Tuesday, August 2, 2011

Announcement

From now on, all blog posts will appear on nephronpower.com for this blog.

Thanks

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.



Monday, July 18, 2011

Advagraf Study

There has been talk about using prograf once a day for quite sometime now.  When it is used once a day its a tacrolimus prolonged use and its called Advagraf.  A recent  multicenter, 1:1-randomized, parallel-group, noninferiority study compared the efficacy of twice a day tacrolimus to advagraf.; combined with steroids and low-dose mycophenolate mofetil without antibody induction, in 667 de novo kidney transplant recipients. 
Per paper:


Biopsy-proven acute rejection rate at 24 weeks  was 15.8% for Tacrolimus BID versus 20.4% for Tacrolimus QD (p = 0.182; treatment ).
Kaplan-Meier 12-month patient and graft survival rates were 97.5% and 92.8% for Tacrolimus BID and 96.9% and 91.5% for QD. 
Both treatment groups showed equally well-maintained renal function at 12 months  by GFR
Overall, it was not inferior to twice a day dosing.


The original Ref is at:
http://www.ncbi.nlm.nih.gov/pubmed/20840480

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.

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

Friday, June 24, 2011

Innate vs Adaptive Immune system

http://allergycases.org/2005/10/innate-immune-system-short-review.html

Check out the above website. Especially the nice break down of innate vs adaptive immune system.


Friday, June 17, 2011

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 16th 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.


by Dr. Vinay Nair

Wednesday, June 15, 2011

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 and can be divided into HHV-6 A and B.  Primary infection is mild and occurs usually in childhood; therefore the majority of healthy adults have serologic evidence of prior infection.  HHV-6 can re-activate in the immunocompromised transplant recipient leading to asymptomatic viral replication or less commonly active infection.  The highest prevalence by pcr has been shown to occur in bone marrow transplant recipients (28% to 75%) but viral replication has also been shown to occur 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 to specific antiviral treatments.   
How does HHV-6 infection present?
HHV-6 infection commonly presents with high fever often associated with leukopenia, and encephalitis between 2-4 weeks post transplantation.  Other clinical manifestations include pneumonitis, hepatitis, colitis and bone marrow suppression.  Rash typical of a leukocytoclastic vasculitis can also be seen.  Encephalitis may be associated with seizure activity and hyponatremia.  Encephalitis is more commonly seen in BMT patients but has been described in solid organ transplant patients as well.  HHV-6 infections commonly co-exist with other viral infections including CMV. 
HHV-6 reactivation has also been associated with drug induced hypersensitivity syndromes, malignancies, multiple sclerosis, fulminant hepatitis and mycocarditis though causality has not been demonstrated.
What are the associated laboratory and imaging findings?
CBC: Bone marrow suppression, leucopenia, thrombocytopenia
Chemistry: Transaminitis, hyponatremia
CSF:  High lymphocyte cell count with elevated protein.  HHV-6 can be detected in CSF by pcr. 
MRI of brain:  Symmetric non-enhancing white matter lesions.  MRI may be normal in patients infected with HHV-6.
How can you diagnose active infection?
Serologic testing:  Sensitivity varies and most tests cross react with HHV-7.  A fourfold increase in titers or seroconversion is considered diagnostic.
Virus culture from affected tissue or blood can be done but are difficult to perform.
Viral detection:  Virus may be present in PMBC’s of patients with latent infection leading to a “false” positive pcr.   Therefore HHV-6 should be identified in affected tissue or acellular plasma or serum. 
What are the treatment options?
No therapy has been clearly documented to treat HHV-6 although several agents with in-vitro activity have been tried.  Ganciclovir is effective against HHV-6B but may not be active against HHV-6A (minority of infections).  Foscarnet has activity against both A and B however; its use is complicated by nephrotoxicity.  In severe cases both agents can be tried and whenever possible a reduction in immunosuppression should be considered.

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

By
Dr. Vinay Nair

Tuesday, June 7, 2011

Sunday, June 5, 2011

BANFF 2011

The agenda for the meeting of Banff in Paris

Friday, May 20, 2011

Alemtuzumab for Induction- the 2011 update

A recent NEJM May 2011 article has one article that compares use of Alemtuzumab and early steroid removal to Basiliximab and Thymo.  Its a nicely done randomized controlled trial that is multi centered.
On face value:- appears that rate of biopsy confirmed acute rejection was lower in the alemtuzumab group in the low risk patients when compared to basiliximab and similar to thymo when compared in high risk groups.

Few points from the trial:
1. All were steroid sparing making things not standard around all programs
2. The infection events were statistically more higher in the Alemtuzumab group especially in the low risk population
3. WBC count was also <3000 in the treatment arm
4. Cancer, renal injury other complications were similar
5. Rate of late rejection (after 12 months) was higher in both low and high risk groups compared to standard treatment
6. If steroids were withdrawn, and infections were more in the alemtuzumab group, wonder what the rate of infection would have been with steroids!

