BACKGROUND: Urine biomarkers of kidney tubule injury associate with incident hypertension in older adults with comorbidities, but less is known about these associations in younger adults. METHODS: In 1170 participants of the CARDIA study (Coronary Artery Risk Development in Young Adults; mean age, 45 years; 40% Black people; 56% women) without hypertension, cardiovascular disease, or kidney disease at baseline, we examined associations of urine MCP-1 (monocyte chemoattractant protein-1), α1m (alpha-1-microglobulin), KIM-1 (kidney injury molecule-1), EGF (epidermal growth factor), IL (interleukin)-18, YKL-40 (chitinase-3-like protein 1), and UMOD (uromodulin) with incident hypertension (onset of systolic blood pressure [BP] ≥130 mm Hg or diastolic BP ≥80 mm Hg or initiation of hypertension medications) and longitudinal BP change in models adjusted for hypertension risk factors, estimated glomerular filtration rate, and albuminuria. RESULTS: After a median 9.9 (interquartile range, 5.9-10.2) years, 376 participants developed incident hypertension. In demographic-adjusted analyses, higher tertiles of EGF associated with lower risk of incident hypertension in both Black and White participants. After multivariable adjustment, the risk of incident hypertension remained lower in tertile 2 (hazard ratio, 0.70 [95% CI, 0.50-0.97]) and tertile 3 (hazard ratio, 0.58 [0.39-0.85]) of EGF versus tertile 1. In fully adjusted models, participants in EGF tertile 3 had smaller 10-year increases in systolic (-3.4 [95% CI, -6.1 to -0.7] mm Hg) and diastolic BP (-2.6 [95% CI, -4.6 to -0.6] mm Hg) than tertile 1. Other biomarkers showed inconsistent associations with incident hypertension and BP change. CONCLUSIONS: In middle-aged adults without hypertension, cardiovascular disease, or kidney disease, higher urine EGF associated with lower risk of incident hypertension and lower 10-year BP elevations.

Deficiency of 25-hydroxyvitamin D (25[OH]D) is common in patients with chronic kidney disease stages 3 and 4 and is associated with poor outcomes. However, the evaluation and management of vitamin D deficiency in nephrology remains controversial. This article reports on the proceedings from a "controversies conference" on vitamin D in chronic kidney disease that was sponsored by the National Kidney Foundation. The report outlines the deliberations of the 3 work groups that participated in the conference. Until newer measurement methods are widely used, the panel agreed that clinicians should classify 25(OH)D "adequacy" as concentrations > 20ng/mL without evidence of counter-regulatory hormone activity (ie, elevated parathyroid hormone). The panel also agreed that 25(OH)D concentrations < 15ng/mL should be treated irrespective of parathyroid hormone level. Patients with 25(OH)D concentrations between 15 and 20ng/mL may not require treatment if there is no evidence of counter-regulatory hormone activity. The panel agreed that nutritional vitamin D (cholecalciferol, ergocalciferol, or calcifediol) should be supplemented before giving activated vitamin D compounds. The compounds need further study evaluating important outcomes that observational studies have linked to low 25(OH)D levels, such as progression to end-stage kidney disease, infections, fracture rates, hospitalizations, and all-cause mortality. We urge further research funding in this field.

