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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.

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

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.

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

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.

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 16^th 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.

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 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/15196083

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

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

By

Dr. Vinay Nair

Banff 2011 Updates 2