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Graph showing estimated glomerular filtration rate (mL/min/1.73 m2) at different time points in the two groups. Patients in the SIR group showed a significant improvement in GFR over baseline, and the difference between groups was significant at 6 months.
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Measures to prevent chronic calcineurin inhibitor (CNI) toxicity have included limiting exposure by switching to sirolimus (SIR). SIR may favorably influence T regulator cell (Treg) population. This randomized controlled trial compares the effect of switching from CNI to SIR on glomerular filtration rate (GFR) and Treg frequency.
In this prospectiv...
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Mammalian target of rapamycin (mTOR) inhibitors have been used in transplantation with the hope of minimizing calcineurin inhibitor (CNI)-induced nephrotoxicity. However, mTOR inhibitors are also associated with a range of side effects, including metabolic complications. We aimed to determine the risks of metabolic complications after the conversio...
Citations
... Treg numbers in RT patients taking sirolimus are up to four times higher than CNI-based regimens (111,113,132,205). In a randomised controlled trial of live donor RT, switch to sirolimus at 2 months increases Treg numbers compared to controls continuing on CNI (208) CXCR3 + Treg (Tregs activated by Th1 response) are present in blood of CNI-treated patients, but in lower proportions than in HV (133). Patients treated with mTOR inhibitors have more CXCR3 + Treg than those treated with CNIs (130). ...
The immune response to an allograft activates lymphocytes with the capacity to cause rejection. Activation of CD4⁺CD25⁺Foxp3⁺T regulatory cells (Treg) can down-regulate allograft rejection and can induce immune tolerance to the allograft. Treg represent <10% of peripheral CD4⁺T cells and do not markedly increase in tolerant hosts. CD4⁺CD25⁺Foxp3⁺T cells include both resting and activated Treg that can be distinguished by several markers, many of which are also expressed by effector T cells. More detailed characterization of Treg to identify increased activated antigen-specific Treg may allow reduction of non-specific immunosuppression. Natural thymus derived resting Treg (tTreg) are CD4⁺CD25⁺Foxp3⁺T cells and only partially inhibit alloantigen presenting cell activation of effector cells. Cytokines produced by activated effector cells activate these tTreg to more potent alloantigen-activated Treg that may promote a state of operational tolerance. Activated Treg can be distinguished by several molecules they are induced to express, or whose expression they have suppressed. These include CD45RA/RO, cytokine receptors, chemokine receptors that alter pathways of migration and transcription factors, cytokines and suppression mediating molecules. As the total Treg population does not increase in operational tolerance, it is the activated Treg which may be the most informative to monitor. Here we review the methods used to monitor peripheral Treg, the effect of immunosuppressive regimens on Treg, and correlations with clinical outcomes such as graft survival and rejection. Experimental therapies involving ex vivo Treg expansion and administration in renal transplantation are not reviewed.
... This influence occurs in parallel to the effect of drugs used. The de novo schemes with, or the switch to mammalian Target Of Rapamycin (mTOR) inhibitors with/without belatacept (a second-generation cytotoxic T-lymphocyte-associated antigen 4 -IgG1) favor expansion of the FoxP3 regulatory T-cell (Treg) population [14][15][16][17][18][19][20][21][22][23], which is correlated with the stability or even an improvement of kidney graft function being attributed to the use of these immunosuppressants [15,16,18]. A large body of evidence leading to assume a protective effect of this and other regulatory lymphocyte populations constitutes the basis for the clinical trials that have attempted pharmacological induction of this effect, by preserving interleukin-2 signaling pathway [14][15][16][17][18][19][20][21][22][23]. ...
... This influence occurs in parallel to the effect of drugs used. The de novo schemes with, or the switch to mammalian Target Of Rapamycin (mTOR) inhibitors with/without belatacept (a second-generation cytotoxic T-lymphocyte-associated antigen 4 -IgG1) favor expansion of the FoxP3 regulatory T-cell (Treg) population [14][15][16][17][18][19][20][21][22][23], which is correlated with the stability or even an improvement of kidney graft function being attributed to the use of these immunosuppressants [15,16,18]. A large body of evidence leading to assume a protective effect of this and other regulatory lymphocyte populations constitutes the basis for the clinical trials that have attempted pharmacological induction of this effect, by preserving interleukin-2 signaling pathway [14][15][16][17][18][19][20][21][22][23]. ...