Till further studies, looking ahead. Awaiting to see what the transplant community thinks

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21591943
http://www.ncbi.nlm.nih.gov/pubmed/21591949

Wednesday, May 11, 2011

Donor Risk Scores?

A recent review in Nature Nephrology discuses this important concept.  A large study out of Finland is discussed in this review and how the donor risk score was developed. What they describe is a donor allograft damage index which involves clinical components as well pathology components.
What constitutes the clinical components are: age >50, smoking, unstable blood pressure, HTN, need for CPR, alcohol abuse, untreated HTN, ischemic heart disease, arteriosclerosis, oliguria and the biopsy component is vascular intimal sclerosis, tubular atrophy, interstitial fibrosis, interstitial inflammation, mesangial matrix increase and glomerulosclerosis.  The Biopsies of the donors were graded with a 0-3 point system with each of the six histological criteria and the higher the points- the worse the kidney was.  The authors showed that the presence of >5 risk factors(clinical) and associated with an increase in mean allograft damage score from 0.5 to 1.4 and an increase in percent glomerulosclerosis from 1.5% to 8.1%.  And eventually higher donor risk scores were associated with long term graft outcomes over 5 years as well.
One of the few large studies to look at histological allograft data and comparing that to the clinical data.  Interesting to see what comes next.

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21303414
http://www.ncbi.nlm.nih.gov/pubmed/21522192

Friday, May 6, 2011

Dual Live Transplants performed

Check out the latest on dual liver and kidney( live donor) combined transplants done recently.

http://www.ldnews.com/news/ci_17976156

Thursday, April 28, 2011

Fascinating Wordle in AJT 2011

Check out this picture that was created on most cited surgical articles in ten surgical journals.
Turns out Transplantation topics rule and show the most results.
Nice
http://onlinelibrary.wiley.com/doi/10.1111/j.1600-6143.2011.03459.x/full

Monday, April 25, 2011

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

Monday, April 18, 2011

Sunday, April 17, 2011

Pancreas Transplantation in the Treatment of Diabetes


A nice treat from Nephrology on Demand

Wednesday, April 13, 2011

Transplant Tourism and Malignancy

Transplant Tourism does still continue and many patients continue to get kidneys from other countries where it could be commercial possible.  A recent study showed that when groups were compared( tourism kidneys to home country based kidneys):- the graft and patient survivals were equal but the 10 year cumulative cancer risk was significantly higher in the transplant tourism kidneys; especially in the older age group.  What might be contributing to this? - immunosuppresive therapy, difficulty in follow ups and were some of the thoughts mentioned in this article. Check it out


Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21270768

Saturday, April 2, 2011

Neutropenia from Tacrolimus


Post transplant neutropenia has many causes.  Etiology is usually medications, infections, cancer.
In a retrospective evaluation, 28% neutropenia was noted after first year of transplantation.  Most of this was sought to be from MMF-tacrolimus combination.
The drugs we usually consider are: MMF, azathioprine, acyclovir, gancyclovir, bactrim, valcyte.
A recent review on CJASN 2011, presents three patients with pure tacrolimus induced neutropenia and the mechanism behind it. All improved after they were switched to cyclosporine.

Why does it happen?
1. Direct inhibition of myeloid cells
2. effect of the drug on mononuclear accessory cells
3. pharmacokinetic interaction between MMF and tacrolimus
4. autoantibodies against myeloid precursors or mature neutrophils

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21258040
http://www.ncbi.nlm.nih.gov/pubmed/19538494

Monday, March 28, 2011

Who gets kidney first?- the thoughts in 2011

Organ allocation system always has been going down the list on a first come first basis. A discussion has been ongoing in the transplant circles and organizations on age based distribution of organs. Hence, someone who is young getting a "better" kidney then someone "older".  Is that reasonable or is that age based discrimination?

Take a look at the reactions of many below. There must be a better way!

http://onpoint.wbur.org/2011/03/01/allocating-kidney-organs

Then look at this opinion
http://www.azcentral.com/arizonarepublic/opinions/articles/2011/03/06/20110306newcomb-transplants-07.html

Wednesday, March 23, 2011

Kidney transplant and donation cancer risks

What are the risks of getting cancer from the donor?
Check out this report from UK regarding a recent case.

http://www.guardian.co.uk/society/2011/mar/22/kidney-transplants-donated-organs-cancer-risks

Tuesday, March 15, 2011

Hematuria Post Kidney Transplantation

An entity often not talked about and not much out there in the literature. a nice review below by Dr.Krish.


