Ana C. Ricardo

Fibroblast Growth Factor 23 and Inflammation in CKD

BACKGROUND AND OBJECTIVES Levels of fibroblast growth factor 23 (FGF23) and inflammatory markers are commonly elevated in CKD, and each is associated with adverse clinical outcomes. This study tested the hypothesis that FGF23 is independently associated with inflammation in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The association between levels of FGF23 and the inflammatory markers IL-6, C-reactive protein (CRP), TNF-α, and fibrinogen was assessed in a cross-sectional analysis of 3879 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study between June 2003 and September 2008. RESULTS FGF23 correlated directly with IL-6 (r=0.4), CRP (r=0.2), TNF-α (r=0.4), and fibrinogen (r=0.3; P<0.001 for each). In univariate and multivariable-adjusted linear regression analyses, natural log (ln) transformed FGF23 was significantly associated with lnIL-6, lnCRP, lnTNF-α, and fibrinogen (P<0.001 for each). Each unit higher lnFGF23 was associated with severe inflammation, defined as levels of all inflammatory markers in the highest 25th percentile, in univariate (odds ratio [OR], 2.4 [95% confidence interval (CI), 2.0-2.9]) and multivariable-adjusted (OR, 2.0 [95% CI, 1.6-2.5]) logistic regression analyses. Ascending FGF23 quartiles were independently associated with severe inflammation (OR, 5.6 for the highest versus lowest FGF23 quartile [95% CI, 2.3-13.9]; P for trend < 0.001). CONCLUSIONS Higher FGF23 levels are independently associated with higher levels of inflammatory markers in patients with CKD and with significantly greater odds of severe inflammation. Future studies should evaluate whether inflammation modifies the association between FGF23 and adverse outcomes in CKD.

CKD in Hispanics: Baseline characteristics from the CRIC (Chronic Renal Insufficiency Cohort) and Hispanic-CRIC Studies

BACKGROUND Little is known regarding chronic kidney disease (CKD) in Hispanics. We compared baseline characteristics of Hispanic participants in the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC (H-CRIC) Studies with non-Hispanic CRIC participants. STUDY DESIGN Cross-sectional analysis. SETTING & PARTICIPANTS Participants were aged 21-74 years with CKD using age-based estimated glomerular filtration rate (eGFR) at enrollment into the CRIC/H-CRIC Studies. H-CRIC included Hispanics recruited at the University of Illinois in 2005-2008, whereas CRIC included Hispanics and non-Hispanics recruited at 7 clinical centers in 2003-2007. FACTOR Race/ethnicity. OUTCOMES Blood pressure, angiotensin-converting enzyme (ACE)-inhibitor/angiotensin receptor blocker (ARB) use, and CKD-associated complications. MEASUREMENTS Demographic characteristics, laboratory data, blood pressure, and medications were assessed using standard techniques and protocols. RESULTS Of H-CRIC/CRIC participants, 497 were Hispanic, 1,650 were non-Hispanic black, and 1,638 were non-Hispanic white. Low income and educational attainment were nearly twice as prevalent in Hispanics compared with non-Hispanics (P < 0.01). Hispanics had self-reported diabetes (67%) more frequently than non-Hispanic blacks (51%) and whites (40%; P < 0.01). Blood pressure >130/80 mm Hg was more common in Hispanics (62%) than blacks (57%) and whites (35%; P < 0.05), and abnormalities in hematologic, metabolic, and bone metabolism parameters were more prevalent in Hispanics (P < 0.05), even after stratifying by entry eGFR. Hispanics had the lowest use of ACE inhibitors/ARBs among the high-risk subgroups, including participants with diabetes, proteinuria, and blood pressure >130/80 mm Hg. Mean eGFR was lower in Hispanics (39.6 mL/min/1.73 m(2)) than in blacks (43.7 mL/min/1.73 m(2)) and whites (46.2 mL/min/1.73 m(2)), whereas median proteinuria was higher in Hispanics (protein excretion, 0.72 g/d) than in blacks (0.24 g/d) and whites (0.12 g/d; P < 0.01). LIMITATIONS Generalizability; observed associations limited by residual bias and confounding. CONCLUSIONS Hispanics with CKD in the CRIC/H-CRIC Studies are disproportionately burdened with lower socioeconomic status, more frequent diabetes mellitus, less ACE-inhibitor/ARB use, worse blood pressure control, and more severe CKD and associated complications than their non-Hispanic counterparts.

Sleep Disturbances as Nontraditional Risk Factors for Development and Progression of CKD: Review of the Evidence

Despite the high prevalence and enormous public health implications of chronic kidney disease (CKD), the factors responsible for its development and progression are incompletely understood. To date, only a few studies have attempted to objectively characterize sleep in patients with CKD prior to kidney failure, but emerging evidence suggests a high prevalence of sleep disorders, particularly obstructive sleep apnea. Laboratory and epidemiologic studies have shown that insufficient sleep and poor sleep quality promote the development and exacerbate the severity of 3 important risk factors for CKD, namely hypertension, type 2 diabetes, and obesity. In addition, sleep disturbances might have a direct effect on CKD through chronobiological alterations in the renin-angiotensin-aldosterone system and sympathetic nervous system activation. The negative impact of sleep disorders on vascular compliance and endothelial function also may have a deleterious effect on CKD. Sleep disturbances therefore may represent a novel risk factor for the development and progression of CKD. Optimizing sleep duration and quality and treating sleep disorders may reduce the severity and delay the progression of CKD.

Apolipoprotein L1 gene variants associate with prevalent kidney but not prevalent cardiovascular disease in The Systolic Blood Pressure Intervention Trial

Apolipoprotein L1 gene (APOL1) G1 and G2 coding variants are strongly associated with chronic kidney disease (CKD) in African Americans. Here APOL1 association was tested with baseline estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (UACR), and prevalent cardiovascular disease (CVD) in 2,571 African Americans from the Systolic Blood Pressure Intervention Trial (SPRINT), a trial assessing effects of systolic blood pressure reduction on renal and CVD outcomes. Logistic regression models that adjusted for potentially important confounders tested for association between APOL1 risk variants and baseline clinical CVD (myocardial infarction, coronary or carotid artery revascularization) and CKD (eGFR under 60 ml/min/1.73m2 and/or UACR over 30 mg/g). African American SPRINT participants were 45.3% female with mean (median) age of 64.3 (63) years, mean arterial pressure 100.7 (100) mmHg, eGFR 76.3 (77.1) ml/min/1.73m2, UACR 49.9 (9.2) mg/g, and 8.2% had clinical CVD. APOL1 (recessive inheritance) was positively associated with CKD (odds ratio 1.37, 95% confidence interval 1.08–1.73) and log UACR estimated slope [β] 0.33) and negatively associated with eGFR (β −3.58), all significant. APOL1 risk variants were not significantly associated with prevalent CVD (1.02, 0.82–1.27). Thus, SPRINT data show that APOL1 risk variants are associated with mild CKD but not prevalent CVD in African American with a UACR under 1000 mg/g.

Sodium excretion and the risk of cardiovascular disease in patients with chronic kidney disease

IMPORTANCE Patients with chronic kidney disease (CKD) are at an increased risk of cardiovascular disease (CVD) compared with the general population. Prior studies have produced contradictory results on the association of dietary sodium intake with risk of CVD, and this relationship has not been investigated in patients with CKD. OBJECTIVE To evaluate the association between urinary sodium excretion and clinical CVD events among patients with CKD. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study of patients with CKD from 7 locations in the United States enrolled in the Chronic Renal Insufficiency Cohort Study and followed up from May 2003 to March 2013. EXPOSURES The cumulative mean of urinary sodium excretion from three 24-hour urinary measurements and calibrated to sex-specific mean 24-hour urinary creatinine excretion. MAIN OUTCOMES AND MEASURES A composite of CVD events defined as congestive heart failure, stroke, or myocardial infarction. Events were reported every 6 months and confirmed by medical record adjudication. RESULTS Among 3757 participants (mean age, 58 years; 45% women), 804 composite CVD events (575 heart failure, 305 myocardial infarction, and 148 stroke) occurred during a median 6.8 years of follow-up. From lowest (<2894 mg/24 hours) to highest (≥4548 mg/24 hours) quartile of calibrated sodium excretion, 174, 159, 198, and 273 composite CVD events occurred, and the cumulative incidence was 18.4%, 16.5%, 20.6%, and 29.8% at median follow-up. In addition, the cumulative incidence of CVD events in the highest quartile of calibrated sodium excretion compared with the lowest was 23.2% vs 13.3% for heart failure, 10.9% vs 7.8% for myocardial infarction, and 6.4% vs 2.7% for stroke at median follow-up. Hazard ratios of the highest quartile compared with the lowest quartile were 1.36 (95% CI, 1.09-1.70; P = .007) for composite CVD events, 1.34 (95% CI, 1.03-1.74; P = .03) for heart failure, and 1.81 (95% CI, 1.08-3.02; P = .02) for stroke after multivariable adjustment. Restricted cubic spline analyses of the association between sodium excretion and composite CVD provided no evidence of a nonlinear association (P = .11) and indicated a significant linear association (P < .001). CONCLUSIONS AND RELEVANCE Among patients with CKD, higher urinary sodium excretion was associated with increased risk of CVD.

