P0221SOLUBLE UROKINASE RECEPTOR (SUPAR) IS A PREDICTOR OF DISEASE STATE AND RENAL PROGNOSIS IN PRIMARY NEPHROTIC SYNDROME

Abstract Background and Aims A hypothesis has been proposed that serum (s-) soluble urokinase receptor (suPAR) activates glomerular podocyte β3 integrin to cause podocyte injury and onset of proteinuria in primary nephrotic syndrome (pNS). However, s-suPAR has been questioned as a disease marker for pNS because it did not correlate with urinary protein (UP). Furthermore, there are a few reports that suggested a correlation between urinary (u-) suPAR and UP by univariate analysis, but the correlation between the two has not been studied by multivariate analysis taking confounding factors into account. In addition, it is unclear how u-suPAR is involved in the pathogenesis of pNS. Method In 36 patients with pNS including minimal change (n=18), focal segmental glomerulosclerosis (n=7), membranous nephropathy (n=9) and membranoproliferative glomerulonephritis (n=2), the relationship between u-suPAR (pg/mgCr) and UP (g/gCr) was examined by cross-sectional analysis of baseline values before treatment and longitudinal analysis of changes during the first 2 months of treatment (⊿). In addition, the localization and staining intensity of activated β3 integrin in renal tissue were examined by immuno-histochemistry methods. We also examined whether s-suPAR (pg/ml) or u-suPAR is useful for predicting renal prognosis (1.5-fold increase from baseline in s-Cr) using Cox proportional hazard analysis. Results In cross-sectional analysis, u-suPAR was a UP predictor independent of s-suPAR, eGFR and selectivity index (S.I.) [standardized partial regression coefficient (stdβ) = 0.879, p <0.00001]. Also in the longitudinal analysis, ⊿u-suPAR was a ⊿UP predictor independent of ⊿s-suPAR, ⊿eGFR and S.I. (stdβ = 0.574, p = 0.003). Furthermore, there were significant correlations between u-suPAR and u-L-FABP (r = 0.522, p = 0.001), and between ⊿u-suPAR and ⊿u-L-FABP (r = 0.395, p = 0.017). Activated β3 integrin was mainly detected on proximal tubular brush-border (PTBB), but not glomerular capillaries, moderate to strongly positive in pNS. ⊿s-suPAR was the only predictor of 1.5-fold increase from baseline in s-Cr (Hazard Ratio: 1.361 per 500 pg/ml increase of s-suPAR, p=0.006). Conclusion In pNS, u-suPAR was a proteinuria predictor independent of s-suPAR, suggesting the possibility of the mechanisms of proteinuria through β3 integrin activation in PTBB by u-suPAR. In addition, s-suPAR was useful in predicting renal prognosis.