Bortezemib and highly sensitized patients

Another fascinating study at the ATC 2010 talked about the role of bortezomib in decreasing HLA

Bortezomib is a proteosomal inhibitor shown in small studies to have a pronounced effect on decreasing HLA-antibodies post transplantation.  Previously it has been studied in patients with humoral rejection and coupled with other treatments including plasmapheresis, steroids, and rituximab.  The mechanism of antibody reduction is depletion of long lived plasma cells which are very difficult to eradicate by conventional therapy.  The abstracts presented in the ATC revealed Bortezomib to have some effect on both anti HLA antibodies and plasma cells pre-transplant; as a method of desensitization.  Unfortunately neither abstracts revealed hard endpoints such as percentage of patients transplanted or comparison to a control group.  In addition both studies had relatively small numbers and were single center studies.  The most common side effect seems to be peripheral neuropathy however most cases were mild and at least partially reversible.  

Conclusions/ Comments:  Expert opinion seems to be that the optimal use and effect of bortezomib is currently unknown.  It does have some effect on HLA antibodies but will not magically decrease PRA to 0%.  It may also work better with concurrent plasmapheresis, as stimulated plasma cells are probably more susceptible to proteosomal inhibitor induced apoptosis.  Large multicenter studies need to be performed in sensitized patients with bortezomib.  Some type of control group needs to be employed and hard endpoints (transplantation) will be needed.  The use of proteosomal inhibitors at this time should remain in a properly conducted study.

by Vinay Nair

H1N1 and Transplantation

A study at ATC 2010 showed the following

Novel H1N1 caused the 2009-10 pandemic, however the effect on Single Organ Transplants( SOT) is not well known.  The outcomes of H1N1 were reported in a large multicenter study by Kumar et al. from 4/2009 to 11/2009.  115 medically attended H1N1 infections were reported from US and Canada.  61% of patients described were lymphopenic and 65.2% were hospitalized.  Fever and recent ATG use was predictive of requiring hospitalization.  Complications included pneumonia (25.2%), ICU stay and 1 death.  Antiviral therapy was used in 91% of cases predominantly being oseltamivir monotherapy. Patients started on antiviral therapy before 48hrs of symptom onset were less likely to require ICU stay (0% vs. 22.4%).  

Conclusions/ comments:  H1N1 may cause significant morbidity in SOT patients.  If suspected, antiviral treatment should be started immediately and prior to confirmation of H1N1.  Unfortunately the effect of the H1N1 vaccine is not well characterized since the majority of reported cases occurred before vaccine availability.  The optimum dose, course and antiviral therapy remains unknown.  

Reported by Vinay Nair

Complement activation and Antibody mediated rejection

Recently at the ATC 2010, there was a presentation about Terminal Complement Inhibition Decreases Early Acute Humoral Rejection in Sensitized Renal Transplant Recipients.

Transplanting highly sensitized patients remains a significant problem in kidney transplantation.  Methods of decreasing alloantibody include plasma exchange, IVIG and Rituximab, however the effect on HLA-antibodies are limited.  Eculizumab inhibits the complement cascade at C5 and therefore may be able to block the effector pathway of antibody mediated rejection.  A study presented at ATC 2010 had 17 incompatible (B flow cytometry crossmatch median channel shift > 340) highly sensitized recipients of living donor allografts received eculizumab post transplant and were compared to 51 historic controls treated with plasmapheresis and IVIG.  Patients received weekly doses of Eculizumab post transplant until they had a spontaneous decrease in donor specific antibody (B flow crossmatch <200 channel shift).   1 of the 16 patients treated with Eculizumab experienced antibody mediated rejection (6.25%) compared to 40% of the historic controls.  However, in the relatively short f/u period (1-17 months) four patients developed signs of chronic injury including 2 with transplant glomerulopathy.  

Conclusions/ comments:  Terminal complement inhibition significantly reduces humoral rejection.  However, the optimum dosing is unknown and long term graft survival may be jeopardized by chronic antibody mediated damage.  Long term f/u will be needed in these patients and a trial evaluating it in sensitized waitlisted patients would also be useful.

Reported by Vinay Nair

ATC Conference highlights 2010

The Renal and Urology News website has nicely summarized some good work from this ATC 2010
Check it out!

http://www.renalandurologynews.com/conference-highlights/section/809/

American Transplant Congress from ECU

Check out the live blogging from ATC 2010

http://blog.ecu.edu/sites/nephrologyondemand/?p=3634