Intravenous Immunoglobulin Reduces Anti-HLA Alloreactivity and Shortens Waiting Time to Cardiac Transplantation in Highly Sensitized Left Ventricular Assist Device Recipients Ranjit John, MD; Katherine Lietz, MD, PhD; Elizabeth Burke, RN; Jan Ankersmit, MD; Donna Mancini, MD; Nicole Suciu-Foca, PhD; Niloo Edwards, MD; Eric Rose, MD; Mehmet Oz, MD; Silviu Itescu, MD Background—Recipients of left ventricular assist devices (LVADs) develop prominent B-cell hyperreactivity. We investigated the influence of anti-HLA antibodies on waiting time to cardiac transplantation in LVAD recipients and compared the effects of 2 immunomodulatory regimens on anti-HLA serum reactivity. Methods and Results—Fifty-five previously nonsensitized LVAD recipients of a TCI device implanted between 1990 and 1996 were studied. Patients with anti-HLA antibodies received monthly courses of either intravenous immunoglobulin (IVIg) or plasmapheresis, in conjunction with cyclophosphamide. The effects of these regimens on anti-HLA alloreactivity and waiting time to transplantation were then determined by Kaplan-Meier log-rank statistics, nonpara- metric Wilcoxon rank-sum test, and Student’s t test. Prolongation in transplant waiting time was related to serum IgG anti–HLA class I alloreactivity. Infusion of IVIg (2 g/kg) caused a mean reduction of 33% in anti–HLA class I alloreactivity within 1 week. Waiting time to transplantation was significantly reduced by IVIg therapy and subsequently approximated that in nonsensitized patients. Side effects of IVIg (2 g/kg) were minimal and related primarily to immune complex disease. Although plasmapheresis caused a similar reduction in alloreactivity to IVIg, this effect was achieved after longer treatment. Moreover, plasmapheresis was associated with an unacceptably high frequency of infectious complications. In patients resistant to low-dose (2 g/kg) IVIg therapy, high-dose (3 g/kg) IVIg was effective in reducing alloreactivity but was associated with a high incidence of reversible renal insufficiency. Conclusions—These results indicate that IVIg is an effective and safe modality for sensitized recipients awaiting cardiac transplantation, reducing serum anti-HLA alloreactivity and shortening the duration to transplantation. The therapeutic and safety profile of IVIg would appear to be superior to plasmapheresis. (Circulation. 1999;100[suppl II]:II-229 –II-235.) Key Words: antibodies  immune system  transplantation  ventricular assist devices A ntibodies in the serum of a cardiac allograft recipient that are directed against donor HLA class I major histocompatibility complex (MHC) antigens constitutively expressed by allograft endothelium portend a significant risk for early graft failure (ie, within the first 24 to 48 hours) and poorer patient survival as a result of complement-mediated humoral rejection. 1–3 Because T lymphocytes constitutively express MHC class I antigens, the presence of preformed lymphocytotoxic antibodies, particularly IgG isotype, de- tected in a routine T-cell cross-match is considered a contra- indication to solid organ transplantation. 1 To identify patients at high risk of having a positive donor-specific cross-match, cardiac transplantation candidates are screened for anti-HLA antibodies reactive with lymphocytes from a panel of volun- teers representative of the major HLA allotypes, collectively referred to as measurements of panel-reactive antibodies (PRAs). Patients with high PRA levels are considered to be “sensitized” to various alloantigens and require donor- specific cross-matches before transplantation. The proportion of highly sensitized patients on cardiac transplant waiting lists has been progressively expanding as a result of both widespread use of left ventricular assist devices (LVADs) and increasing numbers of patients undergoing retransplantation. LVAD recipients develop prominent B-cell activation, as evidenced by heightened production of anti– HLA class I and II antibodies. 4–6 Although use of leukocyte- filtered platelets can partially reduce anti–HLA class I anti- body production, 6 B-cell hyperreactivity associated with LVAD implantation results from a multifactorial immunolog- ical dysregulatory process involving heightened T-cell apo- From the College of Physicians and Surgeons of Columbia University, New York, NY. Correspondence to Silviu Itescu, MD, Department of Surgery, College of Physicians and Surgeons of Columbia University, 622 W 168th St, PH 14 W, Room 1485, New York, NY 10032. © 1999 American Heart Association, Inc. Circulation is available at http://www.circulationaha.org II-229 by guest on February 21, 2016 http://circ.ahajournals.org/ Downloaded from