Abstract
Blacks, compared with whites, have an increased risk of progression to end-stage renal disease (ESRD). Emerging evidence suggests that, in addition to APOL1 high-risk genotypes, hemoglobin variants, including sickle cell trait (SCT) and hemoglobin C trait, have a role in kidney disease in blacks. However, the association between these hemoglobin traits and ESRD remains unknown. In a large population-based cohort, the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, we evaluated 9909 self-reported blacks (739 with SCT and 243 with hemoglobin C trait). Incident ESRD occurred in 40 of 739 (5.4%) individuals with SCT, six of 243 (2.5%) individuals with hemoglobin C trait, and 234 of 8927 (2.6%) noncarriers. The incidence rate for ESRD was 8.5 per 1000 person-years for participants with SCT and 4.0 per 1000 person-years for noncarriers. Compared with individuals without SCT, individuals with SCT had a hazard ratio for ESRD of 2.03 (95% confidence interval, 1.44 to 2.84). Hemoglobin C trait did not associate with prevalent CKD or ESRD. The incidence rate for ESRD among participants with APOL1 high-risk genotypes was 6.6 per 1000 person-years, with a hazard ratio for ESRD of 1.77 (95% confidence interval, 1.31 to 2.38) for participants with, compared with those without, APOL1 high-risk genotypes. In this cohort, SCT strongly associated with risk of progression to ESRD in blacks, and this degree of risk for ESRD was similar to that conferred by APOL1 high-risk genotypes. These results may have important public policy implications for genetic counseling of SCT carriers.
Keywords: end stage kidney disease, genetic renal disease, epidemiology and outcomes
Blacks have a three- to five-fold increased risk of end-stage renal disease (ESRD) compared with whites.1 This disproportionate burden of ESRD appears to relate to a higher rate of progression of CKD to advanced-stage kidney disease, rather than an increased risk of CKD alone.2,3 Socioeconomic, lifestyle, and clinical factors only partially explain this observed racial disparity in CKD,4 suggesting that genetic variation likely plays a considerable role in the progression of kidney disease in blacks.
APOL1 high-risk genotypes, which are present in about 11%–13% of blacks and are thought to confer resistance to certain trypanosomal infections in African-ancestry populations, are the most widely recognized genetic contributors to the risk of ESRD progression in blacks.5 However, it has recently been recognized that another African ancestral genetic variant, sickle cell trait (SCT), may also be an important risk factor for CKD in this population.6 Similar to APOL1 high-risk genotypes, SCT is common, occurring in 8%–9% of blacks, and is thought to have evolutionarily persisted due to its strong protective effect against malaria in endemic regions.7 Despite emerging evidence of the association between SCT and CKD in blacks, the risk of progression to ESRD in SCT carriers has yet to be established.6,8,9 In addition, prevalence studies have suggested a possible association between kidney disease and hemoglobin C trait, another common hemoglobin variant,8 but prospective studies have not been performed.
Using a large, geographically diverse cohort of blacks in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, we sought to determine whether SCT and hemoglobin C trait contribute to prevalent CKD and incident ESRD risk. In addition, we aimed to characterize the gene-gene interaction between APOL1 renal risk variants and hemoglobin S/C trait to the risk of kidney disease.
Results
Baseline Characteristics
After exclusion of participants with missing data on genotypes for hemoglobin S, C, or APOL1 renal risk variants (n=306), missing relevant covariate (n=166) or outcome data (n=413), and those with hemoglobin SS or SC disease (n=6), 9909 black individuals were included in the primary analysis. The baseline characteristics of these participants are described in Table 1. The prevalence of SCT and hemoglobin C trait was 7.5% (n=739) and 2.5% (n=243), respectively. There were no significant differences in age, sex, hypertension, diabetes, smoking, and socioeconomic status between SCT, hemoglobin C trait carriers, and noncarriers. APOL1 high-risk genotypes were present in 12.8% (n=1142) of individuals, with similar prevalence of APOL1 high-risk genotype among hemoglobin trait groups. Baseline mean eGFR was significantly lower and median urine albumin-to-creatinine ratio (UACR) significantly higher among SCT carriers compared with noncarriers (P<0.001 and P<0.001, respectively).
