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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 .

  • Hernández D
  • Alonso-Titos J
  • Vázquez T
  • León M
  • Caballero A
  • et al.
J Clin Med. 2021 May 7;10(9) doi: 10.3390/jcm10092005.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This interesting multicentre study investigates the impact of late steroid withdrawal on graft histology following renal transplantation. Low risk patients 3 months post-transplant were randomized to withdrawal or continuation. Steroid withdrawal appeared safe for the majority of patients, with no increase in rejection or de-novo DSA and improved cardiovascular risk profile in keeping with previous studies. Of note, patients with subclinical inflammation at baseline (prior to withdrawal) demonstrated increased chronicity scores at 24 months if undergoing steroid withdrawal. This implies that baseline biopsy might be useful when considering steroid withdrawal, even in a low-risk cohort.
Aims: This study aimed to examine the impact of corticosteroid withdrawal (CSW) on inflammatory and chronic histological changes in kidney transplant recipients following transplantation.
Interventions: Participants were randomised to either the corticosteroid continuation group or the corticosteroid withdrawal group.
Participants: 105 low-immunological-risk kidney transplant recipients.
Outcomes: Acute rejection, inflammatory and chronicity scores, Banff scores, occurrence of de novo donor-specific antibodies (dnDSA), clinical and biochemical data during follow up, patient survival, graft survival and safety.
Follow Up: 24 months

The impact of corticosteroid withdrawal on medium-term graft histological changes in kidney transplant (KT) recipients under standard immunosuppression is uncertain. As part of an open-label, multicenter, prospective, phase IV, 24-month clinical trial (ClinicalTrials.gov, NCT02284464) in low-immunological-risk KT recipients, 105 patients were randomized, after a protocol-biopsy at 3 months, to corticosteroid continuation (CSC, n = 52) or corticosteroid withdrawal (CSW, n = 53). Both groups received tacrolimus and MMF and had another protocol-biopsy at 24 months. The acute rejection rate, including subclinical inflammation (SCI), was comparable between groups (21.2 vs. 24.5%). No patients developed dnDSA. Inflammatory and chronicity scores increased from 3 to 24 months in patients with, at baseline, no inflammation (NI) or SCI, regardless of treatment. CSW patients with SCI at 3 months had a significantly increased chronicity score at 24 months. HbA1c levels were lower in CSW patients (6.4 ± 1.2 vs. 5.7 ± 0.6%; p = 0.013) at 24 months, as was systolic blood pressure (134.2 ± 14.9 vs. 125.7 ± 15.3 mmHg; p = 0.016). Allograft function was comparable between groups and no patients died or lost their graft. An increase in chronicity scores at 2-years post-transplantation was observed in low-immunological-risk KT recipients with initial NI or SCI, but CSW may accelerate chronicity changes, especially in patients with early SCI. This strategy did, however, improve the cardiovascular profiles of patients.

  • Hernández D
  • Vázquez T
  • Alonso-Titos J
  • León M
  • Caballero A
  • et al.
J Clin Med. 2021 Apr 29;10(9) doi: 10.3390/jcm10091934.
CET Conclusion
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This paper reports on sub-clinical inflammation in low-risk renal transplantation. It was performed within a trial of corticosteroid withdrawal, and hence the randomisation is not related directly to this paper. Protocol biopsies were performed at 3 months after transplant, during which time no patient had acute rejection or developed de novo DSA. The biopsies showed that 54% of recipients had sub-clinical inflammation (which is in agreement with previous studies). This inflammation was correlated significantly with the absolute number of HLA mismatches, and independently with Class II mismatches in multivariate analysis, but not Class I. At this level of breakdown, however, there is a question of adequate power to make this assessment. In the multivariate analysis, several other factors were assessed and found not to be independent predictors of sub-clinical inflammation: recipient age, DGF, transfusion prior to transplant, and tacrolimus. Subclinical inflammation is present in half of kidney transplants on protocol biopsies and there is evidence from other studies that these changes can lead to chronic damage and dysfunction. The study is limited by its small sample size and ethnic homogeneity (100% Caucasian). It also represents an analysis of results from an RCT, and therefore may show association but has not proven causation and does not have significant or novel implications for clinical practice.
Aims: This study is a part of a randomised controlled trial comparing corticosteroid withdrawal versus standard immunosuppression in low-immunological-risk renal transplantation. The aim of this study was to determine the effect of human leukocyte antigen (HLA)-mismatching on early subclinical inflammation (SCI) in low-immunological-risk renal transplant patients.
Interventions: Participants in the original trial were randomised to either the prednisone continuation group or the prednisone withdrawal group.
Participants: 105 Caucasian renal transplant patients.
Outcomes: Association between HLA mismatches and SCI risk.
Follow Up: 3 months

