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Antibody-mediated Rejection - an Ounce of Prevention is Worth a Pound of Cure
07:40: The 2 Key Questions for Desensitization: Who and How?
Denis Glotz, Hôpital Saint Louis, Paris, France
There are 2 major issues when considering desensitization protocols: choice of the desensitizing regimen and selection of the patients.
The most common desensitization protocols are high-dose intravenous immunoglobulin (IVIg), a combination of plasmapheresis and low-dose IVIg (PP/IVIg), or a combination of Rituxan (rituximab) and high-dose IVIg. Newer drugs such as bortezomib are under investigation.
- The high-dose IVIg protocol consists of multiple administrations of 2 g/kg body weight of IVIg over 2 consecutive days, repeated every 3 or 4 weeks. Three or four courses yield a success rate of around 80%, allowing access to transplant, however with a significant occurrence of antibody-mediated rejection (ABMR). This protocol is best adapted to wait-list patients, as the reduction in anti-HLA antibodies is sustained over a number of weeks.
- The association of repeated plasmapheresis sessions followed by low-dose IVIg (0.1 g/kg body weight) is also used with excellent results, but is limited to patients with a potential living donor, as in the absence of transplantation, cessation of the PP/IVIg leads to a rebound in the anti-HLA antibodies in a matter of days. The PP/IVIg protocol success rate seems higher than the high-dose IVIg protocol and might be successful in patients with high titers of anti-HLA antibodies.
- A combination of high-dose IVIg and Rituxan can be used in wait-listed as well as patients with a potential living donor. The rate of success seems comparable to high-dose IVIg, although, interestingly, Rituxan alone does not seem efficacious.
- A number of new drugs aimed at B cells, such as bortezomib, are used in pilot trials, and it may well be that, as for Rituxan, their efficacy might only exist in combination with PP or IVIg.
Patients might be eligible for a desensitization protocol in 2 very different situations:
- in case of a positive crossmatch with a potential living donor;
- when it seems that their access to transplantation through the deceased donor waiting list is virtually impossible.
For wait-listed patients, access to transplant is nowadays best assessed by calculating the virtual panel reactive antibody (PRA). It is now clear that the mere presence of an anti-donor antibody does not automatically preclude transplantation. Thus, an arbitrary level of antibody deemed unacceptable, assessed for example by median fluorescence intensity (MFI) value in a Luminex assay, has to be defined. This level must take into account the clinical events associated with the antibody presence:
- if too high, it entails the risk of a positive crossmatch on the one hand, and the risk of (ABMR) with its poorer prognosis on the other hand once transplant is performed;
- if too low, it severely restricts the access to transplant, even with donors with whom a negative crossmatch would have been found. Unfortunately, as of now, this value is defined by each center, introducing major differences in the transplantation access rates of the patients.
We will present results showing that clinical relevance of potential donor-specific antibodies (DSA) can be assessed through quantification of MFI, thus allowing a clear estimation of the risks.
Denis Glotz is Chief of the Department of Nephrology and Renal Transplantation, Saint-Louis Hospital in Paris, France. After receiving his M.D. in 1984, he was granted a research fellowship at the Medical Biology Institute, then at University of California San Diego, La Jolla, California, USA. He later specialised in nephrology and became Professor of Nephrology at Université Paris VI and subsequently assumed his current role as Professor of Nephrology at Université Paris VII. Dr. Glotz has published over 120 articles in peer-reviewed medical journals including the American Journal of Transplantation, Transplantation and the Journal of Immunology. Dr Glotz is Head of the INSERM Transplant and Immunology group and is a member of a number of national and international societies including the American Society of Nephrology, the European Dialysis and Transplantation Association and the French Society of Immunology. He is a Councillor for the French Society of Transplantation.