*4.2.2. Urinary excretion of uromodulin*

of vascular occlusion in SCA. In a recent article published by Duarte et al. [132], the author demonstrated that IL18 is associated with diastolic function in SCD patients, and may be involved in the pathogenesis of the disease. Genetic polymorphisms within the IL-18 gene regions are also associated with diastolic function in SCD, likely by affecting expression levels

N-acetyl-b-d glucosaminidase (NAG) is a lysosomal enzyme produced in proximal tubular epithelial cells. The levels increased during kidney injury, a marker of proteinuria both in patients with diabetes and in patients with SCD [115, 133]. Sundaram et al. [57] showed that urine NAG activity was higher than baseline levels (>2 U/l) and worse in the presence of albuminuria. The elevations in NAG may precede moderately increased albuminuria, a likely

Transforming growth factor-b1 (TGF-b1) is a potent fibrogenic growth factor that may play a significant role in pathogenesis of SN [134]. It is a peptide of low molecular weight and has pleiotropic action. In the kidneys, it stimulates fibrogenesis through enhanced production of extracellular matrix proteins and nephron loss by various mechanisms, such as apoptosis of endothelial cells and podocytes [135]. Whether the urinary levels of TGF-b1 has a diagnostic significance in the early prediction of SN in children with SCD is still to be determined [136]. However in the article published by Sundaram et al. [57], urinary TGF-β was present at very low to undetectable levels in their patient population and showed no association with the degree of albuminuria. These data are in contrast with those published by Ghobrial et al. [137]. In their study, the authors have found a strong positive correlation between urinary TGF-b1

Neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte (PLR) ratios, as indicators of subclinical inflammation, rarely were been investigated in SCD patients. Emokpae et al. [138] recently reported a positive association between NLR, PLR and the increase of inflammatory markers in SCD patients such as C-reactive protein (CRP) and fibrinogen. The highest values of NLR and PLR were detected in patients with proteinuria and altered renal function. This data suggest that these markers may be predictive of a proinflammatory state with underlying renal damage.

Metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been identified as a markers of cell-cycle arrest and are induced in renal tubules following AKI. It is supposed that the resulting cell-cycle arrest then limits proliferation of damaged tubule cells. The metabolites of TIMP-2 and IGFBP7 can be measured in the urine. In a small study of children undergoing CPB, the urinary TIMP-1/IGFBP7 product was increased 4 h

and urinary proteins and eGFR in all groups of SCD patients studied.

*4.1.9. Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio*

**4.2. Biomarkers not been investigated in sickle cell disease**

post-CPB in children who developed AKI [139].

*4.2.1. Markers of cell-cycle arrest*

of the genes [132].

*4.1.7. N-acetyl-b-d glucosaminidase*

168 Hematology - Latest Research and Clinical Advances

diagnostic tool for early renal damage.

*4.1.8. Transforming growth factor-b1*

Urinary excretion of uromodulin (UMOD), also known as Tamm-Horsfall Protein (THP), is the most abundant protein excreted in urine. It is a glycoprotein that is expressed in the thick ascending limb (TAL) of the loop of Henle [140–143]. It has also several roles in salt transport in the tubules, in the innate immunity and in the protection against kidney stones [144]. Recently, UMOD has been studied as a marker of acute renal injury both in mouse models of ischemia-reperfusion injury and in studies conducted in adult and pediatric patients prior to CPB [140, 143, 145]. These encouraging results suggest the possibility of studying UMOD also for the early determination of renal damage in SCD patients.
