title: Validation of some pathophysiological mechanisms of the CKD progression theory and outcome prediction in IgA nephropathy.
abstract: BACKGROUND
  The "remnant kidney" chronic kidney disease (CKD) progression theory based on hemodynamic, proteinuric and inflammatory mechanisms consequent to nephron loss has not been confirmed in a human disease. The aim of this study was to evaluate whether some of these mechanisms are present in IgA nephropathy (IgAN) and predict functional outcome.
  
  
  METHODS
  In 132 IgAN patients (68 untreated, 64 angiotensin-converting enzyme inhibitor [ACEi]-treated) fractional excretion of IgG (FEIgG) and α1-microglobulin, proteinuria/day and β-NAG excretion were divided by percentage of nonglobally sclerotic glomeruli ("surviving glomeruli" [SG]) to assess the effective glomerular loss and tubular load of proteins in surviving nephrons. Proteinuric markers were compared between 4 SG groups: group 1: ≤50%; group 2: >50% and <80%; group 3: ≥80% and <100%; and group 4: 100%. The outcome prediction (estimated glomerular filtration rate [eGFR] improvement and stability, progression) was assessed comparing low- and high-risk groups for each marker.
  
  
  RESULTS
  Proteinuric markers showed increasing values in parallel with reduction of percentages of SG (p<0.0001). FEIgG/SG, 40-fold higher in patients with SG ≤50% vs. SG=100% (0.00040 ± 0.00039 vs. 0.00001 ± 0.00002, p<0.0001), was the most powerful outcome predictor: in ACEi-untreated patients, FEIgG/SG less or greater than 0.00010 predicted eGFR improvement and stability (88% vs. 12%, p<0.0001) and end-stage renal disease (ESRD) + eGFR reduction ≥50% (2% vs. 87.5%, p<0.0001); ACEi treatment reduced ESRD+eGFR reduction ≥50%: 36% vs. 87.5% (p=0.002). In patients with FEIgG/SG <0.00010 the eGFR increase is significantly higher in ACEi-treated for ≥70 months versus ACEi-untreated with follow up ≥70 months (+35% ± 23% vs. +13% ± 8%, p=0.004).
  
  
  CONCLUSIONS
  In IgAN, progressive nephron loss is associated with an increase of proteinuric markers of glomerular and tubular damage. FEIgG/SG is the best outcome predictor. These data represent the first validation in a human disease of some pathophysiological mechanisms of CKD progression theory.
authors.affiliation: D'Amico Foundation for Renal Diseases Research, Milan, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Bazzi
authors.forename: Virginia
authors.initials: V
authors.lastname: Rizza
authors.forename: Daniela
authors.initials: D
authors.lastname: Casellato
authors.forename: Gilda
authors.initials: G
authors.lastname: Stivali
authors.forename: Gregorio
authors.initials: G
authors.lastname: Rachele
authors.forename: Pietro
authors.initials: P
authors.lastname: Napodano
authors.forename: Giulia
authors.initials: G
authors.lastname: Olivieri
authors.forename: Maurizio
authors.initials: M
authors.lastname: Gallieni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Amico
mesh_terms: D000328:Adult; D000510:Alpha-Globulins / Q000652:urine; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D015415:Biomarkers / Q000652:urine; D001706:Biopsy; D016009:Chi-Square Distribution; D018450:Disease Progression; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005922:Glomerulonephritis, IGA / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000503:physiopathology* / Q000652:urine; D006801:Humans; D007074:Immunoglobulin G / Q000652:urine; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009399:Nephrons / Q000503:physiopathology; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011507:Proteinuria / Q000503:physiopathology; D012372:ROC Curve; D051436:Renal Insufficiency, Chronic / Q000401:mortality / Q000473:pathology / Q000503:physiopathology* / Q000652:urine; D015203:Reproducibility of Results; D013997:Time Factors; D016896:Treatment Outcome; D016482:Urinalysis; D055815:Young Adult
chemical_list: D000510:Alpha-Globulins; D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D007074:Immunoglobulin G; C016001:alpha-1-microglobulin