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Kim HJ, Edelstein CL. Mammalian target of rapamycin inhibition in polycystic kidney disease: From bench to bedside. Kidney Res Clin Pract. 2012;31(3):132-8doi: 10.1016/j.krcp.2012.07.002.
Kim, H. J., & Edelstein, C. L. (2012). Mammalian target of rapamycin inhibition in polycystic kidney disease: From bench to bedside. Kidney research and clinical practice, 31(3), 132-8. https://doi.org/10.1016/j.krcp.2012.07.002
Kim, Hyun-Jung, and Edelstein, Charles L. "Mammalian target of rapamycin inhibition in polycystic kidney disease: From bench to bedside." Kidney research and clinical practice vol. 31,3 (2012): 132-8. doi: https://doi.org/10.1016/j.krcp.2012.07.002
Kim HJ, Edelstein CL. Mammalian target of rapamycin inhibition in polycystic kidney disease: From bench to bedside. Kidney Res Clin Pract. 2012 Sep;31(3):132-8. doi: 10.1016/j.krcp.2012.07.002. Epub 2012 Aug 10. PMID: 26894018; PMCID: PMC4716095.
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Kidney Res Clin Pract. 2012 Sep;31(3):132-8. doi: 10.1016/j.krcp.2012.07.002. Epub 2012 Aug 10.

Mammalian target of rapamycin inhibition in polycystic kidney disease: From bench to bedside.

Kidney research and clinical practice

Hyun-Jung Kim, Charles L Edelstein

Affiliations

  1. Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Aurora, Colorado, USA; Department of Internal Medicine, School of Medicine, Gyeongsang National University, Jinju, Korea.
  2. Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Aurora, Colorado, USA.

PMID: 26894018 PMCID: PMC4716095 DOI: 10.1016/j.krcp.2012.07.002

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening hereditary disease in the USA resulting in chronic kidney disease and the need for dialysis and transplantation. Approximately 85% of cases of ADPKD are caused by a mutation in the Pkd1 gene that encodes polycystin-1, a large membrane receptor. The Pkd1 gene mutation results in abnormal proliferation in tubular epithelial cells, which plays a crucial role in cyst development and/or growth in PKD. Activation of the proliferative mammalian target of rapamycin (mTOR) signaling pathway has been demonstrated in polycystic kidneys from rodents and humans. mTOR inhibition with sirolimus or everolimus decreases cysts in most animal models of PKD including Pkd1 and Pkd2 gene deficient orthologous models of human disease. On the basis of animal studies, human studies were undertaken. Two large randomized clinical trials published in the New England Journal of Medicine of everolimus or sirolimus in ADPKD patients were very unimpressive and associated with a high side-effect profile. Possible reasons for the unimpressive nature of the human studies include their short duration, the high drop-out rate, suboptimal dosing, lack of randomization of "fast" and "slow progressors" and the lack of correlation between kidney size and kidney function in ADPKD. The future of mTOR inhibition in ADPKD is discussed.

Keywords: Everolimus; Mammalian target of rapamycin; Polycystic kidney; Polycystic kidney disease; Sirolimus

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