pool imposed by their anti-HLA antibody specificities[9,35] (Fig. 4).

The initial step in managing allosensitized transplantcandidates is to avoid further exposure to foreign humanantigens by minimizing the transfusion of blood products asmuch as possible. Once a cardiac transplant candidate hasbecome sensitized, traditionally indicated by a PRA of 10%or higher, the time required to wait for a donor that iscrossmatch-negative may be prohibitive. Therefore, mea-sures to decrease the likelihood of having a positiveprospective crossmatch, which could result in transplantationdelays and a higher chance of dying on the wait-list, shouldbe considered.

In patients ill enough to require VAD support, decreasingthe levels of circulating alloantibodies is of particularimportance. Contemporary VADs have limited durabilityand continuously expose patients to serious complications,including systemic infection, hemolysis, and thromboembo-lism. Some of these complications can jeopardize thecandidate's eligibility for transplantation and also canprofoundly affect quality of life and survival. Until furtherimprovements are made to mechanical circulatory supportdevices, the goal at most centers is to transplant VADrecipients as expeditiously as possible after an initial periodof postoperative recovery, to allow improvement in end-organ function and physical rehabilitation. High degrees ofallosensitization pose a great threat for this patient subset,and broader regional sharing for status 1A and 1B heartrecipients makes crossmatching challenging.

ig. 5. (A) Effect of IVIG therapy on reduction of serum anti-HLA class IG alloreactivity. Maximal reduction in serum alloreactivity occurs within 1eek of IVIG therapy. (B) Effect of plasmapheresis on anti-HLA class I IgGlloreactivity. Maximal reduction in alloreactivity occurs 4 weeks aftereatment. Reprinted with permission from John et al [45].


4.1. Methods to decrease levels of allosensitization

4.1.1. PlasmapheresisMechanical removal of circulating antibodies with

plasmapheresis has been used in highly allosensitizedcardiac transplant candidates to decrease the likelihood ofallograft rejection. It can be implemented in patients with ahigh PRA, either en route to the operating room on the daythey will receive their transplant or while on the wait-list todecrease their PRA and increase the likelihood of finding anegative crossmatch donor. It has been often combined withvarying doses of intravenous immunoglobulin (IVIG). Thereare data that support the preoperative use of plasmapheresisand IVIG, showing post-transplantation outcomes similar tothose of nonallosensitized patients. In a study by Pisani et al[41], 16 of 118 cardiac transplant candidates were found tohave a PRA of 10% or higher, with a high rate of positivecrossmatch. All sensitized patients underwent plasmapher-esis in combination with IVIG immediately before trans-plantation. The frequency of rejection and allograft survivalwas similar between sensitized patients who underwentplasmapheresis and IVIG and nonsensitized controls [41].Similar results have been reported by other investigators withsmall case series [42,43].

4.1.2. Intravenous immunoglobulinIntravenous immunoglobulin has also been used alone to

decrease the level of allosensitization before heart transplan-tation, especially in VAD recipients. In a series of 4 VADrecipients who developed high levels of allosensitizationafter device implantation, treatment with IVIG resulted indecreases in their PRA to levels below 10% within 4 monthsfrom administration [44]. John et al [45] published a head-to-head comparison of IVIG and plasmapheresis in 55allosensitized VAD recipients before transplantation. Intra-venous immunoglobulin resulted in a mean reduction of 33%in anti-HLA class I reactivity 1 week after treatment, withminimal adverse effects. Plasmapheresis achieved similarresults but required longer treatments and was associatedwith a higher rate of infectious complications (Fig. 5). Inpatients whose PRA did not respond to low-dose IVIG,higher doses achieved comparable reductions in the degreeof allosensitization, with an observed increased incidence ofacute renal failure. Notably, in this series, treatment withIVIG significantly reduced wait time to transplantation [45].

