**3. Assessment of kidney function**

*2.2.8. Urinary acidification deficit*

162 Hematology - Latest Research and Clinical Advances

aldosterone may exist [81, 87].

*2.2.10. Sickle cell nephropathy and acute kidney injury*

*2.2.9. Hematuria*

The defect in urinary acidification may be a combination of ischemic changes in the medulla and reduced capacity of the collecting duct to maintain hydrogen gradient. It is not clear what is responsioble for this defect but it has been suggested a resistance of the distal nephron to

**Table 1.** Risk and protective factors associated with progression of CKD to ESRD.

One of the most frequent featurs of SCN is hematuria which is also found in individuals with sickle trait [88], it may be micro or macroscopic and it is usually painless [63, 81]. The mecahanism is not well defined but capillary congestion due to vaso-oclusive and ischemic injury may account for it. It is reported that the left kidney is more likely to be involved due to the fact that the left renal vein is compressed between the aorta and the superior mesenteric artery; also referred to as a "nutcracker-like" phenomenon [37]. Hematuria might also be due to renal papillary necrosis from vaso-occlusion of vasa recta but rarely from renal medullary carcinoma [63]. Nevertheless it is important to exclude other causes such as urinary tract infections, neoplasms, vascular malformations, vasculitis, glomerulonephritis and coagulation disturbances [61, 88].

The prevalence of acute kidney injury (AKI) in children with SCD presenting to the hospital emergency room may be as high as 17% [89], AKI is underreported in pediatric SCD patients. In adults, AKI is reported in 4–10% of patients, and in up to 14% of adults with acute chest syndrome. AKI in SCD may also reflect the frequent use of non-steroidal anti-inflammatory drugs (NSAIDs) to treat painful crises in this patient population [52]. A recent retrospective analysis reported 8% of AKI in 149 pediatric patients admitted for acute chest syndrome using the Kidney Disease Improving Global Outcomes (KDIGO) and higher with increased hospital The gold standard for assessing how well the kidneys are working is direct measurement of the GFR. CKD is classified based on the eGFR and the level of proteinuria and helps to risk stratify patients (**Table 2A** and **B**). In individuals with SCD, a GFR greater than 120 mL/min/1.73 m2 is an additional indicator of abnormal kidney function. However, direct measurement of GFR is invasive and time consuming and so estimations of GFR based on the serum creatinine are more commonly used. A number of equations exist, including the `Modification of Diet in Renal Disease' (MDRD), CKD-EPI and Cockcroft-Gault equations [98–100]. Different estimated GFR calculations have been compared to the measured GFR in people with HbSS from the Caribbean and sub-Saharan Africa, the CKD-EPI equation was found to provide the most accurate estimate in two small studies [101, 102]. In individuals with SCD, increased proximal tubule secretion of creatinine results in the serum creatinine level being a poor estimate of GFR [103]. The diagnostic performance of cystatin C in comparison to serum creatinine was analyzed in a meta-analysis of 46 studies, including children and adults. The data compared correlation coefficients between GFR and the reciprocals of serum creatinine and cystatin C in 3703 participants and showed significantly better correlations for cystatin C, suggesting that cystatin is superior to serum creatinine for the detection of impaired GFR in cross-sectional studies [104].

Proteinuria, albumin-to-creatinine ratio (ACR) is greater than 2.5 mg/mmol in men or 3.5 mg/mmol in women, or a protein-to-creatinine ratio (PCR) is greater than 15 mg/mmol is sufficient for a diagnosis of CKD. Proteinuria may be classified as moderately increased albuminuria (3–30 mg/mmol creatinine) or severely increased albuminuria (greater than 30 mg/mmol creatinine) [105].



population-based studies and in patients with non-ST-elevation acute coronary syndrome [110]. Therefore CysC is an ideal biomarker for study the renal function in SCD patients which is ongoing hemolysis and inflammation secondary to the sickling phenomenon and in which creatinine clearance is generally increased and serum creatinine is low. Tantawy et al. [111] have found significantly higher serum CysC in patients with SCD compared to healthy controls. In particular, patients of their court of study with nephropathy had higher cystatin levels than those without, and a significant positive correlation was found with ACR. The authors have demonstrated also that patients with SCD treated with hydroxyurea had lower CysC levels than untreated patients, possibly due to the role of hydroxyurea in decreasing inflammation [111]. In agreement with Tantawy's results, Alvarez et al. [108] examined the value of serum CysC as a marker for GFR in small cohort of 20 children with SCD with and without albuminuria, compared to serum creatinine and creatinine clearance. The mean GFR derived from serum cystatin was significantly different among these subgroups, becoming abnormal

Sickle Cell Nephropathy: Current Understanding of the Presentation, Diagnostic and…

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or creatinine clearance did not change significantly with the level of albuminuria. The authors concluded that serum CysC was higher than serum creatinine in SCD, and this probably relates to the fact that serum CysC is not secreted by the kidney, as creatinine. Moreover other studies have demonstrated the utility of CysC in patients with SCD. Asnani and Reid [109] have proved in 98 adults with SCD that CysC levels were significantly correlated with measured GFR, hemoglobin, serum creatinine, urinary albumin-creatinine ratio (UACR) and systolic blood pressure. In addition to urine, screening for albuminuria may help in the diagnosis of early renal impairment in the patients with SCD before a significant rise in serum

), compared to 94 mL/min per 1.73 m2

for the normal subgroups. Serum creatinine

for the

in the proteinuric cohort (63 mL/min per 1.73 m2

**Table 3.** Novel urinary biomarkers.

microalbuminuric and 103 mL/min per 1.73 m2

**Table 2.** (A) GFR categories in CKD; (B) ACR categories (KDIGO 2012) [105].
