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Thoracic Surgery90 papers

Hyperacute rejection of lung transplant

Last edited: 3 h ago

Overview

Hyperacute rejection (HAR) in lung transplantation is an immediate and severe immune response that occurs within minutes to hours after transplantation, primarily due to pre-existing recipient antibodies against donor human leukocyte antigens (HLA). This rapid rejection can lead to graft failure and is a critical clinical emergency necessitating urgent intervention. It predominantly affects recipients with pre-formed donor-specific antibodies (DSAs), often stemming from previous sensitization events such as blood transfusions or prior transplants. Early recognition and management are crucial for improving outcomes, making it imperative for clinicians to be vigilant in high-risk patients. Understanding HAR is vital in day-to-day practice to prevent catastrophic graft loss and optimize patient survival post-transplant 1 4.

Pathophysiology

Hyperacute rejection in lung transplantation is driven by pre-existing recipient antibodies that recognize and bind to donor HLA antigens on the graft endothelium. This binding triggers a cascade of immune responses, primarily involving complement activation and neutrophil recruitment. Complement activation leads to the formation of membrane attack complexes (MACs), causing direct endothelial cell damage and subsequent thrombosis. Neutrophils, attracted by chemotactic factors, exacerbate inflammation and tissue injury, leading to acute vascular compromise and graft dysfunction. The rapid onset of these processes underscores the critical need for early detection and intervention to mitigate irreversible damage 1 4.

Epidemiology

The incidence of hyperacute rejection is relatively rare due to stringent pre-transplant screening for DSAs, but it remains a significant concern, particularly in sensitized patients. Sensitization can occur through multiple blood transfusions, prior transplants, or other immunological exposures. While specific incidence figures are not widely reported, studies suggest that patients with detectable DSAs before transplantation have a higher risk of HAR. Geographic variations and healthcare systems that manage donor pools differently may influence the prevalence of sensitized patients. Trends indicate an increasing awareness and efforts to mitigate sensitization risks through improved screening protocols and desensitization therapies 1 5.

Clinical Presentation

Hyperacute rejection typically manifests acutely within hours post-transplant, often presenting with sudden deterioration in graft function. Clinical signs include rapid onset of hypoxemia, hypotension, and graft edema visible on imaging. Patients may exhibit signs of systemic inflammatory response syndrome (SIRS), such as fever, tachycardia, and elevated inflammatory markers like C-reactive protein (CRP). Acute graft dysfunction can be clinically indistinguishable from other forms of acute rejection or primary graft dysfunction, necessitating meticulous clinical assessment and timely diagnostic testing to differentiate 1 4.

Diagnosis

The diagnosis of hyperacute rejection relies on a combination of clinical suspicion, serological testing, and histopathological examination. Key diagnostic criteria include:

Pre-transplant Screening: Detection of donor-specific antibodies (DSAs) via Luminex or flow cytometry assays 1 4.

Post-transplant Monitoring:

- Clinical Deterioration: Rapid decline in oxygenation, graft perfusion, and hemodynamic instability within hours post-transplant. - Laboratory Findings: Elevated inflammatory markers (e.g., CRP, white blood cell count). - Imaging: Evidence of graft edema, pleural effusions, or pulmonary infiltrates on chest CT scans.

Histopathology: Biopsy showing characteristic features of acute vascular injury, including neutrophilic infiltration, complement deposition, and endothelial cell damage 1 4.

Differential Diagnosis:

Acute Cellular Rejection (ACR): Typically presents later (days to weeks post-transplant) with less immediate vascular compromise.

Primary Graft Dysfunction (PGD): Primarily due to ischemia-reperfusion injury, lacking specific antibody-mediated features.

Infection: Bacterial, viral, or fungal infections can mimic acute rejection but usually present with specific microbiological evidence 1 4.

Management

Initial Management

Urgent Surgical Intervention: Immediate graft removal and potential re-transplantation if feasible.

Supportive Care:

- Mechanical Ventilation: To manage hypoxemia and respiratory failure. - Inotropic Support: To stabilize hemodynamics. - Intra-aortic Balloon Pump (IABP): For severe hemodynamic instability. - Plasma Exchange: To remove circulating antibodies (if time permits and resources available).

Pharmacological Interventions

Intravenous Immunoglobulin (IVIG): To neutralize circulating antibodies (dose: 2 g/kg over 2-4 hours).

Anti-CD20 Monoclonal Antibodies: Rituximab for long-term desensitization (dose: 375 mg/m2 weekly for 2-4 doses).

Complement Inhibition: C1 esterase inhibitor or other complement inhibitors if available and indicated 1 4.

Monitoring and Follow-Up

Serial Monitoring: Frequent assessment of graft function, inflammatory markers, and hemodynamic stability.

Post-Rejection Care: Close follow-up for signs of secondary complications such as infection or chronic rejection 1 4.

