Joseph Kahwaji

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.

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.

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

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

219,914 per patient compared with

Benefits of rituximab combined with intravenous immunoglobulin for desensitization in kidney transplant recipients.

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

Cause of death with graft function among renal transplant recipients in an integrated healthcare system.

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.

A Phase I/II Trial of the Interleukin-6 Receptor-Specific Humanized Monoclonal (Tocilizumab) + Intravenous Immunoglobulin in Difficult to Desensitize Patients.

Background Antibody-mediated rejection (AMR) is a severe form of rejection, mediated primarily by antibody-dependent complement (C) activation. C1 inhibitor (C1-INH, Berinert) inhibits the classical and lectin pathways of C activation. We performed a randomized, placebo-controlled study using C1-INH in highly sensitized renal transplant recipients for prevention of AMR. Methods Twenty highly sensitized patients desensitized with IVIG + rituximab ± plasma exchange were enrolled and randomized 1:1 to receive plasma-derived human C1-INH (20 IU/kg/dose) versus placebo intraoperatively, then twice weekly for 7 doses. Renal function, adverse events (AEs)/serious AEs, C3, C4, and C1-INH levels were monitored and C1q+ HLA antibodies were also blindly assessed. Results One patient in the C1-INH group versus 2 patients in the placebo group developed serious AEs, but none were related to study drug. Delayed graft function developed in 1 C1-INH subject and 4 in the placebo. The C1-INH trough levels increased with C1-INH treatment. C3 and C4 levels also increased significantly in the C1-INH group compared to placebo. No C1-INH patient developed AMR during the study. Two patients developed AMR after the study. Three placebo patients developed AMR, one during the study. C1q+ donor specific antibodies were reduced in 2 C1-INH treated patients tested, while immunoglobulin G DSA levels showed decreased binding for both groups. Conclusions The C1-INH appears safe in the posttransplant period. The C1-INH treatment may reduce ischemia-reperfusion injury. The C1-INH also resulted in significant elevations of C1-INH levels, C3, C4, and reduced C1q+ HLA antibodies. Taken together, the combination of antibody reduction and C1-INH may prove useful in prevention of AMR. Further controlled studies are warranted.

Factors Predicting Risk for Antibody-Mediated Rejection and Graft Loss in Highly Human Leukocyte Antigen Sensitized Patients Transplanted After Desensitization

Background Highly HLA-sensitized (HS) patients have difficulty accessing compatible donors, especially deceased donor (DD) transplants. Desensitization protocols (DES) have evolved, but rigorous evaluation is lacking. Here, we examined the efficacy of rituximab as a DES agent in a placebo-controlled trial. Methods Candidates were randomized to IVIG+placebo versus IVIG+rituximab. End points included rates of transplantation, antibody-mediated rejection (ABMR), and renal function. Protocol biopsies were performed at 1 year and analysis of patient and graft survival and donor-specific HLA antibodies (DSA) were performed. Results Initially, 15 HS DDs were randomized with 13 receiving transplants. However, we discontinued study entry after five serious adverse events were observed. The study was un-blinded and attribution of patients was noted (IVIG+placebo N=7, IVIG+rituximab N=6). No significant differences were seen in DSA levels at transplant. All ABMR episodes occurred in the IVIG+placebo arm and required intense therapy (P=0.06). The two graft losses were in the placebo group. DSA rebound associated with severe ABMR was seen in three patients in the IVIG+placebo group. No rebound was seen in the IVIG+rituximab group. Renal function at 6 and 12 months showed a significant benefit for IVIG+rituximab (P=0.04). Conclusions Based on limited assessment with acknowledged limitations, both protocols appear effective in achieving levels of DSA allowable for transplantation. However, IVIG+rituximab appeared more effective in preventing DSA rebound and, more importantly, preventing ABMR and development of transplant glomerulopathy.