**2.1. Pathobiology/histology**

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, sup-

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 homozy-

notype, hemoglobin SC disease (HbSC), occurs due to co-inheritance of the β<sup>S</sup>

organ injury including the stroke, pulmonary hypertension and kidney injury.

Renal involvement in SCD is a complex phenomenon resulting from an increased tendency of sickling in the renal medulla due to hypoxia, acidosis and hyperosmolar conditions [13]. Abnormally, high hemodynamic renal blood flow leads to early onset hypertrophic and impaired urinary concentrating ability, distal nephron dysfunction and progressive glomerulopathy. The combination of cortical hyperperfusion, medullary hypoperfusion and

a β-thalassemia allele [7], those with a thalassemia null mutation (HbSβ0

and presents a more moderate phenotype. HbS/β-thalassemia is the co-inheritance of β<sup>S</sup>

phenotype that is clinically indistinguishable from SCA, whereas individuals with HbSβ<sup>+</sup>

assemia 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

which is referred to as sickle cell anemia (SCA). The second most common phe-

and βC alleles,

) presenting with a

with

thal-

port and coordination of much needed research in SCD [6].

gous β<sup>S</sup>

/β<sup>S</sup>

156 Hematology - Latest Research and Clinical Advances

**2. Sickle cell nephropathy**

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].

in the patients with FSGS-type lesions showed irregular staining for IgM and C3 in areas of sclerosis [15, 16, 18]. Complement deposition occur in the glomeruli coinciding with various degrees of proteinuria including nephrotic syndrome [19].

pathogenesis of tissue injury in SCD as well as the production of ET-1 [27–29]. NO is a suppressor of ET-1 synthesis and vascular ET-1 production may also increase when the vascular system is depleted due to NO binding to HbS plasma. ET-1 causes RBC dehydration by activating the

Mouse models provide opportunities to explore the mechanisms of globin gene regulation and the feasibility of gene therapy for this condition and the molecular basis of end-organ damage, including SCN [32]. The use of established mouse models is of invaluable help to investigate the pathogenesis of SCD-associated multiple organ complications and to identify

Several murine models have been developed to mimic human SCD.Of these, the Berkeley model (BERK mice) has targeted deletions of murine α and β globins (α−/−, β−/−) with a transgene con-

β−/−, transgene +); thus, these mice almost exclusively express human sickle hemoglobin [33]. The BERK mouse model exhibits a wide spectrum of hematologic and histopathologic findings that are similar to those found in humans with SCD. Erythrocyte sickling is significant in BERK mice, and erythrocyte survival is very short resulting in massive amounts of heme being released into the plasma. As seen in humans with SCD, BERK mice showed a wide spectrum of kidney pathologies such as increased cortical hypertrophy, gross and microscopic infarcts, iron deposition, enlarged glomeruli associated with mesangial cell and mononuclear

Another mouse model of SCD, the transgenic SAD mouse bears the human α-globin gene

its hemoglobin to polymerize [35]. The SAD mice display renal hemosiderosis, microvascular occlusions, vascular thrombosis, cortical infarcts and papillary necrosis. Most mice show glomerular hypertrophy and mesangial sclerosis. The glomerular damage is associated with abnormal function, characterized by increased blood urea nitrogen levels and proteinuria [35]. The glomerular lesions of SAD mice faithfully mimic sickle cell glomerulosclerosis, the most severe renal complication observed in individuals with SCD. Therefore, the SAD mouse constitutes a valuable model to investigate the pathophysiology of the thrombotic and glomerulosclerotic complications of human SCD. Ischemic injury contributes to end-organ damage and other complications of SCD. Increased sensitivity of tissues in SCD to ischemic insults has been demonstrated in SCD mice. As it has been showed by Nath et al., after induction of bilateral renal ischemia, transgenic SCD mice exhibited massive vascular congestion, sickling of red blood cells and more prominent capillary congestion in the lungs and heart compared to control mice [36]. These results demonstrated increased susceptibility to vascular congestion and to ischemia in tissues from SCD mice, suggesting that ischemic episodes may contribute to the renal complications observed in SCD. Abnormal leukocyte-endothelium attachment associated with endothelial activation was observed in SCD mice, showing interesting parallels between the vascular injury after reperfusion and kidney damage. In addition, this study suggested that allopurinol, that prevents ischemia-reperfusion generation of reactive oxygen species, might be a potential therapy for SCD [37]. The anti-sickling property of fetal hemoglobin was also demonstrated in SCD mice [38]. Patients with SCD suffer from

, Aγ, Gγ and β globins (Hba0/0 Hbb0/0 TG (Hu-miniLCRα1GγAγδβS) (α−/−,

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

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, as well as βAntilles and βD−Punjab which greatly enhance the tendency of

Gardos channel present in the plasma membrane of RBCs [30, 31].

cell hypercellularity are observed in kidneys from BERK mice [34].

*2.2.3. Mouse models*

taining human α, β<sup>s</sup>

and the HbS mutation, β<sup>S</sup>

targets for prevention and therapy.
