Monday, November 7, 2011

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

1 comment:

  1. Great review.
    There seems to be an increasing number of papers that show conversion from CNI to mTOR inhibitors to be beneficial in terms of short term outcome (the trial you mention, Spare-the-Nephron, the Concept Study, and ZEUS study (with everolimus)). What I would really like to see is medium to long term outcomes. It is expected that stopping CNI will immediately improve GFR by removing intrarenal vasoconstriction. So the real question is will this transplant into long term benefits? MTOR inhibitors are associated with their own renal toxicities. It is interesting that in this trial, Spare-the-Nephron, measured GFR decreased between years 1 and 2 in both the MMF/SRL group and MMF/CNI group – but only significantly so in the MMF/SRL group. In addition at 24 months there was more proteinurea in the MMF/SRL group, suggesting potentially unrecognized renal injury in the sirolimus arm. So again, long term data is needed in these conversion trials and perhaps protocol biopsies, as you mentioned, to compare the progression of renal fibrosis.

    Vinay Nair

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