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.

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.

Serum insulin-like growth factor binding protein-1 levels and bone mineral density in older adults: the Rancho Bernardo Study.

Insulin-like growth factor-I (IGF-I) stimulates osteoblast function, inhibits collagen matrix degradation, and is positively associated with bone mineral density in most but not all studies. We previously reported that IGF-I was positively associated with BMD at the spine and hip in women but not men. Insulin-like growth factor binding protein-1 (IGFBP-1), a potent modulator of IGF-I, is expressed in normal osteoblasts and inhibits collagen gene expression in bone, but little is known about the relationship between IGFBP-1 and bone mineral density (BMD). We report a cross-sectional study of serum IGFBP-1 levels and BMD in 1,139 community-dwelling men and postmenopausal women (not using estrogen), aged 44-98. In both sexes, IGFBP-1 levels increased linearly with age (p<0.001) and decreased with body mass index (BMI) quartile (p<0.001). After adjusting for age and BMI, there was no significant association between IGFBP-1 and BMD at the hip or spine. IGF-I and IGFBP-1 were weakly and inversely associated with each other. These findings suggest that if there is an important role for IGFBP-1 in bone metabolism, it is mediated or confounded by weight. Studies are needed to further investigate the relationship between inhibitory components of IGF-1 and bone loss.