Cystatin C Use for CKD Detection in the Veterans Health Administration System: A Qualitative Study of Barriers and Facilitators.

Rationale & Objective: The measurement of cystatin C has been recommended to enhance chronic kidney disease (CKD) detection and risk stratification in clinical practice. This study gathered insights into the perceptions and experiences of clinical staff regarding the use of cystatin C in CKD detection within the Veterans Health Administration (VHA) system. Study Design: A qualitative approach was employed to explore barriers and facilitators of clinical staff regarding the use of cystatin C in CKD detection within the VHA system. The Organizational Theory of Implementation Effectiveness informed the development of a semistructured interview guide. Setting & Participants: Health care providers, nurses, and clinical pharmacists from the VHA systems in San Francisco, San Diego, and Houston were interviewed between October 2021 and May 2022. Exposures: Participants' experiences with cystatin C testing. Outcomes: Perceived barriers and facilitators to cystatin C testing. Analytical Approach: Participant responses from individual interviews were analyzed by a multidisciplinary team using rapid qualitative analysis methods. Results: Fourteen in-depth interviews were conducted across the 3 VHA systems. Ten of 11 providers worked in primary care. Five key barriers to using cystatin C for CKD detection were identified. These included lack of patient awareness of CKD testing, lack of provider awareness about cystatin C, knowledge barriers about cystatin C testing, unclear roles and ownership of CKD detection, and lack of clinic support to enhance CKD detection. Suggested interventions to overcome these barriers included educational and training programs, improved clinic workflows, and electronic health record aids to support CKD detection and use of cystatin C. Limitations: The results may not be generalizable to other health care systems outside the VHA. Conclusions: The findings indicate a need for targeted interventions such as educational and training programs, improved clinical workflows, and electronic health record aids to address barriers limiting the use of cystatin C in clinical practice for enhanced CKD detection.

This study assessed how clinical staff at the Veterans Health Administration (VHA) feel about using a test called cystatin C to help detect chronic kidney disease (CKD) earlier and more accurately. The research team spoke to healthcare providers, nurses, and clinical pharmacists in San Francisco, San Diego, and Houston between October 2021 and May 2022. We conducted 14 detailed interviews to understand the challenges and opportunities in using cystatin C for CKD detection. We found that participants often lacked awareness of CKD and the benefits of testing with cystatin C. There were also gaps in knowledge about how to use the test effectively, confusion over who should be responsible for CKD detection, and a need for better support within clinics to use cystatin C. To address these issues, there should be more educational programs for both staff and patients, improvements in clinic processes, and enhancements to electronic health records to better support CKD detection using cystatin C. However, the results from this study might not apply to other healthcare systems outside the VHA.

Development and Validation of the American Heart Association's PREVENT Equations.

BACKGROUND: Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the American Heart Association Predicting Risk of CVD EVENTs (PREVENT) equations among US adults 30 to 79 years of age without known CVD. METHODS: The derivation sample included individual-level participant data from 25 data sets (N=3 281 919) between 1992 and 2017. The primary outcome was CVD (atherosclerotic CVD and heart failure). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, antihypertensive or statin use, and diabetes) and estimated glomerular filtration rate. Models were sex-specific, race-free, developed on the age scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each data set and meta-analyzed. Discrimination was assessed using the Harrell C-statistic. Calibration was calculated as the slope of the observed versus predicted risk by decile. Additional equations to predict each CVD subtype (atherosclerotic CVD and heart failure) and include optional predictors (urine albumin-to-creatinine ratio and hemoglobin A1c), and social deprivation index were also developed. External validation was performed in 3 330 085 participants from 21 additional data sets. RESULTS: Among 6 612 004 adults included, mean±SD age was 53±12 years, and 56% were women. Over a mean±SD follow-up of 4.8±3.1 years, there were 211 515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval, 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (interquartile interval, 0.81-1.16) and 0.94 (0.81-1.13) among female and male participants, respectively. Similar estimates for discrimination and calibration were observed for atherosclerotic CVD- and heart failure-specific models. The improvement in discrimination was small but statistically significant when urine albumin-to-creatinine ratio, hemoglobin A1c, and social deprivation index were added together to the base model to total CVD (ΔC-statistic [interquartile interval] 0.004 [0.004-0.005] and 0.005 [0.004-0.007] among female and male participants, respectively). Calibration improved significantly when the urine albumin-to-creatinine ratio was added to the base model among those with marked albuminuria (>300 mg/g; 1.05 [0.84-1.20] versus 1.39 [1.14-1.65]; P=0.01). CONCLUSIONS: PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults by using routinely available clinical variables.

