Growing evidence implicates B cells in transplant tolerance. RESTARRT is a 6-center ISW study in adult living-related-donor KTR receiving ATG induction and rituximab with a goal of promoting a tolerogenic immune milieu during B cell repopulation.

Methods: 10 (4 haplo/6 HLA matched) KTR were enrolled 7/11–10/15. 8 received full induction followed by MMF, tacrolimus and sirolimus. IS was withdrawn over <1.7 yr with early MMF discontinuation followed by tacrolimus then sirolimus ISW. KTR off IS without histologic evidence of rejection 52 wk post-ISW met primary endpoint. Flow cytometry gauged peripheral cell depletion and repopulation.

Results: 2/4 haplo KTR completed induction. 1 was ineligible for ISW (IgA recurrence) and 1 completed only tacrolimus ISW.

6 matched KTR completed ISW (median [min-max] time from transplant to ISW completion, 20.9 [18.5-22.5] mo): 1 remains off IS at 29.7 mo; 1 was off IS for 9.7 mo when lost to follow-up; 4 were off IS for 10.7 (0.5-21.0) mo before restarting IS for biopsy-proven or presumed rejection. 2/6 met primary endpoint. Induction depleted peripheral lymphocytes: NK, CD8+ and CD19+ cells approached baseline at 20.9 (18.5-22.5) mo; CD4+ T cells and Tregs remained depleted at 35.1 (12.8-53.8) mo. Based on CD197 and CD45RA/RO detection, repopulation resulted in a change from primarily naïve to memory T cells. Naïve B cells (IgM+IgD+) initially expanded 2-fold for some KTR and on average returned to baseline 20.9 (18.5-22.5) mo post-transplant.

A stopping rule was met when 4/10 KTR rejected. Study therapy ended after a 5^th rejection. Median GFR at last follow-up (32.9 [7.4-51.1] mo) was 60.2 (23.7-81.7) mL/min/1.73 m².

Conclusion: B cell depletion with the IS regimen resulted in a preponderance of naïve B cells compared to pre-transplant. Prolonged IS-free survival was obtained in most matched KTR but many ultimately had rejection or biopsy findings necessitating IS resumption. Future interventions may focus on maintaining a naïve B cell phenotype to improve the stability of IS-free survival.

CITATION INFORMATION: Burrell B, Bromberg J, Hartono C, Posselt A, Naji A, Kaufman D, Redfield III R, Kanaparthi S, Ikle D, Much K, Bridges N, Sun L, Priore A, DesMarais M, Crisalli K, Chandran S, Markmann J. Immunosuppression (IS) Withdrawal (ISW) After ATG and Rituximab in Kidney Transplant Recipients (KTR): RESTARRT Early Results (NCT01318915). Am J Transplant. 2017;17 (suppl 3).

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