Showing posts with label transplantation. Show all posts
Showing posts with label transplantation. Show all posts

Thursday, January 10, 2013

Clinical Case 67: Answers and Summary


WHICH TRANSPLANTED ORGAN HAD THE FIRST EVER CONSENSUS CLASSIFICATION ON ORGAN REJECTION AND PATHOLOGY ?

Pancreas
  0 (0%)
Kidney
  15 (65%)
 
Heart
  2 (8%)
 
Lung
  1 (4%)
 
Liver
  1 (4%)
 
Skin
  4 (17%)
 


Most of you said "Kidney". Perhaps we shouldn't be that "nephrocentric". In a recent history related paper in Kidney International, Dr.Kim Solez et al discuss the history of the Banff classification and how it came about. 
The need was as early as 1991 when the classification began.  Kidney transplant pathology had no mentors and no classifications. The first consensus guidelines that came for any organ was heart allograft rejection and that served as a model for the Banff Kidney transplant classification.  There began the history of pathology behind the kidney transplant.  So the historically accurate answer is the "heart". 

Friday, February 24, 2012

eAJKD: Advanced age and Kidney Transplantation

Geriatric nephrology is on the rise as the baby boomers age, and more and more patients will encounter nephrologists. Transplant nephrology is facing this challenge as well. Check out the two part interview series in eAJKD with the author of a recent article on transplantation outcomes in the elderly.


Interview Part 1
Interview Part 2

Tuesday, January 10, 2012

IN THE NEWS: Face Transplantation

Many decades ago, the first human kidney transplant was done at BWH Hospital and ever since then multiple organ transplantations have happened- including liver, lung, heart, small bowel and so forth.
The field of transplantation has expanded so rapidly and hard to keep up with the newest developments. 

One of the Indian Hindu Gods, Ganesha can be considered the first xeno transplantation and hence certain books mention his story at the start of the history of transplantation.  Ganesha is the elephant head with the human body who's surgeon was Lord Shiva. Lord Ganesha is considered the God of wisdom and knowledge and good luck. Of all the prayers, a Ganesh Prayer is the first prayer usually performed at most Hindu ceremonies.  

I once read a very interesting interpretation of Lord Ganesha. Of all the Gods in Hindu mythology, he is very overweight. Perhaps he was on steroids for this transplant.  He is always shown in a picture next to his favorite mouse: perhaps a subtle hint of research done even back then on mice on transplantation. Finally, after surgery, Lord Shiva has given elixir drink to Lord Ganesha speculating perhaps that was the ancient version of "thyme" or "simulect"

In the midst of this, last last issue in Dec 2011 of NEJM sheds light on face transplantation. They report a series of 3 patients with complete successful face transplantation.  Similar induction as kidney transplantation was used with thymoglobulin and same triple drug regimen for maintenance regimen.  They present their data case by case with good follow up and steroids withdrawn in all cases.  

Take a look at the full article

Saturday, November 5, 2011

In the News: Inducible Apoptosis- but could it work in a solid organ transplant model?

Immunology is evolving rapidly in the medical field. A recent article of mention is the NEJM Nov 2011 issue that talks about the inducible apoptosis as a safety switch for adoptive cell therapy.
This article is more of a cancer paper that discusses an inducible T cell safety switch that was based on the fusion of human caspase 9 to a modified human FK-binding protein - allowing for dimerization.  Eventually, when exposed to a synthetic dimerizing drug, caspase 9 was induced and activated leading to cell death.  So, they tested this hypothesis using the stem cell transplant model and GVHD treatment. Five patients who had undergone stem-cell transplantation were treated with the genetically modified T cells.  A single dose of dimerizing drug, given to four patients in whom GVHD developed, eliminated more than 90% of the modified T cells within 30 minutes after administration and ended the GVHD without recurrence.

Interesting, look back at the literature on icasp9, this was tested apparently in erythropoietin transgene expression in animals. The effectiveness of the caspase-9-based artificial "death switch" as a safety measure for gene therapy based on the erythropoietin (Epo) hormone was tested in vitro and in vivo using the chemical inducer of dimerization. They concluded that inducible caspase 9 did not interfere with gene transfer, gene expression or tetracycline control and may be used as a safety mechanism for gene therapy. 