Estimated Glomerular Filtration Rate, Albuminuria, and Adverse Outcomes: An Individual-Participant Data Meta-Analysis.

Importance: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. Objective: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. Design, Setting, and Participants: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. Exposures: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). Main Outcomes and Measures: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. Results: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). Conclusions and Relevance: In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.

Including measures of chronic kidney disease to improve cardiovascular risk prediction by SCORE2 and SCORE2-OP.

AIMS: The 2021 European Society of Cardiology (ESC) guideline on cardiovascular disease (CVD) prevention categorizes moderate and severe chronic kidney disease (CKD) as high and very-high CVD risk status regardless of other factors like age and does not include estimated glomerular filtration rate (eGFR) and albuminuria in its algorithms, systemic coronary risk estimation 2 (SCORE2) and systemic coronary risk estimation 2 in older persons (SCORE2-OP), to predict CVD risk. We developed and validated an 'Add-on' to incorporate CKD measures into these algorithms, using a validated approach. METHODS: In 3,054 840 participants from 34 datasets, we developed three Add-ons [eGFR only, eGFR + urinary albumin-to-creatinine ratio (ACR) (the primary Add-on), and eGFR + dipstick proteinuria] for SCORE2 and SCORE2-OP. We validated C-statistics and net reclassification improvement (NRI), accounting for competing risk of non-CVD death, in 5,997 719 participants from 34 different datasets. RESULTS: In the target population of SCORE2 and SCORE2-OP without diabetes, the CKD Add-on (eGFR only) and CKD Add-on (eGFR + ACR) improved C-statistic by 0.006 (95%CI 0.004-0.008) and 0.016 (0.010-0.023), respectively, for SCORE2 and 0.012 (0.009-0.015) and 0.024 (0.014-0.035), respectively, for SCORE2-OP. Similar results were seen when we included individuals with diabetes and tested the CKD Add-on (eGFR + dipstick). In 57 485 European participants with CKD, SCORE2 or SCORE2-OP with a CKD Add-on showed a significant NRI [e.g. 0.100 (0.062-0.138) for SCORE2] compared to the qualitative approach in the ESC guideline. CONCLUSION: Our Add-ons with CKD measures improved CVD risk prediction beyond SCORE2 and SCORE2-OP. This approach will help clinicians and patients with CKD refine risk prediction and further personalize preventive therapies for CVD.

Virtual interviewing for graduate medical education recruitment and selection: A BEME systematic review: BEME Guide No. 80.

BACKGROUND: The COVID-19 pandemic caused graduate medical education (GME) programs to pivot to virtual interviews (VIs) for recruitment and selection. This systematic review synthesizes the rapidly expanding evidence base on VIs, providing insights into preferred formats, strengths, and weaknesses. METHODS: PubMed/MEDLINE, Scopus, ERIC, PsycINFO, MedEdPublish, and Google Scholar were searched from 1 January 2012 to 21 February 2022. Two authors independently screened titles, abstracts, full texts, performed data extraction, and assessed risk of bias using the Medical Education Research Quality Instrument. Findings were reported according to Best Evidence in Medical Education guidance. RESULTS: One hundred ten studies were included. The majority (97%) were from North America. Fourteen were conducted before COVID-19 and 96 during the pandemic. Studies involved both medical students applying to residencies (61%) and residents applying to fellowships (39%). Surgical specialties were more represented than other specialties. Applicants preferred VI days that lasted 4-6 h, with three to five individual interviews (15-20 min each), with virtual tours and opportunities to connect with current faculty and trainees. Satisfaction with VIs was high, though both applicants and programs found VIs inferior to in-person interviews for assessing 'fit.' Confidence in ranking applicants and programs was decreased. Stakeholders universally noted significant cost and time savings with VIs, as well as equity gains and reduced carbon footprint due to eliminating travel. CONCLUSIONS: The use of VIs for GME recruitment and selection has accelerated rapidly. The findings of this review offer early insights that can guide future practice, policy, and research.

