The Effect of Steroid Pulse Therapy for the Reduction of Acute Rejection Episode in Subclinical Borderline Changes

Chronic Renal Failure Clinical Trial

Official title: The Effect of Steroid Pulse Therapy for the Reduction of Acute Rejection Episode in Subclinical Borderline Changes: An Open-Label, Randomized Clinical Trial

Status Recruiting

Clinical Trial Summary

• Several studies have shown that about 30% of transplanted kidneys with stable function present with tubule-interstitial mononuclear cell infiltration in protocol biopsies and therefore meet criteria for acute rejection. This subclinical rejection (SCR) has also been correlated with subsequent chronic allograft nephropathy and allograft dysfunction.

• The Banff scheme defines the minimal threshold for acute T-cell mediated rejection as infiltration of 25% or more of the renal cortex with five or more mononuclear cells in a focus of tubulitis or intimal arteritis (histological indices i2t2 or v1) and refers to borderline changes as those with insufficient for a diagnosis of acute T-cell mediated rejection, including mild to moderate (<50%) cortical infiltration and one to four mononuclear cells per tubule in cross section (i1t1 or i2t1)

• No consensus for the treating patients with borderline changes has been reached. Borderline changes with graft dysfunction are occasionally routinely treated with steroid pulse and, whereas subclinical borderline changes are simply 'ignored'. Particularly, a previous study demonstrated that most cases designated borderline by histopathology are found to be non-rejection by molecular phenotyping

• The aim of this study is to investigate the effect of early steroid pulse therapy for the reduction of acute rejection episode during the first year after renal transplantation in the patients who will show subclinical borderline changes at 2-week protocol biopsy.

Clinical Trial Description

Background

Several studies have shown that about 30% of transplanted kidneys with stable function present with tubule-interstitial mononuclear cell infiltration in protocol biopsies and therefore meet criteria for acute rejection (1). This subclinical rejection (SCR) has also been correlated with subsequent chronic allograft nephropathy and allograft dysfunction (2,3).

The Banff 97 working classification of renal allograft pathology was introduced to standardize the histological definition of acute allograft rejection and to guide treatment of renal transplant recipients (4,5). The Banff scheme defines the minimal threshold for acute T-cell mediated rejection as infiltration of 25% or more of the renal cortex with five or more mononuclear cells in a focus of tubulitis or intimal arteritis (histological indices i2t2 or v1) and refers to borderline changes as those with insufficient for a diagnosis of acute T-cell mediated rejection, including mild to moderate (<50%) cortical infiltration and one to four mononuclear cells per tubule in cross section (i1t1 or i2t1) (6).

The averaged prevalence of borderline SCR at 1-2 week is 24% (range 12-38%), at 1-2 months is 23% (range 21-27%), at 2-3 months is 23% (range 11-41%) and 1 year is 17% (range 7-44%) from selected studies (7). However, the pathogenic role of such limited cortical mononuclear infiltration is not well established and no consensus for the treating patients with borderline changes has been reached. In practice, borderline changes with graft dysfunction are occasionally routinely treated with steroid pulse and, whereas subclinical borderline changes are simply 'ignored'. Particularly, a previous study demonstrated that most cases designated borderline by histopathology are found to be non-rejection by molecular phenotyping (8). Furthermore, some previous studies have shown that the risk of infection is higher in patients receiving high dose steroid (9-12), and a previous study suggested that the infection risk was increased, up to as 1.5-fold, in patients receiving steroid pulse therapy (SPT) for acute rejection (13).

Some previous studies revealed that the graft survival rates with treated borderline SCR was 99.1% at 1-year, 95.1% at 5-years, and 93.7% at 10-years (14) and the graft survival rates with untreated borderline SCR was 90.9% at 1-year (15). However, there was no randomized controlled study on the effect of steroid pulse therapy in stable renal transplant recipients with subclinical borderline changes.

Purpose

• The reduction in risk of graft failure is the pivotal measure of effectiveness for evaluating immunosuppressive regimens for renal transplantation. However, because of the long follow-up periods and large sample size required for such an endpoint, randomized controlled trials of immunosuppressive therapies have mostly relied on the surrogate endpoints.

• In our institution, since routine protocol biopsies are performed at 2 weeks, 1 year, and 2 years after renal transplantation, it is practically difficult that graft survival is used as an endpoint for randomized controlled trials.

• From a meta-analysis for 31 observational studies (16), acute rejection was associated with an increased risk of graft loss risk ratios ranged from 1.2 - 10.5. Furthermore, chronic allograft nephropathy and graft survival is strongly correlated with acute rejection episode during the first year after renal transplantation (17,18).

• Therefore, the aim of this study is to investigate the effect of early steroid pulse therapy for the reduction of acute rejection episode during the first year after renal transplantation in the patients who will show subclinical borderline changes at 2-week protocol biopsy.

• To evaluate the benefit over the risk, this study also investigates the effect of early steroid pulse therapy on the opportunistic infection including bacterial, fungal, and viral infections. ;

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Renal Failure
• Kidney Failure, Chronic

• NCT number: NCT02664493
• Study type: Interventional
• Source: Samsung Medical Center
• Contact: Kyo Won Lee, M.D.
• Phone: +821099335192
• Email: kw1980.lee@gmail.com
• Status: Recruiting
• Phase: N/A
• Start date: February 2016
• Completion date: July 2020