Paricalcitol and CNI injury?

The most recent issue of Kidney International talks about an animal model that showed that paricalcitol attenuated cyclosporine induced kidney injury. This is interesting to note.
First, why do we get CNI related toxicity. CNI exposure leads to increased inflammatory response in addition to its beneficial effects and as a result increased TGF-B expression and fibrosis and nephropathy.
Also the renal vasomotor impairment leads to RAAS activation and oxidative stress and nephropathy.
The trial shown in the issue is an excellent start of a set of trials that might follow in animal models and hopefully this will one day make it to clinical world.

Reference
http://www.ncbi.nlm.nih.gov/pubmed/20237458
Image source
http://dailymed.nlm.nih.gov/dailymed/archives/image.cfm?archiveid=1741&type=img&name=zemplar-injection-structure.jpg

Role Playing in Transplant Teaching

Today at our transplant conference we did something fun.
A month ago, each fellow in training was assigned a transplant drug( MMF, imuran, cyclosporine, prograf, sirolimus, steroids and belatecpt).
In the one hour, each fellow had to play a role of the drug and stay in character. Initial rounds were introduction rounds and then followed debate rounds where major debates between Steroids vs no steroids, CNI vs belatecept, Cyclo vs prograf, sirolimus vs CNI and Imuran vs MMF happened.
It was tons of fun and fellows enjoyed it. Role playing of drugs taught them the strengths, mechanism of actions and their weaknesses.

Hoping to use tools like this to teach nephrology as we more forward; and make it lot of fun!!

The SPLEEN in ANTIBODY MEDIATED REJECTION

The recent AJT May 2010 issue has a nice histopathology and immunotyping of the spleen in a case of renal allograft antibody mediated rejection. Splenectomy is done in rare cases to treat ABMR.  What this case illustrates is what they found in the spleen that might have been causing the damage.
The spleen biopsy was abundant with clusters of CD 138+ plasma cells.  This can explain the rapid response that we see once the spleen is removed.  They postulate that the spleen might be a reservoir for converting CD 20+ B cells to antibody secreting CD138+ plasma cells at the time of stress.
The HLA antibody is specific. Is the spleen really producing that specific antibody is unclear.
But this staining showed something novel about the plasma cells.
It has been noted that the kidney biopsy that is rich in plasma cells and ABMR has a worse prognosis.
It might be coming in bursts and splenectomy might help. Anti Plasma cells agents like Bortezomib might also be possible options in a case like this. I think it might worked as well as the splenectomy.

Regardless a nice read!

Image source: http://www.lifespan.org/tmh/services/surgery/mininvasive/images/spleenlarge.jpg

Kidney Autotransplantation

Autotransplantation is something not that talked about. It is mainly used to recover or stabalize renal impairment due to renovascular or ureteric disorders to avoid nephrectomies. Perhaps due to major advances in interventional nephrology and radiology and immunosuppresive agents, this mode of treatment has fallen out of favor. Renal autotransplantation was first performed successfully in 1963 on a patient with severe
ureteral damage.  Bodie et al. reported the longest series of 23 patients who underwent renal
autotransplantation for extensive ureteral injuries, and were followed up for up to 14 years.  

What are some of the reasons that leads to autotransplantation of the kidney? at least historically

1. Iatrogenic ureter lesion 
2. Gross hematuria due to kidney vascular abnormalities
3. Renal artery stenosis
4. Long ureteric stenosis
5. Ureteral strictures
6. TCC of upper GU organs
7. RP Fibrosis


Some good references
http://www.ncbi.nlm.nih.gov/pubmed/15134964
http://www.ncbi.nlm.nih.gov/pubmed/13960761
http://www.ncbi.nlm.nih.gov/pubmed/12556645
http://www.ncbi.nlm.nih.gov/pubmed/3534311

Risk of PTLD post transplant?

Why and when is someone with a kidney transplant prone to get PTLD?
PTLD is a lymphoproliferative disorder that occurs because of impaired T-cell immunity after solid-organ or allogeneic stem cell transplant. 90% of the time these are EBV associated.


What are the risk factors for development of PTLD?
1. EBV-negative serostatus at time of transplant
2. Mismatching EBV-negative recipients with EBV positive donors
3. Intestinal Transplants have the highest incidence, then heart-lung, lung, heart, liver and then kidney
4. Children
5. Simultaneous CMV infection within 1 year of transplant
6. Certain HLA subtypes.

http://www.ncbi.nlm.nih.gov/pubmed/12621474
http://www.ncbi.nlm.nih.gov/pubmed/14986084

Size and the Kidney from NephrologyWorld

http://nephrologyworld.blogspot.com/2010/05/size-does-matter-for-renal-transplant.html

Cellcept vs Myfortic? any difference!!

