Impact of Belatacept Conversion on Renal Function, Histology, and Gene Expression in Kidney Transplant Patients With Chronic Active Antibody-mediated Rejection.
Abatacept
/ pharmacology
Biopsy
Chronic Disease
Drug Substitution
Female
Gene Expression
/ drug effects
Glomerular Filtration Rate
/ drug effects
Graft Rejection
/ diagnosis
Graft Survival
Humans
Immunosuppressive Agents
/ pharmacology
Kidney
/ pathology
Kidney Transplantation
/ adverse effects
Male
Middle Aged
Prospective Studies
Tacrolimus
/ pharmacology
Journal
Transplantation
ISSN: 1534-6080
Titre abrégé: Transplantation
Pays: United States
ID NLM: 0132144
Informations de publication
Date de publication:
01 03 2021
01 03 2021
Historique:
pubmed:
9
6
2020
medline:
21
7
2021
entrez:
9
6
2020
Statut:
ppublish
Résumé
Here, we present our initial experience with a prospective protocol of belatacept conversion in patients with chronic active antibody-mediated rejection (caAMR) and a high degree of chronicity at the time of diagnosis. We converted 19 patients (mean age, 45 ± 12 y) with biopsy-proven caAMR from tacrolimus to belatacept at a median of 44 months post-kidney transplant. At a median of 29 months (interquartile range, 16-46 mo) postconversion, death-censored graft and patient survivals were 89% and 95%, respectively. When compared to a 1:2 propensity-matched control cohort from the INSERM U970 registry maintained on calcineurin inhibitor, the belatacept group had progressive improvement (P = 0.02) in estimated glomerular filtration rate from a mean of 33.9 ± 10 at baseline to 37.8 ± 13 at 6 months and 38.5 ± 12 mL/min/1.73 m2 at 12 months postconversion, as compared to a steady decline noted in the controls (36.2 [baseline] → 33.1 [6 mo] → 32.7 mL/min/1.73 m2 [12 mo] of follow-up). A paired histologic comparison of preconversion and postconversion (performed at median 9.5 mo postconversion) biopsies showed no worsening in microvascular inflammation or chronicity. The paired tissue gene expression analysis showed improved mean total rejection score (0.68 ± 0.26-0.56 ± 0.33; P = 0.02) and a trend toward improved antibody-mediated rejection score (0.64 ± 0.34-0.56 ± 0.39; P = 0.06). Here, we report that in patients diagnosed with caAMR who were not subjected to intensive salvage immunosuppressive therapies, isolated belatacept conversion alone was associated with stabilization in renal function. These results are bolstered by molecular evidence of improved inflammation.
Sections du résumé
BACKGROUND
Here, we present our initial experience with a prospective protocol of belatacept conversion in patients with chronic active antibody-mediated rejection (caAMR) and a high degree of chronicity at the time of diagnosis.
METHODS
We converted 19 patients (mean age, 45 ± 12 y) with biopsy-proven caAMR from tacrolimus to belatacept at a median of 44 months post-kidney transplant.
RESULTS
At a median of 29 months (interquartile range, 16-46 mo) postconversion, death-censored graft and patient survivals were 89% and 95%, respectively. When compared to a 1:2 propensity-matched control cohort from the INSERM U970 registry maintained on calcineurin inhibitor, the belatacept group had progressive improvement (P = 0.02) in estimated glomerular filtration rate from a mean of 33.9 ± 10 at baseline to 37.8 ± 13 at 6 months and 38.5 ± 12 mL/min/1.73 m2 at 12 months postconversion, as compared to a steady decline noted in the controls (36.2 [baseline] → 33.1 [6 mo] → 32.7 mL/min/1.73 m2 [12 mo] of follow-up). A paired histologic comparison of preconversion and postconversion (performed at median 9.5 mo postconversion) biopsies showed no worsening in microvascular inflammation or chronicity. The paired tissue gene expression analysis showed improved mean total rejection score (0.68 ± 0.26-0.56 ± 0.33; P = 0.02) and a trend toward improved antibody-mediated rejection score (0.64 ± 0.34-0.56 ± 0.39; P = 0.06).
CONCLUSIONS
Here, we report that in patients diagnosed with caAMR who were not subjected to intensive salvage immunosuppressive therapies, isolated belatacept conversion alone was associated with stabilization in renal function. These results are bolstered by molecular evidence of improved inflammation.
