Orlando M. Gutiérrez

Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease.

CONTEXT A high level of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) is associated with mortality in patients with end-stage renal disease, but little is known about its relationship with adverse outcomes in the much larger population of patients with earlier stages of chronic kidney disease. OBJECTIVE To evaluate FGF-23 as a risk factor for adverse outcomes in patients with chronic kidney disease. DESIGN, SETTING, AND PARTICIPANTS A prospective study of 3879 participants with chronic kidney disease stages 2 through 4 who enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008. MAIN OUTCOME MEASURES All-cause mortality and end-stage renal disease. RESULTS At study enrollment, the mean (SD) estimated glomerular filtration rate (GFR) was 42.8 (13.5) mL/min/1.73 m(2), and the median FGF-23 level was 145.5 RU/mL (interquartile range [IQR], 96-239 reference unit [RU]/mL). During a median follow-up of 3.5 years (IQR, 2.5-4.4 years), 266 participants died (20.3/1000 person-years) and 410 reached end-stage renal disease (33.0/1000 person-years). In adjusted analyses, higher levels of FGF-23 were independently associated with a greater risk of death (hazard ratio [HR], per SD of natural log-transformed FGF-23, 1.5; 95% confidence interval [CI], 1.3-1.7). Mortality risk increased by quartile of FGF-23: the HR was 1.3 (95% CI, 0.8-2.2) for the second quartile, 2.0 (95% CI, 1.2-3.3) for the third quartile, and 3.0 (95% CI, 1.8-5.1) for the fourth quartile. Elevated fibroblast growth factor 23 was independently associated with significantly higher risk of end-stage renal disease among participants with an estimated GFR between 30 and 44 mL/min/1.73 m(2) (HR, 1.3 per SD of FGF-23 natural log-transformed FGF-23; 95% CI, 1.04-1.6) and 45 mL/min/1.73 m(2) or higher (HR, 1.7; 95% CI, 1.1-2.4), but not less than 30 mL/min/1.73 m(2). CONCLUSION Elevated FGF-23 is an independent risk factor for end-stage renal disease in patients with relatively preserved kidney function and for mortality across the spectrum of chronic kidney disease.

Healthy behaviors, risk factor control and awareness of chronic kidney disease

Background/Aims: The association between chronic kidney disease (CKD) awareness and healthy behaviors is unknown. We examined whether CKD self-recognition is associated with healthy behaviors and achieving risk-reduction targets known to decrease risk of cardiovascular morbidity and CKD progression. Methods: CKD awareness, defined as a ‘yes’ response to ‘Has a doctor or other health professional ever told you that you had kidney disease?’, was examined among adults with CKD (eGFR <60 ml/min/1.73 m2) who participated in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Odds of participation in healthy behaviors (tobacco avoidance, avoidance of regular nonsteroidal anti-inflammatory drug use, and physical activity) and achievement of risk-reduction targets (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, systolic blood pressure control and glycemic control among those with diabetes) among those aware versus unaware of their CKD were determined by logistic regression, controlling for sociodemographics, access to care and comorbid conditions. Systolic blood pressure control was defined as <130 mm Hg (primary definition) or <140 mm Hg (secondary definition). Results: Of 2,615 participants, only 6% (n = 166) were aware of having CKD. Those who were aware had 82% higher odds of tobacco avoidance compared to those unaware (adjusted OR = 1.82, 95% CI 1.02–3.24). CKD awareness was not associated with other healthy behaviors or achievement of risk-reduction targets. Conclusions: Awareness of CKD was only associated with participation in one healthy behavior and was not associated with achievement of risk-reduction targets. To encourage adoption of healthy behaviors, a better understanding of barriers to participation in CKD-healthy behaviors is needed.

