Antibody-Mediated Rejection in Organ Transplantation

Antibody-mediated rejection (AMR) presents a major barrier to long-term success in solid organ transplantation. This process is characterised by recipient-derived antibodies targeting donor antigens, primarily human leucocyte antigens (HLA), leading to immune complex formation, complement activation and microvascular injury. Clinically, AMR manifests as deteriorating graft function—detected through rising serum creatinine in renal transplantation or via functional decline in other organs—and may occur acutely or develop insidiously over time. Histopathological hallmarks include endothelial cell swelling, peritubular capillaritis and deposition of complement fragment C4d. Advances in donor-specific antibody (DSA) detection, refinements in biopsy classification and emerging molecular diagnostics have increased recognition of AMR subtypes—acute, chronic active and subclinical. Despite this, treatment options remain guided largely by expert consensus, with plasmapheresis, intravenous immunoglobulin and complement inhibitors employed in the absence of large-scale randomised trials. Noninvasive biomarkers and mechanistic insights are therefore crucial for early detection, risk stratification and the design of personalised therapies, while global efforts continue to harmonise diagnostic criteria and therapeutic protocols.

Research from Nature Portfolio

Recent studies have highlighted the utility of donor-derived cell-free DNA (dd-cfDNA) as a noninvasive indicator of allograft injury. In a large multicentre cohort, circulating dd-cfDNA levels were strongly associated with antibody-mediated rejection, improving diagnostic discrimination when added to standard clinical monitoring. This approach demonstrated high sensitivity and specificity for both subclinical and overt AMR, and showed consistent performance across diverse patient populations, including validation in external cohorts. Another investigation challenged the prevailing view that microvascular inflammation in graft biopsies is driven solely by alloantibody. This work revealed that natural killer (NK) cells can mediate chronic vascular injury via a “missing self” mechanism when donor HLA class I molecules fail to engage inhibitory receptors on recipient NK cells. It identified mTORC1 dependence of this pathway and suggested that mTOR inhibition may prevent this form of antibody-independent vascular rejection, thus broadening the conceptual framework for AMR and indicating novel therapeutic targets.

Research from all publishers

An authoritative guide to the Banff Classification of renal allograft pathology provides a concise reference for scoring histological lesions and diagnostic categories, facilitating standardised biopsy interpretation and underpinning multicentre trials. Expert consensus recommendations on the treatment of AMR in kidney transplantation review underlying biology, diagnostic criteria and clinical phenotypes, and propose protocols combining plasma exchange, immunoadsorption, complement blockade and B cell–directed therapies, while underscoring the urgent need for robust clinical trials. Furthermore, longitudinal surveillance studies of dd-cfDNA in kidney recipients demonstrated that serial elevations above a defined threshold predict the development of DSAs and impending graft dysfunction. These findings support the use of dd-cfDNA monitoring for early intervention and personalisation of immunosuppression to preserve long-term graft health.

Antibody-Mediated Rejection in Organ Transplantation publication trend

The graph below shows the total number of articles in antibody-mediated rejection in organ transplantation across all publications each year (not limited to Nature Index journals).

Technical terms

Antibody-mediated rejection (AMR): Immune injury of a transplanted organ caused by recipient antibodies binding donor antigens and activating complement.

Donor-specific antibody (DSA): Antibodies produced by the recipient that specifically target donor HLA molecules.

Donor-derived cell-free DNA (dd-cfDNA): Fragments of DNA released from graft cells into the recipient’s circulation, used as a biomarker of allograft injury.

Complement fragment C4d: A stable split product of the classical complement pathway, deposited in capillaries and indicative of antibody–complement activation.

Banff Classification: An internationally accepted schema for grading and reporting pathological changes in allograft biopsies.

References

1. Cell-free DNA for the detection of kidney allograft rejection. Nature Medicine (2024).
2. A 2018 Reference Guide to the Banff Classification of Renal Allograft Pathology. Transplantation (2018).
3. Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantion Society Working Group. Transplantation (2020).
4. Missing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants. Nature Communications (2019).
5. Clinical outcomes from the Assessing Donor-derived cell-free DNA Monitoring Insights of kidney Allografts with Longitudinal surveillance (ADMIRAL) study. Kidney International (2021).