Cardiovascular disease (CVD), which includes coronary artery disease and stroke, is the leading cause of mortality in the nation. Excess CVD morbidity and premature mortality in the African American community is one of the most striking examples of racial/ethnic disparities in health outcomes. African Americans also suffer from increased rates of hypovitaminosis D, which has emerged as an independent risk factor for all-cause and cardiovascular mortality. This overview examines the potential role of hypovitaminosis D as a contributor to racial and ethnic disparities in cardiovascular disease (CVD). We review the epidemiology of vitamin D and CVD in African Americans and the emerging biological roles of vitamin D in key CVD signaling pathways that may contribute to the epidemiological findings and provide the foundation for future therapeutic strategies for reducing health disparities.

Background

Obesity is a known cardiometabolic risk factor in children. In adults, pulse pressure (PP) is a known predictor and a risk factor of cardiovascular (CV) diseases. In this study, we examined the association between measures of obesity and PP in children.

Methods

A retrospective analysis of 4667 children ages 6–17 years from the National Health and Nutrition Survey (1988–1994) was performed. We defined wide PP as 4th quartile PP and high waist circumference (WC) as >75th percentile based on age and gender.

Results

There were 51% boys, 74% whites, 16% blacks, 10% Hispanics, 12% obese, 26% with high WC, 26% with wide PP, and 9% with high blood pressure (BP). Prevalence of wide PP was high among obese children. A significantly higher mean PP was observed in boys, Blacks, obese, those with high WC and high BP. The adjusted odds ratio (OR) for wide PP was higher in boys, Blacks, and those with high WC.

Conclusion

There was a statistically significant independent association observed between wide PP and high WC, but not with obesity based on BMI. Further exploration of wide PP as a CV risk factor in childhood and its relationship to CV outcomes appears warranted.

Background: Cell-cell communication occurs via a variety of mechanisms, including long distances (hormonal), short distances (paracrine and synaptic) or direct coupling via gap junctions, antigen presentation, or ligand-receptor interactions. We evaluated the possibility of neuro-hormonal independent, non-diffusible, physically disconnected pathways for cell-cell communication using dorsal root ganglion (DRG) neurons. Methods: We assessed intracellular calcium ([Ca2+]) in primary culture DRG neurons that express ATP-sensitive P2X3, capsaicinsensitive TRPV1 receptors modulated by estradiol. Physically disconnected (dish-in-dish system; inner chamber enclosed) mouse DRG were cultured for 12 hours near: a) media alone (control 1), b) mouse DRG (control 2), c) human neuroblastoma SHSY-5Y cells (cancer intervention), or d) mouse DRG treated with KCl (apoptosis intervention). Results: Chemosensitive receptors [Ca2+]i signaling did not differ between control 1 and 2. ATP (10 μM) and capsaicin (100nM) increased [Ca2+]i transients to 425.86 + 49.5 nM, and 399.21 ± 44.5 nM, respectively. 17β-estradiol (100 nM) exposure reduced ATP (171.17 ± 48.9 nM) and capsaicin (175.01±34.8 nM) [Ca2+]i transients. The presence of cancer cells reduced ATP- and capsaicin-induced [Ca2+]i by >50% (p<0.05) and abolished the 17β-estradiol effect. By contrast, apoptotic DRG cells increased initial ATP-induced [Ca2+]i, flux four fold and abolished subsequent [Ca2+]i, responses to ATP stimulation (p<0.001). Capsaicin (100nM) induced [Ca2+]i responses were totally abolished. Conclusion: The local presence of apoptotic DRG or human neuroblastoma cells induced differing abnormal ATP and capsaicin-mediated [Ca2+]i fluxes in normal DRG. These findings support physically disconnected, non-diffusible cell-to-cell signaling. Further studies are needed to delineate the mechanism(s) of and model(s) of communication.

Background

Albuminuria is an important marker for chronic kidney disease and progression to end-stage renal disease in the general population; understanding racial and ethnic differences can help inform efforts to reduce health disparities. We sought to estimate independent associations of race/ethnicity with albuminuria to determine whether observed differences were attributable to known kidney disease risk factors.

Methods

This cross-sectional study included 64,161 Kidney Early Evaluation Program (KEEP) participants, 2000–2008, with estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2, not on regular dialysis, and without previous kidney transplant. Albuminuria (urine albumin-creatinine ratio [ACR] ≥ 30 mg/g) was examined by self-reported race and ethnicity. Covariates were age, sex, educational level, body mass index, diabetes status or glucose level, hypertension status or blood pressure measurement, smoking status, health insurance status, and geographic region.

Results

Albuminuria prevalence was 8% (n = 2303) in whites, 11% (n = 2310) in African Americans, 9% (n = 730) in Hispanics, 10% (n = 381) in Asians, and 15% (n = 344) in American Indians/Alaska Natives. Compared with whites, odds of albuminuria were higher for all groups after multivariate adjustment. Odds were highest for American Indians/Alaska Natives (adjusted odds ratio 1.93, 95% confidence interval 1.70–2.20), then Asians (1.42, 1.26–1.61), African Americans (1.38, 1.29–1.47), and Hispanics (1.19, 1.08–1.31).

