ASN2011: late breaking trials: RESCUE TRIAL

A trial was presented about looking at Sirolimus(SRL) in primary prevention of skin cancer in kidney transplant recipients.  Patients with history of known skin cancer who had received a kidney transplant were randomized to continue their current CNI based regimen or change to a SRL based regimen.
Use of SRL based regimen showed a 67% risk reduction of skin cancer. Data on post CrCl and proteinuria was not presented. It shows again and again to use that SRL is a very good cancer preventive agent but can it prevent acute rejection episodes and proteinuria is not clear. Data from Canada in mice studies discussed earlier in the Onco Nephrology pre course by Dr. Susan Quaggin shed light on the mTOR pathway. It appears that if the mTOR pathway is completely knocked out in mice, they developed collapsing FSGS and ESRD in 3-4 weeks. Clinically, perhaps SRL doesn't do a complete blockade and hence we don't get such drastic findings but here and there we do hear about the significant proteinuria from SRL.

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21610495
http://www.ncbi.nlm.nih.gov/pubmed/21792049

Journal Club: Can Sirolimus ever replace a CNI??

Sirolimus (SRL) has long been known as an antineoplastic agent and has played an important role as an adjuvant immunosuppressant in kidney transplant recipients who are high-risk candidates for Calcineurin inhibitor (CNI) based regimen such as those with history of active malignancy after the induction phase. Very little is known about its efficacy as compared to CNI’s in prolonging graft function and preventing acute and chronic rejection when they are used as primary immunosuppression agents in the post induction phase. Weir et al tried to investigate the efficacy of SRL based CNI free regimen in its head to head comparison with a CNI based regimen

In their Multicentric randomized control trial, 305 kidney transplant recipients receiving either Cyclosporine (Cys A) or Tacrolimus with Mycophenolate Mofetil (MMF) were randomized in their post induction phase into CNI continuation plus MMF or SRL plus MMF arms. Both the arms were similar in terms of demographics; African American composition and most patients in both arms were moderate risk for allograft rejection. Patients in both the arms were followed for 24 months for a primary end point of mean percentage change of Iothalamate based measured GFR at 12 months and secondary end points of measured GFR at 24 months, eGFR, biopsy proven acute rejection (BPAR) and patient or physician reported adverse effects. The authors found a significant higher mean % change in GFR (p-value 0.012) at 12 months in the SRL /MMF arm as compared to CNI/MMF based arm in their Intention to treat analysis. The difference became insignificant at 24 months (p-value 0.5). The difference was less significant in the per protocol analyses. The SRL arm had significantly more incidence of adverse events like mouth ulcerations, hypertriglyceridemia, higher proteinuria but no significant difference in biopsy proven acute rejection(BPAR)’s was found. In addition, they reported a significant 6 deaths in the CNI based arm as compared to none in the SRL arm

The study was one of the first ones comparing CNI and SRL based regimens head to head. In spite of the observed higher GFR’s attained in SRL arms, the study suffered major drawbacks. Being a non-inferiority study, the observations would have been much more compelling had the significant differences been found in both the per-protocol and intention to treat analyses and at both 12 and 24 month period. In addition, about 77 participants switched from the SRL arm to the CNI arm during the 24-month study duration and might have directly affected the results in case the change of regimen was from an adverse reaction or intolerance. Also, the mean Tacrolimus and Cys A trough levels were on the higher side after the 6 month post transplant period, falsely decreasing the GFR’s in the CNI arms. The lack of significance in BPAR’s and the cause of 6 deaths in the CNI arms not being directly related to the medications per se further undermine the overall safety differences.
Also, protocol biopsies would have been helpful to help out with the differences. 

SRL might be important medication in high-risk patients and those unable to tolerate the CNI’s but more studies are required to definitively prove the efficacy of CNI’s in preserving GFR’s and preventing BPAR’s when used as a primary agent.


Reference-
http://www.ncbi.nlm.nih.gov/pubmed/21191361
http://www.ncbi.nlm.nih.gov/pubmed/21792049

Post by Dr. Ashish Kataria,
Nephrology Fellow, Hofstra NSLIJ, NY

TOPIC DISCUSSION: SIROLIMUS , not all that benign

The complications that can occur with use of sirolimus are not that benign. The agent is good in certain cases but not all. Besides the known side effects of FSGS, proteinuria and TMA in the kidney, there are other non renal side effects that one needs to be aware of.
1. Leukopenia, Anemia, Thrombocytopenia
2. Impaired wound healing
3. Mouth Ulcers
4. Oligospermia
5. Interstitial Pneumonitis
6. Hyperlipidemia( all increased LDL, HDL and VLDL)
7. Hyperglycemia

Remember to monitor especially for lipids and glycemic control

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