Improving chronic kidney disease detection and treatment in the United States: the chronic kidney disease cascade of care (C3) study protocol.

BACKGROUND: There are major gaps in the implementation of guideline-concordant care for persons with chronic kidney disease (CKD). The CKD Cascade of Care (C3) initiative seeks to improve CKD care by improving detection and treatment of CKD in primary care. METHODS: C3 is a multi-modal initiative deployed in three major academic medical centers within the Department of Veterans Affairs (VA) Health Care System: San Francisco VA, San Diego VA, and Houston VA. The main objective of the first phase of C3 described in this protocol is to establish the infrastructure for universal CKD detection among primary care patients at high-risk for CKD with a triple-marker screen comprising cystatin C, creatinine, and albuminuria. Across the three sites, a comprehensive educational intervention and the integration of primary care-based clinical champions will be employed with the goal of improving CKD detection and treatment. The San Francisco VA will also implement a practice-facilitation intervention leveraging telehealth and health informatics tools and capabilities for enhanced CKD detection. Parallel formative evaluation across the three sites will assess the feasibility and acceptability of integrating cystatin C as part of routine CKD detection in primary care practice. The effectiveness of the interventions will be assessed using a pre-post observational design for change in the proportion of patients tested annually for CKD. Secondary outcomes will assess change in the initiation of cardio-kidney protective therapies and in nephrology referrals of high-risk patients. DISCUSSION: The first phase of C3 is a multi-facility multi-modal initiative that aims to improve CKD care by implementing a triple-marker screen for enhanced CKD detection in primary care.

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.

BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Association of Gender and Race/Ethnicity with Internal Medicine In-Training Examination Performance in Graduate Medical Education.

BACKGROUND: Disparities in objective assessments in graduate medical education such as the In-Training Examination (ITE) that disadvantage women and those self-identifying with race/ethnicities underrepresented in medicine (URiM) are of concern. OBJECTIVE: Examine ITE trends longitudinally across post-graduate year (PGY) with gender and race/ethnicity. DESIGN: Longitudinal analysis of resident ITE metrics at 7 internal medicine residency programs, 2014-2019. ITE trends across PGY of women and URiM residents compared to non-URiM men assessed via ANOVA. Those with ITE scores associated with less than 90% probability of passing the American Board of Internal Medicine certification exam (ABIM-CE) were identified and odds of being identified as at-risk between groups were assessed with chi square. PARTICIPANTS: A total of 689 IM residents, including 330 women and URiM residents (48%). MAIN MEASURES: ITE score KEY RESULTS: There was a significant difference in ITE score across PGY for women and URiM residents compared to non-URiM men (F(2, 1321) 4.46, p=0.011). Adjusting for program, calendar year, and baseline ITE, women and URiM residents had smaller ITE score gains (adjusted mean change in score between PGY1 and PGY3 (se), non-URiM men 13.1 (0.25) vs women and URiM residents 11.4 (0.28), p<0.001). Women and URiM residents had greater odds of being at potential risk for not passing the ABIM-CE (OR 1.75, 95% CI 1.10 to 2.78) with greatest odds in PGY3 (OR 3.13, 95% CI 1.54 to 6.37). CONCLUSION: Differences in ITE over training were associated with resident gender and race/ethnicity. Women and URiM residents had smaller ITE score gains across PGY translating into greater odds of potentially being seen as at-risk for not passing the ABIM-CE. Differences in ITE over training may reflect differences in experiences of women and URiM residents during training and may lead to further disparities.

Albuminuria Testing in Hypertension and Diabetes: An Individual-Participant Data Meta-Analysis in a Global Consortium.

[Figure: see text].

Incorporating kidney disease measures into cardiovascular risk prediction: Development and validation in 9 million adults from 72 datasets.