Table 1.
Baseline characteristics, by hemoglobin trait statusa
| Characteristics | Noncarriers | SCT | Hemoglobin C Trait |
|---|---|---|---|
| Demographics | |||
| N (% total sample) | 8927 (90) | 739 (7.5) | 243 (2.5) |
| Mean age (SD) | 64.0 (9.2) | 63.5 (9.2) | 64.1 (9.6) |
| Women, N (%) | 5473 (61.4) | 474 (64.1) | 157 (64.6) |
| Education, N (%) | |||
| Less than high school | 1735 (19.5) | 138 (18.7) | 46 (18.9) |
| High school graduate | 2464 (27.7) | 209 (28.3) | 56 (23.1) |
| Some college | 2378 (26.7) | 208 (28.2) | 73 (30.0) |
| College graduate and above | 2331 (26.2) | 184 (24.9) | 68 (27.9) |
| Income/yr, N (%) | |||
| <$20,000 | 2357 (30.0) | 216 (33.0) | 52 (24.8) |
| $20,000–34,999 | 2356 (30.0) | 191 (29.2) | 67 (31.9) |
| $35,000–74,999 | 2312 (29.5) | 174 (26.6) | 73 (34.8) |
| ≥$75,000 | 824 (10.5) | 73 (11.2) | 18 (8.57) |
| Comorbidities, N (%) | |||
| Hypertension | 6363 (71.3) | 514 (69.6) | 181 (74.5) |
| Diabetes | 2586 (29.0) | 222 (30.0) | 78 (32.1) |
| Smoking | 1558 (17.5) | 128 (17.3) | 45 (18.5) |
| APOL1 high-risk genotype | 1142 (12.8) | 89 (12.0) | 30 (12.3) |
| Renal markers | |||
| Mean eGFR (SD) | 89.4 (23) | 84.8 (24)b | 88.9 (24) |
| Median UACR (IQR) | 7.62 (4.5–18.7) | 11.47 (5.4–36.4)b | 8.57 (4.5–22) |
SCT, sickle cell trait; UACR, spot UACR; IQR, interquartile range.
Values listed on the basis of available included data; not all characteristics were available in all participants.
Unadjusted P value for difference between SCT and noncarriers was <0.001.
Association of SCT, Hemoglobin C Trait, and APOL1 High-Risk Genotypes with CKD and ESRD
Prevalent CKD was present in 272 of 739 (36.8%) individuals with SCT and 63 of 243 (25.9%) participants with hemoglobin C trait, compared with 2244 of 8927 (25.1%) blacks with neither SCT nor hemoglobin C trait. After adjusting for age, sex, smoking status, diabetes, hypertension, and APOL1 high-risk genotype status, individuals with SCT had an increased risk of prevalent CKD compared with those without SCT (odds ratio [OR], 1.89; 95% confidence interval [95% CI], 1.59 to 2.23) (Table 2). Hemoglobin C trait was not associated with increased odds of prevalent CKD (OR, 0.97; 95% CI, 0.71 to 1.31).
Table 2.
Association of SCT and hemoglobin C trait with prevalent CKD and incident ESRD
| Variables | Noncarriers | SCT | Hemoglobin C Trait |
|---|---|---|---|
| Prevalent CKD | |||
| N (%) | 2244 (25.1) | 272 (36.8) | 63 (25.9) |
| Adjusted OR (95% CI) | 1.00 (ref) | 1.89 (1.59 to 2.23) | 0.97 (0.71 to 1.31) |
| Incident ESRD | |||
| N (%) | 234 (2.6) | 40 (5.4) | 6 (2.5) |
| Incidence rate (N/1000 person-yr) | 4.0 | 8.5 | 3.9 |
| Adjusted HR (95% CI) | 1.00 (ref) | 2.03 (1.44 to 2.84) | 0.82 (0.36 to 1.84) |
Prevalent CKD was defined as a baseline eGFR<6 0ml/min per 1.73 m2 and/or UACR≥30 mg/g. All models were adjusted for age, sex, smoking, diabetes, hypertension, and APOL1 high-risk genotype status. SCT, sickle cell trait; ref, reference.