... The de novo schemes with, or the switch to mammalian Target Of Rapamycin (mTOR) inhibitors with/without belatacept (a second-generation cytotoxic T-lymphocyte-associated antigen 4 -IgG1) favor expansion of the FoxP3 regulatory T-cell (Treg) population [14][15][16][17][18][19][20][21][22][23], which is correlated with the stability or even an improvement of kidney graft function being attributed to the use of these immunosuppressants [15,16,18]. A large body of evidence leading to assume a protective effect of this and other regulatory lymphocyte populations constitutes the basis for the clinical trials that have attempted pharmacological induction of this effect, by preserving interleukin-2 signaling pathway [14][15][16][17][18][19][20][21][22][23]. ...
Background
The kinetics of the FoxP3 regulatory T-cell (Treg) population in kidney transplant recipients (KTR) are related to the clinical effect of immunosuppression based on mammalian Target Of Rapamycin inhibitors (mTORi) with/without belatacept (predictive biomarker).
Methods
A multistage systematic review of published and unpublished literature is presented [registration IDs in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42017057570, CRD42018085019, CRD42018084941, CRD42018085186]. A multidisciplinary supervision mechanism for contextualizing of search findings was required. The peripheral blood immune cell phenotypes encompassing all regulatory cells in KTRs were assessed in order to suggest new markers of acute rejection-associated acute allograft dysfunction (AR/AAD) events in KTRs treated with mTORi alone or combined to belatacept. Quantitative estimates and evaluation of the body of evidence are provided.
Results
An increase in Tregs and other regulatory cell types in the circulation in KTRs under mTORi with/without belatacept were observed. Patients with increased Tregs presented a low frequency of AR/AAD events compared to those in which the number of Tregs remained unchanged or even diminished [Odds Ratio (OR)/95% confidence interval (95% CI)/I²/number of studies (n): 0.31/0.10–0.93/0%/6]. Nevertheless, there are too few trials to consider Tregs in the circulation as a predictive biomarker. Inadequate reporting prevents appreciating clinical relevance in such studies.
Conclusions
Despite advances, clinical qualification of potential predictive biomarkers continues to be difficult. Clinical evidence on Tregs in KTRs needs to be enlarged. Biomarkers should be able to evaluate the effect of medicines targeted to specific patient populations.
... En este caso las Treg podrían considerarse como un factor pronóstico 11 . Sin embargo, se ha visto que los inhibidores de la mammalian target of rapamycin (mTOR, «diana de rapamicina en células de mamífero») se asocian a un aumento de Treg circulantes [12][13][14][15][16][17][18][19][20] , pudiendo este aumento explicar la mejora de la función del injerto observada con el tratamiento con estos fármacos [21][22][23][24][25] . Los resultados de grandes metaanálisis concuerdan, además, en que tanto los inhibidores de mTOR (I-mTOR) como los inhibidores de la calcineurina (ICN) son similares previniendo el rechazo [26][27][28][29] . ...
... Se compararon el clásico esquema inmunosupresor con ciclosporina o tacrolimus, derivados del ácido micofenólico, con/sin corticoides, con el empleo de novo de sirolimus, o con la conversión a sirolimus o everolimus. Casi el mismo número de pacientes recibió ICN (n = 307) o I-mTOR (n = 308), pero fue más frecuente la conversión a I-mTOR [13][14][15][18][19][20][22][23][24][25] que el empleo de novo de estos fármacos 12,16,17,21,24 . Todos los pacientes que recibieron sirolimus desde el primer día después del trasplante habían sido sometidos a una inducción con timoglobulina (n = 14) 12,24 , alemtuzumab (n = 40) 16,21 o no habían recibido tratamiento de inducción (n = 56) 17 . ...
... Los niveles objetivo para tacrolimus fueron de 5-10 ng/ml. Para evaluar el empleo de novo de I-mTOR (n = 105) 12,16,17,21 y la conversión de ICN a I-mTOR (n = 113) 13,14,18,22,25 se planificó un seguimiento prospectivo de los pacientes (9 trabajos). Dicho seguimiento llegó a ser de hasta 36 meses para el empleo de novo (n = 29) 16 y de hasta 24 para la conversión antes del año (n = 30) 13 y después del año postrasplante (n = 38) 14,18 . ...
