Low prevalence of apolipoprotein L1 gene variants in Black South Africans with hypertension-attributed chronic kidney disease
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Variants in apolipoprotein L1 (APOL1) gene were shown to be associated with higher rates of nondiabetic kidney disease in black patients compared with white patients. Frequencies of these variants differ substantially in African populations, suggesting that their contribution to kidney disease might differ. We determined the frequency and association of (APOL1) risk alleles with markers of kidney disease in black South Africans with hypertension-attributed chronic kidney disease (CKD) and their first-degree relatives. Black patients with hypertension-attributed CKD with an estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73m2 were included, together with their first-degree relatives. G1 (rs60910145 and rs73885319) and G2: rs71785313 single nucleotide polymorphisms were genotyped by restriction fragment length polymorphism. Similar to previous association studies, we mainly tested recessive genetic models. The allele frequencies of both the G1 and G2 (APOL1) risk alleles were similar amongst all the groups. There was no difference in the two-risk-allele frequency in CKD patients (10%) compared to controls (8.6%), p = 0.790. Carriage of two (APOL1) risk alleles (vs. zero or one risk allele) was not a predictor of hypertension-attributed CKD (OR, 0.85; 95% CI, 0.25 - 2.83; p = 0.790). Patients with CKD and first-degree relatives with and without (APOL1) risk alleles had statistically indistinguishable blood pressures, creatinine and HDL-cholesterol levels. Apolipoprotein L1 risk variants are present in black South Africans with similar frequencies between CKD patients, first-degree relatives, and healthy controls. The lack of association of these variants with hypertension-attributed CKD in this population needs to be explored further in studies with larger sample sizes.
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Longitudinal changes in hematocrit in hypertensive chronic kidney disease: results from the African-American Study of Kidney Disease and Hypertension (AASK).

BACKGROUND: Anemia is common in chronic kidney disease (CKD) and associated with poor outcomes. In cross-sectional studies, lower estimated glomerular filtration rate (eGFR) has been associated with increased risk for anemia. The aim of this study was to determine how hematocrit changes as eGFR declines and what factors impact this longitudinal association. METHODS: We followed 1094 African-Americans with hypertensive nephropathy who participated in the African-American Study of Kidney Disease and Hypertension. Mixed effects models were used to determine longitudinal change in hematocrit as a function of eGFR. Interaction terms were used to assess for differential effects of age, gender, baseline eGFR, baseline proteinuria, malnutrition and inflammation on eGFR-associated declines in hematocrit. In sensitivity analyses, models were run using iGFR (by renal clearance of I(125) iothalamate) in place of eGFR. RESULTS: At baseline, mean hematocrit was 39% and 441 (40%) individuals had anemia. The longitudinal relationship between eGFR and hematocrit differed by baseline eGFR and was steeper when baseline eGFR was <45 mL/min/1.73 m(2). For example, the absolute decline in hematocrit per 10 mL/min/1.73 m(2) decline in longitudinal eGFR was -3.7, -1.3 and -0.5% for baseline eGFR values of 20, 40 and 60 mL/min/1.73 m(2), respectively (P < 0.001 comparing the longitudinal association between baseline eGFR = 40 or 60 versus baseline eGFR = 20 mL/min/1.73 m(2)). Similarly, male sex, younger age (<65 years) and higher baseline proteinuria (protein-to-creatinine ratio >0.22) were associated with greater hematocrit declines per unit decrease in longitudinal eGFR compared with female sex, older age and low baseline proteinuria, respectively (P-interaction <0.05 for each comparison). The longitudinal eGFR-hematocrit association did not differ by body mass index, serum albumin or C-reactive protein. CONCLUSIONS: Men, younger individuals and those with low baseline eGFR (<45 mL/min/1.73 m(2)) or baseline proteinuria are particularly at risk for eGFR-related declines in hematocrit.

Hypertension, glomerular hypertrophy and nephrosclerosis: the effect of race.