Wednesday, March 9, 2011

Elimination of anti rejection medicaitons

ASN news recently reported a study that is ongoing using specially processed stem cells from the same kidney donor being transplanted along with the kidney to that recipient, allowing that to continue in chimerism leading to an early presumed tolerance and hence no anti rejection medications for long term.
This concept is not new and has been attempted in the recent past. In 2008, NEJM paper by David Sachs et al showed that 5 patients could come off all immunosuppresion after a combined stem cell and kidney transplantation. This theory is used in myeloma treatment as well when patients get an allogenic and kidney transplant at the same time allowing to help both the organs of treatment.
A similar concept was presented recently in CJASN Feb 2011 issue about using autologous  mesanchymal stromal cells during kidney transplants. They showed that in two patients, this allowed engraftment of T regs in the peripheral blood and control memory CD8 T cells function.  In vitro studies have shown that mesenchymal stromal cells abrogate allo immune response  and could function as anti T cell agents in a "different" manner.


here is some older data on this topic:
http://www.ncbi.nlm.nih.gov/pubmed/18216355
http://www.ncbi.nlm.nih.gov/pubmed/20605588
http://www.ncbi.nlm.nih.gov/pubmed/20930086

Tuesday, March 8, 2011

Tissue Engineering Renal Tissue

The Regenerative Division at Wake Forrest University has been doing some ground breaking work.
One study done there allowed for some initial work regarding re generation of kidney cells.  This system involves the cultivation of expanded primary renal cells in a three-dimensional collagen-based culture system. After one week of growth, individual renal cells began to form renal structures resembling tubules and glomeruli. Histologically, these structures show phenotypic resemblance to native kidney structures. The reconstituted tubules stained positively for Tamm-Horsfall protein, which is expressed in the thick ascending limb of Henle's Loop and distal convoluted tubules. These results show that renal structures can be reconstituted in a three-dimensional culture system, which may eventually be used for renal cell therapy applications. The article listed below presents a three-dimensional culture system that allows for reconstituting single renal cells into kidney structures in vitro, thus providing a controlled platform for renal tissue formation in vivo.

ref:
http://www.ncbi.nlm.nih.gov/pubmed/18845258

Sunday, March 6, 2011

Bortezomib for desensitization!

Donor specific alloantibody producing plasma cells might be a good target for proteosomic inhibition by bortezomib. Bortezomib has some data in case series and reports of treating antibody mediated rejection. A recent study published in Transplantation 2011 discussed case series of 4 patients with extremely high DSA and couldn't just get apheresis alone.  They received 4 doses of bortezomib alone in one group and other 4 received 16 doses and  plasma exchange.  The response of these 8 patients was compared to 8 patients with plasma exchange alone.  Bortezomib alone didn't do much but bortezomib + plasma exchange did better than just plasma exchange alone in terms of DSA decrease.  This might lead to more protocols that might develop using this agent for treatment of desensitization.
This study is small and not well designed. IVIG has been used in many centers and Anti CD20 agents as well. Is it bortezomib alone that is doing the magic or is it that we just need two agents along with plasma exchange.  So plasma exchange + IVIG pr plasma exchange + rituximab or plasma exchange + bortezomib.

Have a look


Thursday, February 24, 2011

Skin cancer and Transplants

Talking to your patients and just educating them regarding regular skin cancer screening might be just enough to raise awareness and prevent skin cancer. Regular yearly dermatology visits for skin check ups are essential for prevention. Check out this latest healhday article.

http://consumer.healthday.com/Article.asp?AID=650075

Tuesday, February 15, 2011

Risk factors for post transplant Hypertension

Here are a list of factors that contribute to post kidney transplant development of Hypertension.
1. Pre existing HTN
2. Body Mass Index
3. Native Kidney disease
4. Donor age
5. Donor sex
6. Donor Hypertension
7. Longer Cold Ischemia time
8. Delayed graft function
9. Steroids
10. CNI( cyclosporine>tacrolimus)
11. Acute rejection
12. Anti body mediated rejection
13. Chronic Allograft Nephropathy
14. TMA
15. Recurrent glomerular disease
16. Transplant renal artery stenosis
17. Lymphocele leading to obstruction
18. Ureteric stenosis

Take a look at the more comprehensive article in AJKD
http://www.ncbi.nlm.nih.gov/pubmed/21251543

Monday, February 7, 2011

Male Fertility and Transplantation

Male fertility has not been studied in detail in transplantation.  Does immunosuppresive therapy have impact on sperm production or motility?
Most reports suggest that male transplant recipients have successfully fathered healthy kids.
The one drug that might have led to problems is sirolimus: On observational study showed that sperm count was decreased in the sirolimus arm of the study and that could affect pregnancy outcomes.  No data exists on other agents at this point.

