3-month Screening Biopsy to Optimize the Immunosuppression in Renal Transplantation (I4BiS)

Evaluation of a Strategy Based on the 3-month Screening Biopsy to Optimize the Immunosuppression in Renal Transplantation: the I4BiS Study

Renal transplantation represents currently the best therapeutic alternative for end-stage renal failure, not only in terms of patient outcomes (better quality of life and longer survival), but also in terms of costs for the society.

Progress achieved in the last 20 years has resulted in a drastic reduction of the incidence of "classic" (i.e. clinically patent) acute cellular rejection episodes.

Unfortunately, and rather unexpectedly, this progress has had hardly any effect on the frequency of the loss of kidney transplants beyond the first year, as shown by the stagnation of grafts' half lives.

Furthermore, the use of immunosuppressant combinations that are more and more powerful has an impact on adverse effects in recipients, including an increased incidence of infections, cancers, but also metabolic complications (diabetes, osteoporosis, dyslipidemia, etc.), which are cause of significant morbi-mortality.

In an attempt to improve on these disappointing outcomes, some teams have offered to perform screening biopsies: i.e. routine biopsies at specific time points during the follow up, irrespective of graft function. Their primary interest is to allow a pathological analysis of the graft at an early stage, i.e. when potential histological lesions allow for a diagnosis but before these lesions impact on graft's function. Indeed, it has been clearly demonstrated that therapeutic adjustments intended to protect the grafts are most effective when introduced early. There is a fairly broad consensus to perform these biopsies three months and one year after the transplantation. Performing screening biopsies has led to the identification of "subclinical" forms of rejection, i.e. graft infiltration by recipient immune effectors meeting the Banff histological criteria, but without increase in creatininemia.

Assuming that about 10% of screening biopsies performed at 3 months reveal a subclinical rejection, which needs to be treated, the management strategy for the remaining 90% of patients, whose biopsies show either i) a mild inflammatory infiltrates: i.e. "borderline changes", or ii) the complete absence of immune effectors in the graft is, poorly standardized.

The investigators therefore propose to conduct a prospective randomized trial to answer these questions simultaneously by evaluating a strategy to optimize the immunosuppression of renal graft recipients based on the presence or absence of subclinical intragraft inflammatory infiltrates in the screening biopsy performed at 3 months post transplantation. Patients with borderline changes (sub-study A) will be randomized to receive a treatment for rejection (corticosteroid boluses). Patients without inflammation in their graft (sub-study B) will be randomized for corticosteroid withdrawal. Impact on graft function, progression of histological lesions and incidence of morbidity will be evaluated.

Study Overview

• Status: Completed
• Conditions: Renal Transplantation
• Intervention / Treatment: Drug: Corticosteroid boluses Methylprednisolone; Other: No therapeutic modification; Other: Stop maintenance corticotherapy

• Study Type: Interventional
• Enrollment (Actual): 346
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Bordeaux, France, 33000
    • Service de Néphrologie,Transplantation, Dialyse I - Hôpital Pellegrin - CHU Bordeaux
  • Brest, France, 29609
    • Service de Néphrologie, Hémodialyse, Transplantations Rénales - Hôpital de la Cavale Blanche - CHU de Brest
  • Lille, France, 59037
    • Service de Néphrologie - Hôpital Claude Huriez - CHU de Lille
  • Lyon, France, 69437
    • Service de Néphrologie, Transplantation et Immunologie Clinique - Hôpital Edouard Herriot - Hospices Civils de Lyon
  • Nantes, France, 44093
    • Institut de Transplantation, Urologie et Néphrologie (ITUN) - CHU de Nantes
  • Paris, France, 75015
    • Service de Transplantation - Hôpital Universitaire Necker
  • Strasbourg, France, 67091
    • Service de Néphrologie et Transplantation - Nouvel Hôpital Civil - CHRU Strasbourg
  • Toulouse, France, 31059
    • Département de Néphrologie et Transplantation d'Organes - Hôpital Rangueil - CHU de Toulouse

