Advagraf Study

There has been talk about using prograf once a day for quite sometime now.  When it is used once a day its a tacrolimus prolonged use and its called Advagraf.  A recent  multicenter, 1:1-randomized, parallel-group, noninferiority study compared the efficacy of twice a day tacrolimus to advagraf.; combined with steroids and low-dose mycophenolate mofetil without antibody induction, in 667 de novo kidney transplant recipients. 
Per paper:


Biopsy-proven acute rejection rate at 24 weeks  was 15.8% for Tacrolimus BID versus 20.4% for Tacrolimus QD (p = 0.182; treatment ).
Kaplan-Meier 12-month patient and graft survival rates were 97.5% and 92.8% for Tacrolimus BID and 96.9% and 91.5% for QD. 
Both treatment groups showed equally well-maintained renal function at 12 months  by GFR
Overall, it was not inferior to twice a day dosing.


The original Ref is at:
http://www.ncbi.nlm.nih.gov/pubmed/20840480

FDA approves Belatacept (NULOJIX) for use in kidney transplantation.

It’s been a long time since the FDA approved a new drug for transplantation which makes this news very exciting.  On June 16^th Bristol-Myers Squibb announced that the FDA approved the use of NULOJIX (Belatacept) for use in kidney transplantation as an induction and maintenance agent in combination with mycophenolate mofetil and corticosteroids.  The FDA reviewed the Benefit and Benefit EXT trials prior to coming to their conclusion. 

Belatacept is a selective T-cell co-stimulation blocker that is administered IV which offers comparable results to cyclosporine.  Though the acute rejection rate seems to be slightly higher with Belatacept than cyclosporine, trials reveal a higher GFR in the Belatacept arms at 3 years of follow up.  The obvious hope is that the use of Belatacept will avoid calcineurin inhibitor nephrotoxicity in kidney transplant recipients improving long term allograft outcome.  The major concern with Belatacept is an increased risk for PTLD seen in many of the trials.  For this reason it is contraindicated in EBV seronegative patients or patients with unknown EBV serostatus.  To address the concern of PTLD Bristol-Myers Squibb established the ENLiST Registry.  The registries purpose is to determine the incidence of PTLD, CNS PTLD, and PML in US adult EBV seropositive kidney transplant recipients treated with Belatacept.

Belatacept is administered IV over 30 minutes and the recommended dosing is 10 mg/kg on the day of transplantation then on day 5, then at the end of weeks 2, 4, 8, and 12. After week 16 it is recommended that the maintenance dose be 5 mg/kg every 4 weeks.

Read the full press release by BMS: http://www.bms.com/news/press_releases/pages/default.aspx?RSSLink=http://www.businesswire.com/news/bms/20110616006683/en&t=634438496608678094

by Dr. Vinay Nair

Alemtuzumab for Induction- the 2011 update

A recent NEJM May 2011 article has one article that compares use of Alemtuzumab and early steroid removal to Basiliximab and Thymo.  Its a nicely done randomized controlled trial that is multi centered.
On face value:- appears that rate of biopsy confirmed acute rejection was lower in the alemtuzumab group in the low risk patients when compared to basiliximab and similar to thymo when compared in high risk groups.

Few points from the trial:
1. All were steroid sparing making things not standard around all programs
2. The infection events were statistically more higher in the Alemtuzumab group especially in the low risk population
3. WBC count was also <3000 in the treatment arm
4. Cancer, renal injury other complications were similar
5. Rate of late rejection (after 12 months) was higher in both low and high risk groups compared to standard treatment
6. If steroids were withdrawn, and infections were more in the alemtuzumab group, wonder what the rate of infection would have been with steroids!

Till further studies, looking ahead. Awaiting to see what the transplant community thinks

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21591943
http://www.ncbi.nlm.nih.gov/pubmed/21591949

IVIG - how does it work from the Immunology blog?

http://allergynotes.blogspot.com/2011/04/intravenous-immune-globulin-ivig-in.html

Male Fertility and Transplantation

Male fertility has not been studied in detail in transplantation.  Does immunosuppresive therapy have impact on sperm production or motility?
Most reports suggest that male transplant recipients have successfully fathered healthy kids.
The one drug that might have led to problems is sirolimus: On observational study showed that sperm count was decreased in the sirolimus arm of the study and that could affect pregnancy outcomes.  No data exists on other agents at this point.

Ref
http://www.ncbi.nlm.nih.gov/pubmed/18510638
http://www.ncbi.nlm.nih.gov/pubmed/17714220
http://www.ncbi.nlm.nih.gov/pubmed/19601935

Post transplant TMA, revisiting Atypical HUS

Post Transplantation is a real entity. Many causes have been identified. CNI toxicity, Sirolimus, ischemia, antibody mediated rejection or de novo carcinoma, antiphospholipid syndrome, post transplant SLE are a few possible diagnosis.  One study showed that among 24 patients with post transplant TMA that was de novo, 7 carried a mutation in CFH or CFI or combined mutation, indicating a genetic abnormality that might be the first hit.
In the past decade, work has been very active in the field of Atypical HUS. Many complement abnormalities have been identified namely the CFH , CFI mutations, C3 mutations, CFB mutations, all which are mutations in the alternative pathway of complement leading to activation of MAC and TMA
A recent review in AJT July 2010 issue makes the following recs:
1. Screening for the above mutations to be done with all patients with aHUS prior to transplatation. I think that perhaps any non diarrheal related HUS should be screened as this might be the first hit.
2. Avoid Living related donation in such positive cases due to genetic transmission. Suggest a friend or spouse in such cases.
3. Studies have shown that aHUS MCP mutation can undergo kidney transplantation without increase risk of recurrence.
4. Anti CFH mutations might need pre emptive plasmapheresis, rituximab and steroids to lower the antibody levels.
5. The CFH and CFI mutations, the risk of recurrence is very high and transplant might be a risky procedure.
6. The options for CFH and CFI mutations might be combined liver-kidney transplantion along with TPE pre and post. Kidney alone with Pre and post TPE or kidney alone with eculizumab( anti complement agent).
All are only cases described, so no final decisions can be made. risk benefit has to be discussed with each case. Similar situations play part in C3 and CFB mutations as well. THBD mutations also are at risk but there is no data to do anything in these cases.
Does Nephrectomy of native kidneys help? Again, doesn't seem to be beneficial.

Check out these references:
http://www.ncbi.nlm.nih.gov/pubmed/20642678
http://www.ncbi.nlm.nih.gov/pubmed/20445192
http://www.ncbi.nlm.nih.gov/pubmed/20595690
Image source: http://www.profelis.org/amc/vorlesungen/immunologie/komplementsystem.html

Rituximab for induction?

A trial from Sweden was published last year in Transplantation.  It was a prospective, double blind, randomized, placebo-controlled multicenter study on the efficacy and safety of rituximab as induction therapy, together with tacrolimus, mycophenolate mofetil, and steroids in kidney transplants. The primary endpoint was defined as acute rejection, graft loss, or death during the first 6 months. They randomized 140 patients and found no difference in rejection episodes, infection episodes.  There was a tendency toward fewer and milder rejections during the first 6 months in the rituximab group. A commentary of this also got published in recent May issue of Transplantation.
More trials need to be done with this agent before we think it can be used as an induction agent. Trails of using it as an induction in lupus also have been done in Europe with promising results.
Other areas where it is being used in highly sensitized individuals to desensitize. In cases of historical cross matches that are positive. Rituximab is becoming standard drug to give patients with antibody mediated rejection.

Rituximab induced lung injury

Rituximab is being used for many kidney diseases and now in the post transplant world as well
A recent report in pediatric Nephrology journal discusses a pulmonary complication of the drug.
This first report of rituximab-associated, Cryptogenic Organising Pneumonia  highlights the risk of pulmonary complications after treatment with B-cell depleting agents in solid organ transplant recipients.

http://www.ncbi.nlm.nih.gov/pubmed/20140460
http://www.ncbi.nlm.nih.gov/pubmed/19681063
https://www.pediatric-nephrology.com/daily-updates/2010/05/31/212-ralimore.html

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

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

Drug coverage for transplant from Nephrologyworld blog

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

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

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

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.

