Effects of mTOR inhibitor–related proteinuria on progression of cardiac allograft vasculopathy and outcomes among heart transplant recipients

Asleh, Rabea; Alnsasra, Hilmi; Lerman, Amir; Briasoulis, Αlexandros; Pereira, Naveen L.; Edwards, Brooks S.; Toya, Takumi; Stulak, John M.; Clavell, Alfredo L.; Daly, Richard C.; Kushwaha, Sudhir S.

doi:10.1111/ajt.16155

Cited by 13 publications

(8 citation statements)

References 30 publications

(40 reference statements)

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“…De novo focal segmental glomerulosclerosis lesion has been documented in patients receiving sirolimus, possibly through its effect on mTOR to decrease cell survival 25 . mTOR inhibitor‐induced proteinuria has been demonstrated to be associated with CAV progression and increased all‐cause mortality 26 . Our finding highlighted the importance of monitoring urinary protein in patients on mTOR inhibitors on a regular basis and consider discontinuation of the medication if the proteinuria is progressive.…”

Section: Discussionmentioning

confidence: 66%

“…25 mTOR inhibitor-induced proteinuria has been demonstrated to be associated with CAV progression and increased all-cause mortality. 26 Our finding highlighted the importance of monitoring urinary protein in patients on mTOR inhibitors on a regular basis and consider discontinuation of the medication if the proteinuria is progressive. The higher renal AEs reported in the mTOR inhibitors cohort could also be explained by the patient population as mTOR inhibitors are often used to withdraw or minimize CNI exposure in patients with preexisting chronic renal insufficiency.…”

Section: F I G U R Ementioning

confidence: 82%

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Mtor inhibitors associated with higher cardiovascular adverse events—A large population database analysis

Nguyen

Abagyan

Tsunoda

2021

Clinical Transplantation

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The management of immunosuppressive therapy requires a delicate balance between maximizing immunosuppression to prevent rejection while minimizing the complications of immunodeficiency and the adverse effects (AEs) of therapy. One of the biggest challenges in immunosuppressive management is the acute and chronic nephrotoxicity associated with calcineurin inhibitors (CNIs). Moreover, CNIs have been associated with the development of multiple cardiovascular disease risk factors including hypertension, hyperlipidemia, and new-onset diabetes after transplantation. 1 Metabolic syndrome induced by immunosuppressants is a significant cause of mortality and morbidity. The use of mammalian target of rapamycin (mTOR) inhibitors in maintenance immunosuppression has been increasing steadily in solid organ transplantation in recent years due to their unique mechanism of action and safety profiles. There are limited real-world data available regarding AEs of immunosuppressants, especially for the newer mTOR inhibitors sirolimus and everolimus, which were approved in 1999 and 2009, respectively. The FDA Adverse Event Reporting System (FAERS) database was created to support FDA's postmarketing surveillance on drugs and biologic therapeutics. It contains adverse reaction and medication error reports sent to the FDA through MedWatch, the FDA Safety Information and Adverse Event Reporting Program. The FDA

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Section: Discussionmentioning

confidence: 66%

Section: F I G U R Ementioning

confidence: 82%

Mtor inhibitors associated with higher cardiovascular adverse events—A large population database analysis

Nguyen

Abagyan

Tsunoda

2021

Clinical Transplantation

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“…Recently, proteinuria in heart transplant recipients converted to mTOR inhibitors has been associated with higher all-cause mortality. 45 Therefore, mTOR inhibitors should be used with caution in patients with advanced CKD or proteinuria after lung transplantation.…”

Section: The Effect Of Mtor Inhibitors On Kidney Functionmentioning

confidence: 99%

“…This concurs with findings from Demirjian et al, in which patients with at least trace proteinuria at baseline had a worse renal outcome, especially in combination with eGFR <60 mL/min, in line with the findings of Schneer et al 34,40 Recently, proteinuria in heart transplant recipients converted to mTOR inhibitors has been associated with higher all-cause mortality. 45 Therefore, mTOR inhibitors should be used with caution in patients with advanced CKD or proteinuria after lung transplantation.…”

Section: Proteinuria For Prediction Of Mtor Inhibitor Responsementioning

confidence: 99%

Mammalian Target of Rapamycin Inhibitors and Kidney Function After Thoracic Transplantation: A Systematic Review and Recommendations for Management of Lung Transplant Recipients

et al. 2022

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Background. Chronic kidney disease (CKD) after lung transplantation is common and limits the survival of transplant recipients. The calcineurin inhibitors (CNI), cyclosporine A, and tacrolimus being the cornerstone of immunosuppression are key mediators of nephrotoxicity. The mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, are increasingly used in combination with reduced CNI dosage after lung transplantation. Methods. This systematic review examined the efficacy and safety of mTOR inhibitors after lung transplantation and explored their effect on kidney function. Results. mTOR inhibitors are often introduced to preserve kidney function. Several clinical trials have demonstrated improved kidney function and efficacy of mTOR inhibitors. The potential for kidney function improvement and preservation increases with early initiation of mTOR inhibitors and low target levels for both mTOR inhibitors and CNI. No defined stage of CKD for mTOR inhibitor initiation exists, nor does severe CKD preclude the improvement of kidney function under mTOR inhibitors. Baseline proteinuria may negatively predict the preservation and improvement of kidney function. Discontinuation rates of mTOR inhibitors due to adverse effects increase with higher target levels. Conclusions. More evidence is needed to define the optimal immunosuppressive regimen incorporating mTOR inhibitors after lung transplantation. Not only the indication criteria for the introduction of mTOR inhibitors are needed, but also the best timing, target levels, and possibly discontinuation criteria must be defined more clearly. Current evidence supports the notion of nephroprotective potential under certain conditions.

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“…They were compared to 134 patients treated with CNI, of whom 99 had sequential IVUS studies 10,11 . From this same group, an observation published in the current issue of the American Journal of Transplantation , regarding the prognostic implications of proteinuria in 137 of the patients switched to sirolimus and who had sequential IVUS studies 12 . One hundred one of these patients had no significant proteinuria, with a median of 126 mg/24 h at baseline, increasing to 168 mg/24 h at 1 year posttransplant compared to 36 patients with significant increases in proteinuria with a median of 235 mg/24 h at baseline to 1265.5 mg/24 h 1 year later.…”

mentioning

confidence: 99%

CAVEAT mTOR: You’ve heard about the benefits of using mTOR inhibitors, here are some of the risks

Eisen

2021

American Journal of Transplantation

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Effects of mTOR inhibitor–related proteinuria on progression of cardiac allograft vasculopathy and outcomes among heart transplant recipients

Cited by 13 publications

References 30 publications

Mtor inhibitors associated with higher cardiovascular adverse events—A large population database analysis

Mtor inhibitors associated with higher cardiovascular adverse events—A large population database analysis

Mammalian Target of Rapamycin Inhibitors and Kidney Function After Thoracic Transplantation: A Systematic Review and Recommendations for Management of Lung Transplant Recipients

CAVEAT mTOR: You’ve heard about the benefits of using mTOR inhibitors, here are some of the risks

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