Treatment of Early Borderline Lesions in Low Immunological Risk Kidney Transplant Patients (TRAINING)

Study Overview
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Brief Summary
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Background: Subclinical inflammation, including borderline lesions (BL), is very common (30-40%) after kidney transplantation (KT), even in low immunological risk patients, and can lead to interstitial fibrosis/tubular atrophy (IFTA) and worsening of renal function with graft loss. Few controlled studies have analyzed the therapeutic benefit of these BL on renal function and graft histology. Furthermore, these studies have only used bolus steroids, which may be insufficient to slow the progression of these lesions. Klotho, a transmembrane protein produced mainly in the kidney with antifibrotic properties, plays a crucial role in the senescence-inflammation binomial of kidney tissue. Systemic and local inflammation decrease renal tissue expression and soluble levels of α-klotho. It is therefore important to determine whether treatment of BL prevents a decrease in α klotho levels, progression of IFTA, and loss of kidney function. Methods: The TRAINING study will randomize 80 patients with low immunological risk who will receive their first KT. The aim of the study is to determine whether the treatment of early BL (3rd month post-KT) with polyclonal rabbit antithymocyte globulin (Grafalon®) (6 mg/kg/day) prevents or decreases the progression of IFTA and the worsening of graft function compared to conventional therapy after two years post-TX, as well as to analyze whether treatment of BL with Grafalon® can modify the expression and levels of klotho, as well as the pro-inflammatory cytokines that regulate its expression.

Official Title
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Treatment of Early Borderline Lesions in Low Immunological Risk Kidney Transplant Patients: a Spanish Multicenter, Randomized, Controlled Parallel-group Trial: The TRAINING Study

Conditions
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Kidney Transplant Failure and Rejection

Intervention / Treatment
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* Drug: Grafalon
* Drug: Normal Treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients of either sex, older than 18 years, with no immunological risk (PRA<20% and absence of DSA), who receive their first deceased donor or living donor KT. Presence of BL, excluding isolated inflammation (t0, i>0) and isolated tubulitis (t>0, i0). Patients receiving tacrolimus in combination with mycophenolic acid (MPA) and steroids. Absence of clinical or subclinical and histological immunological dysfunction before randomization. Absence of de novo DSA anti-HLA antibodies at the time of randomization. Provision of written informed consent. Acceptance of efficient contraception in women. Exclusion Criteria: Recipients of a multi-organ transplant. Re-transplants. Patients without inflammation in the third month protocol biopsy (i0,t0), or with isolated inflammation without tubulitis (t0,i>0) or isolated tubulitis without inflammation (t>0,i0). Presence of DSA antibodies before transplantation or at randomization. Cold ischemia time >30 hours. Serum creatinine >2.5 mg/dl or proteinuria >1 g/day at randomization. Presence of significant thrombopenia (<100,000/mm3) or leukopenia (<3000 mm/3) at randomization. Previous episode of clinical or subclinical rejection (≥IA) before randomization. CMV disease in the first three months after transplantation. BK-polyomavirus nephropathy at randomization. Recurrent or de novo glomerulonephritis. Treatment with immunosuppressive drugs other than those in this clinical trial. Patients who are positive for the human immunodeficiency virus (HIV) or with severe systemic infection, who, in the opinion of the investigator, require continued therapy. Previous (within the last 5 years) or present malignancy, except excised basal or squamous cell carcinoma.

Ages Eligible for Study
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Minimum Age: 18 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: Experimental<br>Normal treatment (Steroids, tacrolimus and mycophenolate) for first 90 days, then add Grafalon single-dose if borderline lesions are present in protocol biopsy (performed at third month post-transplantation). | Drug: Grafalon<br>* When Borderline lesions are present in protocol biopsy, administer Grafalon ® 6 mg/kg/day in a single day. Then continue with the normal treatment: Steroids (5 mg/day), tacrolimus (0.1 mg/kg/day) and mycophenolate (1000 mg/day).<br>|
| Active Comparator: Normal treatment<br>Normal treatment (Steroids, tacrolimus and mycophenolate) arm | Drug: Normal Treatment<br>* When Borderline lesions are present in protocol biopsy, administer the normal treatment: Steroids (5 mg/day), tacrolimus (0.1 mg/kg/day) and mycophenolate (1000 mg/day)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence of interstitial fibrosis/tubular atrophy (IFTA) | Measurement at 24 months according to the Banff classification. The Banff Classification of Allograft Pathology is an international consensus classification for the reporting of biopsies from solid organ transplant. | 24 months | 
| Renal function measured with CKD-EPI | Renal function after kidney transplant in both groups at 24 months measured according to glomerular filtration rate determined by CKD-EPI formula | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Graft Survival | Graft survival after kidney transplant in both groups | 24 months | 
| Patient Survival | Patient survival after kidney transplant in both groups | 24 months | 
| Assess the Adherence to Immunosuppressive Therapy in the Two Treatment Groups | The Basle scale was used to assess adherence to immunosuppressive therapy. | 24 months | 
| Incidence of Diabetes Mellitus | Incidence of diabetes mellitus after kidney transplant in both groups at 1, 2, 3, 4, 6, 9, 12, 18 and 24 months | 24 months | 
| Blood Pressure mmHg | Blood pressure after kidney transplant in both groups at 24 months | 24 months | 
| Number of Participants With Acute Rejection Lesions | Patients with acute rejection lesions (including subclinical rejection) at 24 months according to Banff classification | 24 months | 
| Lipid Profile cholesterol, triglycerides | Lipid profile after kidney transplant in both groups at 24 months | 24 months | 
| Klotho levels pg/ml | Klotho levels after kidney transplant in both groups at 1, 3, 6, 12 and 24 months | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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borderline lesions, α-klotho, low immunological risk, subclinical inflammation, kidney transplant