We use cellcept often and some centers prefer Myfortic.  A common reason to switch usually is GI side effects more noted in cellcept.  
Is there any difference? otherwise in outcomes of both patients.A retrospective analysis was done of over 45,000 patients from the UNOS database.  They measured graft failure, death with graft, acute rejection, NODAT, and renal function. 
To answer this question, a nice paper in Transplantation talks about this.  A large retrospective trial of 48,000 patients using the UNOS database was done. End points were graft failure, death with functioning graft, NODAT, acute rejection, and renal function.  around 10% were on myfortic and remaining on cellcept.
Propensity score-adjusted regression analysis showed that patients who received myfortic were at increased risk of biopsy proven acute rejection. The adjusted biopsy proven acute rejection rate difference at 3 years post transplant was less than 2% statistically significant due to large number of patients.  There was no difference in graft survival, NODAT, renal function and other measures. 


Interesting to note this difference. Overall, in terms of graft survival , this RETROSPECTIVE LARGE study showed no major difference. The authors think that due to the large numbers, this difference was less meaningful. 


http://www.ncbi.nlm.nih.gov/pubmed/20445488

EVEROLIMUS FOR KIDNEY TRANSPLANTS

Everolimus, a sister drug of sirolimus; MTOR inhibitor is now FDA approved for use in Transplant patients.
It is commonly used in renal cell cancer patients and in Europe in transplants as well. A phase 3 trial showed that this medication prevented acute rejection and preserved kidney function and it allowed reduction of CNIs. It was promoted as a CNI lowering agent

Using Mtor inhibitors is a topic of discussion at different centers all the time. They might not be that great of immunosuppresive agents as we thought they were initially, they are certainly great antiproliferative agents.
The risk of cancer is likely going to decrease if one of these are used. The use has to be monitored with the baseline proteinuria and renal function.

A nice review is listed below
http://www.ncbi.nlm.nih.gov/pubmed/20155724
http://www.ncbi.nlm.nih.gov/pubmed/20420793

The effect of Mycophenolic Acid (MPA) on donor specific Antibody (DSA) strength

The effect of Mycophenolic Acid (MPA) on donor specific Antibody (DSA) strength

Rituximab for recurrent idiopathic Membranous GN

A recent article in CJASN 2010 talks about the role of anti CD20 agent in treatment of recurrent membranous GN. The article is a retrospective review and more of a case series of 4 patients that responded to rituximab for recurrent idiopathic GN.
Its a small group of patients as most of them that they had responded well to just anti proteinuric agents.
This is not unusual to see a small number of patients with recurrence of such diseases as some of the drugs we are using for rejection are also controlling the autoimmune disease.  But then why do some patients get it and some don't get recurrence. Perhaps it might have to do with compliance, the nature of their membranous disease or their age perhaps. When they compared the patients with recurrent membranous to ones without recurrence, nothing was significant( nor progression to ESRD, age, BUN, GFR, TP, proteinuria amount) except for albumin.
Interestingly, 3/4 patients with recurrent membranous that got rituxan also were on steroid sparing protocol.
Also, interesting to note, 10/15 that were recurrent were LRRTx and only 60% of them received induction treatment. I think even though those didn't meet significance,( perhaps due to small numbers), matter a lot.
Related relatives, steroid sparing and no induction could be possible risk factors for recurrence in any autoimmune disease, perhaps!
Something to ponder on

CD4 T cell lymphopenia is bad!

A recent article in JASN 2010 May edition talks about the prolonged CD4 T cell loss seen with thymoglobulin.
They studied the mortality and morbidity associated with this prolonged effect.  They evaluated >300 patients and found that if after 1 year the CD4 T cell lymphopenia was present, it was an independent risk factor for death in these patients. They suggest evaluating pre transplant thymic function and identifying these high risk patients.
If you now look at the the KDIGO transplant guidelines, that came out late last year, anti CD20 are the standard and first line choice to be used for induction and not thymoglobulin. Perhaps centers who use thymo for all their patients should re consider this. It should be from a case by case base and not just a protocol of a center.
As we are seeing more and more long survivors of transplant, things like infection and cancer have to be kept in mind and avoid the imbalance to shift.