4.1.3. RituximabIn recent years, rituximab, a chimeric monoclonal anti-

body to CD20, has been used anecdotically to diminish thedegree of allosensitization in cardiac transplant candidates.Rituximab depletes B lymphocytes through complement-dependent cytotoxicity, antibody-dependent cytotoxicity,and induction of apoptosis [46]. Animal studies in baboonshave shown that this agent effectively depletes CD20+ Blymphocytes, resulting in significant blunting of IgM andIgG responses. Studies in humans have focused mostly onthe use of rituximab to treat B-cell lymphomas; however, it

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has also been used to treat autoimmune disorders and inorgan transplantation, recognizing its immunomodulatoryproperties [47]. A study in allosensitized patients on dialysisawaiting kidney transplantation found that while rituximabwas a powerful B-cell ablational agent, some B-cellsubpopulations such as CD19+/CD5+ B cells recovered tobaseline levels within 6 months. Other subsets, such as Bmemory cells, may remain suppressed for up to 2 years aftertreatment [48]. These findings suggest that alloreactivitymay not be fully suppressed after rituximab administration.

Most of the available data on treating allosensitizedtransplant candidates with rituximab come from the renaltransplant literature. Vieira et al [49] selected 9 highlysensitized kidney transplant candidates to be treated withescalating single doses of rituximab. They achievedsignificant B-lymphocyte depletion with a moderatedecrease in PRA in 2 patients and the suggestion of loss ofantibody specificities in 5 patients. Two patients showed no


change in their PRA after rituximab. These effects wereassociated with infectious complications in some patients.

Among very few early reports in the heart transplantliterature, Balfour et al [50] reported the use of rituximab in apediatric transplant candidate who had failed previoustreatments with IVIG, plasmapheresis, and mycophenolatemofetil. The patient was successfully transplanted after acrossmatch-negative donor was found [50].

Unfortunately, published experience with rituximab inallosensitized cardiac transplant candidates is scarce at thistime. Further data are needed to determine the usefulness ofrituximab in allosensitized transplant candidates.

5. Clinical outcomes in allosensitized cardiactransplant candidates

Pretransplantation allosensitization increases the like-lihood of AMR and CAV and decreases overall allograftsurvival (Fig. 6) [3,15,16,51-53]. The relationship betweenanti-HLA antibodies before transplantation and the devel-opment of these conditions is well recognized, emphasizingthe importance of proper PRA screening and assignment ofappropriate donor-recipient matches.

5.1. Antibody-mediated rejection

Antibody-mediated rejection is not an unusual occurrence[54]. Institutional experience suggests that the incidence ofAMR may be approximately 15% [5]; however, this figurevaries depending on the patients studied and the diagnosticmethods used. In a series where patients were commonlygiven OKT3, AMR was evident in up to 52% of cases,whereas in a series where C4d deposition associated withallograft dysfunction is used as the diagnostic criterion, thereported incidence has been as low as 3% [53]. Acute AMRtypically occurs shortly after transplantation, usually withinthe first 4 months but more commonly during the first 4

Fig. 6. Survival according to CDC crossmatch results in 636 cardiactransplant recipients between 1982 and 1992. Reprinted from TransplImmunol volume 1, Smith et al, The effect of panel reactive antibodies andthe donor specific crossmatch on graft survival after heart and heart-lungtransplantation, pages 60-5, copyright 1993, with permission from Elsevier.

weeks after transplantation [55]. However, it can occasion-ally present several months or years after transplantation. Upto 68% of patients who develop AMR early on showevidence of significant allograft dysfunction, in contrast withthose in whom AMR presents late, in whom the frequency ofallograft dysfunction is estimated at 13% [5,53].

The pathophysiology of AMR is not fully understood. It islikely the result of antibody-induced, complement-mediatedactivation of endothelial cells. The process continues withcytokine release and increased endothelial adherence ofleukocytes, culminating in allograft ischemic injury [56].C4d, an inactive byproduct of complement activation, hasbeen observed in the capillaries of cardiac allografts withAMR, suggesting recent complement activity [57].