Background and objective
Circulating regulatory T cells could become a suitable biomarker for kidney recipients. The objective of this study was to evaluate the effect of mammalian target of rapamycin (mTOR) inhibitors on regulatory T cell numbers, and the clinical interest of this effect.
Material and methods
Systematic review of published and unpublished studies. Worldwide databases or repositories. Randomized controlled trials and cohort studies comparing regulatory T cell counts and rejection episodes between patients with and without mTOR inhibitors were searched. Correlation of regulatory T cells-glomerular filtration rate might be supplied. Co-dependency regulatory T cells-mTOR inhibitors efficacy was evaluated.
Results
Five trials and 9 studies were included. Clinical differences made it difficult to obtain quantitative estimates of the effect of immunosuppression on regulatory T cell numbers. Nevertheless, we found that there are higher regulatory T cell numbers under treatment with sirolimus or everolimus. Rejection episodes were similar under calcineurin inhibitors and mTOR inhibitors despite different regulatory T cell numbers. Pooled correlation regulatory T cells-glomerular filtration rate was, prospectively 0.114 (95% confidence interval [95% CI] 0.062–0.406), and retrospectively 0.13 (95% CI 0.0–0.361). There is direct evidence although of low level (biomarker-stratified randomization) on the co-dependency regulatory T cells-mTOR inhibitors efficacy.
Conclusions
Regulatory T cells counts may be associated with better outcomes under treatment with mTOR inhibitors (anti-rejection efficacy), considering that there is a relationship between these cells and kidney graft function.
Registration
PROSPERO (CRD42016046285).
... Three trials did not give any induction therapy (29,37,38), whereas one trial did not provide any details concerning the induction therapy (18,19). One trial did not specify the type of induction therapy; however, it used it in 18% of the population in a way balanced between the two arms (23). In most of the included trials, as highlighted in Table 2, CMV prophylaxis was administered according to local center practice. ...
Background and objectives:
The objective of this meta-analysis is to compare the incidences of cytomegalovirus and BK polyoma virus infections in renal transplant recipients receiving a mammalian target of rapamycin inhibitor (mTOR)-based regimen compared with a calcineurin inhibitor-based regimen.
Design, setting, participants, & measurements:
We conducted a comprehensive search for randomized, controlled trials up to January of 2016 addressing our objective. Other outcomes included acute rejection, graft loss, serious adverse events, proteinuria, wound-healing complications, and eGFR. Two review authors selected eligible studies, abstracted data, and assessed risk of bias. We assessed quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation methodology.
Results:
We included 28 randomized, controlled trials with 6211 participants classified into comparison 1: mTOR inhibitor versus calcineurin inhibitor and comparison 2: mTOR inhibitor plus reduced dose of calcineurin inhibitor versus regular dose of calcineurin inhibitor. Results showed decreased incidence of cytomegalovirus infection in mTOR inhibitor-based group in both comparison 1 (risk ratio, 0.54; 95% confidence interval, 0.41 to 0.72), with high quality of evidence, and comparison 2 (risk ratio, 0.43; 95% confidence interval, 0.24 to 0.80), with moderate quality of evidence. The available evidence neither confirmed nor ruled out a reduction of BK polyoma virus infection in mTOR inhibitor-based group in both comparisons. Secondary outcomes revealed more serious adverse events and acute rejections in mTOR inhibitor-based group in comparison 1 and no difference in comparison 2. There was no difference in graft loss in both comparisons. eGFR was higher in the mTOR inhibitor-based group in comparison 1 (mean difference =4.07 ml/min per 1.73 m(2); 95% confidence interval, 1.34 to 6.80) and similar to the calcineurin inhibitor-based group in comparison 2. More proteinuria and wound-healing complications occurred in the mTOR inhibitor-based groups.
Conclusions:
We found moderate- to high-quality evidence of reduced risk of cytomegalovirus infection in renal transplant recipients in the mTOR inhibitor-based compared with the calcineurin inhibitor-based regimen. Our review also suggested that a combination of a mTOR inhibitor and a reduced dose of calcineurin inhibitor may be associated with similar eGFR and rates of acute rejections and serious adverse events compared with a standard calcineurin inhibitor-based regimen at the expense of higher incidence of proteinuria and wound-healing complications.
