Outcome of desensitization in human leukocyte antigen- and ABO-incompatible living donor kidney transplantation: a single-center experience in more than 100 patients.

BACKGROUND: Antibody-mediated rejection (AMR) and inferior graft outcome remain the 2 most important obstacles to successful kidney transplantation in human leukocyte antigen (HLA)- and ABO-incompatible recipients. We report a single-center experience in the outcome of desensitized living donor HLA- and ABO-incompatible kidney transplantation. METHODS: Since 2007 we included 2 groups in our desensitization program. HLA-incompatible living donor kidney transplant candidates displaying donor-specific antibodies (DSA) with or without a positive T-cell and/or B-cell flow crossmatch (FCXM). Second, those displaying DSA with positive T-cell immunoglobulin (Ig)G AHG CDC CXM with a titer of ≤1:8, as well as all ABO-incompatible living donor kidney transplant candidates with an IgM isoagglutinin titer ≤ 256. They were risk stratified for AMR and underwent individualized desensitization protocol: ABO-incompatible and HLA-incompatible candidates with either positive AHG CDC CXM or positive T and/or B IgG flow CXM with repeat HLA mismatch from a previous transplantation were deemed to be high risk and received a single dose of Rituximab, therapeutic plasma exchange and high-dose intravenous immunoglobulin (IVIG) (2 g/kg). HLA-incompatible candidates with negative CDC but positive T and/or B IgG FCXM were deemed intermediate risk, receiving rituximab and high-dose IVIG. Those with positive DSA but negative flow and CDC CXM were deemed low risk, receiving low-dose IVIG (1 g/kg). All patients received induction with thymoglobulin and were maintained on a tacrolimus-based immunosuppressive regimen. RESULTS: Among 124 incompatible recipients, 85 received HLA-incompatible and 39 ABO-incompatible living donor kidney transplantations after desensitization. Risk stratification for HLA-incompatible transplants revealed 61 high-risk, 42 intermediate-risk, and 21 low-risk cases. Ninety-nine (80%) were primary transplants. At a median follow-up of 23 (range 1-53) months, patient survival was 98% and death censored graft survival 96%. Mean serum creatinine was 84 µmol/L (range 41-169). Acute cellular rejection was observed in 15 (12%) and AMR in 5 (4%) patients. All rejection episodes responded to treatment except 1 AMR in an ABO-incompatible transplant that led to graft failure. CONCLUSION: Our risk stratification for desensitization strategy achieved a low incidence of AMR among HLA- and ABO-incompatible kidney transplant recipients. Their 2-year data appear to be comparable to HLA- and ABO-compatible transplantations.

Targeted monitoring of donor-specific HLA antibodies following renal transplantation.

Development of de novo donor-specific anti-HLA antibody (DSA) with antibody-mediated rejection (AMR) is the most important cause of renal allograft loss. Therefore, DSA monitoring might identify grafts susceptible to chronic humoral injury. However, implementing universal monitoring is logistically difficult, costly, and not yet supported by management guidelines, especially in patients with stable graft function. To gain further insight into humoral alloimmunity in transplant patients, we conducted a single center, retrospective study of AMR due to de novo DSA. We excluded patients without full characterization of the HLA specificities by single antigen solid phase immunoassay, and those where the clinical relevance of the DSA could not be determined. The clinical scenarios preceding AMR, HLA mismatches and alloantibody specificities, the histopathological phenotypes, and graft outcome were studied. We identified 44 renal transplant recipients with indication and protocol biopsies (44 biopsies for cause and 2 protocol biopsies), revealing 46 episodes of AMR and DSA (2 episodes in two patients). Most were late (more than 6 months after transplant). Suboptimal immunosuppression was an important prelude, usually due to non-adherence. DSA to DQ was prevalent and most biopsies were C4d positive. In all, 20 graft losses were attributed to AMR. From this study, we propose DSA monitoring in the patients with the following: (1) an episode of late (> 6 months) rejection; (2) history of non-adherence to immunosuppression; (3) immunosuppression minimization; (4) a class II loci (DR and DQ) mismatch transplant; or, (5) history of previous transplants. Close surveillance and protocol biopsies in those who develop de novo DSA is suggested.

Bortezomib as an adjuvant to conventional therapy in the treatment of antibody mediated rejection (AMR): the full spectrum.

Antibody-mediated rejection (AMR) is a well-known complication of kidney transplantation. Its incidence is higher in HLA and ABO incompatible transplant recipients and in patients who develop de novo HLA antibodies. Different clinical and histological phenotypes of HLA-related AMR have been described with variable responses to conventional AMR treatment (Plasmapheresis, IVIG, thymoglobulin (ATG), and anti-CD20 antibodies). Regardless of the phenotype, once the HLA primed B cells have differentiated into antibody producing long-lived plasma cells, they become less vulnerable to conventional AMR treatment. Bortezomib (Velcade) is a proteasome inhibitor approved by the FDA for the treatment of multiple myeloma. It targets mature plasma cells, and hence it is intriguing to study its role in the suppression of long-lived plasma cells. Several previous reports have suggested effectiveness of Bortezomib in the treatment of AMR. We report our experience with Bortezomib as an adjuvant to conventional therapy in five distinct phenotypes of AMR: early acute AMR in the context of desensitization; subclinical acute AMR in the context of desensitization; late acute AMR due to de novo HLA antibody; late ACR and acute AMR due to de novo HLA antibody and chronic AMR due to de novo HLA antibody.