This iCasp9 cell suicide system is interesting and perhaps might have role in Renal transplantation. It seems that prior hematology literature have demonstrated the feasibility of engineering allogeneic T cells with two distinct safety mechanisms, selective allodepletion and suicide gene-modification. Could these suicides genes be selectively allowed to target reactive T cells in organ transplants and let the T regs flourish? Unclear data on that.  Unclear how successful it would be in a solid organ transplant model. Any thoughts?

Thursday, October 20, 2011

Topic Discussion: TIM molecules and Kidney Transplantation

TIM is "T cell immunoglobulin mucin". They are molecules that have shown to play a major role in immune responses. TIM 1,3 and 4 are the ones mainly noted in the literature.  TIM-1 and 3 are more on T cells and Tim-4 on Antigen presenting cells.

TIM 1:- Expression is on CD4+T cells, B cells, Mast cells and NK cells.  The proposed ligands for this molecule are TIM-4, IM3, and IgA and heavy chain to name a few.  The role in innate immunity is mediating clearance of apoptotic bodies and maintenance of peripheral tolerance.  In adaptive immunity, it increased th2 differentiation. Disease models include increased expression Asthma, MS, Sarcoidosis, and epithelial cells in AKI( also called KIM-1)

TIM3:- Expression on TH1 and Th17 cells, CD8+T cells and Antigen presenting cells.  Innate immunity wise limits macrophage expansion and modulates CD80 and CTLA-4 expression on antigen presenting cells.  It also helps in peripheral tolerance.  Disease models include T cells in chronic malignancy and infection.  Down regulated in Asthma and MS

TIM4:- Expression on dendritic cells and macrophages.  Ligands are TIM 1 and CD4+ t cells.  It up regulates Th2 responses and proliferation of activated T cells.  Disease model is food allergies and Asthma.

The TIM family is appearing as modulators of the immune system and helps in co stimulation of T cells. More will come about these molecules to improve our understanding of transplant immunology.


ref:
http://www.ncbi.nlm.nih.gov/pubmed/17331850
http://www.ncbi.nlm.nih.gov/pubmed/21906254
http://www.ncbi.nlm.nih.gov/pubmed/20536563
http://www.ncbi.nlm.nih.gov/pubmed/16938542

Thursday, September 29, 2011

The American Society of Transplantation Blog

American Society of Transplantation
Welcome to the blog sphere!
American Society of Transplantation starts a blog for interaction with their members!
http://members.a-s-t.org/blog/beginning-conversation

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


Tuesday, September 6, 2011

IN the NEWS:- TIM-1 + B cells? and B cell tolerance!

TIM-1 is a costimulatory molecule that regulates immune responses by modulating CD4+ T cell effector differentiation. A recent mice study in JCI showed that it is expressed mainly in B cell subpopulation.  And these TIM-1 positive cells that are B cells also produced IL-10. IL-10 is a very important regulatory molecule like Foxp3.  These B cells were  characterized as CD1dhiCD5+. Some consider these as B cells that have regulatory function.  TIM-1+ B cells were highly enriched for IL-4 and IL-10 expression, promoted Th2 responses, and could directly transfer allograft tolerance. Prior studies have shown such cells in mice to help keep SLE quiet and inflammation under control. Perhaps, just like the T regs, there is a small but strong population that are present called B reg cells. Now studies so far have only found these in mice. Can this hold true in human studies is hard to tell yet. Perhaps! It will be important in the field of transplantation to sought this out as we move forward towards a better world of transplant tolerance. Why do some people have more tolerance than other? Perhaps its a Breg phenomenon.  The current study suggests that TIM-1 may be a novel therapeutic target for modulating the immune response and provide insight into the signals involved in the generation and induction of Bregs.


Check it out
http://www.ncbi.nlm.nih.gov/pubmed/21821911

Monday, August 15, 2011

Mohan foundation: First of its Kind in ASIA


MOHAN FOUNDATION

Most physicians know, transplants just don’t begin or end with one person’s death. A whole mechanism has to come into play – to confirm that the dead person’s organ is healthy, that his or her family is willing to donate, that the grieving family’s religious and spiritual needs are met, that trained professionals offer grief counseling and information about organ donation in a non-judgmental way, that a patient waiting for an organ on a list is notified timely, that doctors are prepared to walk into the operating room at any time day or night when such an event occurs, that this altruistic process is not corrupted by money or favoritism, that the public is sensitized to the true nature of this process, that this process perpetuates and spreads through society and that awareness amongst the general public reaches a level of acceptance that a majority come forward to donate their organs after death.   

