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

Outcomes of kidney transplantation from HCV positive donors

Given the global organ shortage for transplantation, use of expanded criteria donors and donors with potentially transmissible diseases has been established as a way to mitigate this problem somewhat. While there is universal consensus on rejecting kidneys from HCV antibody positive donors for transplantation in HCV antibody negative recipients, there is controversy regarding the use of these kidneys for HCV antibody positive recipients. Well, we have the first study that reported the long-term experience in this area (Morales et al, Am J Transplant. Nov 2010). This study was done in Spain. Outcomes of 162 HCV antibody positive recipients (97% of them are HCV RNA positive as well) that received a kidney from HCV antibody positive donors were compared with outcomes of 306 HCV antibody positive recipients that recieved kidney from HCV antibody negative donors. Mean follow-up was 74.5 months. There was no difference in patient survial and decompensated liver disease between the two groups. 5-year and 10-year graft survival was 58.9% and 34.4% versus 65.5% and 47.6% respectively (p = 0.006) while death-censored graft survival was 69% and 47% versus 72.7% and 58.5% (p = 0.055). Cox-regression analysis could not identify the donor's HCV serology as a significant risk factor for death, graft failure and severe liver disease in HCV antibody positive recipients. These findings prove that use of this strategy is safe and helps the problem of severe organ shortage that we are facing now.

Salivary Prograf levels

Check out this interesting post from Pediatric Nephrology on salivary tacrolimus  levels

https://www.pediatric-nephrology.com/daily-updates/2010/10/26/329-salivatac.html

U 002 Nierentransplantation / kidney transplant

A nice you tube video ( cartoon) of a transplant surgery

FGF-23 and PTH and Bone Disease post transplant

Patients with ESRD have bone disease of various types. The three that are commonly seen are adynamic bone disease, increased bone turnover related or a combination of both.
BMD loss is common complication following kidney transplantation.
Few points to take home from a recent paper published in CJASN 2010, October edition.

1. The bone loss is accelerated in the post transplant period- why? Steroids and perhaps CNI worsen the rate.
2. Other risk factors are pre existing renal disease, hypogonadism, and metabolic acidosis.
3. 90% of post transplant patients have hypophosphatemia( CNI related and or tertiary hyperparathyroidism)
4. Renal phosphate wasting has bad effects  on bone
5. The renal phosphate wasting in part might be caused by elevated FGF23 levels or phosphatonin hormone.
6. PTH levels don't return completely to normal in most transplant patients post transplant
7. FGF 23 levels usually return to normal after one year post transplant
8. A recent study found that a high FGF23 level and low pth at time of transplant are the highest risk of developing bone disease post transplant
9. The most common bone biopsy finding post transplant is adynamic bone disease.

Image source: clipartheaven.com
References:
http://www.ncbi.nlm.nih.gov/pubmed/20634326
http://www.ncbi.nlm.nih.gov/pubmed/17359508
http://www.ncbi.nlm.nih.gov/pubmed/16941023

Aspergilloma in the transplant kidney

A recent issue of AJKD talks about a case of aspergilloma in the transplanted kidney. The fact that it affected the kidney is the novelty of the case and the also they used a novel way of treating this patient. Please see the link below.


http://www.ajkd.org/article/S0272-6386(10)01257-6/fulltext