The criteria to diagnose AMR have not been uniform.Clinically, it presents with hemodynamic compromise in29% to 47% of cases, especially when it occurs early aftertransplantation. The criteria for hemodynamic compromisealso vary between centers but generally include a decrease inleft ventricular ejection fraction, unexplained elevationin cardiac filling pressures with a simultaneous decrease incardiac output, and the need for inotropic support. Inaddition to clinical signs, pathologic markers of AMR haveto be present.

In 2005, the International Society for Heart and LungTransplantation proposed criteria for the immunopathologicdiagnosis of AMR [5]. In the presence of clinical evidenceof allograft dysfunction, the following diagnostic criteriawere suggested:

• Histologic evidence of acute capillary injury (endothe-lial swelling or denudation with congestion andmacrophage infiltration, with possible neutrophilinfiltration and interstitial edema and/or hemorrhagein more severe cases),

• Immunopathologic evidence for antibody-mediatedinjury (tissue immunofluorescence positive for IgMor IgG + complement deposition [C3d, C4d, or C1q],or CD68-positive macrophages in endothelium; endo-vascular fibrin can be seen in more severe cases).

• Serologic evidence of donor-specific anti-HLA class Ior class II antibodies, or other antidonor antibodies atthe time of biopsy.

Even though immunoglobulin deposits are part of theproposed diagnostic criteria for AMR, immunofluorescencefor endothelial immunoglobulin deposits does not correlatewell with clinical AMR or with circulating anti-HLAantibodies [58]. Recently, immunofluorescence for C4d hasshown a high degree of correlation with serum anti-HLAantibodies [57]. Rodriguez et al [59] studied 665 consecutiveendomyocardial biopsies from 165 cardiac transplantrecipients with immunofluorescence for the presence ofimmunoglobulin and complement deposits. The combineddetection of C4d and C3d correlated well with acute AMRand clinical evidence of heart failure. The additional


detection of immunoglobulin and C1q did not improvediagnostic accuracy [59]. In addition, some early evidencesuggests that immunofluorescence for C4d may be helpful inassessing the response to treatment for AMR in cardiactransplant recipients [57,60].

Antibody-mediated rejection causes very severe episodesof rejection, often with hemodynamic compromise, that maynot respond to intensification of immunosuppressive therapyalone. In addition to hemodynamic support with inotropicagents, current therapeutic strategies center on inactivationof circulating antibodies.

5.1.1. Treatment of AMRRecognizing the importance of antibody production and

complement deposition in allograft endothelium as theunderlying pathophysiology in AMR, mechanical removalof circulating antibodies with plasmapheresis was one of thefirst therapies tested on affected patients. In a series of 328cardiac transplant recipients in the late 1980s, 3.4% ofpatients were found to have a positive prospective IgGcrossmatch. These patients experienced acute AMR muchearlier than did controls with a negative crossmatch.Moreover, AMR was associated with hemodynamic com-promise in 73% of cases. In addition to intensification ofimmunosuppression, plasmapheresis was used in the patientswith AMR, with a treatment success rate of 75% [55]. Othersmaller series in Europe and Asia have documented similarexperiences [61,62]. High-dose intravenous corticosteroids,T-lymphocyte depleting agents such as rabbit anti-thymocyteglobulin, and tacrolimus have been used in addition toplasmapheresis, with varying degrees of success. Intrave-nous immunoglobulin has also been used to provide further

Fig. 7. Intravascular ultrasound example of a de novo lesion of transplantation vascsite is identified on follow-up examination, significant intimal thickening is seenvasculopathy. Note that this lesion is circumferential and noneccentric. Reprinted w1999;14:140-150.

immune modulation in some patients with AMR. More than90% of patients treated aggressively for AMR recover butremain with a high risk of recurrence [53].

A few case series and case reports have alsodocumented successful treatment of AMR with rituxi-mab-based therapy [63-65]. Garrett et al [66] treated8 patients with pathologic evidence of AMR with weeklydoses of rituximab for 4 weeks. All patients recoveredtheir baseline LVEF without associated infectious or otherdrug-related complications [66].

