The medical cost and outcome of desensitization protocol in kidney transplantation recipients with high immunological risks.

BACKGROUND: Kidney transplantation is a well-established alternative in renal replacement therapy. Compared with hemodialysis, low-immunological-risk kidney transplantation can reduce the medical treatment costs associated with end-stage renal disease. However, there are few reports on whether high-immunological-risk kidney transplantation reduces the financial burden on governments. We investigated the medical costs of high-immunological-risk kidney transplantation in comparison with the cost of hemodialysis in Japan. METHODS: We compared the medical costs of high-immunological-risk kidney transplantation with those of hemodialysis. 15 patients who underwent crossmatch-positive and/or donor-specific antibody-positive kidney transplantations between 2020 and 2021 were enrolled in this study. The patients received intravenous immunoglobulin, plasmapheresis, and rituximab as desensitizing therapy. RESULTS: Acute antibody-mediated rejection was detected in nine (60%) recipients, while there were no indications of graft function deterioration during the follow-up. For each patient, the transplant hospitalization cost was 38 428 ± 8789 USD. However, the cumulative costs were 59 758 ± 10 006 USD and 79 781 ± 16 366 USD, at 12 and 24 months, respectively. Compared with hemodialysis (34 286 USD per year), high-immunological-risk kidney transplantation tends to be expensive in the first year, but the cost is likely to be lower than that of hemodialysis after 3 years. CONCLUSIONS: Although kidney transplantation is initially expensive compared with hemodialysis, the medical cost becomes advantageous after 3 years even in kidney transplant recipients with high immunological risk.

Desensitization in Iron Product Allergy.

Iron deficiency is the main cause of anemia in both sexes, with women being more commonly affected. Iron therapy is currently considered an effective and safe remedy to replenish the iron storages. Iron can be administrated both orally and intravenously. In particular, intravenous (IV) iron therapy is widely used when oral iron preparations are either not tolerated or ineffective. Indeed, IV iron improves iron stores more rapidly. Two main immunological responses have been described for iron hypersensitivity reactions (HSRs): IgE-mediated allergy and complement activation-related pseudo-allergy. Here, we report 3 cases of adult patients with iron allergy, who were successfully treated with two different desensitization procedures, respectively. Analysis of these cases demonstrates that, in the presence of HSRs to iron products, desensitization is an effective and safe procedure that prevents treatment discontinuation and hence allows therapeutic target achievement.

Hypersensitivity to alemtuzumab. A safe and effective desensitization protocol: A case report.

We describe a successful desensitization to alemtuzumab in one patient diagnosed with T-cell prolymphocytic leukaemia. Alemtuzumab treatment was initiated during infusion number 18, the patient showed cutaneous eruption with a miliary pattern, despite premedication with corticosteroids and antihistamines. The eruption returned with successive alemtuzumab infusions (infusions 19, 20 and 21), remained present for longer and was more severe with each infusion. The patient was referred to our Allergy Unit as it was necessary to maintain alemtuzumab treatment. Total immunoglobulin E level was 3 UI/ml and specific immunoglobulin E against more common pneumo-allergens, food, latex and hamster were inferior to 0.35 UI/ml. Prick test using the undiluted drug (30 mg/ml) and intradermal tests using serial dilutions (1/10, 1/100) were performed. The result of alemtuzumab skin prick test was 4 mm. The intradermal skin test result was positive at 1/100 dilution (papule: 8 mm; erythema: 12 mm). The basophil activation test with alemtuzumab was performed concluding that 10% of the basophils were activated by alemtuzumab. The patient underwent alemtuzumab desensitization according to a 12-step protocol that resolved to be safe and efficacious. Our experience may be helpful for similar clinical cases where the therapeutic options are very limited and a life-threatening condition such T-cell prolymphocytic leukaemia is present. In addition, a careful risk/benefit ratio should be considered and accurate informed consent is mandatory.

