Ashley Vo

Rituximab and Intravenous Immune Globulin for Desensitization during Renal Transplantation

BACKGROUND Few options for transplantation currently exist for patients highly sensitized to HLA. This exploratory, open-label, phase 1-2, single-center study examined whether intravenous immune globulin plus rituximab could reduce anti-HLA antibody levels and improve transplantation rates. METHODS Between September 2005 and May 2007, a total of 20 highly sensitized patients (with a mean [+/-SD] T-cell panel-reactive antibody level, determined by use of the complement-dependent cytotoxicity assay, of 77+/-19% or with donor-specific antibodies) were enrolled and received treatment with intravenous immune globulin and rituximab. We recorded rates of transplantation, panel-reactive antibody levels, cross-matching results at the time of transplantation, survival of patients and grafts, acute rejection episodes, serum creatinine values, adverse events and serious adverse events, and immunologic factors. RESULTS The mean panel-reactive antibody level was 44+/-30% after the second infusion of intravenous immune globulin (P<0.001 for the comparison with the pretreatment level). At study entry, the mean time on dialysis among recipients of a transplant from a deceased donor was 144+/-89 months (range, 60 to 324). However, the time to transplantation after desensitization was 5+/-6 months (range, 2 to 18). Sixteen of the 20 patients (80%) received a transplant. At 12 months, the mean serum creatinine level was 1.5+/-1.1 mg per deciliter (133+/-97 micromol per liter), and the mean survival rates of patients and grafts were 100% and 94%, respectively. There were no infusion-related adverse events or serious adverse events during the study. Long-term monitoring for infectious complications and neurologic problems revealed no unanticipated events. CONCLUSIONS These findings suggest that the combination of intravenous immune globulin and rituximab may prove effective as a desensitization regimen for patients awaiting a transplant from either a living donor or a deceased donor. Larger and longer trials are needed to evaluate the clinical efficacy and safety of this approach. (ClinicalTrials.gov number, NCT00642655.)

Intravenous immune globulin treatment inhibits crossmatch positivity and allows for successful transplantation of incompatible organs in living-donor and cadaver recipients.

Background. Sensitization to human leukocyte antigens (HLA) is a significant barrier to transplantation. Currently, no proven therapy exists to improve access to transplantation for highly sensitized patients. Here, we report a novel approach using intravenous immune globulin to modulate anti-HLA antibody and improve the chances for successful transplantation. Patients and methods. Forty-five highly HLA-sensitized patients presented as candidates for living-donor kidney transplantation (n=28), cadaveric kidney transplantation (n=15), or heart transplantation (n=2). All patients had a positive CDC crossmatch (CMX) with their donors. In living-donor recipients, intravenous immune globulin (IVIG) was added to the CMX evaluation to determine whether blocking antibodies present in IVIG could inhibit cytotoxicity. For those who showed in vitro inhibition with IVIG (n=26), IVIG was administered (usually as a single dose, 2 g/kg) and the CDC CMX was repeated against the prospective donor immediately after IVIG infusion. If negative, the patient underwent transplantation with their living-donor kidney within 24 to 72 hr. A similar but modified protocol was performed for cadaver donor candidates, all of whom were highly sensitized and had had CMX positivity with multiple donors, negating transplantation. Reductions in CMX positivity, posttransplantation serum creatinine level, number and severity of rejection episodes, and patient and graft survival rates were determined. Results. Forty-two patients underwent transplantation. IVIG treatment completely abrogated the donor-specific CMXs in 35 of 42 patients. In the remaining 7 patients, the CDC CMX was inhibited, but flow cytometry CMXs remained positive. A total of 13 (31%) of 42 recipients developed rejection episodes 3 to 49 days after transplantation. Three grafts (7%) were lost to rejection. Mean serum creatinine level at 24 months was 1.4±0.4 mg/dL. Patient and graft survival rates were 97.6% and 89.1%, respectively, at 24 months. Conclusions. The in vitro IVIG CMX technique predicts the ability of IVIG to reduce anti-HLA antibody levels in highly sensitized patients. Subsequent in vivo IVIG treatment of responders eliminates the positive CDC CMX and allows for successful transplantation. Thus a positive CMX result is not necessarily a contraindication for transplantation and allows access to transplantation for patients for whom it was previously contraindicated.

Use of intravenous immune globulin and rituximab for desensitization of highly HLA-sensitized patients awaiting kidney transplantation.

Background. We have shown that high-dose intravenous immune globulin (IVIG; 2 g/kg ×2 doses)+rituximab (1 g ×2 doses) was effective in lowering anti-human leukocyte antigen (HLA) antibodies and improving rates of transplantation. The aim of this report was to evaluate the efficacy of IVIG+rituximab on reduction of anti-HLA antibodies to a level that was permissive for living donor (LD) or deceased donor (DD) transplantation without incurring the risk of antibody-mediated rejection and immediate graft loss. Methods. From July 2006 to February 2009, 76 HLA-sensitized (HS) patients who met strict sensitization criteria received kidney transplants after desensitization using IVIG 2 g/kg (days 1 and 30)+rituximab (1 g, day 15). Parameters evaluated included rates of transplantation, previous transplants, panel reactive antibodies, donor specific antibody, crossmatches (CMXs), patient and graft survival, acute rejection, serum creatinines, and infections. Results. Seventy-six HS CMX+ treated patients (31 LD/45 DD) were transplanted. For LD and DD recipients, significant reductions were seen in T-cell flow cytometry CMXs from pretreatment (T cell 183.5±98.4 mean channel shifts (MCS) for LD and 162.8±41 MCS for DD) to time of transplant (T cell 68.2±58 MCS for LD [P<0.00006] and 125±49 for DD [P=0.05]), respectively. Time on wait list for DD recipients was reduced from 95±46 months to 4.2±4.5 months after treatment. Twenty-eight patients (37%) experienced acute rejection (29% C4d+/8% C4d−). Patient and graft survival up to 24 months was 95% and 84%, respectively. The mean serum creatinines, at 12 and 24 months were 1.5±1.1 and 1.3±0.3 mg/dL, respectively. Viral infections were seen in six patients. Conclusions. IVIG and rituximab seems to offer significant benefits in reduction of anti-HLA antibodies allowing improved rates of transplantation for HS patients, especially those awaiting DD, with acceptable antibody-mediated rejection and survival rates at 24 months.

Intravenous gammaglobulin (IVIG) : A novel approach to improve transplant rates and outcomes in highly HLA-sensitized patients

Intravenous immunoglobulin (IVIG) products are derived from pooled human plasma and have been used for the treatment of primary immunodeficiency disorders for more than 24 years. Shortly after their introduction, IVIG products were also found to be effective in the treatment of autoimmune and inflammatory disorders. Over the past 2 decades, the list of diseases where IVIG has a demonstrable beneficial effect has grown rapidly. These include Kawasaki disease, Guillain‐Barre syndrome, myasthenia gravis, dermatomyositis and demyelinating polyneuropathy. Recently, we have described a beneficial effect on the reduction of anti‐HLA antibodies with subsequent improvement in transplantation of highly HLA‐sensitized patients as well as a potent anti‐inflammatory effect that is beneficial in the treatment of antibody‐mediated rejection (AMR). These advancements have enabled transplantation of patients previously considered untransplantable. These studies and relevant mechanism(s) of action will be discussed here.

Anti-angiotensin type 1 receptor antibodies associated with antibody mediated rejection in donor HLA antibody negative patients.

