*2.2.5. Proteinuria and chronic kidney disease*

painful crises associated with vaso-occlusion. Increased circulating erythrocyte membrane microparticles (MPs) have been associated with occlusion of capillaries. Interestingly, MPs triggered immediate renal vaso-occlusion in mice. In vitro studies showed that MPs stimulate the production of reactive oxygen species by endothelial cells, stimulate RBC adhesion and induce endothelial apoptosis. This work introduced a novel concept that associates the shedding of MPs from sickled RBC with vascular disease [39]. An interaction of free heme with TLR4 receptor was shown to mediate the nephrotoxicity of heme, in particular, the effects of

Glomerular changes in SCD occur early in the first decade of life even though SCD patients remain asymptomatic. These are characterized by high renal blood flow, hyperfiltration and hypertrophy. Current data suggest that infants with SCD develop a hyperfiltration phase, which plateaus during early childhood. As early as the first year, renal enlargement is observed in correlation to hyperfiltration. Hyperfiltration is a well-known phenomenon in SCD even though the pathogenesis and pathophysiology is less well understood. As a result of hyperperfusion, increased amount of fluids is presented to the proximal tubule triggering more tubular reabsorption of sodium and water in order to restore glomerulotubular balance. Increased proximal tubular sodium reabsorption is associated with high metabolism and adaptive cellular response leading to overall renal enlargement. This complex phenomenon might be relevant to the glomerular hypertrophy that occurs in SCD [13]. Some studies show that for children with HbSS, there is an age-related increase in the estimated creatinine clearance in the first decade of life, with a decline toward normal values in the second decade [41–43]. In the study by Etteldorf and colleagues, children with SCD aged 4–11 years had a significantly higher mean measured glomerular filtration rate (mGFR) (169 mL/min/1.73 m2

In a cross-sectional study of 410 patients with SCD aged 2–21 (mean age 11) years, 23% of HbSS patients showed elevated urinary albumin excretion (≥30 mg/g), while other investigators have reported a HbSS prevalence of 16–27% in the childhood SCD population [47–49].

Further progressive kidney injury and CKD is reflected in a declining and abnormally low GFR. During adolescence, estimated glomerular filtration rate (eGFR) begins to decline in some patients, and aroud 10% of adolescent patients with SCD develop a GFR of <90 mL/

The prevalence of end-stage renal disease (ESRD) in the pediatric SCD population is also not well described; however, childhood SCD accounts for only 0.3% of incident pediatric

Eventually, renal failure develops in early adulthood (median age 23–37 years) in SCA and in

[50]. Similarly, Bodas et al. recently reported a CKD prevalence of 8% in a cohort

heme on renal blood flow and inflammatory responses [40].

160 Hematology - Latest Research and Clinical Advances

than normal controls (128 mL/min/1.73 m2

of patients with SCD aged 3–17 years [51].

mid-life (median age 50 years) in HbSC disease.

min/1.73 m2

ESRD [52].

*2.2.4. Development of sickle cell nephropathy from infancy to adulthood*

9–19 months had a measured GFR at baseline of 125 mL/min/1.73 m2

cantly higher than published normal values for the same age group [46].

The prevalence of albuminuria in SCD is age dependent. It may be classified as moderately increased albuminuria (previous called microalbuminuria)—urine albumin concentration of 30–300 mg/g creatinine and severely increased albuminuria (macroalbuminuria)—urine albumin concentration of 300 mg/g creatinine. The prevalence of albuminuria in the first three decades of life is up to 27% increasing to 68% in older SCD patients [13]. The understanding of the evolution of CKD in SCD is evolving the extent to which moderate albuminuria progresses to severely increased albuminuria and the relationship with SCN. The development of SCN is likely due to complex interactions between SCD-related risk factors and non-SCD phenotype characteristics. Albuminuria is more likely to occur in patients who express specific single-nucleotide polymorphisms in the MYH9 and APOL1 genes, which are associated with an increased risk of CKD in African Americans [53]. On the other hand, microdeletions in the gene that encodes α-globin (reflecting a form of α-thalassemia trait) leads to a lower prevalence albuminuria [54]. Genetic polymorphisms of bone morphogenetic protein receptor 1B also influence GFR in SCD [55, 56]. SCD patients with albuminuria have increased levels of urinary excretion of markers of tubular injury (KIM-1 and NAG) [57]. The individual contribution of these phenomena to SCN is not clear.