... En este caso las Treg podrían considerarse como un factor pronóstico 11 . Sin embargo, se ha visto que los inhibidores de la mammalian target of rapamycin (mTOR, «diana de rapamicina en células de mamífero») se asocian a un aumento de Treg circulantes [12][13][14][15][16][17][18][19][20] , pudiendo este aumento explicar la mejora de la función del injerto observada con el tratamiento con estos fármacos [21][22][23][24][25] . Los resultados de grandes metaanálisis concuerdan, además, en que tanto los inhibidores de mTOR (I-mTOR) como los inhibidores de la calcineurina (ICN) son similares previniendo el rechazo [26][27][28][29] . ...
... Se compararon el clásico esquema inmunosupresor con ciclosporina o tacrolimus, derivados del ácido micofenólico, con/sin corticoides, con el empleo de novo de sirolimus, o con la conversión a sirolimus o everolimus. Casi el mismo número de pacientes recibió ICN (n = 307) o I-mTOR (n = 308), pero fue más frecuente la conversión a I-mTOR [13][14][15][18][19][20][22][23][24][25] que el empleo de novo de estos fármacos 12,16,17,21,24 . Todos los pacientes que recibieron sirolimus desde el primer día después del trasplante habían sido sometidos a una inducción con timoglobulina (n = 14) 12,24 , alemtuzumab (n = 40) 16,21 o no habían recibido tratamiento de inducción (n = 56) 17 . ...
... Los niveles objetivo para tacrolimus fueron de 5-10 ng/ml. Para evaluar el empleo de novo de I-mTOR (n = 105) 12,16,17,21 y la conversión de ICN a I-mTOR (n = 113) 13,14,18,22,25 se planificó un seguimiento prospectivo de los pacientes (9 trabajos). Dicho seguimiento llegó a ser de hasta 36 meses para el empleo de novo (n = 29) 16 y de hasta 24 para la conversión antes del año (n = 30) 13 y después del año postrasplante (n = 38) 14,18 . ...
Background and objective:
Circulating regulatory T cells could become a suitable biomarker for kidney recipients. The objective of this study was to evaluate the effect of mammalian target of rapamycin (mTOR) inhibitors on regulatory T cell numbers, and the clinical interest of this effect.
Material and methods:
Systematic review of published and unpublished studies. Worldwide databases or repositories. Randomised controlled trials and cohort studies comparing regulatory T cell counts and rejection episodes between patients with and without mTOR inhibitors were searched. Correlation of regulatory T cells-glomerular filtration rate might be supplied. Co-dependency regulatory T cells-mTOR inhibitors efficacy was evaluated.
Results:
Five trials and 9 studies were included. Clinical differences made it difficult to obtain quantitative estimates of the effect of immunosuppression on regulatory T cell numbers. Nevertheless, we found that there are higher regulatory T cell numbers under treatment with sirolimus or everolimus. Rejection episodes were similar under calcineurin inhibitors and mTOR inhibitors despite different regulatory T cell numbers. Pooled correlation regulatory T cells-glomerular filtration rate was, prospectively 0.114 (95% confidence interval [95% CI] 0.062-0.406), and retrospectively 0.13 (95% CI 0.0-0.361). There is direct evidence although of low level (biomarker-stratified randomisation) on the co-dependency regulatory T cells-mTOR inhibitors efficacy.
Conclusions:
Regulatory T cells counts may be associated with better outcomes under treatment with mTOR inhibitors (anti-rejection efficacy), considering that there is a relationship between these cells and kidney graft function.
Registration:
PROSPERO (CRD42016046285).
... Another group showed sirolimus increased Treg numbers by converting CD4 + naïve cells to Treg, leading to inhibition of alloimmunity [39]. In renal allograft recipients, switching from a calcineurin inhibitor to sirolimus several months after transplantation led to a modest but sustained increase in Treg numbers and percentages beginning at 30 days afterwards [40]. This result was also found in another clinical trial with renal transplantation patients showing that patients treated with sirolimus had increased Treg numbers compared with those treated with calcineurin inhibitors [41]. ...
