New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race.

BACKGROUND: Current equations for estimated glomerular filtration rate (eGFR) that use serum creatinine or cystatin C incorporate age, sex, and race to estimate measured GFR. However, race in eGFR equations is a social and not a biologic construct. METHODS: We developed new eGFR equations without race using data from two development data sets: 10 studies (8254 participants, 31.5% Black) for serum creatinine and 13 studies (5352 participants, 39.7% Black) for both serum creatinine and cystatin C. In a validation data set of 12 studies (4050 participants, 14.3% Black), we compared the accuracy of new eGFR equations to measured GFR. We projected the prevalence of chronic kidney disease (CKD) and GFR stages in a sample of U.S. adults, using current and new equations. RESULTS: In the validation data set, the current creatinine equation that uses age, sex, and race overestimated measured GFR in Blacks (median, 3.7 ml per minute per 1.73 m2 of body-surface area; 95% confidence interval [CI], 1.8 to 5.4) and to a lesser degree in non-Blacks (median, 0.5 ml per minute per 1.73 m2; 95% CI, 0.0 to 0.9). When the adjustment for Black race was omitted from the current eGFR equation, measured GFR in Blacks was underestimated (median, 7.1 ml per minute per 1.73 m2; 95% CI, 5.9 to 8.8). A new equation using age and sex and omitting race underestimated measured GFR in Blacks (median, 3.6 ml per minute per 1.73 m2; 95% CI, 1.8 to 5.5) and overestimated measured GFR in non-Blacks (median, 3.9 ml per minute per 1.73 m2; 95% CI, 3.4 to 4.4). For all equations, 85% or more of the eGFRs for Blacks and non-Blacks were within 30% of measured GFR. New creatinine-cystatin C equations without race were more accurate than new creatinine equations, with smaller differences between race groups. As compared with the current creatinine equation, the new creatinine equations, but not the new creatinine-cystatin C equations, increased population estimates of CKD prevalence among Blacks and yielded similar or lower prevalence among non-Blacks. CONCLUSIONS: New eGFR equations that incorporate creatinine and cystatin C but omit race are more accurate and led to smaller differences between Black participants and non-Black participants than new equations without race with either creatinine or cystatin C alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

Associations of Baseline and Longitudinal Serum Uromodulin With Kidney Failure and Mortality: Results From the African American Study of Kidney Disease and Hypertension (AASK) Trial.

RATIONALE & OBJECTIVE: Uromodulin (UMOD) is the most abundant protein found in urine and has emerged as a promising biomarker of tubule health. Circulating UMOD is also detectable, but at lower levels. We evaluated whether serum UMOD levels were associated with the risks of incident kidney failure with replacement therapy (KFRT) and mortality. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: Participants in AASK (the African American Study of Kidney Disease and Hypertension) with available stored serum samples from the 0-, 12-, and 24-month visits for biomarker measurement. PREDICTORS: Baseline log-transformed UMOD and change in UMOD over 2 years. OUTCOMES: KFRT and mortality. ANALYTICAL APPROACH: Cox proportional hazards and mixed-effects models. RESULTS: Among 500 participants with baseline serum UMOD levels (mean age, 54y; 37% female), 161 KFRT events occurred during a median of 8.5 years. After adjusting for baseline demographic factors, clinical factors, glomerular filtration rate, log-transformed urine protein-creatinine ratio, and randomized treatment groups, a 50% lower baseline UMOD level was independently associated with a 35% higher risk of KFRT (adjusted HR, 1.35; 95% CI, 1.07-1.70). For annual UMOD change, each 1-standard deviation lower change was associated with a 67% higher risk of KFRT (adjusted HR, 1.67; 95% CI, 1.41-1.99). Baseline UMOD and UMOD change were not associated with mortality. UMOD levels declined more steeply for metoprolol versus ramipril (P<0.001) as well as for intensive versus standard blood pressure goals (P = 0.002). LIMITATIONS: Small sample size and limited generalizability. CONCLUSIONS: Lower UMOD levels at baseline and steeper declines in UMOD over time were associated with a higher risk of subsequent KFRT in a cohort of African American adults with chronic kidney disease and hypertension. PLAIN-LANGUAGE SUMMARY: Prior studies of uromodulin (UMOD), the most abundant protein in urine, and kidney disease have focused primarily on urinary UMOD levels. The present study evaluated associations of serum UMOD levels with the risks of kidney failure with replacement therapy (KFRT) and mortality in a cohort of African American adults with hypertension and chronic kidney disease. It found that participants with lower levels of UMOD at baseline were more likely to experience KFRT even after accounting for baseline kidney measures. Similarly, participants who experienced steeper annual declines in UMOD also had a heightened risk of kidney failure. Neither baseline nor annual change in UMOD was associated with mortality. Serum UMOD is a promising biomarker of kidney health.

