Association between Endothelial Dysfunction, Biomarkers of Renal Function, and Disease Severity in Sickle Cell Disease : Kidney360

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Original Investigations: Clinical Nephrology

Association between Endothelial Dysfunction, Biomarkers of Renal Function, and Disease Severity in Sickle Cell Disease

Ayoola, Oluwagbemiga Oluwole1,2; Bolarinwa, Rahman Ayodele3; Onwuka, Chidiogo Chukwunweike2; Idowu, Bukunmi Michael4; Aderibigbe, Adeniyi Sunday1,2

Author Information
Kidney360 1(2):p 79-85, February 2020. | DOI: 10.34067/KID.0000142019
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Sickle cell disease (SCD) is an inheritable genetic disorder of hemoglobin structure with variable clinical manifestations. Annually, about 312,000 people are born with hemoglobin SS genotype worldwide, with up to 236,000 of these in sub-Saharan Africa (1,2). Nigeria has the highest disease burden in the world (3). The prevalence of SCD across sub-Saharan Africa is between 10% and 45% (4,5).

The vascular endothelium performs endocrine, autocrine, and paracrine functions, and it is the largest organ in the body (being the one-cell-thick innermost layer lining of all blood vessels) (6). It helps to regulate vascular tone, maintain vascular homeostasis, and regulate blood flow, and it constitutes an antithrombotic surface for smooth passage of blood elements/constituents (6). Endothelial dysfunction (ED) is a known feature of SCD, which is present both in crisis and in steady state (7,8). It has been demonstrated in both children and adults with SCD (8,9), and it is more severe in patients with sickle cell anemia than in patients with sickle cell trait (10). Impaired (reduced) sonographic brachial artery flow-mediated dilation (FMD) is a recognized biomarker for ED in SCD (11). The assessment of FMD is a noninvasive approach to examining vasodilator function in vivo and has been used as a surrogate marker of vascular health. It can describe any vasodilation of an artery following an increase in luminal blood flow and internal wall shear stress (12).

We aimed at evaluating ED in SCD using sonographic brachial artery FMD, compared the FMD in patients with SCD with that of controls with HbAA genotype, and determined any possible association/relationship among the trio of ED and biomarkers of renal function along with indices of SCD severity in patients asymptomatic of renal disease. To the best of our knowledge, no study has shown the relationship between FMD and cystatin C (Cys-C) along with renal artery resistivity index (RARI).

Materials and Methods

We enrolled 44 patients with homozygous SCD (HbSS) in steady state on the basis of the criteria defined by Ballas (13) attending the hematology clinic of the local institution along with 33 age- and sex-matched controls (HbAA) in this cross-sectional comparative study. The study protocol was approved by the institutional review board, and informed written consent was obtained from all of the participants. The genotype of all of the participants had been confirmed previously by hemoglobin electrophoresis. We excluded subjects with risk factors for ED, such as hypertension, diabetes, obesity, hypercholesterolemia, stroke, and smoking. We also excluded the carrier state for thalassemia (α- and β-thalassemia traits) by considering their medical history, full blood count, and the red cell indices (MCV and MCH). None of the subjects were on hydroxyurea or nicosan.

Demographic and Clinical Characteristics

Demographic and clinical data were obtained using a structured data sheet. Systolic BP and diastolic BP were measured over the left arm brachial artery region in resting state using an analog mercury sphygmomanometer.

Laboratory Evaluation

An ELISA using quantitative competitive immunoassays was done to determine fetal hemoglobin (HbF), soluble P-selectin (sP-selectin), kidney injury molecule (KIM-1), homocysteine (HCY), and Cys-C levels according to the manufacturer’s instructions (assay kits were procured from Neobiolab, Cambridge, MA). Serum total cholesterol and LDL were assessed using cardiochek PA analyzer (PTS Diagnostics Headquarters, Indianapolis, IN). Hemoglobin concentration, platelet count, white blood cell count, peripheral capillary oxygen saturation levels, and fasting blood sugar along with serum creatinine were assayed. Creatinine assay along with Hb. conc., white blood cell, and platelet count were not done for the controls. The eGFR was done using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation (14).

