Conversion from calcineurin inhibitors to sirolimus in transplant‐associated thrombotic microangiopathy

Kanunnikov, Mikhail; Rakhmanova, Zhemal Zarifovna; Levkovsky, Nikita V; Vafina, Aliya I; Goloshapov, Oleg V; Shchegoleva, Tatiana S; Vlasova, Julia J.; Paina, Olesya V.; Morozova, Elena; Zubarovskaya, L. S.; Moiseev, Ivan S.

doi:10.1111/ctr.14180

Cited by 6 publications

(4 citation statements)

References 37 publications

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“…The two main groups of immunosuppressants used in all forms of transplantation, i.e. , calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors (mTORi) such as sirolimus, can both trigger the development of PT-TMA[ 39 , 40 ]. The etiologic role of CNIs in causing PT-TMA is well established.…”

Section: Etiology Of Pt-tmasmentioning

confidence: 99%

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Thrombotic microangiopathy after kidney transplantation: Expanding etiologic and pathogenetic spectra

Mubarak,

Raza,

Rashid

et al. 2024

World J Transplant

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Thrombotic microangiopathy (TMA) is an uncommon but serious complication that not only affects native kidneys but also transplanted kidneys. This review is specifically focused on post-transplant TMA (PT-TMA) involving kidney transplant recipients. Its reported prevalence in the latter population varies from 0.8% to 14% with adverse impacts on both graft and patient survival. It has many causes and associations, and the list of etiologic agents and associations is growing constantly. The pathogenesis is equally varied and a variety of pathogenetic pathways lead to the development of microvascular injury as the final common pathway. PT-TMA is categorized in many ways in order to facilitate its management. Ironically, more than one causes are contributory in PT-TMA and it is often difficult to pinpoint one particular cause in an individual case. Pathologically, the hallmark lesions are endothelial cell injury and intravascular thrombi affecting the microvasculature. Early diagnosis and classification of PT-TMA are imperative for optimal outcomes but are challenging for both clinicians and pathologists. The Banff classification has addressed this issue and has developed minimum diagnostic criteria for pathologic diagnosis of PT-TMA in the first phase. Management of the condition is also challenging and still largely empirical. It varies from simple maneuvers, such as plasmapheresis, drug withdrawal or modification, or dose reduction, to lifelong complement blockade, which is very expensive. A thorough understanding of the condition is imperative for an early diagnosis and quick treatment when the treatment is potentially effective. This review aims to increase the awareness of relevant stakeholders regarding this important, potentially treatable but under-recognized cause of kidney allograft dysfunction.

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Section: Etiology Of Pt-tmasmentioning

confidence: 99%

“…The etiologic role of CNIs in causing PT-TMA is well established. However, the role of mTOR inhibitors is still largely controversial[ 40 ]. In vitro studies have suggested that sirolimus causes endothelial cell (EC) injury only when used in combination with tacrolimus.…”

Section: Etiology Of Pt-tmasmentioning

confidence: 99%

Thrombotic microangiopathy after kidney transplantation: Expanding etiologic and pathogenetic spectra

Mubarak,

Raza,

Rashid

et al. 2024

World J Transplant

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“…Treating infections and aGVHD may decrease the severity of TMA by dampening the feedback loop of endothelial damage and inflammation. Removing CNIs may improve TA-TMA, by diminishing the direct toxic effects on the endothelium (studied in vitro) [29][30][31]. However, this strategy is complicated…”

Section: Current Management Paradigmmentioning

confidence: 99%

Emerging therapeutic and preventive approaches to transplant-associated thrombotic microangiopathy

Schoettler

Chonat

Williams

et al. 2021

Current Opinion in Hematology

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Purpose of review Transplant-associated thrombotic microangiopathy (TA-TMA) is a complication that can occur in both allogeneic and autologous haematopoietic cellular therapy (HCT) recipients and is associated with significant morbidity and mortality. Although TA-TMA is a complex disease, there is emerging evidence that complement activation and endothelial dysfunction play a key role in the pathophysiology of the disease. The use of eculizumab has improved survival in patients with high risk and severe disease, but mortality rates in treated patients still exceed 30%, highlighting the need for novel approaches. Recent findings There are multiple ongoing and planned clinical trials investigating novel complement agents in TA-TMA and other TMAs. Drugs vary by targets of the complement system, mechanism, and form of administration. Clinical trial designs include single arm studies that span across multiple age groups including children, and double-blind, randomized, placebo-controlled studies. These studies will provide robust data to inform the care of patients with TA-TMA in the future. In addition to multiple promising therapeutic agents, preventing TA-TMA is an emerging strategy. Agents known to protect the endothelium from damage and augment endothelial function by promoting anti-inflammatory and antithrombotic effects may have a role in preventing TA-TMA or ameliorating the severity, though additional studies are needed. Summary Novel therapeutic agents for TA-TMA inhibition of the complement system are under investigation and prophylactic strategies of endothelial protection are emerging. Further understanding of the pathophysiology of the disease may identify additional therapeutic targets. Multiinstitutional, collaborative clinical trials are needed to determine the safety and efficacy of these agents going forward.

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“…Also, the different centers are testing other type of agents for GVHD prophylaxis instead of CNIs, with effects on survival outcomes. In our single-center analysis, substitution of CNIs by sirolimus in severe GVHD proved to be superior to steroids [53]. Novel agents, like JAK inhibitors, might also facilitate sufficient GVHD control instead of CNIs without additional endothelial damage [54].…”

Section: Treatment Of Transplant-associated Thrombotic Microangiopathymentioning

confidence: 99%

Practical review of current approaches to diagnosis and treatment of transplant-associated thrombotic microangiopathy

Moiseev¹,

Tsvetkova²,

Ruutu³

2021

CTT

Self Cite

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Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare complication of hematopoietic stem cell transplantation with an endothelial damage being the major cause of clinical signs. Currently, four major set of diagnostic criteria exist which capture different populations of patients with variable severity of endothelial dysfunction and target organ involvement. Absence of widely excepted criteria for TA-TMA severity, outcome and response measures complicate the comparison of different treatment approaches. Withdrawal or tapering of calcineurin inhibitors is a widely excepted intervention; however, there are studies that indicate no benefit of this intervention in improving overall survival. Different strategies of substituting calcineurin inhibitors with other immunosuppressive may also have impact on survival in TA-TMA patients.Novel approaches in treatment include oligonucleotides and complement inhibitors. Indications for these treatments according to different diagnostic criteria are still to be defined. Currently published evidence highlight the need for cooperative effort to gather empirical data and harmonize definitions required for comparative clinical studies of novel agents.

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Conversion from calcineurin inhibitors to sirolimus in transplant‐associated thrombotic microangiopathy

Cited by 6 publications

References 37 publications

Thrombotic microangiopathy after kidney transplantation: Expanding etiologic and pathogenetic spectra

Thrombotic microangiopathy after kidney transplantation: Expanding etiologic and pathogenetic spectra

Emerging therapeutic and preventive approaches to transplant-associated thrombotic microangiopathy

Practical review of current approaches to diagnosis and treatment of transplant-associated thrombotic microangiopathy

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