Conclusions

In the KEEP study population, albuminuria prevalence was higher among African Americans, Hispanics, Asians, and American Indians/Alaska Natives than among non-Hispanic whites, suggesting a need for screening for early detection of kidney damage, especially among people at increased risk, in the community primary care setting.

Background

In maintenance hemodialysis (HD) patients, overweight and obesity are associated with survival advantages. Given greater survival of minority maintenance HD patients, we hypothesized that elevated body mass index (BMI) is more strongly associated with lower mortality among Blacks and Hispanics relative to non-Hispanic whites.

Study design

Retrospective, cohort study.

Setting and participants

We examined a 6 year (2001–2007) cohort of 109,605 maintenance HD patients including 39,090 Blacks, 17,417 Hispanics and 53,098 non-Hispanic white maintenance HD outpatients from DaVita dialysis clinics. Cox proportional hazards models examined the association between BMI and survival.

Predictor

Race and BMI.

Outcomes

All cause mortality.

Results

Patients were (mean±SD) 62±15 years old and included 45% women and 45% diabetics. Across 10 a priori selected BMI categories (<18 to ≥40 kg/m2) higher BMI was associated with greater survival in all 3 racial/ethnic groups. Hispanic and Black patients, however, experienced consistently higher survival gains compared to non-Hispanic Whites across almost all BMI categories. Hispanics in the ≥40 kg/m2 category had the lowest death hazard ratio (HR, 0.57; 95% confidence interval [CI], 0.49–0.68) compared to non-Hispanic Whites in the 21.5-<23 kg/m2 group (reference category). While the inverse association was observed for all subgroups, Black maintenance HD patients exhibited the largest decline in death HR with increasing BMI.

Limitations

Race and ethnicity categories were based on self-identified data.

Conclusions

Whereas survival advantage of high BMI is consistent across all racial/ethnic groups, Black maintenance HD patients had the strongest association of high BMI with improved survival.

Background

Black-white disparities in mortality persist after adjustment for socioeconomic status and health behaviors. We examined whether allostatic load, the physiological profile influenced by repeated or chronic life stressors, is associated with black-white mortality disparities independent of traditional sociobehavioral risk factors.

Methods

We studied 4515 blacks and whites aged 35 to 64 years from the third National Health and Nutrition Examination Survey (1988–1994), using the linked mortality file, to ascertain participant deaths through 2006. We estimated unadjusted sex-specific black-white disparities in cardiovascular/diabetes-related mortality and noninjury mortality. We constructed baseline allostatic load scores based on 10 biomarkers and examined attenuation of mortality disparities in 4 sets of sex-stratified multivariate models, sequentially adding risk factors: (1) age/clinical conditions, (2) socioeconomic status (SES) variables, (3) health behaviors, and (4) allostatic load.

Results

Blacks had higher allostatic load scores than whites; for men, 2.5 vs 2.1, p < .01; and women, 2.6 vs 1.9, p < .01. For cardiovascular/diabetes-related mortality among women, the magnitude of the disparity after adjustment for other risk factors (hazard ratio [HR], 1.63; 95% confidence interval [CI], 0.96–2.75) decreased after adjustment for allostatic load (HR, 1.15; 95% CI, 0.70–1.88). For noninjury mortality among women, the magnitude of the disparity after adjustment for other risk factors (HR, 1.43; 95% CI, 1.00–2.04) also decreased after adjustment for allostatic load (HR, 1.26; 95% CI, 0.90–1.78). For men, disparities were attenuated but persisted after adjustment for allostatic load.

Conclusions

Allostatic load burden partially explains higher mortality among blacks, independent of SES and health behaviors. These findings underscore the importance of chronic physiologic stressors as a negative influence on the health and lifespan of blacks in the United States.

Background

Treatment of hypertension is difficult in chronic kidney disease (CKD), and blood pressure goals remain controversial. The association between each blood pressure component and end-stage renal disease (ESRD) risk is less well known.

Methods

We studied associations of systolic and diastolic blood pressure (SBP and DBP, respectively) and pulse pressure (PP) with ESRD risk among 16 129 Kidney Early Evaluation Program (KEEP) participants with an estimated glomerular filtration rate of 60 mL/min/1.73 m2 using Cox proportional hazards. We estimated the prevalence and characteristics associated with uncontrolled hypertension (SBP≥150 or DBP≥90 mm Hg).

