Intravenous Immunoglobulin and Rituximab in HLA Highly Sensitized Kidney Transplant Recipients

Introduction

HLA-sensitized patients are penalized both in the access to kidney transplantation (KT) and, once transplanted, in the incidence of rejections and long-term allograft survival despite aggressive induction and maintenance therapy.

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

Here we report on our experience with subcutaneous (SQ) Alemtuzumab in an uncontrolled study in highly HLA-sensitized patients (HS). From 3/05–4/07, 54 HS patients received Alemtuzumab 30 mg SQ as induction. Patient and graft survival, AR episodes, serum creatinines, absolute lymphocyte counts, monthly PCR monitoring for viruses, AE/SAEs and infectious complications were monitored. No patient to date has developed acute injection-related reactions after SQ Alemtuzumab; however, bone marrow suppression was occasionally seen requiring reduction or elimination of mycophenolate mofetil approximately 1–2 months posttransplant. Patient and graft survival at 12 M was 98%/96%, respectively. AR episodes occurred in 35% with 20% being C4d+ AMR. Mean SCrs at 12 M were 1.4 ± 0.3 mg/dL. The nadir ALC was 0.17 ± 0.19 within 24 h and sustained up to 365 days posttransplant. Infections occurred in eight patients (five with polyoma BK viremia [PBK], one CMV/PBK and two CMV viremia). SQ Alemtuzumab was well tolerated and resulted in prolonged lymphocyte depletion. Compared to our previous experience with daclizumab and rabbit ATG induction in HS patients, single-dose SQ Alemtuzumab was more cost effective, showed similar infection rates and did not reduce the AMR rates posttransplant. Although uncontrolled, these observations suggest that induction therapy with Alemtuzumab appears feasible and indeed promising, but awaits more definitive study.     

Highly Successful and Low-Cost Desensitization Regime for Sensitized Living Donor Renal Transplant Recipients

10–30% of dialysis population awaiting renal transplantation is sensitized. Present desensitization protocols use intravenous immune globulins, rituximab, and plasmapheresis in various combinations; however, these regimens are unaffordable by many in developing countries. We tried desensitization with mycophenolate mofetil and plasmapheresis. Methods. Patients with high PRA titre (≥50%) or positive crossmatch (>10%) were treated with MMF for a month before proposed transplant and were given five sittings of plasmapheresis. Results. 11 of 12 patients had normalization of PRA/crossmatch with this regimen and were successfully transplanted. One patient lost the graft due to graft vein thrombosis, and two patients died within three months after transplant due to septicemia and pulmonary embolism, respectively, with a functioning graft. No patient, including the two who died, developed clinical rejection over a mean follow-up of 10 months (range 1–16 months). Mean serum creatinine at last follow up was 1.1 mg/dL (range 0.9–1.3 mg/dL). Conclusions. Though the number of patients studied is small, we feel that highly sensitized patients awaiting living donor renal transplant should be tried on this simple and cost-effective regime before transplant. The more aggressive and expensive approaches incorporating IVIg and rituximab should be used only if this relatively low-cost regime is unsuccessful.     

Non-HLA Antibodies and Their Role in Highly Sensitized Patients

BackgroundThe role of non-HLA antibody is gaining special attention in solid-organ transplantation and in highly sensitized (HS) patients because of its potential involvement in graft loss (GL) and/or antibody-mediated rejection (ABMR). The identification of non-HLA antibodies while listed may provide deeper information about the increased immunologic risk prior to transplant. We aimed to identify non-HLA antibodies pretransplant that could involve GL in HS patients.MethodsNineteen pretransplant samples from HS patients who underwent transplant at the Marqués de Valdecilla University Hospital were studied for both HLA antibodies and a panel of 39 non-HLA antigens analyzed based on Luminex platform.ResultsEleven patient (57.9%) maintained the graft (KT group), whereas 8 (42.1%) had a GL within a median of 30 days. The median fluorescent intensity (MFI) of the 39 non-HLA antigens were compared within the groups, obtaining a statistically significant differences in protein tyrosine phosphatase receptor type N (P < .04) with a MFI mean of 1408 vs 4931 for KT and GL groups, respectively. However, no significant differences were observed in non-HLA MFI between ABMR and non-ABMR KT recipients.ConclusionsThe presence of non-HLA antibodies in HS is high. The levels of anti–protein tyrosine phosphatase receptor type N before transplant could indicate a potential risk of GL, although longitudinal studies with large number of cases are needed to define anti–non-HLA profiles of risk of ABMR.     

