In the NEWS: Survival of Transplanted Allogeneic Beta Cells with No Immunosuppression

We know that Type 1 DM is a tough condition to have. Type 1 DM is an autoimmune condition where the immune system destroys the insulin-producing beta cells, resulting in a total lack of insulin, without which the body can’t regulate blood sugar. 

The “obvious solution”  would be to replace these lost cells, but transplantation introduces another problem: the immune system attacks any foreign cells, requiring toxic immunosuppression that comes with significant risks. We know this from our world in pancreas and kidney transplantation. 

In a brief report in NEJM, a group in Europe showed how edited cells that survived transplantation by becoming completely invisible to the immune system—a development that circumvents the immune rejection hurdle—and potentially removes the need for hostile immunosuppression. What the investigators did was to make the transplanted cells INVISIBLE to the immune system. They used CRISPR technology to remove HLA markers and then a viral technology to increase levels of CD47-- don't attack me signal. This made foreign cells look like your own.  What a clever idea.. The exact opposite of immunotherapy for cancer. 

They then went on to test this in a 42-year-old individual with Type 1 DM. And injected these edited cells into his forearm muscle with NO immunosuppression drugs and monitored him for 12 weeks. What happened?-- Edited cells SURVIVED and are not visible to the immune system, and started producing insulin within days. The patient responded to meals and was glucose responsive, and PET scans showed living functioning grafts. This is a fascinating move in science. They only used 7% of the possible dose, so the person still needed insulin. But this was a fascinating proof of concept we may be able to use in other autoimmune diseases, and introducing gene editing cells without the need for immunosuppression.

GVHD after Kidney transplantation? Can this happen?

GVHD is mainly associated with allogenic hematopoietic stem cell transplantation, and occurs much less frequently after transplantation of immunologically active solid organs such as liver and small intestine. GVHD after solid organ transplantation(SOT) is a very rare and frequently lethal complication caused by the engraftment and proliferation of allograft-associated lymphocytes in the immunosuppressed recipient, with subsequent immune-mediated attack by donor-origin effector cells directed against HLA-disparate host tissues. SOT-GVHD occurs most frequently following small bowel and liver transplantation, followed by lung and kidney transplantation in decreasing order of frequency. Risk factors for SOT-GVHD are the quantity of lymphoid tissue in the donor organ, greater degrees of HLA match between donor and recipient and recipient age over 65 years. Given there are immune system related tissue when one does solid transplants such as small bowel or liver is not uncommon.

80 cases of GVHD after liver transplant were reported in 2008, with published incidence rates of 1-2%.  worldwide. GVHD is the consequence of an immunologic reaction of engrafted lymphoid cells against the tissues of the host. It is known that transient lymphocyte chimerism occurs in recipients of SOT, and in fact it is thought to be necessary for the establishment of organ tolerance; however, lymphocyte chimerism usually rapidly decreases over time so that by the third postoperative week not allowing the risk of GVHD.

Only 4 cases of kidney transplantation associated GVHD ( what I found) have been reported. Typical symptoms and signs of GVHD are skin rash, severe diarrhea, and the elevation of total bilirubin, but these findings were often attributed by drug reactions or infections. These may make the delay of GVHD diagnosis.  The earliest time frame reported is 17 days after transplantation and latest up to 240 days following it.  Majority of those cases presented with diarrhea or rash and 50% mortality.

Specific tests have been used in diagnosis of GVHD. One is detection of macrochimerism which was defined as more than 1% donor nucleated cells in the peripheral blood of recipient, and the other is single-tandem repeat (STR) DNA analysis which quantifies relative amounts of different DNA in a single tissue sample.  A gastrointestinal source based disease usually reveals apoptotic cells in the endoscopy or colonoscopy findings.

A recent article discusses a case report from Korea. The other 3 cases have been from Japan and USA.

http://www.ncbi.nlm.nih.gov/pubmed/16627604

http://www.ncbi.nlm.nih.gov/pubmed/9496741

http://www.ncbi.nlm.nih.gov/pubmed/19917421

Role Playing in Transplant Teaching

Today at our transplant conference we did something fun.
A month ago, each fellow in training was assigned a transplant drug( MMF, imuran, cyclosporine, prograf, sirolimus, steroids and belatecpt).
In the one hour, each fellow had to play a role of the drug and stay in character. Initial rounds were introduction rounds and then followed debate rounds where major debates between Steroids vs no steroids, CNI vs belatecept, Cyclo vs prograf, sirolimus vs CNI and Imuran vs MMF happened.
It was tons of fun and fellows enjoyed it. Role playing of drugs taught them the strengths, mechanism of actions and their weaknesses.

Hoping to use tools like this to teach nephrology as we more forward; and make it lot of fun!!

Risk of PTLD post transplant?

Why and when is someone with a kidney transplant prone to get PTLD?
PTLD is a lymphoproliferative disorder that occurs because of impaired T-cell immunity after solid-organ or allogeneic stem cell transplant. 90% of the time these are EBV associated.