The median follow-up for ESRD was 6.49 years. The incidence rate for ESRD was 8.5 per 1000 person-years for blacks with SCT compared with 3.9 per 1000 person-years for hemoglobin C trait and 4.0 per 1000 person-years for noncarriers. The adjusted hazard ratio (HR) for ESRD comparing individuals with SCT to those without SCT was 2.03 (95% CI, 1.44 to 2.84) (Table 2). Hemoglobin C trait was not associated with an increased risk of incident ESRD (HR, 0.82; 95% CI, 0.36 to 1.84).
In sensitivity analyses adjusting for principal components of ancestry, the prevalence and incidence of CKD and ESRD among SCT, hemoglobin C carriers, and noncarriers were the same as in the overall cohort. In this subcohort, risk estimates additionally adjusting for genetic ancestry yielded similar results for risk of CKD and ESRD for both SCT and hemoglobin C trait analyses as in the overall cohort (Table 3).
Table 3.
Association of SCT and hemoglobin C trait with prevalent CKD and incident ESRD after adjustment for PCA
| Variables | Noncarriers | SCT | Hemoglobin C Trait |
|---|---|---|---|
| Prevalent CKD | |||
| N (%) | 1601 (24.9) | 193 (37.6) | 41 (23.9) |
| Adjusted OR (95% CI) | 1.00 (ref) | 1.93 (1.57 to 2.37) | 0.81 (0.55 to 1.21) |
| Incident ESRD | |||
| N (%) | 143 (2.13) | 26 (4.85) | 3 (1.67) |
| Incidence rate (N/1000 person-yr) | 3.9 | 10.0 | 3.9 |
| Adjusted HR (95% CI) | 1.00 (ref) | 2.38 (1.57 to 3.61) | 0.81 (0.30 to 2.20) |
Prevalent CKD was defined as a baseline eGFR<6 0ml/min per 1.73 m2 and/or UACR≥30 mg/g. All models were adjusted for age, sex, smoking, diabetes, hypertension, APOL1 high-risk genotype status, and were additionally adjusted for PCA in this subset. PCA, principal components of ancestry; SCT, sickle cell trait; ref, reference.
APOL1 high-risk genotypes were present in 12.8% of blacks without SCT or hemoglobin C trait, 12.0% of those with SCT, and 12.3% of individuals with hemoglobin C trait. The incidence rate for ESRD among individuals with APOL1 high-risk genotypes was 6.6 per 1000 person-years compared with 3.8 per 1000 person-years in those without high-risk genotypes. In the adjusted model, blacks with APOL1 high-risk genotypes had 1.28 (95% CI, 1.1 to 1.4) higher odds of prevalent CKD, and a 1.77 (95% CI, 1.3 to 2.4) higher hazard of incident ESRD compared with those without high-risk genotypes.
Interaction of SCT and Hemoglobin C Trait with APOL1 Variants
In order to assess the interaction between hemoglobin variants and APOL1 high-risk genotypes, we performed a stratified analysis of prevalent CKD in individuals with and without APOL1 high-risk genotypes (Table 4). SCT did not interact with APOL1 high-risk genotypes in either the main model or in the sensitivity analysis (P-interaction, 0.14 and 0.29, respectively).
Table 4.
Association of SCT and hemoglobin C trait with prevalent CKD, by APOL1 high-risk genotype status
| Variables | Noncarriers | SCT | Hemoglobin C Trait |
|---|---|---|---|
| With APOL1 high-risk variants | |||
| N (%) | 324 (28.4) | 30 (33.7) | 15 (50.0) |
| Adjusted OR (95% CI) | 1.00 (ref) | 1.29 (0.80 to 2.09) | 2.60 (1.21 to 5.58) |
| Without APOL1 high-risk variants | |||
| N (%) | 1920 (24.7) | 242 (37.2) | 48 (22.5) |
| Adjusted OR (95% CI) | 1.00 (ref) | 2.00 (1.67 to 2.39) | 0.86 (0.57 to 1.14) |
Prevalent CKD was defined as a baseline eGFR<60 ml/min per 1.73 m2 and/or UACR≥30 mg/g. “With APOL1 high-risk variants” was defined as individuals with two renal risk variants, G1/G1, G2/G2, or G1/G2, such that “Without APOL1 high-risk variants” refers to those with either 0 or one renal risk variant. All models were adjusted for age, sex, smoking, diabetes, and hypertension. SCT, sickle cell trait; ref, reference.