Brachial Artery Sonographic FMD

The lead author, O. Chidiogo Chukwunweike performed the brachial artery FMD assessment on all of the subjects using a Doppler-enabled MINDRAY DC-7 ultrasound scanner (Shenzhen Mindray Bio-medical Electronics, Nanshan, Shenzhen, China) with a 7.5- to 12-MHz linear array transducer. The right brachial artery FMD protocol was the same as described previously (15,16). After a 10- to 15-minute rest at room temperature, the subjects were requested to lie supine, and their right arm was exposed and abducted to 15°C. Acoustic gel was applied proximal to the antecubital fossa, and the brachial artery was scanned in a longitudinal section 5–10 cm to get a clear view of both walls of the artery. After an optimal image was obtained, the surface of the skin was marked, and the arm was kept in the same position throughout the study. The brachial artery luminal diameter was measured as the distance between the anterior intima-lumen interface and the posterior intima-lumen interface and labeled as D1. A BP cuff was then applied to the forearm below the elbow and inflated to 50 mm Hg above the systolic BP for 5 minutes to elicit an endothelium-mediated response, and then, it was deflated after 5 minutes of cuff occlusion. The same brachial artery segment underneath the area of the skin marked was interrogated continuously for 30 seconds before and for 90 seconds after cuff deflation. The second arterial diameter (D2) was taken as the maximum diameter obtained between 60 and 90 seconds after cuff release.

All measurements were obtained during the systolic phase. The average of three measurements was used for FMD calculation.

FMD was calculated as the percentage change in diameter after reactive hyperemia relative to the baseline using the formulaFMD=D2D1 ×100%D1.Timing, room temperature, and experience of the examiner could affect the results obtained (15).

Renal Arterial Doppler Sonography

Doppler sonography of the right renal artery was done with the subject in the left lateral decubitus position to visualize the artery on greyscale imaging. Spectral Doppler of the interlobar or segmental arteries was then performed with a small sample volume (1 mm). Angle correction was not carried out because only the resistive index (RI) and pulsatility index are of interest.

Statistical analysis was done using the Statistical Package for Social Sciences software version 20 (SPSS Inc., Chicago, IL). Data normality was determined using the Kolmogorov–Smirnov test. Chi-squared test/Fisher’s exact test was used to compare proportions. An independent samples Mann–Whitney U test was used to compare the medians. An independent samples t test was used to compare the means, whereas Spearman’s Rho was used for correlational analysis. Statistical significance was set at P≤0.05.


Forty-four subjects with HbSS SCD and a median age of 24.5 years old (interquartile range [IQR], 19.5–32.0 years old) were enrolled along with a control group with a median age of 24.0 years old (IQR, 21.0–27.0 years old). The subjects with SCD included 23 (52.3%) men and 21 (47.7%) women, whereas the control subjects included 17 (51.5%) men and 16 (48.5%) women. No significant difference was noted between the ages of the subjects in both groups (Table 1).

Table 1. - Characteristics of subjects with sickle cell disease and controls
Variables SCD, n=44 Controls, n=33 P Value
Age, yr 24.5 (19.5–32.0) 24.0 (21.0–27.0) 0.31 a
Height, m 1.6 (1.6–1.7) 1.6 (1.5–1.7) 0.90 a
Weight, kg 49.1±10.0 61.3±12.3 <0.001 b
BMI, kg/m2 18.1 (16.8–20.4) 21.6 (19.9–25.7) <0.001 a
SpO2, % 95.0 (92.0–98.0) 98.0 (96.0–98.5) <0.001 a
Hb conc., g/dl 8.3 (7.3–8.7)
WBC, 103/μl 9.5 (7.3–11.7)
Platelet, 103/μl 295.5 (192.0–367.5)
HbF, ng/ml 373.3 (316.8–448.28) 273.9 (212.2–335.7) <0.001 a
sP-selectin, ng/ml 78.7 (68.9–84.0) 72.7 (67.1–78.5) 0.007 a
HCY, µmol/L 16.4 (10.1–28.8) 8.3 (5.0–19.3) 0.008 a
Cys-C, mg/L 4.8 (1.6–7.9) 1.1 (0.5–1.6) <0.001 a
KIM-1, pg/ml 445.0 (320.0–623.0) 125.0 (120.0–184.0) <0.001 a
Creatinine, µmol/L 87.5 (64.5–124.3)
eGFRCKD-EPI, ml/min per 1.73 m2 87.5 (59.0–118.8)
UACR, mg/g, n (%)
 <30 26 (59.1) 33 (100) <0.001 c
 <30–300 14 (31.8) 0 (0)
 >300 4 (9.1) 0 (0)
RARI 0.70 (0.66–0.72) 0.59 (0.54–0.64) <0.001 a
SCD, sickle cell disease; BMI, body mass index; SpO2, oxygen saturation; Hb conc., hemoglobin concentration; WBC, white blood cell count; HbF, hemoglobin F; sP-selectin, soluble P-selectin; HCY, homocysteine; Cys-C, cystatin C; KIM-1, kidney injury molecule-1; eGFRCKD-EPI, eGFRChronic Kidney Disease Epidemiology Collaboration; UACR, urine albumin-to-creatinine ratio; RARI, renal artery resistivity index.
aIndependent samples Mann–Whitney U test was used to compare the medians.
bIndependent samples t test was used to compare the means.
cChi-squared test/Fisher’s exact test statistic was used to compare proportions.

The median FMD of 3.44 (IQR, 0.00–7.08) in subjects with SCD was significantly lower than that of controls, which was 5.35 (IQR, 3.60–6.78; P=0.04) (Table 1). No significant sex difference was noted in the FMD among subjects with (P=0.98) and among control subjects (P=0.79).

There was significant modest negative correlation between FMD and serum Cys-C levels (r=−0.372; P=0.01) and between FMD and RARI (r=−0.307; P=0.04) (Table 2) in subjects with SCD. No significant correlation was noted between FMD and other biomarkers of SCD severity (Table 2), like HbF, sP-selectin, and HCY.

Table 2. - Spearman correlation of percentage of flow-mediated dilation with other variables in subjects with SCD versus controls
Variables Subjects with SCD Control Subjects
Correlation Coefficient P Value Correlation Coefficient P Value
Age, yr 0.153 0.32 0.079 0.31
Height, m 0.117 0.45 −0.210 0.29
Weight, kg −0.063 0.68 −0.179 0.37
BMI, kg/m2 −0.088 0.5 0.014 0.94
SpO2, % 0.127 0.410 0.147 0.42
Hb conc., g/dl 0.125 0.42
WBC, 103/μl 0.077 0.62
Platelet, 103/μl −0.182 0.24
HbF, ng/ml 0.011 0.95 0.114 0.53
sP-selectin, ng/ml −0.182 0.24 0.003 0.99
HCY, µmol/L −0.204 0.18 −0.022 0.91
Cys-C, mg/L −0.372 0.01 0.020 0.91
KIM-1, pg/ml 0.179 0.25 0.156 0.38
Creatinine, µmol/L −0.166 0.28
eGFRCKD-EPI, ml/min per 1.73 m2 0.111 0.47
UACR −0.074 0.63 −0.146 0.42
RARI −0.307 0.04 −0.017 0.92

Using an FMD cutoff of 5.35, which is the median value obtained in the control population, subjects with SCD were separated into two groups: the median Cys-C level in subjects with SCD and FMD<5.35 (4.9; IQR, 3.1–7.4) was significantly higher than that of subjects with SCD and FMD≥5.35 (1.6; IQR, 1.4–9.3) (Table 3). A significant difference was also noted in the KIM-1 values of both groups. Although RARI was slightly higher in subjects with SCD and FMD<5.35 than in those with FMD≥5.35, this was not statistically significant (Table 3).

Table 3. - Categorization of subjects with SCD on the basis of flow-mediated dilation
Variables SCD FMD <5.35, n=29 SCD FMD ≥5.35, n=15 P Value
Sex, n (%)
 Men 14 (48.3) 9 (60.0) 0.54 a
 Women 15 (51.7) 6 (40.0)
Age, yr 24.0 (19.0–31.5) 26.0 (21.0–32.0) 0.64 b
Height, m 1.6 (1.5–1.7) 1.6 (1.6–1.8) 0.10 b
Weight, kg 48.5±11.1 50.3±7.7 0.59 c
BMI, kg/m2 18.1 (16.6–20.5) 17.7 (16.8–20.2) 0.79 b
SpO2, % 94.0 (89.0–97.5) 95.0 (93.0–98.0) 0.18 b
Hb conc., g/dl 8.1±1.3 8.3±1.1 0.50 c
WBC, 103/μl 9.9±4.1 10.0±3.8 0.92 c
Platelet, 103/μl 302.9±148.6 274.7±146.7 0.55 c
HbF, ng/ml 383.6 (328.8–444.5) 349.3 (260.3–472.6) 0.42 b
sP-selectin, ng/ml 79.4 (65.9–84.8) 78.5 (76.0–82.5) 0.92 b
HCY, µmol/L 18.7 (11.9–32.7) 14.4 (7.4–25.6) 0.36 b
Cys-C, mg/L 4.9 (3.1–7.4) 1.6 (1.4–9.3) 0.04 b
KIM-1, pg/ml 420.0 (297.5–540.0) 560.0 (380.0–798.0) 0.04 b
Creatinine, µmol/L 90.0 (69.0–105.5) 78.0 (49.0–128.0) 0.77 b
eGFRCKD-EPI ml/min per 1.73 m2 87.0 (60.5–115.0) 92.0 (58.0–146.0) 0.69 b
RARI 0.70 (0.67–0.73) 0.69 (0.62–0.71) 0.16 b
FMD, flow-mediated dilation.
aChi-squared test/Fisher’s exact test statistic was used to compare proportions.
bIndependent samples Mann–Whitney U test was used to compare the median.
cIndependent samples t test was used to compare the means.

Among subjects with SCD and FMD<5.35, serum Cys-C levels were significantly higher in those with urine albumin-to-creatinine ratio (UACR) >300 mg/g (13.4; IQR, 1.6–13.4) than in those with UACR=30–300 mg/g (6.4; IQR, 5.6–10.5) and those with UACR<30 mg/g in that order (3.4; IQR, 2.1–5.0) (Figure 1) with P=0.006. In this subgroup, there was significant correlation between FMD and UACR (r=0.576; P=0.001), between FMD and serum creatinine levels (r=0.418; P=0.02), between FMD and eGFRCKD-EPI levels (17) (r=0.430; P=0.02), and between FMD and serum sP-selectin levels (r=0.389; P=0.04) (Table 4). However, in subjects with FMD≥5.35, there was no significant difference in serum Cys-C levels on the basis of their UACR values (Figure 1) (P=0.53). In addition, there was no significant correlation between FMD and UACR, serum creatinine levels, eGFRCKD-EPI, or sP-selectin (Table 4).

Figure 1.:
Clustered box plot showing the distribution of cystatin C (Cys-C) levels in subjects with sickle cell disease (SCD) on the basis of the flow-mediated dilation (FMD) category and the urine albumin-to-creatinine ratio (UACR) category. Higher levels of Cys-C were shown in those with FMD <5.35 in the 3 UACR categories.
Table 4. - Spearman correlation of Cys-C with other variables in the two groups of subjects with SCD
Groups UACR, mg/g Creatinine, µmol/L GFR, ml/min per 1.73 m2 sP-selectin, ng/ml RARI KIM-1, pg/ml
Subjects with FMD<5.35
 Spearman’s Rho 0.576 0.418 0.430 0.389 0.129 0.032
P value 0.001 0.02 0.02 0.04 0.51 0.87
Subjects with FMD≥5.35
 Spearman’s Rho −0.232 −0.268 0.352 −0.396 −0.059 0.566
P value 0.41 0.34 0.20 0.14 0.83 0.03

No significant correlation was observed between Cys-C and RARI in both subjects with FMD<5.35 and those with FMD≥5.35 (Table 4).


ED has been implicated in the chronic arterial vasculopathy seen in patients with SCD, which is said to be responsible for diverse multiorgan pathologies (18). Ultrasonography has proven to be useful in assessing vasculopathic changes of the cerebral arteries (19,20), renal arteries (21,22), and femoral arteries (23) in SCD. In contrast to these arteries, which reflect changes to localized regions of the body, FMD of the brachial artery has the advantage of giving an overview of the overall vascular health of the body.

Several possible etiologies have been proposed for ED in SCD, including abnormal shear-stress–mediated vasodilation (24), adhesion, and interaction between sickled red blood cells (SRBCs) and endothelial cells; SRBC membrane stiffness; hypoxia; nitric oxide deficiency; blood hyperviscosity; and renal function (10,25262728–29).

