Phosphorylation of S6RP in peritubular capillaries of kidney grafts and circulating HLA donor-specific antibodies

Dalia Raïch-Regué; Javier Gimeno; Laura Llinàs-Mallol; Silvia Menéndez; David Benito; Dolores Redondo; M José Pérez-Sáez; Marta Riera; Elaine F Reed; Julio Pascual; Marta Crespo

doi:10.3389/fmed.2022.988080

Phosphorylation of S6RP in peritubular capillaries of kidney grafts and circulating HLA donor-specific antibodies

Front Med (Lausanne). 2022 Oct 18:9:988080. doi: 10.3389/fmed.2022.988080. eCollection 2022.

Authors

Dalia Raïch-Regué^{1

2}, Javier Gimeno^{1

3}, Laura Llinàs-Mallol^{1

2}, Silvia Menéndez^{1

3}, David Benito^{1

2}, Dolores Redondo^{1

2}, M José Pérez-Sáez^{1

2}, Marta Riera^{1

2}, Elaine F Reed⁴, Julio Pascual^{1

2}, Marta Crespo^{1

2}

Affiliations

¹ Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
² Department of Nephrology, Hospital del Mar, Barcelona, Spain.
³ Department of Pathology, Hospital del Mar, Barcelona, Spain.
⁴ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

Abstract

Antibody-mediated rejection (ABMR) caused by donor-specific HLA-antibodies (DSA) is a mediator of allograft loss after kidney transplantation (KT). DSA can activate microvascular endothelium damage through the mTOR pathway. In this study we assessed the mTOR pathway activation by DSA in KT with ABMR (ABMR + DSA+) compared to controls (ABMR-DSA-), biopsies with ABMR changes without DSA (ABMR + DSA-) and DSA without ABMR changes (ABMR-DSA+), and the potential modulation by mTOR inhibitors (mTORi). We evaluated 97 biopsies: 31 ABMR + DSA+, 33 controls ABMR-DSA-, 16 ABMR + DSA-, and 17 ABMR-DSA+ cases. Regarding immunosuppression of full ABMR + DSA+ and controls, 21 biopsies were performed under mTORi treatment (11 of them ABMR + DSA+ cases) and 43 without mTORi (20 of them ABMR + DSA+) so as to explore its effect on the mTOR pathway. Biopsies were stained for C4d, Ki67, and phosphorylated (p) S6RP, ERK, and mTOR by immunohistochemistry. Labeling was graded according to peritubular capillary staining. ABMR biopsies showed significantly higher C4d, p-S6RP, and Ki67 staining in peritubular capillaries (PTC) compared to controls, and light differences in p-ERK or p-mTOR. mTORi treatment did not modify p-S6RP, p-mTOR, and p-ERK staining. Diffuse p-S6RP in PTC in the biopsies significantly associated with circulating HLA-DSA independently of graft rejection, and with worse death-censored graft survival. These findings suggest that activation of endothelium through the mTOR pathway evidence different mechanisms of damage in ABMR + DSA+ and ABMR + DSA- despite similar histological injury.

Keywords: antibody mediated allograft rejection; donor specific antibodies; mammalian target of rapamycin (mTOR); peritubular capillaries; phosphorylation; ribosomal protein S6 (S6RP); transplantation—kidney.