Coinheritance of hemoglobin C trait and APOL1 high-risk genotypes did appear to interact to further potentiate the risk of prevalent CKD (P-interaction, 0.003). Subset analysis adjusting for principal components of ancestry, however, attenuated the strength of this interaction (P-interaction, 0.03), with confidence intervals that overlapped between the APOL1 strata (Table 5). Neither SCT nor hemoglobin C trait demonstrated significant interaction with the presence of only a single APOL1 renal risk allele (data not shown).
Table 5.
Association of SCT and hemoglobin C trait with prevalent CKD after adjustment for PCA, by APOL1 high-risk genotype status
| Variables | Noncarriers | SCT | Hemoglobin C Trait |
|---|---|---|---|
| With APOL1 high-risk variants | |||
| N (%) | 239 (28.8) | 22 (36.6) | 9 (42.8) |
| Adjusted OR (95% CI) | 1.00 (ref) | 1.33 (0.73 to 2.43) | 1.98 (0.77 to 5.12) |
| Without APOL1 high-risk variants | |||
| N (%) | 1362 (24.4) | 171(37.5) | 32 (21.3) |
| Adjusted OR (95% CI) | 1.00 (ref) | 2.02 (1.62 to 2.51) | 0.67 (0.43 to 1.04) |
Prevalent CKD was defined as a baseline eGFR<60 ml/min per 1.73 m2 and/or UACR≥30 mg/g. “With APOL1 high-risk variants” was defined as individuals with two renal risk variants, G1/G1, G2/G2, or G1/G2, such that “Without APOL1 high-risk variants” refers to those with either 0 or one renal risk variant. All models were adjusted for age, sex, smoking, diabetes, hypertension, and were additionally adjusted for PCA in this subset. PCA, principal components of ancestry; SCT, sickle cell trait; ref, reference.
Subgroup Analyses by Baseline Hypertension, Diabetes, and Socioeconomic Status
There were no significant interactions between hemoglobin C trait and hypertension, diabetes, income, or education on the risk of prevalent CKD (data not shown). SCT also did not confer a differential risk among the subgroups defined by diabetes, income, or education. However, the association of SCT with prevalent CKD differed significantly by hypertension status (P-interaction, 0.01). Specifically, as shown in Table 6, among individuals with hypertension, SCT carriers had 1.63-fold (95% CI, 1.34 to 1.98) increased odds of prevalent CKD compared with noncarriers, whereas among those without hypertension, SCT was associated with a considerably higher risk of prevalent CKD (OR, 2.94; 95% CI, 2.09 to 4.12) compared with those without SCT. This interaction between SCT and hypertension status for prevalent CKD remained significant on sensitivity analysis adjusting for principal components of ancestry (P-interaction, 0.01; Table 7).
Table 6.
Association of SCT with prevalent CKD, by hypertension status
| Variables | Noncarriers | SCT |
|---|---|---|
| With hypertension | ||
| N (%) | 1944 (30.6) | 208 (40.5) |
| Adjusted OR (95% CI) | 1.00 (ref) | 1.63 (1.34 to 1.98) |
| Without hypertension | ||
| N (%) | 324 (12.6) | 58 (25.8) |
| Adjusted OR (95% CI) | 1.00 (ref) | 2.94 (2.09 to 4.12) |
Prevalent CKD was defined as a baseline eGFR<60 ml/min per 1.73 m2 and/or UACR≥30 mg/g. All models were adjusted for age, sex, smoking, diabetes, and APOL1 high-risk genotype status. SCT, sickle cell trait; ref, reference.
Table 7.
