In the News: Immune checkpoint inhibitors in the renal transplant patient

 

Use of immunotherapy in the renal transplant patient is challenging. Initial case reports had shown over and over acute rejections. In 2017, we had tried a novel way to prevent rejection in a single case report published in NEJM( using mini steroid pulse and mTOR over CNI use). Since then, we have used this approach successfully in several patients to allow for good tumor response and prevent rejection. But one case, two cases, three cases cannot tell the whole story.  More data is needed. A recent meta-analysis done on use of immunotherapy and transplant patients showed of 44 patients,  18 were reported to have acute rejection. Median time from immune checkpoint inhibitors to acute rejection diagnosis was 24 (interquartile range, 10–60) days. Reported types of acute allograft rejection were cellular rejection (33%), mixed cellular and antibody-mediated rejection (17%), and unspecified type (50%). Fifteen (83%) had allograft failure and 8 (44%) died. Three patients had a partial remission (17%), 1 patient achieved cancer response (6%), and 5 patients had stable disease (28%).

Other studies similar to this have showed similar rejection rates of 40%. No studies have tested the clinical efficacy of the use of these agents in renal transplant patients.

In a recent study published in Kidney International, we collected 69 cases from 23 institutions from US, Canada and Europe. This is the largest study to look at both transplant outcomes and efficacy of these agents in renal transplants patients.

Acute rejection rate 42% (29 out of 69), median ICI to rejection=24 days. Rejection is severe: cellular rejection and mixed cellular and antibody-mediated rejection are both common. Once rejection happened, 65% lost allograft.

What are the risk factors of rejection? Being on 3-agents immunosuppression and mTOR inhibitor use were associated with LOWER risk of rejection. This is an interesting finding. This is to tell us the obvious- the less the immunosuppression- the risk for rejection increases but the mTOR finding is interesting( caution- still low Ns). Take a look at this paper as well.
We looked at rejection rate and cancer objective response rate in skin squamous cell carcinoma (cSCC) and melanoma, two most common cancer types in our cohort. In cSCC, rejection rate 37.5%, ORR 36.4% and ICI may be associated with longer overall survival. In melanoma: rejection rate 54.5% (# of immunosuppression agent-dependent), ORR 40%. OS did not differ but limited by small # of patients and short follow-up.

An important figure that is hidden in the supplemental content is below: This tell us the majority of the changes done by centers when immunotherapy was initiated, see the % who increased steroids, converted CNI to mTOR inhibitors, dc CNI , dc MMF. etc.  Interesting changes which were made are not at all standardized. 

Although our study is to our knowledge the largest multicenter cohort of patients with advanced solid malignancies with kidney transplant who received ICI to date, there are several limitations Firstly it is retrospective and small-sample nature of our cohort limited our ability to adjust for a number of confounders in multivariable analysis for the risk of graft rejection. Also less than half of acute rejection were biopsy proven, which limits the accuracy of the diagnosis of rejection. The comparison of outcomes using these historical cohorts suffers from the lack of power due to the small number of cases, but provides a pragmatic approach to address the risk of rejection and objective response rate. Lastly, immunosuppression modification was the providers’ choice at each institution and not standardized.

So what now? This tells us that immunotherapy is a feasible option for kidney transplant pts but with very high risk of rejection.

mTOR inhibitor plus steroid mini-pulse may be effective in preventing rejection?
Or should we continue the immunosuppressive meds “as is” or at least 2 of them and then give the immunotherapy as efficacy was amazing in cSCC and prevent the rejection as well.
What this study also told us is that- stopping the immunosuppression when planning to give immunotherapy doesn’t really help in cancer outcomes or renal transplant outcomes? So should we be even stopping them??

A collaborative effort led by Naoka Murakami from around the world. 

IMMUNOSUPPRESSION IN THE ELDERLY: WHATS THE BEST INDUCTION AGENT???