High-Dose Intravenous Immunoglobulin and Rituximab Treatment for Antibody-Mediated Rejection After Kidney Transplantation: A Cost Analysis

Antibody-mediated rejection (AMR) generally occurs in highly sensitized patients. A pilot study was performed on 7 consecutive patients with AMR to assess the efficacy of high-dose intravenous immunoglobulin (IVIG; 2 g/kg) + rituximab (RTX; 375 mg/m²) without plasmapheresis. After a 24-month follow-up, 1- and 2-year allograft survivals were 86% and 58%, respectively. C4d became negative in 1 patient posttreatment. Donor-specific antibody (DSA) titers decreased to less than 1:4 in 2 cases. There were 4 infectious complications and 1 case of aseptic meningitis followed by cranial nerve VI palsy. The average hospital charge for 1 administration of IVIG + RTX, including hospital stay and renal biopsy expenses, was approximately $49,000. A combination of IVIG + RTX in late AMR may be beneficial but is an expensive treatment approach for selected renal transplant patients.     

Desensitization and Subsequent Kidney Transplantation of Patients Using Intravenous Immunoglobulins (IVIg)

Transplantation of patients possessing antibodies against allo-HLA antigens can be delayed for years. We have shown that administration of intravenous immunoglobulins (IVIg) can induce a profound and sustained decrease in the titers of anti-HLA antibodies. We report here the first series of patients desensitized, then transplanted using IVIg therapy. Fifteen patients have been included and treated with IVIg, given as 3 monthly courses of 2g/kg body weight. Thirteen of those 15 patients (87%) were effectively desensitized and underwent immediate transplantation. Eleven were transplanted with a cadaveric donor, and two with a living donor against which the pretreatment cross-match was positive. One graft was lost from thrombosis and one from rejection. All other patients had uneventful courses, without any episodes of rejection, with a follow-up of more than 1 year. Thus, IVIg therapy allows safe and prompt kidney transplantation of immunized patients.     

ABO‐Incompatible Adult Living Donor Liver Transplantation Under the Desensitization Protocol With Rituximab

ABO incompatibility is no longer considered a contraindication for adult living donor liver transplantation (ALDLT) due to various strategies to overcome the ABO blood group barrier. We report the largest single‐center experience of ABO‐incompatible (ABOi) ALDLT in 235 adult patients. The desensitization protocol included a single dose of rituximab and total plasma exchange. In addition, local graft infusion therapy, cyclophosphamide, or splenectomy was used for a certain time period, but these treatments were eventually discontinued due to adverse events. There were three cases (1.3%) of in‐hospital mortality. The cumulative 3‐year graft and patient survival rates were 89.2% and 92.3%, respectively, and were comparable to those of the ABO‐compatible group (n = 1301). Despite promising survival outcomes, 17 patients (7.2%) experienced antibody‐mediated rejection that manifested as diffuse intrahepatic biliary stricture; six cases required retransplantation, and three patients died. ABOi ALDLT is a feasible method for expanding a living liver donor pool, but the efficacy of the desensitization protocol in targeting B cell immunity should be optimized.     

