Sensitized Renal Transplant Recipients: Current Protocols and Future Directions

1. Sensitized Renal Transplant Recipients: Current Protocols and Future Directions Reference: Gloor J, Stegall MD. Sensitized renal transplant recipients: Current protocols and future directions. Nat Rev Nephrol. 2010;6: 297–306.

2. Overview • Kidney transplantation is performed on patients with chronic kidney failure, or end-stage renal disease (ESRD). • The success of a kidney transplant graft depends on the strength of the match between donor and recipient and the source of the kidney. • The major human leukocyte antigen (HLA) antigens are essential elements for immune function. • Historically, HLA genes were identified as a result of the ability to successfully transplant organs between HLA similar individuals. • Classically, donor-specific antibodies (DSAs)—anti- HLA antibodies with reactivity against a potential donor have constituted a contraindication for proceeding to transplantation, and testing for these antibodies has been an important component of the pretransplantation evaluation.

3. Overview • Innovative protocols have been developed to acutely lower DSA activity to below the level that causes immediate renal allograft injury, and to maintain this reduced level during the first weeks to months after transplantation. • During this time, the renal allograft develops resistance to antibody-mediated injury, which is due to upregulation of protective genes. This condition is referred to as ‘accommodation’. • Multiple investigations have revealed satisfactory short-term to intermediate-term allograft survival by positive crossmatch kidney transplantations. • Positive crossmatch kidney transplantation requires comprehensive characterization of DSAs, protocols that lower DSA activity, and prompt diagnosis and treatment of antibody-mediated rejection (AMR).

4. Antibody Characterization • Anti-HLA antibodies play a vital role in kidney transplantation and has been recognized over 40 years. • Researchers Patel and Terasaki in the year 1969 established that hyperacute rejection resulted from allograft injury caused by preformed antibodies directed against donor antigens. • Hence, testing transplant candidates for these antibodies became an essential component for the evaluation of pretransplantation. • Various laboratories chose to use sensitive assays in which low level DSAs were present.

5. Antibody Characterization • Another important technique was the implementation of solid-phase anti-HLA antibody testing. • Here, the purified HLA antigens are bound to solid surfaces such as flow beads or incubation wells are incubated with recipient sera. • These are analyzed by flow cytometric assay or enzymelinked immune sorbent assay (ELISA). • The solid phase tests employ individual HLA antigens and the reactivity of individual anti-HLA antibodies can be determined easily. • This allows recognition of donor specificity. Anti-HLA class II antibodies technique became available only after the recognition of solid phase testing. • The identification of HLA antigens has led to several clinical implications & has shortened the waiting time for highly sensitized decreased donor kidney transplantation in highly sensitized candidates.

6. Antibody Characterization • High-dose intravenous immunoglobulin has been used for the desensitization of highly allosensitized transplant candidates for nearly 20 years. • An open label, single center study published in 2008 showed that high-dose intravenous immunoglobulin administered in conjunction with the anti-CD20 antibody rituximab improved transplantation rates of highly allosensitized living and deceased donor kidney transplant candidates. • In another study by Lefaucheur et al. on positivecrossmatch kidney transplantation, high-dose intravenous immunoglobulin used reported a series of 18 transplantations. • The incidence of acute AMR was 28%. Another study of positive-crossmatch kidney transplantation following intravenous immunoglobulin preconditioning in a series of 8 patients demonstrated acute AMR of 13% and allograft survival was about 88% over a mean follow-up of 15 months.

7. Antibody Characterization • Plasma exchange involves physically removing the DSAs before the transplantation procedure. • In this case, patients are supplemented with low-dose intravenous immunoglobulin prior to transplantation in order to reduce DSA level. • Thielke et al. reported that a negative crossmatch was successfully achieved in 51 of 57 positive crossmatch patients treated with antithymocyte and anti-CD20 antibody induction therapy in addition to plasma exchange and low dose intra venous immunoglobulin. • The allograft survival rate was 93% at 1 year and 81% at two years. AMR was about 43%. • Magee et al. reported a series of 28 positive crossmatch transplantations in which allograft survival rate was 90% at 1 year and 80% at 2 years. • AMR was about 42% A similar study in which 41 patients positive crossmatch transplantations recipients were treated with preconditioning plasma exchange and intravenous immunoglobulin. • The 1- year and 5-year allograft survival rates were 89.9% and 69.4%, respectively. The AMR was about 12% (see Table 1).

8. Table 1: Acute AMR incidence and its effect on 1-year and 2-year allograft survival • The two methods, high-dose intravenous immunoglobulin and plasma exchange with or without immunoglobulin, have disadvantages of resource utilization and administering high volumes of fluid to anuric dialysis patients was hard.

9. Antibody Mediated Rejection • The incidence of AMR has often been considered as the one which complicates antibody-incompatible transplantation. • It begins with acute histological lesions and progresses to chronic changes. • Primarily acute histological injury is characterized by endothelial cell swelling, detachment from the basement membrane, and fragmentation, predominantly affects peritubular and glomerular capillaries. • Chronic injury leads to remodeling of the peritubular and glomerular capillary basement membrane, producing the characteristic multilayering or lamellation pattern indicative of transplant glomerulopathy (see Fig. 1).

11. Many of the acute histological changes associated with acute AMR are mediated through complement activation. • Haas et al. in 2007 reported histological evidence of subclinical acute AMR consisting of peritubular capillary monolytic infiltration (see Fig. 2). • One of the key points in the treatment of AMR is the inhibition of antibody synthesis along with lowering the level of DSA. • Proteasome inhibition plays an important role in cell cycle regulation, cell–cell interactions, and apoptosis. • Everlyet al. demonstrated the use of bortezomib, which showed rapid improvement in the allograft function and suppression of recurrent rejection.

13. Conclusion • Technological advantages in antibody characterization have led to more comprehensive assessment of anti-HLA antibody activity. • Recent protocols developed have led to new insights for successful transplantation. • However, AMR remains a significant challenge occurring in 20–50% of antibody incompatible kidney transplantation. • New interventions for preventing acute AMR that are based on complement blockade and proteasome inhibition seem promising.

14. Key Points