Topic Discussion: Lenalidomide and the Transplanted Kidney

Lenalidomide has multiple immunomodulatory effects that provide antitumor properties and has been used in treatment of myeloma and AL amyloidosis. Recently, several cases have been reported of acute allograft rejection in patients who got this agent with a renal transplant.

Activation of the immune system by lenalidomide has been shown to result in immune-mediated complications. In a retrospective analysis, Montefusco et al discovered a 4-fold increased risk for the development of autoimmune disease following the administration of lenalidomide for the treatment of multiple myeloma, most of which occurred in the first 3 to 5 weeks after initiating therapy.

Meyers et al had reported the first case of rejection in a patient after heart-kidney transplantation with stable immunosuppression following lenalidomide administration. Since then two additional cases are reported in the renal transplant population both in the recent years.

The two cases are listed below

The AJKD case report

Transplantation Proceedings case report

Why does this happen? The authors of most articles postulate that lenalidomide might activate T cells by directly inducing tyrosine phosphorylation of CD28, an essential T-cell−signaling protein in the costimulatory pathway. Direct activation of this pathway allows for T-cell activation in the presence of CTLA4 immunoglobulin blockade, increased secretion of interferon γ and IL-2, and stimulation of cytotoxic CD8-positive and CD4-positive helper cells.

In addition to CTLA-4 antagonist and PD1 and PDL1 inhibitors that activate the immune system and cause transplant rejection, we will have to add Lenalidomide to the list as well.

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

REJECTION and TOLERANCE

This week is a transplant week in the journals.

The NEJM has a nice review on Rejection of the Kidney Allograft. Have a look. its very well written and combines the latest information on all concepts of rejection(with excellent visual portrayals)
Antibody Mediated and Cellular Mediated are discussed. It even goes into details of T cell activation and co stimulation and is a simple read for all.
It ends with a nice summary on even Late Acute rejection and Chronic Rejection

Another treat this week is the Nephrology Nature Review Journal- features an entire issue on Transplantation Tolerance, the holy grail of Transplantation. It reviews nice articles on Tolerance review, T Regs, Tregs and B cell interactions, Mixed chimerism and Biomarkers and proteonomics in transplant tolerance.

The references are below:
http://www.nejm.org/doi/full/10.1056/NEJMra0902927
http://www.ncbi.nlm.nih.gov/pubmed/20717099

Histopathology Kidney --Chronic transplant rejection

Histopathology Kidney--Acute transplant rejection

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

Photopheresis therapy for renal allograft rejection?

The technique involves three stages: 1-leucapheresis, 2- photoactivation with photosensitizer plus UV A irradiation, and 3- re-infusion of the buffy coat.

Extra Corporal Photopheresis (ECP) was first introduced for the treatment of Cutaneous T-Cell Lymphoma. Now has been widely used in the treatment of acute allograft rejection; most extensively in cases of cardiac transplant rejection. It has also shown success and high efficacy in reversing renal allograft rejection as well. Only one cohort study has been done by Jardine et al; ECP been used in 10 kidney recipients with therapy resistant rejection, and to our surprise, it showed that rejection has been resolved in all patients treated with ECP!

The exact mechanism of action remains unclear, but believe it has an immunomodulatory rather than immunosuppressive effect: The irradiation therapy induces high rate of apoptosis of the T-cells with sparing of the monocytes, and this eventually creates changes in the patient’s cytokine profile towards “type 2” cytokines; with significant increase of IL-5 and decrease of IFN-Gamma - “which is associated with allograft rejection!” also, it has a stimulatory effect on the T-regulatory cells as well..

Safety profile is excellent with <1% adverse effect, considered more safe than any other modality of apheresis!

ECP been mainly used for CTCL, and GVHD. Also, has been used in other autoimmune diseases including MS, scleroderma, DM-1, RA, psoriasis, Crohn’s, Nephrogenic Fibrosing Dermopathy. ECP is an effective, tolerable, and safe immunomodulatory therapy that can be used theoretically for resistant renal allograft rejection “T-cell rejection”. We still need more data and large cohort trials for this promising technique/therapy.

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.

Are you aware of MICA antibodies?

