title: Urine podocin:nephrin mRNA ratio (PNR) as a podocyte stress biomarker.
abstract: BACKGROUND
  Proteinuria and/or albuminuria are widely used for noninvasive assessment of kidney diseases. However, proteinuria is a nonspecific marker of diverse forms of kidney injury, physiologic processes and filtration of small proteins of monoclonal and other pathologic processes. The opportunity to develop new glomerular disease biomarkers follows the realization that the degree of podocyte depletion determines the degree of glomerulosclerosis, and if persistent, determines the progression to end-stage kidney disease (ESKD). Podocyte cell lineage-specific mRNAs can be recovered in urine pellets of model systems and in humans. In model systems, progressive glomerular disease is associated with decreased nephrin mRNA steady-state levels compared with podocin mRNA. Thus, the urine podocin:nephrin mRNA ratio (PNR) could serve as a useful progression biomarker. The use of podocyte-specific transcript ratios also circumvents many problems inherent to urine assays.
  
  
  METHODS
  To test this hypothesis, the human diphtheria toxin receptor (hDTR) rat model of progression was used to evaluate potentially useful urine mRNA biomarkers. We compared histologic progression parameters (glomerulosclerosis score, interstitial fibrosis score and percent of podocyte depletion) with clinical biomarkers [serum creatinine, systolic blood pressure (BP), 24-h urine volume, 24-h urine protein excretion and the urine protein:creatinine ratio(PCR)] and with the novel urine mRNA biomarkers.
  
  
  RESULTS
  The PNR correlated with histologic outcome as well or better than routine clinical biomarkers and other urine mRNA biomarkers in the model system with high specificity and sensitivity, and a low coefficient of assay variation.
  
  
  CONCLUSIONS
  We concluded that the PNR, used in combination with proteinuria, will be worth testing for its clinical diagnostic and decision-making utility.
authors.affiliation: Nephrology Division, Departments of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Fukuda
authors.forename: Larysa T
authors.initials: LT
authors.lastname: Wickman
authors.forename: Madhusudan P
authors.initials: MP
authors.lastname: Venkatareddy
authors.forename: Su Q
authors.initials: SQ
authors.lastname: Wang
authors.forename: Mahboob A
authors.initials: MA
authors.lastname: Chowdhury
authors.forename: Jocelyn E
authors.initials: JE
authors.lastname: Wiggins
authors.forename: Kerby A
authors.initials: KA
authors.lastname: Shedden
authors.forename: Roger C
authors.initials: RC
authors.lastname: Wiggins
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism / Q000652:urine; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000652:urine; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism* / Q000652:urine; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D011507:Proteinuria / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000652:urine*; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D012333:RNA, Messenger; C113267:nephrin