Every year thousands of patients in India die without an organ transplant. Others either slowly wither away under the weight of their disease while waiting, or sometimes turn to organ traffickers to buy organs from the poor who have been tricked into “donating” their kidneys. These donations are done under the table, in terrible hospitals, with bad hygiene and sanitary conditions leading to poor outcomes for both donor and recipient. It is a terrible situation with a great need that goes unmet because of the lack of organization critical to run an organ donation program.

And yet, the solution is right under our noses! Statistics show that in the West, almost 37,500 organs are transplanted annually from cadaver donors where donation rates are about 25-35 per million people. In India we are able to retrieve organs from only about 70- 100 donors annually because our donation rate is 0.08 per million. If we are able to increase our donation rate to 2-3 per million, it can take care of ALL the current needs for organs in India!
But India doesn’t have its UNOS.

MOHAN Foundation

MOHAN (Multi Organ Harvesting Aid Network) Foundation is a not for profit organization that leads this mission to facilitate deceased organ donation in India. Since the inception in 1997, MOHAN have facilitated the donation of over 2000 organs and tissues. The core objectives are to create awareness about organ donation, to counsel the families of “brain dead” victims about donating their loved ones’ organs, to train transplant coordinators on the nuances of counseling, to coordinate organ donations with hospitals and patients, to lobby with government to pass appropriate legislation that will promote organ donation and to ensure that all this is done in an ethical and transparent manner.


Mohan will have a booth this year at ASN 2011.

Learn about the UNOS like foundation of India- MOHAN 
To be part of this or see what is going on visit www.mohanfoundation.org 

 Dr. Anirban Bose

Tuesday, August 9, 2011

IN THE NEWS: Rituximab Targeting Podocytes in Recurrent FSGS

Rituximab might be working in a non B cell mediated manner in FSGS recurrence post transplant.
A new study by Fornoni et al showed this in an elegant way.
Some summary points

1. 41 patients were studied, post transplant and 14 were controls and remaining received rituxian as part of their induction.
2. Fewer podocytes with SMPDL-3b protein in biopsies from recurrent FSGS were found.
3. Serum from patients with recurrent FSGS had a decrease in both SMPDL -3b and sphingomyelinase activity.
4 They predicated that rituximab preserves SMPDL-3b expression in podocytes.
5.The above part was prevented with anti CD20 treatment.
6. They studied SMPDL-3b protein, cytoskeleton remodeling in cultured normal human podocytes that had been exposed to patient sera with or without rituximab.
7. Over-expression of SMPDL-3b or treatment with Anti CD20 was able to prevent recurrent FSGS and showed preservation of cytoskeleton.
8.These data suggest that modulation of the sphigolipid related proteins might be playing a role in causing recurrent FSGS and perhaps anti CD20 agents are inhibiting this process in a B cell independent fashion.

Key: SMPDL= sphingomyelin phosphdiesterase acid like.

ref:
http://www.ncbi.nlm.nih.gov/pubmed/21632984


Saturday, August 6, 2011

Green tea and Tacrolimus

Its seems like tacrolimus gets in trouble with lot of things.  Since its a substrate for the P450 system, it is good to monitor with any new medication.
Recent report suggests that green tea might increase tacrolimus levels. In this particular case discussed in AJKD, poor metabolism was also a culprit but green tea is something to watch out for.

Take a look
http://www.ncbi.nlm.nih.gov/pubmed/21787983

Thursday, July 21, 2011

T regulatory Cells: A short review


T regulatory cells have now come out and made a splash in the transplant world but also in the immunology and glomerular disease world.  Treg are usually CD4+, CD25+, CTLA4+.
A common misconception is that all are Foxp3 positive.  
There are many types of Tregs.
Natural kind that do express Foxp3 and CD25 and they usually are IL-2 dependent
Induced Tregs are induced in the periphery and can express Foxp3 but after development
Regulatory Tregs do not express Foxp3 and CD25. They depend on IL-10 on development.

IL-10 has always been associated with regulatory function.
Now given above information, immunology always is evolving and who knows what will be new in 2011.



Sunday, July 17, 2011

New Informative Transplant News Website

please check out www.transplantnow.com.
This is similar to Nephrology now and compiles latest articles in Transplantation from major journals and will allow for good compilation.