The incidence of elderly patients with ESRD is increasing, as is the number of elderly listed for kidney transplantation. In fact, we are transplanting more and more elderly patients over the age of 70. Studies suggest that the elderly have excellent graft survival, possibly due to a less robust immune response, but unfortunately still have a higher mortality than younger patients. This dichotomy led me to wonder what the best immunosuppression is for the elderly. Logic would suggest they need less intense induction immunosuppression to avoid infectious complications. At the same time however, perhaps more intense induction can reduce the incidence of rejection and allow reduced maintenance immunosuppression (such as steroid free or low CNI) improving both infectious and cardiac outcomes. Reviewing the literature led me to 3 interesting papers on induction immunosuppression and outcome in the elderly.

Two studies were registry analysis^1,2 and one was a single center study³. The registry analysis compared 3 agents: IL-2 inhibitors (anti-CD25), antilymphocyte globulin (thymoglobulin), and alemtuzumab. They suggested worse outcome with alemtuzumab compared to thymoglobulin or anti-CD25. Although outcomes with thymoglobulin and anti-CD25 were similar, thymoglobulin had a lower incidence of rejection and surprisingly revealed a trend to better patient survival! This was especially prevalent in high risk recipients whom also enjoyed better graft survival. It is possible that this effect is due to less maintenance immunosuppression and less requirement for high doses of immunosuppression to treat rejection. The single center study evaluated different cumulative doses of Thymoglobulin and outcome within different age groups. What they found was elderly (age > 60) patients had a reduced survival if they received > 6mg/kg of Thymoglobulin.

Looks like low dose thymo induction wins again!

References:

1. Clin J Am Soc Nephrol 2011;6: 1168-1178 PMID:21511836

2. Am J Nephrol 2011; 34:534-541 PMID:22104284

3. Clin Transplant 2011;25:E250-E256 PMID:21231963

Azathioprine vs MMF: Transplantation for the society?

Every year, our fellows do role playing as part of their transplantation training lectures. Last week, the fellows were assigned immunosuppressive agents and each played a specific drug that was "assigned to them" based on their personality. 
What was very fascinating to me was that fellows bring articles that are supporting their existence and what can make their agent more superior.  In our vast medical literature, one can always find articles that support one side and then enough to support the other. Debates as a result lead to a more fun and exciting discussion that enhances learning.
One of the most interesting debates was AZA vs MMF.  The AZA arm pulled out these two articles that were very interesting. 


Article 1: MYSS trial from LANCET 2004: Mycophenolate mofetil has replaced azathioprine in immunosuppression regimens worldwide to

prevent graft rejection. The mycophenolate steroids sparing multicentre, prospective, randomised, parallel-group trial compared acute rejections and adverse events in recipients of DDRT over 6-month treatment with MMF or azathioprine along with Neoral and steroids (phase A), and over 15 more months without steroids (phase B). The primary endpoint was occurrence of acute rejection episodes. This trial showed no major advantage to preventing acute rejection when MMF was used.  

Article 2: MYSS trial follow up results: In kidney transplantation, the long-term risk/benefit profile of MMF andazathioprine therapy in combination with cyclosporine Neoral is similar. In view of the cost, standard immunosuppression regimens for kidney transplantation should perhaps include azathioprine rather than MMF.

The cost to oneself vs cost to the society is the question when we embark on expensive therapies that are equal to a cheaper alternative.  Nevertheless, MMF has fewer side effects and less interactions with other medications.  

If you needed a transplant:- what would you choose to have? MMF or AZA?

IN THE News: A report about inducing tolerance in kidney transplants

A nice letter from investigators at Stanford published this week in NEJM Oct 2011 issue shows a proof of concept. 12 patients, got a HLA matched kidney and a donor cell infusion of CD34+ progenitor cells mixed with CD3+ T cells and irridiation and anti thymoglobuliun. The irridiation was not total body but more to spleen, thymus and lymph nodes. Giving stem cell transplantation and kidney transplant to a well matched patient led to chimerism and ultimately majority patients came off immunosuppresion and renal function is stable. Take a look at the full letter at

http://www.nejm.org/doi/full/10.1056/NEJMc1107841

TOPIC DISCUSSION: SIROLIMUS , not all that benign

The complications that can occur with use of sirolimus are not that benign. The agent is good in certain cases but not all. Besides the known side effects of FSGS, proteinuria and TMA in the kidney, there are other non renal side effects that one needs to be aware of.
1. Leukopenia, Anemia, Thrombocytopenia
2. Impaired wound healing
3. Mouth Ulcers
4. Oligospermia
5. Interstitial Pneumonitis
6. Hyperlipidemia( all increased LDL, HDL and VLDL)
7. Hyperglycemia