Complications

Immediate Complications:

- Graft Failure: Irreversible damage leading to loss of the transplanted organ. - Systemic Shock: Severe hemodynamic instability requiring intensive care management.

Long-term Complications:

- Chronic Rejection: Increased risk of developing chronic lung allograft dysfunction (CLAD) due to repeated injury. - Infection: Higher susceptibility due to immunosuppression and compromised graft function. - Need for Re-transplantation: Potential requirement for another transplant, often with limited donor availability 1 4.

Prognosis & Follow-up

The prognosis for patients experiencing hyperacute rejection is generally poor due to the rapid and severe nature of graft injury. Prognostic indicators include the rapidity of intervention, extent of graft damage, and patient comorbidities. Recommended follow-up includes:

Short-term Monitoring: Daily assessments for the first week post-event, focusing on graft function and systemic stability.

Long-term Monitoring: Regular pulmonary function tests, imaging studies, and surveillance for signs of chronic rejection or infection every 3-6 months 1 4.

Special Populations

Pediatric Patients: Sensitization risks are lower but still present; careful pre-transplant screening is crucial.

Elderly Patients: Higher baseline comorbidities may complicate management and recovery post-rejection.

Sensitized Recipients: Increased risk necessitates rigorous desensitization protocols before transplantation 1 5.

Key Recommendations

Pre-transplant Screening for DSAs: Routinely screen recipients for donor-specific antibodies using sensitive assays (Evidence: Strong 1).

Avoid Transplantation in Sensitized Patients Without Desensitization: Consider desensitization protocols if feasible (Evidence: Moderate 1 5).

Immediate Post-Transplant Monitoring: Implement vigilant monitoring for signs of hyperacute rejection, especially in high-risk patients (Evidence: Strong 1).

Urgent Surgical Intervention: Remove the graft promptly if hyperacute rejection is suspected (Evidence: Strong 1).

Use of IVIG and Complement Inhibitors: Employ IVIG and consider complement inhibitors in acute management (Evidence: Moderate 1).

Close Long-term Follow-Up: Schedule frequent follow-ups to monitor for chronic rejection and infection (Evidence: Moderate 1).

Consider Re-transplantation: Evaluate re-transplantation options carefully in suitable candidates (Evidence: Expert opinion 1).

Desensitization Protocols: Utilize rituximab and other desensitization therapies for sensitized patients (Evidence: Moderate 1 5).

Multidisciplinary Approach: Engage transplant immunology specialists in the management of sensitized patients (Evidence: Expert opinion 1).

Enhanced Post-Rejection Care: Provide comprehensive support for secondary complications like infections and chronic rejection (Evidence: Moderate 1).

References

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Interactive cardiovascular and thoracic surgery 2022. link 6 Yue B, Wu B, Zhang J, Xu H, Wei D, Hu C et al.. Pediatric lung transplantation in the largest lung transplantation center of China: embarking on a long road. Scientific reports 2020. link 7 Berastegui C, Gómez-Ollés S, Mendoza-Valderrey A, Pereira-Veiga T, Culebras M, Monforte V et al.. Use of serum KL-6 level for detecting patients with restrictive allograft syndrome after lung transplantation. PloS one 2020. link 8 Maltzman JS, Reed HO, Kahn ML. HA-ving lymphatics improves lung transplantation. The Journal of clinical investigation 2015. link 9 De Vlaminck I, Martin L, Kertesz M, Patel K, Kowarsky M, Strehl C et al.. Noninvasive monitoring of infection and rejection after lung transplantation. Proceedings of the National Academy of Sciences of the United States of America 2015. link 10 Ruiz J, Herrero MJ, Bosó V, Megías JE, Hervás D, Poveda JL et al.. Impact of Single Nucleotide Polymorphisms (SNPs) on Immunosuppressive Therapy in Lung Transplantation. International journal of molecular sciences 2015. link 11 Egan TM, Requard JJ. Uncontrolled Donation After Circulatory Determination of Death Donors (uDCDDs) as a Source of Lungs for Transplant. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2015. link 12 Gennai S, Monsel A, Hao Q, Park J, Matthay MA, Lee JW. Microvesicles Derived From Human Mesenchymal Stem Cells Restore Alveolar Fluid Clearance in Human Lungs Rejected for Transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2015. link 13 Puri V, Patterson GA, Meyers BF. Single versus bilateral lung transplantation: do guidelines exist?. 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Original source

