Fibrosis in Renal Allografts

Interstitial Fibrosis in Protocol Biopsies of Renal Allografts: A Prospective, Randomised Trial of Sirolimus Versus Cyclosporine.(Fibrasic)

This prospective, randomized study, comparing sirolimus to cyclosporine in renal transplant recipients, has two major objectives:

1. -To determine the incidence and the degree of interstitialfibrosis and arteriosclerosis, as wel as the glomerular volume in protocol biopsies at 6 months in sirolimus-and in cyclosporine-treated renal allograft recipients, by means of quantitative computerized image analysis.

   • To determine the prognostic implication of these morphologic changes.
2. To study the expression of genes, involved in inflammation and fibrosis, in protocol biopsies at 6 months in sirolimus-and cyclosporine-treated renal allograft recipients.

Study Overview

• Status: Unknown
• Conditions: Kidney Failure, Chronic; Immunosuppression; Transplantation; Interstitial Fibrosis
• Intervention / Treatment: Drug: cyclosporine; Drug: sirolimus; Drug: daclizumab

Detailed Description

Calcineurin inhibitors have significantly improved the one-year graft survival of renal allografts. However, chronic nephrotoxicity caused by calcineurin inhibitors contributes to the long-term decline in renal function in kidney transplant recipients. Approximately ninety percent of the protocol biopsies of renal allografts, performed at 18 months post transplantation, show histological lesions of chronic calcineurin nephrotoxicity . In recent years, two new non-nephrotoxic immunosuppressive drugs, i.e. mycophenolate mofetil and sirolimus, have become available for the prophylaxis of graft rejection in renal transplantation.

Three randomized clinical trials, comparing cyclosporine with sirolimus in combination with mycophenolate mofetil, reported a superior graft function at one year in sirolimus treated renal allograft recipients. However, data on long-term graft survival and histological lesions of protocol biopsies in sirolimus-treated renal transplant recipients, are currently lacking.

In analogy with previous observations in native kidney disease, Grimm et al. recently reported that interstitial fibrosis in protocol biopsies of renal allografts, at 6 months post transplantation, significantly inversely correlates with the subsequent graft survival One hundred recipients of a first renal allograft will be randomized to an immunosuppressive protocol based on cyclosporine (50 patients) or sirolimus (50 patients). Concommittant immunosuppression will be similar in both groups, and consists of Daclizumab as induction treatment (five iv gifts every two weeks), and mycophenolate mophetil and steroids as maintenance immunosuppression.

Randomization will be performed by centre to avoid centre-related bias. All patients will complete a follow-up of 12 months. Two core biopsies of the graft will be obtained in each recipient, at implantation and at 6 months. Serum creatinine and the estimated creatinine clearance (by the Nankivell and the Jellife method) will be monthly recorded.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jean-Louis Bosmans, MD Ph.D; Phone Number: ..32/3/821 37 92; Email: JeanLouis.Bosmans@ua.ac.be
• Study Contact Backup: Name: Angelika Jurgens, Coordinator; Phone Number: ..32/3/821.34.68; Email: Angelika.Jurgens@uza.be

Study Locations

• Belgium
  • Antwerp
    • Edegem, Antwerp, Belgium, 9260
      • Recruiting
      • University Hospital Antwerp
      • Contact: Angelika Jurgens, Coordinator; Phone Number: ..32/3/821.34.68; Email: Angelika.Jurgens@uza.be
      • Contact: Jean-Louis Bosmans, M.D. Ph.D.; Phone Number: ..32/3/821 37 92; Email: JeanLouis.Bosmans@ua.ac.be
      • Principal Investigator: Jean-Louis Bosmans, MD. Ph.D.
  • Brabant
    • Brussels (Jette), Brabant, Belgium, 1090
      • Recruiting
      • University Hospital Brussels
      • Contact: Jacques Sennesael, M.D.; Phone Number: ..32/2/477.60.55; Email: hemofsn@az.vub.ac.be
      • Contact: Katrien Van Bever, Study-nurse; Phone Number: ..32/2/477.60.55; Email: Katrien.VanBever@az.vub.ac.be
      • Principal Investigator: Jacques Sennesael, M.D.
  • Oost-Vlaanderen
    • Gent, Oost-Vlaanderen, Belgium, 9000
      • Recruiting
      • University Hospital Gent
      • Contact: Patrick Peeters, M.D.; Phone Number: ..32/9/240.45.13; Email: p.peeters@ugent.be
      • Contact: Cathy Vandermeulen, Study-Nurse; Phone Number: ..32/9/240.61.68; Email: Cathy.Vandermeulen@uzgent.be
      • Principal Investigator: Patrick Peeters, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Recipients of a renal allograft, with a minimum age of 18 years.
2. Male or female recipients. Women of child-bearing age must practice adequate contraception
3. For renal allografts from living donors, at least one HLA-mismatch is required.
4. Written informed consent, compliant with local regulations.