Postoperative rebound of antiblood type antibodies and antibody-mediated rejection after ABO-incompatible living-related kidney transplantation.

The purpose of this study is to examine whether postoperative antiblood type antibody rebound is attributed to kidney allograft rejection in ABO blood type-incompatible (ABO-I) living-related kidney transplantation (KTx). A total of 191 ABO-I recipients who received ABO-I living-related KTx between 2001 and 2013 were divided into two groups: Group 1 consisted of low rebound [(≦1:32), N = 170] and Group 2 consisted of high rebound [(≧1:64), N = 21], according to the levels of the rebounded antiblood type antibodies within 1 year after transplantation. No prophylactic treatment for rejection was administered for elevated antiblood type antibodies, regardless of the levels of the rebounded antibodies. Within 1 year after transplantation, T-cell-mediated rejection was observed in 13 of 170 recipients (13/170, 8%) in Group 1 and in 2 of 21 recipients (2/21, 10%) in Group 2 (Groups 1 vs. 2, P = 0.432). Antibody-mediated rejection was observed in 15 of 170 recipients (15/170, 9%) and 2 of 21 recipients (2/21, 10%) in Groups 1 and 2, respectively (P = 0.898). In this study, we found no correlation between the postoperative antiblood type antibody rebound and the incidence of acute rejection. We concluded that no treatment is necessary for rebounded antiblood type antibodies.

Outcome of kidney transplantations performed with preformed donor-specific antibodies of unknown etiology.

The detection of preformed donor-specific alloantibodies (DSA) with multiplex-bead arrays has led to the common observation that individuals without a history of pregnancy, transfusion or transplantation can have circulating anti-HLA antibodies of unknown etiology. We retrospectively analyzed the risk of antibody-mediated rejection (AMR) and graft outcome in 41 kidney transplant recipients with DSA of unknown etiology (DSA cause-unk) at the time of transplantation. Twenty-one patients received a posttransplantation desensitization protocol, and 20 received standard immunosuppressive therapy. The mean number of DSA was 1.4 ± 0.8, ranging from 1 to 5. Complement-dependent cytotoxicity crossmatches were negative for all the patients. Flow cytometry crossmatches were positive in 47.6% of cases. The incidence of acute AMR was 14.6% at 1 year, regardless of the immunosuppressive regimen. No patients experienced graft loss following AMR. At month 12, across the entire population of patients with DSA cause-unk, the outcomes were favorable: the measured glomerular filtration rate was 63.8 ± 16.4 mL/min/1.73 m(2), the screening biopsies showed low frequencies of microvascular inflammation and no transplant glomerulopathy, and graft and patient survival were 100%. In conclusion, patients with DSA cause-unk are able to mount AMR but have favorable 1-year outcomes.

Influence of preoperative anti-HLA antibodies on short- and long-term graft survival in recipients with or without rituximab treatment.

We investigated the relationship between preoperative anti-HLA antibodies (donor-specific antibody, DSA) and the graft survival rate in recipients who had or had not received rituximab (Rit) treatment. The subjects were categorized into four groups as follows: DSA+Rit-, n = 39; DSA-Rit-, n = 121; DSA+Rit+, n = 74; and DSA-Rit+, n = 47. We examined the influence of preoperative DSA on the incidence of graft rejection and the survival rate of recipients who had or who had not received rituximab before transplantation. The 6-month acute rejection rates based on graft biopsies were 39%, 19%, 15%, and 0% for the DSA+Rit-, DSA-Rit-, DSA+Rit+, and DSA-Rit+ groups. The rates of chronic antibody-mediated rejection after more than 6 months were 50%, 22%, 18%, and 0%. The 5-year graft survival rate was significantly lower in the DSA+Rit- group (84%) than in the other groups (95% for DSA-Rit-, 98% for DSA+Rit+, and 91% for DSA-Rit+). The rate of the appearance of de novo anti-HLA antibodies was higher in the groups that did not receive rituximab treatment. The rate of graft loss associated with chronic antibody-mediated rejection was also higher in the DSA+Rit- group than in the other groups (P = 0.01). The presence of DSA and the administration of rituximab had strong impacts on not only short-term graft rejection, but also long-term graft rejection and its association with the graft survival time.