Wednesday, July 6, 2011

TOPIC DISCUSSION: Dendritic Cells and Renal disease

Dendritic cells(DC) are traditional thought to be anti infectious and a link between the innate and the adaptive immune system.  A nice breakdown of DC role in kidney disease recently discusses its role in homeostatic, anti inflammatory and pro inflammatory roles in kidney diseases.
In terms of homeostatic roles: there is evidence that DCs can do some immune tolerance in renal allografts, and small molecular weight antigens.  The anti inflammatory roles have been in mostly nephrotoxic nephritis(drug induced) especially cisplatin nephrotoxicity. Some data is also present in suppressing pro inflammatory cytokines in ischemic reperfusion injury. Most of the data is in being pro inflammatory in nature and that is in causing proteinuria, promoting ANCA through Th cells, IL-12 secretion in lupus and Th1 response in tubular insterstitial disease.
This leads us to believe that there might be many types of DC and there are.  CD11B like DC due immune surveillance and activate Th cells and are present in kidney in certain glomerular diseases.  CD8 like DC are found in renal lymph nodes and have some T cell activation role.  Inflammatory DC regulate Th cells and Plasmacytoid DC may have some role in lupus nephritis.

Check out these recent references.

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21613986
http://www.ncbi.nlm.nih.gov/pubmed/19276627
http://www.ncbi.nlm.nih.gov/pubmed/19381017

Saturday, July 2, 2011

Many guidelines equal no guildelines for cardiac evaluation before renal tranplantation

The degree of cardiac testing for potential transplant recipients is highly variable and depends on the practices of the particular transplant center. Multiple guidelines have been proposed by experts in the field however there is a huge variability between each guideline. At the two ends of the spectrum are the KDOQI guidelines which suggest universal testing for CAD at regular intervals depending on risk, and the ACC/ AHA who recommend testing only for symptomatic patients or patients who can not achieve 4 mets of activity. A recent article in cJASN by Friedman et al. demonstrates this beautifully(1). The authors had performed cardiac testing in 87% of their patients then retrospectively applied the KDOQI, AST, Lisbon and ACC/AHA criteria to thier patients to assess how many would have been tested. Turns out that 100%, 92%, 68% and 20% would have been screened respectively. The authors discovered ischemic disease in 17 (10%) of their patients and 10 of them underwent revascularization (7 had single vessel PCI). KDOQI and AST guidelines would have picked up all of the cases, Lisbon criteria would have picked up 16 patients and ACC/AHA would have picked up 4 of the patients with ischemia. The problem is that it is not clear whether identifying ischemia or performing revascularization in such patients is of any benefit in reducing cardiovascular event rates! In fact there are well designed studies that show pre-surgical revascularization in all patients with ischemic heart disease does not reduce cardiovascular morbidity and mortality in patients undergoing major vascular surgery(2) - but of course these studies were not in dialysis patients...

What we need is a large multicenter randomized controlled trial to evaluate the potential benefit in pre-transplant cardiac testing +/- revascularization in reducing cardiac morbidity and mortality in patients undergoing renal transplantation - to settle the question once and for all.

Reference:
1. Friedman et al. A Call to Action: Variability in Guidelines for Cardiac Evaluation before Renal Transplantation. cJASN 2011;6:1185
2. McFalls et al. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med 2004;351: 2795
2804, 2004

Saturday, May 14, 2011

TOPIC DISCUSSION: Micro Rnas and Chronic Kidney Disease

CKD has been associated with IF/TA ( interstitial fibrosis and tubular atrophy) and progressive organ function loss. Micro RNAs or miRNAs are endogenous single stranded short RNA molecules that regulate 50% of the gene. So basically tell a gene to turn on or off or regulate the protein expression. miRNAs are deregulated in kidney diseases and in transplantation and perhaps might influence the kidney fibrosis and dysfunction.
Knowledge of these molecules could lead to good treatment options in the near future.

Some interesting points about miRNAs and kidney disease:
1. miRNAs were first mentioned as early as in 1990s, the first one was lin-4.
2. 851 miRNAs have been identified in humans
3. miRNAs in the pheontypic transition of the JG cells were studied in hypertension
4. many miRNAs have been noted in renal biopsy samples of HTN nephrosclerosis
5. miRNA patterns have been noted in transplant allograft rejection as well
6. mir192 is the prototype Diabetic nephropathy mRNA
7. Podocyte biology and especially IgA nephropathy have identified miRNAs as well.
8. miRNAs modulators might be future drug targets for certain renal and non renal diseases.