5.2. Cardiac allograft vasculopathy

Allosensitization also contributes significantly to anincreased risk of developing CAV [52,56,59,67,68]. Cardiacallograft vasculopathy is a major cause of cardiac allograftfailure and decreased survival after the first post-transplanta-tion year [67]. Although it is possible that both T- andB-lymphocyte–mediated immunity play a role in itspathogenesis, patients who demonstrate circulating donor-specific anti-HLA antibodies, or an immunohistologicpattern of AMR early after transplantation, are more like todevelop CAV [52].

Cardiac allograft vasculopathy causes diffuse concentricstenosis of the coronary arteries because of intimal expansionand adventitial sclerosis. Although detailed human studieson the pathogenesis of CAVare lacking, it is believed that thepathologic process is initiated by antibody- and complement-mediated injury to endothelial cells and may be acceleratedby common coronary disease risk factors such as hyperten-sion and hyperlipidemia. The antibodies most frequentlyassociated with CAV are those against donor HLA, in

ulopathy. No lesions are shown at baseline examination (A). When the sameat that site (B). This lesion is defined as a de novo lesion of transplantationith permission from Kapadia SR, Nissen SE, Tuzcu EM. Curr Opin Cardiol

Fig. 8. Survival curve comparing patients who exhibit de novo anti-HLAclass II antibodies vs patients without anti-HLA class II antibodies. Patientswho produce class II antibodies have significantly worse survival (P = .006).Reprinted with permission from Tambur et al [80].


particular to class I antigens, which are richly expressed inhuman endothelial cells. HLA class II antigens areconstitutively expressed in human endothelium, and theirsynthesis can be stimulated by proinflammatory moleculessuch as interferon-γ [59]. Anti-HLA IgG can stimulate theproliferation of endothelial and smooth muscle cells, causingintimal expansion. Although lytic levels of complementcause hyperacute rejection, the role of complement in CAV isnot well understood. Complement activation can result in therelease of tissue growth factors that cause endothelialproliferation and the migration of fibroblasts and smoothmuscle cells. In addition to this, sublytic doses of themembrane attack complex of complement can induceendothelial production of tissue factor. This phenomenonhas been deemed responsible for the procoagulant character-istics and intimal fibrin formation seen in coronary arterieswith CAV. The presence of fibrin has been independentlyassociated with CAV, allograft failure, and death [67,69].

The diagnosis of CAV is challenging because of the oftendiffuse nature of the disease. Comparative coronary angio-graphy and intravascular ultrasound [70] are widely used todemonstrate progressive narrowing of allograft coronaryarteries (Fig. 7). Serial dobutamine stress echocardiographyis also used to detect clinically significant CAV, and somedata suggest that it may have prognostic value comparable tointravascular ultrasound and coronary angiography in pre-dicting the occurrence of cardiac events [71].

The therapeutic options for CAVare limited. In contrast tonative coronary artery disease, percutaneous coronaryinterventions are not commonly possible because of thediffuse nature of stenotic process. Stents have been usedoccasionally for palliative purposes in patients withsymptomatic ischemia. Coronary artery bypass grafts areof limited applicability for similar reasons. Retransplantationmay be an option for select candidates with severe multi-vessel CAV with evidence of allograft dysfunction. How-ever, patients must be chosen carefully to allow acceptableoutcomes of retransplantation to be achieved [72].

Contemporary immunosuppressive agents such as siroli-mus and everolimus have demonstrated benefits in delayingthe onset of clinically evident CAV [73,74]. When CAV isdetected with angiography, intensification of immunosup-pression with these agents is an acceptable choice to slow theprogression of CAV [75].

