Association of Sickle Cell Trait With Chronic Kidney Disease and Albuminuria in African Americans

Sickle cell anemia (SCA) is a common hematological disorder among individuals of African descent in the United States; the disorder results in the production of abnormal hemoglobin. It is caused by homozygosity for a genetic mutation in HBB; rs334. While the presence of a single mutation (sickle cell trait, SCT) has long been considered a benign trait, recent research suggests that SCT is associated with renal dysfunction, including a decrease in estimated glomerular filtration rate (eGFR) and increased risk of chronic kidney disease (CKD) in African Americans. It is currently unknown whether similar associations are observed in Hispanics. Therefore, our study aimed to determine if SCT is associated with mean eGFR and CKD in a sample of 340 Dominican Hispanics from the Northern Manhattan Study. Using regression analyses, we tested rs334 for association with eGFR and CKD, adjusting for age and sex. eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation and CKD was defined as eGFR < 60 mL/min/1.73 m2. Within our sample, there were 16 individuals with SCT (SCT carriers). We found that SCT carriers had a mean eGFR that was 12.12 mL/min/1.73m2 lower than non-carriers (P=.002). Additionally, SCT carriers had 2.72 times higher odds of CKD compared with non-carriers (P=.09). Taken together, these novel results show that Hispanics with SCT, as found among African Americans with SCT, may also be at increased risk for kidney disease.Ethn Dis. 2017; 27(1):11-14; doi:10.18865/ed.27.1.11.

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Cardiovascular Outcomes in African Americans with Sickle Cell Trait and Chronic Kidney Disease

American Journal of Nephrology ◽

10.1159/000496058 ◽

2019 ◽

Vol 49 (2) ◽

pp. 93-102 ◽

Cited By ~ 3

Author(s):

Kabir O. Olaniran ◽

Nwamaka D. Eneanya ◽

Andrew S. Allegretti ◽

Sophia H. Zhao ◽

Maureen M. Achebe ◽

...

Keyword(s):

Chronic Kidney Disease ◽

African American ◽

Cardiovascular Risk ◽

African Americans ◽

Kidney Disease ◽

Sickle Cell ◽

Sickle Cell Trait ◽

Increased Risk ◽

The Mean

Background: Sickle cell trait (SCT) is common among African Americans and has been historically considered to be benign. Recently, SCT has been associated with an increased risk for chronic kidney disease (CKD) and cardiovascular disease in the general population. Our understanding of SCT has been extrapolated largely from data of patients with sickle cell disease (SCD). Notably, in SCD, the outcomes differ by sex. The effect of SCT on cardiovascular risk in the African American CKD population is unknown, and the interaction between SCT and sex on cardiovascular risk has not been investigated. Methods: We performed a 2-center retrospective cohort study of all African American patients with SCT using international classification of disease diagnosis codes and CKD (using the 2012 Kidney Disease Improving Global Outcomes criteria) with at least 1 year of follow-up between January 2005 and December 2017. A reference group of African American CKD patients without SCT was used as a comparator during the same period. SCT patients and the reference patients were matched at baseline for age, sex, comorbidities, and proteinuria. Primary outcomes were incident coronary artery disease (CAD), incident stroke, and all-cause mortality. Analysis of effect modification between sex and SCT on primary outcomes was performed. Results: We identified 621 African American CKD patients, 217 SCT patients, and 404 reference patients. The mean age was 56 ± 13 years and 66% were female. The mean estimated glomerular filtration rate was 69 ± 30 mL/min. The mean follow-up time was 8 ± 4 years. There were no significant differences in the primary outcomes comparing SCT patients to matched controls. The interaction term between SCT and sex, however, was significant in the CAD model (p < 0.01). Stratification by sex showed no increased risk in females but a significantly increased risk for CAD in male SCT patients (hazard ratio [HR] 2.14; 95% CI 1.18–3.86), which persisted after multivariable analysis (HR 2.13; 95% CI 1.17–3.86). Conclusion: SCT is associated with an increased risk for CAD in African American males with CKD. The excess risk in males with SCT appears to follow the same pattern as risk in males with SCD. Larger studies are needed to confirm these findings.

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Abstract 342: A Description of Cardiac Outcomes in Patients With Sickle Cell Trait and Chronic Kidney Disease: Evaluated in a National Inpatient Data Sample

Circulation Cardiovascular Quality and Outcomes ◽

10.1161/hcq.13.suppl_1.342 ◽

2020 ◽

Vol 13 (Suppl_1) ◽

Author(s):