Association between Soluble Klotho and Change in Kidney Function: The Health Aging and Body Composition Study

CKD appears to be a condition of soluble klotho deficiency. Despite known associations between low soluble klotho levels and conditions that promote kidney damage, such as oxidative stress and fibrosis, little information exists regarding the longitudinal association between soluble klotho levels and change in kidney function. We assayed serum soluble α-klotho in 2496 participants within the Health Aging and Body Composition study, a cohort of older adults. The associations between soluble klotho levels and decline in kidney function (relative decline: eGFR decline ≥30%; absolute decline: eGFR decline >3 ml/min per year) and incident CKD (incident eGFR <60 ml/min per 1.73 m2 and >1 ml/min per year decline) were evaluated. We adjusted models for demographics, baseline eGFR, urine albumin-to-creatinine ratio, comorbidity, and measures of mineral metabolism. Among participants, the mean (SD) age was 75 (3) years, 52% were women, and 38% were black. Median (25th, 75th percentiles) klotho level was 630 (477, 817) pg/ml. In fully adjusted models, each two-fold higher level of klotho associated with lower odds of decline in kidney function (odds ratio, 0.78 [95% confidence interval, 0.66 to 0.93] for 30% decline in eGFR, and 0.85 [95% confidence interval, 0.73 to 0.98] for >3 ml/min per year decline in eGFR), but not of incident CKD (incident rate ratio, 0.90 [95% confidence interval, 0.78 to 1.04]). Overall, a higher soluble klotho level independently associated with a lower risk of decline in kidney function. Future studies should attempt to replicate these results in other cohorts and evaluate the underlying mechanism.

Statement of Concern about a Commercial Assay Used to Measure Soluble Hemojuvelin in Humans

pany to detect and measure recombinant human HJV protein and sHJV in cell-conditioned media from HJV-transfected cells. We examined the ability of the USCN ELISA to detect known quantities of fulllength, purified recombinant human HJV protein (hHJV.his; RD USCN Life Science Inc., Wuhan, China). In order to assess the performance of this ELISA, we acquired this kit from the same comPublished online: September 22, 2012

Oxidative Balance Score and Chronic Kidney Disease

Background: The oxidative balance score (OBS) is a composite estimate of the overall pro- and antioxidant exposure status in an individual. The aim of this study was to determine the association between OBS and renal disease. Methods: Using the Reasons for Geographic and Racial Differences in Stroke cohort study, OBS was calculated by combining 13 a priori-defined pro- and antioxidant factors by using baseline dietary and lifestyle assessment. OBS was divided into quartiles (Q1-Q4) with the lowest quartile, Q1 (predominance of pro-oxidants), as the reference. Multivariable logistic regression and Cox proportional hazards models were used to estimate adjusted ORs for albuminuria defined as urine albumin/creatinine ratio (ACR) >30 mg/g, macroalbuminuria defined as ACR >300 mg/g and chronic kidney disease (CKD) defined as estimated glomerular filtration rate <60 ml/min/1.73 m2 according to the Chronic Kidney Disease Epidemiology Collaboration and hazards ratios for end-stage renal disease (ESRD), respectively. Results: Of the 19,461 participants analyzed, 12.9% had albuminuria and 10.1% had CKD at baseline; over a median follow-up of 3.5 years (range 2.14-4.32 years), 0.46% developed ESRD. Higher OBS quartiles were associated with lower prevalence of CKD (OR vs. Q1: Q2 = 0.93 [95% CI 0.80-1.08]; Q3 = 0.90 [95% CI 0.77-1.04] and Q4 = 0.79 [95% CI 0.67-0.92], p for trend <0.01). The associations between OBS and albuminuria (p for trend 0.31) and incident ESRD (p for trend 0.56) were not significant in the fully adjusted models. Conclusions: These findings suggest that higher OBS is associated with lower prevalence of CKD. Lack of association with ESRD incidence in the multivariable analyses indicates that temporal relation between OBS and renal damage remains unclear.