BACKGROUND: African Americans have more severe hypertensive nephrosclerosis than white Americans, possibly at similar levels of blood pressure. Glomerular volume is increased in African Americans relative to whites, but it is uncertain how this relates to nephrosclerosis and whether it contributes to or compensates for glomerulosclerosis. METHODS: Stereological disector/fractionator estimates of glomerular number (N(glom)) and average glomerular volume (V(glom)) were obtained on autopsy kidneys of 171 African Americans and 131 whites. Eighty-eight African Americans and 49 whites were identified as hypertensive. Nephrosclerosis was measured morphometrically as the percentage of glomerulosclerosis, proportion of cortical fibrosis and interlobular artery intimal thickness, and analyzed with V(glom) by age, race, gender, body mass index (BMI) and blood pressure. RESULTS: African Americans were more frequently hypertensive (58.5%) than whites (35.8%) and when hypertensive had higher levels of blood pressure (P = 0.02). N(glom) was significantly lower in hypertensive compared with non-hypertensive subjects among white women (P = 0.02) but not white males (P = 0.34) or African American females (P = 0.10) or males (P = 0.41). For each race and gender, glomerulosclerosis, cortical fibrosis and arterial intimal thickening were statistically correlated with age (P < 0.001) and hypertension (P < 0.001) and increased V(glom) with hypertension (P < 0.001) and BMI (P < 0.001). In multivariate analysis, African American race was associated with increased V(glom) (P = 0.01) and arterial intimal thickening (P < 0.01), while interactions between race and blood pressure indicated that the severity of nephrosclerosis including increased V(glom) was linked most directly to hypertension without significant contributions from race. The hypertension-associated enlargement of V(glom) was present with mild degrees of glomerulosclerosis and changed little as the severity of glomerulosclerosis increased. CONCLUSIONS: Glomerular hypertrophy was identified as an integral feature of hypertensive nephropathy and appeared to precede rather than compensate for glomerulosclerosis. An effect of race on V(glom) and arterial intimal thickening seemed to be related to the more frequent and more severe hypertension among African Americans.

Loss of GSTM1, a NRF2 target, is associated with accelerated progression of hypertensive kidney disease in the African American Study of Kidney Disease (AASK).

Oxidative stress is acknowledged to play a role in kidney disease progression. Genetic variants that affect the capacity to handle oxidative stress may therefore influence the outcome of kidney disease. We examined whether genetic variants of the GSTM1 gene, a member of a superfamily of glutathione S-transferases, influence the course of kidney disease progression in participants of the African American Study of Kidney Disease (AASK) trial. Groups with and without the common GSTM1 null allele, GSTM1(0), differed significantly in the time to a glomerular filtration rate (GFR) event or dialysis (P = 0.04) and in the time to GFR event, dialysis, or death (P = 0.02). The hazard ratios (HR) for the time to a GFR event or dialysis in those with two or one null allele relative to those possessing none were 1.88 [95% confidence interval (CI), 1.07 to 3.30, P = 0.03] and 1.68 (95% CI, 1.00 to 2.84, P < 0.05), respectively. For the time to GFR event, dialysis, or death, the HR for two null alleles was 2.06 (95% CI, 1.20 to 3.55, P = 0.01) and for one null allele 1.70 (95% CI, 1.02 to 2.81, P = 0.04). We demonstrated that GSTM1 directly regulates intracellular levels of 4-hydroxynonenal (4-HNE) in vascular smooth muscle cells. Furthermore, we showed that renal 4-HNE levels and GSTM1 are both increased after reduction of renal mass (RRM) in the mouse. We conclude that GSTM1 is normally upregulated in chronic kidney disease (CKD) in a protective response to increased oxidative stress. A genetic variant that results in loss of GSTM1 activity may be deleterious in CKD.

Hypertension-misattributed kidney disease in African Americans.

