Sirolimus - The negative aspects

A recent article in Kidney International discusses the negative and positive aspects of this interesting drug- sirolimus, mTOr inhibitor.  Initially designed to fight renal cancer, fast caught on to treat rejection and be used as an immunosuppression.
1. Six trials so far have randomized sirolimus vs a calcineurin inhibitor that were mentioned in this article. They all had more acute rejection episodes with sirolimus. So graft survival is a concern.
2. Renal toxicity has been described- from TMA to collapsing FSGS and severe proteinuria making it not as promising as CNI. But CNI have a more chronic toxicity to the kidney
3. Dyslipidemia has been noted as well more with this agent. - close to 60% of the patients getting mTor in clinical trials required lipid lowering agents
4. NODAT was also noted to be higher in this group; 25% more chance than CNI
5. Wound healing:- preventing the surgical wound healing or in future if patients need other surgeries makes it tough.
6. Other- mouth ulcers, myelosuppresion and infertility were more common in this agent as well.
7. Finally, they mention the new findings lately described pulmonary toxicities that are leading to a restrictive disease in the lung.

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/20703217

The Kidney Transplant in HIV patients- the NEJM study

Kidney Transplantation was rare in HIV+ cases few years ago and now many centers have developed protocols that have allowed this to happen with relatively good outcomes.
No prospective studies were ever done in this matter for rejection rates, outcome measures and so forth,
This month in NEJM 2010, a nice multi center study takes a look at this particular question. The investigators evaluated 150 patients for close to 2 years, multicenter fashion, non randomized prospective fashion.
The mean graft survival was 90% at one year and 3 years was 73.7%.  The ones that didn't do well were the ones with rejection episodes, use of thymoglobulin, and non living donors.  The rejection rate was higher than expected, close to 31% at 1 year and 41% in 3 years.

This study shows that graft survival is good but the rejection rates are high still and needs some work. Perhaps the drug interaction with HAART therapy play a role in the fluctuation of perhaps CNI levels and higher rejection risk or the immunosuppresive agents we have now are not the ideal ones for an immunodeficiency diseases model?


ref:
http://www.nejm.org/doi/full/10.1056/NEJMoa1001197
http://www.ncbi.nlm.nih.gov/pubmed/19776780

Quiz 8 answers

Immunology Quiz: There are two types of Tregs:- the natural kind and the induced kind. Which of these statements is FALSE?

1.The natural T regs are thymus derived   0 (0%)

2.The induced T regs are generated in the periphery   0 (0%)

3.The natural T regs are derived from T effector cells  5 (50%)

4.The natural T regs suppress autoimmunity  2 (20%)

5. The induced T regs induction requires CD28 signalling, and possibly TGF-B and other cytokines

  1 (10%)

6.The natural T regs are selected by autoantigens

  2 (20%)

There are two types of T regulatory cells, one that is natural Tregs and the other that is induced T regs.

But are Foxpe+T reg cells.

Natural T regs: are Thymus derived, selected by autoantigens and could be autoreactive.

They cross react to alloantigens and suppress autoimmunity.

Induced T regs: are generated in the periphery, derived from T effector cells.  Their induction requires cytokine activation and CD28 signialling.  They are positively and negatively regulated by many pathways.

Hence, the choice number 3 is wrong.

Nice review below:

http://www.ncbi.nlm.nih.gov/pubmed/20683480

Top Transplant Programs "by volume" in 2009, check out the list

http://nephronline.com/news.asp?N_ID=4188