title: Renal phenotype in Bardet-Biedl syndrome: a combined defect of urinary concentration and dilution is associated with defective urinary AQP2 and UMOD excretion.
abstract: The renal phenotype in Bardet-Biedl syndrome (BBS) is highly variable. The present study describes renal findings in 41 BBS patients and analyzes the pathogenesis of hyposthenuria, the most common renal dysfunction. Five of 41 patients (12%) showed an estimated glomerular filtration rate < 60 ml·min-1·1.73 m-2Urine protein and urine albumin-to-creatinine ratio were over 200 and 30 mg/g in 9/24 and 7/23 patients, respectively. Four of 41 patients showed no renal anomalies on ultrasound. Twenty of 34 patients had hyposthenuria in the absence of renal insufficiency. In all 8 of the hyposthenuric patients studied, dDAVP failed to elevate urine osmolality (Uosm), suggesting a nephrogenic origin. Interestingly, water loading (WL) did not result in a significant reduction of Uosm, indicating combined concentrating and diluting defects. dDAVP infusion induced a significant increase of plasma Factor VIII and von Willebrand Factor levels, supporting normal function of the type 2 vasopressin receptor at least in endothelial cells. While urinary aquaporin 2 (u-AQP2) abundance was not different between patients and controls at baseline, the dDAVP-induced increased u-AQP2 and the WL-induced reduction of u-AQP2 were blunted in patients with a combined concentrating and diluting defect, suggesting a potential role of AQP2 in the defective regulation of water absorption. Urine Uromodulin excretion was reduced in all hyposthenuric patients, suggesting a thick ascending limb defect. Interestingly, renal Na, Cl, Ca, but not K handling was impaired after acute WL but not at basal. In summary, BBS patients show combined urinary concentration and dilution defects; a thick ascending limb and collecting duct tubulopathy may underlie impaired water handling.
authors.affiliation: Section of Nephrology, Department of Cardiothoracic and Respiratory Sciences-Second University of Naples, Naples, Italy; miriamzacchia@virgilio.it.
authors.forename: Miriam
authors.initials: M
authors.lastname: Zacchia
authors.affiliation: Section of Nephrology, Department of Cardiothoracic and Respiratory Sciences-Second University of Naples, Naples, Italy; Institute of Genetics and Biophysics of the National Research Council (CNR), Naples, Italy.
authors.forename: Enza
authors.initials: E
authors.lastname: Zacchia
authors.affiliation: Section of Nephrology, Department of Cardiothoracic and Respiratory Sciences-Second University of Naples, Naples, Italy; Institute of Genetics and Biophysics of the National Research Council (CNR), Naples, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Zona
authors.affiliation: Section of Nephrology, Department of Cardiothoracic and Respiratory Sciences-Second University of Naples, Naples, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Capolongo
authors.affiliation: Section of Nephrology, Department of Cardiothoracic and Respiratory Sciences-Second University of Naples, Naples, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Raiola
authors.affiliation: Section of Nephrology, Department of Cardiothoracic and Respiratory Sciences-Second University of Naples, Naples, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Rinaldi
authors.affiliation: Section of Nephrology, Department of Cardiothoracic and Respiratory Sciences-Second University of Naples, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Trepiccione
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Ingrosso
authors.affiliation: Section of Nephrology, Department of Cardiothoracic and Respiratory Sciences-Second University of Naples, Naples, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Perna
authors.affiliation: Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences-Second University of Naples, Naples, Italy; and.
authors.forename: Valentina
authors.initials: V
authors.lastname: Di Iorio
authors.affiliation: Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences-Second University of Naples, Naples, Italy; and.
authors.forename: Francesca
authors.initials: F
authors.lastname: Simonelli
authors.affiliation: Departments of Internal Medicine and Physiology and the Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Orson W
authors.initials: OW
authors.lastname: Moe
authors.affiliation: Section of Nephrology, Department of Cardiothoracic and Respiratory Sciences-Second University of Naples, Naples, Italy.
authors.forename: Giovambattista
authors.initials: G
authors.lastname: Capasso
mesh_terms: D000293:Adolescent; D000328:Adult; D051399:Aquaporin 2 / Q000652:urine*; D020788:Bardet-Biedl Syndrome / Q000503:physiopathology* / Q000652:urine; D002648:Child; D002675:Child, Preschool; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000503:physiopathology*; D007671:Kidney Concentrating Ability / Q000502:physiology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D058949:Uromodulin / Q000652:urine*; D055815:Young Adult
chemical_list: D051399:Aquaporin 2; C548612:UMOD protein, human; D058949:Uromodulin
keywords: AQP2; BBS; UMOD; hyposthenuria