#### *2.2.6. Chronic kidney disease and end-stage renal disease*

The reported prevalence of ESRD in SCD varies from 5 to 18% depending on the age of the cohort but reamins a significant cause of mortality [58, 59]. Similarly, CKD (defined based on eGFR) which is usually diagnosed between 30 and 40 years is also a risk factor death [47, 60]. In a recent study in Rio de Janeiro, Brazil, 4.3% of patients admitted with SCD had CKD [61]. A lower incidence was observed in a study from Senegal, where CKD was identified in 2.6% of 229 adults with SCD [62]. The manifestations of CKD in SCD include hypertension, proteinuria and anemia. Vaso-occlusive history, legs ulcers, osteonecrosis, retinopathy, proteinuria, hematuria, hypertension and severe anemia were all identified as predictive factors for CKD in SCD [58, 61, 63]. In a recent study from Nigeria, 50% of SCD patients with proteinuria had CKD [64]. Risk factors associated with progression of CKD to ESRD (**Table 1**) include increased blood pressure, low hemoglobin levels, haemolysis, leukocytosis, hematuria, prior vaso-occlusive crisis, the βS Central African Republic (CAR) haplotype, pulmonary hypertension, stroke, acute chest syndrome and infection with parvovirus B19 [65–78]. The mean survival of patients with ESRD and SCD is estimated to be 4 years, even with dialytic treatment [79].

#### *2.2.7. Urinary concentration abnormalities*

)

[45], which was signifi-

) [44]. In the BABY HUG trial, 176 children aged

The onset of urinary concentration defects begins in early infancy (6–12 months) and may account for nocturia, polyuria and enuresis in later childhood. The defect in urinary concentration does not respond to vasopressin but it is reported to improve with chronic blood transfusions in young children [47, 63, 64, 80–83]. Further deterioration of the defect in urinary concentration is observed from the second decade of life due to the onset of medullary fibrosis and the loss of the collecting ducts system. High HBF levels are associated with better urinary concentration [84–86]. There may be a role for drugs therapy that enhance the production of HbF such as hydroxyurea and decitabine.


length of stay [90]. The true incidence of AKI in pediatric SCD patients may be underestimated in retrospective studies [89, 90]. In addition, serum creatinine may be an inaccurate marker of renal function in SCD due to the relatively high proximal tubular secretion of creatinine found in this population [91]. Interestingly, a recent adult study showed that even in patients with a normal creatinine level during a pain crisis, acute tubular injury likely occurs, as evidenced by a more than twofold rise in urinary neutrophil gelatinase-associated lipoprotein excretion [92]. NSAID use is common in children with SCD [93], without evidence to support its benefit compared to other less nephrotoxic options. Similarly, the use of non-steroid anti-inflammatory agents (NSAIDS) in children with SCD hospitalized for various indications, including dehydration due to gastroenteritis, was associated with a significant increase in the incidence of AKI [94, 95]. Therefore hemodynamic changes may increase the risk of AKI secondary to NSAIDs, Another contributing factor includes potential toxic tubular effects of free hemoglobin during a sickle crisis. Some SCD patients with CYP2C9 allele variants that alter NSAID metabolism may be at increased risk of toxicity. During vaso-occlusive pain crises and acute chest syndrome, the risk of AKI is increased by the drop in hemoglobin leading to hypoxic-ischemic events, hemolysis or inflammation. In murine SCD models, brief episodes of hypoxic-ischemic events produce profound acute renal injury [36, 96]. The murine model of SCD has shown that an increase in hemolysis or exposure to excess cell-free hemoglobin can also lead to renal injury [97].

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

http://dx.doi.org/10.5772/intechopen.76588

163

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].

creatinine) or severely increased albuminuria (greater than 30 mg/mmol creatinine) [105].

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

**3. Assessment of kidney function**

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

## *2.2.8. Urinary acidification deficit*

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 aldosterone may exist [81, 87].

#### *2.2.9. Hematuria*

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].
