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/

Are Generics trustworthy?

This month on AJT report, there was a discussion that might be very important.. can generics be trusted?
Some physicians have concerns about the efficacy and safety of many generic immunosuppresive agents for our transplant patients.  The small article in AJT nicely points out few important points: we need more data to show to FDA that generic drugs might not be working as well or are working equally well.  Name brand drugs go through much more of a validation process.  Bio equivalence might vary as high as 40% based on this summary.  
Its an important topic that needs further prospective trials in this field.

American Transplant Congress from ECU

Check out the live blogging from ATC 2010

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

Kidney Biopsy in Heart Transplant Candidates?

A recent study in Transplantation highlights this issue in detail. Lot of times we have patients with severe CHF and are also going into acute renal failure due to pre renal or what we are now calling cardio renal syndrome sort of in the same fashion as hepatorenal syndrome? When do we think its just ATN or when is it intrinsic renal disease? When can we say this patient needs just a heart transplant and when a combined heart and kidney?

In this study, thirty heart transplant candidates with an GFR < 40 mL/min or proteinuria greater than 500 mg/day or a history of amyloidosis underwent kidney biopsies between June 2001 and March 2009. The renal pathologic diagnosis as well as the percent tubular atrophy and interstitial fibrosis on renal biopsy were assessed. On the basis of the biopsy results, nine patients were listed for only heart transplantation and eight patients were listed for heart and kidney.
Based on this small study, the conclusion was that renal biopsy provides useful diagnostic information to differentiate intrinsic renal disease from renal hypoperfusion and helps guide the decision for OHT alone versus combined HKT.

I think that it makes sense but the sample size here is too small to make a general statement. In general, clinically if the patient is not behaving like CHF induced hypoperfusion, most of us will get a kidney biopsy to make sure no other cause is lingering around.

Dual Liver and Kidney Transplantations

Tips from the NKF 2010 sessions


1. When to do both and when to do just Liver? It’s hard to figure this out as most of the kidney damage in liver associated kidney injury is ischemia and we don’t have good markers
2. A good strategy suggested was using biopsy as a guide and using the Interstitial fibrosis, tubular injury as a tool for seeing if they need a SLK or just a liver transplant.
3. When this strategy was used in some centers, and crt compared after going ahead with a respective transplants ( SLK or just liver), crt were 1.2 at 6 months in both groups.
4. Most common biopsy finding: ischemic ATN, followed by other primary GNs, (MPGN, IgA, FSGS, TMA) and vascular disease
5. If the patient has ESLD and is on dialysis < 6 weeks, perhaps just a liver is fine but otherwise might need a SLK. But with the biopsy method, we might achieve more accuracy

HIV and the Kidney Transplant

What I learned at the NKF 2010 , some few points.


1. A large NIH sponsored study basically showed that the outcomes of large number of patients when compared to non hiv patients transplanted was no different.
2. The 3 year follow up showed no major difference in graft survival
3. HIV disease didn’t progress either, perhaps because they didn’t get induction therapy or they were carefully selected patients or there is data that almost all immunosuppresive drugs we use has anti HIV viral activity from cellcept to CNI to sirolimus
4. The major problems people run into these transplants are drug toxicities as anti retrovirals have significant effect on CNI levels and high doses of CNI and increased intervals are needed.
5. There is usually more rejection in these patients,perhaps because of point number 5, but also perhaps because they don’t get much induction
6. Some centers are using induction with thymo, but their acute bacterial infection rates are high. Ideally, a anti CD20 induction is a good choice.


A nice website to look at is: hivtransplant.com