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Chronic rejection--definition and correlates
1Department of Surgery, University of Minnesota, Minneapolis.
Insights
Chronic rejection remains a significant cause of graft loss despite advances in immunosuppression. Understanding risk factors like prior acute rejection and immunoregulatory factors is key to improving long-term transplant outcomes.
Area of Science:
- Transplantation immunology
- Graft rejection mechanisms
Background:
- Acute rejection incidence reduced by immunosuppression, but chronic rejection remains a challenge.
- Diagnosis of chronic rejection is difficult, requiring both clinical and biopsy data.
- Focus is shifting towards prevention and management of chronic rejection.
Purpose of the Study:
- To define chronic rejection by incorporating both clinical course and biopsy findings.
- To identify risk factors for chronic rejection in kidney and extrarenal transplant recipients.
- To explore the role of immunoregulatory factors in chronic rejection pathogenesis.
Main Methods:
- Review of clinical data and laboratory studies on transplant rejection.
- Identification of risk factors including previous acute rejection, immunosuppression levels, infection, and noncompliance.
- Analysis of immunoregulatory factors such as anti-HLA and anti-idiotypic antibodies.
Main Results:
- Previous acute rejection is a major risk factor for kidney transplant chronic rejection.
- CMV and HLA mismatch implicated in extrarenal transplant chronic rejection.
- Anti-HLA antibodies correlate with increased graft loss; anti-idiotypic antibodies and hyporesponsiveness correlate with better outcomes.
Conclusions:
- Chronic rejection may result from inadequately treated acute rejection, insufficient immunosuppression, infection, noncompliance, or an imbalance of immunoregulatory factors.
- Multiple hypotheses regarding chronic rejection pathogenesis require further clinical and laboratory investigation.
- Further studies are needed to elucidate the complex interplay of factors contributing to chronic rejection and to develop effective interventions.
Abstract:
With current immunosuppressive protocols, the incidence of graft loss to acute rejection has been markedly reduced; however, there has been no change in graft loss to chronic rejection. Recently, attention has been focused on the prevention and management of chronic rejection. Because neither the clinical course nor the biopsy is definitive for the diagnosis of chronic rejection, we believe both should be included in the definition. For kidney transplant recipients, the major risk factor for development of chronic rejection appears to be a previous acute rejection episode. Other risk factors include low-dose maintenance immunosuppression and previous infection. For extrarenal transplant recipients, CMV and HLA mismatch have been implicated. Noncompliance probably plays a role for all patients. Laboratory studies have suggested that the development of chronic rejection (or lack thereof) may be due to an interplay of immunoregulatory factors. Patients with anti-HLA antibodies have an increased incidence of late graft loss whereas those with antiidiotypic antibodies or with donor-specific hyporesponsiveness (in MLC) have improved outcome and less chronic rejection. These findings have led to five testable hypotheses as to the pathogenesis of chronic rejection: 1) chronic rejection is inadequately treated acute rejection; 2) chronic rejection can be prevented by maintaining adequate long-term immunosuppression; 3) preventing or adequately treating infection will prevent chronic rejection; 4) the balance of immunoregulatory factors determines chronic rejection; 5) chronic rejection is the result of noncompliance. Each may play a role in some patients. Clinical and laboratory studies of risk factors and of the influence of intervention are necessary.