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  • 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 .

  • López V
  • Vázquez-Sánchez T
  • Casas C
  • Schuldt R
  • Alonso-Titos J
  • et al.
Transplant Proc. 2021 Nov;53(9):2685-2687 doi: 10.1016/j.transproceed.2021.06.029.
BACKGROUND:

The coronavirus disease 2019 (COVID-19) pandemic has especially affected kidney transplant (KT) recipients, who are more vulnerable than the general population because of their immunosuppressive status and added comorbidities. The purpose of this study was to determine risk factors related to infection and mortality from COVID-19 in KT recipients.

METHODS:

The study included 113 stable KT recipients who had polymerase chain reaction-confirmed COVID-19 infection between March 2020 and February 2021, from a total of 2150 KT recipients. Outcomes related to patient survival were analyzed.

RESULTS:

The mean (standard deviation) age of the patients was 56 (14) years; 62% (n = 70) were men. The median time between KT and infection was 88 months (interquartile range, 39-155 months); 90% (n = 102) were on tacrolimus therapy and 81% (n = 92) on mycophenolate mofetil. The clinical presentation was pneumonia (n = 57; 51%), fever (n = 61; 54%), cough (n = 62; 55%), dyspnea (n = 43; 38%), lymphopenia (n = 57; 50%), and gastrointestinal symptoms (n = 28; 25%). A total of 21% (n = 24) required intubation and intensive care unit admission, and 27 patients (25%) were asymptomatic. A total of 9% (n = 10) received hydroxychloroquine therapy plus azithromycin, 11% (n = 12) tocilizumab, 3.7% (n = 4) lopinavir/ritonavir, 49% (n = 55) steroids, 0.9% (n = 1) remdesivir, and 9.3% (n = 11) convalescent plasma. Immunosuppression was reduced in all symptomatic patients. Nineteen patients (17%) died. Cox univariate analysis showed that the factors significantly associated with death were patient age, presence of pneumonia or lymphopenia, and elevated C-reactive protein on admission.

CONCLUSIONS:

Mortality in KT recipients with COVID-19 is very high, more than for the general population. Risk factors are patient age, presence of pneumonia or lymphopenia, and a higher C-reactive protein level at the time of diagnosis.

  • Coll E
  • Fernández-Ruiz M
  • Padilla M
  • Moreso F
  • Hernández-Vicente A
  • et al.
Transplantation. 2021 Oct 1;105(10):2146-2155 doi: 10.1097/TP.0000000000003873.
BACKGROUND:

Few studies have analyzed differences in clinical presentation and outcomes in solid organ transplant (SOT) recipients with coronavirus disease 2019 (COVID-19) across different pandemic waves.

METHODS:

In this multicenter, nationwide, prospective study, we compared demographics and clinical features, therapeutic management, and outcomes in SOT recipients diagnosed with COVID-19 in Spain before (first wave) or after (second wave) 13 July 2020.

RESULTS:

Of 1634 SOT recipients, 690 (42.2%) and 944 (57.8%) were diagnosed during the first and second periods, respectively. Compared with the first wave, recipients in the second were younger (median: 63 y [interquartile range, IQR: 53-71] versus 59 y [IQR: 49-68]; P < 0.001) and less likely to receive anti-severe acute respiratory syndrome coronavirus 2 drugs (81.8% versus 8.1%; P < 0.001), with no differences in immunomodulatory therapies (46.8% versus 47.0%; P = 0.931). Adjustment of immunosuppression was less common during the second period (76.4% versus 53.6%; P < 0.001). Hospital admission (86.7% versus 58.1%; P < 0.001), occurrence of acute respiratory distress syndrome (34.1% versus 21.0%; P < 0.001), and case-fatality rate (25.8% versus 16.7%; P < 0.001) were lower in the second period. In multivariate analysis, acquiring COVID-19 during the first wave was associated with an increased risk of death (OR: 1.47; 95% confidence interval [CI], 1.12-1.93; P = 0.005), although this impact was lost in the subgroup of patients requiring hospital (OR: 0.97; 95% CI, 0.73-1.29; P = 0.873) or intensive care unit admission (OR: 0.65; 95% CI, 0.35-1.18; P = 0.157).

CONCLUSIONS:

We observed meaningful changes in demographics, therapeutic approaches, level of care, and outcomes between the first and second pandemic waves. However, outcomes have not improved in the more severe cases of posttransplant COVID-19.

  • Vazquez-Sanchez T
  • Caballero A
  • Ruiz-Esteban P
  • Sola E
  • Marques E
  • et al.
TTS 2018. 27th International Congress of The Transplantation Society. June 30-July 5 Madrid, Spain. Introduction Monocytes comprise a heterogeneous population divided according to the membrane expression level of their molecules. One of these populations is the CD14++CD16+, which presents proinflammatory characteristics. Our aim was to evaluate the role of this monocyte population in renal transplant recipients with borderline rejection. Material and Methods This controlled clinical trial (NCT02284464) recruited patients with a low immunological risk to randomly receive conventional triple therapy (steroids, TAC and MMF) versus steroid withdrawal three months after the protocol biopsy. We analysed 66 patients with either a normal histology or borderline rejection. In all the patients we studied pre-randomisation levels of CD14++CD16+ at the third month in peripheral blood (PB) and blood extracted from the graft by fine needle aspiration cytology (FNAP). The monocytes were analysed by flow cytometry using CD14 and CD16 monoclonal antibodies. Results Of the 66 patients, 38 (51.1±12.8 years; 68.4% men) had a normal biopsy and 28 (57.8±9.5 years; 67.9% men) had borderline rejection. The percentage of proinflammatory monocytes was similar in the PB and FNAP samples from the patients with a normal biopsy (PB: 13.2±12.9 vs FNAP:16.3±14.3%; p=0.070). However, in the group with borderline rejection the difference in the percentage of these monocytes was significantly greater in the FNAP sample compared to the PB sample (PB: 7.9±5.4 vs FNAP: 16.9±16.5%; p=0.006). No differences were seen at the time of biopsy in renal function or proteinuria (Normal: Cr=1.6±0.6 vs Borderline: 1.7±0.5 mg/dL; p=0.536 and Normal: 268.2±197.9 vs Borderline: 269.3±239.8 mg/24h; p=0.986). Conclusion These preliminary results show that patients with a diagnosis of borderline rejection in the protocol biopsy present a significant difference in CD14++CD16+ monocytes between peripheral blood and graft blood, despite having a stable renal function. This suggests recruitment of these proinflammatory monocytes. Spanish Ministry of Economy and Competitiveness (MINECO) (grant ICI14/00016) from the Instituto de Salud Carlos III co-funded by the Fondo Europeo de Desarrollo Regional-FEDER, RETICS (REDINREN RD16/0009/0006). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.