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Treatment of early borderline lesions in low immunological risk kidney transplant patients: a Spanish multicenter, randomized, controlled parallel-group study protocol: the TRAINING study
  • Hernández D
  • Vázquez-Sánchez T
  • Sola E
  • Lopez V
  • Ruiz-Esteban P
  • et al.
BMC Nephrol. 2022 Nov 7;23(1):357 doi: 10.1186/s12882-022-02989-z.
CET Conclusion
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This is a clearly written protocol for a multicentre randomised controlled trial. The hypothesis is that treatment of early borderline lesions (within 3 months of transplant) will prevent or decrease progression of IFTA. The treatment used will be rabbit ATG, so a safety study will be as important as any improvement at a histological level. The study is based on the fact that early, subclinical lesions are an indicator of subsequent drop in graft function and reduced graft survival, and that treatment at this stage will have a positive impact. Length of follow up is 24 months, which should be long enough to assess efficacy and safety in general. Patients will require a 3-month protocol biopsy to then determine whether or not they enter randomisation. The sample size calculation has made reference to previous data and expected dropout rates.
Aims: This study aims to investigate the effects of treating early borderline lesions with polyclonal rabbit antithymocyte globulin (Grafalon®) in comparison to conventional therapy, in low immunological risk kidney transplant recipients.
Interventions: Participants will be randomly assigned to either the Grafalon® group or the standard treatment group.
Participants: The study will randomise 80 kidney transplant recipients with low immunological risk.
Outcomes: The primary outcomes are the presence of interstitial fibrosis/tubular atrophy (IFTA) and graft function. The main efficacy outcomes are function and histological lesions.
Follow Up: N/A
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 treating 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-KT, 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.

DISCUSSION:

This phase IV investigator-driven, randomized, placebo-controlled clinical trial will examine the efficacy and safety of Grafalon® treatment in low-immunological-risk KT patients with early BL.

TRIAL REGISTRATION:

clinicaltrials.gov : NCT04936282. Registered June 23, 2021, https://clinicaltrials.gov/ct2/show/NCT04936282?term=NCT04936282&draw=2&rank=1 . Protocol Version 2 of 21 January 2022.

SPONSOR:

Canary Isles Institute for Health Research Foundation, Canary Isles (FIISC). mgomez@fciisc.org .
Optimizing a Protocol to Assess Immune Responses after SARS-CoV-2 Vaccination in Kidney-Transplanted Patients: In Vivo DTH Cutaneous Test as the Initial Screening Method
  • Barrios Y
  • Rodriguez A
  • Franco A
  • Alava-Cruz C
  • Marrero-Miranda D
  • et al.
Vaccines (Basel). 2021 Nov 12;9(11) doi: 10.3390/vaccines9111315.
UNLABELLED:

Previously, the delayed-type hypersensitivity (DTH) cutaneous test with the spike protein of SARS-CoV-2 has been shown to be a simple in vivo method to measure T-cell functionality after natural infection and in vaccinated individuals.

METHODS:

Twenty-five kidney-transplanted recipients were immunized with two doses of the mRNA-based Pfizer-BioNTech COVID19 vaccine three weeks apart. Cell-immune response (CIR) was evaluated ten weeks later using an in vivo DTH skin test and in vitro with an interferon gamma release assay (IGRA). Humoral Immune Response (HIR) was determined by the measurement of specific IgG anti-S1 SARS-CoV-2.

RESULTS:

Ten weeks after the second dose of the vaccine, 23 out of 25 transplanted patients had a positive DTH skin test, while in vitro CIR was considered positive in 20 patients. Unspecific stimulation was positive in all 25 patients, showing no T-cell defect. Seven out of twenty-five patients had a negative specific anti-spike IgG. CIR was positive in all immune-competent control patients.

CONCLUSIONS:

DTH is a useful, simple, and cheaper tool that can be used to assess cellular immune response, with an excellent correlation with the in vitro CIR. CIR assessment after vaccination in these immunocompromised patients is an excellent complement to HIR-based methods. This skin test could be used if classical in vitro methods cannot be applied.