Results

The mean (SD) age of participants was 69 (12) years; 25% were black, 6% were Hispanic, and 43% had diabetes mellitus. Over 2.87 years, there were 320 ESRD events. Higher SBP was associated with higher ESRD risk, starting at SBP of 140 mm Hg or higher. After sex and age adjustment, compared with SBP lower than 130 mm Hg, hazard ratios (HRs) were 1.08 (95% CI, 0.74–1.59) for SBP of 130 to 139 mm Hg, 1.72 (95% CI, 1.21–2.45) for SBP of 140 to 149 mm Hg, and 3.36 (95% CI, 2.51–4.49) for SBP of 150 mm Hg or greater. After full adjustment, HRs for ESRD were 1.27 (95% CI, 0.88–1.83) for SBP of 140 to 149 mm Hg and 1.36 (95% CI, 1.02–1.85) for SBP of 150 mm Hg or higher. Persons with DBP of 90 mm Hg or higher were at higher risk for ESRD compared with persons with DBP of 60 to 74 mm Hg (HR, 1.81; 95% CI, 1.33–2.45). Higher PP was also associated with higher ESRD risk (HR, 1.44 [95% CI, 1.00–2.07] for PP≥80 mm Hg compared with PP<50 mm Hg). Adjustment for SBP attenuated this association. More than 33% of participants had uncontrolled hypertension (SBP≥150 mm Hg or DBP≥90 mm Hg), mostly due to isolated systolic hypertension (54%).

Conclusions

In this large, diverse, community-based sample, we found that high SBP seemed to account for most of the risk of progression to ESRD. This risk started at SBP of 140 mm Hg rather than the currently recommended goal of less than 130 mm Hg, and it was highest among those with SBP of at least 150 mm Hg. Treatment strategies that preferentially lower SBP may be required to improve BP control in CKD.

Background

Recent reports have suggested a close relationship between education and health, including mortality, in the United States.

Study Design

Observational cohort

Setting and Participants

We studied 61,457 participants enrolled in a national health screening initiative, the National Kidney Foundation’s Kidney Early Evaluation Program (KEEP).

Predictor

Self-reported educational attainment

Outcomes

Chronic diseases (hypertension, diabetes, cardiovascular disease, reduced kidney function, and albuminuria) and mortality

Measurements

We evaluated the cross-sectional associations between self-reported educational attainment with the chronic diseases listed above using logistic regression models adjusted for demographics, access to care, behaviors, and co-morbidities. The association of educational attainment with survival was determined by multivariable Cox proportional hazards regression.

Results

Higher educational attainment was associated with lower prevalence of each of the chronic conditions listed above. In multivariable models, compared with persons not completing high school, college graduates had a lower risk of each chronic condition, ranging from 11% lower odds of reduced kidney function to 37% lower odds of cardiovascular disease. Over a mean follow-up time of 3.9 years (median, 3.7 years), 2,384 (4%) deaths occurred. In the fully adjusted Cox model, those who had completed college had a 24% lower mortality, compared to participants who had completed at least some high school.

Limitations

A lack of income data does not allow us to disentangle the independent effects of education from income.

Conclusions

In this diverse, contemporary cohort, higher educational attainment was independently associated with lower prevalence of chronic diseases and short-term mortality among all age and race/ethnicity groups.

Background

Oxidative stress and inflammation promote the development and progression of chronic kidney disease. Oxidative stress is associated with depletion of tissue glutathione (GSH), the most abundant endogenous intracellular antioxidant, but degradation of oral GSH by digestive enzymes limits its therapeutic use. We hypothesized that GSH repletion with F1, a novel oral GSH precursor containing cystine as a cysteine carrier, would restore tissue GSH and attenuate oxidative stress and inflammation, and thereby reduce the severity of interstitial nephropathy in chronic renal failure (CRF).

Methods

Male Sprague-Dawley rats (n=5-8) were assigned to 3 groups: Control (regular rat chow), CRF (rat chow containing 0.7% adenine), and F1-treated CRF (rat chow containing 0.7% adenine and F1, 0.5g/kg/day) for 2-weeks. Animals were switched to regular chow and euthanized after 2 additional weeks.

Results

Consumption of 0.7% adenine-containing diet caused azotemia; severe kidney swelling; heavy tubular and glomerular damage; massive tubulointerstitial nephropathy; impaired urinary concentrating capacity; severe anemia; increased markers of oxidative stress, plasma oxidized glutathione disulfide (GSSG); reduced GSH/GSSG ratio and manganese superoxide dismutase; increased expression of inflammatory mediators (cyclooxygenase-2, cytoplasmic NF-κB, p-IκBα, nuclear NF-κB p65), and 3-nitrotyrosine, p<0.05. Co-treatment with F1 significantly attenuated tubulointerstitial inflammation and edema, improved urinary concentrating capacity, azotemia and anemia, and normalized markers of tissue oxidative and nitrosative stress, p<0.05.

Conclusions

The novel oxidative stress modulator, F1, markedly attenuated oxidative stress indicators, inflammation, renal injury and dysfunction in the rat model of CRF. Studies to determine the effects of F1 in other models of acute and CRF are warranted.