Lipkowitz et al. extend the African American Study of Kidney Disease and Hypertension to the level of genetic epidemiology, in a case-control study design. Analysis of genotypes at the APOL1 kidney disease risk region supports a paradigm shift in which genetic risk is proximate to both kidney disease and hypertension. The findings mandate urgency in clarifying mechanisms whereby APOL1 region risk variants interact with environmental triggers to cause progressive kidney disease accompanied by dangerous hypertension.

Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans.

Despite intensive antihypertensive therapy there was a high incidence of renal end points in participants of the African American Study of Kidney Disease and Hypertension (AASK) cohort. To better understand this, coding variants in the apolipoprotein L1 (APOL1) and the nonmuscle myosin heavy chain 9 (MYH9) genes were evaluated for an association with hypertension-attributed nephropathy and clinical outcomes in a case-control study. Clinical data and DNA were available for 675 AASK participant cases and 618 African American non-nephropathy control individuals. APOL1 G1 and G2, and MYH9 E1 variants along with 44 ancestry informative markers, were genotyped with allele frequency differences between cases and controls analyzed by logistic regression multivariable models adjusting for ancestry, age, and gender. In recessive models, APOL1 risk variants were significantly associated with kidney disease in all cases compared to controls with an odds ratio of 2.57. In AASK cases with more advanced disease, such as a baseline urine protein to creatinine ratio over 0.6 g/g or a serum creatinine over 3 mg/dl during follow-up, the association was strengthened with odds ratios of 6.29 and 4.61, respectively. APOL1 risk variants were consistently associated with renal disease progression across medication classes and blood pressure targets. Thus, kidney disease in AASK participants was strongly associated with APOL1 renal risk variants.

Rethinking hypertensive kidney disease: arterionephrosclerosis as a genetic, metabolic, and inflammatory disorder.

PURPOSE OF REVIEW: Hypertension is the attributed cause of approximately 30% of end-stage kidney disease cases in the United States, but there has been controversy as to whether benign hypertension is a cause of chronic kidney disease. RECENT FINDINGS: The histology of chronic kidney disease attributed to nonmalignant hypertension is arterionephrosclerosis, with pathology in the terminal branches of the interlobular arteries, together with global glomerulosclerosis. The identification of coding region variants in APOL1, encoding apolipoprotein L1, has opened a new perspective on this debate. These variants are restricted to populations of recent African descent and are strongly associated with clinically diagnosed arterionephrosclerosis, particularly when there is moderate-grade or high-grade proteinuria or progression to more advanced levels of kidney dysfunction. Nevertheless, not all African Americans with hypertension who progress to end-stage kidney disease have two APOL1 risk variants, and individuals of European and Asian descent also manifest arterionephrosclerosis. Further, we do not understand the mechanisms by which APOL1 initiates pathology in the renal microcirculation. SUMMARY: APOL1 nephropathy comprises a disease spectrum (perhaps with distinct endophenotypes), including focal segmental glomerulosclerosis, collapsing glomerulopathy, and arterionephrosclerosis. The terms hypertensive kidney disease and hypertensive nephrosclerosis have outlived their usefulness. It may be time to use the established, etiologically neutral term, arterionephrosclerosis, to consider whether this is a disease rather than a pathologic description, and to determine the causal role of various clinical correlates including aging, obesity, hyperlipidemia, smoking, chronic inflammation, and oxidative stress.

Kidney function can improve in patients with hypertensive CKD.