The impact of human leukocyte antigen (HLA)-mismatching on the early appearance of subclinical inflammation (SCI) in low-immunological-risk kidney transplant (KT) recipients is undetermined. We aimed to assess whether HLA-mismatching (A-B-C-DR-DQ) is a risk factor for early SCI. As part of a clinical trial (Clinicaltrials.gov, number NCT02284464), a total of 105 low-immunological-risk KT patients underwent a protocol biopsy on the third month post-KT. As a result, 54 presented SCI, showing a greater number of total HLA-mismatches (p = 0.008) and worse allograft function compared with the no inflammation group (48.5 ± 13.6 vs. 60 ± 23.4 mL/min; p = 0.003). Multiple logistic regression showed that the only risk factor associated with SCI was the total HLA-mismatch score (OR 1.32, 95%CI 1.06-1.64, p = 0.013) or class II HLA mismatching (OR 1.51; 95%CI 1.04-2.19, p = 0.032) after adjusting for confounder variables (recipient age, delayed graft function, transfusion prior KT, and tacrolimus levels). The ROC curve illustrated that the HLA mismatching of six antigens was the optimal value in terms of sensitivity and specificity for predicting the SCI. Finally, a significantly higher proportion of SCI was seen in patients with >6 vs. ≤6 HLA-mismatches (62.3 vs. 37.7%; p = 0.008). HLA compatibility is an independent risk factor associated with early SCI. Thus, transplant physicians should perhaps be more aware of HLA mismatching to reduce these early harmful lesions.

  • Torres A
  • Hernández D
  • Moreso F
  • Serón D
  • Burgos MD
  • et al.
Kidney Int Rep. 2018 Jul 11;3(6):1304-1315 doi: 10.1016/j.ekir.2018.07.009.
INTRODUCTION:

Despite the high incidence of posttransplant diabetes mellitus (PTDM) among high-risk recipients, no studies have investigated its prevention by immunosuppression optimization.

METHODS:

We conducted an open-label, multicenter, randomized trial testing whether a tacrolimus-based immunosuppression and rapid steroid withdrawal (SW) within 1 week (Tac-SW) or cyclosporine A (CsA) with steroid minimization (SM) (CsA-SM), decreased the incidence of PTDM compared with tacrolimus with SM (Tac-SM). All arms received basiliximab and mycophenolate mofetil. High risk was defined by age >60 or >45 years plus metabolic criteria based on body mass index, triglycerides, and high-density lipoprotein-cholesterol levels. The primary endpoint was the incidence of PTDM after 12 months.

RESULTS:

The study comprised 128 de novo renal transplant recipients without pretransplant diabetes (Tac-SW: 44, Tac-SM: 42, CsA-SM: 42). The 1-year incidence of PTDM in each arm was 37.8% for Tac-SW, 25.7% for Tac-SM, and 9.7% for CsA-SM (relative risk [RR] Tac-SW vs. CsA-SM 3.9 [1.2-12.4; P = 0.01]; RR Tac-SM vs. CsA-SM 2.7 [0.8-8.9; P = 0.1]). Antidiabetic therapy was required less commonly in the CsA-SM arm (P = 0.06); however, acute rejection rate was higher in CsA-SM arm (Tac-SW 11.4%, Tac-SM 4.8%, and CsA-SM 21.4% of patients; cumulative incidence P = 0.04). Graft and patient survival, and graft function were similar among arms.

CONCLUSION:

In high-risk patients, tacrolimus-based immunosuppression with SM provides the best balance between PTDM and acute rejection incidence.

  • Neuberger JM
  • Bechstein WO
  • Kuypers DR
  • Burra P
  • Citterio F
  • et al.
Transplantation. 2017 Apr;101(4S Suppl 2):S1-S56 doi: 10.1097/TP.0000000000001651.