BACKGROUND: Chronic kidney disease (CKD) measures (estimated glomerular filtration rate [eGFR] and albuminuria) are frequently assessed in clinical practice and improve the prediction of incident cardiovascular disease (CVD), yet most major clinical guidelines do not have a standardized approach for incorporating these measures into CVD risk prediction. "CKD Patch" is a validated method to calibrate and improve the predicted risk from established equations according to CKD measures. METHODS: Utilizing data from 4,143,535 adults from 35 datasets, we developed several "CKD Patches" incorporating eGFR and albuminuria, to enhance prediction of risk of atherosclerotic CVD (ASCVD) by the Pooled Cohort Equation (PCE) and CVD mortality by Systematic COronary Risk Evaluation (SCORE). The risk enhancement by CKD Patch was determined by the deviation between individual CKD measures and the values expected from their traditional CVD risk factors and the hazard ratios for eGFR and albuminuria. We then validated this approach among 4,932,824 adults from 37 independent datasets, comparing the original PCE and SCORE equations (recalibrated in each dataset) to those with addition of CKD Patch. FINDINGS: We confirmed the prediction improvement with the CKD Patch for CVD mortality beyond SCORE and ASCVD beyond PCE in validation datasets (Δc-statistic 0.027 [95% CI 0.018-0.036] and 0.010 [0.007-0.013] and categorical net reclassification improvement 0.080 [0.032-0.127] and 0.056 [0.044-0.067], respectively). The median (IQI) of the ratio of predicted risk for CVD mortality with CKD Patch vs. the original prediction with SCORE was 2.64 (1.89-3.40) in very high-risk CKD (e.g., eGFR 30-44 ml/min/1.73m2 with albuminuria ≥30 mg/g), 1.86 (1.48-2.44) in high-risk CKD (e.g., eGFR 45-59 ml/min/1.73m2 with albuminuria 30-299 mg/g), and 1.37 (1.14-1.69) in moderate risk CKD (e.g., eGFR 60-89 ml/min/1.73m2 with albuminuria 30-299 mg/g), indicating considerable risk underestimation in CKD with SCORE. The corresponding estimates for ASCVD with PCE were 1.55 (1.37-1.81), 1.24 (1.10-1.54), and 1.21 (0.98-1.46). INTERPRETATION: The "CKD Patch" can be used to quantitatively enhance ASCVD and CVD mortality risk prediction equations recommended in major US and European guidelines according to CKD measures, when available. FUNDING: US National Kidney Foundation and the NIDDK.

Vitamin D Insufficiency and Cognitive Function Trajectories in Older Adults: The Rancho Bernardo Study.

BACKGROUND: Evidence of a role for vitamin D (VitD) in cognitive aging is mixed and based primarily on extreme VitD deficiency. We evaluated the association of VitD insufficiency with cognitive function in older, community-dwelling adults living in a temperate climate with year-round sunshine. METHODS: A population-based longitudinal study of 1,058 adults (median age 75; 62% women) who had cognitive function assessed and serum levels of 25-hydroxyvitaminD (25OHD) measured in 1997-99 and were followed for up to three additional cognitive function assessments over a 12-year period. RESULTS: Overall, 14% (n = 145) of participants had VitD insufficiency defined as 25OHD <30 ng/ml. Adjusting for age, sex, education, and season, VitD insufficiency was associated with poorer baseline performance on the Mini-Mental Status Exam (MMSE) (p = 0.013), Trails Making Test B (Trails B) (p = 0.015), Category Fluency (p = 0.006), and Long Term Retrieval (p = 0.019); differences were equivalent to 5 years of age. For those with VitD insufficiency, the odds of mildly impaired performance at baseline were 38% higher for MMSE (p = 0.08), 78% higher for Trails B (p = 0.017), and 2-fold higher for Category Fluency and Long Term Retrieval (both p = 0.001). VitD insufficiency was not related to the rate of cognitive decline on any test or the risk of developing impaired performance during follow-up. CONCLUSION: In this population with little VitD deficiency, even moderately low VitD was associated with poorer performance on multiple domains of cognitive function. Low VitD did not predict 12-year cognitive decline. Clinical trials are essential to establish a causal link between VitD and cognitive well-being.

Global Cardiovascular and Renal Outcomes of Reduced GFR.