Modification of Association of Cystatin C With Kidney and Cardiovascular Outcomes by Obesity.

RATIONALE & OBJECTIVE: Cystatin C-based estimated glomerular filtration rate (eGFRcys) has stronger associations with adverse clinical outcomes than creatinine-based eGFR (eGFRcr). Obesity may be associated with higher cystatin C levels, independent of kidney function, but it is unknown whether obesity modifies associations of eGFRcys with kidney and cardiovascular outcomes. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 27,249 US adults in the Reasons for Geographic and Racial Differences in Stroke Study. PREDICTORS: eGFRcys, eGFRcr, waist circumference, and body mass index (BMI). OUTCOME: All-cause mortality, kidney failure, incident atherosclerotic cardiovascular disease (ASCVD), and incident heart failure (HF). ANALYTICAL APPROACH: Multivariable Cox and Fine-Gray models with multiplicative interaction terms were constructed to investigate whether waist circumference quartiles or BMI categories modified associations of eGFRcys with risks of 4 clinical outcomes. RESULTS: Participants had a mean age of 65 years; 54% were women, 41% were Black, and 21% had an eGFRcys<60mL/min/1.73m2. The baseline prevalence of abdominal obesity (waist circumference≥88cm for women or≥102cm for men) was 48% and obesity was 38%. In multivariable adjusted analyses, each 15mL/min/1.73m2 lower eGFRcys was associated with higher HR and 95% CI of mortality in each waist circumference quartile (first quartile, 1.19 [1.15-1.24]; second quartile, 1.22 [1.18-1.26]; third quartile, 1.20 [1.16-1.24]; fourth quartile, 1.19 [1.15-1.23]) as well as within each BMI category (BMI<24.9: 1.21 [1.17-1.25]; BMI 25.0-29.9: 1.21 [1.18-1.25]; BMI 30.0-34.9: 1.20 [1.16-1.25]; BMI≥35: 1.17, [1.12-1.22]). Neither waist circumference nor BMI modified the association of eGFRcys with mortality, kidney failure, incident ASCVD, or incident HF (all Pinteraction>0.05). LIMITATIONS: Included only Black and White persons in the United States. CONCLUSION: Obesity did not modify the association of eGFRcys with all-cause mortality, kidney failure, incident ASCVD, or incident HF. Among individuals with obesity, cystatin C may be used to provide eGFR-based risk prognostication for adverse outcomes. PLAIN-LANGUAGE SUMMARY: Cystatin C is increasingly used in clinical practice to estimate kidney function, and cystatin C-based eGFR (eGFRcys) may be used to determine risk for adverse clinical outcomes. Adiposity may increase serum levels of cystatin C, independent of kidney function. This cohort study investigated whether associations of eGFRcys with adverse kidney and cardiovascular outcomes are modified by measures of obesity, waist circumference, and body mass index. We found that obesity does not modify associations of eGFRcys with 4 clinical outcomes and conclude that among individuals with obesity, cystatin C may be used to provide eGFR-based risk prognostication for adverse outcomes.

CKD-EPI and EKFC GFR Estimating Equations: Performance and Other Considerations for Selecting Equations for Implementation in Adults.

SIGNIFICANCE STATEMENT: New eGFR equations from Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and European Kidney Function Consortium (EKFC) using creatinine (eGFRcr), cystatin C (eGFRcys), and both (eGFRcr-cys) have sufficient accuracy for use in clinical practice, leading to uncertainty in selecting equations for implementation. The authors evaluated performance of equations in an independent population of 4050 adults and evaluated other considerations important for implementation. They found that CKD-EPI and EKFC equations are approaching convergence, with better performance of eGFRcr-cys equations in the overall group and fewer differences among race, sex, and age subgroups than eGFRcr equations. Larger differences among eGFRcr equations reflect regional population differences in creatinine, forcing a trade-off between accuracy and uniformity in global implementation of eGFRcr equations. More widespread use of cystatin C could avoid this trade-off. BACKGROUND: New CKD-EPI and EKFC eGFR equations using eGFRcr, eGFRcys, and both (eGFRcr-cys) have sufficient accuracy for use in clinical practice. A better understanding of the equations, including their performance in race, sex and age subgroups, is important for selection of eGFR equations for global implementation. METHODS: We evaluated performance (bias and P 30 ) of equations and methods used for equation development in an independent study population comprising 4050 adults pooled from 12 studies. The mean (SD) measured GFR was 76.4 (29.6) ml/min per 1.73 m 2 and age 57.0 (17.4) years, with 1557 (38%) women and 579 (14%) Black participants. RESULTS: Coefficients for creatinine, cystatin C, age, and sex in the CKD-EPI and EKFC equations are similar. Performance of the eGFRcr-cys equations in the overall population (bias <±5 ml/min per 1.73 m 2 and P 30 >90%) was better than the eGFRcr or eGFRcys equations, with fewer differences among race, sex, and age subgroups. Differences in performance across subgroups reflected differences in diversity of source populations and use of variables for race and sex for equation development. Larger differences among eGFRcr equations reflected regional population differences in non-GFR determinants of creatinine. CONCLUSION: CKD-EPI and EKFC equations are approaching convergence. It is not possible to maximize both accuracy and uniformity in selecting one of the currently available eGFRcr equations for implementation across regions. Decisions should consider methods for equation development in addition to performance. Wider use of cystatin C with creatinine could maximize both accuracy and uniformity of GFR estimation using currently available equations.