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Common to both sub-studies (A and B)

   • Renal transplant patient aged between 18 and 75.
   • Patient who received a first or second renal graft
   • Immunosuppressive treatment consisting of an anti-calcineurin [cyclosporine (trough levels: 150<T0<300)], or tacrolimus (trough levels: 8<T0<12), mycophenolate mofetil and corticosteroids.
   • Patient who benefited from a screening renal biopsy 3 months after the graft
   • Patient who gave their informed consent
   • Patient affiliated to a social security scheme or being a beneficiary of such a scheme

2. Specific to sub-study A

   • Presence of "borderline" inflammatory infiltrates on the screening biopsy at 3 months as defined by the Banff classification 2013:

   • Absence of vascular lesions (v0) and:

     • tubulitis regardless of its significance (t1-3) with minimum interstitial infiltrate (i0-i1) OR
     • interstitial infiltrates (i2-3) without significant tubulitis (≤ t1)
3. Specific to sub-study B Absence of significant inflammatory infiltrates (i0-1 and t0) on the screening biopsy at 3 months

Exclusion Criteria:

1. Common to both sub-studies (A and B)

   • Histological subclinical rejection criteria on the screening biopsy at 3 months (Banff 2009: > i2+t2)
   • Donor specific antibodies in historical serum or de novo appearance during the first 3 months
   • Humoral lesions on the 3-month biopsy (Banff score g+ptc>2)
   • "Classic" acute rejection episode proven by biopsy during the first 3 months
   • Multiorgan transplantation
   • 3rd (or subsequent) renal transplantation
   • BK virus-associated nephropathy on the screening biopsy
   • Contraindication to the 1-year screening biopsy
2. Specific to sub-study B Initial nephropathy with a high risk of recurrence on corticosteroid withdrawal: segmental and focal and segmental glomerulosclerosis, lupus nephritis, vasculitis, or membranous glomerulonephritis