RATIONALE & OBJECTIVE: The diagnosis and prognostication of chronic kidney disease (CKD) largely rely on glomerular measures that may not reflect tubular damage. We investigated the associations of urine kidney tubule biomarkers with estimated glomerular filtration rate (eGFR) change among middle-aged adults, when chronic diseases typically emerge. STUDY DESIGN: An observational cohort study. SETTING & PARTICIPANTS: A total of 1,145 participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study without CKD, hypertension, or cardiovascular disease at the year 20 visit. EXPOSURES: Seven different biomarkers of tubular health: urine epidermal growth factor (EGF), alpha-1-microglobulin (α1m), interleukin-18, kidney injury molecule-1, monocyte chemoattractant protein-1, uromodulin, and chitinase-3-like protein 1. OUTCOMES: Ten-year eGFR change and incident reduced eGFR (new onset of eGFR < 60 mL/min/1.73 m2). ANALYTICAL APPROACH: We examined associations of tubular health biomarkers with 10-year eGFR change and incident reduced eGFR with linear mixed models and interval-censored proportional hazards regression models, respectively. Both minimally and fully adjusted models were controlled for urine creatinine levels. RESULTS: The mean age of participants was 44.8 ± 3.7 years, with 39% African American and 56% female. The average 10-year change in eGFR was -18.6 mL/min/1.73 m2 (95% CI, -19.4 to -17.8). In contrast to the other tubular biomarkers, which showed conflicting results, EGF demonstrated strong, consistent associations with both kidney outcomes. Each 1-standard deviation (SD) higher EGF was associated with a 2.37 mL/min/1.73 m2 (95% CI, 0.64-4.10) smaller 10-year decrease in eGFR and a 42% (95% CI, 4%-64%) lower risk of incident reduced eGFR in the fully adjusted model. LIMITATIONS: Observational design, measurements of eGFR were done only at 5-year intervals during follow-up. CONCLUSIONS: In middle-aged, community-dwelling adults without hypertension, cardiovascular disease or CKD, higher urine EGF concentrations are associated with slower eGFR decline, whereas other kidney tubule biomarkers lacked a consistent association with kidney function decline.

Elevations in plasma phosphate concentrations (hyperphosphatemia) occur in chronic kidney disease (CKD), in certain genetic disorders, and following the intake of a phosphate-rich diet. Whether hyperphosphatemia and/or associated changes in metabolic regulators, including elevations of fibroblast growth factor 23 (FGF23) directly contribute to specific complications of CKD is uncertain. Here, we report that similar to patients with CKD, mice with adenine-induced CKD develop inflammation, anemia, and skeletal muscle wasting. These complications are also observed in mice fed high phosphate diet even without CKD. Ablation of pathologic FGF23-FGFR4 signaling did not protect mice on an increased phosphate diet or mice with adenine-induced CKD from these sequelae. However, low phosphate diet ameliorated anemia and skeletal muscle wasting in a genetic mouse model of CKD. Our mechanistic in vitro studies indicate that phosphate elevations induce inflammatory signaling and increase hepcidin expression in hepatocytes, a potential causative link between hyperphosphatemia, anemia, and skeletal muscle dysfunction. Our study suggests that high phosphate intake, as caused by the consumption of processed food, may have harmful effects irrespective of pre-existing kidney injury, supporting not only the clinical utility of treating hyperphosphatemia in CKD patients but also arguing for limiting phosphate intake in healthy individuals.

Background

Antiretroviral therapy (ART) durability, time to modification or cessation, has declined. The study objective was to determine whether kidney dysfunction is contributing to reduced durability.

Methods

This retrospective follow-up study of CNICS evaluated treatment-naive PLWH initiating ART between 2007 and 2014. Regimen modification was defined as cessation/modification of any part of the 3-drug ART regimen. We evaluated the role of kidney dysfunction in initial regimen modification as both a mediator and effect measure modifier. Associations of the variables with the ART modification were examined using univariable and multivariable Cox proportional hazard models.

Results

Of 4515 PLWH included in the analysis, 1967 modified their ART. Of those receiving TDF-based ART (n = 3888), 1580 (41%) modified their regimen compared with 387 (62%) receiving other regimens. Overall, the median eGFR decreased by 5 mL/min/1.73 m (quartiles: first = -16, third = 0) from baseline to follow-up. Of the 128 patients with low baseline eGFR (<60 mL/min/1.73 m), the final eGFR remained low in 73% while it increased to above 60 mL/min/1.73 m in 27%. Of the 4387 with normal baseline eGFR, only 135 (3%) had a final eGFR <60 mL/min/1.73 m. Those with low eGFR at the baseline and/or final visits were more likely to modify ART than others (hazards ratio = 1.75, 95% confidence interval: 1.39 to 2.19, P < 0.001). Relative to other regimens, TDF-based ART was less likely to be modified when accounting for numerous clinical and demographic traits.

Conclusions

For patients in our study initiated on ART, including TDF-based ART, in the last decade, kidney dysfunction is not a major factor leading to regimen modification.

Objectives

Fibroblast growth factor (FGF)-23 is a key regulator of mineral metabolism and has been linked with left ventricular hypertrophy in animal models. Most existing epidemiologic studies evaluated a C-terminal FGF23 assay which measures both the intact (active) hormone and inactive fragments. The relationship of intact FGF23 with cause-specific mortality is unknown.