Association of SCT with prevalent CKD after adjustment for PCA, by hypertension status
| Variables | Noncarriers | SCT |
|---|---|---|
| With hypertension | ||
| N (%) | 1338 (29.4) | 137 (39.9) |
| Adjusted OR (95% CI) | 1.00 (ref) | 1.66 (1.31 to 2.11) |
| Without hypertension | ||
| N (%) | 217 (12.8) | 41 (28.6) |
| Adjusted OR (95% CI) | 1.00 (ref) | 3.25 (2.15 to 4.90) |
Prevalent CKD was defined as a baseline eGFR<60 ml/min per 1.73 m2 and/or UACR≥30 mg/g. All models were adjusted for age, sex, smoking, diabetes, APOL1 high-risk genotype status, and were additionally adjusted for PCA in this subset. PCA, principal components of ancestry; SCT, sickle cell trait; ref, reference.
Discussion
Blacks experience a substantially higher risk of progression to ESRD than whites, but this increased risk cannot be explained by environmental and clinical factors alone. Using a large, population-based cohort from throughout the contiguous United States, we found that SCT, a common hemoglobin variant in blacks, was associated with a two-fold higher risk of incident ESRD compared with noncarriers. This relationship was independent of known risk factors for ESRD, including age, hypertension, diabetes, and APOL1 high-risk genotype status. Our study demonstrates that SCT is not only a significant genetic risk factor for the development of ESRD in blacks, but also that it confers a similar degree of risk for ESRD as APOL1 high-risk genotypes, which are currently the most widely recognized genetic variant associated with kidney disease in this population.5,10
The disproportionate burden of ESRD among blacks appears to be due to a higher rate of progression of CKD to advanced-stage kidney disease, rather than increased risk of baseline CKD itself.2,3 Although SCT has been associated with CKD and albuminuria in prior large cohort analyses,6 cross-sectional studies of SCT and ESRD have demonstrated conflicting results. A study of black patients across four hemodialysis units showed a two-fold increased prevalence of SCT among blacks with ESRD compared with the expected prevalence in that region.8 However, a subsequent case-control study of blacks with ESRD and non-CKD controls failed to show an association with SCT.9 Differences in the design of these studies may have contributed to these disparate findings, potentially through confounding in selection and inadequate sample size. In addition, a previous meta-analysis of five large United States–based general population cohorts investigated the association of SCT and CKD in blacks and was unable to verify an association of SCT with ESRD because of a limited number of ESRD events in the available studies.6 In a large, prospective population-based cohort with linkage to United States Renal Data System (USRDS) data, we now demonstrate that SCT is not only associated with prevalent CKD but is also associated with progression to ESRD. SCT, therefore, importantly offers an additional genetic basis for the high risk of advanced-stage kidney disease in blacks, independent of APOL1.
Our findings have potentially far-reaching public policy implications. Routine SCT screening is currently performed in the United States as part of the Newborn Screening Program for sickle cell disease, which has been in effect in a majority of states since 1990 and in all 50 states since 2006.11,12 This is in stark contrast to APOL1 high-risk genotypes, for which testing is not generally performed in the clinical setting.13 Because individuals with SCT are identified soon after birth, genetic counseling about ESRD risk could allow for early CKD screening and risk factor modification such as smoking cessation, weight loss, hypertension/glucose control, and avoiding nephrotoxic agents. Further investigation is needed to assess whether these measures are effective in attenuating CKD risk in this population. In addition, individuals at high risk for SCT-related kidney disease may benefit from early intervention. Renal protective therapies such as angiotensin-converting enzyme inhibition and targeted sickle disease–modifying therapies such as hydroxyurea have shown efficacy in decreasing albuminuria in patients with sickle cell disease.14,15 Future studies will be required to determine if similar therapies are effective in SCT.
Although the pathophysiology of nephropathy in SCT is not yet understood, several mechanisms can be proposed on the basis of the sickle cell disease literature. Injection radiographs of the renal medulla have demonstrated vascular disruption in individuals with homozygous SS disease and SCT compared with those with normal hemoglobin, suggesting a common pathway of renal injury in both genotypes.16 In sickle cell disease, the hypoxic environment of the renal medulla leads to ischemic-reperfusion injury, release of vasoactive factors, hyperfiltration, and progressive glomerulosclerosis.17,18 An analogous mechanism may underlie the risk of progression to ESRD observed in adults with SCT.
