Pravastatin Therapy and Biomarker Changes in Children and Young Adults with
Autosomal Dominant Polycystic Kidney Disease.
Author(s): Klawitter J(1), McFann K(2), Pennington AT(3), Wang W(2), Klawitter J(3),
Christians U(3), Schrier RW(2), Gitomer B(2), Cadnapaphornchai MA(4).
Affiliation(s): Author information:
(1)Division of Renal Diseases and Hypertension, Department of Anesthesiology, and
jelena.klawitter@ucdenver.edu. (2)Division of Renal Diseases and Hypertension.
(3)Department of Anesthesiology, and. (4)Division of Renal Diseases and
Hypertension, Department of Pediatrics, University of Colorado, Aurora, Colorado.
Publication date & source: 2015, Clin J Am Soc Nephrol. ,
BACKGROUND AND OBJECTIVES: Disease-specific treatment options for autosomal
dominant polycystic kidney disease are limited. Clinical intervention early in
life is likely to have the greatest effect. In a 3-year randomized double-blind
placebo-controlled phase 3 clinical trial, the authors recently showed that
pravastatin decreased height-corrected total kidney volume (HtTKV) progression of
structural kidney disease over a 3-year period. However, the underlying
mechanisms have not been elucidated.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Participants were recruited
nationally from July 2007 through October 2009. Plasma and urine samples
collected at baseline, 18 months, and 36 months from 91 pediatric patients
enrolled in the above-mentioned clinical trial were subjected to mass
spectrometry-based biomarker analysis. Changes in biomarkers over 3 years were
compared between placebo and pravastatin-treated groups. Linear regression was
used to evaluate the changes in biomarkers with the percent change in HtTKV over
3 years.
RESULTS: Changes in plasma concentrations of proinflammatory and oxidative stress
markers (9- hydroxyoctadecadienoic acid, 13-hydroxyoctadecadienoic acid, and
15-hydroxyeicosatetraenoic acid [HETE]) over 3 years were significantly different
between the placebo and pravastatin-treated groups, with the pravastatin group
showing a lower rate of biomarker increase. Urinary 8-HETE, 9-HETE, and 11-HETE
were positively associated with the changes in HtTKV in the pravastatin group.
CONCLUSIONS: Pravastatin therapy diminished the increase of cyclooxygenase- and
lipoxygenase-derived plasma lipid mediators. The identified biomarkers and
related molecular pathways of inflammation and endothelial dysfunction may
present potential targets for monitoring of disease severity and therapeutic
intervention of autosomal dominant polycystic kidney disease.
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