Human leukocyte antigen-incompatible living donor kidney transplantation after desensitization: experience from a major transplant centre in Mexico

Kidney transplant recipients (KTRs) sensitized against human leukocyte antigens (HLA) represent a major clinical challenge because multiple donor-specific antibodies (DSAs) often lead to positive crossmatches and a high risk of graft loss from antibody-mediated rejection (AMR) (1). This challenge is worsened in Latin America by scarce kidney-exchange programs and DSA biobanks, reducing access to compatible donors. Consequently, our institution-one of the most active transplant centres in Latin america expanded living-donor transplantation for HLAincompatible pairs through individualized desensitization.We performed a single-centre retrospective cohort of 65 highly sensitized living- AR occurred in 20% (all AMR), with no differences between regimens; 12-month eGFR and graft survival were favorable and comparable. Infection-related mortality was low (6.2%). Infectious complications predominantly urinary tract infections [UTIs) were comparable between regimens; viral rates were low (cytomegalovirus CMV 1.5%, poliomavirus BK 6.2%). All variables with p1000.Notably, lower MFI values (<1000) have also been linked to immunological risk (4), so patients treated with IVIG alone despite appearing lower risk remain vulnerable and require close monitoring and individualized management. Overall AR rates, 1year graft function and survival were favorable and comparable to other desensitization series, including contemporary meta-analytic evidence showing high 1-year graft survival after IVIg/plasmapheresis/rituximab desensitization(5), and single-center cohorts reporting AR incidences in the same range with acceptable longer-term graft survival(6) and align with evidence that desensitization may offer survival comparable to, or better than, remaining on dialysis or awaiting a compatible deceased-donor transplant. (7) Complement-activating anti-HLA DSAs associate with higher risk of allograft loss and AMR(3), but we could not determine whether preformed DSAs were complement fixing or were eliminated after desensitization. A notable proportion of patients underwent transplantation despite a positive crossmatch. Although desensitization is sometimes used for recipients with positive flow-cytometry or CDC crossmatches and/or very high pre-transplant DSA MFI, prior studies report higher AMR rates and poorer graft survival in such cases. (1) In our cohort, ~50% of IVIG-only and 53.3% of triple-therapy patients had a positive crossmatch, predominantly by flow cytometry; only 3.1% had a positive CDC crossmatch and underwent triple therapy, achieving CDC negativization prior to transplantation. One developed AMR at 12 months successfully treated with preserved graft function (creatinine 1.0 mg/dL), while the other died from pneumonia and sepsis with a functioning graft. We observed no significant outcome differences by crossmatch status, whether comparing positive versus negative or flow-cytometry versus CDC positivity. Desensitization practices are heterogeneous across centres. (8,9). We assessed immunological risk using flow cytometry and CDC crossmatches, and Luminex SAB donor-specific antibody testing before desensitization. At our centre, regimen selection was clinician-driven, influenced by immunological risk, and the decision of the nephrology committee. We defined a sensitized patient (high risk) as one with a positive or negative flow cytometry crossmatch, with donor-specific antibodies (DSA) greater than 1000 MFI, and a history of exposure to sensitizing risk factors (10), with triple therapy used preferentially for higher DSA MFI (4000-5000), introducing indication bias that limits causal comparisons. Nevertheless, outcomes were encouraging, since sensitized recipients including those with lower MFI remain at substantial risk of AMR.( 4) Protocol biopsies at 3-6 months are a strength: no subclinical AR was detected and all AR episodes were diagnosed on indication. Post-transplant DSA profiles were not available, so we could not determine whether AR episodes were driven by de novo or preformed DSAs.Beyond MFI, donor-recipient HLA compatibility was also relevant: in our regression analysis fewer shared haplotypes was the only factor independently associated with increased AR risk, consistent with evidence that greater histocompatibility reduces rejection. Although follow-up was limited to 12 months, graft survival did not differ between groups and was comparable to other reports with similar AMR rates (5,6). Graft loss occurred in 5 recipients (6.2%), primarily due to immunological causes, including hyperacute rejection (n=1), acute antibodymediated rejection (n=2), and mixed rejection (n=1), with one additional case attributable to BK virus-associated nephropathy.Finally, although desensitization-related immunosuppression may increase infection risk, overall infectious complications-predominantly UTIs were similar between regimens and comparable to non-sensitized KTRs at our centre, (11) with infrequent viral infections (CMV and BK). Overall mortality was 6.2%, entirely due to infectious causes, with deaths resulting from pneumonia and sepsis (n=3) and COVID-19 (n=1), consistent with contemporary desensitization cohorts( 5) and was higher among patients with DSAs to both HLA classes (p=0.032), with no differences between regimens. Extended follow-up is warranted to better define late infectious risk. Although desensitization remains controversial regarding rejection risk and graft survival, recent consensus supports individualized strategies based on each patient's immunological risk profile. (9) Limitations include retrospective design and short follow-up. Lack of systematic post-transplant immunomonitoring limit analysis of DSA kinetics, distinction of de novo versus preformed DSAs, and assessment of long-term antibody-mediated injury and graft survival. Protocol biopsies at 3-6 months are strength-no subclinical AR was detected and all AR episodes were diagnosed on indication.Overall, these findings support individualized desensitization as a feasible strategy to safely expand access to living-donor kidney transplantation in Latin America.