The burden of premature death and health loss from ESRD is well described. Less is known regarding the burden of cardiovascular disease attributable to reduced GFR. We estimated the prevalence of reduced GFR categories 3, 4, and 5 (not on RRT) for 188 countries at six time points from 1990 to 2013. Relative risks of cardiovascular outcomes by three categories of reduced GFR were calculated by pooled random effects meta-analysis. Results are presented as deaths for outcomes of cardiovascular disease and ESRD and as disability-adjusted life years for outcomes of cardiovascular disease, GFR categories 3, 4, and 5, and ESRD. In 2013, reduced GFR was associated with 4% of deaths worldwide, or 2.2 million deaths (95% uncertainty interval [95% UI], 2.0 to 2.4 million). More than half of these attributable deaths were cardiovascular deaths (1.2 million; 95% UI, 1.1 to 1.4 million), whereas 0.96 million (95% UI, 0.81 to 1.0 million) were ESRD-related deaths. Compared with metabolic risk factors, reduced GFR ranked below high systolic BP, high body mass index, and high fasting plasma glucose, and similarly with high total cholesterol as a risk factor for disability-adjusted life years in both developed and developing world regions. In conclusion, by 2013, cardiovascular deaths attributed to reduced GFR outnumbered ESRD deaths throughout the world. Studies are needed to evaluate the benefit of early detection of CKD and treatment to decrease these deaths.

Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data.

BACKGROUND: The usefulness of estimated glomerular filtration rate (eGFR) and albuminuria for prediction of cardiovascular outcomes is controversial. We aimed to assess the addition of creatinine-based eGFR and albuminuria to traditional risk factors for prediction of cardiovascular risk with a meta-analytic approach. METHODS: We meta-analysed individual-level data for 637 315 individuals without a history of cardiovascular disease from 24 cohorts (median follow-up 4·2-19·0 years) included in the Chronic Kidney Disease Prognosis Consortium. We assessed C statistic difference and reclassification improvement for cardiovascular mortality and fatal and non-fatal cases of coronary heart disease, stroke, and heart failure in a 5 year timeframe, contrasting prediction models for traditional risk factors with and without creatinine-based eGFR, albuminuria (either albumin-to-creatinine ratio [ACR] or semi-quantitative dipstick proteinuria), or both. FINDINGS: The addition of eGFR and ACR significantly improved the discrimination of cardiovascular outcomes beyond traditional risk factors in general populations, but the improvement was greater with ACR than with eGFR, and more evident for cardiovascular mortality (C statistic difference 0·0139 [95% CI 0·0105-0·0174] for ACR and 0·0065 [0·0042-0·0088] for eGFR) and heart failure (0·0196 [0·0108-0·0284] and 0·0109 [0·0059-0·0159]) than for coronary disease (0·0048 [0·0029-0·0067] and 0·0036 [0·0019-0·0054]) and stroke (0·0105 [0·0058-0·0151] and 0·0036 [0·0004-0·0069]). Dipstick proteinuria showed smaller improvement than ACR. The discrimination improvement with eGFR or ACR was especially evident in individuals with diabetes or hypertension, but remained significant with ACR for cardiovascular mortality and heart failure in those without either of these disorders. In individuals with chronic kidney disease, the combination of eGFR and ACR for risk discrimination outperformed most single traditional predictors; the C statistic for cardiovascular mortality fell by 0·0227 (0·0158-0·0296) after omission of eGFR and ACR compared with less than 0·007 for any single modifiable traditional predictor. INTERPRETATION: Creatinine-based eGFR and albuminuria should be taken into account for cardiovascular prediction, especially when these measures are already assessed for clinical purpose or if cardiovascular mortality and heart failure are outcomes of interest. ACR could have particularly broad implications for cardiovascular prediction. In populations with chronic kidney disease, the simultaneous assessment of eGFR and ACR could facilitate improved classification of cardiovascular risk, supporting current guidelines for chronic kidney disease. Our results lend some support to also incorporating eGFR and ACR into assessments of cardiovascular risk in the general population. FUNDING: US National Kidney Foundation, National Institute of Diabetes and Digestive and Kidney Diseases.

Urine creatinine-based estimates of fat-free mass in community-dwelling older persons: the Rancho Bernardo study.

