**6. Immunological mediators of inflammatory state and fibrosis of renal tissue**

**Urinary chemokines CXCL9 and CXCL10** may be treated as noninvasive screening markers of renal graft rejection in patients with interstitial fibrosis and tubular atrophy (IF/TA), leading to shorter life span of renal graft (Jackson et al., 2011; Schaub et al., 2009). Urinary CXCL10 may be a useful noninvasive screening test for tubulitis in renal graft recipients, and urinary CXCL10 concentration above 1,97 ng /mmol of creatinine is a threshold for consideration of renal biopsy (Ho et al., 2011).

**Granzymes (***granule-associated enzymes***)** are serine proteases (27-32kDa) of the chymotrypsin family. Granzyme B (GzmB) and Fas-ligand (FAS-L) are cytotoxic molecules involved in the acute renal graft rejection (AR) by the induction of DNA fragmentation of damaged cells (Yannaraki et al., 2006). Granzyme A (GzmA) is a specific noninvasive immunological biomarker for monitoring renal graft condition which facilitate diagnosis and treatment after transplant complications. Granzyme A (GzmA) besides involvement in apoptosis may act as mitogen of B lymphocytes. GzmA is a noninvasive biomarker differentiating patients with subclinical and acute renal graft rejection from patients with renal tubular necrosis or persons

Utility of Urinary Biomarkers in Kidney Transplant Function Assessment

http://dx.doi.org/10.5772/54746

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**Chemokine regulated upon activation in normal T cells expressed and secreted (RANTES/ CCL5)** is a chemokine of the beta subfamily secreted by macrophages and T lymphocytes. RANTES can signal through CCR1, CCR3, CCR5 and US28(cytomegalovirus receptor) receptors. It is chemoattractant towards monocytes, memory T cells(CD4+/CD45RO+), basophils, and neutrophils. RANTES occurs in increased amounts in diseased kidneys and indicate on interstitial inflammatory changes of the tubular cells at the early stages of acute kidney injury, skin or heart graft rejection (Koga et al., 2000; Gwinner, 2007). RANTES expressed in renal different cells (mesanglial cells, endothelium of renal tubules, fibroblasts, lymphocytes) plays an active role in acute and chronic kidney inflammation and development of tubule-interstitial damage. (Baer et al., 2005) reported absence of significant differences in plasma and urinary RANTES in patients with acute renal graft rejection and recipients with normal graft function. Therefore RANTES is not suitable for detection of early kidney graft rejection. However an significant increase in the serum and urinary RANTES was observed immediately after renal transplantation which may reflect an activation of the immunological

**Transforming growth factor beta (TGF-β)** is responsible for exacerbation of fibrosis, controls growth and differentiation of cells and production of extracellular matrix as well as regulates cellular migration. A participation of TGF-ß1 in lung and kidney fibrosis during chronic allograft rejection was reported by (Awad et al.,1998; Bartnard et al., 1990). Increased excretion of urinary TGF-β was proposed as a marker of the intrarenal production and activity of TGFß1 in kidney. An increase in the urinary TGF-ß1 was reported in different nephropathies particularly significant in patients with heavy proteinuria (Schnaper et al., 2003; Böttinger & Bitzer, 2002). The 6-12 month immunosuppression with cyclosporine in renal-transplant recipients caused development of a chronic interstitial nephropathy with decreased GFR. Cyclosporine A (CsA) facilitate the expression of TGF-β in renal tubular cells and cells of renal juxtaglomerular apparatus. Furthermore, CsA stimulates T lymphocytes and endothelial cell to a TGF-β 1 production. Expression of TGF-β 1 is CsA dose dependent. High doses of CsA are risk factors of chronic graft dysfunction, among kidney recipients (Boratyńska et al., 2003).

**Vascular endothelial growth factor (VEGF)** a dimeric protein containing subunits constituted of 121, 165, 189 or 206 amino acids is a proangiogenic growth factor. In patients with symptoms of acute renal graft rejection high urinary VEGF concentration was found in comparison to

with stabile renal graft (van Ham et al., 2010 ).

**6.2. Immunological markers of renal fibrosis**

systems.
