title: Evaluation of urine biomarkers of kidney injury in polycystic kidney disease.
abstract: Progressive disruption of renal tubular integrity in the setting of increased cellular proliferation and apoptosis is a feature of autosomal dominant polycystic kidney disease (ADPKD). Here we evaluated the effect of these processes on the expression of Lcn2 (NGAL) and interleukin (IL)-18, markers of tubular injury, in rodent models and in the cyst fluid and urine of patients with ADPKD. Two mouse models where Pkd2 was inactivated, which resulted in early- or adult-onset cysts, were used to evaluate NGAL levels. Further, the Han:SPRD rat model of polycystic disease was used to study IL-18 levels. In four annual serial urine samples collected from 107 patients with ADPKD in the Consortium for Radiologic Imaging for the Study of Polycystic Kidney Disease (CRISP) study, NGAL and IL-18 excretion rates were determined in conjunction with measures of total kidney volume and estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease equation. Kidneys from affected mice and rats showed prominent expression of NGAL and IL-18/IL-18R, respectively, in epithelial cells lining kidney cysts. In human ADPKD cyst fluid, both NGAL and IL-18 were elevated. In CRISP patients, the mean percentage increase in total kidney volume was 5.4/year and the mean decline in eGFR 2.4 ml/min/year. The trend of increased mean urine NGAL and IL-18 over 3 years was statistically significant; however, there was no association between tertiles of IL-18 or quartiles of NGAL and change in total kidney volume or eGFR over this period. Thus, urinary NGAL and IL-18 excretion is mildly and stably elevated in ADPKD, but does not correlate with changes in total kidney volume or kidney function. This may be due, in part, to the lack of communication between individual cysts and the urinary collecting system in this disorder.
authors.affiliation: Department of Medicine (Nephrology), Yale University School of Medicine, New Haven, Connecticut 06516, USA. chirag.parikh@yale.edu
authors.forename: Chirag R
authors.initials: CR
authors.lastname: Parikh
authors.forename: Neera K
authors.initials: NK
authors.lastname: Dahl
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.forename: James E
authors.initials: JE
authors.lastname: Bost
authors.forename: Charles L
authors.initials: CL
authors.lastname: Edelstein
authors.forename: Diane M
authors.initials: DM
authors.lastname: Comer
authors.forename: Raoul
authors.initials: R
authors.lastname: Zeltner
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Grantham
authors.forename: Stefan
authors.initials: S
authors.lastname: Somlo
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism / Q000652:urine; D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism / Q000652:urine*; D018450:Disease Progression; D005260:Female; D006801:Humans; D020382:Interleukin-18 / Q000652:urine; D007668:Kidney / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000652:urine*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism / Q000652:urine; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015513:Oncogene Proteins / Q000652:urine; D016891:Polycystic Kidney, Autosomal Dominant / Q000150:complications / Q000378:metabolism / Q000652:urine*; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000652:urine; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D053724:Receptors, Interleukin-18 / Q000378:metabolism; D050396:TRPP Cation Channels / Q000172:deficiency / Q000235:genetics
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; D020382:Interleukin-18; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D053724:Receptors, Interleukin-18; D050396:TRPP Cation Channels; C489506:LCN2 protein, human; C097278:Lcn2 protein, rat; C071332:Lcn2 protein, mouse