AngiotensinII (AngII), the main effector of the renin-angiotensin system (RAS), causes kidney interstitial fibrosis/tubular atrophy (IFTA). However, there are presently no markers of AngII renal activity. We report on the urine excretion of 6 AngII-regulated proteins (BST1, GLNA, LAMB2, LYPLA1, RHOB and TSP1), and show that they 1) reflect IFTA in kidney transplant recipients; 2) are modified by RAS inhibition.

Mass spectrometry-based assay was used to quantify 6 AngII signature proteins in 2 cohorts of kidney transplant recipients from a Canadian centre: 1) 19 patients with IFTA and 19 stable controls with concomitant urine and biopsy samples; 2) 20 patients with urine and biopsy samples before and after RAS inhibition. Differences in creatinine-adjusted urine levels of AngII signature proteins between IFTA and control patients were assessed using t-test. Spearman's rank correlation was used to show relationships between AngII signature proteins and traditional markers of kidney function. Fixed-effects model was used to assess changes in AngII signature proteins following RAS therapy. Immunohistochemistry (IHC) was employed to measure levels of AngII signature proteins in kidney micrographs.

Urine excretion of all AngII signature proteins was significantly higher in IFTA compared to control (In fmol/[micro]mol of creatinine ±SD, BST1: 17.46±0.65 vs 9.76±0.20, p=0.01; GLNA: 9.73±0.52 vs 1.62±0.17, p=0.009; LAMB2: 90.22±2.99 vs 54.05±1.55, p=0.03; LYPLA1: 6.61±0.77 vs 2.13±0.05, p=0.0002; RHOB: 9.02±3.42 vs 1.10±0.13, p=0.004; TSP1: 8.05±0.81 vs 3.47±0.16; p=0.002). These proteins separated IFTA and control patients in unsupervised hierarchical clustering analysis. Urine AngII signature protein levels correlated with each other, but not with serum creatinine and total urine protein. AngII signature proteins negatively correlated with RAS inhibitor use over time (fixed effects coefficient<0);GLNA and TSP-1 were most significantly decreased (p<0.05). IHC analysis showed increased staining for TSP1 and GLNA in IFTA vs control.

Urine AngII signature proteins was significantly increased in patients with IFTA and was modified by RAS inhibition. These proteins may represent markers of kidney fibrosis, and may be valuable in guiding therapy with RAS inhibitors.

CITATION INFORMATION: Mohammed-Ali Z., Reid S., Tokar T., Tavares A., Yip P., Cardinal H., Li Y., Kim S., Jurisica I., John R., Konvalinka A. Urine AngiotensinII Signature Proteins as Biomarkers of Fibrosis in Kidney Transplant Recipients Am J Transplant. 2017;17 (suppl 3).

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