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

Dichotomous Effects of Rapamycin

A recent review in AJT 2011 April issue reviews this concept nicely.

Rapamycin has many faces and many different effects on different cells. Lets summarize
1. Suppression of CD4 T+ differentiation
2. Increased T reg development
3. Decreased response to skin graft
4. Decreased dendritic cell maturation
5. Increased CD8 + T cell  memory differentiation
6. Increased CD8 T cell activation
7. Increased response to pathogen
8. Increased IL-12 production

Commonly noted side effects:- hyperlipidemia, thrombocytopenia, decreased wound healing
Ref and information obtained from:
http://www.ncbi.nlm.nih.gov/pubmed/21446969

JOURNAL CLUB: BELATACEPT and Transplantation

Co Stimulation Blockade and The Allograft

View more presentations from Nephrology, NSLIJ.

Quiz 9 Answers

Which drug is paired incorrectly with the target molecule?
Rituximab -- CD20
Alemtuzumab -- CD52
Belatacept -- CD198
Belimumab --- TNFSF13B
Atacicept ---TACI-Ig

The correct answer is Belatacept CD198, that is incorrect pairing. Most of you got it right.
We all are familiar with Rituximab which is a B cell antagonist and since all B cells besides plasma cells are CD20 Positive, its an anti CD20. Alemtuzumab(campath) targets cd52 a protein present on the surface of mature lymphocytes. Atacicept(TACI-Ig) is a human recombinant fusion protein that comprises the binding portion of a receptor for both BLyS (B-Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand), two cytokines that have been identified as important regulators of B-cell maturation, function and survival. Atacicept has shown selective effects on cells of the B-cell lineage, acting on mature B cells and blocking plasma cells and late stages of B-cell development while sparing B-cell progenitors and memory cells. The efficacy of atacicept in animal models of autoimmune disease and the biological activity of atacicept in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) has been demonstrated. The selective inhibitor of T-cell costimulation, belatacept, blocks CD28-mediated T-cell activation by binding CD80 and CD86 on antigen-presenting cells. Understanding the extent to which belatacept binds to its targets in patients may enable correlation of belatacept exposure to receptor saturation as a pharmacodynamic measure of costimulation blockade. Belimumab (registered name Benlysta previously known as LymphoStat-B), is a fully human monoclonal antibody that specifically recognizes and inhibits the biological activity of B-Lymphocyte stimulator (BLyS), also known as B cell activation factor of the TNF family (BAFF).

Sirolimus- the Positive aspects

The same issue of KI shares another view- the positive aspects of sirolimus
As we mentioned earlier that this agent was discovered as a cancer drug and has antiproliferative properties

Recent animal data and human data have shown it to be beneficial in preventing cancer post transplant
So the benefits of this agents are:

1. Prevention of cancer, as mTOR is responsible for transcription and translation for cell growth.  Definite evidence against Kaposi, Skin cancers and renal cancers.
2. Increase in T regs
3. Anti viral effects - CMV, BK and EBV viral infections ( still not sure- conflicting data)
4. Tolerance inducing potential
5. Control of fibrotic process - conflicting data when compared to CNI alone

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/20981120

Sirolimus - The negative aspects

A recent article in Kidney International discusses the negative and positive aspects of this interesting drug- sirolimus, mTOr inhibitor.  Initially designed to fight renal cancer, fast caught on to treat rejection and be used as an immunosuppression.
1. Six trials so far have randomized sirolimus vs a calcineurin inhibitor that were mentioned in this article. They all had more acute rejection episodes with sirolimus. So graft survival is a concern.
2. Renal toxicity has been described- from TMA to collapsing FSGS and severe proteinuria making it not as promising as CNI. But CNI have a more chronic toxicity to the kidney
3. Dyslipidemia has been noted as well more with this agent. - close to 60% of the patients getting mTor in clinical trials required lipid lowering agents
4. NODAT was also noted to be higher in this group; 25% more chance than CNI
5. Wound healing:- preventing the surgical wound healing or in future if patients need other surgeries makes it tough.
6. Other- mouth ulcers, myelosuppresion and infertility were more common in this agent as well.
7. Finally, they mention the new findings lately described pulmonary toxicities that are leading to a restrictive disease in the lung.

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/20703217

Salivary Prograf levels

Check out this interesting post from Pediatric Nephrology on salivary tacrolimus  levels

https://www.pediatric-nephrology.com/daily-updates/2010/10/26/329-salivatac.html

Can BK Virus serum PCR be a good marker for Net immunosuppression?

In the field of transplantation, we are struggling to figure out is the patient on which end of the spectrum, too little immunosuppresion or too much immunosuppression.  Markers for rejection have been studied extensively and based on Luminex DSA one can monitor early signs of impending antibody rejection.  But many centers are also developing aggressive screening strategies for BK Nephritis.  This entity is usually seen as early as 2 weeks post transplant to as late as 7 years post transplant but usually in the first year or so.