Effects of Intensive BP Control in CKD

The appropriate target for BP in patients with CKD and hypertension remains uncertain. We report prespecified subgroup analyses of outcomes in participants with baseline CKD in the Systolic Blood Pressure Intervention Trial. We randomly assigned participants to a systolic BP target of <120 mm Hg (intensive group; n=1330) or <140 mm Hg (standard group; n=1316). After a median follow-up of 3.3 years, the primary composite cardiovascular outcome occurred in 112 intensive group and 131 standard group CKD participants (hazard ratio [HR], 0.81; 95% confidence interval [95% CI], 0.63 to 1.05). The intensive group also had a lower rate of all-cause death (HR, 0.72; 95% CI, 0.53 to 0.99). Treatment effects did not differ between participants with and without CKD (P values for interactions ≥0.30). The prespecified main kidney outcome, defined as the composite of ≥50% decrease in eGFR from baseline or ESRD, occurred in 15 intensive group and 16 standard group participants (HR, 0.90; 95% CI, 0.44 to 1.83). After the initial 6 months, the intensive group had a slightly higher rate of change in eGFR (-0.47 versus -0.32 ml/min per 1.73 m2 per year; P<0.03). The overall rate of serious adverse events did not differ between treatment groups, although some specific adverse events occurred more often in the intensive group. Thus, among patients with CKD and hypertension without diabetes, targeting an SBP<120 mm Hg compared with <140 mm Hg reduced rates of major cardiovascular events and all-cause death without evidence of effect modifications by CKD or deleterious effect on the main kidney outcome.

Non-GFR Determinants of Low-Molecular-Weight Serum Protein Filtration Markers in CKD

BACKGROUND Unlike the case with creatinine, conditions affecting the non-glomerular filtration rate (GFR) determinants of low-molecular-weight serum proteins, β-trace protein (BTP), β2-microglobulin (B2M), and cystatin C, are not well characterized. STUDY DESIGN Pooled cross-sectional analysis of 3 studies. SETTING & PARTICIPANTS 3,156 persons with chronic kidney disease from the MDRD (Modification of Diet in Renal Disease) Study, AASK (African American Study of Kidney Disease and Hypertension), and CRIC (Chronic Renal Insufficiency Cohort) Study. PREDICTORS Demographic and clinical factors hypothesized to be associated with non-GFR determinants of the filtration markers, selected from literature review and physiologic and clinical considerations. OUTCOMES Serum creatinine, BTP, B2M, and cystatin C levels. RESULTS In multivariable-adjusted errors-in-variables regression models that included adjustment for measured GFR (mGFR) and mGFR measurement error, creatinine level had stronger associations with male sex, black race, and higher urine creatinine excretion than the other filtration markers. BTP was associated less strongly with age, similar in direction with sex, and opposite in direction with race than creatinine level. Like cystatin C, B2M level was associated less strongly with age, sex, and race than creatinine level. BTP, B2M, and cystatin C levels were associated more strongly than creatinine level with other factors, including urine protein excretion and weight for BTP, smoking and urine protein excretion for B2M, and smoking for cystatin C. LIMITATIONS Findings may not be generalizable to populations without chronic kidney disease, and residual confounding with GFR due to incomplete adjustment for GFR measurement error. CONCLUSIONS Like creatinine, serum levels of low-molecular-weight proteins are affected by conditions other than GFR. Knowledge of these conditions can aid the interpretation of GFR estimates and risk using these markers and guide the use of these filtration markers in developing GFR estimating equations.

Limited health literacy is associated with low glomerular filtration in the Chronic Renal Insufficiency Cohort (CRIC) study.

Background: Low health literacy in the general population is associated with increased risk of death and hospitalization. The evaluation of health literacy in individuals with predialysis chronic kidney disease (CKD) is limited. Methods: We conducted a cross-sectional study to evaluate the associations of limited health literacy with kidney function and cardiovascular disease (CVD) risk factors in 2,340 non-Hispanic (NH) Whites and Blacks aged 21 – 74 years with mild-to-moderate CKD. Limited health literacy was defined as a Short Test of Functional Health Literacy in Adults (STOFHLA) score ≤ 22. Outcomes evaluated included estimated glomerular filtration rate (eGFR), 24-hour urine protein excretion, and CVD risk factors. Results: The prevalence of limited health literacy was 28% in NH-Blacks and 5% in NH-Whites. Compared with participants with adequate health literacy, those with limited health literacy were more likely to have lower eGFR (34 vs. 42 mL/min/1.73 m2); higher urine protein/24-hours (0.31 vs. 0.15 g); and higher self-reported CVD (61 vs. 37%); and were less likely to have BP < 130/80 mmHg (51 vs. 58%); p ≤ 0.01 for each comparison. After adjustment, limited health literacy was associated with self-reported CVD (OR 1.51, 95% CI 1.13 – 2.03) and lower eGFR (β –2.47, p = 0.03). Conclusion: In this CKD cohort, limited health literacy was highly prevalent, especially among NH-Blacks, and it was associated with lower eGFR and a less favorable CVD risk factor profile. Further studies are needed to better understand these associations and inform the development of health literacy interventions among individuals with CKD.