What are the risk factors for development of PTLD?
1. EBV-negative serostatus at time of transplant
2. Mismatching EBV-negative recipients with EBV positive donors
3. Intestinal Transplants have the highest incidence, then heart-lung, lung, heart, liver and then kidney
4. Children
5. Simultaneous CMV infection within 1 year of transplant
6. Certain HLA subtypes.

http://www.ncbi.nlm.nih.gov/pubmed/12621474
http://www.ncbi.nlm.nih.gov/pubmed/14986084

CMV in organ transplantation

CMV is a hard infection to treat in solid organ transplants. A nice consensus statement came out recently in Transplantation April 2010 issue going over medications. ( similar post on nephronpower for question discussion)
Based on these recs, 
1.IV ganciclovir is " gold standard" for CMV disease
2. The VICTOR trial compared valcyte to ganciclovir and was equally effective ( 900mg PO BID)
3. Do genotype resistance testing for CMV and if it is UL97 major mutation, likely will have ganciclovir resistance. If its a minor mutation or a pol mutation can still use ganciclovir but high doses. A major mutation requires switching to foscarnet.
4. If foscarnet is causing renal damage and or not working, other drugs have been tried.
5. Cidofovir has been tried in adenovirus, bk virus and CMV as well. There is little information on efficacy of cidofivir in single organ transplants but its use in stem cell transplants is also with mixed results.
6. Immunoglobulins containing CMV antibodies or cytogam has been used with good results in Stem cell transplants.  IVIG might have similar effects but no cases that I could find have been documented use of it. This should more likely be reserved for organ damage from CMV( retinitis, pulmonary damage, GI)
7. Leflunomide was reported to clear CMV in one case of Stem cell and one of a renal transplant patient.
8. Other drugs that have shown some anti CMV properties are sirolimus, artesunate and maribavir( experimental)


So the question we have up here, really there is no right answer as all of those drugs have shown some effect on CMV but IVIG is the least evidence about. I am sure its being used for CMV viremia or disease as the concept is the same as cytogam.


Check out the review article with good statements on how to manage difficult CMV viremia and disease patients.

Paired Donor Exchange Programs

At the ATC 2010, Speakers from the Alliance for Paired Donation, and other paired exchange programs reported their experience with paired exchange for ABO incompatible and HLA incompatible donor recipient pairs.  They spoke about shipping living donor kidneys; currently there does not seem to be a increase risk for DGF or graft dysfunction up to a CIT of 15 hours.  However they only reported short term results.  All groups agree that a national level paired exchange program needs to be created and apparently UNOS is attempting to do so.  Finding a way to organize such a project and work out financial agreements and oversight will be challenging.

by
Vinay Nair

H1N1 and Transplantation

A study at ATC 2010 showed the following

Novel H1N1 caused the 2009-10 pandemic, however the effect on Single Organ Transplants( SOT) is not well known.  The outcomes of H1N1 were reported in a large multicenter study by Kumar et al. from 4/2009 to 11/2009.  115 medically attended H1N1 infections were reported from US and Canada.  61% of patients described were lymphopenic and 65.2% were hospitalized.  Fever and recent ATG use was predictive of requiring hospitalization.  Complications included pneumonia (25.2%), ICU stay and 1 death.  Antiviral therapy was used in 91% of cases predominantly being oseltamivir monotherapy. Patients started on antiviral therapy before 48hrs of symptom onset were less likely to require ICU stay (0% vs. 22.4%).  

Conclusions/ comments:  H1N1 may cause significant morbidity in SOT patients.  If suspected, antiviral treatment should be started immediately and prior to confirmation of H1N1.  Unfortunately the effect of the H1N1 vaccine is not well characterized since the majority of reported cases occurred before vaccine availability.  The optimum dose, course and antiviral therapy remains unknown.  

Reported by Vinay Nair

Bone marrow transplantation and solid organs

The recent issue of Transplantation embarks on two articles on simultaneously doing a bone marrow transplantation and pancreas and islet cell respectively.
The first paper is a basic science study that showed bone marrow derived pancreatic cells are mobilized into injured pancreatic tissue and contribute to β-cell regeneration. Transplantation of BM-derived cells improved the function of injured pancreas, although the response is not sufficient to restore sustained normoglycemia is their conclusion.
The second paper was on islet cell transplants, another basic science study. Cotransplantation of bone marrow cells with islets was associated with enhanced islet graft vascularization and function in this paper.


This concept of bone marrow transplantation along with solid organs is not novel now. It was first reported few years ago in NEJM of actual 5 cases of kidney transplants along with bone marrow and the need for immunosuppresion was eliminated in these patients.  This is true thinking out of the box. Long terms outcomes of these patients is still underway.

Bowel Transplantations, not enough!

Interestingly, just read in AJT that bowel transplantations are not happening as much as they should.
The AJT report summarizes some of the reasons why.
1. Experience of Physicians and surgeons taking care of these patients
2. Knowledge gap and some physicians even not knowing this option exists.
3. TPN might be a better options in some viewpoints
4. There are not enough recipients
5. Some physicians consider this an experimental procedure.

As a Nephrologists, I think that its fascinating that the field of transplantation and immunology has come this far and hopefully in future, bowel transplantation might become a more standard of care option for patients with intestinal failure.

Adrenal Gland Transplantation

The recent issue of AJT Feb 2010 describes a case report of human intramuscular adrenal gland transplantation.
Intramuscular endocrine gland transplantations have been described and we do have cases of that in the renal world of parathyroid glands being retransplanted in the muscles forearms to help continue some function on ESRD patients.  Adrenal transplantation is less common. This case describes a story of a young girl who had adrenal insufficiency and had renal failure and received a renal and adrenal transplantation from her mother.
This is the first case of a successful adrenal transplant for adrenal insufficiency.
Chronic medical treatment for adrenal insufficiency includes steroids and treatment for the transplant also includes steroids, the risk and benefits have to be weighed eventually.
At this point, the authors recommend that adrenal gland allotransplantation is only indicated in patients who already are maintained on immunosuppression for either concomitant or prior solid organ transplants.