The typical assumption is that patients with CKD will have progressive nephropathy. Methodological issues, such as measurement error and regression to the mean, have made it difficult to document whether kidney function might improve in some patients. Here, we used data from 12 years of follow-up in the African American Study of Kidney Disease and Hypertension to determine whether some patients with CKD can experience a sustained improvement in GFR. We calculated estimated GFR (eGFR) based on serum creatinine measurements during both the trial and cohort phases. We defined clearly improved patients as those with positive eGFR slopes that we could not explain by random measurement variation under Bayesian mixed-effects models. Of 949 patients with at least three follow-up eGFR measurements, 31 (3.3%) demonstrated clearly positive eGFR slopes. The mean slope among these patients was +1.06 (0.12) ml/min per 1.73 m(2) per yr, compared with -2.45 (0.07) ml/min per 1.73 m(2) per yr among the remaining patients. During the trial phase, 24 (77%) of these 31 patients also had clearly positive slopes of (125)I-iothalamate-measured GFR during the trial phase. Low levels of proteinuria at baseline and randomization to the lower BP goal (mean arterial pressure ≤92 mmHg) associated with improved eGFR. In conclusion, the extended follow-up from this study provides strong evidence that kidney function can improve in some patients with hypertensive CKD.

Methylenetetrahydrofolate reductase (MTHFR) polymorphism A1298C (Glu429Ala) predicts decline in renal function over time in the African-American Study of Kidney Disease and Hypertension (AASK) Trial and Veterans Affairs Hypertension Cohort (VAHC).

BACKGROUND: Hyperhomocysteinemia is associated with increased venous thrombosis and cardiovascular disease (CVD). Mutations in the human methylenetetrahydrofolate reductase (MTHFR) gene have been associated with increased homocysteine levels and risks of CVD in various populations including those with kidney disease. Here, we evaluated the influence of MTHFR variants on progressive loss of kidney function. METHODS: We analyzed 821 subjects with hypertensive nephrosclerosis from the longitudinal National Institute of Diabetes and Digestive and Kidney Diseases African-American Study of Kidney Disease and Hypertension (AASK) Trial to determine whether decline in glomerular filtration rate (GFR) over ∼4.2 years was predicted by common genetic variation within MTHFR at non-synonymous positions C677T (Ala222Val) and A1298C (Glu429Ala) or by MTHFR haplotypes. The effect on GFR decline was then supported by a study of 1333 subjects from the San Diego Veterans Affairs Hypertension Cohort (VAHC), followed over ∼4.5 years. Linear effect models were utilized to determine both genotype [single-nucleotide polymorphism (SNP)] and genotype (SNP)-by-time interactions. RESULTS: In AASK, the polymorphism at A1298C predicted the rate of GFR decline: A1298/A1298 major allele homozygosity resulted in a less pronounced decline of GFR, with a significant SNP-by-time interaction. An independent follow-up study in the San Diego VAHC subjects supports that A1298/A1298 homozygotes have the greatest estimated GFR throughout the study. Haplotype analysis with C677T yielded concurring results. CONCLUSION: We conclude that the MTHFR-coding polymorphism at A1298C is associated with renal decline in African-Americans with hypertensive nephrosclerosis and is supported by a veteran cohort with a primary care diagnosis of hypertension. Further investigation is needed to confirm such findings and to determine what molecular mechanism may contribute to this association.

Pattern of hypertensive kidney disease in a black Kenyan population.

BACKGROUND: Hypertensive kidney disease is a major cause of morbidity and mortality. Its pattern displays geographical and ethnic variations. Data on these patterns are important for informing management and prevention strategies, but on Kenyans such data are scarce. OBJECTIVE: By means of a retrospective study at Kenyatta National Hospital, Nairobi, we aimed to describe the pattern of hypertensive kidney disease in a black Kenyan population. METHODS: Records of hypertensive patients who had impaired kidney function between January 2000 and December 2010 were examined for mode of diagnosis, age, gender, comorbid factors, treatment and outcome. Data were analyzed using the Statistical Package for Social Sciences, version 16.0 for Windows, and are presented using tables and bar charts. RESULTS: A total of 114 cases (72 males, 42 females) were analyzed. The mean age was 42.7 years (range 12-83), peaking at 51-70 years. The male to female ratio was 1.7:1. Comorbid factors included left ventricular hypertrophy (21.1%), congestive heart failure (15.8%), alcohol (11.4%), cerebrovascular accidents, smoking and retinopathy (10.5% each). Multiple comorbid factors were present in 8.8% of the cases. The majority (52.6%) of the patients survived on hemodialysis, 8.8% underwent successful renal transplant and 22.8% died. CONCLUSION: Hypertensive kidney disease affects all age groups, males more than females. It is commonly associated with other cardiovascular conditions and carries a high morbidity. Vigilant control of blood pressure is recommended.