Identifiants
pubmed: 32510913
pii: 00007890-202103000-00029
doi: 10.1097/TP.0000000000003278
doi:
Substances chimiques
Immunosuppressive Agents
0
Abatacept
7D0YB67S97
Tacrolimus
WM0HAQ4WNM
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
660-667Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Déclaration de conflit d'intérêts
P.H. has received ownership interest from transcriptome Sciences. G.G. has received honoraria CareDx, Mallinckrodt, Thermo Fisher. The other authors declare no conflicts of interest.
Références
Sellarés J, de Freitas DG, Mengel M, et al. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant. 2012; 12:388–399. doi:10.1111/j.1600-6143.2011.03840.x
doi: 10.1111/j.1600-6143.2011.03840.x
Halloran PF, Reeve JP, Pereira AB, et al. Antibody-mediated rejection, T cell-mediated rejection, and the injury-repair response: new insights from the Genome Canada studies of kidney transplant biopsies. Kidney Int. 2014; 85:258–264. doi:10.1038/ki.2013.300
doi: 10.1038/ki.2013.300
Redfield RR, Ellis TM, Zhong W, et al. Current outcomes of chronic active antibody mediated rejection—a large single center retrospective review using the updated BANFF 2013 criteria. Hum Immunol. 2016; 77:346–352. doi:10.1016/j.humimm.2016.01.018
doi: 10.1016/j.humimm.2016.01.018
Halloran PF, Merino Lopez M, Barreto Pereira A. Identifying subphenotypes of antibody-mediated rejection in kidney transplants. Am J Transplant. 2016; 16:908–920. doi:10.1111/ajt.13551
doi: 10.1111/ajt.13551
Kulkarni S, Kirkiles-Smith NC, Deng YH, et al. Eculizumab therapy for chronic antibody-mediated injury in kidney transplant recipients: a pilot randomized controlled trial. Am J Transplant. 2017; 17:682–691. doi:10.1111/ajt.14001
doi: 10.1111/ajt.14001
Moreso F, Crespo M, Ruiz JC, et al. Treatment of chronic antibody mediated rejection with intravenous immunoglobulins and rituximab: a multicenter, prospective, randomized, double-blind clinical trial. Am J Transplant. 2018; 18:927–935. doi:10.1111/ajt.14520
doi: 10.1111/ajt.14520
Eskandary F, Regele H, Baumann L, et al. A randomized trial of bortezomib in late antibody-mediated kidney transplant rejection. J Am Soc Nephrol. 2018; 29:591–605. doi:10.1681/ASN.2017070818
doi: 10.1681/ASN.2017070818
Muduma G, Odeyemi I, Smith-Palmer J, et al. Review of the clinical and economic burden of antibody-mediated rejection in renal transplant recipients. Adv Ther. 2016; 33:345–356. doi:10.1007/s12325-016-0292-y
doi: 10.1007/s12325-016-0292-y
Clayton PA, McDonald SP, Russ GR, et al. Long-term outcomes after acute rejection in kidney transplant recipients: an ANZDATA analysis. J Am Soc Nephrol. 2019; 30:1697–1707. doi:10.1681/ASN.2018111101
doi: 10.1681/ASN.2018111101
Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and long-term outcomes in kidney transplantation. N Engl J Med. 2016; 374:333–343. doi:10.1056/NEJMoa1506027
doi: 10.1056/NEJMoa1506027
Gupta G, Abu Jawdeh BG, Racusen LC, et al. Late antibody-mediated rejection in renal allografts: outcome after conventional and novel therapies. Transplantation. 2014; 97:1240–1246. doi:10.1097/01.TP.0000442503.85766.91
doi: 10.1097/01.TP.0000442503.85766.91
Kim EJ, Kwun J, Gibby AC, et al. Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection. Am J Transplant. 2014; 14:59–69. doi:10.1111/ajt.12526
doi: 10.1111/ajt.12526
Leibler C, Thiolat A, Hénique C, et al. Control of humoral response in renal transplantation by belatacept depends on a direct effect on B cells and impaired T follicular helper-B cell crosstalk. J Am Soc Nephrol. 2018; 29:1049–1062. doi:10.1681/ASN.2017060679
doi: 10.1681/ASN.2017060679
Gupta G, Regmi A, Kumar D, et al. Safe conversion from tacrolimus to belatacept in high immunologic risk kidney transplant recipients with allograft dysfunction. Am J Transplant. 2015; 15:2726–2731. doi:10.1111/ajt.13322
doi: 10.1111/ajt.13322