Short-term patient and graft outcomes continue to improve after kidney and liver transplantation, with 1-year survival rates over 80%; however, improving longer-term outcomes remains a challenge. Improving the function of grafts and health of recipients would not only enhance quality and length of life, but would also reduce the need for retransplantation, and thus increase the number of organs available for transplant. The clinical transplant community needs to identify and manage those patient modifiable factors, to decrease the risk of graft failure, and improve longer-term outcomes.COMMIT was formed in 2015 and is composed of 20 leading kidney and liver transplant specialists from 9 countries across Europe. The group's remit is to provide expert guidance for the long-term management of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant.The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year. In addition, the provision of a checklist increases the clinical utility and accessibility of these recommendations, by offering a systematic and efficient way to implement screening and monitoring of modifiable risks in the clinical setting.

  • Cruzado JM
  • Pascual J
  • Sánchez-Fructuoso A
  • Serón D
  • Díaz JM
  • et al.
Transpl Int. 2016 Dec;29(12):1317-1328 doi: 10.1111/tri.12862.
CET Conclusion
Reviewer: Centre for Evidence in Transplantation
Conclusion: This study of the effect of everolimus versus tacrolimus on left ventricular hypertrophy was well conducted and reported. The study was run over 4 years at 9 centres, this equates to roughly 2 patients per centre, per year. Initially it is hard to work out if the treatment improved LVH as all of the parameters of morphological and functional echocardiography are presented. It actually looks like patients continuing on tacrolimus saw a significant reduction in percentage with LVH at 24 months, whereas a similar proportion converted to everolimus still had LVH. Whilst both groups had reductions in concentric hypertrophy, the reduction in concentric remodelling seen with everolimus was offset by an increase in eccentric hypertrophy. Left ventricular mass index was reduced in both treatment arms after 24 months.
Aims: To assess whether conversion to everolimus (EVR) is associated with reduction of left ventricular hypertrophy (LVH) at 24 months in renal allograft recipients receiving maintenance immunosuppression therapy with tacrolimus (TAC) and mycophenolate mofetil (MMF)/mycophenolic acid (MPA).
Interventions: Participants were randomized to either remain on a TAC regimen or to convert to EVR regimen, both in combination with MPA.
Participants: Recipients of a first or second single-kidney transplant within the last 3 years who were ≥ 6 months postttransplant, aged 18-70years and receiving TAC plus MPA prior to the study.
Outcomes: The primary outcome measured was LVH. Secondary outcomes include cardiovascular profile improvement, safety assessments and biopsy-proven acute rejection, graft loss and death.
Follow Up: 24 months

Left ventricular hypertrophy (LVH) regression after kidney transplantation may be influenced by immunosuppression. In a 24-month open-label, multicenter, phase-IV study, 71 kidney allograft recipients without previous acute rejection, showing eGFR >40 ml/min and proteinuria <500 mg/day and between 6 months and 3 years post-transplantation, were randomized to receive everolimus (EVR) + mycophenolic acid (MPA) or were maintained on tacrolimus (TAC) + MPA. The aim was to assess whether the conversion to EVR could reduce left ventricular mass index (LVMi) at month-24. LVMi at month-24 decreased without differences between groups (TAC: 54.0 vs. 48.2 g/m2.7 ; EVR: 53.4 vs. 49.4 g/m2.7 ). The LVH prevalence at baseline and month-24 was 59.4% and 40.6% in TAC group and 57.1% and 50.0% in EVR group. EVR conversion was associated with nearly disappearance of concentric LVH and concentric remodeling pattern. The procollagen type I N-terminal propeptide at month-24 showed greater reduction in EVR group (51.6 vs. 58.2 mg/l; P = 0.004). Conversion from TAC to EVR was associated with a significant improvement of eGFR (P = 0.0315, ancova). Adverse events were similar between groups without rejection episode or graft loss. Conversion from TAC to EVR did not further reduce LVMi after 24 months, although its effect on concentric LVH deserves further investigation (NCT01169701).

