*4.1.5. Kidney injury molecule-I*

creatinine is observed. Receiver-operating characteristic curve (ROC) analysis has revealed that the cut-off value of CysC at 580 ng/mL could differentiate patients having SCD with and without nephropathy with 87.8% sensitivity and 84.6% specificity. Further prospective studies are needed to validate this threshold. On the other hand, Cho et al. [112] have evaluated the significance of serum cystatin C levels in pediatric patients with chronic kidney disease diagnosed by renal biopsy and showed normal serum creatinine levels. The authors have found that 95% of the patients showed only slightly increased cystatin C levels from the upper normal limit of the reference range and suggested that mildly increased cystatin C without

As it has been showed in several preclinical gene expression analyses performed in AKI murine and human models, neutrophil gelatinase-associated lipocalin (NGAL) gene has been revealed the to be one of the most upregulated genes in the kidney soon after an ischemic or a nephrotoxic insult [113, 114]. NGAL is filtered across the glomerulus, is reabsorbed in proximal tubules and its urinary concentration increases early during ischemic insults [115, 116]. The NGAL protein is also highly induced in regenerating and recovering kidney tubule cells. NGAL binds iron; chelation of toxic iron is an important mechanism that protects the kidney tubules from worsening injury. Thus, the biological role of NGAL in AKI is one of enhanced tubule cell proliferation and recovery [117]. Measurement of urinary NGAL (uNGAL) has been demonstrated to be an early, non-invasive marker of AKI due to a variety of etiologies, such as cardiac surgery [118], intravenous contrast administration [119], critical care settings [120] and kidney transplantation [121]. NAGL has an enormous dynamic range, responds in a dosedependent fashion to injury, responds within 3 h of injury, and responds to a wide range of injuries, easy to measure due to the recent availability of clinical platforms including a new NGAL dipstick. Thus, uNGAL values may then be used to initiate AKI patient care algorithms earlier than serum creatinine alone. Although multiple investigations have demonstrated that uNGAL is a promising AKI biomarkers, a study by Sundaram et al. [57] has not showed any relationship with albuminuria in patients with SCD. This study has also showed that uNGAL levels were significantly subnormal (<50 ng/mL) in most patients with SCA and the overall uNGAL in most patients were well below levels usually seen in patients with acute or chronic renal injury. The authors have explained the results obtained based on the fact that proximal tubular function is supra-normal in SCA, and it is likely that any filtered NGAL may be reab-

sorbed much more efficiently, resulting in subnormal urinary NGAL levels in SN.

Soluble FMS-like tyrosine kinase-1 (sFLT-1) is a member of the vascular endothelial growth factor receptor family (VEGFR) and has an antiangiogenic effect. Soluble FLT-1 is increased in SCD due to its over-expression by vascular endothelial cells, vascular smooth muscles, activated blood monocytes and proximal tubular cells of the renal epithelia [122]. A recent study by Youssry et al. [123] investigated the relationship between serum levels of sFLT-1 and other conventional biomarkers of renal damage. The serum level of sFLT-1 in SCD patients was significantly higher than controls and its median level showed no significant difference when comparing patients with SS and Sβ genotypes, hydroxyurea therapy and iron chelation. On

increased creatinine might not have clinical significance.

*4.1.2. Urine neutrophil gelatinase-associated lipocalin*

166 Hematology - Latest Research and Clinical Advances

*4.1.3. Soluble FMS-like tyrosine kinase-1*

Preclinical studies have identified the kidney injury molecule-I (KIM-1) gene to be induced in the proximal tubule cells of ischemic rat kidneys [114]. KIM-1 protein regulates phagocytosis of damaged cells and thereby limits injury. An extracellular domain of KIM-1 can be detected by enzyme-linked immunosorbent assays and is useful as a urinary biomarker in patients with AKI. In fact, in a study conducted by Han WK et al., it was shown that in 40 children undergoing CPB, urinary KIM-1 levels were markedly increased in those who have developed AKI [126]. On the other hand, a prospective multi-center study of 311 children undergoing cardiac surgery confirmed the delay in upregulation of urinary KIM-1 in AKI patients and showed that KIM-1 was not significantly associated with AKI after adjusting for other injury biomarkers [127]. This data is in contrast with the results published by Sundaram et al. [57]. Indeed when KIM-1 levels, detected in all SCA urine samples, were compared within the different albuminuria groups, they were detected at lowest levels in patients with normal albuminuria, significantly increased in patients with moderately increased albuminuria and further increased in the severely increased albuminuria group, suggesting this may be another biomarker of relevance in sickle nephropathy that needs to be confirmed in longitudinal studies.