Rostaing L, Massari P, Garcia VD, et al. Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase II study. Clin J Am Soc Nephrol. 2011; 6:430–439. doi:10.2215/CJN.05840710
doi: 10.2215/CJN.05840710
Haas M, Loupy A, Lefaucheur C, et al. The Banff 2017 kidney meeting report: revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant. 2018; 18:293–307. doi:10.1111/ajt.14625
doi: 10.1111/ajt.14625
Halloran PF, de Freitas DG, Einecke G, et al. The molecular phenotype of kidney transplants. Am J Transplant. 2010; 10:2215–2222. doi:10.1111/j.1600-6143.2010.03267.x
doi: 10.1111/j.1600-6143.2010.03267.x
Einecke G, Broderick G, Sis B, et al. Early loss of renal transcripts in kidney allografts: relationship to the development of histologic lesions and alloimmune effector mechanisms. Am J Transplant. 2007; 7:1121–1130. doi:10.1111/j.1600-6143.2007.01797.x
doi: 10.1111/j.1600-6143.2007.01797.x
Einecke G, Kayser D, Vanslambrouck JM, et al. Loss of solute carriers in T cell-mediated rejection in mouse and human kidneys: an active epithelial injury-repair response. Am J Transplant. 2010; 10:2241–2251. doi:10.1111/j.1600-6143.2010.03263.x
doi: 10.1111/j.1600-6143.2010.03263.x
Famulski KS, de Freitas DG, Kreepala C, et al. Molecular phenotypes of acute kidney injury in kidney transplants. J Am Soc Nephrol. 2012; 23:948–958. doi:10.1681/ASN.2011090887
doi: 10.1681/ASN.2011090887
Halloran PF, Reeve J, Akalin E, et al. Real time central assessment of kidney transplant indication biopsies by microarrays: the INTERCOMEX study. Am J Transplant. 2017; 17:2851–2862. doi:10.1111/ajt.14329
doi: 10.1111/ajt.14329
Choi J, Aubert O, Vo A, et al. Assessment of tocilizumab (anti-interleukin-6 receptor monoclonal) as a potential treatment for chronic antibody-mediated rejection and transplant glomerulopathy in HLA-sensitized renal allograft recipients. Am J Transplant. 2017; 17:2381–2389. doi:10.1111/ajt.14228
doi: 10.1111/ajt.14228
Kumar D, Safavi F, Sandhu R, et al. Lack of response to tocilizumab in kidney transplants with chronic antibody-mediated rejection. In: Presented at: American Transplant Congress. June 1, 2019, Boston, MA
Aubert O, Higgins S, Bouatou Y, et al. Archetype analysis identifies distinct profiles in renal transplant recipients with transplant glomerulopathy associated with allograft survival. J Am Soc Nephrol. 2019; 30:625–639. doi:10.1681/ASN.2018070777
doi: 10.1681/ASN.2018070777
Kasiske BL, Israni AK, Snyder JJ, et al.; Patient Outcomes in Renal Transplantation (PORT) Investigators. The relationship between kidney function and long-term graft survival after kidney transplant. Am J Kidney Dis. 2011; 57:466–475. doi:10.1053/j.ajkd.2010.10.054
doi: 10.1053/j.ajkd.2010.10.054
Talreja H, Akbari A, White CA, et al. Predicting kidney transplantation outcomes using proteinuria ascertained from spot urine samples versus timed urine collections. Am J Kidney Dis. 2014; 64:962–968. doi:10.1053/j.ajkd.2014.07.027
doi: 10.1053/j.ajkd.2014.07.027
Bachelet T, Nodimar C, Taupin JL, et al. Intravenous immunoglobulins and rituximab therapy for severe transplant glomerulopathy in chronic antibody-mediated rejection: a pilot study. Clin Transplant. 2015; 29:439–446. doi:10.1111/ctr.12535
doi: 10.1111/ctr.12535
Lam NN, Tonelli M, Lentine KL, et al. Albuminuria and posttransplant chronic kidney disease stage predict transplant outcomes. Kidney Int. 2017; 92:470–478. doi:10.1016/j.kint.2017.01.028
doi: 10.1016/j.kint.2017.01.028
Piñeiro GJ, De Sousa-Amorim E, Solé M, et al. Rituximab, plasma exchange and immunoglobulins: an ineffective treatment for chronic active antibody-mediated rejection. BMC Nephrol. 2018; 19:261. doi:10.1186/s12882-018-1057-4
doi: 10.1186/s12882-018-1057-4
Loupy A, Lefaucheur C, Vernerey D, et al. Molecular microscope strategy to improve risk stratification in early antibody-mediated kidney allograft rejection. J Am Soc Nephrol. 2014; 25:2267–2277. doi:10.1681/ASN.2013111149
doi: 10.1681/ASN.2013111149