OBJECTIVES: To determine whether a previously developed and externally validated equation using common variables (demographics and weight) that are important determinants of muscle mass to estimate 24-hour urine creatinine excretion rate (eCER) is associated with muscle mass and whether spot urine creatinine (UCr) provides similar estimates of muscle mass. DESIGN: Observational cross-sectional cohort study. SETTING: The Rancho Bernardo Study, San Diego, California. SUBJECTS: A total of 1,371 Caucasian, middle class, community-dwelling older adults. INTERVENTION: Morning spot UCr and fat-free mass (FFM) by dual-energy x-ray absorptiometry were measured. eCER was calculated: eCER (mg/day) = 879.89 + 12.51 × weight (kilogram) - 6.19 × age + 34.51 if black - 379.42 if female. Pearson correlation coefficients and linear regression were used to determine strengths of association of eCER and spot UCr with FFM. RESULTS: Mean age was 70 years, and 58% were women. eCER was strongly correlated with FFM (r = 0.95, P < .001), a correlation that was superior to that of spot UCr (r = 0.40, P < .001). CONCLUSIONS: An equation incorporating age, weight, sex, and race to estimate eCER is highly correlated with FFM in community-dwelling older persons and provides a more precise estimate than spot UCr. A simple screening tool for sarcopenia in older persons may allow interventions to maintain or improve muscle mass. Future studies should evaluate whether eCER predicts sarcopenia-related frailty and mortality in older persons.

Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: a meta-analysis.

OBJECTIVE: To assess for the presence of a sex interaction in the associations of estimated glomerular filtration rate and albuminuria with all-cause mortality, cardiovascular mortality, and end stage renal disease. DESIGN: Random effects meta-analysis using pooled individual participant data. SETTING: 46 cohorts from Europe, North and South America, Asia, and Australasia. PARTICIPANTS: 2,051,158 participants (54% women) from general population cohorts (n=1,861,052), high risk cohorts (n=151,494), and chronic kidney disease cohorts (n=38,612). Eligible cohorts (except chronic kidney disease cohorts) had at least 1000 participants, outcomes of either mortality or end stage renal disease of ≥ 50 events, and baseline measurements of estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation (mL/min/1.73 m(2)) and urinary albumin-creatinine ratio (mg/g). RESULTS: Risks of all-cause mortality and cardiovascular mortality were higher in men at all levels of estimated glomerular filtration rate and albumin-creatinine ratio. While higher risk was associated with lower estimated glomerular filtration rate and higher albumin-creatinine ratio in both sexes, the slope of the risk relationship for all-cause mortality and for cardiovascular mortality were steeper in women than in men. Compared with an estimated glomerular filtration rate of 95, the adjusted hazard ratio for all-cause mortality at estimated glomerular filtration rate 45 was 1.32 (95% CI 1.08 to 1.61) in women and 1.22 (1.00 to 1.48) in men (P(interaction)<0.01). Compared with a urinary albumin-creatinine ratio of 5, the adjusted hazard ratio for all-cause mortality at urinary albumin-creatinine ratio 30 was 1.69 (1.54 to 1.84) in women and 1.43 (1.31 to 1.57) in men (P(interaction)<0.01). Conversely, there was no evidence of a sex difference in associations of estimated glomerular filtration rate and urinary albumin-creatinine ratio with end stage renal disease risk. CONCLUSIONS: Both sexes face increased risk of all-cause mortality, cardiovascular mortality, and end stage renal disease with lower estimated glomerular filtration rates and higher albuminuria. These findings were robust across a large global consortium.

Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies.

