Immunosuppression Minimization and Avoidance Protocols: When Less Is Not More

Prashar, Rohini; Venkat, K. K.

doi:10.1053/j.ackd.2016.09.007

Cited by 20 publications

(21 citation statements)

References 38 publications

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“…The resulting cellular injury increases DAMPs that further activates the innate immune system in a feed-forward loop. That such a compromised immunosuppressed state can cause rejection is supported by clinical studies documenting increased risk of rejection in immunosuppression minimization/withdrawal protocols (74).…”

Section: Discussionmentioning

confidence: 96%

Landscape of innate immune system transcriptome and acute T cell–mediated rejection of human kidney allografts

Mueller¹,

Yang²,

Lubetzky³

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 96%

Landscape of innate immune system transcriptome and acute T cell–mediated rejection of human kidney allografts

Mueller¹,

Yang²,

Lubetzky³

et al. 2019

JCI Insight

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“…During the past 2 decades, early corticosteroid withdrawal (ESW) regimens have enabled significant reductions in corticosteroid‐related morbidity with modest risk in mild early acute cellular rejection (ACR), a form of rejection that confers minimal risk to renal allograft survival . In contrast, calcineurin inhibitor avoidance (CNIA) has been more challenging, due to greater rejection risks . A major advance in CNIA occurred in 2011 with regulatory approval of belatacept, a drug that blocks CD28‐mediated T cell costimulation.…”

Section: Introductionmentioning

confidence: 99%

“…8 In contrast, calcineurin inhibitor avoidance (CNIA) has been more challenging, due to greater rejection risks. 9 A major advance in CNIA occurred in 2011 with regulatory approval of belatacept, a drug that blocks CD28-mediated T cell costimulation. In registration trials, belatacept allowed CNIA with a modest increase in acute rejection that was counterbalanced by reduced nephrotoxicity 10,11 and reduced de novo DSA rates.…”

Section: Introductionmentioning

confidence: 99%

Belatacept-based immunosuppression with simultaneous calcineurin inhibitor avoidance and early corticosteroid withdrawal: A prospective, randomized multicenter trial

Woodle

Kaufman

Leone

et al. 2020

American Journal of Transplantation

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Simultaneous calcineurin inhibitor avoidance (CNIA) and early corticosteroid withdrawal (ESW) have not been achieved primarily due to excessive acute rejection. This trial compared 2 belatacept‐based CNIA/ESW regimens with a tacrolimus‐based ESW regimen. Kidney transplant recipients were randomized to receive alemtuzumab/belatacept, rabbit anti‐thymocyte globulin (rATG)/belatacept, or rATG/tacrolimus. The combinatorial primary endpoint consisted of patient death, renal allograft loss, or a Modification of Diet in Renal Disease–calculated eGFR of <45 mL/min/1.73 m2 at 12 months. Results are reported by treatment group (alemtuzumab/belatacept, rATG/belatacept, and rATG/tacrolimus). Superiority was not observed at 1 year for the primary endpoint (9/107 [8.4%], 15/104 [14.4%], and 14/105 [13.3%], respectively; P = NS) for either belatacept‐based regimen. Differences were not observed for secondary endpoints (death, death‐censored graft loss, or estimated glomerular filtration rates < 45 mL/min/1.73 m2). Differences were observed in biopsy‐proved acute cellular rejection (10.3%, 18.3%, and 1.9%, respectively) (P < .001), but not in antibody‐mediated rejection, mixed acute rejection, or de novo donor‐specific anti‐HLA antibodies. Neurologic and electrolyte abnormality adverse events were less frequent under belatacept. Belatacept‐based CNIA/ESW regimens did not prove to be superior for the primary or secondary endpoints. Belatacept‐treated patients demonstrated an increase in biopsy‐proved acute cellular rejection and reduced neurologic and metabolic adverse events. These results demonstrate that simultaneous CNIA/ESW is feasible without excessive acute rejection.

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“…Since the 1980s, several options have been developed to reduce kidney transplant rejection. Monoclonal muromonab-CD3/ OKT3, monoclonal interleukin-2 receptor (IL-2R) antibodies (daclizumab and zenapax), and antiproliferative agents (mycophenolate mofetil) are part of a large list of options currently available in renal transplantation [43]. Nevertheless, some transplant experts propose a reduction in the use of immunosuppressive drugs in order to reduce the nephrotoxicity that can also end in fibrosis and graft rejection.…”

Section: Immunosuppressive Therapy In Renal Transplantationmentioning

confidence: 99%

Immunopathology of Kidney Transplantation

Melo¹,

Ruiz-Pacheco²,

Mendoza-Cerpa³

et al. 2018

Pathophysiology - Altered Physiological States

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Renal transplantation is currently the best alternative for patients with end-stage renal disease. Immune responses activated against the allograft are a decisive factor in transplantation outcomes and patient survival. Although short-term graft and patient survival have improved significantly as a result of better donor matching systems, novel immunosuppressive agents and enhanced care, long-term outcomes remain unfavorable and reflect sub-clinical injury caused by chronic rejection. The immune system lies at the intersection of immunogenic tolerance and graft failure; thus, it is a major determinant of pathology in the context of renal transplantation. During the early stages of transplantation increased expression of cytokines has been observed in addition to increased expression of adhesion proteins and immune cells. This early inflammatory response does not necessarily end in graft rejection, although this will depend on the severity of the inflammation. Activation of Toll-like Receptors (TLRs), damaging molecular patterns (DAMPs), and other components of innate immunity is key to the formation of atherosclerotic plaques and the development of autoimmune diseases. Initially the donor antigens are presented to the T lymphocytes of the recipient. This activation induces their proliferation, differentiation and cytokine production. Successful kidney transplant recipients need to develop immunologic tolerance against donor antigens. In this chapter, we address some of the innate and adaptive immune mechanisms associated with kidney transplantation; emphasizing their role in allograft rejection.

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Immunosuppression Minimization and Avoidance Protocols: When Less Is Not More

Cited by 20 publications

References 38 publications

Landscape of innate immune system transcriptome and acute T cell–mediated rejection of human kidney allografts

Landscape of innate immune system transcriptome and acute T cell–mediated rejection of human kidney allografts

Belatacept-based immunosuppression with simultaneous calcineurin inhibitor avoidance and early corticosteroid withdrawal: A prospective, randomized multicenter trial

Immunopathology of Kidney Transplantation

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