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21423249
http://www.ncbi.nlm.nih.gov/pubmed/20883280
http://www.ncbi.nlm.nih.gov/pubmed/19424061
http://www.ncbi.nlm.nih.gov/pubmed/19289845

Wednesday, May 11, 2011

CLINICAL CASE 37, ANSWERS AND SUMMARY

Dendritic Cells(DC) are important players in transplant immunology. Which one of these syndromes is associated with loss of IL-12 producing myeloid dendritic cells?
IPEX syndrome 16%IRF8 syndrome 41%BCG syndrome 33%OPES syndrome 8%

Nice work but slightly tough question. Not many responders. No such syndromes as BCG and OPES( made it up).  IPEX syndrome is a T reg FOXP3 deficiency syndrome. Hence, the right answer is IRF8 syndrome.  A recent article in NEJM May 2011 talks about description of this syndrome in few cases.  Infants were evaluated and looked at genetic analysis.  Disseminated infection caused by BCG vaccines is the early manifestation of primary immunodeficiencies - such as SCID.  Two distinct disease causing mutations were noted.  Both effecting Interferon regulatory factor 8 or IRF8 and leading to the disorder.  IRF8 is critical for development of monocytes and dendritic cells and anti mycobacterial immunity.  This is an interesting finding.
As we discover more and more of such associations ( FOXP3 deficiency and T regs) and this one now- we can use this information for better understanding immunology and hence transplant medicine benefits. Dendritic cells are antigen presenting cells and knowing that IRF8 is crucial in their functioning, perhaps an inhibitory molecule to IRF8 might be a target for future drug development in transplantation.  Lets see where this new disease entity takes us: as everyone knows- its not that simple.

take a look:

Tuesday, March 1, 2011

In the News: Transplant rules changing

Proposed Kidney Transplant Rules Favor Younger, Healthier Recipients
Kidney transplants would be given preferentially to younger, healthier patients, under rules being considered by the United Network for Organ Sharing (UNOS), according to the Washington Post.
Current rules favor recipients who have been on waiting lists longest, but the shift is an attempt "to get the most out of a scarce resource," according to Dr. Kenneth Andreoni, the chair of the UNOS committee considering the changes, as quoted in the Post.
Bioethicist Arthur Caplan, also quoted in the article, says that the change has implications for other areas of medicine: "This is moving it away from a save-the-sickest strategy to trying to get a greater yield in terms of years of life saved."
UNOS has circulated a document describing the proposal and is seeking comments. We link to it below.
Washington Post article (Free)

Saturday, November 20, 2010

ASN 2010 Live Update - Transplantation in the Elderly

TRANSPLATATION IN THE ELDERLY - TOO OLD TO TRANSPLANT??

This was a nice discussion by Dr. Gabriel Danovitch, MD from UCLA during the Medically High-Risk Kidney transplant candidates lecture series.

Take home points:
1.  Decreased relative risk of death after kidney transplant as compared to dialysis leads to increased survival, but Quality of life seems to be worse.
2.  Pre transplant work up is the same Standard w/u for elderly as in the general population.
3.  Overall, lower incident of rejection in elderly (? Weaker immune system)
4.  But Increased donor age seems to be associated with increased risk of Acute rejection and AR treatment in elderly is associated with worse morbidity/mortality than AR treatments in younger patients
5.  Older patients statistically get older patients’ Kidneys and more likely to be listed for ECD kidney.
6.  Dilemma – should living donation be encouraged in Elderly?….. Studies have shown that older patients usually receive suboptimal kidney (read ECD) and have high waiting list time….. But given lower life expectancy is this perhaps a “wasted” younger living kidney??
7.  Elderly patients have higher risk of infectious complication leading to death post transplant.  Also increased risk of lymphoma at this extreme of life
8.  Also have to worry about Polypharmacy in elderly while on immunosuppression.  There are great transplant research drug protocols that are targeted to elderly patients.

Overall, Dr. Danovitch recommends  --  choose patients carefully
Use biological age vs chronological age to help decide?
Make sure patients know what they are getting into – (i.e risk/benefits pertaining to Quality of life issues, other complications, death)
Do not take their immune systems for granted
Older patients do better with younger kidneys
Higher risk of DGF in ECD kidneys
Do not take their immune systems for granted
? Risk of thymo in elderly?  But there is no good data
watch out for infections

By Stanley Crittenden, MD

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