Samuel I Ogbuchi ◽

Temidayo Abe ◽

Kapil Bhatia ◽

Leondus S McIver ◽

Michelle Lee ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Risk Factor ◽

Kidney Disease ◽

Sickle Cell ◽

Sickle Cell Trait ◽

Sudden Cardiac Arrest ◽

Protective Role ◽

Significant Difference ◽

Inflammatory State ◽

Overall Mortality

Introduction: Sickle cell trait (SCT) is an independent risk factor for chronic kidney disease (CKD). CKD is a well-established risk factor for progressive cardiovascular dysfunction. Sickle Cell trait has been noted to promote a persistent systemic pro-inflammatory state. This pro-inflammatory state could potentially increase the risk of systemic endothelial dysfunction when accompanied with other cardiotoxic conditions. We aim to investigate cardiovascular outcomes in patients with SCT and CKD, compared to SCT alone. Methods: Patients with CKD were identified in the National Inpatient Sample (NIS) database 2016 using the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM), and subsequently were divided into two groups, those with and without SCT. Both population sets were paired using 1:1 propensity score matching based on Age, Sex and co-morbidities to address potential confounding factors. Outcomes of interest were overall mortality, rates of stroke, sudden cardiac arrest (SCA) and cardiomyopathy. Results: Mean age of patients with CKD alone was 72.98 ± 13.2 years, while for CKD and SCT 56.68 ± 17.3 years. There was no significant difference between the two group in the rates of stroke (1.3% vs 1.0%; P= 0.125), and SCA (1.0% vs 1.1%; P= 0.841). Overall mortality (5.7% vs 2.2%; P<0.0001) and rates of cardiomyopathy (10.1% vs 2.9%; P<0.0001) were significantly lower in patients with CKD and SCT, compared to CKD alone. Multivariate logistic regression followed a similar trend, compared to those with CKD alone, the adjusted odds ratio (aOR) for overall mortality aOR; 0.625 (0.372-1.049) and cardiomyopathy aOR; 0.451 (0.293-0.696) were significantly lower in patients with CKD and SCT. Conclusion: Compared to patients with CKD alone, those with CKD and SCT have a lower risk for overall mortality and cardiomyopathy. Further studies are needed to replicate this finding and look at the possible protective role of SCT in patients with CKD.

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ID: 139: PROGRESSIVE GLOMERULAR DAMAGE IN SICKLE CELL TRAIT AND SICKLE CELL ANEMIA MOUSE MODELS

Journal of Investigative Medicine ◽

10.1136/jim-2016-000120.95 ◽

2016 ◽

Vol 64 (4) ◽

pp. 957.2-958

Author(s):

SL Saraf ◽

JR Sysol ◽

JA Arruda ◽

RF Machado ◽

VR Gordeuk ◽

...

Keyword(s):

Gene Expression ◽

African Americans ◽

Kidney Disease ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Sickle Cell Trait ◽

Linear Trend ◽

Mesangial Expansion ◽

Urine Protein ◽

Increased Risk

The hemoglobin S mutation, a glutamic acid to valine substitution in the β-globin chain, results in hemoglobin polymerization under hypoxic conditions and leads to vaso-occlusion and hemolysis. Homozygous inheritance (Hb SS; sickle cell anemia) affects 1 in 500 African Americans and is consistently associated with an increased risk for kidney disease which may be due to cell-free hemoglobin toxicity, ischemic injury, or hyperfiltration-mediated damage to the kidney. Heterozygous inheritance (Hb AS; sickle cell trait) affects 1 in 8 African Americans and has also been associated with an increased risk for kidney disease, although not in all cohorts and the mechanisms are not well understood.We investigated whether inheritance of the Hb S mutation resulted in incremental kidney damage in Hb AS and Hb SS mice compared to Hb AA mice by histology, proteinuria, and candidate gene expression using transgenic sickle mice ≥6 months of age (Townes model, Jackson Laboratory). Values are presented as mean±standard error and analyses are adjusted for age.Using Masson trichrome stained sections of the kidney, progressive patterns of mesangial expansion were observed in age-matched Hb AS and Hb SS mice versus Hb AA mice by renal pathologists blinded to the hemoglobin genotype (figure 1). Hb AS mice had diffuse (>50% of the glomeruli per slide being involved) mesangial expansion while Hb SS mice had diffuse and global (>50% of the individual glomerulus being involved) mesangial expansion. Glomerular perimeters were measured using NanoZoomer Whole Slide Imaging in 26 randomly selected glomeruli from 2 age-matched mice per genotype. Using the upper quartile as the definition for an enlarged glomerulus, the proportion of enlarged glomeruli progressively increased from Hb AA (15%) to Hb AS (31%) to Hb SS mice (58%) (Cochran's test of linear trend, P=0.001) (figure 2). Progressively higher kidney weights were also observed from Hb AA (429±28 mg, n=8) to Hb AS (446±27 mg, n=18) to Hb SS (567±19 mg, n=5) mice (Test for linear trend, P=0.047). We then measured urine protein and urine creatinine concentrations using the Bio-Rad dye method and Jaffé reaction, respectively. Progressively higher urine protein-to-creatinine ratios were observed from Hb AA to Hb AS to Hb SS mice (figure 3) (Test for linear trend, P=0.09). Gene expression of candidate genes (TGFB1, IL6, MMP9, Klotho, HMOX1, and SHROOM3) was determined by rt-PCR from kidneys of age-matched, female Hb AA and Hb AS mice (n=5). Increased expression of Klotho (P=0.09) was observed in Hb AS mice (figure 4). Klotho is a β-glucoronidase that is highly expressed in the kidney and acts as a cofactor that increases the affinity of the FGF23 ligand for the FGF receptor.In conclusion, we observed progressive glomerular injury, determined by mesangial expansion, proportion of enlarged glomeruli, and urine protein concentrations in Hb AS and Hb SS mice compared to Hb AA mice. Klotho was upregulated in Hb AS mice and may play a role in the pathophysiology of kidney damage in Hb AS which will require further investigation.Abstract ID: 139 Figure 1

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