Elsevier

Transplantation Proceedings

Volume 46, Issue 7, September 2014, Pages 2263-2268
Transplantation Proceedings

37th Congress of the Italian Transplantation Society
Renal transplantation
Everolimus, Cyclosporine, and Thrombotic Microangiopathy: Clinical Role and Preventive Tools in Renal Transplantation

https://doi.org/10.1016/j.transproceed.2014.07.062Get rights and content

Abstract

Introduction

Thrombotic microangiopathy (TMA) is characterized by endothelial cell injury and formation of fibrin thrombi within capillary and arterioles. In renal allograft recipients, TMA mainly presents as hemolytic uremic syndrome. Its occurrence is rare, and diagnosis requires a high degree of suspicion. Drug toxicity, in particular from calcineurin inhibitors (CNIs) and mTOR inhibitors (mTORi), is the most common cause posttransplant and has recently been emphasized in the setting of lung transplantation.

Objective

The goal of this study was to investigate the role of mTORi as an added risk factor in the development of TMA to propose strategies for modulation of immunosuppressive (IS) therapy.

Patients and Methods

From a database of 496 renal graft recipients, we analyzed 350 renal graft biopsy specimens gathered at our center from 1998 to 2012. In patients undergoing combined therapy with mTORi and CNI, we compared drugs levels in TMA-affected and TMA-free groups, using mTORi and CNI TLC and the summation of [everolimus TLC + (cyclosporine C2/100)] (Σ) as a surrogate marker of combined exposition to 2 drugs. Receiver-operating characteristic analysis of association of EVL TLC + (C2/100) was performed for patients exposed to mTORi.

Results

Histologic features of TMA were found in 36 patients (prevalence of 7.3%). The caseload was divided into 2 groups: not drug-related TMA (n = 19) and drug-related TMA (n = 17). Despite the prevalence of TMA in patients exposed to mTORi being greater (8 of 153; prevalence, 5.3%) compared with therapies without mTORi (9 of 324; prevalence, 2.8%), statistical difference was not reached. Patients treated with mTORi who developed de novo drug-related TMA had higher blood levels of IS drugs compared with those who did not develop TMA. Receiver-operating characteristic analysis found a significant threshold of 12.5 ng/mL (area under the curve, 0.803; P = .006).

Conclusions

Results confirm the pivotal role of IS drugs in the onset of de novo TMA. On the basis of literature, we could speculate a sequence of endothelial damage by CNI, on which everolimus fits hindering the repair of endothelial injury. Therefore, high blood levels of CNI and mTORi seem to predispose patients to posttransplant TMA. Combined monitoring of these 2 drugs might be used to prevent the complication. Σ [everolimus TLC + (cyclosporine C2/100)] >12.5 ng/mL should be avoided as a surrogate risk factor for adverse effects.

Section snippets

Materials and Methods

We analyzed 350 renal graft biopsy specimens gathered from 1998 to 2012 in 496 renal graft recipients (excluding kidney/pancreas, kidney/liver allografts, and primary nonfunction). Patients provided written informed consent before graft biopsy; the biopsy was indicated on clinical grounds (worsening renal function and/or proteinuria, signs of hemolitic anemia such as lactate dehydrogenase elevation, without other explanation). No protocol biopsies were performed.

In each patient with

Results

Thirty-six cases of TMA were found in 350 renal biopsy specimens in a population of 496 patients receiving a renal allograft. Prevalence was 7.3% (36 of 496). TMA that was not drug related (n = 19) included AMR (n = 11), viral infection (cytomegalovirus, human immunodeficiency virus) (n = 5), vasculitis (n = 1), systemic lupus erythematosus (n = 1), and recurrent atypical HUS (n = 1); drug-related TMA was found in 3.4% of patients (n = 17). Statistical analysis found no significant differences

Discussion

The goal of this study was to investigate the role of IS drugs in posttransplant TMA. We selected a TMA population not influenced by classical risk factors (eg, AMR, viral infections, vasculitides, systemic lupus erythematosus, recurrence of atypical HUS), in whom the role of the antirejection medication appeared predominant. However, we could not exclude the possible presence of underlying causes unknown at the time of onset.

According to the literature, drug-induced HUS represents 13% of all

Cited by (22)

  • Management of the kidney transplant patient with Cancer: Report from a Multidisciplinary Consensus Conference

    2021, Transplantation Reviews
    Citation Excerpt :

    Thrombotic microangiopathy [66] is a further rare, but typical adverse event of anti-angiogenic agents. In KTRs, CNI and mTORi are regularly used, and they might enhance the risk of thrombotic microangiopathy [67]. Therefore, proteinuria and early signs of thrombotic microangiopathy (anemia, lowering platelet count and aptoglobin levels) have to be carefully evaluated in these patients.

  • De novo thrombotic microangiopathy after kidney transplantation

    2018, Transplantation Reviews
    Citation Excerpt :

    Interestingly, not only were the CNI and the m-TOR inhibitor levels higher in the TMA group compared to those who did not develop this complication, the sum of concentrations of these two drugs was also higher in the former group (cyclosporine + everolimus: 15.2 ± 6.3 ng/dL in those with TMA vs 10.7 ± 2.1 ng/dL in those without TMA, and tacrolimus + everolimus: 21.1 ± 11.3 ng/dL in those with TMA vs 9.6 ± 1.3 ng/dL in those without TMA. Endothelial damage by CNI, in setting of mTOR inhibitor related impediment to repair of endothelial injury is postulated as the reason for this additive risk [32,35,36]. Based on these studies, we recommend caution with use of combination of these two classes of medications in the early post-transplant period when higher therapeutic levels are desirable, or in the presence of other risk factors for endothelial injury, for example presence of mutations in complement regulatory genes [19].

  • Secondary thrombotic microangiopathy and eculizumab: A reasonable therapeutic option

    2017, Nefrologia
    Citation Excerpt :

    The mTOR inhibitors enhance post-transplant TMA by inhibiting VEGF synthesis by podocytes, enhancing endothelial damage and reducing endothelial regeneration capacity. The risk of SOT-TMA increases significantly when associated with both drugs.92,98–100 Management of SOT-TMA is not well established.

  • Use of Eculizumab in Transplant-Associated Thrombotic Microangiopathy in a Patient With Polycystic Kidney Disease Immediately Post–Kidney Transplant: A Case Report

    2020, Kidney Medicine
    Citation Excerpt :

    Calcineurin inhibitors (CNIs) are frequently implicated in transplant-associated TMA, especially in the early period (3-6 months) after transplantation.3,4 Mammalian target of rapamycin inhibitors have also been associated with TMA and only belatacept (cytotoxic T lymphocyte antigen 4–immunoglobulin fusion protein that inhibits T-cell function) exists as an alternative to these agents.5,6 Withdrawal of CNI treatment alone may not be sufficient to fully reverse the adverse effects of the alternative pathway of complement activation associated with this condition.2,3

  • Onconephrology: Mitigation of renal injury in chemotherapy administration

    2024, Current Opinion in Nephrology and Hypertension
View all citing articles on Scopus
View full text