Some kidney transplants fail despite good HLA matches. The main targets for antibody mediated rejection are HLA antigens. Among non-HLA antigens that can induce an antibody response, MHC class 1-related chain A (MICA) antigens appear significant enough to affect acute and chronic graft outcomes. MICA antigens are expressed on endothelial cells, dendritic cells, fibroblasts, epithelial cells but not on peripheral blood lymphocytes. As they are expressed on endothelial cells, it seems that antibodies against MICA antigens are harmful especially to vascularized allografts like renal allograft. In a landmark study (Zou et al, NEJM Sep 2007), pretransplantation MICA antibodies were found in about 11% of 1910 renal transplant recipients. It was found that recipients with pre-transplantation MICA antibodes had lower 1-year graft survival compared to those without MICA antibodies suggesting adverse role of these antibodies. However, a more recent but smaller study (Lemy et al, Transplantation, May 2010) failed to replicate same findings. In this study, MICA antibodies did not adverse affect renal allograft outcomes.

B cell signature and Tolerance

Recently we discussed B regulatory cells. Before one could think, a study in JCI discusses this very topic of B cell signature in tolerant renal transplant recipients.  This is the largest cohort of tolerant renal patients and when they did compared gene expression profiles, they found that the predominant Cell was a B cell that was regulating the maturing of most B cells. IL -10 was also significant.  This B cell signature was associated with upregulation of CD20 mRNA in urine sediment cells and elevated numbers of peripheral blood naive and transitional B cells in tolerant participants compared with those receiving immunosuppression. 
Finally, B cells are making a mark, just lagging slightly behind the T cells.
Hmmm. is Rituximab all good then???


Reference
http://www.ncbi.nlm.nih.gov/pubmed/20501946
http://www.ncbi.nlm.nih.gov/pubmed/20501943

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

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

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

Obesity and Kidney Transplantation

What I learned at the NKF 2010. Some key points

1. BMI < 18 and >30 are both associated with worsening graft survival
2. Why does obesity affect transplant outcomes: The risk factors after few studies have been: increased insulin resistance, increased BP, hyperlipidemia, increased proteinuria and development of NODAT

3. There has been a higher incidence of acute rejection in high BMI patients? The reason: obesity has been associated with mild continuous chronic inflammation and increased proteinuria.

4. Should obese patients be trasnplanted? Yes as a comparative study showing how they do on dialysis still shows they do better on transplant. Yes, when compared to non obese patients getting transplanted, the risk is low, the overall benefit vs dialysis is more.
5. Should their immunosuppresion be treated differently? No real headway. When compared steroid free vs steroid + protocols in obese patients, no difference was noted in outcomes.

Antibody Mediated Rejection Review

https://www.pediatric-nephrology.com/daily-updates/2010/04/04/175-amrcedars.html

Check out the link to this nice review posted on a pediatric nephrology blog.
A nice read!

JOURNAL CLUB: DNA Methylation controls Foxp3 gene expression

A basic science article was discussed at immunology journal club. It discusses the role of T regs and its how they come from naive T cells and what other factors triggers them.
The vast experiments done elegantly in the study concluded the following:
1. TGF-B induces FoxP3 expression in T regs but its unstable in vitro
2. Azacytidine derivatives( demethylation agent) stabalizes foxp3 expression in induced Tregs.
3. The T reg specific demthylated region (TSDR) determines transcriptional activity
4. Azacytidine promotes stable Foxp3 expression in vitro
5. In vivo induced Tregs exhibit stable Foxp3 expression and complete TSDR demethylation
6. Foxp3 Treg generated invivo by targeting of agonist ligands to dendritic cells showed long term survival in the absence of the inducing antigen and exhibited efficient TSDR demythylation.

Besides the specifics of epigenomic imprinting in the mehylation region of the T cell region which might be critical for T cell lineage, this paper I thought highlighted something very alarming. One is that TGF-B is an important promoter of T reg cells. There are drugs out there currently under development that are inhibitory to TGF-B for anti fibrotic effects. Again, we have to think  of these molecules as possible bimodal and perhaps they have different functions in different disease entities.
Second is that the dendritic cells might be important players in the long term survival of Tregs. Since there are studies that show that the patients that has increase Foxp3+ Tregs, those patients post transplant do better.
Perhaps, sustaining that positive effect should be the goal in transplantation. We can perhaps then achieve tolerance. Perhaps!!
This is interesting to me as a clinician as there might be promise ahead for tolerance.
The article source is here.
A review of the Foxp3 T regs is nicely shown in recent Nature Immunology as well
Image source: http://www.scielo.br/img/revistas/abd/v81n3/e10f1.jpg

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.