FGF23 (Fibroblast Growth Factor-23) and Incident Hypertension in Young and Middle-Aged AdultsNovelty and Significance: The CARDIA Study

Blacks have the highest prevalence of hypertension in the United States. Higher levels of FGF23 (fibroblast growth factor-23) have been associated with worse cardiovascular outcomes. Whether FGF23 is associated with rising blood pressure (BP) and racial differences in incident hypertension is unclear. We studied 1758 adults (45.0±3.7 years; 57.8% female; 36.9% black) without hypertension or cardiovascular disease who participated in the year 20 (2005–2006) follow-up examination of the CARDIA study (Coronary Artery Risk Development in Young Adults). We investigated the associations of baseline (year 20) cFGF23 (C-terminal FGF23) levels with longitudinal BP patterns and incident hypertension (defined as being on antihypertensive medication, systolic BP ≥130 or diastolic BP ≥80 mm Hg) during 2 follow-up visits (years 25 and 30). During follow-up, 35.2% of participants developed hypertension. In multivariable linear mixed models, there were greater increases in systolic BP from year 20 to 25 and year 25 to 30 in the highest FGF23 quartile relative to the lowest quartile (+2.1 mm Hg, P=0.0057 and +2.2 mm Hg, P=0.0108, respectively for each time period), whereas there were greater increases in diastolic BP from year 20 to 25 in the highest quartile relative to the lowest (+1.6 mm Hg; P=0.0024). In multivariable modified Poisson regression analyses, the highest FGF23 quartile was associated with a 45% greater risk of developing hypertension during follow-up compared with the lowest quartile (relative risk, 1.45 [1.18–1.77]). Results did not vary by race (Pinteraction=0.1523). Higher FGF23 levels are independently associated with rising BP over time and an increased risk of incident hypertension but not racial differences in hypertension.

Oxidative Balance Score and the Risk of End-Stage Renal Disease and Cardiovascular Disease

Background: Oxidative balance score (OBS) is a composite measure of oxidative stress-related exposures. The aim of this study was to investigate the association between OBS, end-stage renal disease (ESRD), and cardiovascular disease (CVD). Methods: Using data from the Chronic Renal Insufficiency Cohort, we calculated the main exposure OBS by summing up 12 apriori-defined pro- and antioxidant factors obtained from the diet history questionnaire and lifestyle assessment. We divided OBS into quartiles (Q1-Q4), with Q1 (predominance of pro-oxidants) as the reference. We analyzed OBS quartiles as an ordinal variable. Crude and adjusted hazards ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models for time to ESRD and CVD. Results: Compared to Q1, Q4 (high antioxidant) was associated with ESRD in the crude model (HR 1.35, 95% CI 1.08-1.69) and adjusting for age, sex, and race (HR 1.36, 95% CI 1.09-1.71) but not in the fully adjusted model (HR 1.12, 95% CI 0.84-1.51). HR of ESRD increased as the OBS quartiles increased in the crude model (ptrend < 0.05) but not in the fully adjusted model (ptrend = 0.30). Compared to Q1, Q4 was associated with CVD in the crude (HR 1.33, 95% CI 1.06-1.68) but not adjusted models. The HR of CVD increased with an increase in OBS quartiles in the crude model (ptrend < 0.05). Conclusion: The reverse association between OBS and progression to ESRD suggests that perhaps the effect of oxidative balance-related exposure is different in the setting of established chronic kidney disease.

Vitamin D and Racial Differences in Chronic Kidney Disease

Compared to Caucasians, African Americans have lower circulating concentrations of 25-hydroxyvitamin D (25(OH)D), the major storage form of vitamin D, leading to the widespread assumption that blacks are at higher risk of vitamin D deficiency. Since low 25(OH)D is associated with adverse cardiovascular and kidney outcomes, this has supported the notion that low 25(OH)D concentrations partly underlie racial disparities in health outcomes, including faster progression of chronic kidney disease (CKD) in blacks vs. whites. However, the finding that blacks maintain better indices of musculoskeletal health than whites throughout their lifespan despite having lower circulating 25(OH)D concentrations suggests that the relationship between vitamin D deficiency and racial health disparities may not be so straight forward. This has been further underscored by epidemiologic studies showing major racial heterogeneity in the association of 25(OH)D with cardiovascular outcomes. When coupled with emerging data showing genetically determined differences in the bioavailability of vitamin D by race, these data suggest that there are important differences in vitamin D metabolism by race which need to inform and perhaps revise our current understanding of the role of vitamin D in racial disparities in CKD outcomes.