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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Chronic Renal Failure

Intervention / Treatment
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* Drug: Methylprednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patients who fulfill all the following conditions Age 19 - 70 years. The patients who underwent renal transplantation. The patients who will show borderline change in 2-week protocol biopsy with stable graft function will be included in this study. (Stable function is defined as serum creatinine ≤1.5 mg/dl and ≤15% increase in serum creatinine in the 2 weeks before biopsy.) Exclusion Criteria: The patients who had clinical uremic symptom within 2 weeks after kidney transplantation.. The patients who had elevated serum creatinine level more than 1.5mg/dl or 15% compared to previous result. The patients' age under 19 years or over 70 years. The patients who underwent preoperative desensitization. The patients who had multiple organ transplantation. The patients who showed an allergic reaction to steroid. The patients who had psychologic disease (eg. depression) or history of psychologic medication. The patients participated in another clinical trial within 30 days before this study. The patients who did not agree with a consent form.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SPT group<br>The patients who will show borderline change in 2-week protocol biopsy with stable graft function will be included in this study. Methylprednisolone 0.5 g daily for 3 days will be administered in (Steroid pulse therapy) SPT group. | Drug: Methylprednisolone<br>* Steroid pulse therapy : Methylprednisolone 0.5 g daily for 3 days, followed by a tapered dose of 60 mg per day for a period of five days.<br>* Other names: high dose steroid therapy;|
| No Intervention: non-SPT group<br>The patients who will show borderline change in 2-week protocol biopsy with stable graft function will be included in this study. Steroid pulse therapy (SPT) will not be applied and no additional treatment will be added in non-SPT group | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Persistent subclinical rejection and chronic graft nephropathy at 1 year protocol biopsy | the rejection will be defined according to Banff criteria including borderline rejection. the degree of chronic graft nephropathy will be calculated based on a chronic sum score of the sum of the Banff chronic indices (cg + ci + ct + cv). the persistent subclinical rejection rate and the degree of chronic graft nephropahty according to the groups will be compared. | 1 year | 
| The effect of early steroid pulse therapy on the opportunistic infection including bacterial, fungal, and viral infections. | infection episodes will be recorded. cytomegalovirus (CMV), BK polyomavirus (BKV), varicella zoster virus (VZV), bacteria, fungus, TB, pneumocystis carinii infection will be included. rate of infection according to groups will be compared. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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kidney transplantation, subclinical borderline rejection, steroid pulse therapy