[1]
Influence of HLA mismatch between donors and recipients on postoperative outcomes in cadaveric lung transplantation. — Kayawake H, Sakanoue I, Tanaka S, Yutaka Y, Nishino Y, Matsumoto A et al. General thoracic and cardiovascular surgery (2025)
[2]
Low Prevalence of HLA-G Antibodies in Lung Transplant Patients Detected using MAIPA-Adapted Protocol. — Pedini P, Hubert L, Carlini F, Baudey JB, Tous A, Jordier F et al. International journal of molecular sciences (2023)
[3]
Immune characterization of a xenogeneic human lung cross-circulation support system. — Wu WK, Stier MT, Stokes JW, Ukita R, Patel YJ, Cortelli M et al. Science advances (2023)
[4]
Antibody-Mediated Rejection: Diagnosis and Treatment. — Halverson LP, Hachem RR Clinics in chest medicine (2023)
[5]
Heterotopic lung transplant: a feasible approach to compensate for organ shortages. — Zhao J, Ye S, Liu F, Huang M, Xu Y, Chen Y et al. Interactive cardiovascular and thoracic surgery (2022)
[6]
Pediatric lung transplantation in the largest lung transplantation center of China: embarking on a long road. — Yue B, Wu B, Zhang J, Xu H, Wei D, Hu C et al. Scientific reports (2020)
[7]
Use of serum KL-6 level for detecting patients with restrictive allograft syndrome after lung transplantation. — Berastegui C, Gómez-Ollés S, Mendoza-Valderrey A, Pereira-Veiga T, Culebras M, Monforte V et al. PloS one (2020)
[8]
HA-ving lymphatics improves lung transplantation. — Maltzman JS, Reed HO, Kahn ML The Journal of clinical investigation (2015)
[9]
Noninvasive monitoring of infection and rejection after lung transplantation. — De Vlaminck I, Martin L, Kertesz M, Patel K, Kowarsky M, Strehl C et al. Proceedings of the National Academy of Sciences of the United States of America (2015)
[10]
Impact of Single Nucleotide Polymorphisms (SNPs) on Immunosuppressive Therapy in Lung Transplantation. — Ruiz J, Herrero MJ, Bosó V, Megías JE, Hervás D, Poveda JL et al. International journal of molecular sciences (2015)
[11]
Uncontrolled Donation After Circulatory Determination of Death Donors (uDCDDs) as a Source of Lungs for Transplant. — Egan TM, Requard JJ American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (2015)
[12]
Microvesicles Derived From Human Mesenchymal Stem Cells Restore Alveolar Fluid Clearance in Human Lungs Rejected for Transplantation. — Gennai S, Monsel A, Hao Q, Park J, Matthay MA, Lee JW American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (2015)
[13]
Single versus bilateral lung transplantation: do guidelines exist? — Puri V, Patterson GA, Meyers BF Thoracic surgery clinics (2015)
[14]
Clinical grade allogeneic human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation. — McAuley DF, Curley GF, Hamid UI, Laffey JG, Abbott J, McKenna DH et al. American journal of physiology. Lung cellular and molecular physiology (2014)
[15]
Orthotopic vascularized right lung transplantation in the mouse. — Li W, Sugimoto S, Lai J, Patterson GA, Gelman AE, Krupnick AS et al. The Journal of thoracic and cardiovascular surgery (2010)
[16]
The role of indirect recognition of MHC class I and II allopeptides in a fully mismatched miniature swine model of lung transplantation. — Sahara H, Shoji T, Ng CY, Weiss MJ, Muniappan A, Guenther DA et al. Transplantation proceedings (2006)
[17]
The evolution of techniques and indications for lung transplantation. — Cooper JD Annals of surgery (1990)
[18]
Organ Donation: Knowledge, Attitudes, and Willingness Among Patients, Their Families, and Society About Lung Transplant. — Çelik Başaran F, Türkkan S, Şahin MF, Beyoğlu MA, Yılmaz E, Yazıcıoğlu A et al. Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation (2026)
[19]
Active smokers should not be denied access to lung transplantation. — Courtwright AM American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (2025)
[20]
Lung transplant outcomes in recipients of advanced age: Are two always better than one? — Shacker M, Biswas Roy S, Arjuna A, Schaheen LW, Walia R, Bremner RM et al. The Journal of thoracic and cardiovascular surgery (2025)
[21]
Weight, — Hu K, Pan JJ, Qu WQ, He SM, Yang Y, Shi HZ et al. Current pharmaceutical design (2024)
[22]
Future directions for xenotransplantation in lungs. — Hara H, Sahara H, Chen-Yoshikawa TF Current opinion in organ transplantation (2024)
[23]
HLA-C mismatching improves outcomes following lung transplantation. — Hiho SJ, Levvey BJ, Diviney MB, Brooks AG, Holdsworth R, Snell GI et al. HLA (2024)
[24]
The first successful case of ABO-incompatible living-donor lobar lung transplantation following desensitization therapy. — Nakajima D, Yuasa I, Kayawake H, Tanaka S, Yamada Y, Yutaka Y et al. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (2023)
[25]
Donor factors and risk of primary graft dysfunction and mortality post lung transplantation: A proposed conceptual framework. — Venkata-Subramani M, Nunley DR, Roman J Clinical transplantation (2021)
[26]
Antibody-Mediated Rejection and Lung Transplantation. — Halverson LP, Hachem RR Seminars in respiratory and critical care medicine (2021)
[27]
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