  • Morales J
  • Pascual J
  • Sanchez-Fructuoso A
  • Serón D
  • Díaz J
  • et al.
American Transplant Congress 2015. May 2-6, Philadelphia, Pennsylvania, America.. 2015.
American Transplant Congress 2015. May 2-6, Philadelphia, Pennsylvania, America.
  • Pascual J
  • Alonso A
  • Burgos D
  • Cruzado JM
  • Serón D
  • et al.
Nefrologia. 2012;32 Suppl 2:1-28 doi: 10.3265/Nefrologia.pre2012.Mar.11433.
Clinical Appraiser: Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Methodological Appraisers:
  • Rhiannon Deierhoi Reed, University of Alabama at Birmingham, Comprehensive Transplant Institute, USA
  • Katriona O'Donoghue, Centre for Evidence in Transplantation, The Royal College of Surgeons of England
Overall Guideline Assessment: ★★★☆☆☆☆ (3 of 7)
Appraiser 1 Appraiser 2 Appraiser 3
2 4 3
Recommendation for future use
Appraiser 1 Appraiser 2 Appraiser 3
No Yes with modifications No
Domain 1 - Scope and Purpose 72%
Appraiser 1 Appraiser 2 Appraiser 3
1. The overall objective(s) of the guideline is (are) specifically described 4 3 7
2. The health question(s) covered by the guideline is (are) specifically described 4 7 6
3. The population (patients, public, etc.) to whom the guideline is meant to apply is specifically described 4 7 6
Domain 2 - Stakeholder Involvement 30%
Appraiser 1 Appraiser 2 Appraiser 3
4. The guideline development group includes individuals from all the relevant professional groups 3 4 3
5. The views and preferences of the target population (patients, public, etc.) have been sought 2 2 1
6. The target users of the guideline are clearly defined 2 6 2
Domain 3 - Rigour of Development 43%
Appraiser 1 Appraiser 2 Appraiser 3
7. Systematic methods were used to search for evidence 2 4 2
8. The criteria for selecting the evidence are clearly described 2 2 1
9. The strengths and limitations of the body of evidence are clearly described 1 7 3
10. The methods for formulating the recommendations are clearly described 4 7 5
11. The health benefits, side effects, and risks have been considered in formulating the recommendations 4 3 4
12. There is an explicit link between the recommendations and the supporting evidence 3 7 6
13. The guideline has been externally reviewed by experts prior to its publication 4 7 5
14. A procedure for updating the guideline is provided 1 1 1
Domain 4 - Clarity of Presentation 46%
Appraiser 1 Appraiser 2 Appraiser 3
15. The recommendations are specific and unambiguous 4 4 3
16. The different options for management of the condition or health issue are clearly presented 3 7 4
17. Key recommendations are easily identifiable 3 4 2
Domain 5 - Applicability 12%
Appraiser 1 Appraiser 2 Appraiser 3
18. The guideline describes facilitators and barriers to its application 4 1 1
19. The guideline provides advice and/or tools on how the recommendations can be put into practice 2 1 1
20. The potential resource implications of applying the recommendations have been considered 2 1 1
21. The guideline presents monitoring and/ or auditing 3 3 1
Domain 6 - Editorial Independence 92%
Appraiser 1 Appraiser 2 Appraiser 3
22. The views of the funding body have not influenced the content of the guideline 7 7 6
23. Competing interests of guideline development group members have been recorded and addressed 6 7 6
  • Holdaas H
  • Rostaing L
  • Serón D
  • Cole E
  • Chapman J
  • et al.
Transplantation. 2011 Aug 27;92(4):410-8 doi: 10.1097/TP.0b013e318224c12d.
CET Conclusion
Reviewer: Centre for Evidence in Transplantation
Conclusion: At 24 months following randomisation at a mean of 5.6 years after transplantation there was no difference in measured GFR in the 3 arms in the trial. Conversion to everolimus was associated with more frequent adverse events and discontinuation of everolimus.
Aims: To determine whether introduction of everolimus with elimination or minimization of a Calcineurin Inhibitor (CNI) would improve graft function in renal transplant patients with renal impairment at the time of conversion.
Interventions: Continuing CNI-based immunosuppressive therapy (CNI continuation) versus everolimus with a predefined reduction in CNI exposure (CNI minimization) versus everolimus with discontinuation of CNI (CNI discontinuation). All patients received cyclosporine A or tacrolimus with or without MPA/ azathioprine, and with/without steroids.
Participants: 398 patients who had undergone a primary or secondary renal transplant at least 6 months previously from a living or deceased donor and had renal impairment.
Outcomes: Outcomes: The primary endpoint was measured glomerular filtration rate (GFR) at month 24 post transplantation. Secondary endpoints were graft and patient survival, number and severity of BPAR episodes, the change in serum creatinine, 1/creatinine, and creatinine clearance at 24 month. Safety assessment was adverse event recording.
Follow Up: 24 months
BACKGROUND:

