**1. Introduction**

Sickle cell disease (SCD) is one of the most frequent genetic disorders in the world. It predominantly affects people of African descent as well as individuals from the Middle East, India and

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Mediterranean regions. Recent estimates report about 305,800 babies with SCD are born every year in the word and over two-thirds are in sub-Saharan Africa rising to over 404,200 by 2050 [1, 2]. The disease is associated with a high lifetime morbidity and premature mortality [3], as described in the 2013 Global Burden of Disease Study [4]. The age-standardized death rate in sickle cell anemia increased from 1990 to 2013 (median change 28) [5]. The World Health Organization (WHO) has addressed the significant public health implication of sickle cell anemia, urging implementation of equitable and effective programs for the prevention and management of SCD [6]. Furthermore, encouragement was provided for the promotion, support and coordination of much needed research in SCD [6].

vasoconstriction leads to further vasculopathy in the kidney. Sickle cell nephropathy (SCN) is a spectrum of changes resulting from a cascade of events occurring in the kidney. This is triggered by RBC vascular occlusion, infarction and reperfusion injury occurring within the renal medullar, cortex and collecting system. These may present as hyperfiltration, microalbuminuria, impaired urinary concentrating ability complicated by episodes of acute kidney disease (AKD) features early in childhood. In young adults, there is progressive increase in albuminuria and regression of the glomerular filtration rate (GFR). Further deterioration of renal function with the development of chronic kidney disease (CKD) (defined as estimated GFR of less than

Early stages of SCN are characterized by glomerular hypertrophy, hemosiderin deposits with focal areas of hemorrhage or necrosis. This is followed by interstitial inflammation, edema, fibrosis, tubular atrophy and papillary infarcts [14–16]. Some of these features were reported in a multi-center, retrospective analysis of renal biopsies of 18 SCD patients (16-HbSS, 1-HbSC, 1 HbSβ thalassemia) who presented with proteinuria, acute or progressive impairment of renal function [17]. The study reported focal segmental glomerulosclerosis (FSGS) in seven cases, membranoproliferative glomerulonephritis (MPGN) in five and thrombotic microangiopathic glomerulopathy in three; while glomerular hypertrophy with or without mesangial hypercellularity was reported in three cases. Furthermore immunofluorescence microscopy

**Figure 1.** The pathogenetic processes in the development of sickle cell nephropathy [13].

) eventually leads to end-stage renal disease (ESRD) in adulthood (**Figure 1**).

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

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**2.1. Pathobiology/histology**

The term'sickle cell disease' refers to all genotypes that cause the clinical syndrome. It occurs due to the inheritance of abnormal beta globin S (βS) alleles with the substitution of valine for glutamic acid in position 6 of the beta globin; the most common phenotype is homozygous β<sup>S</sup> /β<sup>S</sup> which is referred to as sickle cell anemia (SCA). The second most common phenotype, hemoglobin SC disease (HbSC), occurs due to co-inheritance of the β<sup>S</sup> and βC alleles, and presents a more moderate phenotype. HbS/β-thalassemia is the co-inheritance of β<sup>S</sup> with a β-thalassemia allele [7], those with a thalassemia null mutation (HbSβ0 ) presenting with a phenotype that is clinically indistinguishable from SCA, whereas individuals with HbSβ<sup>+</sup> thalassemia have a milder disorder [8]. The resulting sickle hemoglobin (HbS) polymerizes when the concentration of its deoxygenated form (deoxyHbS) exceeds a critical threshold. Low oxygen levels, increased acidity and cellular dehydration facilitate the polymerization of HbS and the distortion of the red blood cells leading to sickle-shaped erythrocytes [9]. The co-inheritance of genetic factors such as α-thalassemia or hereditary persistence of fetal hemoglobin are known to reduce the rate of HbS polymerization [10]. Sickling of red blood cells results in both obstruction of blood flow leading to organ and tissue ischemia, and hemolytic anemia [2, 11]. Reduced blood flow is mediated via a dynamic interaction between sticky HbS-containing red blood cells, white blood cells and the vessel wall [2]. Chronic intravascular hemolysis leads to the release of free hemoglobin that sequesters nitric oxide, a potent vasodilator and antiinflammatory molecule, leading to vasoconstriction in different organs. Stroke and pulmonary hypertension are thought to be consequences of the diminished vascular relaxation caused by nitric oxide deficiency [12]. In addition, intravascular hemolysis in SCD leads to high plasma levels of cell-free heme and hemoglobin (Hb), sources of redox active iron. Iron-derived reactive oxygen species are implicated in the pathogenesis of numerous vascular disorders including atherosclerosis, microangiopathic hemolytic anemia, vasculitis and reperfusion injury [13]. Exposure of endothelium to heme greatly potentiates cell death. Recurrent cycles of ischemiareperfusion injury in the microvasculature might amplify endothelial dysfunction and further organ injury including the stroke, pulmonary hypertension and kidney injury.
