Evaluation and Treatment of Acute Rejection in Kidney Allografts

Abstract

Advances in immunosuppressive therapy have drastically improved acute rejection rates in kidney transplant recipients over the past five decades. Nevertheless, it should remain high on any differential diagnosis of unexplained graft dysfunction because of the potential negative effect on graft longevity. Understanding the pre- and post-transplant risk factors for acute rejection can help estimate the probability of immunologic graft damage, and accurate identification of the type and severity of acute rejection will guide appropriate treatment. Tissue biopsy remains the gold standard for evaluating immunologic graft damage, and the histologic definition of acute rejection has evolved in recent years. Intravenous steroids and T cell depletion remain the standard therapy for T cell-mediated rejection and are effective in reversing most cases. Plasma exchange and intravenous Ig, with or without rituximab, are most commonly used for the treatment of antibody-mediated rejection and several newer agents have recently been investigated for severe cases. This review aims to provide the general nephrologist caring for transplant recipients with an approach to immunologic risk assessment and a summary of recent advances in the diagnosis and treatment of acute graft rejection.

Keywords: Immunology and pathology; acute allograft rejection; allografts; antibodies; biopsy; differential diagnosis; graft rejection; humans; immunosuppression; intravenous immunoglobulins; kidney transplantation; longevity; nephrologists; plasma exchange; plasmapheresis; renal transplantation; risk assessment; risk factors; rituximab; t-lymphocytes; transplant recipients.

Figure 1.

Decline of 1-year incidence of acute rejection over time with approximate date of immunosuppression medication introduction. Acute rejection rates have steadily declined over time with the introduction of increasingly effective immunosuppression. Modified and updated from Zand (3).

Figure 2.

Histologic presentation of acute rejection. (A) Banff grade 1a with moderate lymphocytic infiltration of the tubules (arrows). (B) Banff grade 1b with severe lymphocytic interstitial infiltration and tubulitis (arrows). (C) Banff grade 2a with arterial intimal lymphocytic infiltration (arrows). (D) Peritubular lymphocytic infiltration characteristic of antibody-mediated rejection (arrows). (E) Positive C4d staining of the peritubular capillaries by immunohistochemistry.

Figure 3.

Proposed algorithm for treatment of presumed and biopsy-proven acute kidney allograft rejection. Once non-immunologic etiologies of graft dysfunction are ruled out, allograft biopsy and assessment of DSA should be pursued with treatment dictated by biopsy findings. In cases where biopsy is not feasible, empirical treatment is indicated and can be tailored based on clinical response and results of DSA screening. DSA, donor-specific antibody; rATG, rabbit anti-thymocyte globulin; IVIG, intravenous IG.

Figure 4.

Target sites for current available and experimental therapeutic agents for antibody-mediated allograft rejection. B cells (inhibited by rituximab) differentiate to plasma cells (inhibited by bortezomib), which generate donor-specific anti-HLA antibodies (removed by plasma exchange, modulated by IVIG). Upon binding to HLA molecules on graft endothelium, donor-specific antibodies (DSA) fix complement (inhibited by C1-esterase inhibitors [C1-INH]) and initiate a cascade resulting in C5 cleavage (inhibited by eculizumab) and formation of the membrane attack complex (MAC), leading to apoptosis and tissue damage.