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MTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases.

ABSTRACT: Mitochondrial diseases represent a significant clinical challenge. Substantial efforts have been devoted to identifying therapeutic strategies for mitochondrial disorders, but effective interventions have remained elusive. Recently, we reported attenuation of disease in a mouse model of the human mitochondrial disease Leigh syndrome through pharmacological inhibition of the mechanistic target of rapamycin (mTOR). The human mitochondrial disorder MELAS/MIDD (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes/Maternally Inherited Diabetes and Deafness) shares many phenotypic characteristics with Leigh syndrome. MELAS/MIDD often leads to organ failure and transplantation and there are currently no effective treatments. To examine the therapeutic potential of mTOR inhibition in human mitochondrial disease, four kidney transplant recipients with MELAS/MIDD were switched from calcineurin inhibitors to mTOR inhibitors for immunosuppression. Primary fibroblast lines were generated from patient dermal biopsies and the impact of rapamycin was studied using cell-based end points. Metabolomic profiles of the four patients were obtained before and after the switch. pS6, a measure of mTOR signaling, was significantly increased in MELAS/MIDD cells compared to controls in the absence of treatment, demonstrating mTOR overactivation. Rapamycin rescued multiple deficits in cultured cells including mitochondrial morphology, mitochondrial membrane potential, and replicative capacity. Clinical measures of health and mitochondrial disease progression were improved in all four patients following the switch to an mTOR inhibitor. Metabolomic analysis was consistent with mitochondrial function improvement in all patients.

SUBMITTER: Johnson SC

PROVIDER: S-EPMC6389356 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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mTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases.

Johnson Simon C SC Martinez Frank F Bitto Alessandro A Gonzalez Brenda B Tazaerslan Cagdas C Cohen Camille C Delaval Laure L Timsit José J Knebelmann Bertrand B Terzi Fabiola F Mahal Tarika T Zhu Yizhou Y Morgan Philip G PG Sedensky Margaret M MM Kaeberlein Matt M Legendre Christophe C Suh Yousin Y Canaud Guillaume G

Kidney international 20181122 2

Mitochondrial diseases represent a significant clinical challenge. Substantial efforts have been devoted to identifying therapeutic strategies for mitochondrial disorders, but effective interventions have remained elusive. Recently, we reported attenuation of disease in a mouse model of the human mitochondrial disease Leigh syndrome through pharmacological inhibition of the mechanistic target of rapamycin (mTOR). The human mitochondrial disorder MELAS/MIDD (Mitochondrial Encephalopathy with Lact ...[more]

PMID: 30471880

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Project description:BackgroundKidney transplant recipients are commonly prescribed proton-pump inhibitors (PPIs), but due to concern for polypharmacy, chronic use should be limited.ObjectiveThe objective was to describe PPI use in kidney transplant recipients beyond their first year of transplant to better inform and support deprescribing initiatives.DesignWe conducted a retrospective, population-based cohort study using linked health care databases.SettingThis study was conducted in Alberta, Canada.PatientsWe included all prevalent adult, kidney-only transplant recipients between April 2008 and December 2017 who received their transplant between May 2002 and December 2017.MeasurementsThe primary outcome was ongoing or new PPI use and patterns of use, including frequency and duration of therapy, and assessment of indication for PPI use.MethodsWe ascertained baseline characteristics, covariate information, and outcome data from the Alberta Kidney Disease Network (AKDN). We compared recipients with evidence of a PPI prescription in the 3 months prior to study entry to those with a histamine-2-receptor antagonist (H2Ra) fill and those with neither.ResultsWe identified 1823 kidney transplant recipients, of whom 868 (48%) were on a PPI, 215 (12%) were on an H2Ra, and 740 (41%) were on neither at baseline. Over a median follow-up of 5.4 years (interquartile range [IQR] = 2.6-9.3), there were almost 45 000 unique PPI prescriptions dispensed, the majority (80%) of which were filled by initial PPI users. Recipients who were on a PPI at baseline would spend 91% (IQR = 70-98) of their graft survival time on a PPI in follow-up, and nephrologists were the main prescribers. We identified an indication for ongoing PPI use in 54% of recipients with the most common indication being concurrent antiplatelet use (26%).LimitationsOur kidney transplant recipients have access to universal health care coverage which may limit generalizability. We identified common gastrointestinal indications for PPI use but did not include rare conditions due to concerns about the validity of diagnostic codes. In addition, symptoms suggestive of reflux may not be well coded as the focus of follow-up visits is more likely to focus on kidney transplant.ConclusionsMany kidney transplant recipients are prescribed a PPI at, or beyond, the 1-year post-transplant date and are likely to stay on a PPI in follow-up. Almost half of the recipients in our study did not have an identifiable indication for ongoing PPI use. Nephrologists frequently prescribe PPIs to kidney transplant recipients and should be involved in deprescribing initiatives to reduce polypharmacy.

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MTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases.

Publications

mTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases.

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