Remember to monitor especially for lipids and glycemic control

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

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

Belatacept is a selective T-cell co-stimulation blocker thatis administered IV which offers comparable results to cyclosporine.  Though the acute rejection rate seems to beslightly higher with Belatacept than cyclosporine, trials reveal a higher GFR inthe Belatacept arms at 3 years of follow up. The obvious hope is that the use of Belatacept will avoid calcineurininhibitor nephrotoxicity in kidney transplant recipients improving long termallograft outcome.  The major concern withBelatacept is an increased risk for PTLD seen in many of the trials.  For this reason it is contraindicated in EBVseronegative patients or patients with unknown EBV serostatus.  To address the concern of PTLD Bristol-MyersSquibb 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 withBelatacept.

Belatacept is administered IV over 30 minutes and the recommendeddosing is 10 mg/kg on the day of transplantation then on day 5, then at the endof weeks 2, 4, 8, and 12. After week 16 it is recommended that the maintenancedose 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

Human Herpes Virus – 6: An uncommon but potentially treatable infectious agent in transplant recipients

HHV-6 is a DNA virus part of the beta-herpesvirus family andcan be divided into HHV-6 A and B. Primary infection is mild and occurs usually in childhood; therefore themajority of healthy adults have serologic evidence of prior infection.  HHV-6 can re-activate in theimmunocompromised transplant recipient leading to asymptomatic viralreplication or less commonly active infection. The highest prevalence by pcr has been shown to occur in bone marrowtransplant recipients (28% to 75%) but viral replication has also been shown tooccur in liver (28% to 32%) and renal transplant recipients (23% to 36%).  Although asymptomatic viremia is common,clinically active infection carries a high mortality and may be susceptible tospecific antiviral treatments.   

How does HHV-6infection present?

HHV-6 infection commonly presents with high fever oftenassociated with leukopenia, and encephalitis between 2-4 weeks posttransplantation.  Other clinicalmanifestations include pneumonitis, hepatitis, colitis and bone marrowsuppression.  Rash typical of a leukocytoclasticvasculitis can also be seen. Encephalitis may be associated with seizure activity andhyponatremia.  Encephalitis is morecommonly seen in BMT patients but has been described in solid organ transplantpatients as well.  HHV-6 infectionscommonly co-exist with other viral infections including CMV. 

HHV-6 reactivation has also been associated with druginduced hypersensitivity syndromes, malignancies, multiple sclerosis, fulminanthepatitis and mycocarditis though causality has not been demonstrated.

What are theassociated laboratory and imaging findings?

CBC: Bone marrow suppression, leucopenia, thrombocytopenia

Chemistry: Transaminitis, hyponatremia

CSF:  High lymphocytecell count with elevated protein.  HHV-6can be detected in CSF by pcr. 

MRI of brain: Symmetric non-enhancing white matter lesions.  MRI may be normal in patients infected withHHV-6.

How can youdiagnose active infection?

Serologic testing: Sensitivity varies and most tests cross react with HHV-7.  A fourfold increase in titers orseroconversion is considered diagnostic.

Virus culture from affected tissue or blood can be done butare difficult to perform.

Viral detection: Virus may be present in PMBC’s of patients with latent infection leadingto a “false” positive pcr.   ThereforeHHV-6 should be identified in affected tissue or acellular plasma orserum. 

What are thetreatment options?

No therapy has been clearly documented to treat HHV-6although several agents with in-vitro activity have been tried.  Ganciclovir is effective against HHV-6B butmay not be active against HHV-6A (minority of infections).  Foscarnet has activity against both A and Bhowever; its use is complicated by nephrotoxicity.  In severe cases both agents can be tried andwhenever possible a reduction in immunosuppression should be considered.

References:

http://www.ncbi.nlm.nih.gov/pubmed/15196083

http://www.ncbi.nlm.nih.gov/pubmed/11241800                     

http://www.ncbi.nlm.nih.gov/pubmed/19920774

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