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Renal Transplant RejectionPhase 4NCT01239472

Cytokines Evaluation in Early Calcineurin Inhibitors Withdrawn on Renal Transplant

A Phase 4 study testing Everolimus in people with Renal Transplant Rejection and Immunosuppression, run by Andre Barreto Pereira at 1 site in Brazil.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 65 years
Conditions the study is for
Renal Transplant Rejection, Immunosuppression
What is being tested?
Everolimus
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
1 siteBrazil
Study dates
Jan 2011to Jun 2015
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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)

Trial locations and contacts

1 site in 1 country.

Brazil1 site
  • Santa Casa de Misericórdia de Belo Horizonte

    Belo Horizonte, Minas Gerais, 30150221

Other trials in Brazil

About this study

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.

Read the 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.
  1. 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.

Being tested
Everolimus
Keywords
chronic allograft nephropathy, cytokines, kidney transplant, calcineurin inhibitors withdrawn

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EverolimusDrug

    Also called Certican

    Replacement of tacrolimus by everolimus, 30 days after transplat. It was done after kidney biopsy (excluding acute rejection), blood and urine analysis.

Study groups in NCT01239472
Study groupRoleWhat they receive
tacrolimusNo interventionKidney transplant patients with living or deceased donors using tacrolimus, mycophenolate sodium and prednisone.
everolimusActive comparatorKidney 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.
Receives: Drug: Everolimus

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: Urine and biopsy data are collected 90 days and 365 days after transplant.

Secondary outcomes (1)
  1. Evaluation of Renal Function

    Evaluation of renal function (serum creatinine) 90 days after transplant and 365 days after transplant.

    Measured: 90 days after transplant and 365 days after transplant

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Nov 2010 (estimated)
  2. Study startJan 2011
  3. Primary completionJun 2015
  4. Study completionJun 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
30 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01239472
Sponsor's protocol ID
CRAD001ABR14T
Status last verified
Jan 2020
First submitted
10 Nov 2010
Last updated
7 Feb 2020
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: All collected IPD will be shared in this website, and in the publication that is already being written.

Publications

  • Devarajan P. Emerging biomarkers of acute kidney injury. Contrib Nephrol. 2007;156:203-12. doi: 10.1159/000102085.

    PubMed 17464129
  • Hu H, Knechtle SJ. Elevation of multiple cytokines/chemokines in urine of human renal transplant recipients with acute and chronic injuries: potential usage for diagnosis and monitoring. Transpl Rev 2006;20:165-71

  • Ruster M, Sperschneider H, Funfstuck R, Stein G, Grone HJ. Differential expression of beta-chemokines MCP-1 and RANTES and their receptors CCR1, CCR2, CCR5 in acute rejection and chronic allograft nephropathy of human renal allografts. Clin Nephrol. 2004 Jan;61(1):30-9. doi: 10.5414/cnp61030.

    PubMed 14964455
  • Sibbring JS, Sharma A, McDicken IW, Sells RA, Christmas SE. Localization of C-X-C and C-C chemokines to renal tubular epithelial cells in human kidney transplants is not confined to acute cellular rejection. Transpl Immunol. 1998 Dec;6(4):203-8. doi: 10.1016/s0966-3274(98)80009-9.

    PubMed 10342733
  • Di Paolo S, Gesualdo L, Stallone G, Ranieri E, Schena FP. Renal expression and urinary concentration of EGF and IL-6 in acutely dysfunctioning kidney transplanted patients. Nephrol Dial Transplant. 1997 Dec;12(12):2687-93. doi: 10.1093/ndt/12.12.2687.

    PubMed 9430873
  • Smith SD, Wheeler MA, Lorber MI, Weiss RM. Temporal changes of cytokines and nitric oxide products in urine from renal transplant patients. Kidney Int. 2000 Aug;58(2):829-37. doi: 10.1046/j.1523-1755.2000.00232.x.