Successful immunosuppressive drug-free immune tolerance induction in hemophilia B with inhibitor and anaphylaxis to factor IX: A case report.

Recommendations advise factor IX desensitization before immune tolerance induction in severe hemophilia B, supported by immunosuppression. A child with inhibitor and anaphylaxis to factor IX showed successful immunosuppression-free immune tolerance induction using very low and slowly increasing doses of a factor IX extended-half-life product. Immune tolerance to factor IX based on this protocol merits further study.

Chimeric HLA antibody receptor T cells for targeted therapy of antibody-mediated rejection in transplantation.

The presence of donor-specific antibodies (DSA), mainly against HLA, increases the risk of allograft rejection. Moreover, antibody-mediated rejection (ABMR) remains an important barrier to optimal long-term outcomes after solid organ transplantation. The development of chimeric autoantibody receptor T lymphocytes has been postulated for targeted therapy of autoimmune diseases. We aimed to develop a targeted therapy for DSA desensitization and ABMR, generating T cells with a chimeric HLA antibody receptor (CHAR) that specifically eliminates DSA-producing B cells. We have genetically engineered an HLA-A2-specific CHAR (A2-CHAR) and transduced it into human T cells. Then, we have performed in vitro experiments such as cytokine measurement, effector cell activation, and cytotoxicity against anti-HLA-A2 antibody-expressing target cells. In addition, we have performed A2-CHAR-Tc cytotoxic assays in an immunodeficient mouse model. A2-CHAR expressing T cells could selectively eliminate HLA-A2 antibody-producing B cells in vitro. The cytotoxic capacity of A2-CHAR expressing T cells mainly depended on Granzyme B release. In the NSG mouse model, A2-CHAR-T cells could identify and eradicate HLA-A2 antibody-producing B cells even when those cells are localized in the bone marrow. This ability is effector:target ratio dependent. CHAR technology generates potent and functional human cytotoxic T cells to target alloreactive HLA class I antibody-producing B cells. Thus, we consider that CHAR technology may be used as a selective desensitization protocol or an ABMR therapy in transplantation.

Exogenous recombinant human insulin-induced severe hypersensitivity reaction precipitating hyperglycemic crisis: A clinical conundrum.

Hypersensitivity reactions against exogenous insulin are a rare clinical entity after the advent of recombinant human insulin; however, there are still case reports wherein patients develop hypersensitivity reactions against insulin. We present the case of a type 1 diabetes mellitus patient who developed type 1 hypersensitivity reaction against subcutaneous insulin. He had recurrent episodes of diabetic ketoacidosis after developing hypersensitivity reactions against insulin, requiring multiple hospital admissions. When he presented to us, he was on both insulin infusion and subcutaneous insulin, requiring a daily insulin dose of about 800 units and having severe insulin hypersensitivity reactions and hyperglycemia. He had multiple subcutaneous erythematous nodules at the insulin injection sites, however, had no evidence of systemic allergy. Investigations revealed eosinophilic leukocytosis, and high IgE levels and skin biopsy showing evidence of insulin hypersensitivity. He was desensitized to insulin according to Heinzerling et al. insulin desensitization protocol and subsequently with immunomodulation therapy using steroids (pulse methylprednisolone) and mycophenolate mofetil as well as by installation of insulin pump.

A rapid desensitization protocol in a case of drotaverine-induced serum sickness-like reaction in a pregnant woman: A case report.