Exclusion Criteria:

1. Recipients of a second or third renal allograft, with a past history of graft failure due to rejection.
2. Recipients of a renal allograft from a haplotype-identical living donor or a non-heart beating donor.
3. Cold ischemia time > 24 hours
4. Recipients of a kidney from donors ≥ 65 years of age
5. Recipients of multiple organs.
6. Pregnant women.
7. Immunological high-risk recipients, defined as current or historical PRA > 50 %
8. Recipients with focal segmental sclerosis as primary renal disease.
9. Recipients with leucopenia (WBC < 3000/mm³), thrombocytopenia (Thr < 100.000/mm³),or hyperlipidemia (Tot Chol > 300 mg/dl or Triglycerides > 300 mg/dl)
10. Previous history of malignancy, except completely excised basocellular skin tumor
11. Chronic active infection.
12. Inadequate compliance to treatment.
13. Use of specific drugs: Terfenadine, pimozide, astemizole, fluconazole, ketoconazole and cimetidine.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
The primary end-point of this study will be the cortical fractional interstitial fibrosis volume (V IntFib) in protocol biopsies at 6 months. The V IntFib will be determined on Sirius red stained slides by means of a computerized image analysis program,

Secondary Outcome Measures

Outcome Measure
Secundary end-points:
-Patient and graft-survival at one year.
-The serum creatinine and the estimated creatinine
clearance at 6 and 12 months.
-The 24 hour proteinuria at 6 and 12 months.
-The intimal area and arterial wall thickness in protocol
biopsies at 6 months.
-The glomerular volume in protocol biopsies at 6 months.
-The incidence of acute rejection episodes during the
first year.
-The severity of acute rejection episodes according to
the Banffâ 97 classification.
-The incidence of infectious complications.
-The incidence of hematological adverse effects.
-The number of antihypertensive and lipid-lowering drugs
at 6 and 12 months.
-The incidence of treatment failure.

Collaborators and Investigators

• Sponsor: University Hospital, Antwerp
• Collaborators: Wyeth is now a wholly owned subsidiary of Pfizer; Hoffmann-La Roche
• Investigators: Principal Investigator: Jean-Louis Bosmans, M.D. Ph.D., University Hospital, Antwerp

Publications and helpful links

General Publications

• Flechner SM, Goldfarb D, Modlin C, Feng J, Krishnamurthi V, Mastroianni B, Savas K, Cook DJ, Novick AC. Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine. Transplantation. 2002 Oct 27;74(8):1070-6. doi: 10.1097/00007890-200210270-00002.
• Groth CG, Backman L, Morales JM, Calne R, Kreis H, Lang P, Touraine JL, Claesson K, Campistol JM, Durand D, Wramner L, Brattstrom C, Charpentier B. Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation. 1999 Apr 15;67(7):1036-42. doi: 10.1097/00007890-199904150-00017.
• Kreis H, Cisterne JM, Land W, Wramner L, Squifflet JP, Abramowicz D, Campistol JM, Morales JM, Grinyo JM, Mourad G, Berthoux FC, Brattstrom C, Lebranchu Y, Vialtel P. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation. 2000 Apr 15;69(7):1252-60. doi: 10.1097/00007890-200004150-00009.
• Grimm PC, Nickerson P, Gough J, McKenna R, Stern E, Jeffery J, Rush DN. Computerized image analysis of Sirius Red-stained renal allograft biopsies as a surrogate marker to predict long-term allograft function. J Am Soc Nephrol. 2003 Jun;14(6):1662-8. doi: 10.1097/01.asn.0000066143.02832.5e.

Study record dates

Study Major Dates

• Study Start: May 1, 2005
• Study Completion (Anticipated): July 1, 2007

Study Registration Dates

• First Submitted: June 27, 2007
• First Submitted That Met QC Criteria: June 27, 2007
• First Posted (Estimate): June 28, 2007

Study Record Updates

• Last Update Posted (Estimate): November 26, 2008
• Last Update Submitted That Met QC Criteria: November 25, 2008
• Last Verified: October 1, 2005

More Information

Terms related to this study

• Keywords: Sirolimus; Chronic allograft nephropathy; Interstitial Fibrosis; Cyclosporine toxicity
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Kidney Diseases; Urologic Diseases; Renal Insufficiency, Chronic; Fibrosis; Kidney Failure, Chronic; Renal Insufficiency; Lung Diseases, Interstitial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Calcineurin Inhibitors; Sirolimus; Cyclosporine; Cyclosporins; Daclizumab
• Other Study ID Numbers: 2004-004115-38