Cytokines Evaluation in Early Calcineurin Inhibitors Withdrawn on Renal Transplant

The recruitment status of this study is unknown because the information has not been verified recently.
Verified June 2012 by Santa Casa de Misericórdia de Belo Horizonte.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Andre Barreto Pereira, Santa Casa de Misericórdia de Belo Horizonte
ClinicalTrials.gov Identifier:
NCT01239472
First received: November 10, 2010
Last updated: June 5, 2012
Last verified: June 2012
  Purpose

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 and throughout its course with the development of interstitial fibrosis and tubular atrophy ubiquitously present in grafts of long-term survival. Moreover, the evaluation of changes in urinary cytokines may predict renal function and 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 propose to study the inflammatory consequences on blood and urine with the early withdrawal of calcineurin inhibitors (ICN), with renal biopsy in renal transplant patients before the change of immunosuppression and 9 months after.


Condition Intervention Phase
Transplantation, Homologous
Immunosuppression
Drug: everolimus
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Cytokines Evaluation in Early Calcineurin Inhibitors Withdrawn on Renal Transplant

Resource links provided by NLM:


Further study details as provided by Santa Casa de Misericórdia de Belo Horizonte:

Primary Outcome Measures:
  • Evaluation of cytokines after calcineurin inhibitors withdrawn [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    MCP-1/CCL2, sTNFR2, IL-1Ra, MIP-δ, OPG, TGF-β, and IP-10/CXCL10 MIG/CXCL9 in urine and blood for measurement before and after conversion to tacrolimus everolimus, and evaluation of cytokines even among patients with and without conversion.


Secondary Outcome Measures:
  • Evaluation of renal function [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    Evaluation of renal function (serum creatinine, GFR, Cockcroft-Gault, Cr-1 slope) before and after conversion. Correlation of renal function with measurements of cytokines. Correlation of cytokine levels with the biopsy results.


Estimated Enrollment: 30
Study Start Date: January 2011
Estimated Study Completion Date: November 2013
Estimated Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: tacrolimus
Kidney transplant patients with living donors starting with the use of tacrolimus, mycophenolate sodium and prednisone without induction.
Active Comparator: everolimus
Kidney transplant patients with living donors starting with the use of tacrolimus, mycophenolate sodium and prednisone without induction, and converted for use of mycophenolate sodium, everolimus, and prednisone after 90 days of kidney transplantation.
Drug: everolimus
Kidney transplant patients with living donors starting with the use of tacrolimus, mycophenolate sodium and prednisone without induction, and converted for use of mycophenolate sodium, everolimus, and prednisone after 90 days of kidney transplantation.
Other Name: Certican

Detailed Description:
  1. Research objectives

    OBJECTIVES

    Main Objectives:

    • Evaluate the chemokines blood and urine 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 Cockroft-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 (1). 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. According to Hu and Knechtle (2), 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 RA and 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 MIP-3α/CCL20, IL-8/CXCL8, IL-6, TNF, IL10, IFN, MCP-1 / CCL2, IP10/CXCL10, MIG/CXCL9, I-TAC/CXCL11, RANTES/CCL5 (2, 3, 4,5-10,11-13,14,15). Only MIP-1β/CCL4 (4) urine was not increased, while EGF decreased (5). As predictors of complications and future changes in renal function, levels of TGF-β and IP-10/CXCL10 were associated with renal function 6 months and 4 years after transplantation (16,17). IP-10/CXCL10, MIG/CXCL9, CXCR3, RANTES/CCL5 and the percentage of binding of IL-2 were associated with the occurrence of RA (6,13,18). IP-10/CXCL10 and MIG/CXCL9 were also considered useful as predictors of response to treatment of RA (2,11,13). Nankivell et al reported that after 1year of renal transplant, 94% of patients present with chronic rejection grade I (BANFF) and 76% present with calcineurin nephrotoxicity, although there is insufficient data about urinary cytokines at these situations (19). In a recent study, Hu et al reported urinary MIP-δ, OPG, IP-10/CXCL10, MIG/CXCL9 as good biomarkers for acute renal rejection and IF/TA (20).

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 suppose to study the inflammatory consequences of early CNI withdrawn in renal transplant patients together with renal biopsy before the immunosuppression modification and 9 months after.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients over 18 years and under 65
  • Recipients of first kidney transplants
  • Donor less than 65 years
  • PRA (panel reactive antigen) ≤ 30%
  • No acute rejection
  • Proteinuria <1000 mg / d

Exclusion Criteria:

  • multiple organ recipient
  • recipient with less than 18 years
  • Re-transplant
  • Recipients with PRA> 30%
  • Chronic liver failure
  • Asymptomatic bacteriuria
  • Creatinine ≥ 2 mg / dL at the time of ICN withdrawal
  • Proteinuria ≥ 1g/24h at the time of ICN withdrawal
  • Presence of uncontrolled hypercholesterolemia (≥ 350 mg / dL, ≥ 9.1 mmol / L) or hypertriglyceridemia (≥ 500 mg / dL, ≥ 5.6 mmol / L)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01239472

Contacts
Contact: Andre B Pereira, PhD 55-31-87270853 andrebarper@yahoo.com.br
Contact: Pedro Augusto M Souza, MD 55-31-87270853 pmacedosouza@gmail.com

Locations
Brazil
Santa Casa de Misericórdia de Belo Horizonte Recruiting
Belo Horizonte, Minas Gerais, Brazil, 30150221
Principal Investigator: Andre B Pereira, PhD         
Sub-Investigator: Pedro Augusto M Souza, MD         
Sub-Investigator: Milton C Soares, MD         
Sub-Investigator: Gustavo MC Silva, MD         
Sub-Investigator: Cláudia Ribeiro, PhD         
Sponsors and Collaborators
Andre Barreto Pereira
Novartis
Investigators
Principal Investigator: Andre B Pereira, PhD Santa Casa de Misericórdia de Belo Horizonte
  More Information

No publications provided

Responsible Party: Andre Barreto Pereira, Doctor, Santa Casa de Misericórdia de Belo Horizonte
ClinicalTrials.gov Identifier: NCT01239472     History of Changes
Other Study ID Numbers: CRAD001ABR14T
Study First Received: November 10, 2010
Last Updated: June 5, 2012
Health Authority: Brazil: National Committee of Ethics in Research

Keywords provided by Santa Casa de Misericórdia de Belo Horizonte:
chronic allograft nephropathy
cytokines
kidney transplant
calcineurin inhibitors withdrawn

Additional relevant MeSH terms:
Mycophenolic Acid
Sirolimus
Mycophenolate mofetil
Everolimus
Tacrolimus
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antifungal Agents

ClinicalTrials.gov processed this record on August 26, 2014