Background

Observational studies indicate greater survival in African American and Hispanic maintenance hemodialysis (HD) patients compared to their Non-Hispanic White counterparts, even though Blacks have shorter life expectancy than Whites in the general population. We hypothesized that this apparent survival advantage is due to a more favorable nutritional/inflammatory profile in minority HD patients.

Study Design

We examined the association between race/ethnicity and 5-year survival before and after adjustment for case-mix and surrogates of the malnutrition-inflammation complex syndrome (MICS), using Cox regression with or without matched sampling in a large cohort of adult HD patients.

Setting and Participants

124,029 adult HD patients including 16% Hispanics, 49% non-Hispanic whites, and 35% African Americans.

Predictors

Race/ethnicity before and after adjustment for MICS including BMI, serum albumin, TIBC, ferritin; creatinine, phosphorus, calcium, bicarbonate, white blood cell count, lymphocyte percentage, hemoglobin and protein intake.

Outcomes

5-year (7/2001–6/2006) survival

Results

Among dialysis patients, Blacks and Hispanics had lower mortality overall than Non-Hispanic Whites after traditional case-mix adjustment. However, after additional control for MICS, Hispanics had mortality similar to non-Hispanic whites and African American had ever higher mortality. The unadjusted, case-mix and MICS adjusted hazard ratios (and 95% confidence intervals) of African American vs. Whites in the unmatched cohort were 0.68 (0.66–0.69), 0.89 (0.86–0.91) and 1.06 (1.03–1.09), and in the matched cohort 0.95 (0.90–0.99), 0.89 (0.84–0.94) and 1.16 (1.07–1.26), respectively; and for Hispanics vs. Whites in the unmatched cohort were 0.66 (0.64–0.69), 0.84 (0.81–0.87) and 0.97 (0.94–1.00), and in the matched cohort 0.89 (0.84–0.95), 0.88 (0.83–0.95) and 0.98 (0.91–1.06), respectively.

Limitations

Unmeasured confounders cannot be adjusted for.

Conclusions

Survival advantages of African American and Hispanic HD patients may be related to differences in nutritional and inflammatory status. Further studies are required to explore these differences.

Background

The National Kidney Foundation has recommended that the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation replace the Modification of Diet in Renal Disease (MDRD) Study equation. Before implementing this change in the Kidney Early Evaluation Program (KEEP), we compared characteristics of reclassified individuals and mortality risk predictions using the new equation.

Methods

Of 123,704 eligible KEEP participants, 116,321 with data available for this analysis were included. Glomerular filtration rate (GFR) was estimated using the MDRD Study (eGFRMDRD) and CKD-EPI (eGFRCKD-EPI) equations with creatinine level calibrated to standardized methods. Participants were characterized by eGFR category: >120, 90-119, 60-89, 45-59, 30-44, and <30 mL/min/1.73 m2. Clinical characteristics ascertained included age, race, sex, diabetes, hypertension, coronary artery disease, congestive heart failure, cerebrovascular disease, peripheral vascular disease, and anemia. Mortality was determined over a median of 3.7 years of follow-up.

Results

The prevalence of eGFRCKD-EPI <60 mL/min/1.73 m2 was 14.3% compared with 16.8% using eGFRMDRD. Using eGFRCKD-EPI, 20,355 participants (17.5%) were reclassified to higher eGFR categories, and 3,107 (2.7%), to lower categories. Participants reclassified upward were younger and less likely to have chronic conditions, with a lower risk of mortality. A total of 3,601 deaths (3.1%) were reported. Compared with participants classified to eGFR of 45-59 mL/min/1.73 m2 using both equations, those with eGFRCKD-EPI of 60-89 mL/min/1.73 m2 had a lower mortality incidence rate (6.4 [95% CI, 5.1-7.7] vs 18.5 [95% CI, 17.1-19.9]). Results were similar for all eGFR categories. Net reclassification improvement was 0.159 (P < 0.001).

Conclusions

The CKD-EPI equation reclassifies people at lower risk of CKD and death into higher eGFR categories, suggesting more accurate categorization. The CKD-EPI equation will be used to report eGFR in KEEP.

Background

Low awareness of chronic kidney disease (CKD) may reflect uncertainty about the accuracy or significance of a CKD diagnosis in individuals otherwise perceived to be low-risk. Whether reclassification of CKD severity using the CKD Epidemiology Collaboration (CKD-EPI) equation to estimate glomerular filtration rate (GFR) modifies estimates of CKD awareness is unknown.

Methods

In this cross-sectional study, we used data collected from 2000 to 2009 for 26,213 participants in the Kidney Early Evaluation Program (KEEP), a community-based screening program, with CKD based on GFR estimated using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation and measurement of albuminuria. We assessed CKD awareness after CKD stage was reclassified using the CKD-EPI equation.

