Treatment strategies and clinical trial design in ADPKD.
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ABSTRACT:
SUBMITTER: Torres VE
PROVIDER: S-EPMC4127876 | biostudies-literature | 2010 Mar
REPOSITORIES: biostudies-literature
Publications
Treatment strategies and clinical trial design in ADPKD.
Advances in chronic kidney disease 20100301 2
More frequent utilization and continuous improvement of imaging techniques has enhanced appreciation of the high phenotypic variability of autosomal dominant polycystic kidney disease, improved understanding of its natural history, and facilitated the observation of its structural progression. At the same time, identification of the PKD1 and PKD2 genes has provided clues to how the disease develops when they (genetic mechanisms) and their encoded proteins (molecular mechanisms) are disrupted. In ...[more]
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Project description:BackgroundAutosomal dominant polycystic kidney disease (ADPKD) has been associated with metabolic disturbances characterized by downregulation of AMP-activated protein kinase (AMPK), a critical sensor of the cellular energy status. Therapeutic activation of AMPK by metformin could inhibit cyst enlargement by inhibition of both the mammalian target of rapamycin pathway and fluid secretion via the CFTR chloride channel.MethodsWe designed a phase-2, randomized, placebo-controlled, clinical trial to assess the safety, tolerability, and efficacy of metformin on total kidney volume in adults without diabetes (age 18-60 years) with ADPKD and eGFR of ≥50 ml/min per 1.73 m2. There were no eligibility criteria relating to kidney volume. In addition to demographics and clinical/family history, baseline parameters included eGFR, total kidney and liver volumes measured by MRI, and patient-reported outcomes were ascertained by the Medical Outcomes Study Short Form-36, the Gastrointestinal Safety Rating Scale, and the HALT-PKD pain questionnaire.ResultsWe successfully randomized 97 participants recruited from two university-based clinical sites in Baltimore and Boston. The mean age of participants was 41.9 years, 72% were female, and 94% of participants were White. The majority of study participants had early stage disease, with a mean eGFR of 86.8±19.0 ml/min per 1.73 m2. Approximately half of the study participants (48%) were classified as high risk for progression (Mayo imaging classes 1C, 1D, or 1E). There was no correlation between kidney and/or liver size and health-related quality of life (HRQoL) or gastrointestinal symptom severity.ConclusionsWe report successful recruitment in this ongoing, novel, clinical trial of metformin in ADPKD, with a study sample comprising patients with early stage disease and nearly a half of participants considered at high estimated risk for progression. Participants reported a low gastrointestinal symptom burden at baseline, and HRQoL similar to that of the general population, with no differences in symptoms or HRQoL related to organomegaly.Clinical trial registry name and registration numberMetformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease (TAME), NCT02656017.
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