Cytokines Evaluation in Early Calcineurin Inhibitors Withdrawn on Renal Transplant
Condition: Renal Transplant Rejection; Immunosuppression
Study type: Interventional
Phase: Phase 4

Summary: 
      Currently, acute kidney injury is diagnosed by increased serum creatinine. However,
      creatinine is not a reliable marker for acute changes in renal function.

      The biology of the renal graft is influenced by chemokines from reperfusion (just after the
      kidney transplant) and throughout its course, when acute and chronic inflammatory changes
      occurs. Moreover, the evaluation of changes in urinary cytokines reflects kidney interstitial
      patterns, and can predict renal function, acute rejection episodes and their response to
      treatment.

      Today there are several studies comparing the relative immunosuppression of renal function,
      but few noticed its relationship with cytokines and chemokines. Thus, we proposed studying
      the inflammatory consequences of early calcineurin inhibitors (ICN) withdrawing in transplant
      patients by urine analysis. Kidney biopsy was done before ICN withdrawn and replaced by
      everolimus (3 months after transplant), and 1 year after transplant.
    

Detailed description: 
      1. Research objectives

           OBJECTIVES

           Main Objectives:

           • Evaluate the urinary chemokines in kidney transplant patients taking prednisone,
           tacrolimus and mycophenolate sodium compared to those in use prednisone, mycophenolate
           sodium and everolimus as maintenance immunosuppression.

           Secondary Objectives:

           • Assess renal function (serum creatinine and its clearance estimated by the
           Cockcroft-Gault) and a composite outcome (acute rejection, graft loss, death and
           abandonment of the study) in patients taking prednisone, tacrolimus and mycophenolate
           sodium compared to those taking prednisone, mycophenolate sodium and everolimus as
           maintenance immunosuppression.

        2. Scientific background, relevance and justification of the research

      In current clinical practice, acute kidney injury is typically diagnosed by measuring serum
      creatinine. Unfortunately, creatinine is an unreliable indicator during acute changes in
      kidney function. First, serum creatinine concentrations may not change until about 50% of
      kidney function has already been lost. Second, serum creatinine does not accurately depict
      kidney function until a steady state has been reached, which may require several days.
      Chemokines can influence at least three aspects of the biology of the renal graft: 1 - the
      restoration of blood flow in the graft can lead to injury type ischemia / reperfusion in
      which chemokines recruit leukocytes; 2 - receptor responses to infection during immune
      suppression involve chemokines and 3 - the inflammatory components in the acute rejection
      (RA) and interstitial fibrosis / tubular atrophy (IF/TA) are controlled by chemokines.

      Current data have showed urinary cytokines predicting renal function by months in renal
      transplanted patients. In the evaluation of urinary cytokines and chemokines in the presence
      of acute rejection, taken together the studies reported elevations of urinary levels of
      Protein-3 alpha (MIP-3α/CCL20), interleuxin-8 (IL-8/CXCL8), interleuxin-6 (IL-6), tumoral
      necrosis factor (TNF), interleukin- 10 (IP-10), interferon (IFN), monocyte chemoattractant
      protein-1 (MCP-1 / CCL2), Interferon gamma-induced protein 10 (IL-10), Monokine induced by
      gamma interferon (MIG/CXCL9), Interferon-inducible T-cell alpha chemoattractant
      (I-TAC/CXCL11), regulated upon activation normal T cell expressed and secreted (RANTES/CCL5).
      As predictors of complications and future changes in renal function, levels of Transforming
      growth factor beta (TGF-β) and interferon-gamma inducible protein 10 (IP-10/CXCL10) were
      associated with renal function 6 months and 4 years after transplantation (15-16).
      IP-10/CXCL10, MIG/CXCL9, G protein-coupled receptor 9 (GPR9/CXCR3), RANTES/CCL5 and the
      percentage of binding of interleukin-2 (IL-2) were associated with the occurrence of RA.
      IP-10/CXCL10 and MIG/CXCL9 were also considered useful as predictors of response to treatment
      of RA. Nankivell et al reported in 2003 that after 1year of renal transplant, 94% of patients
      present with chronic rejection grade I (BANFF score) and 76% present with calcineurin
      nephrotoxicity, although there is insufficient data about urinary cytokines at these
      situations. And adding new information, Hu et al reported in 2009 urinary major intrinsic
      protein-delta (MIP-δ), osteoprotegerin (OPG), IP-10/CXCL10, MIG/CXCL9 as good biomarkers for
      acute renal rejection and IF/TA.

      Nowadays there is a lot of studies comparing immunosuppression in relation to renal function
      but not so much in relation to chemokines and cytokines, which are more representative of
      allograft inflammation and fibrosis.

      So, we proposed studying the inflammatory consequences of early CNI withdrawn in renal
      transplant patients before the immunosuppression modification (3 months after transplant) and
      1 year after kidney transplant.
    

Intervention name(s): Everolimus
Intervention type(s): Drug
Intervention description(s): Replacement of tacrolimus by everolimus, 30 days after transplat. It was done after kidney biopsy (excluding acute rejection), blood and urine analysis.
Other intervention name(s): Certican
Intervention MeSH terms: Everolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: chronic allograft nephropathy; cytokines; kidney transplant; calcineurin inhibitors withdrawn