Response to treatment and long-term outcomes in kidney transplant recipients with acute T cell–mediated rejection

Bouatou, Yassine; Viglietti, Denis; Pievani, Daniele; Louis, Kévin; Huyen, Jean–Paul Duong Van; Rabant, Marion; Aubert, Olivier; Taupin, Jean‐Luc; Glotz, Denis; Legendre, Christophe; Loupy, Alexandre; Lefaucheur, Carmen

doi:10.1111/ajt.15299

Cited by 69 publications

(87 citation statements)

References 26 publications

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“…The key finding in this study is that in the absence of donor-specific memory (ie, no preformed DSA by solid phase single antigen bead assay) alloimmune risk assessment for TCMR can be more precisely Whereas some have argued that TCMR has limited relevance as a correlate of allograft loss, 9,21 others have shown a correlation between early clinical or subclinical TCMR and functional decline, interstitial fibrosis and tubular atrophy, and allograft loss. [12][13][22][23][24][25] Furthermore, multiple studies have reported that early TCMR correlates with later development of dnDSA, ABMR, and chronic glomerulopathy. [26][27][28][29][30][31][32] We found a significant correlation between those with Banff Borderline TCMR or Banff ≥ IA TCMR and death-censored allograft survival (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

“…7 Immune-mediated allograft injury is the most common cause of death-censored allograft failure posttransplant. [8][9][10][11][12] In this context, and in the absence of pretransplant donor-specific memory, an essential requirement for a prognostic/predictive biomarker is an accurate assessment of the risk for a primary alloimmune response posttransplant.…”

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confidence: 99%

“…Precise risk factors for T cell-mediated rejection (TCMR) in the modern era are poorly defined resulting in one-size-fits-all prevention/treatment strategies for most patients and high recurrence rates reported in serial biopsy studies. [11][12][13][14][15] As the underlying driver of alloimmunity is the dissimilarity between donor and recipient at the molecular level, we hypothesized that the alloimmune risk categories developed using dnDSA free survival would also apply to TCMR. Indeed, we reported that the HLA-DR/DQ molecular mismatch score correlated with Banff ≥ IA TCMR in the first year posttransplant.…”

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confidence: 99%

“…10 In the present paper, we sought to determine whether the HLA-DR/DQ molecular mismatch risk categories correlated with the severity, frequency, and persistence of TCMR and with graft survival independent of dnDSA. [9][10][11][12]…”

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confidence: 99%

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Evidence for the alloimmune basis and prognostic significance of Borderline T cell–mediated rejection

Wiebe

Rush

Gibson

et al. 2020

American Journal of Transplantation

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Prognostic biomarkers of T cell–mediated rejection (TCMR) have not been adequately studied in the modern era. We evaluated 803 renal transplant recipients and correlated HLA‐DR/DQ molecular mismatch alloimmune risk categories (low, intermediate, high) with the severity, frequency, and persistence of TCMR. Allograft survival was reduced in recipients with Banff Borderline (hazard ratio [HR] 2.4, P = .003) and Banff ≥ IA TCMR (HR 4.3, P < .0001) including a subset who never developed de novo donor‐specific antibodies (P = .002). HLA‐DR/DQ molecular mismatch alloimmune risk categories were multivariate correlates of Banff Borderline and Banff ≥ IA TCMR and correlated with the severity and frequency of rejection episodes. Recipient age, HLA‐DR/DQ molecular mismatch category, and cyclosporin vs tacrolimus immunosuppression were independent correlates of Banff Borderline and Banff ≥ IA TCMR. In the subset treated with tacrolimus (720/803) recipient age, HLA‐DR/DQ molecular mismatch category, and tacrolimus coefficient of variation were independent correlates of TCMR. The correlation of HLA‐DR/DQ molecular mismatch category with TCMR, including Borderline, provides evidence for their alloimmune basis. HLA‐DR/DQ molecular mismatch may represent a precise prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Evidence for the alloimmune basis and prognostic significance of Borderline T cell–mediated rejection

Wiebe

Rush

Gibson

et al. 2020

American Journal of Transplantation

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“…Furthermore, other laboratory examinations involving serum creatinine, proteinuria and donor-speci c antibodies as well as some non-invasive tests like renal ultrasound with doppler for renal arterial and venous indices also can help to evaluate the condition of AR. However, these methods for AR diagnosis display poor speci city and e ciency, which are di cult for us to gain accurate diagnosis and proper treatment early, so that some patients with AR lost the best chance for therapy, thereby causing graft dysfunction and even improving the death risk [6] . Hence, the identi cation of speci c and sensitive biomarkers is essential to assist us accurate diagnosis and treatment of AR as soon as possible, especially noninvasive biomarkers.…”

Section: Introductionmentioning

confidence: 99%

Noninvasive Identification of Core Gene Biomarkers in Patients with Acute Kidney Transplant Rejection

