Donor-Specific Antibodies Adversely Affect Kidney Allograft Outcomes

Abstract

The effect of low titers of donor-specific antibodies (DSAs) detected only by sensitive solid-phase assays (SPAs) on renal transplant outcomes is unclear. We report the results of a systematic review and metaanalysis of rejection rates and graft outcomes for renal transplant recipients with such preformed DSAs, defined by positive results on SPA but negative complement-dependent cytotoxicity and flow cytometry crossmatch results. Our search identified seven retrospective cohort studies comprising a total of 1119 patients, including 145 with isolated DSA-SPA. Together, these studies suggest that the presence of DSA-SPA, despite a negative flow cytometry crossmatch result, nearly doubles the risk for antibody-mediated rejection (relative risk [RR], 1.98; 95% confidence interval [CI], 1.36-2.89; P,0.001) and increases the risk for graft failure by 76% (RR, 1.76; 95% CI, 1.13-2.74; P=0.01). These results suggest that donor selection should consider the presence of antibodies in the recipient, identified by the SPA, even in the presence of a negative flow cytometry crossmatch result. In 1969, Patel and Terasaki published their landmark study that definitively established the detrimental effect of preformed donor-specific antibodies (DSAs) detected by complement-dependent cytotoxicity (CDC) crossmatch on short-term allograft survival, but they noted the limited sensitivity of the technique in the detection of preformed DSAs. 1 Since that time, technological advances have led to increasingly more sensitive tests for the detection of anti-HLA DSAs, including flow cytometry crossmatch and the more recent solid-phase assays (SPAs), such as Luminex. 2,3 The clinical significance of DSAs detected by sensitive SPA remains unclear, with disparate findings being reported in the literature. 4 Further, the clinical utility of these tests, particularly for prognostication or modifying immunosuppressive therapy, when used individually or in some sequential manner remains unclear. Our aim was to perform a systematic review and meta-analysis of published reports of rejection rates and graft outcomes among renal transplant recipients with preformed DSA at levels detectable only by SPA but not by CDC or flow crossmatch. RESULTSWe ultimately identified seven studies that met our inclusion criteria for the primary quantitative analysis (group 1). [5][6][7][8][9][10][11] All seven studies were retrospective cohort studies; three were from the United States and four from Europe. Our ability to compare

Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant

“…Recently published studies on pretransplant DSAs focused mainly on deceased donor transplants, as these are most prevalent in, for example, France, Germany, and the United States 17, 18, 19. Studies on living donor transplant are scarce; in a single‐center study, where 324 living donor transplants were analyzed, no significant difference in the 5‐year graft survival of patients with DSAs was found compared with patients with anti–blood type antibody, anti–HLA‐Abs, or no DSAs 20.…”

“…Studies on living donor transplant are scarce; in a single‐center study, where 324 living donor transplants were analyzed, no significant difference in the 5‐year graft survival of patients with DSAs was found compared with patients with anti–blood type antibody, anti–HLA‐Abs, or no DSAs 20. Mohan et al19 reported a meta‐analysis of DSAs detected with, among others, SAB assays and calculated an increased risk for graft failure in the presence of SAB assay–detected DSAs with negative CDC‐XM, similar to our study. The effect of DSAs in living donor transplant has not been investigated so far in large cohorts.…”

“…While recent large‐cohort studies of the impact of DSAs on graft survival have mainly focused on deceased donor transplants,17, 18, 19 the effect of SAB assay–detected DSAs on living donor transplants has not been studied in large cohorts. In a Japanese single‐center study, 324 living donor kidney transplant recipients were analyzed to investigate the outcome of the 92 kidney transplant recipients with DSAs in combination with anti–blood type, anti–HLA antibodies, or both; all were desensitized before transplant 20.…”

HLA-DR and -DQ Eplet Mismatches and Transplant Glomerulopathy: A Nested Case–Control Study

“…Though the risk for immune-mediated allograft injury may be recognized prior to transplantation in the form of preformed HLA class II DSA (63,70,71) and positive cross-matches (47), anti-class II DSA may also appear posttransplant (72)(73)(74)(75). Knowledge of the eplet load and the immunogenicity of particular eplets, may be used for risk stratification and inform personalized surveillance (DSA monitoring and surveillance biopsies) and therapeutic regimens.…”

De novo donor-specific antibodies in belatacept-treated vs cyclosporine-treated kidney-transplant recipients: Post hoc analyses of the randomized phase III BENEFIT and BENEFIT-EXT studies

“…In kidney‐transplant recipients, the presence of donor‐specific antibodies (DSAs) is associated with an increased risk of antibody‐mediated rejection and graft failure 6. Approximately 11% of kidney‐transplant recipients develop de novo DSAs within the first year after transplantation; this proportion increases to 20% by 5 years posttransplant 7.…”