title: Defective glycolysis and the use of 2-deoxy-D-glucose in polycystic kidney disease: from animal models to humans.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited renal disease characterized by bilateral renal cyst formation. ADPKD is one of the most common rare disorders, accounting for ~10% of all patients with end-stage renal disease (ESRD). ADPKD is a chronic disorder in which the gradual expansion of cysts that form in a minority of nephrons eventually causes loss of renal function due to the compression and degeneration of the surrounding normal parenchyma. Numerous deranged pathways have been identified in the cyst-lining epithelia, prompting the design of potential therapies. Several of these potential treatments have proved effective in slowing down disease progression in pre-clinical animal studies, while only one has subsequently been proven to effectively slow down disease progression in patients, and it has recently been approved for therapy in Europe, Canada and Japan. Among the affected cellular functions and pathways, recent investigations have described metabolic derangement in ADPKD as a major trait offering additional opportunities for targeted therapies. In particular, increased aerobic glycolysis (the Warburg effect) has been described as a prominent feature of ADPKD kidneys and its inhibition using the glucose analogue 2-deoxy-D-glucose (2DG) proved effective in slowing down disease progression in preclinical models of the disease. At the same time, previous clinical experiences have been reported with 2DG, showing that this compound is well tolerated in humans with minimal and reversible side effects. In this work, we review the literature and speculate that 2DG could be a good candidate for a clinical trial in humans affected by ADPKD.
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Via Olgettina, 58, 20132, Milan, Italy.|Division of Nephrology and Hypertension, San Raffaele Hospital, Milan, Italy.|Division of Nephrology and Dialysis, AOU Policlinico di Modena, Università di Modena e Reggio Emilia, Modena, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Magistroni
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Via Olgettina, 58, 20132, Milan, Italy. boletta.alessandra@hsr.it.
authors.forename: Alessandra
authors.identifier: http://orcid.org/0000-0002-4704-4006
authors.initials: A
authors.lastname: Boletta
mesh_terms: D000818:Animals; D003847:Deoxyglucose / Q000009:adverse effects / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018450:Disease Progression; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D016891:Polycystic Kidney, Autosomal Dominant / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D012076:Renal Agents / Q000009:adverse effects / Q000627:therapeutic use*; D057170:Translational Research, Biomedical; D016896:Treatment Outcome
chemical_list: D012076:Renal Agents; D003847:Deoxyglucose
keywords: Glucose; Glycolysis; Metabolism; PKD; Polycystic Kidney Disease; Polycystin