Background. Angiotensin type 1 receptor (AT1R) mediates most physiologic and pathophysiologic actions of its endogenous ligand, angiotensin II, with overactivity leading to vascular remodeling and hypertension. Antibodies to AT1R are implicated in several vascular pathologies. The aim of our study was to determine the impact of antibody to AT1R on clinical outcomes including antibody mediated rejection (AMR), with or without C4d deposition, in patients whose sera contained no donor human leukocyte antigen (HLA)-specific antibody (HLA-DSA). Methods. Pretransplant sera from 97 recipients and sera obtained at the time of acute rejection (AR) were tested by Luminex-based single-antigen bead assays to determine HLA-DSA and antibodies to major histocompatibility class I chain-related gene A (MICA). The presence of antibody to AT1R was determined by a cell-based ELISA method using a cutoff of 17 units to distinguish high from low binding. Results. Sera from 63 recipients were determined to have no HLA-DSA and no donor-specific MICA antibodies pretransplant and at the time of AR, and 16 of these recipients were diagnosed with AR including 7 with AMR and 9 with cellular AR (cell-mediated rejection). High-binding AT1R antibodies were identified for six of seven in the AMR+ group and zero of nine in the cell-mediated rejection+ group (P=0.0009). Conclusions. A strong association was observed between the presence of high binding to AT1R and AMR in recipients whose sera contained no antibody to donor HLA or MICA. Assessing the AT1R antibody status along with the HLA-DSA provides additional information to determine the immunologic risk for recipients.

Acceptable donor-specific antibody levels allowing for successful deceased and living donor kidney transplantation after desensitization therapy

Background. The aims of this study were to determine the level of donor-specific antibody (DSA) that allows for successful transplantation after desensitization with IVIG and rituximab and to identify patients at risk for antibody-mediated rejection (AMR). Methods. Pre- and posttransplant sera from 16 patients with DSA before desensitization were tested. Strength of DSA was determined by single antigen Luminex bead assay and results expressed as standard fluorescence intensity (SFI). T-cell flow crossmatch results were expressed as mean channel shifts (MCS). AMR was determined by biopsy and C4d deposition. Results. Six had negative pretransplant flow crossmatches with a mean DSA of 8,805 SFI. Five had positive flow crossmatches (78-192 MCS) with mean DSA of 55,869 SFI. No patients in either group had AMR. Five had positive flow crossmatches (222-266 MCS) with mean DSA of 118,063 SFI. Three experienced AMR. The MCS and DSA levels for patients with AMR were significantly higher than patients without (P≤0.001). For patients without complications (n=7), DSA remained less than 105 SFI and usually decreased to approximately 104 SFI posttransplant for both class I and II. For patients with AMR (n=3), predominant increases in class II DSA more than 105 SFI were observed. All three patients continue to have DSA approximately 105 SFI with stable creatinine after treatment for AMR. Conclusions. Approximately 63% of patients were transplanted with a positive flow crossmatch. The results show that patients with DSA more than 105and FCM more than 200 MCS are at higher risk for AMR. Treatment of AMR improves renal function without significant changes in DSA.

Acute Hemolysis After High-Dose Intravenous Immunoglobulin Therapy in Highly HLA Sensitized Patients

BACKGROUND AND OBJECTIVES Intravenous Ig (IVIG) is used in renal transplantation for desensitization and treatment of antibody-mediated rejection (AMR). The infusion of high-dose IVIG is generally well tolerated, but there are reports of hemolytic anemia induced by anti-blood group antibodies present in IVIG. Here, we report our experience with IVIG-induced hemolytic anemia (IH) in ESRD patients receiving IVIG for desensitization or treatment of AMR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS All patients receiving IVIG for desensitization or for treatment of AMR were monitored for evidence of acute anemia and hemolysis. Markers of hemolysis, including direct antiglobulin tests, were recorded. Five different IVIG products were tested for isohemagglutinin titers. RESULTS There were 18 cases of IH in 16 patients. All identified cases received the IVIG product Gamunex, Gammagard liquid, or Privigen. All patients developing hemolysis were non-O blood types. Isohemagglutinin titers ranged from 1:2 to 1:64 in the various IVIG products, with higher titers noted in the liquid, nonlyophilized products. CONCLUSIONS Acute IH is a significant complication of high-dose IVIG infusion. Identified risk factors include non-O blood type of the recipient and administration of liquid IVIG preparations with high titer anti-A/B IgG antibodies. We recommend monitoring hemoglobin 48 to 72 h after IVIG infusion. If the hemoglobin decreases, a hemolytic work-up is recommended. Hemolysis could be avoided in at risk patients by choosing a low titer product. However, other complications such as acute renal failure or thrombosis may be seen because the low titer products are usually hyperosmotic.