BACKGROUND: Vitamin D status has been linked to the risk of cardiovascular disease (CVD). However, the optimal 25-hydroxy-vitamin D (25[OH]-vitamin D) levels for potential cardiovascular health benefits remain unclear. METHODS AND RESULTS: We searched MEDLINE and EMBASE from 1966 through February 2012 for prospective studies that assessed the association of 25(OH)-vitamin D concentrations with CVD risk. A total of 24 articles met our inclusion criteria, from which 19 independent studies with 6123 CVD cases in 65 994 participants were included for a meta-analysis. In a comparison of the lowest with the highest 25(OH)-vitamin D categories, the pooled relative risk was 1.52 (95% confidence interval, 1.30-1.77) for total CVD, 1.42 (95% confidence interval, 1.19-1.71) for CVD mortality, 1.38 (95% confidence interval, 1.21-1.57) for coronary heart disease, and 1.64 (95% confidence interval, 1.27-2.10) for stroke. These associations remained strong and significant when analyses were limited to studies that excluded participants with baseline CVD and were better controlled for season and confounding. We used a fractional polynomial spline regression analysis to assess the linearity of dose-response association between continuous 25(OH)-vitamin D and CVD risk. The CVD risk increased monotonically across decreasing 25(OH)-vitamin D below ≈60 nmol/L, with a relative risk of 1.03 (95% confidence interval, 1.00-1.06) per 25-nmol/L decrement in 25(OH)-vitamin D. CONCLUSIONS: This meta-analysis demonstrated a generally linear, inverse association between circulating 25(OH)-vitamin D ranging from 20 to 60 nmol/L and risk of CVD. Further research is needed to clarify the association of 25(OH)-vitamin D higher than 60 nmol/L with CVD risk and assess causality of the observed associations.

Sex differences in the association of Framingham Cardiac Risk Score with cognitive decline in community-dwelling elders without clinical heart disease.

OBJECTIVE: To investigate a possible link between cardiovascular risk factors and age-related cognitive decline, the association of the 1998 Framingham Cardiac Risk Score (FCRS) with the trajectory of cognitive function test (CFT) performance over an 18 year period was examined in adults 50 years and older without clinical heart disease at baseline. METHODS: Participants were 985 men and women who had assessments of cognitive function at 3- to 4-year intervals. The association of FCRS category with CFT score trajectory was examined using mixed-effects models stratified by sex and controlling for age, educational level, and number of successive cognitive assessments. RESULTS: At baseline, median FCRS corresponded to a 14% risk of a coronary heart disease event within 10 years for men and an 8% risk for women; 31% of men and 6% of women were at high (>20%) risk. In longitudinal analyses, women with FCRS risk higher than 7% had a higher rate of decline on tests of verbal fluency (p values < .05) and long-term recall (p values < .01) compared with low-risk women; modest, but significant (p values < .05), differences in the trajectory of Mini-Mental State Examination and Trail-Making Test B scores were also apparent. FCRS category was not related to the rate of decline in CFT performance in men. CONCLUSIONS: For older women, very low levels of risk of coronary heart disease were associated with preservation of cognitive function for 10 years, suggesting that the maintenance of cardiovascular health may slow cognitive decline. The minimal association in men, who were at higher baseline risk, may be due to the selective attrition of men with greater cognitive decline.

Vitamin d, parathyroid hormone, and cardiovascular mortality in older adults: the Rancho Bernardo study.

BACKGROUND: recent systematic reviews have cast doubt on the association between vitamin D and cardiovascular disease. No prior studies have investigated the association between 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH](2)D), or intact parathyroid hormone and cardiovascular mortality in a temperate climate. METHODS: a total of 1073 community-dwelling older adults were evaluated in 1997-1999; serum levels of 25(OH)D (mean 42 ng/mL), 1,25(OH)(2)D (median 29 pg/mL), and intact parathyroid hormone (median 46 pg/mL) were measured; mean estimated glomerular filtration rate was 74 mL/min/1.73 m(2). Participants were followed up to 10.4 (mean 6.4) years with 111 cardiovascular deaths. RESULTS: in unadjusted Cox proportional hazards models, higher levels of 1,25(OH)(2)D were protective against cardiovascular mortality, whereas higher levels of intact parathyroid hormone predicted increased risk of cardiovascular death. After adjusting for age alone or multiple covariates, there was no significant association between 25(OH)D, 1,25(OH)(2)D, or intact parathyroid hormone and cardiovascular mortality; results did not differ by an estimated glomerular filtration rate ≥ 60 mL/min/1.73 m(2) or<60 mL/min/1.73 m(2). CONCLUSION: in this prospective study of Caucasian, middle-income, community-dwelling older adults living in sunny southern California, serum levels of 25(OH)D, 1,25(OH)(2)D, and intact parathyroid hormone were not independently associated with cardiovascular mortality.

A prospective study of albuminuria and cognitive function in older adults: the Rancho Bernardo study.