Results

Of 26,213 participants with CKD based on eGFRMDRD, 23,572 (90%) were also classified with CKD based on eGFRCKD-EPI. Based on eGFRMDRD, 9.5% of participants overall were aware of CKD, as were 4.9%, 6.3%, 9.2%, 41.9%, and 59.2% with Stages 1-5, respectively. Based on eGFRCKD-EPI, 10.0% of participants overall were aware of CKD, as were 5.1%, 6.6%, 10.0%, 39.3%, and 59.4% with Stages 1-5, respectively. Reclassification to a less advanced CKD stage with eGFRCKD-EPI was associated with lower odds for awareness (OR, 0.58; 95% CI, 0.50-0.67); reclassification to a more advanced stage was associated with higher odds for awareness (OR, 1.50; 95% CI, 1.05-2.13) after adjustment for confounding factors. Of participants unaware of CKD, 10.6% were reclassified as not having CKD using eGFRCKD-EPI.

Conclusions

Using eGFRCKD-EPI led to a modest increase in overall awareness rates, primarily due to reclassification of low-risk unaware participants.

Background

Racial/ethnic disparities prevail among hemodialysis patients. We hypothesized that significant differences exist between Black and non-Hispanic and Hispanic White hemodialysis patients in nutritional status, dietary intake and inflammation, and that they account for racial survival disparities.

Methods

In a 6-year (2001–2007) cohort of 799 hemodialysis patients, we compared diet and surrogates of nutritional-inflammatory status and their mortality-predictabilities between 279 Blacks and 520 Whites using matched and regression analyses and Cox with cubic splines.

Results

In age-, gender- and diabetes-matched analyses, Blacks had higher lean body mass and serum prealbumin, creatinine and homocysteine levels than Whites. In case-mix-adjusted analyses, dietary intakes in Blacks versus Whites were higher in energy (+293 ± 119 cal/day) and fat (+18 ± 5 g/day), but lower in fiber (−2.9 ± 1.3 g/day) than Whites. In both races, higher serum albumin, prealbumin and creatinine were associated with greater survival, whereas CRP and IL-6, but not TNF-α, were associated with increased mortality. The highest (vs. lowest) quartile of IL-6 was associated with a 2.4-fold (95% CI: 1.3–3.8) and 4.1-fold (2.2–7.2) higher death risk in Blacks and Whites, respectively.

Conclusions

Significant racial disparities exist in dietary, nutritional and inflammatory measures, which may contribute to hemodialysis outcome disparities. Testing race-specific dietary and/or anti-inflammatory interventions is indicated.

Objective

To determine the association between diabetes mellitus (DM) and marijuana use.

Design

Cross-sectional study.

Setting

Data from the National Health and Nutrition Examination Survey (NHANES III, 1988–1994) conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention.

Participants

The study included participants of the NHANES III, a nationally representative sample of the US population. The total analytic sample was 10 896 adults. The study included four groups (n=10 896): non-marijuana users (61.0%), past marijuana users (30.7%), light (one to four times/month) (5.0%) and heavy (more than five times/month) current marijuana users (3.3%). DM was defined based on self-report or abnormal glycaemic parameters. We analysed data related to demographics, body mass index, smoking status, alcohol use, total serum cholesterol, high-density lipoprotein, triglyceride, serum 25-hydroxy vitamin D, plasma haemoglobin A1c, fasting plasma glucose level and the serum levels of C reactive protein and four additional inflammatory markers as related to marijuana use.

Main outcome measures

OR for DM associated with marijuana use adjusted for potential confounding variables (ie, odds of DM in marijuana users compared with non-marijuana users).

Results

Marijuana users had a lower age-adjusted prevalence of DM compared to non-marijuana users (OR 0.42, 95% CI 0.33 to 0.55; p<0.0001). The prevalence of elevated C reactive protein (>0.5 mg/dl) was significantly higher (p<0.0001) among non-marijuana users (18.9%) than among past (12.7%) or current light (15.8%) or heavy (9.2%) users. In a robust multivariate model controlling for socio-demographic factors, laboratory values and comorbidity, the lower odds of DM among marijuana users was significant (adjusted OR 0.36, 95% CI 0.24 to 0.55; p<0.0001).

Conclusions

Marijuana use was independently associated with a lower prevalence of DM. Further studies are needed to show a direct effect of marijuana on DM.

Article summary

Article focus

We hypothesised that the prevalence of DM would be reduced in marijuana users due to the presence of one or more cannabinoids because of their immunomodulatory and anti-inflammatory properties.

Key messages

Marijuana use was associated with a decreased prevalence of DM.

Prospective studies in rodents and humans are needed to determine a causal relationship between cannabinoid receptor activation and DM.

Until those studies are performed, we do not advocate the use of marijuana in patients at risk for DM.

Strengths and limitations of this study

Population-based national representative sample of the USA.

Cross-sectional data.

Marijuana use was based on self-report, and self-report of illicit substances is often underestimated on self-reports. Self-report is subjected to recall bias. However, we expect that recall bias would be similar in those with DM as those without DM and would be unlikely to bias our results.

Although current marijuana users were divided into heavy and light users based on the number of times they reported using marijuana per month, the amount of marijuana consumed, route of consumption (inhaled vs oral), duration of use and time when they quit were not reported.