Effect of Adopting the New Race-Free 2021 Chronic Kidney Disease Epidemiology Collaboration Estimated Glomerular Filtration Rate Creatinine Equation on Racial Differences in Kidney Disease Progression Among People With Human Immunodeficiency Virus: An Observational Study.

BACKGROUND: The impact of adopting a race-free estimated glomerular filtration rate (eGFR) creatinine (eGFRcr) equation on racial differences in chronic kidney disease (CKD) progression among people with human immunodeficiency virus (PWH) is unknown. METHODS: We defined eGFR stages using the original race-adjusted Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFRcr equation and the new race-free CKD-EPI eGFRcr equation. We then estimated 5-year probabilities of transitioning from baseline kidney function to more advanced eGFR stages and examined the association of race (black vs white) with rates of CKD progression using Markov models. RESULTS: With the race-adjusted eGFRcr equation, black participants (n = 31 298) had a lower risk of progressing from eGFR stage 1 to 2 (hazard ratio [HR], 0.77; 95% confidence interval [CI], .73-.82), an equal risk of progressing from stage 2 to 3 (1.00; .92-.07) and a 3-fold risk of progressing from stage 3 to 4 or 5 (3.06; 2.60-3.62), compared with white participants (n = 27 542). When we used the race-free eGFRcr equation, 16% of black participants were reclassified into a more severe eGFR stage at baseline. The reclassified black individuals had a higher prevalence of CKD risk factors than black PWH who were not reclassified. With the race-free eGFRcr equation, black participants had a higher risk of disease progression across all eGFR stages than white participants. CONCLUSIONS: The original eGFRcr equation systematically masked a subgroup of black PWH who are at high-risk of CKD progression. The new race-free eGFRcr equation unmasks these individuals and may allow for earlier detection and management of CKD.

Associations between abrupt transition, dialysis-requiring AKI, and early mortality in ESKD among U.S. veterans.

BACKGROUND: Mortality is high within the first few months of starting chronic dialysis. Pre-ESKD trajectory of kidney function has been shown to be predictive of early death after dialysis initiation. We aim to better understand how two key aspects of pre-dialysis kidney function-an abrupt transition pattern and an episode of dialysis-requiring AKI (AKI-D) leading directly to ESKD-are associated with early mortality after dialysis initiation. METHODS: We extracted national data from U.S. Veterans Health Administration cross-linked with the United States Renal Data System (USRDS) to identify patients who initiated hemodialysis during 2009-2013. We defined abrupt transition as having a mean outpatient eGFR ≥ 30 ml/min/1.73m2 within 1 year prior to ESKD. AKI-D was identified using inpatient serum creatinine measurements (serum Cr increase by at least 50% from baseline) along with billing codes for inpatient receipt of dialysis for AKI within 30 days prior to the ESKD start date. We used multivariable proportional hazards models to examine the association between patterns of kidney function prior to ESKD and all-cause mortality within 90 days after ESKD. RESULTS: Twenty-two thousand eight hundred fifteen patients were identified in the final analytic cohort of Veterans who initiated hemodialysis and entered the USRDS. We defined five patterns of kidney function decline. Most (68%) patients (N = 15,484) did not have abrupt transition and did not suffer an episode of AKI-D prior to ESKD (reference group). The remaining groups had abrupt transition, AKI-D, or both. Patients who had an abrupt transition with (N = 503) or without (N = 3611) AKI-D had the highest risk of early mortality after ESKD onset after adjustment for demographics and comorbidities (adjusted HR 2.10, 95% CI 1.66-2.65 for abrupt transition with AKI-D; adjusted HR 2.10, 95% CI 1.90-2.33 for abrupt transition without AKI-D). In contrast, patients who experienced AKI-D without an abrupt transition pattern (N = 2141 had only a modestly higher risk of early death (adjusted HR 1.19, 95% CI 1.01-1.40). CONCLUSIONS: An abrupt decline in kidney function within 1 year prior to ESKD occurred in nearly 1 in 5 incident hemodialysis patients (18%) in this national cohort of Veterans and was strongly associated with higher early mortality after ESKD onset.

