Alice Peng

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.

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.

Infectious Complications in Kidney-Transplant Recipients Desensitized with Rituximab and Intravenous Immunoglobulin

BACKGROUND AND OBJECTIVES Rituximab and intravenous Ig (IVIG) are commonly used for desensitization of HLA and blood group-incompatible (ABOi) transplants. However, serious infections have been noted in association with rituximab administration. In this study, we retrospectively compared infectious outcomes in those who received rituximab plus IVIG for HLA or ABOi transplants (RIT group) with a group of nonsensitized, ABO-compatible transplant recipients (non-RIT group). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Patients undergoing kidney transplantation at Cedars-Sinai Medical Center were included in the analysis. A total of 361 patients were identified. All received antimicrobial prophylaxis and viral surveillance. The primary outcome was infection. RESULTS Overall patient survival was 97 and 96%, and graft survival was 91 and 89% in the RIT and non-RIT groups, respectively, after an average follow-up of 18 months. There were equal rates of bacterial (34.7% versus 39.1%), viral (21.8% versus 25.1%), fungal (5.9% versus 5.2%), and serious infections (22.9% versus 25.5%) in the RIT and non-RIT groups respectively. Urinary tract infection was the most common infection, accounting for 50% of all bacterial infections. Cytomegalovirus viremia was nonsignificantly more common in the nonrituximab-treated group (15.2% versus 10%), whereas BK viremia was marginally more frequent in the rituximab-treated group (10.6% versus 5.8%). There were no graft losses caused by BK-associated nephropathy. There were two deaths in each group related to infection (1%). CONCLUSION Rituximab does not increase infection risk when used with intravenous Ig for desensitization.

Efficacy, outcomes, and cost-effectiveness of desensitization using IVIG and rituximab.

Background Transplantation rates are very low for the broadly sensitized patient (panel reactive antibody [PRA]>80%; HS). Here, we examine the efficacy, outcomes, and cost-effectiveness of desensitization using high-dose intravenous immunoglobulin (IVIG) and rituximab to improve transplantation rates in HS patients. Methods From July 2006 to December 2011, 207 HS (56 living donors/151 deceased donors) patients (donor-specific antibody positive, PRA>80%) were desensitized using IVIG and rituximab. After desensitization, responsive patients proceeded to transplantation with an acceptable crossmatch. Cost and outcomes of desensitization were compared with dialysis. Results Of the 207 treated patients, 146 (71%) were transplanted. At 48 months, patient and graft survival by Kaplan–Meier were 95% and 87.5%, respectively. The total 3-year cost for patients treated in the desensitization arm was

Dual Kidneys from Marginal Adult Donors as a Source For Cadaveric Renal Transplantation in the United States

219,914 per patient compared with

A Phase I/II Placebo-Controlled Trial of C1-Inhibitor for Prevention of Antibody-Mediated Rejection in HLA Sensitized Patients

238,667 per patient treated in the dialysis arm. Thus, each patient treated with desensitization is estimated to save the U.S. healthcare system

Analysis of Subcutaneous (SQ) Alemtuzumab Induction Therapy in Highly Sensitized Patients Desensitized With IVIG and Rituximab

18,753 in 2011 USD. Overall, estimated patient survival at the end of 3 years was 96.6% for patients in the desensitization arm of the model (based on Cedars-Sinai survival rate) compared with 79.0% for an age, end-stage renal disease etiology, and PRA matched group of patients remaining on dialysis during the study period. Conclusions We conclude that desensitization with IVIG+rituximab is clinically and cost-effective, with both financial savings and an estimated 17.6% greater probability of 3-year survival associated with desensitization versus dialysis alone. However, the benefits of desensitization and transplantation are limited by organ availability and allocation policies.