FMD, from this study, was significantly lower in patients with SCD than in controls. This corroborates with the findings in Indians (6,10,30). The mean ages of the sample populations were similar to this study (25.39±6.14 years old; sample size =44). In the study by Raghuwanshi and Raghuvanshi (30), men =24.41±6.59 years old, and women =25.00±7.56 years old (sample size =25). In the study by Zawar et al. (10), mean age was 23.15±5.27 years old (sample size =37), and in the study by Al-Janabi et al. (6), mean age was27.0±8.9 years old (sample size =30). However, Hadeed et al. (9) in France studied 30 younger children with SCD (mean age of 12.3±4.5 years old) and found no significant difference in FMD between the patients with SCD and age- and sex-matched controls, concluding that manifestations of ED may be more evident in life as the disease progresses. However, their finding was at variance with that of an earlier French study (8) in children (mean age =10.4±3.3 years old; sample size =21), which reported that FMD was significantly lower in children with sickle cell anemia than in controls and that it did not correlate with age (8). Hadeed et al. (9) also reported, as we found in our study, no correlation between FMD and age. Given the mean age in all of these studies, it is conceivable to surmise that increasing age might play a role in the advent of ED in SCD, although further studies designed purposely to address that question are desirable.

Regarding the relationship among FMD, RARI, and biochemical parameters of renal function, we observed a statistically significant negative correlation between FMD and Cys-C along with RARI. Furthermore, Cys-C was significantly higher in subjects with SCD and FMD<5.35 than in those with FMD≥5.35. These findings suggest that patients with SCD and impaired FMD are more likely to have impaired renal function, buttressing similar observations by Tharaux (31) and Ataga et al. (29). Albuminuria, an early marker of renal injury, which was used by Ataga et al. (29), has several causes other than impaired renal function and may not be a reliable marker of renal function compared with the use of Cys-C, which was used in our study. Ataga et al. (29) examined the FMD in 23 subjects with SCD and varying degrees of albuminuria, and they found that UACR and serum endothelin-1 levels were inversely correlated with FMD. They concluded that their study established an association of albuminuria with ED in SCD and that elevated serum endothelin-1, by mediating ED, may be contributory to SCD-related glomerulopathy (29). We noted a strong positive correlation between UACR and serum Cys-C in subjects with FMD<5.35 and none in those with FMD≥5.35. To the best of our knowledge, our study is the first to report a significant relationship between FMD and Cys-C along with RARI in SCD. This finding may imply that, because biomarkers of renal function correlate with FMD in SCD, whereas other biomarkers of SCD disease severity do not, monitoring and management of renal function will be critical in SCD to preserve FMD and prevent ED. Although RARI is a proven tool for evaluating various renal diseases (3233–34), it should also be noted that RARI is also an indicator of cardiovascular outcome (35). In a study by Ikee et al (36), biochemical and histopathologic parameters showed statistically significant correlations with RI. However, stepwise multiple regression analysis showed that only atherosclerosis was chosen as an independent risk factor for increased RI. The consistent renal Doppler finding in SCD across the board has been a statistically significant elevated intrarenal arteries RI above those of HbAA controls, with a reported a sensitivity of 100% and a specificity of 66.7% for RI>0.70 in detecting increased resistance within the intrarenal arteries of patients with HbSS (21,37).

Our study did not demonstrate any relationship between serum creatinine, a biomarker of renal function, and FMD. The discordance in the relationship between Cys-C and creatinine with FMD, relating to glomerular filtration, may be because, although Cys-C is freely filtered by the glomerular membrane, it is neither reabsorbed nor secreted in the kidney tubular system, unlike creatinine (38). Similarly, no relationship was noted between eGFR and FMD. These findings may be because serum creatinine is less sensitive to renal function derangement than serum Cys-C (39). Additionally, Coll et al. (40) noted that serum creatinine started to increase above normal values when GFR was 75 ml/min per 1.73 m2 in contrast to serum Cys-C, which started to rise at a higher GFR value of 88 ml/min per 1.73 m2. In this study, the median eGFR was 87 ml/min per 1.73 m2.

KIM-1 is released by proximal tubular cells in response to acute ischemic or hypoxic injury to the kidney (41). In this study, it was significantly higher in the group with FMD≥5.35 than in those with FMD<5.35. This might reflect acute ischemic (or hypoxic) kidney injury that predates the more chronic ED.

