Everolimus, Cyclosporine, and Thrombotic Microangiopathy: Clinical Role and Preventive Tools in Renal Transplantation

Nava, F B; Cappelli, Gianni; Mori, Giacomo; Granito, M.; Magnoni, G.; Botta, Celine; Solazzo, Andrea; Fontana, Francesco; Baisi, Alessandro; Bonucchi, Decenzio

doi:10.1016/j.transproceed.2014.07.062

Cited by 30 publications

(22 citation statements)

References 10 publications

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“…antigen) antibodies may be associated to microvascular inflammation, early acute rejection and allograft loss as previously reported. [27][28][29] TMA associated only to drug toxicity was relatively infrequent in our findings, compared to what was observed by Nava et al [30]. On the other hand, in accordance with what was recently published by Bayer et al [31], the usual presence of multiples conditions causing or precipitating TMA supports the "multiple hit hypothesis" [8,32] that speculates that TMA is the consequence of the combination of genetic predisposition and several trigger factors/conditions in both native and transplanted kidneys.…”

Section: Timelinesupporting

confidence: 92%

Clinical and pathological features of thrombotic microangiopathy influencing long-term kidney transplant outcomes

et al. 2020

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Introduction Thrombotic microangiopathy (TMA) in post-transplant setting has heterogeneous clinical manifestations. Methods We retrospectively studied data of 89 patients with post-transplant TMA, which was characterized by thrombi in at least one glomerulus and/or arteriole. Systemic TMA was defined by thrombocytopenia and microangiopathic anemia and early onset TMA, when occurred less than 90 days post transplant. Results The cumulative incidence was 0.93%. The majority of the recipients were young (mean age 39 years), female (52%) and Caucasian (48%) with primary kidney disease of unknown etiology (37%). Early TMA occurred in 51% of the patients and systemic TMA, in 25%. Underlying precipitating factors were: infection (54%), acute rejection (34%), calcineurin inhibitor toxicity (13%) and pregnancy (3%). 18% of the patients had several triggers. Glomerular TMA was observed in 50% of the biopsies and endothelial cell activation, in 61%. The 1year patient survival was 97% and corresponding graft survival, 66%. Allograft survival was inferior when acute antibody mediated rejection (ABMR) occurred (with 41%; without 70%, p = 0.01), however no differences were determined by hemolysis, time of onset, thrombi location or endothelial cell activation. Conclusions Our results suggest that post-transplant TMA is a rare but severe condition, regardless of its clinical and histological presentation, mainly when associated to ABMR.

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Section: Timelinesupporting

confidence: 92%

Clinical and pathological features of thrombotic microangiopathy influencing long-term kidney transplant outcomes

et al. 2020

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“…cancer) has forced the need to find a balance between rigorous immunosuppression and adverse drug side effects. Effective modern immunosuppression requires blockade of one or more of the three stages in the life-cycle of lymphocytes to aid in increasing graft half-life by suppressing graft rejection [38] . The site of action defines the immunosuppressive therapy such as lymphocyte depletion, lymphocyte diversion, and lymphocyte-activation blockade.…”

Section: Immunosuppressive Strategies In Current Practicementioning

confidence: 99%

Immunomodulator alemtuzumab therapy in kidney transplantation

2016

Macrophage

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Owing to an insufficient understanding of molecular mechanisms, currently the best treatment available for chronic kidney failure is transplantation. There is a heightened need for effective immunosuppressants to counteract rejection. Alemtuzumab, a humanized anti-CD52 antibody, is a powerful lymphocyte-depleting agent. Recently, it has been increasingly used as induction therapy in renal transplantation but its role is not yet fully defined. Indications that early withdrawal of corticosteroids in kidney transplant patients is associated with a better prognosis, has necessitated a hunt for an effective induction agent that supports early corticosteroid withdrawal. In this regard, alemtuzumab is an attractive agent because of its prolonged lymphocyte depleting properties. Long-term studies in kidney transplant patients are still needed for it to be considered as an effective induction agent. Trends in lower acute rejection rates in groups using alemtuzumab induction, particularly in association with tacrolimus maintenance therapy, have been noted and acute rejections were not as severe. Lymphocyte depletion is expected to be associated with an increased incidence of infection and any new immunosuppressive agents should be observed closely for development of infection. Initial studies have not established increased infection rates with alemtuzumab induction, possibly because of the preservation of function of the remaining T-lymphocytes other than CD4+ cells. Further randomized control trials with larger populations are needed to draft a protocol for alemtuzumab's more effective use in transplantation.

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“…These effects are proven to be implicated in TMA pathogenesis[ 15 , 16 ]; (2) The VEGF inhibition has been recently proven to be associated with reduced renal levels of complement factor H (CFH)[ 17 ]. Patients with underlying CFH genetic mutations are more susceptible to develop de novo TMA, particularly with mTORi exposure[ 7 ]; (3) Repair of endothelial injury could be hampered by mTORi use[ 18 - 20 ]; and (4) Furthermore, the procoagulant and the antifibrinolytic activity of mTORi might play additional roles in de novo TMA development[ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

“…The risk of development of TMA with combined CNI and mTORi protocols is higher than using mTORi alone, an effect that has been documented in several studies. While Fortin et al[ 18 ] reported that the highest risk of de novo TMA was in the group using CNI and mTORi, Nava et al[ 20 ] studied 396 KTR, 36 (7.3%) developed TMA and 17 of them were drug-related. Not only were the drug levels of CNI and mTORi higher in the TMA group, but the sum of both drug levels in the TMA group was also higher[ 18 - 20 ].…”

Section: Introductionmentioning

confidence: 99%

Thrombotic microangiopathy after renal transplantation: Current insights inde novoand recurrent disease

Abbas¹,

Kossi

Kim

et al. 2018

WJT

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Thrombotic microangiopathy (TMA) is one of the most devastating sequalae of kidney transplantation. A number of published articles have covered either de novo or recurrent TMA in an isolated manner. We have, hereby, in this article endeavored to address both types of TMA in a comparative mode. We appreciate that de novo TMA is more common and its prognosis is poorer than recurrent TMA; the latter has a genetic background, with mutations that impact disease behavior and, consequently, allograft and patient survival. Post-transplant TMA can occur as a recurrence of the disease involving the native kidney or as de novo disease with no evidence of previous involvement before transplant. While atypical hemolytic uremic syndrome is a rare disease that results from complement dysregulation with alternative pathway overactivity, de novo TMA is a heterogenous set of various etiologies and constitutes the vast majority of post-transplant TMA cases. Management of both diseases varies from simple maneuvers, e.g., plasmapheresis, drug withdrawal or dose modification, to lifelong complement blockade, which is rather costly. Careful donor selection and proper recipient preparation, including complete genetic screening, would be a pragmatic approach. Novel therapies, e.g., purified products of the deficient genes, though promising in theory, are not yet of proven value.

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Everolimus, Cyclosporine, and Thrombotic Microangiopathy: Clinical Role and Preventive Tools in Renal Transplantation

Cited by 30 publications

References 10 publications

Clinical and pathological features of thrombotic microangiopathy influencing long-term kidney transplant outcomes

Clinical and pathological features of thrombotic microangiopathy influencing long-term kidney transplant outcomes

Immunomodulator alemtuzumab therapy in kidney transplantation

Thrombotic microangiopathy after renal transplantation: Current insights inde novoand recurrent disease

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