Cytokines Evaluation in Early Calcineurin Inhibitors Withdrawn on Renal Transplant

Study Description

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Brief 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 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 or disease	Intervention/treatment	Phase
Transplantation, Homologous; Immunosuppression	Drug: everolimus	Phase 4

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	30 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Prevention
Official Title:	Cytokines Evaluation in Early Calcineurin Inhibitors Withdrawn on Renal Transplant
Study Start Date :	January 2011
Estimated Primary Completion Date :	June 2013
Estimated Study Completion Date :	November 2013

Arms and Interventions

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Arm	Intervention/treatment
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

Outcome Measures

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Primary Outcome Measures :

1. Evaluation of cytokines after calcineurin inhibitors withdrawn [ Time Frame: 2 years ]
   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 :

1. Evaluation of renal function [ Time Frame: 2 years ]
   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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 65 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
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

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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

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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
First Posted:	November 11, 2010
Last Update Posted:	June 6, 2012
Last Verified:	June 2012

Keywords provided by Andre Barreto Pereira, Santa Casa de Misericórdia de Belo Horizonte:

chronic allograft nephropathy; cytokines; kidney transplant; calcineurin inhibitors withdrawn

Additional relevant MeSH terms:

Prednisone; Everolimus; Sirolimus; Mycophenolic Acid; Tacrolimus; Calcineurin Inhibitors; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal	Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antibiotics, Antitubercular; Antitubercular Agents