Similar to prior studies,6,9 SCT and APOL1 renal risk variants did not demonstrate a gene-gene interaction to potentiate the risk of prevalent CKD in blacks in our analysis. By contrast, in a study of sickle cell disease, the presence of APOL1 high-risk genotypes conferred a three-fold increased risk of prevalent albuminuria assessed by dipstick evaluation.19 However, because APOL1 risk variants confer their greatest risk with progression of CKD,13 a potentiating effect of APOL1 in SCT-related nephropathy may only be apparent in the risk of eGFR decline or incident ESRD. We were unable to evaluate this in the current analysis due to relatively low numbers of ESRD events. Our study also suggests a potential interaction between hemoglobin C trait and APOL1 high-risk genotypes for prevalent CKD; however, this finding will need to be validated in other large cohorts.
APOL1 renal risk variants increase susceptibility to certain variants of glomerular disease, including hypertension-attributed nephropathy. Although the pathophysiologic cause of this entity was historically ascribed to hypertension itself, further studies have suggested that elevated BP is likely a secondary rather than initiating event in these cases.20,21 In this study, SCT was associated with substantially higher odds of CKD among nonhypertensive blacks compared with those with hypertension. Individuals with sickle cell disease have lower BPs than race-matched controls, and although the reasons for this are unclear, it is speculated that this relative hypotension may be due to impaired urinary concentrating ability and urinary sodium loss from progressive renal tubular damage.22,23 This hypothesized mechanism suggests that relative hypotension may be a symptom of renal dysfunction in SCT individuals, similar to hypertension in APOL1-related nephropathy, but whether SCT-related nephropathy results in the same pathophysiologic changes as sickle cell disease is unknown. In our study, we did not have biopsy or clinical data to determine the cause of CKD. Further studies are required to confirm this observation and to determine the role of SCT in progression of disease-specific nephropathies.
The strengths of our study include the large, population-based sample of blacks with extensive data on measured risk factors, including direct genotyping for both APOL1 and hemoglobin S/C variants. We also had robust phenotypic outcomes including linkage to USRDS ESRD data. Our study does have limitations. We did not have alternate measures of kidney function decline such as incident CKD in the current analysis. In addition, we did not have data on genetic ancestry within the entire cohort; however, a sensitivity analysis using a large subset of our sample with available data revealed similar results as the primary analyses.
In conclusion, in a large, population-based study of blacks from throughout the contiguous United States, SCT was associated with two-fold increased risk of progression to ESRD. This degree of risk for ESRD was similar to that conferred by APOL1 high-risk genotypes in a general black population. Unlike APOL1, testing for SCT is widely performed in newborn screening programs, in athletics, and in pregnancy counseling, therefore, these findings may have immediate implications for policy and treatment recommendations in SCT.
Concise Methods
Study Population
The REGARDS cohort is a large, population-based cohort of black and white American adults of age≥45 years, designed to investigate stroke epidemiology in the United States. This study is described in detail elsewhere.24 In brief, a total of 30,239 participants from the 48 contiguous United States were enrolled in the study between January of 2003 and October of 2007. The study oversampled blacks and individuals from the stroke belt region (North Carolina, South Carolina, Georgia, Tennessee, Mississippi, Alabama, Louisiana, and Arkansas). All participants provided informed consent, and the REGARDS study was approved by the Institutional Review Boards of the participating centers.