Adherence to a Healthy Lifestyle and All-Cause Mortality in CKD

BACKGROUND AND OBJECTIVE Among general populations, a healthy lifestyle has been associated with lower risk of death. This study evaluated this association in individuals with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 2288 participants with CKD (estimated GFR < 60 ml/min per 1.73 m(2) or microalbuminuria) in the Third National Health and Nutrition Examination Survey were included. A weighted healthy lifestyle score was calculated (range, -4 to 15, with 15 indicating healthiest lifestyle) on the basis of the multivariable Cox proportional hazards model regression coefficients of the following lifestyle factors: smoking habit, body mass index (BMI), physical activity, and diet. Main outcome was all-cause mortality, ascertained through December 31, 2006. RESULTS After median follow-up of 13 years, 1319 participants had died. Compared with individuals in the lowest quartile of weighted healthy lifestyle score, adjusted hazard ratios (95% confidence intervals) of all-cause mortality were 0.53 (0.41-0.68), 0.52 (0.42-0.63), and 0.47 (0.38-0.60) for individuals in the second, third, and fourth quartiles, respectively. Mortality increased 30% among individuals with a BMI of 18.5 to <22 kg/m(2) versus 22 to <25 kg/m(2) (P<0.05); decreased mortality was associated with never-smoking versus current smoking (0.54 [0.41-0.70]) and regular versus no physical activity (0.80 [0.65-0.99]). Diet was not significantly associated with mortality. CONCLUSIONS Compared with nonadherence, adherence to a healthy lifestyle was associated with lower all-cause mortality risk in CKD. Examination of individual components of the healthy lifestyle score, with adjustment for other components, suggested that the greatest reduction in all-cause mortality was related to nonsmoking.

Association of Fibroblast Growth Factor 23 With Atrial Fibrillation in Chronic Kidney Disease, From the Chronic Renal Insufficiency Cohort Study

IMPORTANCE Levels of fibroblast growth factor 23 (FGF23) are elevated in chronic kidney disease (CKD) and strongly associated with left ventricular hypertrophy, heart failure, and death. Whether FGF23 is an independent risk factor for atrial fibrillation in CKD is unknown. OBJECTIVE To investigate the association of FGF23 with atrial fibrillation in CKD. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of 3876 individuals with mild to severe CKD who enrolled in the Chronic Renal Insufficiency Cohort Study between June 19, 2003, and September 3, 2008, and were followed up through March 31, 2013. EXPOSURES Baseline plasma FGF23 levels. MAIN OUTCOMES AND MEASURES Prevalent and incident atrial fibrillation. RESULTS The study cohort comprised 3876 participants. Their mean (SD) age was 57.7 (11.0) years, and 44.8% (1736 of 3876) were female. Elevated FGF23 levels were independently associated with increased odds of prevalent atrial fibrillation (n = 660) after adjustment for cardiovascular and CKD-specific factors (odds ratio of highest vs lowest FGF23 quartile, 2.30; 95% CI, 1.69-3.13; P < .001 for linear trend across quartiles). During a median follow-up of 7.6 years (interquartile range, 6.3-8.6 years), 247 of the 3216 participants who were at risk developed incident atrial fibrillation (11.9 events per 1000 person-years). In fully adjusted models, elevated FGF23 was independently associated with increased risk of incident atrial fibrillation after adjustment for demographic, cardiovascular, and CKD-specific factors, and other markers of mineral metabolism (hazard ratio of highest vs lowest FGF23 quartile, 1.59; 95% CI, 1.00-2.53; P = .02 for linear trend across quartiles). The results were unchanged when further adjusted for ejection fraction, but individual adjustments for left ventricular mass index, left atrial area, and interim heart failure events partially attenuated the association of elevated FGF23 with incident atrial fibrillation. CONCLUSIONS AND RELEVANCE Elevated FGF23 is independently associated with prevalent and incident atrial fibrillation in patients with mild to severe CKD. The effect may be partially mediated through a diastolic dysfunction pathway that includes left ventricular hypertrophy, atrial enlargement, and heart failure events.