Benefits of conversion from calcineurin inhibitor (CNI) to mammalian target of rapamycin inhibitor-based immunosuppression in long-term kidney transplant patients remain uncertain.

METHODS:

ASCERTAIN was a 24-month, open-label, multicenter study. Kidney transplant patients more than 6 months posttransplant receiving CNI (baseline glomerular filtration rate [GFR] 30-70 mL/min/1.73 m) were randomized to everolimus with CNI elimination (n=127) or CNI minimization (n=144), or continued CNI unchanged (controls, n=123) to assess the effect on measured GFR at month 24 after randomization.

RESULTS:

Renal function was stable in all groups to month 24. Mean measured GFR at month 24, the primary endpoint, was 48.0±22.0 mL/min/1.73 m, 46.6±21.1 mL/min/1.73 m, and 46.0±20.4 mL/min/1.73 m in the CNI elimination, CNI minimization, and control groups, respectively. Differences between CNI elimination (1.12 mL/min/1.73 m, 95% confidence interval [CI] -3.51 to 5.76, P=0.63) and CNI minimization (0.59 mL/min/1.73 m, 95% CI -3.88 to 5.07, P=0.79) versus controls at month 24 were nonsignificant that is, the primary endpoint was not met. No efficacy endpoint differed significantly between groups. Post hoc analyses showed that patients with baseline creatinine clearance (CrCl) more than 50 mL/min had a significantly greater increase in measured GFR after CNI elimination versus controls (difference 11.4 mL/min/1.73 m, 95% CI 2.1 to 20.8 mL/min/1.73 m, P=0.017). Adverse events resulted in discontinuation in 36 (28.3%) CNI elimination patients, 24 (16.7%) CNI minimization patients, and 5 (4.1%) controls (P<0.001 vs. CNI elimination; P=0.020 vs. CNI minimization).

CONCLUSION:

Conversion to everolimus with CNI elimination or minimization a mean of 5.6 years after kidney transplantation had no overall renal benefit and was associated with more frequent adverse events and discontinuations. Patients with CrCl more than 50 mL/min may benefit from a change in therapy more than 6 months after renal transplantation.

  • Hernández D
  • Sánchez-Fructuoso A
  • González-Posada JM
  • Arias M
  • Campistol JM
  • et al.
Transplantation. 2009 Sep 27;88(6):803-9 doi: 10.1097/TP.0b013e3181b4ac2f.
BACKGROUND:

All-cause mortality is high after kidney transplantation (KT), but no prognostic index has focused on predicting mortality in KT using baseline and emergent comorbidity after KT.

METHODS:

A total of 4928 KT recipients were used to derive a risk score predicting mortality. Patients were randomly assigned to two groups: a modeling population (n=2452), used to create a new index, and a testing population (n=2476), used to test this index. Multivariate Cox regression model coefficients of baseline (age, weight, time on dialysis, diabetes, hepatitis C, and delayed graft function) and emergent comorbidity within the first posttransplant year (diabetes, proteinuria, renal function, and immunosuppressants) were used to weigh each variable in the calculation of the score and allocated into risk quartiles.

RESULTS:

The probability of death at 3 years, estimated by baseline cumulative hazard function from the Cox model [P (death)=1-0.993592764 (exp(score/100)], increased from 0.9% in the lowest-risk quartile (score=40) to 4.7% in the highest risk-quartile (score=200). The observed incidence of death increased with increasing risk quartiles in testing population (log-rank analysis, P<0.0001). The overall C-index was 0.75 (95% confidence interval: 0.72-0.78) and 0.74 (95% confidence interval: 0.70-0.77) in both populations, respectively.

CONCLUSION:

This new index is an accurate tool to identify high-risk patients for mortality after KT.