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sub-study A experimental arm; This experimental arm corresponds to patients with "borderline" infiltrates at 3 months, who will be randomized to receive a treatment for rejection (intensification of the corticotherapy with corticosteroid boluses = Corticosteroid boluses Methylprednisolone )	Drug: Corticosteroid boluses Methylprednisolone; Intensification of the corticotherapy in accordance with the validated protocol for the treatment of "classic" and subclinical acute rejections: 3 bolus Methylprednisolone 500 mg IV at D1, D2 and D3 then decreasing during 10-15 days at 1mg/kg/d and down to the maintenance dose. An anti-pneumocystis and anti-CMV prophylaxis will be systemically introduced for 3 months. The rest of maintenance immunosuppressive regimen (mycophenolate mofetil and anti-calcineurin) will remain unaltered
Active Comparator: Sub-study A control arm; This control arm corresponds to patients with "borderline" infiltrates at 3 months, who will be randomized to not change their immunosuppressive treatment (No therapeutic modification)	Other: No therapeutic modification; No therapeutic modification: continuation of the corticotherapy at the maintenance dose and maintaining unaltered the rest of immunosuppressive treatment (mycophenolate mofetil and anti-calcineurin).
Experimental: Sub-study B experimental arm; This experimental arm corresponds to patients without significant infiltrates 3 months, who will be randomized to stop maintenance corticotherapy (Stop maintenance corticotherapy )	Other: Stop maintenance corticotherapy; Immediate withdrawal of maintenance corticotherapy. Maintaining unaltered the rest of immunosuppressive treatment (mycophenolate mofetil and anti-calcineurin).
Active Comparator: Sub-study B control arm; This control arm corresponds to patients without significant infiltrates 3 months, who will be randomized to not change their immunosuppressive treatment (No therapeutic modification)	Other: No therapeutic modification; No therapeutic modification: continuation of the corticotherapy at the maintenance dose and maintaining unaltered the rest of immunosuppressive treatment (mycophenolate mofetil and anti-calcineurin).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evolution of graft inflammatory lesions	Interstitial infiltrate (i) and tubulitis (t) will be scored at 3 months and 1 year post transplantation using Banff classification (patients will be recruted 3 months after transplantation) A) Patient with "borderline" infiltrates at 3 months will be randomized to receive a treatment for rejection (sub-study A), with the aim of demonstrating the superiority of this strategy in terms of infiltrates involution (superiority study). B) Patient without significant infiltrates at 3 months will be randomized for maintenance corticotherapy withdrawal (sub-study B), with the aim of showing that this strategy does not cause an increase in the percentage of "borderline" infiltrates compared to the strategy that maintains the corticotherapy (non-inferiority study).	9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Graft function at 1 year post-transplantation	Measurement of the glomerular filtration rate by iohexol clearance at 1 year post transplantation (unit: ml/min:1.73m2)	9 months
Graft function at 1 year post-transplantation	Evolution of proteinuria between 3 months and 1 year (unit: g/24h).	9 months
Evolution of chronic histological lesions	Interstitial fibrosis will be quantified at 3 months and 1 year using a computerized color image analysis technique (unit = % fibrosis = 100*(green interstitial pixels / total interstitial pixels))	9 months
Evolution of chronic histological lesions	The 4 basic chronic lesions (unit = chronic glomerular damage [cg]; interstitial fibrosis [ci]; tubular fibrosis [ct]; vascular intimal thickening [cv]) will be scored at 3 months and 1 year using Banff classification)	9 months
Evaluation of the immunological risk associated with the different strategies of corticosteroid treatment adaptation	Percentage of patients showing the appearance of donor specific anti-HLA antibodies using the Luminex method® between the randomization (3 months) and the end of follow-up (1 year). (unit = % of patient)	9 months
Evaluation of the immunological risk associated with the different strategies of corticosteroid treatment adaptation	Proportion of patients showing an increase in humoral lesions (Banff score g+ptc) ≥ 2 on the screening biopsy at 1-year between the randomization (3 months) and the end of follow-up (1 year). (unit = % of patient)	9 months
Evaluation of the immunological risk associated with the different strategies of corticosteroid treatment adaptation	Proportion of patients showing ≥ 1 acute rejection episodes (cellular or humoral) proven by biopsy between the randomization (3 months) and the end of follow-up (1 year). (unit = % of patient)	9 months
Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation	Comparison of the data from the Holter monitor taken between 3 months and 1 year post-transplantation. (unit = mm of Hg)	9 months
Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation	Comparison of the data from the orally induced hyperglycemia test taken between 3 months and 1 year post-transplantation. (unit = mmol/l)	9 months
Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation	Comparison of the data from the lipid profile taken between 3 months and 1 year post-transplantation. (unit = mmol/l)	9 months
Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation	Comparison of the data from the bone mineral density, taken between 3 months and 1 year post-transplantation. (unit = g/cm2)	9 months
Evaluation of the infectious tolerance profile associated with the different strategies of corticosteroid treatment adaptation	Number of infectious episodes requiring treatment during the follow-up period between the randomization (3 months) and the end of follow-up (1 year). (unit = nb of episode)	9 months
Evaluation of the impact of the different strategies for corticosteroid use on quality of life.	Evolution of the patients' quality of life using self-questionnaires, adapted and validated for the French language (SF36), between the randomization (3 months) and the end of follow-up (1 year). (unit = SF 36 score)	9 months

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Olivier THAUNAT, MD, Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Actual): September 2, 2015
• Primary Completion (Actual): June 21, 2024
• Study Completion (Actual): June 21, 2024

Study Registration Dates

• First Submitted: March 25, 2015
• First Submitted That Met QC Criteria: May 13, 2015
• First Posted (Estimated): May 14, 2015

Study Record Updates

• Last Update Posted (Estimated): October 1, 2025
• Last Update Submitted That Met QC Criteria: September 25, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Immunosuppression; Screening renal biopsy
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate
• Other Study ID Numbers: 2014.848; 2014-005425-13 (EudraCT Number)