Risk Factors With Intravenous Sedation for Patients With Disabilities

The purpose of this study was to identify the risk factors associated with low peripheral oxygen saturation (SpO₂) and delayed recovery of dental patients with disabilities after intravenous sedation. A total of 1213 patients with disabilities were retrospectively investigated with respect to demographic parameters and sedation conditions. Multivariate logistic analyses were conducted for patients with an SpO₂ <90% and a recovery period of >60 minutes to identify the risk factors for poor sedation conditions. A significant odds ratio related to decreased SpO₂ was observed for age, sex, midazolam and propofol levels, concurrent use of nitrous oxide, cerebral palsy, Down syndrome, and mental retardation. The most problematic patients were those diagnosed with Down syndrome (odds ratio, 3.003–7.978; 95% confidence interval; P < .001). Decision tree analysis showed an increased risk of decreased SpO₂ in males with Down syndrome or after administration of >0.493 mg/kg propofol in combination with midazolam. An increased risk of delayed awakening was seen in patients aged less than 21 years and in males administered >0.032 mg/kg of midazolam. Intravenous sedation for dental patients with disabilities, particularly those with cerebral palsy, Down syndrome, or mental retardation, increases the risk of decreased SpO₂. In addition, delayed recovery is expected after midazolam administration.Key Words: Dental sedation, Low peripheral oxygen saturation, Delayed recoveryDental practices are currently challenged by the rapidly growing number of patients with intellectual or physical disabilities.^1,2 Excessive mental strain during dental treatment can cause systemic complications such as vasovagal reflex, neurogenic shock, pain shock, and hyperventilation. Furthermore, patients with cardiovascular diseases, including cerebrovascular disorders, or decreased vital organ reserve capacity can encounter serious complications. A strategy for relieving mental strain is important for safe dental treatment of such patients, and to this end, intravenous sedation is often used.^3,4 However, when using intravenous sedative drugs that have strong systemic actions on the central nervous, respiratory, and circulatory systems, systemic management to ensure patient safety is a prerequisite.^5,6Conscious sedation is generally preferred to maintain independent breathing and biological defense mechanisms such as coughing and swallowing reflexes. However, dental treatment of patients with disabilities may require behavioral control, especially in the case of mentally challenged individuals with strong treatment refusal reactions. In these cases, deeper levels of intravenous sedation are a safer option.Depending upon the individual case, increased drug doses can cause deep sedation until the patient becomes completely unconscious, which is a deeper degree of sedation compared with conscious sedation.^6,7 If this deep sedative state overrides the nervous system, basic defense mechanisms may also be lost. Therefore, careful perioperative management, similar to that for general anesthesia, is necessary.Therefore, dental treatment of mentally or physically impaired patients using intravenous anesthetics requires careful perioperative management, similar to general anesthesia. Unfortunately, there is little information available on the disabilities and sedation conditions particularly at risk of causing low peripheral oxygenation and delayed recovery.^8,9In this study, we investigated and analyzed the risk factors that may be involved in causing decreased peripheral oxygen saturation (SpO₂) and delayed recovery, including age, sex, treatment duration, type of disability or disease, and type and dose of anesthetic, in dental patients with disabilities.     

Effect of Treatment With Tabalumab,a B Cell–Activating Factor Inhibitor,on Highly Sensitized Patients With End‐Stage Renal Disease Awaiting Transplantation

