title: Urinary soluble urokinase receptor levels are elevated and pathogenic in patients with primary focal segmental glomerulosclerosis.
abstract: BACKGROUND
  Focal segmental glomerulosclerosis (FSGS) is a major cause of end-stage renal disease. Recent studies have proposed that plasma soluble urokinase receptor (suPAR) might be a causative circulating factor but this proposal has caused controversy. This study aimed to measure urinary suPAR levels in patients with primary FSGS and its significance in the pathogenesis of FSGS.
  
  
  METHODS
  Sixty-two patients with primary FSGS, diagnosed between January 2006 and January 2012, with complete clinical and pathologic data were enrolled, together with disease and normal controls. Urinary suPAR levels were measured using commercial ELISA kits and were corrected by urinary creatinine (Cr). The associations between urinary suPAR levels and clinical data at presentation and during follow up were analyzed. Conditionally immortalized human podocytes were used to study the effect of urinary suPAR on activating β3 integrin detected by AP5 staining.
  
  
  RESULTS
  The urinary suPAR level of patients with primary FSGS (500.56, IQR 262.78 to 1,059.44 pg/μmol Cr) was significantly higher than that of patients with minimal change disease (307.86, IQR 216.54 to 480.18 pg/μmol Cr, P = 0.033), membranous nephropathy (250.23, IQR 170.37 to 357.59 pg/μmol Cr, P <0.001), secondary FSGS (220.45, IQR 149.38 to 335.54 pg/μmol Cr, P <0.001) and normal subjects (183.59, IQR 103.92 to 228.78 pg/μmol Cr, P <0.001). The urinary suPAR level of patients with cellular variant was significantly higher than that of patients with tip variant. The urinary suPAR level in the patients with primary FSGS was positively correlated with 24-hour urine protein (r = 0.287, P = 0.024). During follow up, the urinary suPAR level of patients with complete remission decreased significantly (661.19, IQR 224.32 to 1,115.29 pg/μmol Cr versus 217.68, IQR 121.77 to 415.55 pg/μmol Cr, P = 0.017). The AP5 signal was strongly induced along the cell membrane when human differentiated podocytes were incubated with the urine of patients with FSGS at presentation, and the signal could be reduced by a blocking antibody specific to uPAR.
  
  
  CONCLUSIONS
  Urinary suPAR was specifically elevated in patients with primary FSGS and was associated with disease severity. The elevated urinary suPAR could activate β3 integrin on human podocytes.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Yi-miao
authors.initials: YM
authors.lastname: Zhang
authors.forename: Zhao
authors.initials: Z
authors.lastname: Cui
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Xiao-jing
authors.initials: XJ
authors.lastname: Liu
authors.forename: Rong
authors.initials: R
authors.lastname: Chu
authors.affiliation: Renal Division, Peking University First Hospital, Beijing, PR China. mhzhao@bjmu.edu.cn.
authors.forename: Ming-hui
authors.initials: MH
authors.lastname: Zhao
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003404:Creatinine / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015433:Glomerulonephritis, Membranous / Q000097:blood / Q000652:urine; D005923:Glomerulosclerosis, Focal Segmental / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000652:urine*; D006801:Humans; D039661:Integrin beta3 / Q000032:analysis / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D050199:Podocytes / Q000737:chemistry; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D012720:Severity of Illness Index
chemical_list: D039661:Integrin beta3; D055293:Receptors, Urokinase Plasminogen Activator; D003404:Creatinine