The clinical impact of humoral immunity in pediatric renal transplantation

Abstract

The development of anti-donor humoral responses after transplantation associates with higher risks for acute rejection and 1-year graft survival in adults, but the influence of humoral immunity on transplant outcomes in children is not well understood. Here, we studied the evolution of humoral immunity in low-risk pediatric patients during the first 2 years after renal transplantation. Using data from 130 pediatric renal transplant patients randomized to steroid-free (SF) or steroid-based (SB) immunosuppression in the NIH-SNSO1 trial, we correlated the presence of serum anti-HLA antibodies to donor HLA antigens (donor-specific antibodies) and serum MHC class 1-related chain A (MICA) antibody with both clinical outcomes and histology identified on protocol biopsies at 0, 6, 12, and 24 months. We detected de novo antibodies after transplant in 24% (23% of SF group and 25% of SB group), most often after the first year. Overall, 22% developed anti-HLA antibodies, of which 6% were donor-specific antibodies, and 6% developed anti-MICA antibody. Presence of these antibodies de novo associated with significantly higher risks for acute rejection (P=0.02), chronic graft injury (P=0.02), and decline in graft function (P=0.02). In summary, antibodies to HLA and MICA antigens appear in approximately 25% of unsensitized pediatric patients, placing them at greater risk for acute and chronic rejection with accelerated loss of graft function. Avoiding steroids does not seem to modify this incidence. Whether serial assessments of these antibodies after transplant could guide individual tailoring of immunosuppression requires additional study.

Figure 1.

Study outline. This study used 440 serum samples and 440 matched blinded biopsy scores for CADI, CNIT, Banff rejection grading, and C4d stains on 440 matched protocol biopsies from the SNSO1 multicenter randomized trial of SF and SB immunosuppression in pediatric renal transplantation.^, Samples and biopsies were assayed at 0 (pretransplant), 6, 12, and 24 months post-transplantation. Of 130 patients in the trial, 124 patients had at least three of four sera samples collected and were included in the analysis.

Figure 2.

De novo antibody titers in SF versus SB immunosuppression. Antibody titers. The highest MFIs are shown for DSA, NDSA, Cw, DQ, and DP (where donor typing for these antigens were not available), and MICA antigens.

Figure 3.

Significant association of Ab positivity and biopsy-confirmed AR. Anti-HLA DSA and MICA Ab titers in patients in the entire study with and without AR.

Figure 4.

Correlation between the intensity of DSA titers and decline in graft function. The x axis represents ΔMFI; the y axis represents ΔGFR between 6 months post-transplantation (taken as the baseline serum creatinine in milligrams per deciliter) and the last patient follow-up at 24 months post-transplantation.

Figure 5.

There was an increase of CADI/CNIT scores due to time post-transplantation. Progression of the (A) CADI and (B) CNIT scores in the protocol biopsies over time after transplantation. Both CADI and CNIT scores increased significantly with time post-transplantation (significance shown by highlights for P<0.001; protocol biopsies at times 0, 6, 12, and 24 months post-transplantation marked as t0, t6, t12, and t24, respectively).

Figure 6.

Significant association of Ab positivity and graft loss. Anti-HLA DSA and anti-MICA Ab positivity in patients associates with greater risk of graft loss over the course of the SNSO1 study, even in low-risk pediatric renal transplant recipients.