Zhao

2020

Preprint

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Background: Acute rejection (AR) is one of common and critical complications after kidney transplantation, which gives rise to an increasing of allograft loss and even death. However, the potential mechanisms of AR remain incompletely understood at present. This study aimed to reveal the underlying mechanisms and identify core biomarkers of AR.Methods: The AR gene expression profile GSE1563 involving 6 renal transplant patients undergoing AR and 9 patients with well-functioning transplant with no clinical evidence of rejection was selected to analyze the differentially expressed genes (DEGs) from purified RNA of peripheral blood lymphocytes. DAVID was used to carry out Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. A protein-protein interaction (PPI) network was built to display the interactions among these DEGs. To get further reliable significant genes and mechanisms, gene set enrichment analysis (GSEA) was applied to evaluate the hub gene analyzing via PPI network.Results: A total of 347 DEGs were captured, including 301 upregulated genes and 46 downregulated genes. Go and KEGG pathway analysis showed the DEGs were particularly enriched in immune response, inflammatory response to antigenic stimulus, RNA transport and protein stabilization. The PPI network indicated 3 modules were also mainly involved in immune response and RNA transport. 18 hub genes were selected in PPI network, among which there were 6 core genes evaluated by DAVID. By the way of GSEA, Oxidative stress was another potential mechanism besides immunity and ncRNA transport. Conclusion: Our analysis uncovered the immune response including humoral and cellular immunity, ncRNA transport as well as oxidative stress was the major mechanisms of AR associated respectively with MAPK8, CCL5, HMGB1, NCBP2, XPO1 and APP, which could be novel noninvasive biomarkers in peripheral blood for early diagnosis and could be helpful to the treatment of AR.

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Early Corticosteroid Cessation vs Long-term Corticosteroid Therapy in Kidney Transplant Recipients

et al. 2021

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IMPORTANCEThe complications of corticosteroids make the inclusion of these drugs in immunosuppressive protocols for kidney transplant patients undesirable. However, cessation of corticosteroids is associated with a higher risk of short-term rejection, and the long-term outcomes of patients withdrawn from corticosteroids remain uncertain. OBJECTIVE To compare long-term kidney transplant outcomes of patients randomized to continue or withdraw corticosteroids. DESIGN, SETTING, AND PARTICIPANTS This prospective multicenter randomized double-blind placebo-controlled trial was conducted between November 1999 and December 2002 with linkage to a mandatory national registry with validated outcome ascertainment until June 8, 2018. The study included 28 kidney transplant centers in the United States, including 386 low-to moderate-immune risk adult recipients of a living or deceased donor kidney transplant without delayed graft function or short-term rejection in the first week after transplant. Analyses were intention to treat. Analysis began September 2018 and ended June 2019. INTERVENTIONS Patients were randomized to receive tacrolimus and mycophenolate mofetil with or without corticosteroids 7 days after transplant. MAIN OUTCOMES AND MEASURES Kidney allograft failure from any cause including death and allograft failure censored for patient death defined by the requirement for long-term dialysis or repeat transplant. RESULTS Of 385 patients, 191 were assigned to withdraw from corticosteroids (mean [SD] age, 46.5 [12.1] years), and 194 patients were assigned to continued corticosteroids (mean [SD] age, 46.3 [12.6] years). The median (interquartile range) follow-up time was 15.8 (12.0-16.3) years after transplant. The adjusted hazard ratios of allograft failure from any cause including death was 0.83 (95% CI, 0.62-1.10; P = .19) and for allograft failure censored for patient death was 0.78 (95% CI, 0.52-1.19; P = .25) and did not differ between the patients assigned to withdraw from corticosteroids vs assigned to continued corticosteroids. Results were consistent in a per-protocol analysis among 223 patients who continued the trial-assigned treatment of corticosteroid withdrawal (n = 114) or corticosteroids (n = 109) through at least 5 years after transplant. The outcomes of trial participants in either treatment group did not differ from similarly treated contemporary registry patients who met trial eligibility criteria and were treated with the same immunosuppressive drugs.CONCLUSIONS AND RELEVANCE Long-term corticosteroids may not be necessary as part of a calcineurin-based multiple drug immunosuppressive regimen in low-to moderate-immune risk kidney transplant recipients.

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Response to treatment and long-term outcomes in kidney transplant recipients with acute T cell–mediated rejection

Cited by 69 publications

References 26 publications

Evidence for the alloimmune basis and prognostic significance of Borderline T cell–mediated rejection

Evidence for the alloimmune basis and prognostic significance of Borderline T cell–mediated rejection

Noninvasive Identification of Core Gene Biomarkers in Patients with Acute Kidney Transplant Rejection

Early Corticosteroid Cessation vs Long-term Corticosteroid Therapy in Kidney Transplant Recipients

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