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

Kidney Transplant Failure and Rejection Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04936282
• Other study ID #: TRAINING
• Status: Recruiting
• Phase: Phase 4
• Start date: July 5, 2022
• Est. completion date: June 30, 2024

Study information

• Verified date: November 2023
• Source: Fundación Canaria de Investigación Sanitaria
• Contact: Pedro Ruiz-Esteban, PhD
• Phone: +34951291542
• Email: pedro_ruiz_esteban[@]hotmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: June 30, 2024
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Kidney Transplant Failure and Rejection

Intervention

Drug:
• Grafalon
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).
• Normal Treatment
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)

Locations

Country	Name	City	State
Spain	Fundación Puigvert	Barcelona
Spain	Hospital Universitari Valld´Hebron	Barcelona
Spain	Veronica Lopez Jimenez	Malaga
Spain	Hospital Universitario de Canarias	Tenerife	None Selected

Sponsors (1)

Lead Sponsor	Collaborator
Fundación Canaria de Investigación Sanitaria

Country where clinical trial is conducted

Spain, 

References & Publications (30)

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Mehta RB, Tandukar S, Jorgensen D, Randhawa P, Sood P, Puttarajappa C, Zeevi A, Tevar AD, Hariharan S. Early subclinical tubulitis and interstitial inflammation in kidney transplantation have adverse clinical implications. Kidney Int. 2020 Aug;98(2):436-447. doi: 10.1016/j.kint.2020.03.028. Epub 2020 Apr 25. — View Citation

Moreno JA, Izquierdo MC, Sanchez-Nino MD, Suarez-Alvarez B, Lopez-Larrea C, Jakubowski A, Blanco J, Ramirez R, Selgas R, Ruiz-Ortega M, Egido J, Ortiz A, Sanz AB. The inflammatory cytokines TWEAK and TNFalpha reduce renal klotho expression through NFkappaB. J Am Soc Nephrol. 2011 Jul;22(7):1315-25. doi: 10.1681/ASN.2010101073. Epub 2011 Jun 30. — View Citation

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Nankivell BJ, Agrawal N, Sharma A, Taverniti A, P'Ng CH, Shingde M, Wong G, Chapman JR. The clinical and pathological significance of borderline T cell-mediated rejection. Am J Transplant. 2019 May;19(5):1452-1463. doi: 10.1111/ajt.15197. Epub 2019 Jan 22. — View Citation

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* Note: There are 30 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Graft Survival	Graft survival after kidney transplant in both groups	24 months
Secondary	Patient Survival	Patient survival after kidney transplant in both groups	24 months
Secondary	Assess the Adherence to Immunosuppressive Therapy in the Two Treatment Groups	The Basle scale was used to assess adherence to immunosuppressive therapy.	24 months
Secondary	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
Secondary	Blood Pressure mmHg	Blood pressure after kidney transplant in both groups at 24 months	24 months
Secondary	Number of Participants With Acute Rejection Lesions	Patients with acute rejection lesions (including subclinical rejection) at 24 months according to Banff classification	24 months
Secondary	Lipid Profile cholesterol, triglycerides	Lipid profile after kidney transplant in both groups at 24 months	24 months
Secondary	Klotho levels pg/ml	Klotho levels after kidney transplant in both groups at 1, 3, 6, 12 and 24 months	24 months