Relationship between body mass index and proteinuria in hypertensive nephrosclerosis: results from the African American Study of Kidney Disease and Hypertension (AASK) cohort.

BACKGROUND: Few studies have examined the association between obesity and markers of kidney injury in a chronic kidney disease population. We hypothesized that obesity is independently associated with proteinuria, a marker of chronic kidney disease progression. STUDY DESIGN: Observational cross-sectional analysis. SETTING & PARTICIPANTS: Post hoc analysis of baseline data for 652 participants in the African American Study of Kidney Disease (AASK). PREDICTORS: Obesity, determined using body mass index (BMI). MEASUREMENTS & OUTCOMES: Urine total protein-creatinine ratio and albumin-creatinine ratio measured in 24-hour urine collections. RESULTS: AASK participants had a mean age of 60.2 ± 10.2 years and serum creatinine level of 2.3 ± 1.5 mg/dL; 61.3% were men. Mean BMI was 31.4 ± 7.0 kg/m(2). Approximately 70% of participants had a daily urine total protein excretion rate <300 mg/d. In linear regression analyses adjusted for sex, each 2-kg/m(2) increase in BMI was associated with a 6.7% (95% CI, 3.2-10.4) and 9.4% (95% CI, 4.9-14.1) increase in urine total protein-creatinine and urine albumin-creatinine ratios, respectively. In multivariable models adjusting for age, sex, systolic blood pressure, serum glucose level, uric acid level, and creatinine level, each 2-kg/m(2) increase in BMI was associated with a 3.5% (95% CI, 0.4-6.7) and 5.6% (95% CI, 1.5-9.9) increase in proteinuria and albuminuria, respectively. The interaction between older age and BMI was statistically significant, indicating that this relationship was driven by younger AASK participants. LIMITATIONS: May not generalize to other populations; cross-sectional analysis precludes statements regarding causality. CONCLUSIONS: BMI is associated independently with urine total protein and albumin excretion in African Americans with hypertensive nephrosclerosis, particularly in younger patients.

Progression of chronic kidney disease: Adrenergic genetic influence on glomerular filtration rate decline in hypertensive nephrosclerosis.

BACKGROUND: African-Americans are likely to develop hypertension and hypertensive nephrosclerosis. This grave prognosis, coupled with familial aggregation of end-stage renal disease (ESRD) in Blacks, prompts a search for genetic risk factors for ESRD. Recent evidence implicates a crucial role for the sympathetic nervous system in progressive renal disease. METHODS: We used the African-American Study of Kidney Disease to probe whether beta2-adrenergic receptor (ADRB2) predicts glomerular filtration rate (GFR) decline rate. A total of 580 participants were included. Baseline GFR was 51.2 +/- 0.5 ml/min/1.73 m2. Subjects were randomized in a 2 x 3 block design: to intensively lowered (MAP < or = 92 mm Hg) versus 'usual' (MAP = 102-107 mm Hg) blood pressure goal groups, and also divided by three randomized antihypertensive drugs (ramipril, metoprolol, or amlodipine). We scored 4 SNPs at the ADRB2 locus. RESULTS: Haplotypes at ADRB2 predicted chronic GFR decline rate, GFR declined more slowly in individuals with haplotype-1 (-804G-->173T-->16Gly-->27GIn), and faster in those who carried haplotype-3 (-804G-->173T-->16Arg-->27Gln). ADRB2 genotype interacted with antihypertensive drug class to influence GFR slope (p = 0.001-0.037). We extended our findings to an independent case/control sample of Black hypertensive ESRD, in which we found that variant Gly16Arg that tagged the GFR slope-determining ADRB2 haplotype also conferred risk for the ESRD trait in Blacks. CONCLUSIONS: The GFR decline/progression rate in hypertensive renal disease is controlled in part by genetic variation within the adrenergic pathway.