This study was designed to examine the impact of elevated depressive affect on health outcomes among participants with hypertensive chronic kidney disease in the African-American Study of Kidney Disease and Hypertension (AASK) Cohort Study. Elevated depressive affect was defined by Beck Depression Inventory II (BDI-II) thresholds of 11 or more, above 14, and by 5-Unit increments in the score. Cox regression analyses were used to relate cardiovascular death/hospitalization, doubling of serum creatinine/end-stage renal disease, overall hospitalization, and all-cause death to depressive affect evaluated at baseline, the most recent annual visit (time-varying), or average from baseline to the most recent visit (cumulative). Among 628 participants at baseline, 42% had BDI-II scores of 11 or more and 26% had a score above 14. During a 5-year follow-up, the cumulative incidence of cardiovascular death/hospitalization was significantly greater for participants with baseline BDI-II scores of 11 or more compared with those with scores <11. The baseline, time-varying, and cumulative elevated depressive affect were each associated with a significant higher risk of cardiovascular death/hospitalization, especially with a time-varying BDI-II score over 14 (adjusted HR 1.63) but not with the other outcomes. Thus, elevated depressive affect is associated with unfavorable cardiovascular outcomes in African Americans with hypertensive chronic kidney disease.

Blacks have high rates of chronic kidney disease, are overrepresented among the US dialysis patients, have higher parathyroid hormone levels, but greater survival compared to nonblacks. We hypothesized that mineral and bone disorders (MBDs) have a bearing on survival advantages of black hemodialysis patients. In 139,328 thrice-weekly treated hemodialysis patients, including 32% blacks, in a large dialysis organization, where most laboratory values were measured monthly for up to 60 months (July 2001 to June 2006), we examined differences across races in measures of MBDs and survival predictabilities of these markers and administered the active vitamin D medication paricalcitol. Across each age increment, blacks had higher serum calcium and parathyroid hormone (PTH) levels and almost the same serum phosphorus and alkaline phosphatase levels and were more likely to receive injectable active vitamin D in the dialysis clinic, mostly paricalcitol, at higher doses than nonblacks. Racial differences existed in mortality predictabilities of different ranges of serum calcium, phosphorus, and PTH but not alkaline phosphatase. Blacks who received the highest dose of paricalcitol (>10 µg/week) had a demonstrable survival advantage over nonblacks (case-mix-adjusted death hazard ratio = 0.87, 95% confidence level 0.83–0.91) compared with those who received lower doses (<10 µg/week) or no active vitamin D. Hence, in black hemodialysis patients, hyperparathyroidism and hypercalcemia are more prevalent than in nonblacks, whereas hyperphosphatemia or hyperphosphatasemia are not. Survival advantages of blacks appear restricted to those receiving higher doses of active vitamin D. Examining the effect of MBD modulation on racial survival disparities of hemodialysis patients is warranted. © 2010 American Society for Bone and Mineral Research.

Background

The outcome-predictability of baseline and instantaneously changing serum calcium in hemodialysis patients has been examined. We investigated the mortality-predictability of time-averaged calcium values to reflect the ‘cumulative’ effect of calcium burden over time.

Methods

We employed a Cox model using up-to-5-year (7/2001–6/2006) time-averaged values to examine the mortality-predictability of cumulative serum calcium levels in 107,200 hemodialysis patients prior to the use of calcimimetics, but during the time where other calcium-lowering interventions, including lower dialysate calcium, were employed.

Results

Both low (<9.0 mg/dl) and high (>10.0 mg/dl) calcium levels were associated with increased mortality (reference: 9.0 to <9.5 mg/dl). Whereas mortality of hypercalcemia was consistent, hypocalcemia mortality was most prominent with higher serum phosphorus (>3.5 mg/dl) and PTH levels (>150 pg/ml). Higher paricalcitol doses shifted the calcium range associated with the greatest survival to the right, i.e. from 9.0 to <9.5 to 9.5 to <10.0 mg/dl. African-Americans exhibited the highest death hazard ratio of hypocalcemia <8.5 mg/dl, being 1.35 (95% CI: 1.22–1.49). Both a rise and drop in serum calcium over 6 months were associated with increased mortality compared to the stable group.

Conclusions

Whereas in hemodialysis patients cumulatively high or low calcium levels are associated with higher death risk, subtle but meaningful interactions with phosphorus, PTH, paricalcitol dose and race exist.

Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver pathologies and is associated with obesity and the metabolic syndrome. Here, we investigated the molecular mechanisms by which a novel cystine based glutathione precursor with added selenomethionine (F1) prevents hepatic steatosis in a moderate high fat dietary model of NAFLD. Adult (8 weeks old), male apolipoprotein E (ApoE)−/− mice were fed with a normal diet (ND) or high fat diet (HFD), consisting of 21% fat and 0.21% cholesterol, with or without dietary supplementation of F1 (3 g/kg food) for 16 weeks. Compared with ApoE−/− mice fed with ND with or without F1, ApoE−/− mice fed with HFD exhibited significant weight gain, hepatomegaly, and increased serum cholesterol and triglycerides levels with no change in serum albumin levels. High resolution light and electron microscopy revealed micro-and macro-vesicular steatosis in ApoE−/− mice fed on a HFD. HFD- induced obesity also led to increased lipogenesis, oxidative stress, activation of c-Jun-NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), perturbation of the BAX/BCL-2 rheostat, hepatocyte apoptosis, and activation of caspases 9 and 3. F1 fully prevented the adverse effects of HFD on serum triglyceride levels, body and liver weights, and hepatic steatosis and substantially attenuated HFD-induced increase in lipogenesis, oxidative stress, kinase activation, apoptotic signaling, and hepatocyte ultrastructural abnormalities. These results demonstrate that administration of F1, a glutathione precursor, ameliorates HFD-induced hepatic steatosis in ApoE−/− mice and emphasizes the role of oxidative stress in diet-induced obesity and hepatic steatosis.

Depression is common in end-stage renal disease and is associated with poor quality of life and higher mortality; however, little is known about depressive affect in earlier stages of chronic kidney disease. To measure this in a risk group burdened with hypertension and kidney disease, we conducted a cross-sectional analysis of individuals at enrollment in the African American Study of Kidney Disease and Hypertension Cohort Study. Depressive affect was assessed by the Beck Depression Inventory II and quality of life by the Medical Outcomes Study-Short Form and the Satisfaction with Life Scale. Beck Depression scores over 14 were deemed consistent with an increased depressive affect and linear regression analysis was used to identify factors associated with these scores. Among 628 subjects, 166 had scores over 14 but only 34 were prescribed antidepressants. The mean Beck Depression score of 11.0 varied with the estimated glomerular filtration rate (eGFR) from 10.7 (eGFR 50–60) to 16.0 (eGFR stage 5); however, there was no significant independent association between these. Unemployment, low income, and lower quality and satisfaction with life scale scores were independently and significantly associated with a higher Beck Depression score. Thus, our study shows that an increased depressive affect is highly prevalent in African Americans with chronic kidney disease, is infrequently treated with antidepressants, and is associated with poorer quality of life. Sociodemographic factors have especially strong associations with this increased depressive affect. Because this study was conducted in an African-American cohort, its findings may not be generalized to other ethnic groups.

The vitamin D receptor (VDR) and its ligand 1,25D, play an important role in regulating cell growth and cell fate. We examined the effect of 1,25D on cell morphology, cell proliferation, cell cycle progression and apoptosis on mesenchymal multipotent cells. Multipotent cells were treated with and without 1,25D in a time and dose dependent manner. Changes in cell morphology were evaluated by a green fluorescence fluorocrome. Cell proliferation was determined by the Formazan assay and PCNA antigen expression. The expression of genes related to the cell cycle was analyzed by DNA microarrays, RT2PCR arrays and western blots. Apoptosis was evaluated by TUNEL assay, and the expression of pro and anti-apoptotic related genes by RT2PCR arrays and western blots. 1,25D inhibited cell proliferation, induced cell cycle arrest, and promoted accumulation of cells in G0/G1 phase without inducing apoptosis. An increase in cell size was associated with a decrease in the GTPase Rho and the atypical Rho family GTPase Rhou/Wrch-1 expression without inducing Wnt-1 expression. Survivin expression was also increased and may represent a novel 1,25D mediated pathway regulating tissue injury and fibrosis. The data provide a mechanistic explanation for the anti-proliferative and anti-apoptototic properties of 1,25D in mesenchymal multipotent cells.

Background

American Indians and Alaska Natives (AIAN) have a high incidence of end-stage renal disease. Less is known about chronic kidney disease (CKD) among AIAN and whether risk factors differ for low estimated glomerular filtration rate (eGFR) versus albuminuria with a normal eGFR.

Methods

Cross-sectional study examining the associations of age, sex, smoking, obesity, diabetes, hypertension, family history, and geographic region with CKD among a screened population of AIAN participants in the Kidney Early Evaluation Program from 2000 to 2006. CKD was defined by the presence of either a low eGFR, <60 ml/min/1.73 m2, or albuminuria, a urine albumin/creatinine ratio ≥30 mg/g.

Results

The prevalence of any CKD was 29%, of low eGFR was 17%, and of albuminuria with a normal eGFR was 12%. Older age was the strongest predictor of low eGFR (61+ years OR 8.42, 95% CI 5.92–11.98), followed by hypertension (OR 2.38, 95% CI 1.74–3.26). In contrast, diabetes (OR 2.04, 95% CI 1.57–2.64) and hypertension (OR 2.63, 95% CI 1.93–3.59) were the only predictors of albuminuria among persons with a normal eGFR.

Conclusion

The burden of CKD was high among this screened population of AIAN, and different risk factor patterns were associated with low eGFR and albuminuria. Innovative programs and longitudinal research are needed to address CKD among AIAN.

