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

Sponsor

Fundación Canaria de Investigación Sanitaria (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04936282

Collaborator

(none)

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Kidney Transplant Failure and Rejection	Drug: Grafalon Drug: Normal Treatment: Steroids, tacrolimus and mycophenolate	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Jan 1, 2022

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Steroids, tacrolimus, mycophenolate and Grafalon Normal treatment 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 When Borderline lesions are present in protocol biopsy, administer Grafalon ® 6 mg/kg/day in a single day.
Active Comparator: Steroids, tacrolimus and mycophenolate Normal treatment arm	Drug: Normal Treatment: Steroids, tacrolimus and mycophenolate When Borderline lesions are present in protocol biopsy, administer treatment according to routine clinical practice

Arm

Intervention/Treatment

Experimental: Steroids, tacrolimus, mycophenolate and Grafalon

Normal treatment 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

When Borderline lesions are present in protocol biopsy, administer Grafalon ® 6 mg/kg/day in a single day.

Active Comparator: Steroids, tacrolimus and mycophenolate

Normal treatment arm

Drug: Normal Treatment: Steroids, tacrolimus and mycophenolate

When Borderline lesions are present in protocol biopsy, administer treatment according to routine clinical practice

Outcome Measures

Primary Outcome Measures

Presence of interstitial fibrosis/tubular atrophy (IFTA) [24 months]
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.
Renal function [24 months]
Renal function after kidney transplant in both groups at 24 months measured according to glomerular filtration rate determined by CKD-EPI formula

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 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.
Presence of BL before randomization.
CMV infection or 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital Universitario de Canarias	Tenerife	None Selected	Spain	38320
2	Fundación Puigvert	Barcelona		Spain	08025
3	Hospital Universitari Valld´Hebron	Barcelona		Spain	08035
4	Hospital Regional Universitario de Málaga	Malaga		Spain	29010