Chronic Rejection After Kidney Transplantation

Abstract

In kidney transplantation, ongoing alloimmune processes-commonly triggered by HLA incompatibilities-can trigger chronic transplant rejection, affecting the microcirculation and the tubulointerstitium. Continuous inflammation may lead to progressive, irreversible graft injury, culminating in graft dysfunction and accelerated transplant failure. Numerous experimental and translational studies have delineated a complex interplay of different immune mechanisms driving rejection, with antibody-mediated rejection (AMR) being an extensively studied rejection variant. In microvascular inflammation, a hallmark lesion of AMR, natural killer (NK) cells have emerged as pivotal effector cells. Their essential role is supported by immunohistologic evidence, bulk and spatial transcriptomics, and functional genetics. Despite significant research efforts, a substantial unmet need for approved rejection therapies persists, with many trials yielding negative outcomes. However, several promising therapies are currently under investigation, including felzartamab, a monoclonal antibody targeting the surface molecule CD38, which is highly expressed in NK cells and antibody-producing plasma cells. In an exploratory phase 2 trial in late AMR, this compound has demonstrated potential in resolving molecular and morphologic rejection activity and injury, predominantly by targeting NK cell effector function. These findings inspire hope for effective treatments and emphasize the necessity of further pivotal trials focusing on chronic transplant rejection.

Graphical abstract

FIGURE 1.

Schematic representation of the dichotomous categorization of rejection according to the latest updates of the Banff scheme. Shown are the diagnostic algorithms for AMR (left column) and TCMR (right column). The upper parts of the columns represent the criteria for active and the lower parts of the column for chronic (active) rejection. For each (sub)category, representative images of the diagnostic Banff lesions, including an ultrustructural picture of ptcml, are shown, with distinct lesions indicated by arrows. For chronic active TCMR, cortical i-IFTA (red arrow) and associated t-IFTA (black arrows) are depicted. The extent of total inflammation within scarred and nonscarred cortical interstitium determines the ti-score. For the diagnosis of active AMR, the Banff 2022 scheme proposes the use of biopsy-based transcript diagnostics as a substitute for MVI, if thoroughly validated and available. *Active lesions: g > 0 in the absence of glomerulonephritis; ptc > 0 in the absence of acute TCMR or borderline (suspicious) for acute TCMR; v > 0; acute TMA in the absence of any other cause. **Included are cases with probable AMR associated with chronic lesions (cg > 0 and severe ptcml). Prior documented diagnosis of active or chronic active AMR, or documented prior evidence of DSA, also count as DSA. AMR, antibody-mediated rejection; DSA, donor-specific antibodies; i-IFTA, interstitial fibrosis with partial inflammation; MVI, microvascular inflammation; ptcml, peritubular capillary basement membrane multilayering; TCMR, T cell–mediated rejection; t-IFTA, tubulitis within the scarred interstitium; TMA, thrombotic microangiopathy.

FIGURE 2.

Pathophysiologic sequence of AMR and potential strategies to interfere with MVI and injury. A primary trigger of humoral donor-specific alloreactivity is the interaction between follicular T helper cells and naive B cells, initiating B cell proliferation and differentiation into B memory cells and antibody-producing plasma cells. The binding of DSA to endothelially expressed HLA molecules can initiate direct intracellular signaling and complement activation through the CP. Additionally, it can trigger FcγRIIIA-dependent NK cell activation, resulting in cellular cytotoxicity and interferon gamma production. MVI may involve distinct T cell subsets and monocytes, the latter activated via FcγR activation, proinflammatory cytokines, or possibly directly through nonself recognition. There are several therapeutic strategies that may target specific steps in the process of B cell activation and differentiation, deplete DSA, or interfere with deleterious effector mechanisms, such as complement activation or NK cells. Via a dual mode of action, including the depletion of both NK cells and antibody-producing plasma cells, monoclonal antibodies targeting CD38, such as felzartamab, have demonstrated promising efficacy in reversing MVI. Experimental data and case reports with the CD38 antibody daratumumab, however, have suggested potential interference with regulatory cells, which could pose a risk of T cell–mediated rejection. Created with Biorender.com. AMR, antibody-mediated rejection; CP, classical pathway; DSA, donor-specific antibodies; FcγRIIIA, Fc gamma receptor IIIA; MVI, microvascular inflammation; NK, natural killer.