Chronic kidney disease is a risk factor for cognitive impairment. Albuminuria is an early manifestation of chronic kidney disease and a marker of endothelial dysfunction and vascular risk. Results of prior studies of albuminuria and cognitive function are contradictory. The authors studied 1,345 community-dwelling women and men in southern California (mean age, 75 years) at a 1992-1996 research clinic visit, when urine albumin/creatinine ratio (ACR) was measured in spot morning urine and cognitive function was evaluated by using the Mini-Mental State Examination Trail-Making Test B, and category fluency test. An ACR of > or =30 mg/g was found in 17% of women and 15% of men in 1992-1996. Analysis of covariance was used to compare cognitive function score by categorical ACR. Between 1999 and 2002, 759 participants returned for repeat cognitive function testing. For men, but not women, baseline albuminuria, but not estimated glomerular filtration rate, was associated with reduced cognitive function at follow-up on all tests (P's < 0.05). An ACR of > or =30 mg/g was associated with greater annual decline in Mini-Mental State Examination and category fluency scores. Albuminuria may be an easily measured marker predicting future cognitive function decline. Results imply a common underlying mechanism affecting the renal and cerebral microvasculature.

Measures of renal function, BMD, bone loss, and osteoporotic fracture in older adults: the Rancho Bernardo study.

UNLABELLED: The association between bone and renal function in healthy seniors is not well studied. In this cross-sectional and longitudinal study in 1713 older men and women, creatinine clearance was significantly associated with hip BMD. If confirmed, this may warrant adding mild to moderate renal dysfunction as an indication for osteoporosis screening. INTRODUCTION: This study determined the cross-sectional and longitudinal association between measures of renal function and BMD, bone loss, and osteoporotic fracture in older adults. It determined which measure of renal function--creatinine clearance by the Cockcroft-Gault (CG) equation, estimated glomerular filtration rate by the Modification of Diet in Renal Disease (MDRD) equation, or serum creatinine--is most strongly associated with BMD and osteoporotic fracture. MATERIALS AND METHODS: This was a cross-sectional and prospective study in older community-dwelling men and women. Between 1992 and 1995, 1713 participants (average age, 71.3 +/- 11.1 years) completed standardized questionnaires, physical examinations, laboratory testing, and bone densitometry; 1023 participants returned for a follow-up visit in 1997-1999, an average of 4.1 +/- 0.9 years later. RESULTS: Calculated renal function declined with age (p < 0.001). Renal function was categorized by Kidney Disease Outcomes Quality Initiative (K/DOQI) chronic kidney disease (CKD) stage. By the CG equation, at baseline, 5.5% of participants had stage 1 CKD (glomerular filtration rate > or = 90 ml/min/1.73 m(2)), 43.0% had stage 2 CKD (60-89 ml/min/1.73 m(2)), 48.8% had stage 3 CKD (30-59 ml/min/1.73 m(2)), and 2.7% had stages 4 and 5 CKD (<30 ml/min/1.73 m(2)). Using the MDRD equation, these percents were 7.0%, 61.7%, 30.9%, and 0.5%, respectively. In cross-sectional analyses, there was a significant linear association between creatinine clearance by CG or glomerular filtration rate by MDRD and hip BMD. In prospective analyses, there was an average annual bone loss of 0.6% and a significant association between baseline CG and 4-year hip bone loss. There was no association between baseline MDRD or serum creatinine and bone loss. At baseline, 180 of 1713 participants (11%) reported at least one clinical fracture of the hip, femur, forearm, or wrist; 79 (8%) reported new clinical fractures during follow-up. Baseline renal function by any measure was not significantly associated with prevalent or incident clinical fractures. CONCLUSIONS: Although renal function measured by both CG and MDRD was associated with BMD in cross-sectional analyses, only creatinine clearance by CG predicted 4-year bone loss. If confirmed, this should be the preferred method for assessing the association between renal function and BMD. Cross-sectional associations between renal function and BMD were strongest at higher CKD stage. None of the baseline renal function estimates was associated with prevalent or incident fractures, perhaps reflecting the multifactorial etiology of fractures beyond BMD. If further studies in the elderly confirm renal function as an important predictor of bone loss and fracture, this may warrant adding mild to moderate renal dysfunction as an indication for osteoporosis screening.