Prehypertensive African-American women have preserved nitric oxide and renal function but high cardiovascular risk.

AIMS: African-Americans, in particular women, exhibit disproportionate levels of hypertension, inflammation, and oxidative stress compared to other ethnic groups. The relationship between prehypertension, renal function, inflammation, and oxidative stress was examined. METHODS: Twenty-eight African-American women (53.5 +/- 1.1 years) followed an AHA diet and then underwent 24-hour ambulatory BP (ABP) monitoring. Urinary albumin (uAlb), serum and urinary creatinine, glomerular filtration rate (GFR), 24-hour urinary Na(+) excretion, plasma superoxide dismutase, total antioxidant capacity (TAC), urinary (uNOx) and plasma (pNOx) nitric oxide levels, and high-sensitivity C-reactive protein (hsCRP) were measured. RESULTS: When the group was divided by average 24-hour ABP into optimal and nonoptimal groups, a significant difference existed between the groups for uNOx (p = 0.001; nonoptimal: 933.5 +/- 140.4, optimal: 425.0 +/- 52.6 mumol/gCr), and for hsCRP (p = 0.018, nonoptimal: 3.9 +/- 0.7, optimal: 1.9 +/- 0.6 mg/l). Significant inverse relationships existed between hsCRP and uNOx and between uAlb and pNOx in the non-optimal group, between GFR and pNOx in the entire group, and positive association existed between TAC and uNOx in the optimal group. CONCLUSIONS: These results suggest that in African-American women as BP levels rise toward hypertension, the NO/NOS balance may be associated with renal function, and may have implications for CV risk based on their hsCRP levels.

Circulating transforming growth factor-beta1 levels and the risk for kidney disease in African Americans.

Transforming growth factor-beta1 (TGF-beta1) is known to induce progression of experimental renal disease. Here we determined whether there is an association between serum levels of TGF-beta1 and the risk factors for progression of clinically relevant renal disorders in 186 black and 147 white adults, none of whom had kidney disease or diabetes. Serum TGF-beta1 protein levels were positively and significantly associated with plasma renin activity along with the systolic and diastolic blood pressure in blacks but not whites after controlling for age, gender, and body mass index. These TGF-beta1 protein levels were also significantly associated with body mass index and metabolic syndrome and more predictive of microalbuminuria in blacks than in whites. The differential association between TGF-beta1 and renal disease risk factors in blacks and whites suggests an explanation for the excess burden of end-stage renal disease in the black population, but this requires validation in an independent cohort. Whether these findings show that it is the circulating levels of TGF-beta1 that contribute to renal disease progression or the findings reflect other unmeasured factors, further longitudinal studies are needed.

Correlates of N-terminal prohormone brain natriuretic peptides in African Americans with hypertensive chronic kidney disease: the African American Study of Kidney Disease and Hypertension.