I think that A BK serum PCR might be a good marker for NET immunosuppression. Someone who has lupus and has been treated with Cytoxan, Cellcept, Rituxan and has failed kidneys recently and then gets a transplant for the kidney and gets inducted with more immunosuppression might be the highest risk for BK Nephritis much earlier on due to their NET immunosuppresion being the highest. No one can really measure NET immunsuppression.  There is a test available called " Cylex" or ImmuKnow . This  is the physiology behind it:  

"Phytohemagglutinin (PHA) is a non‐specific mitogen which can be used to stimulate cell division in CD4 T‐ lymphocytes regardless of their antigenic specificity or memory status. Therefore, PHA is considered to be a “global” stimulator of the immune system. The production of intracellular ATP is one of the first steps in cellular activation following stimulation with mitogens such as PHA.  ATP is a multifunctional nucleotide which plays an indispensible role in the transfer of intracellular chemical energy. The amount of ATP generated can tell us the amount of CD4 T cell activation and the overall immune status of the patient( over or under immunosuppressed). " -from the cylex website( summarized) 

But a cell activation can occur in setting on an infection as well and a similar down stream effect on the kidney. Steady monitoring of infectious agents like BKV might be the BEST marker we have to date to tell us " Hey there is too much immunosuppression on board" !

But might not be as simple as that...

Lets see what future studies hold...

http://www.ncbi.nlm.nih.gov/pubmed/20723175

http://www.cylex.net/

Quiz 4 Answers

What is the most common cause of Denovo Thrombotic Microangiopathy post renal transplant?

Calcineurin inhibitor toxicity 5 (55%)
Antibody mediated rejection 3 (33%)
MPGN 0 (0%)
Malignancy 0 (0%)
Infections 1 (11%)

Denovo TMA post transplant is defined as happening in the early post transplant period.( 6 months). All of the above can cause de novo TMA in post transplant patients. The most common cause as most of you got it is CNI toxicity. Although, Antibody mediated rejection closely follows it and should always be considered. Another cause not listed here is ischemic repefusion injury as well leading to a TMA.
A recent study in AJT August 2010 showed in a retrospective fashion that TMA can be very strongly associated with C4D positive Biopsies showing ABMR as well. 14% with CD4 positive patients had TMA compared to only 3% with C4D negative biopsies. Treatment changes - Plasmapheresis might help in this case as you will remove the donor specific antibodies and also help the process of TMA treatment.

Regardless in any case of TMA, treat the underlying cause if found! CNI induced TMA doesn't NEED to be treated with plasmapheresis

References:
http://www.ncbi.nlm.nih.gov/pubmed/20659088

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

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.

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.

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.

Positive Cross Match, Desensitization

The recent AJT Report talks about fighting the positive Cross Match or desensitization.  Currently, many centers are using the combination of pheresis and low dose IVIG or high dose IVIG and rituximab is thrown in once in a while as well.  The value of rituximab is still questioned.  No one really knows how it is working in some and not in others.
There are few new agents:- one is bortezomib, a proteasome inhibitor that has shown some data in treating antibody mediated rejection.  There are some centers using one cycle pre and one cycle post transplant as densitization technique.  This has become a concern for many as people are starting to use it for indications that have not been systematically tested.  The side effect profile of this drug is not trivial. It includes peripheral neuropathy, pyrexia, anemia, leukopenia  and GI side effects.
Finally, the latest player in the market is eculizumab ( complement protein c5 inhibitor).  It has worked in some centers to treat antibody mediated rejection. Is it a good idea to use it for desensitization. Its early to say.

Lets wait and watch.

B cell agents in Transplantation

A nice review in recent CJASN highlights the use of anti CD20 and other novel b cell agents in transplantation.
The paper actually reviews all of glomerular diseases and transplantation.
Few things about use of B cell agents in Transplantation
1. Use of Rituximab is increasing more and more with desensitizing protocols for ABOI and + DSA patients. Is it a combination of IVIG, Pheresis and Rituximab that really works or is one better than the other, no studies have confirmed that? Although IVIG alone has not been affective.  Hence, it might be an additive effect.
2. Use of anti CD20 in antibody mediated rejection has become an increasingly used agent.  This stems from a simple concept that antibodies are produced by B cells and hence depleting the B cells will deplete the production of antibodies.
3. Bortezomib, has been now used as well in refractory antibody mediated rejection and in biopsies that have enriched plasma cells.  Total IgG were unchanged in those patients treated, so we don't know if this is a one time effect and or long lasting and also there is potential increased risk for infectious complications.
I think we shall see more and more of these agents used for treating transplant patients in the future.
We have to be careful as there are Regulatory B cells and what we are doing to those B cell clones, we don't exactly know!