Cytokines Evaluation in Early Calcineurin Inhibitors Withdrawn on Renal Transplant

NCT01239472 | Completed Phase 4 Results

• 1 other identifier: CRAD001ABR14T
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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 Kidney biopsy was done before ICN withdrawn and replaced by everolimus (3 months after transplant), and 1 year after transplant.

Conditions

Renal Transplant Rejection; Immunosuppression

Keywords

chronic allograft nephropathy; cytokines; kidney transplant; calcineurin inhibitors withdrawn

Outcome Measures

Primary Outcomes (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

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

Secondary Outcomes (1)

• Evaluation of Renal Function

  90 days after transplant and 365 days after transplant

Study Arms (2)

tacrolimus

NO INTERVENTION

Kidney transplant patients with living or deceased donors using tacrolimus, mycophenolate sodium and prednisone.

everolimus

ACTIVE COMPARATOR

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

Interventions

Everolimus DRUG

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

Also known as: Certican

everolimus

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Andre Barreto Pereira: lead
• Novartis: collaborator

Study Sites (1)

Santa Casa de Misericórdia de Belo Horizonte

Belo Horizonte, Minas Gerais, 30150221, Brazil

Location

Related Publications (19)

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

  PMID: 17464129 BACKGROUND

• 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

  BACKGROUND

• 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.

  PMID: 14964455 BACKGROUND

• 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.

  PMID: 10342733 BACKGROUND

• 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.

  PMID: 9430873 BACKGROUND

• 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.

  PMID: 10916108 BACKGROUND

• 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.

  PMID: 16153856 BACKGROUND

• 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.

  PMID: 8671975 BACKGROUND

• 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.

  PMID: 9039933 BACKGROUND

• 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.

  PMID: 14961998 BACKGROUND

• 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.

  PMID: 15480165 BACKGROUND

• 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.

  PMID: 15857922 BACKGROUND

• 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.

  PMID: 15223905 BACKGROUND

• 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.

  PMID: 16283973 BACKGROUND

• 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.

  PMID: 14586721 BACKGROUND

• Teppo AM, Honkanen E, Finne P, Tornroth T, Gronhagen-Riska C. Increased urinary excretion of alpha1-microglobulin at 6 months after transplantation is associated with urinary excretion of transforming growth factor-beta1 and indicates poor long-term renal outcome. Transplantation. 2004 Sep 15;78(5):719-24. doi: 10.1097/01.tp.0000131816.51366.6b.

  PMID: 15371675 BACKGROUND

• Tatapudi RR, Muthukumar T, Dadhania D, Ding R, Li B, Sharma VK, Lozada-Pastorio E, Seetharamu N, Hartono C, Serur D, Seshan SV, Kapur S, Hancock WW, Suthanthiran M. Noninvasive detection of renal allograft inflammation by measurements of mRNA for IP-10 and CXCR3 in urine. Kidney Int. 2004 Jun;65(6):2390-7. doi: 10.1111/j.1523-1755.2004.00663.x.

  PMID: 15149352 BACKGROUND

• Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med. 2003 Dec 11;349(24):2326-33. doi: 10.1056/NEJMoa020009.

  PMID: 14668458 BACKGROUND

• Hu H, Kwun J, Aizenstein BD, Knechtle SJ. Noninvasive detection of acute and chronic injuries in human renal transplant by elevation of multiple cytokines/chemokines in urine. Transplantation. 2009 Jun 27;87(12):1814-20. doi: 10.1097/TP.0b013e3181a66b3e.

  PMID: 19543058 BACKGROUND

MeSH Terms

Interventions

Everolimus

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Limitations and Caveats

Principal Investigator was out of Santa Casa de Misericordia de Belo Horizonte in the periods august-2012 to september-2013, and after december-2014. Data was so restricted mainly to cytokine analysis, acute rejection, graft failure and mortality.

Results Point of Contact

• Title: Dr Andre Barreto Pereira
• Organization: Hospital e Maternidade Marieta Konder Bornhausen

andrebarper@yahoo.com.br

+55 47 984482826

Study Officials

• Andre B Pereira, PhD

  Marieta Konder Bornhausen Hospital and Maternity

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, Msc, PhD

Study Record Dates

• First Submitted: November 10, 2010
• First Posted: November 11, 2010
• Study Start: January 1, 2011
• Primary Completion: June 1, 2015
• Study Completion: June 1, 2015
• Last Updated: February 7, 2020
• Results First Posted: October 21, 2019

Record last verified: 2020-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data are already available in this website, and will keep available with the PI for 1 year after the publication.
• Access Criteria: All data will be available in this website and with the PI, Dr Andre Barreto Pereira, by his e-mail.

Locations

BR (1)