    PubMed 10916108
  • Jimenez R, Ramirez R, Carracedo J, Aguera M, Navarro D, Santamaria R, Perez R, Del Castillo D, Aljama P. Cytometric bead array (CBA) for the measurement of cytokines in urine and plasma of patients undergoing renal rejection. Cytokine. 2005 Oct 7;32(1):45-50. doi: 10.1016/j.cyto.2005.07.009.

    PubMed 16153856
  • Prodjosudjadi W, Daha MR, Gerritsma JS, Florijn KW, Barendregt JN, Bruijn JA, van der Woude FJ, van Es LA. Increased urinary excretion of monocyte chemoattractant protein-1 during acute renal allograft rejection. Nephrol Dial Transplant. 1996 Jun;11(6):1096-103.

    PubMed 8671975
  • Grandaliano G, Gesualdo L, Ranieri E, Monno R, Stallone G, Schena FP. Monocyte chemotactic peptide-1 expression and monocyte infiltration in acute renal transplant rejection. Transplantation. 1997 Feb 15;63(3):414-20. doi: 10.1097/00007890-199702150-00015.

    PubMed 9039933
  • Hu H, Aizenstein BD, Puchalski A, Burmania JA, Hamawy MM, Knechtle SJ. Elevation of CXCR3-binding chemokines in urine indicates acute renal-allograft dysfunction. Am J Transplant. 2004 Mar;4(3):432-7. doi: 10.1111/j.1600-6143.2004.00354.x.

    PubMed 14961998
  • Kanmaz T, Feng P, Torrealba J, Kwun J, Fechner JH, Schultz JM, Dong Y, Kim HT, Dar W, Hamawy MM, Knechtle SJ, Hu H. Surveillance of acute rejection in baboon renal transplantation by elevation of interferon-gamma inducible protein-10 and monokine induced by interferon-gamma in urine. Transplantation. 2004 Oct 15;78(7):1002-7. doi: 10.1097/01.tp.0000134397.55564.71.

    PubMed 15480165
  • Hauser IA, Spiegler S, Kiss E, Gauer S, Sichler O, Scheuermann EH, Ackermann H, Pfeilschifter JM, Geiger H, Grone HJ, Radeke HH. Prediction of acute renal allograft rejection by urinary monokine induced by IFN-gamma (MIG). J Am Soc Nephrol. 2005 Jun;16(6):1849-58. doi: 10.1681/ASN.2004100836. Epub 2005 Apr 27.

    PubMed 15857922
  • Kotsch K, Mashreghi MF, Bold G, Tretow P, Beyer J, Matz M, Hoerstrup J, Pratschke J, Ding R, Suthanthiran M, Volk HD, Reinke P. Enhanced granulysin mRNA expression in urinary sediment in early and delayed acute renal allograft rejection. Transplantation. 2004 Jun 27;77(12):1866-75. doi: 10.1097/01.tp.0000131157.19937.3f.

    PubMed 15223905
  • Sorrentino S, Landmesser U. Nonlipid-lowering effects of statins. Curr Treat Options Cardiovasc Med. 2005 Dec;7(6):459-66. doi: 10.1007/s11936-005-0031-1.

    PubMed 16283973
  • Yamada K, Hatakeyama E, Arita S, Sakamoto K, Kashiwabara H, Hamaguchi K. Prediction of chronic renal allograft dysfunction from evaluations of TGFBeta1 and the renin-angiotensin system. Clin Exp Nephrol. 2003 Sep;7(3):238-42. doi: 10.1007/s10157-003-0237-z.

    PubMed 14586721

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Everolimus in people with Renal Transplant Rejection and Immunosuppression, run by Andre Barreto Pereira at 1 site in Brazil.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 7 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 21 Oct 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Cytokines Evaluation (time frame: Urine and biopsy data are collected 90 days and 365 days after transplant.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01239472, which also lists 19 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Feb 2020.

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