6. The importance of de novo anti-HLA antibodies aftercardiac transplantation

Despite advances in immunosuppressive therapy, theincidence of acute AMR and CAV continues to limit long-term outcomes [54,76]. A study by Rose et al [77]demonstrated that the presence of anti-HLA antibodiesafter cardiac transplantation results in lower survival whencompared with being antibody-free. At 5 years aftertransplantation, survival in the antibody-negative group

was 90% compared with 53% in the antibody-positivegroup. Acute rejection and infection, partly related toaugmented immunosuppression to treat rejection episodes,were the leading causes of death in antibody-positivepatients. Circulating anti-HLA antibodies were also asso-ciated with higher rates of CAV. These findings have beencorroborated by subsequent studies [12,78,79].

Anti-HLA antibodies can develop in patients who werenot allosensitized before transplantation. This suggests thatthe transplanted heart may release alloantigens responsiblefor neosensitization of the recipient. Tambur et al [80]showed that up to 35% of nonallosensitized cardiac allograftrecipients can develop anti-HLA antibodies within the firstyear after transplantation. Antibodies against HLA class Iantigens were more commonly present than anti-HLA class IIantibodies, with PRAs ranging widely from 10% to almost80% for both classes. Female sex, HLA-A mismatch, andlonger ischemic time were identified as risk factors for denovo sensitization after transplantation. Anti-HLA class I andII antibodies showed strong associations with the incidenceof early acute cellular rejection. In addition, de novo class IIantibodies were associated with more severe CAVand highermortality due to allograft failure (Fig. 8). Of all anti-HLAclass I antibodies, 41% represented donor-specific antibo-dies. Donor-specific class II antibodies were uncommon(b10%). The relative infrequency of donor-specific anti-bodies may suggest that most are bound to allograft antigens,therefore being underrepresented in the serum [80].

Although contemporary data in cardiac transplant reci-pients show that de novo anti-HLA antibodies may have amajor impact on post-transplantation outcomes, the availableevidence is not enough to recommend serial PRA screeningin all cardiac allograft recipients. It may be advisable toconduct serial PRAs during the first year after transplantationin patients with features that will place them in a high riskcategory for post-transplantation allosensitization. SerialPRAs in this subset could potentially signal the need formore aggressive immunosuppression to prevent acuterejection episodes and delay allograft failure; however, the


clinical utility and cost-effectiveness of such an approachremain in question.

7. Conclusions

Cardiac transplantation has become the best availabletherapy in select patients with advanced heart failure with ahigh probability of death. However, an inadequate number ofavailable hearts remains rate-limiting in the provision oftransplantation to those in need, leading to longer wait-listtimes for many transplant candidates, with a potential forhigher wait-list mortality.

In view of the limited donor pool, mechanical circulatorysupport with VADs was introduced as a bridge totransplantation. Unfortunately, broad use of VADs hasbeen associated with higher rates of allosensitization,causing delays to transplantation because of difficulty infinding a crossmatch-negative donor. In addition to VAD-related sensitization, cardiac transplant candidates arefrequently exposed to other sources of sensitization such asblood product transfusions.

The consequences of pretransplantation allosensitizationon clinical outcomes after transplantation can be serious.Antibody-mediated rejection and CAV are particularlyprominent and can result in graft failure and decreasedsurvival. The pathophysiology of these conditions is notfully understood; therefore, available treatments are based onexpert opinion and anecdotal clinical data. For this reason,significant emphasis is placed on preventing and decreasingallosensitization before transplantation.

Current strategies to decrease allosensitization focus onthe direct removal of circulating antibodies with plasmapher-esis, inactivation of antibodies with IVIG, and B-lymphocytedepletion with rituximab. These approaches have also beenused to treat AMR after transplantation, with encouragingresults. However, most treatments are based on theoreticalassumptions and scarce clinical data; therefore, their trueefficacy is unknown.

In the future, current strategies to avoid allosensitizationwill be complemented by improvements in VAD design thatwill decrease the likelihood of immune activation. Newergeneration devices may result in lower degrees of allosensi-tization by reducing the surface area in direct contact with thebloodstream, limiting the use of textured surfaces and usingless immunogenic biocompatible materials.

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