Drotaverine is an antispasmodic drug used to treat gastrointestinal and genitourinary smooth muscle spasms. There are very few hypersensitivity reactions reported. Serum sickness-like disease is an immune-complex-mediated hypersensitivity reaction that presents with some typical features that include rash, fever and articular impairment sometimes associated with liver and renal dysfunctions, beginning 1-2 weeks after exposure to a culprit drug. Diagnosis is a clinical one, made usually on the basis of knowledge obtained by medical history and physical examination. Desensitization usually is recommended for type I reaction, but may be a solution for this type of immunological reaction when other therapeutic alternatives are ineffective or do not exist. We report the case of a 29-year-old pregnant female who developed serum sickness-like reaction after 5 days of daily drotaverine oral administration. The patient required antispasmodic treatment, with this drug, having a pregnancy with an imminent risk of abortion and the other therapeutic alternatives being ineffective. She underwent a rapid 7-step oral drotaverine desensitization protocol without recurrence of serum sickness-like reaction. To our knowledge, this is the first case report of desensitization to drotaverine, previously involved in a serum sickness-like reaction.

Acetylsalicylic acid desensitization in patients with coronary artery disease: A comprehensive overview of currently available protocols.

BACKGROUND: Acetylsalicylic acid (ASA) represents the basis of pharmacological therapy for cardiovascular prevention. However, several patients are excluded from the benefits of ASA for hypersensitivity problems, and controversies still exist on their management. The aim of present study was to evaluate the safety and efficacy of ASA desensitization protocols in patients requiring dual antiplatelet therapy for coronary artery disease. METHODS: Literature archives and main scientific sessions' abstracts were scanned for studies describing desensitization protocols for patients with ASA hypersensitivity. Primary endpoint was the tolerance of ASA maintenance therapy (protocol success). Secondary endpoints were: 1) the occurrence of hypersensitivity symptoms during the protocol, 2) the rate of ASA discontinuation at follow-up; 3) recurrent cardiovascular ischemic events. RESULTS: We finally selected 14 studies out of 335 initially screened citation, reporting complete data on protocol desensitization strategies, with a total of 256 patients. Among them 213 (83.2%) underwent an oral desensitization protocol, while 43 received endovenous ASA. The protocol was successfully completed in 238 out of 256 patients (92.9%), who were subsequently kept on chronic daily therapy with ASA. The weighted success proportion was wP [95%CI] = 93[89.8­96.1]%. Hypersensivity symptoms occurred during the desensitization protocol in 29 patients, with a pooled events rate of 11.3[7.5­15.2]%. All adverse reactions were safely faced with pharmacological interventions. In 11 of these patients, slowing the protocol or restarting another ASA challenge could successfully achieve the tolerance. The rate of ASA discontinuation and major cardiovascular events was extremely low (6.1 and 2.3% respectively). CONCLUSIONS: Aspirin desensitization protocols represent a safe and effective option for the management of patients with a cardiovascular indication to ASA and history of allergy to ASA. Future randomized trials are certainly needed to confirm present findings and provide indications for the optimization of these protocols.

Successful living donor intestinal transplantation in cross-match positive recipients: Initial experience.

Sensitized patients tend to have longer waiting times on the deceased donor list and are at increased risk of graft loss from acute or chronic rejection compared to non-sensitized candidates. Desensitization protocols are utilized to decrease the levels of alloantibodies and to convert an initial positive cross-match to prospective donors into a negative crossmatch. These procedures are mostly available in the setting of living donation. Due to the elective nature of the procedure, desensitization protocols can be extended until the desire result is obtained prior to transplantation. We present two cases of successful desensitization protocol applied to living donor intestinal transplant candidates that converted to negative cross-match to their donors. We present two cases of intestinal transplant candidates with a potential living donor to whom they are sensitized. Both cases underwent successful transplantation after desensitization protocol. No evidence of humoral rejection has occurred in either recipient. Living donor intestinal transplantation in sensitized recipients against the prospective donors provides the ability to implement a desensitization protocol to convert to negative cross-match.