Clinical Aspects of Intravenous Immunoglobulin Use in Solid Organ Transplant Recipients

Intravenous immunoglobulin products (IVIG) are derived from pooled human plasma from thousands of donors and have been used for the treatment of primary immunodeficiency disorders for nearly 30 years. IVIG products are also effective in the treatment of autoimmune and inflammatory disorders, however the precise mechanism(s) of immune modulation are unknown. Recent data suggests that IVIG has a much broader ability to regulate cellular immunity, including innate and adaptive components. IVIG is also a recently recognized modifier of complement activation and injury. These attributes suggests IVIG would have clinical applications in solid organ transplantation. Analysis of clinical studies examining the use of IVIG in desensitization protocols and for treatment of antibody‐mediated rejection (AMR) are supportive for kidney transplant recipients, although no clinical trials using IVIG in sensitized patients were performed seeking an Federal Drug Administration indication. Data regarding the use of IVIG for desensitization and treatment of AMR in cardiac and lung allograft recipients is not conclusive. IVIG is useful in the treatment and prevention of posttransplant infectious complications including cytomegalovirus, parvovirus B19 and polyoma BK virus. In addition, we address the risk of adverse events associated with IVIG use in sensitized end‐stage renal disease and transplant patients.

Current approaches to treatment of antibody-mediated rejection.

Abstract:  Antibody‐mediated rejection (AMR) has recently been recognized as a significant and unique form of rejection that is not amenable to treatment with standard immunosuppressive medications aimed at modification of T‐cell function. Recent interest in AMR and the role of B cells in rejection has been aided by the concomitant discovery that C4d staining of renal biopsy tissue is strongly associated with AMR and a poor prognosis, and the emergence of desensitization protocols for treatment of highly human leukocyte antigen (HLA)‐sensitized patients. Treatment options include: (i) the use of high‐dose intravenous immunoglobulin (IVIG) which works by blocking anti‐HLA antibody activity and through complement inhibition, (ii) the use of Rituxan (anti‐CD20 chimeric antibody) to deplete B cells and interfere with antigen‐presenting cell (APC) activity of B cells subsequently decreasing T‐cell activation, and (iii) the use of plasmapheresis (PE) + anti‐cytomegalovirus (CMV) immunoglobulin G (IgG) or IVIG in lower doses. This protocol removes deleterious anti‐HLA antibodies and may also allow complexing of anti‐HLA with anti‐idiotypes in the anti‐CMV IgG. Although early, data support the efficacy of all three approaches. Many centers are now designing protocols that utilize a combination of all three agents. In summary, recent advances in the diagnosis and treatment of AMR has allowed for significant improvements in outcomes of a condition usually associated with rapid graft failure. However, much work needs to be done to better understand the immunologic processes leading to AMR and how current therapies can be best used to effectively prevent and treat it.

Intravenous immunoglobulin a natural regulator of immunity and inflammation.

Intravenous immunoglobulin (IVIG) products are derived from pooled human plasma and have been used for the treatment of primary immunodeficiency disorders for more than 25 years. IVIG products are also effective in the treatment of autoimmune and inflammatory disorders; however, the precise mechanism(s) of action is not known. Recent investigations suggest that IVIG has a much broader ability to regulate cellular immunity including innate and adaptive components. IVIG is also a recently recognized modifier of complement activation and injury. Here, we discuss these important advancements and how this knowledge applies to desensitization protocols and to the treatment of antibody-mediated rejection.