BACKGROUND/AIMS: The N-amino-terminal fragment of the prohormone B-type natriuretic peptide (NT-proBNP) is a marker of cardiac stress and elevated levels are indicative of heart failure. Few correlates of NT-proBNP levels have been identified in persons with moderate chronic kidney disease (CKD), and data from those without heart failure and from African Americans are especially limited. METHODS: The African American Study of Kidney Disease and Hypertension (AASK) enrolled nondiabetic African Americans with hypertensive kidney disease (glomerular filtration rate [GFR] = 20-65 ml/min/1.73 m(2)) and no evidence of clinical heart failure. NT-proBNP was measured in 982 AASK participants. RESULTS: In unadjusted analyses, GFR (r = -0.39; p < 0.001), hematocrit (r = -0.21; p < 0.001) and body mass index (BMI; r = -0.07; p = 0.04) were inversely correlated, and systolic blood pressure (r = 0.30; p < 0.001) and log UPCR (r = 0.32; p < 0.001) were positively correlated with log NT-proBNP levels. After adjustment for potential confounders, lower GFR and hematocrit and higher systolic blood pressure and protein:creatinine ratio remained significantly associated with higher NT-proBNP. CONCLUSION: Lower GFR and hematocrit, and higher urinary protein excretion may be associated with volume expansion in CKD. These results suggest that these processes are associated with increased NT-proBNP in CKD and may play a role in the development of heart failure.

Chromogranin A polymorphisms are associated with hypertensive renal disease.

Chromogranin A is released together with epinephrine and norepinephrine from catecholaminergic cells. Specific endopeptidases cleave chromogranin A into biologically active peptide fragments, including catestatin, which inhibits catecholamine release. Previous studies have suggested that a deficit in this sympathetic "braking" system might be an early event in the pathogenesis of human hypertension. Whether chromogranin A (CHGA) polymorphisms predict end-organ complications of hypertension, such as end-stage renal disease, is unknown. Among blacks, we studied common genetic variants spanning the CHGA locus in 2 independent case-control studies of hypertensive ESRD. Two haplotypes were significantly more frequent among subjects with hypertensive ESRD: 1) in the promoter (5') region, G-462A-->T-415C-->C-89A, haplotype ATC (adjusted odds ratio = 2.65; P = 0.037), and 2) at the 3'-end, C11825T (3'-UTR, C+87T)-->G12602C, haplotype TC (adjusted odds ratio = 2.73, P = 0.0196). Circulating levels of catestatin were lower among those with hypertensive ESRD than controls, an unexpected finding given that peptide levels are usually elevated in ESRD because of reduced renal elimination. We found that the 3'-UTR + 87T variant decreased reporter gene expression, providing a possible mechanistic explanation for diminished catestatin. In summary, common variants in chromogranin A associate with the risk of hypertensive ESRD in blacks.

Urinary sodium and potassium excretion and risk of hypertension in Chinese: report from a community-based cohort study in Taiwan.

BACKGROUND: Dietary sodium intake is associated with blood pressure and hypertension risk. However, most of the studies have been conducted in whites and it is not clear whether the effects exist in Asian populations. OBJECTIVE: The purpose of the present study was to investigate the role of 24-h urinary sodium excretion and hypertension risk among ethnic Chinese. DESIGN: A prospective cohort design on community. SETTING AND PARTICIPANTS: One thousand five hundred and twenty middle-aged and elderly participants who were free from hypertension at baseline and had available urine electrolyte data. MAIN OUTCOME MEASURES: Hypertension incidence. RESULTS: During a median 7.93 years of follow-up (interquartile range = 4.07-9.04 years), we documented 669 cases of incident hypertension. The multivariate risk was 1.26 (95% confidence interval = 1.01-1.57; P = 0.043) for individuals in the highest quartile of urinary sodium excretion as compared with those in the second quartile. A significant J-shape relationship between urinary sodium excretion and the risk of hypertension was observed, with the test for linear relation being rejected (P = 0.046). Participants who were in the highest quartile of urinary sodium excretion and higher baseline blood pressure had a 2.43-fold increased risk of hypertension (95% confidence interval = 1.72-3.22) compared with those in the lowest quartiles of urinary sodium and lower blood pressure. CONCLUSION: Urinary sodium excretion was associated with the risk of hypertension among ethnic Chinese. Urinary sodium excretion, as a marker of dietary sodium intake, can be useful for a comprehensive evaluation of hypertension risk in Asian populations.

