Current Challenges and Unmet Needs in Solid Organ Transplantation

Vincenti, Flavio, MD
Professor of Clinical Medicine
Department of Medicine and Kidney Transplant Service
University of California, San Francisco
San Francisco, CA Also by this Author 

The major challenges in the field of solid organ transplantation are the organ shortage and achieving tolerance. Dr. Flavio Vincenti, Professor, Division of Nephrology, University of California, San Francisco, does not foresee any near-term resolution to the organ shortage but believes the field is making gains in achieving operational rather than immunologic tolerance. Other unmet needs facing the transplant community include treatment of antibody mediated rejection, ischemia-reperfusion injury and immune monitoring.  He reviews the most significant challenges facing the transplant field and discusses developments underway to improve patient monitoring and therapy.

Striking the Right Balance - Minimizing Rejection Risk, While Reducing Toxicity

The twin conditions of antibody sensitization and antibody-mediated rejection remain challenging and frustrating to treat. “The current drugs we use to de-sensitize patients or reverse antibody-mediated rejection, especially chronic antibody mediated rejection, are not totally satisfactory,” says Dr. Vincenti. “We need to develop therapies that are more effective and less toxic than those available at present.” Current regimens used for antibody desensitization and reversal of antibody-mediated rejection include plasmapheresis, immunoglobulin (IVIG), and rituximab, an anti-chimeric, anti-CD20 antibody.  Recently the proteasome inhibitor Velcade has been reported to reverse refractory antibody rejection.  Eculuzimab, a humanized anti-C5 monoclonal antibody appears to protect the renal allograft despite the presence of donor-specific antibodies(DSA).  None of these agents have been tested in rigorous studies.

To reduce toxicity there is also a need to develop robust calcineurin inhibitor (CNI)-free regimens, says Dr. Vincenti. “I think there is general agreement that CNI’s still produce a lot of toxicities and we want to develop regimens that can eliminate those. At the same time the novel regimens need to be effective both against naive and memory cells, so that’s another consideration.”   An advantage of the CNIs is their inhibition of memory T-cells.

Another challenge in improving outcomes is to prevent and minimize ischemia reperfusion. “This is an important issue,” notes Dr. Vincenti, “because an increasing proportion of kidneys are obtained from Expanded Criteria Donors (ECD) and donors after cardiac death (DCD). These kidneys have a higher risk of graft loss when compared to kidneys transplanted from standard criteria donors. We want to minimize the higher rate of delayed graft function in these kidneys and reduce morbidity which may occur during the period of delayed graft function.”

Immunosuppression – Is Minimization The Right Strategy?

In considering immunosuppression, Dr Vincenti raises the question whether minimization is the optimal approach: “Originally the concept that minimizing immunosuppression after an initial, intense regimen provide the best of both worlds, first we reduce acute rejection and then we lower toxicities as the risk of rejection recedes. However several studies have suggested that most late graft loss occurs because of immunologic reasons, frequently antibody-mediated. So the approach of minimizing immunosuppression necessary with the current drugs to reduce toxicities may actually be undermining the long-term survival of the graft. In trying to minimize toxicities we’re allowing more grafts to be rejected by immune mechanisms.”   So we need to develop effective agents that lack long-term toxicities so that we can maintain optimum immunosuppression over the long-term.

More Sensitive Monitoring For More Precise Therapy

A more precise way of monitoring patient response to immunosuppression drugs may help determine the optimal level of immunosuppression and assist in reducing rejection risk.  Dr Vincenti notes that the emergence of donor-specific antibodies as a marker for future graft dysfunction is an important advance. The next step is to identify appropriate biomarkers. “The CNI level, for example, may be relevant,” he says, “but knowing how CNIs affect, in their intended target, the activation of Nuclear Factor of Activated T-cells (NFAT) may be more significant. Monitoring the activity on NFAT especially to avoid over-immunosuppression and cancer risk, as some studies have suggested, may improve the long-term safety of the CNIs.”

Another helpful advance in monitoring, especially in relation to drug minimization, would be the ability to identify the emergence of alloreactivity before the graft suffers any damage.  Cellular assays to identify T cell alloreactivity are promising but require validation.  “Tracking a combination of urinary cytokines through assays for their gene expression or analyzing cytokines expressed in blood lymphocytes could be potentially helpful,” notes Dr. Vincenti, “The work of Dr. Suthanthiran, in particular, has shown that a combination of urinary cytokine mRNAs, can predict rejection days before it occurs clinically.”  Applying this methodology could increase the safety of drug minimization and withdrawal regimens.  When the antigen-specific assays will be more specific and useful remains to be determined.

Toward Individualized Therapy

A therapeutic development much discussed by the transplant community is a move to more individualized immunosuppression. “The way we currently individualize immunosuppression is still far behind how some cancer therapies are increasingly being used (for example Herceptin for HER+ breast cancer),” notes Dr. Vincenti. “In transplantation we individualize therapy by clinical history and simple lab tests. We consider the age of the patient, the ethnicity of the patient, the type of donor the patient is getting, the human leukocyte antigens (HLA) match, the level of antibodies and whether there are donor-specific antibodies and we select and individualize immunosuppression on that basis. We then choose depleting vs. non-depleting biologics and the type of maintenance immunosuppression. But we still have not achieved individualization based either on genetic markers or molecular biomarkers.

The biomarkers to enable such an individualized approach have not yet been identified or validated in our field.

Organ Shortage – The Long-Term Hope

Looking ahead, Dr Vincenti believes there is cause for some optimism in relation to organ supply. He sees the emergence of paired donor exchange networks as very important, since they allow transplantation in individuals who would otherwise have difficulty finding suitable matches long-term. He is also enthusiastic about the promising field of regenerative medicine. “The use of decellularized xenografts, that are re-populated with the recipient induced pluripotent stem cells, offers the hope that we can both address the organ shortage and that we can do so with organs that are fully tolerated by the recipient, because we’re using their own cells. The near-term is still challenging but the future holds great promise.”

 

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Released on Thursday, April 19, 2012