Cytokines Evaluation in Early Calcineurin Inhibitors Withdrawn on Renal Transplant

Study Overview
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Brief Summary
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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 Kidney biopsy was done before ICN withdrawn and replaced by everolimus (3 months after transplant), and 1 year after transplant.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
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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. 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.

Official Title
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Cytokines Evaluation in Early Calcineurin Inhibitors Withdrawn on Renal Transplant

Conditions
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Renal Transplant Rejection, Immunosuppression

Intervention / Treatment
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* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients over 18 years old and under 65 years old Recipients of first kidney transplant Donor younger than 65 years old PRA (panel reactive antigen) ≤ 30% in class I or class II No acute rejection episodes Proteinuria <1000 mg / day Exclusion Criteria: multiple organ transplant recipient Chronic liver failure Asymptomatic bacteriuria or urinary infection at randomization time Creatinine ≥ 2 mg / dL at randomization time (90 days after transplant) Presence of uncontrolled hypercholesterolemia (≥ 350 mg / dL, ≥ 9.1 mmol / L) or hypertriglyceridemia (≥ 500 mg / dL, ≥ 5.6 mmol / L) at randomization time (90 days after transplant)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: tacrolimus<br>Kidney transplant patients with living or deceased donors using tacrolimus, mycophenolate sodium and prednisone. | |
| Active Comparator: everolimus<br>Kidney transplant patients with living or deceased donors using tacrolimus, mycophenolate sodium and prednisone, and converted for everolimus, mycophenolate sodium, and prednisone 90 days after renal transplantation. | Drug: Everolimus<br>* Replacement of tacrolimus by everolimus, 30 days after transplat. It was done after kidney biopsy (excluding acute rejection), blood and urine analysis.<br>* Other names: Certican;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cytokines Evaluation | Cd106(VCAM-1) , IP-10/CXCL10, MIG/CXCL9, MCP-1/CCL2, IL-1, RANTES, IL-8, IL12p70, TNF, IL-10, IL-6, IL-1, VEGF, FGF, CD54(ICAM-1) were analysed in urine 90 days after transplant (before randomization), and 365 days after transplant. Material were conserved at -80 Celsius, and analysed by ELISA at same time. Data was shown in MFI units | Urine and biopsy data are collected 90 days and 365 days after transplant. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of Renal Function | Evaluation of renal function (serum creatinine) 90 days after transplant and 365 days after transplant. | 90 days after transplant and 365 days after transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic allograft nephropathy, cytokines, kidney transplant, calcineurin inhibitors withdrawn