Cardiovascular outcomes in the African American Study of Kidney Disease and Hypertension (AASK) Trial.

BACKGROUND: Patients with chronic kidney disease are at increased risk for cardiovascular (CV) events. METHODS: We randomly assigned 1,094 African Americans with hypertensive nephrosclerosis (glomerular filtration rate [GFR], 20 to 65 mL/min/1.73 m(2) [0.33 to 1.08 mL/s]) to initial antihypertensive treatment with either: (1) a beta-blocker, metoprolol; (2) an angiotensin-converting enzyme inhibitor, ramipril; or (3) a dihydropyridine calcium channel blocker, amlodipine, and either a usual-blood pressure (BP) or low-BP treatment goal. Using a design powered to detect renal outcome differences, we compared the effect of treatment on the CV event rate (cardiac death, myocardial infarction, stroke, and heart failure) during a mean follow-up period of 4.1 years and determined baseline factors that predict CV outcomes. RESULTS: Thirty-one patients died of CV disease (0.7%/patient-year), and 149 patients experienced at least 1 CV outcome (3.3%/patient-year). Overall, 202 CV events (4.5%/patient-year) occurred. The CV outcome rate was not related significantly to randomized interventions. In multivariable analyses, 7 baseline risk factors remained independently associated with increased risk for the CV composite outcome after controlling for age, sex, baseline GFR, and baseline proteinuria group: pulse pressure, duration of hypertension, abnormal electrocardiogram result, non-high-density lipoprotein cholesterol level, serum urea nitrogen level, urine protein-creatinine ratio, urine sodium-potassium ratio, and annual income less than 15,000 dollars. CONCLUSION: Neither randomized class of antihypertensive therapy nor BP level had a significant effect on the occurrence of CV events, possibly because of limited power. However, this analysis identifies unique and potentially modifiable CV risk factors in this high-risk cohort.

A comparison of serum creatinine-based methods for identifying chronic kidney disease in hypertensive individuals and their siblings.

BACKGROUND: The Modification of Diet in Renal Disease (MDRD) equation is often used to determine an estimated glomerular filtration rate (eGFR) from serum creatinine. This study compared kidney disease as defined by reduced eGFR, elevated serum creatinine, or elevated urinary albumin-to-creatinine ratio (ACR). METHODS: As part of the Genetic Epidemiology Network of Arteriopathy study, a community-based sample was ascertained through sibships having at least two members with essential hypertension. Kidney disease was defined by reduced eGFR (<60 mL/min/1.73 m(2)), elevated serum creatinine (>97.5(th) percentile for sex-specific normal individuals), or elevated ACR (>95(th) percentile for sex-specific normal individuals). RESULTS: The sample (n = 2653) was 65% female, 61% African American, and 77% hypertensive, with a mean (+/- SD) age of 61 +/- 10 years. There was greater agreement between kidney disease defined by elevated ACR and an elevated serum creatinine level (kappa = 0.19) than between kidney disease defined by elevated ACR and a reduced eGFR (kappa = 0.07). The multivariable-adjusted odds ratio of kidney disease for male versus female sex was 0.92 (95% CI, 0.75 to 1.12) by reduced eGFR, but was 2.08 (95% CI, 1.62 to 2.67) by elevated serum creatinine and 2.11 (95% CI, 1.63 to 2.74) by elevated ACR. The multivariable-adjusted odds ratio of kidney disease for subjects of African American versus white ethnicity was 0.27 (95% CI, 0.22 to 0.33) by reduced eGFR but was 1.17 (95% CI, 0.91 to 1.51) by elevated serum creatinine and 3.87 (95% CI, 2.89 to 5.25) by elevated ACR. CONCLUSION: In a predominantly hypertensive population, kidney disease identified by elevated ACR was more concordant with elevated serum creatinine than with reduced eGFR. The MDRD equation, derived using kidney disease patients, may misrepresent the gender- and ethnicity-specific risk of kidney disease.