Regulatory T (Treg) cells play a central role in immune tolerance and prevention of aberrant immune responses. Several studies have suggested that the risk of GVHD after allogeneic hematopoietic cell transplantation (HCT) can be ameliorated by increasing Tregs. We have developed an approach of in vivo expansion of Tregs with RGI-2001, a novel liposomal formulation of a synthetic derivative of alpha-galactosylceramide, a naturally occurring ligand that binds to CD1 and activates and expands invariant natural killer cells. In preclinical studies, a single intravenous infusion of RGI-2001 expanded Treg and could ameliorate GVHD in a mouse model of allogeneic HCT. To explore the role of RGI-2001 in clinical HCT, we initiated a Phase IIa clinical trial (n=29), testing two different doses of RGI-2001 administered as a single infusion on day 0 of allogeneic HCT. RGI-2001 was well tolerated and without infusion reactions or cytokine release syndrome. A subset of patients (8/29, 28%) responded to RGI-2001 by inducing a markedly increased number of cells with a Treg phenotype. The Treg had a high Ki-67 index and were almost exclusively Helios(+) and Foxp3(+), indicating that their accumulation was due to expansion of natural Treg. Notably, the incidence of grade 2-4 GVHD in the eight patients who responded to RGI-2001 was 12.5%, compared to 52.4% in the 21 patients who did not respond. No grade 3-4 GVHD was observed in the responder group, compared to a 9.5% incidence among non-responders. Immunosuppression with sirolimus was also associated with a low incidence of GVHD, suggesting that RGI-2001 may have synergized with sirolimus to promote Treg expansion.
... In this approach, mTOR inhibitors are introduced within a period of 2 weeks to 6 months of transplant, a period when increased risks for rejection and wound infection have passed. Several studies that have assessed transplant outcomes with an mTOR inhibitor-based initial conversion regimen include the CENTRAL trial (2013), the ZEUSS trial (2014), the Spare the Nephron trial (2011), the SMART trial (2010), the CONCEPT trial (2012), and the study of Bansal and associates [33][34][35][36][37][38] (Tables 4 and 5). ...
... However, the effects of immunosuppressive medications on regulatory T-cell homeostasis are different as cyclosporine inhibits the conversion of CD4+CD25 naive T cells to CD4+Foxp3+ regulatory T cells. 38 In contrast, Sengundo and associates in 2006 reported an increase in the number of these cells in response to sirolimus. 39 Sixty transplant recipients were randomized 3 months after surgery to receive sirolimus (initial level of 8-15 ng/mL) or a CNI-based regimen. ...
Objectives: This review focuses on the current limited evidence of graft function and graft survival in various immunosuppressive regimens involving mammalian target of rapamycin inhibitors with or without calcineurin inhibitors.
Materials and Methods: We evaluated the current literature for describing the role of mammalian target of rapamycin inhibitors as an alternative to calcineurin inhibitors by searching the PubMed, EMBASE, Cochrane, Crossref, and Scopus databases using medical subject heading terms.
Results: Our detailed analyses of all relevant literature showed use of mammalian target of rapamycin inhibitor-based de novo regimens, early calcineurin inhibitor withdrawal with subsequent introduction of mammalian target of rapamycin inhibitor-based regimens, and late conversion from a calcineurin inhibitor-based regimen to mammalian target of rapamycin inhibitor-based regimens. Notably, early calcineurin inhibitor withdrawal with subsequent introduction of mammalian target of rapamycin inhibitor-based regimen seemed to be a more practical and realistic approach toward immuno-suppressive treatment of renal transplant recipients. However, in view of the high rejection rate observed in these studies, it is advisable not to offer these regimens to patients with moderate to high immunologic risk.
Conclusions: The present evidences suggest that treatment with mammalian target of rapamycin inhibitors allows early and substantial calcineurin inhibitor minimization. The mammalian target of rapamycin inhibitors everolimus and sirolimus are preferred due to their complementary mechanisms of action and favorable nephrotoxicity profile, which have opened the way for calcineurin inhibitor reduction/withdrawal in the early posttransplant period.
... In a recent prospective study on 60 living donor renal transplant recipients, Balal et al. found that patients receiving maintenance therapy with SRL presented a significant improvement in renal function and an increase in total Treg population, compared with those receiving CsA [39]. ...