Hypoxia, resulting from chronic anemia, in SCD has also been shown to be a marker of disease severity (42,43). Hemoglobin concentration, however, did not show any significant correlation with FMD (Table 2).

As renal impairment worsens, the prevalence of anemia increases, which affects nearly all patients with stage 5 CKD (44). Erythropoietin, which is produced by the kidneys and responsible for stimulation of erythropoiesis, is decreased in CKD and thus, accountable for anemia (Figure 2) (45). Sherwood et al. (46) confirmed that patients with SCD had reduced erythropoietin levels in comparison with a control population. Tissue ischemia and infarction resulting from vascular occlusion in SCD are primarily due to the microvascular obstruction by SRBC, although vasculopathic changes in larger vessels are also known to affect the kidneys (Figure 2) (23,47,48).

Figure 2.:
A chart showing the relationship between renal impairment and sickle cell disease pathophysiologic processes.

Circulating microparticles found in patients with end stage renal failure have been associated with ED, which is a significant determinant of cardiovascular risk (49). Likewise, ED has been established in our study and others to be associated with SCD as a result of the endothelial damage and intima hyperplasia (6,10,47). As the disease progresses in SCD and ED worsens along with anemia, renal function depreciates, which further compounds on the degree of endothelial function in a vicious cycle (Figure 2).

Vasculopathy in SCD has been well documented, especially regarding the cerebral arteries. Because SCD, through its complex pathophysiologic processes, results in arterio-occlusive disease, which could result in renal failure due to ischemia, renal failure could also, in addition, contribute to the compromised blood flow by compromising substantial artery compliance (Figure 2) (50).

Other biomarkers of disease severity in subjects with SCD (Table 2) did not show any significant relationship with FMD. HbF is the most potent modulator of the clinical and hematologic features in SCD. Higher HbF levels were associated with a reduced rate of acute painful episodes and fewer leg ulcers along with reduced SCD severity (51). Endothelial sP-selectin plays a crucial role in leukocyte recruitment as well as the adhesion of SRBC to the endothelium, ultimately leading to an impairment of microvascular circulation involved in the development of painful vaso-occlusion (5253–54). HCY, which is elevated in SCD in this study (Table 1) and other studies (55), is a strong risk factor for atherosclerotic disease in the peripheral arteries along with arterial thromboembolism (56). HbF, sP-selectin, and HCY showed no correlation with FMD (Table 2).

Only subjects with homozygous SCD were recruited in this study in steady state. Further studies in subjects with heterozygous SCD and also, in subjects with SCD in vaso-occlusive crisis would add to the body of knowledge regarding FMD in the disease.

In conclusion, brachial artery FMD is an essential test in the management of patients with SCD for noninvasive assessment of the vascular endothelium status. There is a relationship between FMD, RARI, and Cys-C in patients with SCD such that impairment of FMD could also be a proxy marker for the onset of renal impairment in this group of patients. Even though our findings show relationships rather than causation, we believe that they are still a step forward in the ongoing quest to unravel the mysteries of this genetic disease. Determining the exact age at which FMD impairment sets in children with SCD could be the subject of a future study.


A. Aderibigbe, O. Ayoola, R. Bolarinwa, B. Idowu, and C. Onwuka have nothing to disclose.


We acknowledge the management of the Obafemi Awolowo University Teaching Hospital, Ile-Ife, Osun State, Nigeria, for partly funding this project.

Author Contributions

O. Ayoola conceptualized the study and was responsible for the investigation, methodology, and project administration; O. Ayoola, R. Bolarinwa, B. Idowu, and C. Onwuka were responsible for writing the original manuscript, and reviewed and edited the manuscript; R. Bolarinwa was responsible for investigation and methodology; C. Onwuka was responsible for the formal analysis; and A. Aderibigbe reviewed and edited the manuscript.


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Clinical Nephrology; Anemia, Sickle Cell; Biomarkers; Brachial artery; Creatinine; CST3 protein, human; Cystatin C; Endothelial dysfunction; Fetal Hemoglobin; Flow mediated dilatation; P-Selectin; Renal artery resistivity index; Renal function; Sickle Nephropathy; Tertiary Care Centers

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