Ref
http://www.ncbi.nlm.nih.gov/pubmed/18510638
http://www.ncbi.nlm.nih.gov/pubmed/17714220
http://www.ncbi.nlm.nih.gov/pubmed/19601935

Friday, February 4, 2011

Nephsap review: Transplantation

A question encountered on our recent Nephsap review on transplantation:
What regimen would be the safest in pregnancy? If one had to choose between CNI + prednisone or CNI+ azathioprine. The groups were divided.
What is the data?
As you go down the list in immunosuppresive medications: most are C and below and no medication is a Risk category A or B.  Cyclosporine has the most data with tacrolimus with extrapolated data. Aza and MMF would be close to category D compared to CNIs which are more of a category C. Steroids would also fall in category C.  From a clinical prespective, the safest immunosuppression for a woman who wishes to get pregnant seems to be a combination of controlled CNI and prednisione. MMF should be discontinued.
What if you were on a steroid sparing protocol? Would you add steroids or AZA instead of MMF?
Azathioprine is teratogenic in animal studies.  It does cross the placenta/ and hematologic toxicities can happen to the fetus.  But a lot of pregnancies have been documented successfully at many transplant centers with AZA.  So some centers would choose to add AZA in this case but some might just do steroids and CNI. Due to lack of data, there is really no right answer. Risks and benefits of all agents have to be discussed and decisions made on an individual basis.

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21266268
http://www.ncbi.nlm.nih.gov/pubmed/20685549
http://www.ncbi.nlm.nih.gov/pubmed/18368705
http://www.ncbi.nlm.nih.gov/pubmed/16095516

Tuesday, January 25, 2011

The Transplant Web

The most recent issue of AJT, under AJT report discusses the Transplant web and what is on the web for transplantation. It discusses many issues that pertain social media and transplantation. It brings home key points that patients are using the internet for their information and physicians are to be aware of that.  Social media can be a very good and powerful tool to discuss and teach physicians, students and patients. Many centers around the country are using it.  Mayo Clinic has a social media center.  What our role is to make sure patients are looking at association driven or university based websites that have peer reviewed material and accurate information. There is a lot out there -- perhaps that instills a "blogger's bias".

Check it out
http://onlinelibrary.wiley.com/doi/10.1111/j.1600-6143.2010.03394.x/full
http://socialmedia.mayoclinic.org/

Friday, January 21, 2011

Fibrosis with Inflammation at One Year Predicts Transplant Functional Decline

At the ASN 2010, there was an abstract regarding the role of fibrosis and inflammation at one year to predict transplant survival. Kidney transplants with both interstitial fibrosis and subclinical inflammation but not fibrosis alone after 1 year have reduced survival. This study tested whether fibrosis with inflammation at 1 year associates with decline of renal function in a low-risk cohort and characterized the nature of the inflammation.
A group of patients with their biopsies were studied. Over-expression of toll-like receptor signaling, antigen presentation/dendritic cell maturation, interferon production and cytotoxic T lymphocyte-associated and acute rejection-associated genes were noted more in the ones with increased fibrosis. Therefore, the combination of fibrosis and inflammation in 1-year protocol biopsies associates with reduced graft function and survival as well as a rejection-like gene expression signature, even among recipients with no clinical risk factors for poor outcomes.
The abstract can be found at Nephrology Now as well

NSLIJ - Innate B Cell in Humans that Protects Against Infections

NSLIJ - Innate B Cell in Humans that Protects Against Infections

Tuesday, January 11, 2011

Quiz 9 Answers

Which of these statements is TRUE regarding living donor related transplantation in Fabry's Disease?


Renal Transplantation from a heterozygote female relative into a patient with Fabry is risky as globotriaosylceramide accumulation might be present in this donor, without clinical symptoms ( is a true statement)
The measurement of Alpha galactosidase A activity in a potential female living related donor for a patient with Fabry's is not sufficient as a normal value cannot exclude a random X chromosome inactivation( is a true statement as well)
Living related transplantation is possible in donors who do not have the mutation.( this is true)
One has to be careful with male donors as late onset Fabry's disease exists in males and they 
develop proteinuria and renal failure after age of 25 years.( this is true)
Demonstration that the recipient's gene mutation is absent in the potential female relative donor is required before living related transplantation is performed in a patient with Fabry's ( also true)
Hence the answer is all of the above

Check out the Nature Review Nephrology Dec 2010 edition for Kidney Transplantation evals in Hereditary Nephropathies



Wednesday, January 5, 2011

Can Alcohol Consumption be protective post transplant?

One study presented at the recent ASN 2010 at Denver found that alcohol consumption in moderation was indicative of lesser incidence of post transplant diabetes (NODAT). The investigators argue that the belief of interactions with medications might be false and without evidence. Not only did they show that it was a decreased NODAT risk but also decreased risk of death post transplant.  So kind of similar to the general population.  
Check out Renal and Urology news's website for a video on the presenter at ASN 2010