Regulatory T cells (Tregs), defined as CD4+CD25+highFoxP3+CD127- cells, could promote tolerance in renal transplantation (Tx). In an open-label, randomized, controlled trial 62 de-novo Tx recipients received induction with basiliximab and cyclosporine A (CsA) for the first month after Tx and then were assigned to treatment with sirolimus (SRL) or CsA and followed-up for 2years. The primary endpoint was to evaluate the effects of induction and maintenance treatments on circulating Tregs, while the secondary endpoint was the assessment of Treg renal infiltration and the relationship between Treg count and clinical outcomes. There were no significant differences in either circulating or tissue Treg number between the two groups. At 1month post-Tx, all patients presented a profound Treg depletion, followed by a significant increase in Tregs that resulted stable during the follow-up. The same trend was also observed for non-activated Tregs (CD69-) and for other immunocompetent cells (CD4+ and CD8+ T cells, B cells and NK cells). Moreover, the Treg count did not correlate either with renal function or with acute rejection and graft loss. Initial immunosuppression is crucial to regulate circulating Tregs, regardless of subsequent immunosuppressive maintenance regimens. Strategies aiming to promote tolerance should consider the effects of different induction regimens.
Copyright © 2015. Published by Elsevier B.V.
Allogeneic hematopoietic stem cell transplantation (HSCT) is still needed for many children with very high-risk acute leukemia. An HLA-haploidentical family donor is a suitable option for those without an HLA-matched donor. Here we present outcomes of a novel HLA-haploidentical HSCT (haplo-HSCT) strategy with adoptive immunotherapy with thymic-derived CD4⁺CD25⁺ FoxP3⁺ regulatory T cells (Tregs) and conventional T cells (Tcons) performed between January 2017 and July 2021 in 20 children with high-risk leukemia. Median age was 14.5 years (range, 4–21), 15 had acute lymphoblastic leukemia, 5 acute myeloid leukemia. The conditioning regimen included total body irradiation (TBI), thiotepa, fludarabine, cyclophosphamide. Grafts contained a megadose of CD34+ cells (mean 12.4 × 10⁶/Kg), Tregs (2 × 10⁶/Kg) and Tcons (0.5–1 × 10⁶/Kg). All patients achieved primary, sustained full-donor engraftment. Only one patient relapsed (5%). The incidence of non-relapse mortality was 15% (3/20 patients). Five/20 patients developed ≥ grade 2 acute Graft versus Host Disease (aGvHD). It resolved in 4 who are alive and disease-free; 1 patient developed chronic GvHD (cGvHD). The probability of GRFS was 60 ± 0.5% (95% CI: 2.1–4.2) (Fig. 6), CRFS was 79 ± 0.9% (95% CI: 3.2–4.9) as 16/20 patients are alive and leukemia-free. The median follow-up was 2.1 years (range 0.5 months–5.1 years). This innovative approach was associated with very promising outcomes of HSCT strategy in pediatric patients.
Background
A systematic review and meta-analysis were performed to investigate the efficacy and safety of conversion from calcineurin inhibitors (CNIs) to mammalian target of rapamycin inhibitors (mTORi) in kidney transplant recipients (KTRs).
Methods
MEDLINE, EMBASE, PubMed, and Cochrane Library were searched to identify randomized controlled trials (RCTs) that compared the continuation of CNI with conversion to mTORi therapy.
Results
Twenty-nine RCTs (5,747 KTRs) were included in our analysis. Meta-analysis of the glomerular filtration rate (SMD 0.20; 95%CI 0.10–0.31; P<0.01) and malignancy (RR 0.74; 95%CI 0.55–0.99; P=0.04) demonstrated a significant advantage of mTORi conversion over CNI continuation. However, the risk of acute rejection (RR 1.58; 95%CI 1.22–2.04; P<0.01), infection (RR 1.55; 95%CI 1.01–1.31; P=0.04), proteinuria (RR 1.87; 95%CI 1.34–2.59; P<0.01), leukopenia (RR 1.56; 95%CI 1.27–1.91; P<0.01), acne (RR 6.43; 95%CI 3.43–12.04; P<0.01), and mouth ulcer (RR 11.70; 95%CI 6.18–22.17; P<0.01) were higher in the mTORi group. More patients in the conversion group had to discontinue study medication (RR 2.52; 95%CI 1.75–3.63; P<0.01). There was no significant difference between the two groups with regard to death, graft loss, diabetes, chronic allograft nephropathy, and interstitial fibrosis/tubular atrophy.
Conclusions
Posttransplant patients have a better graft function and lower incidence of malignancy after conversion from CNI to mTORi therapy. However, this conversion strategy may be prevented by the higher drug discontinuation rate due to mTORi-associated adverse events, such as more acute rejection, infection, proteinuria, leukopenia, acne, and mouth ulcer, indicating that conversion therapy may only be a treatment option in selected patients.