BACKGROUND

Serum creatinine is commonly used to diagnose chronic kidney disease (CKD), but may underestimate CKD in older adults when compared with using glomerular filtration rates (eGFR). The magnitude of this underestimation is not clearly defined.

OBJECTIVE

Using the Modification of Diet in Renal Disease (MDRD) equation, to describe both the prevalence and the magnitude of underestimation of stage 3 CKD (GFR 30–59 ml/min/1.73 m2), as well as ideal serum creatinine cutoff values to diagnose stage 3 CKD among Americans ≥65 years of age.

DESIGN

Cross-sectional.

PARTICIPANTS

A total of 3,406 participants ≥65 years of age from the 1999–2004 National Health and Nutrition Examination Surveys (NHANES).

MEASUREMENTS

Serum creatinine levels were used to determine eGFR from the MDRD equation. Information on clinical conditions was self-reported.

RESULTS

Overall, 36.1% of older adults in the US have stage 3 or greater CKD as defined by eGFR values. Among older adults with stage 3 CKD, 80.6% had creatinine values ≤1.5 mg/dl, and 38.6% had creatinine values ≤1.2 mg/dl. Optimal cutoff values for serum creatinine in the diagnosis of stage 3 CKD in older adults were ≥1.3 mg/dl for men and ≥1.0 mg/dl for women, regardless of the presence or absence of hypertension, diabetes, or congestive heart failure.

CONCLUSION

Use of serum creatinine underestimates the presence of advanced (stage 3 or greater) CKD among older adults in the US. Automated eGFR reporting may improve the accuracy of risk stratification for older adults with CKD.

Objective

It has yet to be determined whether genotyping at the angiotensin-converting enzyme (ACE) locus is predictive of blood pressure response to an ACE inhibitor.

Methods

Participants from the African American Study of Kidney Disease and Hypertension trial randomized to the ACE inhibitor ramipril (n = 347) were genotyped at three polymorphisms on ACE, just downstream from the ACE insertion/deletion polymorphism (Ins/Del): G12269A, C17888T, and G20037A. Time to reach target mean arterial pressure (≤ 107 mmHg) was analyzed by genotype and ACE haplotype using Kaplan–Meier survival curves and Cox proportional hazard models.

Results

Individuals with a homozygous genotype at G12269A responded significantly faster than those with a heterozygous genotype; the adjusted (average number of medications and baseline mean arterial pressure) hazard ratio (homozygous compared to heterozygous genotype) was 1.86 (95% confidence limits 1.32–3.23; P < 0.001 for G12269A genotype). The adjusted hazard ratio for participants with homozygous ACE haplotypes compared to those heterozygous ACE haplotypes was 1.40 (1.13–1.75; P = 0.003 for haplotype). The ACE genotype effects were specific for ACE inhibition (i.e., not seen among those randomized to a calcium channel blocker), and were independent of population stratification.

Conclusions

African-Americans with a homozygous genotype at G12269A or homozygous ACE haplotypes responded to ramipril significantly faster than those with a heterozygous genotype or heterozygous haplotypes, suggesting that heterosis may be an important determinant of responsiveness to an ACE inhibitor. These associations may be a result of biological activity of this polymorphism, or of linkage disequilibrium with nearby variants such as the ACE Ins/Del, perhaps in the regulation of ACE splicing.

BACKGROUND

African Americans have a disproportionate burden of hypertension and comorbid disease. Pharmacogenetic markers of blood pressure response have yet to be defined clearly. This study explores the association between G-protein-coupled receptor kinase type 4 (GRK4) variants and blood pressure response to metoprolol among African Americans with early hypertensive nephrosclerosis.

METHODS

Participants from the African American Study of Kidney Disease and Hypertension (AASK) trial were genotyped at three GRK4 polymorphisms: R65L, A142V, and A486V. A Cox proportional hazards model, stratified by gender, was used to determine the relationship between GRK4 variants and time to reach a mean arterial pressure (MAP) of 107 mm Hg, adjusted for other predictors of blood pressure response. Potential interactions between the three polymorphisms were explored by analyzing the effects of gene haplotypes and by stratifying the analysis by neighboring sites.

RESULTS

The hazard ratio with 95% confidence interval by A142V among men randomized to a usual MAP (102–107 mm Hg) was 1.54 (1.11–2.44; P = 0.0009). The hazard ratio by A142V with R65/L65 or L65/L65 was 2.14 (1.35–3.39; P = 0.001). Haplotype analyses were consistent but inconclusive. There was no association between A142V and blood pressure response among women.

CONCLUSIONS

Results suggest a sex-specific relationship between GRK4 A142V and blood pressure response among African-American men with early hypertensive nephrosclerosis. Men with a GRK4 A142 were less responsive to metoprolol if they had a GRK4 L65 variant. The effect of GRK4 variants and blood pressure response to metoprolol should be studied in larger clinical trials.