B cell–activation factor (BAFF) is critical for B cell maturation. Inhibition of BAFF represents an appealing target for desensitization of sensitized end‐stage renal disease (ESRD) patients. We conducted a Phase 2a, single‐arm, open‐label exploratory study investigating the effect of tabalumab (BAFF inhibitor) in patients with ESRD and calculated panel reactive antibodies (cPRAs) >50%. The treatment period duration was 24 weeks. Eighteen patients received tabalumab, at doses of 240‐mg subcutaneous (SC) at Week 0 followed by 120‐mg SC monthly for 5 additional months. Patients were followed for an additional 52 weeks. Immunopharmacologic effects were characterized through analysis of blood for HLA antibodies, BAFF concentrations, immunoglobulins, T and B cell subsets, as well as pre‐ and posttreatment tonsil and bone marrow biopsies. Significant reductions in cPRAs were observed at Weeks 16 (p = 0.043) and 36 (p = 0.004); however, absolute reductions were small (<5%). Expected pharmacologic changes in B cell subsets and immunoglobulin reductions were observed. Two tabalumab‐related serious adverse events occurred (pneumonia, worsening of peripheral neuropathy), while the most common other adverse events were injection‐site pain and hypotension. Three patients received matched deceased donor transplants during follow‐up. Treatment with a BAFF inhibitor resulted in statistically significant, but not clinically meaningful reduction in the cPRA from baseline (NCT01200290, Clinicaltrials.gov).     

Transplant Accommodation in Highly Sensitized Patients: A Potential Role for Bcl-xL and Alloantibody

Transplantation of renal allografts into recipients with circulating anti-HLA antibodies results in hyperacute rejection. In some cases, however, antibodies return without causing harm; this phenomenon has been termed 'accommodation'. We have investigated this process in human allotransplantation. We removed anti-HLA antibodies by immunoadsorption in seven highly sensitized dialysis patients who subsequently underwent renal transplantation. Immunohistochemistry of renal biopsies for IgG and antiapoptotic proteins was performed. We also developed a model of 'accommodation' using anti-HLA antibodies eluted from sensitized patients and incubated with human umbilical vein endothelial cells (HUVECs) at different concentrations. Their effect on HUVEC phenotype was then analysed. Anti-donor antibody returned in 4/7 patients, without evidence of hyperacute rejection. Three out of four of these 'accommodated' grafts showed specific endothelial up-regulation of Bcl-xL and 2/2 tested positive for endothelial IgG deposition. HUVECs incubated with subsaturating concentrations of anti-HLA antibody showed increased expression of Bcl-xL, were rendered refractory to endothelial cell activation and became resistant to complement-mediated lysis. In contrast, HUVECs incubated with saturating concentrations underwent activation and expressed low levels of Bcl-xL. In conclusion, endothelial Bcl-xL expression defines the accommodation process in human allografts and this phenotype may be initiated by exposure of endothelium to low concentrations of anti-donor HLA antibodies.     

Therapeutic Effect of Plasmapheresis and Intravenous Immunoglobulin in Recipients of Kidney Transplant With High Panel-reactive Antibody Levels: A Single-center Experience

ObjectiveHigh panel-reactive antibody (PRA) levels limit patients’ access to kidney transplantation from potential living donor candidates and decrease renal graft survival by causing acute antibody-mediated rejection (AAMR). In this article, we report our experiences about the efficiency of plasmapheresis (PP) and intravenous immunoglobulin (IVIG) in reduction of serum PRA levels in candidates for renal transplantation and in patients with AAMR.MethodsWe examined retrospectively 47 patients with high PRA levels (18 for desensitization (DS) and 29 with AAMR) at Ankara University. The reduction in PRA class 1 and PRA class 2 levels before and after the PP, IVIG, and rituximab or eculizumab therapy were evaluated.ResultsIn the DS group, mean reduction in PRA class I ± SD was 28.0 ± 9.10 to 22.1 ± 8.14 (P <.05), and mean reduction in PRA class II ± SD was 40.3 ± 6.89 to 32.2 ± 5.68 (P < .05). In the AAMR group; mean reduction in PRA class I ± SD was 23.9 ± 9.56 to 17.8 ± 8.64 (P > .05), and mean reduction in PRA class II ± SD was 28.1 ± 8.37 to 26.7 ± 7.96 (P > .05). In total, mean reduction in PRA class I was 25.7 ± 6.66 to 19.7 ± 6.00 (P < .01). Mean reduction in PRA class II was 33.8 ± 5.93 to 29.2 ± 4.96 (P > .05). In the DS group, 3 (16.7%) patients were treated with rituximab. In the AAMR group, 9 (31.0%) patients were treated with rituximab, and 1 (5.5%) patient received eculizimab.In the DS group, the mean follow-up period in years ± SD was 5.06 ± 3.01 and no patient had graft loss. In the AAMR group, the mean follow-up period in years was 5.06 ± 2.74 and 6 (33.3%) patients had graft loss with acute rejection.ConclusionsPP and IVIG treatment provide significant reduction in PRA levels and can be used in DS protocols.     