Genotypic Assessment
All self-reported black participants consenting to genetic research were genotyped for SCT, hemoglobin C trait, and APOL1 renal risk variants (G1 and G2). Genotyping for the primary exposure variables, hemoglobin S (HbS) and hemoglobin C (HbC), was performed using TaqMan SNP Genotyping Assays (Applied Biosystems/Thermo Fisher Scientific) as previously described.6 A subset of genotyped samples (hemoglobin S: 244 homozygous normal and 15 heterozygotes; hemoglobin C: 273 homozygous normal and six heterozygotes) was selected for DNA sequencing on an Applied Biosystems 3730 DNA Sequencer and all sequence results were 100% concordant with the TaqMan allele calls. Individuals with hemoglobin SS, SC, or CC genotypes were excluded from further analysis. APOL1 high-risk genotype was defined as the presence of two renal risk variants, G1/G1, G2/G2, or G1/G2. A subset of participants had available genomic array data (Illumina exome chip) to estimate population substructure (n=6714).25 In sensitivity analyses, principal components of ancestry were generated by Eigenstrat to adjust for ancestry in this subset.26
Covariate and Outcome Assessment
Baseline REGARDS study data were collected via telephone interview, self-administered questionnaire, and in-home examination. Computer-assisted telephone interviews administered by trained staff were used to collect information on participant age, smoking status, education, and self-reports of prior physician-diagnosed comorbid conditions. Trained health professionals conducted in-home examinations, which included height, weight, and BP measurements, collection of blood and spot urine samples, and review of medication pill bottles.
Hypertension was defined by a baseline BP≥140/90 mmHg or the self-reported use of antihypertensive medication. Diabetes was defined by a fasting serum glucose ≥126 mg/dl, nonfasting glucose ≥200 mg/dl, or the use of antidiabetes medications. Socioeconomic status was defined by education and income. Education was categorized as less than high school, high school graduate, some college, or college graduate and above. Income was categorized as <$20,000/yr, $20,000 to $34,999/yr, $35,000 to $74,999/yr, or ≥$75,000/yr.
Serum creatinine was measured by colorimetric reflectance spectrophotometry and calibrated to an international isotope dilution mass spectroscopic–traceable reference standard. eGFR was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation.27 Spot UACR was measured by nephelometry (BN ProSpec Nephelometer; Dade Behring, Marburg, Germany) and by a Modular-P chemistry analyzer (Roche/Hitachi, Indianapolis, IN).
Prevalent CKD was defined as a baseline eGFR<60 ml/min per 1.73 m2 and/or UACR≥30 mg/g. Incident ESRD was defined by linkage of the cohort to USRDS through 2013.28 Individuals with ESRD at baseline were excluded.
Statistical Analyses
Logistic regression was used to calculate ORs and 95% CIs of prevalent CKD associated with hemoglobin S or C carrier status, and Cox regression was used to calculate the HRs of incident ESRD. All analyses were adjusted for age, sex, smoking, hypertension, diabetes, and APOL1 high-risk genotype status. We did not adjust for baseline eGFR as we conceptualized it as part of the causal pathway. We tested for an interaction between SCT or hemoglobin C trait and APOL1 high-risk genotypes in relation to prevalent CKD by adding an interaction term to the regression model and by performing stratified analysis. Interaction analyses were not performed on incident ESRD because of a relatively low number of events. To account for underlying genetic population structure in blacks that might confound the association between SCT, hemoglobin C, or APOL1 renal risk variants and kidney outcomes, we also performed a sensitivity analysis using the subset of the sample with available array genotypic data to adjust for global African ancestry using the first ten principal components as described above. In addition, analyses stratified by baseline hypertension, diabetes, and socioeconomic status were evaluated.
Disclosures
None.
Acknowledgments
We thank Victor David and Elizabeth Binns-Roemer for excellent technical support.
The REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort is supported by cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Department of Health and Human Services. This work was also supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program, NIH, Bethesda, and was funded, in part, with federal funds from the National Cancer Institute, NIH, under contract HHSN26120080001E. This work was also funded in part by National Heart, Lung, and Blood Institute grant K08HL12510 (R.P.N.) and grant K08HL096841 (N.A.Z.).
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the NIH. Representatives of the funding agency have been involved in the review of the manuscript but not directly involved in the collection, management, analysis, or interpretation of the data. A full list of participating REGARDS investigators and institutions can be found at http://www.regardsstudy.org. The authors thank the other investigators, the staff, and the participants of the REGARDS study for their valuable contributions. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States government.
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
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