Dataset Information

Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: What is the appropriate serum level?

ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease, and sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to significantly retard cyst expansion in animal models. The optimal therapeutic dose of sirolimus is not yet defined. Here, we report the history of a previously unknown ADPKD deceased donor whose kidneys were engrafted in two different recipients. One of the two received an immunosuppressive regimen based on sirolimus for 5 years while the other did not. After transplantation, both patients developed severe transplant cystic disease. Donor DNA sequence identified a new hypomorphic mutation in PKD1. The rate of cyst growth was identical in the two patients regardless of the treatment. While sirolimus treatment reduced the activation of mTOR in peripheral blood mononuclear cells, it failed to prevent mTOR activation in kidney tubular cells, this could account for the inefficiency of treatment on cyst growth. Together, our results suggest that the dose of sirolimus required to inhibit mTOR varies according to the tissue.

SUBMITTER: Canaud G

PROVIDER: S-EPMC3697013 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: What is the appropriate serum level?

Canaud G G Knebelmann B B Harris P C PC Vrtovsnik F F Correas J-M JM Pallet N N Heyer C M CM Letavernier E E Bienaimé F F Thervet E E Martinez F F Terzi F F Legendre C C

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20100701 7

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease, and sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to significantly retard cyst expansion in animal models. The optimal therapeutic dose of sirolimus is not yet defined. Here, we report the history of a previously unknown ADPKD deceased donor whose kidneys were engrafted in two different recipients. One of the two received an immunosuppressive regimen based on sirolimus f ...[more]

PMID: 20642692

Similar Datasets

Project description:Autosomal dominant polycystic kidney disease is characterized by progressive development and enlargement of kidney cysts, leading to ESKD. Because the kidneys are under high metabolic demand, it is not surprising that mounting evidence suggests that a metabolic defect exists in in vitro and animal models of autosomal dominant polycystic kidney disease, which likely contributes to cystic epithelial proliferation and subsequent cyst growth. Alterations include defective glucose metabolism (reprogramming to favor aerobic glycolysis), dysregulated lipid and amino acid metabolism, impaired autophagy, and mitochondrial dysfunction. Limited evidence supports that cellular kidney metabolism is also dysregulated in humans with autosomal dominant polycystic kidney disease. There are notable overlapping features and pathways among metabolism, obesity, and/or autosomal dominant polycystic kidney disease. Both dietary and pharmacologic-based strategies targeting metabolic abnormalities are being considered as therapies to slow autosomal dominant polycystic kidney disease progression and are attractive, particularly given the slowly progressive nature of the disease. Dietary strategies include daily caloric restriction, intermittent fasting, time-restricted feeding, a ketogenic diet, and 2-deoxy-glucose as well as alterations to nutrient availability. Pharmacologic-based strategies include AMP-activated kinase activators, sodium glucose cotransporter-2 inhibitors, niacinamide, and thiazolidenediones. The results from initial clinical trials targeting metabolism are upcoming and anxiously awaited within the scientific and polycystic kidney disease communities. There continues to be a need for additional mechanistic studies to better understand the role of dysregulated metabolism in autosomal dominant polycystic kidney disease and for subsequent translation to clinical trials. Beyond single-intervention trials focused on metabolic reprograming in autosomal dominant polycystic kidney disease, great potential also exists by combining metabolic-focused therapeutic approaches with compounds targeting other signaling cascades altered in autosomal dominant polycystic kidney disease, such as tolvaptan.

Dataset Information

Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: What is the appropriate serum level?

Publications

Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: What is the appropriate serum level?

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets