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Urine Angiotensin II Signature Proteins as Markers of Fibrosis in Kidney Transplant Recipients.

BACKGROUND
Interstitial fibrosis/tubular atrophy (IFTA) is an important cause of kidney allograft loss; however, noninvasive markers to identify IFTA or guide anti-fibrotic therapy are lacking. Using angiotensin-II (AngII) as the prototypical inducer of IFTA, we previously identified 83 AngII-regulated proteins in vitro. We developed mass spectrometry-based assays for quantification of 6 AngII signature proteins (BST1, GLNA, LAMB2, LYPLA1, RHOB and TSP1) and hypothesized that their urine excretion will correlate with IFTA in kidney transplant patients.


METHODS
Urine excretion of 6 AngII regulated proteins was quantified using selected reaction monitoring (SRM) and normalized by urine creatinine. Immunohistochemistry was used to assess protein expression of TSP1 and GLNA in kidney biopsies.


RESULTS
The urine excretion rates of AngII-regulated proteins were found to be increased in 15 kidney transplant recipients with IFTA compared to 20 matched controls with no IFTA (mean log2[fmol/µmol of creatinine], BST1: 3.8 vs 3.0, p = 0.03; GLNA: 1.2 vs -0.4, p = 0.03; LAMB2: 6.1 vs 5.4, p = 0.06; LYPLA1: 2.1 vs 0.6, p = 0.002; RHOB: 1.2 vs -0.1, p = 0.006; TSP1_GGV: 2.5 vs 1.9; p = 0.15; TSP1_TIV: 2.0 vs. 0.6; p = 0.0006). ROC curve analysis demonstrated an AUC=0.86 for the ability of urine AngII signature proteins to discriminate IFTA from controls. Urine excretion of AngII signature proteins correlated strongly with chronic interstitial fibrosis/tubular atrophy and total inflammation. In a separate cohort of 19 kidney transplant recipients, the urine excretion of these 6 proteins was significantly lower following therapy with AngII inhibitors (p < 0.05).


CONCLUSIONS
AngII-regulated proteins may represent markers of IFTA and may guide anti-fibrotic therapies.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.