Design

Prospective analyses of data from Health, Aging, & Body Composition (HABC) study.

Setting

Community-living adults aged 70 to 79 years with longitudinal follow up.

Rationale & objective

Novel urinary biomarkers have enabled earlier detection of kidney tubular damage, but their prognostic value for adverse cardiovascular outcomes is uncertain. We hypothesized that tubular damage, measured by urine α₁-microglobulin (A1M), amino-terminal propeptide of type III procollagen (PIIINP), and neutrophil gelatinase-associated lipocalin (NGAL), would be associated with higher risks for cardiovascular events and mortality among elders.

Study design

Case-cohort study.

Setting & participants

This study included a randomly selected subcohort (n=502), cardiovascular disease (CVD) cases (n=245), and heart failure cases (n=220) from the Health, Aging, and Body Composition (Health ABC) Study.

Predictors

Baseline urine A1M, PIIINP, and NGAL concentrations.

Outcomes

Incident CVD, heart failure, and all-cause mortality.

Analytical approach

Cox proportional hazards models were used to evaluate biomarker associations with each outcome.

Results

At baseline, mean age was 74 years and estimated glomerular filtration rate was 73mL/min/1.73m². After adjustment for demographics, estimated glomerular filtration rate, albumin-creatinine ratio, and other cardiovascular risk factors, each doubling in biomarker concentration was associated with the following adjusted HRs for CVD: A1M, 1.51 (95% CI, 1.16-1.96); PIIINP, 1.21 (95% CI, 1.00-1.46); and NGAL, 1.12 (95% CI, 1.05-1.20). There were 248 deaths in the subcohort during a median follow-up of 12.4 years. Adjusted associations of each biomarker (HR per doubling) with all-cause mortality were: A1M, 1.29 (95% CI, 1.10-1.51); PIIINP, 1.05 (95%, 0.94-1.18); and NGAL, 1.07 (95% CI, 1.02-1.12). Biomarker concentrations did not have statistically significant associations with heart failure after multivariable adjustment.

Limitations

Urine biomarkers were measured at a single time point; no validation cohort available.

Conclusions

Kidney tubular damage is an independent risk factor for CVD and death among elders. Future studies should investigate mechanisms by which kidney tubular damage may adversely affect cardiovascular risk.

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<.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.

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 m(2)) 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.

Background

APOL1 genetic variants confer an increased risk for kidney disease. Their associations with cardiovascular disease (CVD) are less certain. We aimed to compare the prevalence of subclinical CVD and incidence of atherosclerotic CVD and heart failure by APOL1 genotypes among self-identified black participants of MESA (Multi-Ethnic Study of Atherosclerosis).

Methods and results

Cross-sectional associations of APOL1 genotypes (high-risk=2 alleles; low-risk=0 or 1 allele) with coronary artery calcification, carotid-intimal media thickness, and left ventricular mass were evaluated using logistic and linear regression. Longitudinal associations of APOL1 genotypes with incident myocardial infarction, stroke, coronary heart disease, and congestive heart failure were examined using Cox regression. We adjusted for African ancestry, age, and sex. We also evaluated whether hypertension or kidney function markers explained the observed associations. Among 1746 participants with APOL1 genotyping (mean age 62 years, 55% women, mean cystatin C-based estimated glomerular filtration rate 89 mL/min per 1.73 m², 12% with albuminuria), 12% had the high-risk genotypes. We found no difference in prevalence or severity of coronary artery calcification, carotid-intimal media thickness, or left ventricular mass by APOL1 genotypes. The APOL1 high-risk group was 82% more likely to develop incident heart failure compared with the low-risk group (95% confidence interval, 1.01-3.28). Adjusting for hypertension (hazard ratio, 1.80; 95% confidence interval, 1.00-3.24) but not markers of kidney function (hazard ratio, 1.86; 95% confidence interval, 1.03-3.35) slightly attenuated this association. The APOL1 high-risk genotypes were not significantly associated with other clinical CVD outcomes.

Conclusions

Among blacks without baseline CVD, the APOL1 high-risk variants may be associated with increased risk for incident heart failure but not subclinical CVD or incident clinical atherosclerotic CVD.