New Agents for renal transplantation

Nature reviews Nephrology has a nice review on the new drugs that have been recently tried and are upcoming for the treatment of rejection or for induction.
To name and summarize a few:-
1. Alafacept  which targets Cd2 is a fusion protein that will delete activated T cells only( apoptosis method)
2. Belatacept which targets Cd80 and cd86 is also a fusion protein and can inhibit the second signal to activate T cells.
3. Sotrastaurin is a protein kinase C target and inhibits it to decrease T cell activation.
4. CP-690,550 is a JAK-3 inhibitor.
5. Eculizimab is a C5 inhibitor and inactivates complement cascade, very good use in ab mediated rejection
6. Bortezomib is a NFkB target and can deplete plasma cells and helps in plasma cell rich ab mediated rejection.
For an excellent summary, look at Figure 1 in the review article in Nature Nephrology.

Belatacept approved by FDA

What is Belatacept and is it going to change the face of transplantation? Its a fusion protein composed of components of  TLA-4, extracellular domain of IgG1.  The drug can selectively block the T cell activation by inhibiting this costimulatory molecule CTLA-4.   From the researchers mainly at UCSF, a landmark paper was published few years ago in NEJM.
They assigned renal tranplant patients to receive an intensive or less intensive of belatacept or cyclosporine. All patients were induced with the same agent of basiliximab. All received steroids and MMF.  At six months, they evaluated that the incidence of acute rejection was no different in two groups. CAN, and decrease in GFR was less common in the belatacept arm.

This drug might show promise. Lets see once more widespread use of it is noted. It might allow us to spare cyclosporine or tacrolimus use in many of our patients. This is important as one of the most common causes of graft loss these days is not rejection but chronic calcineurin toxicity or chronic changes due to medications. The effect on the pancreas by these drugs is also not benign and the most common glomerular disease post transplant still remains to be diabetes.
Lets await and see.

Sirolimus and tubular toxicity

The Feb 2010 issue of AJKD talks about a study that nicely depicts the toxicities of Sirolimus.  Since its arrival to the market for preventing rejection, it has met with resistance mostly due to its severe proteinuria.  This paper describes the toxicities of sirolimus - tubules as well as in glomerulus.  Most well know toxicity of this drug is FSGS or severe proteinuria ( sometimes collapsing variant, majority the podocytopenic type of FSGS).  Severe TMA has also been noted with sirolimus use. Most of the reports of sirolimus toxicity are in kidney transplant recipients although there have been 2 reports of proteinuria in a islet cell transplant and BMT patient who had normal kidney function prior to the drug initiation.
This was a single center study done in Switzerland.  But it was open label and randomized prospective trial comparing the tubular toxic affects and rejection outcomes in cyclosporine vs sirolimus group. There were 63 patients randomly assigned to cyclosporine-based regimens, and 64, to sirolimus-based regimens. Kidney function was similar in both groups, but the elevation in markers associated with glomerular damag and tubular damage were statistically significantly more in sirolimus group. Glucosuria incidence was higher in patients randomly assigned to sirolimus therapy.  On histologic examination, the overall severity of tubular lesions was significantly higher in patients randomly assigned to sirolimus therapy. Compared with a cyclosporine-based immunosuppression regimen, a sirolimus-based regimen is associated with de novo low-grade glomerular proteinuria, increased excretion of markers associated with tubular damage, and evidence of tubular damage on kidney biopsy.
Small but nicely done study. Just brings to mind again the utility of sirolimus. Clinically, the KDIGO guidelines have a grade 2C suggestion to use this drug for patients with Kaposi sarcoma, along with reduction in immunosuppresion.
Image source: http://upload.wikimedia.org/wikipedia/commons/d/d4/Sirolimus1.gif