HLA Class II-Like Antiidiotypic Antibodies from Highly Sensitized Patients Inhibit T-Cell Alloresponses

The purpose of this study is to identify factors in the sera of highly sensitized (HS) patients (pts) that inhibit T-cell alloresponses. An in vitro assay was used to measure HLA class I and class II-like antiidiotypic antibodies (anti-ids). The stimulation index (SI) was used to measure PBL and T-cell responses to alloantigens. All HS sera (32 pts) and the IgG fraction inhibited PBL and CD4⁺ T-cell responses to alloantigens. The SI with HS IgG was 7.9 ± 1.7 as compared to 31.5 ± 5.9 with normal IgG (p = 0.0003). In a subset of pts who were transiently sensitized, the SI was 6.6 ± 1.0 with a high panel reactive antibody (PRA), but when their PRA was zero, the SI was 17.8 ± 1.3 (p = 0.0000001). Anti-ids were found in 100% of 17 pts with a high PRA. The T-cell inhibitory factors reduced CD4⁺ T-cell responses of HS pts to alloantigens in the presence of autologous anti-ids, were MHC restricted and were inactivated by in vitro generated antibodies to HLA class II-like anti-ids. The HLA class II-like anti-id IgG molecules bind to the TCR of CD4⁺ T cells and may impair their ability to help in the downregulating antibody response to anti-ids.     

Long-Term Outcome of ABO-Incompatible Kidney Transplantation in Patients Treated With Low-Dose Rituximab Regimen

BackgroundIntroduction of rituximab in the desensitization protocols for ABO-incompatible (ABOI) kidney transplantation (KTX) has afforded excellent results. However, the acceptability of minimal dosage of rituximab in these protocols remains to be defined.MethodsSixty-three patients who underwent ABOI KTX were included in this study. The desensitization protocol consisted of plasmapheresis, tacrolimus, mycophenolate mofetil, methylprednisolone, intravenous immunoglobulin, basiliximab, and low-dose rituximab (100 mg/body). We evaluated the efficacy, safety, and long-term outcome of this protocol (group R, n = 39) and compared them with those of patients who underwent splenectomy (group S, n = 24).ResultsGraft and patient survival at 10 years after KTX were comparable between the groups (94.4% [group R] vs 95.4% [group S] and 94.6% [group R] vs 95.8% [group S], respectively). The incidence of acute antibody-mediated rejection (AAMR) was similar in the 2 groups (10.2% vs 12.5%). There were no significant differences in the incidence of chronic active antibody-mediated rejection. Of the patients, 7 developed AAMR and 3 of these patients (1 in group R and 2 in group S) lost their grafts. There were no significant differences in the incidence of chronic active antibody-mediated rejection. The incidence of postoperative cytomegalovirus infection in group R was significantly lower than that in group S. Furthermore, the incidence of postoperative late-onset neutropenia was low in group R.ConclusionsA low-dose rituximab regimen for ABOI KTX is acceptable for preventing AAMR with a low incidence of delayed adverse events.     

Outcomes of Prolonged Treatment With Intravenous Immunoglobulin Infusions for Acute Antibody-mediated Rejection in Kidney Transplant Recipients

Background

Treatment of antibody-mediated rejection (AMR) is one of the main problems after kidney transplantation (KTx). The results of intensive AMR treatment with plasmapheresis (PF) and repeated infusions of intravenous immunoglobulin (IVIg) are presented.