Nice article

Drug coverage for transplant from Nephrologyworld blog

http://nephrologyworld.blogspot.com/2010/05/blog-post.html

CMV in organ transplantation

CMV is a hard infection to treat in solid organ transplants. A nice consensus statement came out recently in Transplantation April 2010 issue going over medications. ( similar post on nephronpower for question discussion)
Based on these recs, 
1.IV ganciclovir is " gold standard" for CMV disease
2. The VICTOR trial compared valcyte to ganciclovir and was equally effective ( 900mg PO BID)
3. Do genotype resistance testing for CMV and if it is UL97 major mutation, likely will have ganciclovir resistance. If its a minor mutation or a pol mutation can still use ganciclovir but high doses. A major mutation requires switching to foscarnet.
4. If foscarnet is causing renal damage and or not working, other drugs have been tried.
5. Cidofovir has been tried in adenovirus, bk virus and CMV as well. There is little information on efficacy of cidofivir in single organ transplants but its use in stem cell transplants is also with mixed results.
6. Immunoglobulins containing CMV antibodies or cytogam has been used with good results in Stem cell transplants.  IVIG might have similar effects but no cases that I could find have been documented use of it. This should more likely be reserved for organ damage from CMV( retinitis, pulmonary damage, GI)
7. Leflunomide was reported to clear CMV in one case of Stem cell and one of a renal transplant patient.
8. Other drugs that have shown some anti CMV properties are sirolimus, artesunate and maribavir( experimental)


So the question we have up here, really there is no right answer as all of those drugs have shown some effect on CMV but IVIG is the least evidence about. I am sure its being used for CMV viremia or disease as the concept is the same as cytogam.


Check out the review article with good statements on how to manage difficult CMV viremia and disease patients.

New-Onset Diabetes Linked to Post-Transplant Hypomagnesemia - Renal and Urology News

New-Onset Diabetes Linked to Post-Transplant Hypomagnesemia - Renal and Urology News

New News on Belatacept

Currently calcineurin inhibitors are the gold standard for immunosuppression of solid organ transplant recipients.  Unfortunately long term CNI use is associated with both patient morbidity (HTN, hyperuricemia, hyperlipidemia, diabetes) and renal toxicity. 

Belatacept is a selective co-stimulation blocker (given IV), which binds surface costimulatory ligands (CD80 and CD86) of antigen-presenting cells.  After antigen recognition by the T cell receptor (signal 1), the interaction of CD80 and CD86 with the surface costimulatory receptor CD28 of T cells (signal 2) is required for full activation of T cells. Blockade of signal 2 inhibits T-cell activation, promoting anergy and apoptosis. 

The purpose of this study was to switch patients from maintenance CNI use to belatacept in order to reduce toxicity without compromising immunosuppression. 

Rostaing et al. randomized 173 patients (6-36 months post transplant) to remain on CNI based therapy or switch to belatacept.  Primary endpoint was change in EGFR at 12 months.  Secondary outcomes included rejection and safety outcomes.  At month 12 the belatacept group had an increase in GFR of 7 ml/min while the CNI group had an increase in GFR of 2.1 ml/min.  Patient and graft survival was 100% and 99% in the belatacept and CNI group respectively.  7% of the belatacept group had ACR vs. none in the CNI group (including grade IIa and IIb).  There were 3 cases of BK viremia in the belatacept group but none in the CNI group.  There were more fungal skin infections in the belatacept group.  PTLD was not seen. 

Conclusions/ Comments:  Authors concluded that switching to a belatacept based regimen was safe, associated with low risk of rejection and resulted in improved renal function.  However, there are several concerns with this study.  First, even the CNI group had an increase in GFR which does not occur in clinical practice.  Second, patients greater than 1 yr post transplant had a 7% rejection rate which is significant.  In fact, these rejections were not mild (several vascular rejections, all cell mediated).  BK viremia was also increased in the belatacept group and studies have proven that it has a poor prognosis.  Finally other studies with belatacept have been associated with PTLD and this is still a concern.  Longer term f/u is needed to compare graft survival and safety profile of belatacept compared to CNI’s, however belatacept therapy may be beneficial in a subset of patients.  Of note, several experts believe too high of a dose of belatacept may lead to both overimmunosuppression and rejection by blocking negative costimulatory pathways.  Proper dosing may be key in reducing rates of rejection and opportunistic infections.

By Vinay Nair

Paired Donor Exchange Programs

At the ATC 2010, Speakers from the Alliance for Paired Donation, and other paired exchange programs reported their experience with paired exchange for ABO incompatible and HLA incompatible donor recipient pairs.  They spoke about shipping living donor kidneys; currently there does not seem to be a increase risk for DGF or graft dysfunction up to a CIT of 15 hours.  However they only reported short term results.  All groups agree that a national level paired exchange program needs to be created and apparently UNOS is attempting to do so.  Finding a way to organize such a project and work out financial agreements and oversight will be challenging.

by
Vinay Nair

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