Markers of Kidney Tubular Secretion and Risk of Adverse Events in SPRINT Participants with CKD.

BACKGROUND: Kidney tubular secretion is an essential mechanism for clearing many common antihypertensive drugs and other metabolites and toxins. It is unknown whether novel measures of tubular secretion are associated with adverse events (AEs) during hypertension treatment. METHODS: Among 2089 SPRINT (Systolic Blood Pressure Intervention Trial) participants with baseline eGFR <60 ml/min per 1.73 m2, we created a summary secretion score by averaging across the standardized spot urine-to-plasma ratios of ten novel endogenous tubular secretion measures, with lower urine-to-plasma ratios reflecting worse tubular secretion. Multivariable Cox proportional hazards models were used to evaluate associations between the secretion score and risk of a composite of prespecified serious AEs (hypotension, syncope, bradycardia, AKI, electrolyte abnormalities, and injurious falls). The follow-up protocol for SPRINT routinely assessed two laboratory monitoring AEs (hyperkalemia and hypokalemia). RESULTS: Overall, 30% of participants experienced at least one AE during a median follow-up of 3.0 years. In multivariable models adjusted for eGFR and albuminuria, lower (worse) secretion scores at baseline were associated with greater risk of the composite AE outcome (hazard ratio per 1-SD lower secretion score, 1.16; 95% confidence interval, 1.04 to 1.27). In analyses of the individual AEs, lower secretion score was associated with significantly greater risk of AKI, serious electrolyte abnormalities, and ambulatory hyperkalemia. Associations were similar across randomized treatment assignment groups. CONCLUSION: Among SPRINT participants with CKD, worse tubular secretion was associated with greater risk of AEs, independent of eGFR and albuminuria.

Longitudinal TNFR1 and TNFR2 and Kidney Outcomes: Results from AASK and VA NEPHRON-D.

BACKGROUND: Higher baseline levels of soluble TNF receptors (TNFR1 and TNFR2) have been associated with progressive CKD. Whether longitudinal changes in these biomarkers of inflammation are also associated with worse kidney outcomes has been less studied. METHODS: We evaluated associations of longitudinal changes in TNFR1 and TNFR2 with ESKD in the African American Study of Kidney Disease and Hypertension (AASK; 38% female; 0% diabetes) and kidney function decline (first occurrence of ≥30 ml/min per 1.73 m2 or ≥50% eGFR decline if randomization eGFR ≥60 or <60 ml/min per 1.73 m2, respectively; ESKD) in the Veterans Affairs Nephropathy in Diabetes trial (VA NEPHRON-D; 99% male; 100% diabetes) using Cox models. Biomarkers were measured from samples collected at 0-, 12-, and 24-month visits for AASK (serum) and 0- and 12-month visits for VA NEPHRON-D (plasma). Biomarker slopes (AASK) were estimated using linear mixed-effects models. Covariates included sociodemographic/clinical factors, baseline biomarker level, and kidney function. RESULTS: There were 129 ESKD events over a median of 7.0 years in AASK (n=418) and 118 kidney function decline events over a median of 1.5 years in VA NEPHRON-D (n=754). In AASK, each 1 SD increase in TNFR1 and TNFR2 slope was associated with 2.98- and 1.87-fold higher risks of ESKD, respectively. In VA NEPHRON-D, each 1 SD increase in TNFR1 and TNFR2 was associated with 3.20- and 1.43-fold higher risks of kidney function decline, respectively. CONCLUSIONS: Among individuals with and without diabetes, longitudinal increases in TNFR1 and TNFR2 were each associated with progressive CKD, independent of initial biomarker level and kidney function.

The incidence of and risk factors for hospitalized acute kidney injury among people living with HIV on antiretroviral treatment.

OBJECTIVES: The epidemiology of hospitalized acute kidney injury (AKI) among people living with HIV (PLWH) in the era of modern antiretroviral therapy (ART) for all PLWH is not well characterized. We evaluated the incidence of and risk factors for hospitalized AKI from 2005 to 2015 among PLWH on ART. METHODS: We conducted a retrospective analysis of PLWH from the Johns Hopkins HIV Clinical Cohort. We defined hospitalized AKI as a rise of ≥ 0.3 mg/dL in serum creatinine (SCr) within any 48-h period or a 50% increase in SCr from baseline and assessed associations of risk factors with incident AKI using multivariate Cox regression models. RESULTS: Most participants (75%) were black, 34% were female, and the mean age was 43 years. The incidence of AKI fluctuated annually, peaking at 40 per 1000 person-years (PY) [95% confidence interval (CI) 22-69 per 1000 PY] in 2007, and reached a nadir of 20 per 1000 PY (95% CI 11-34 per 1000 PY) in 2010. There was no significant temporal trend (-3.3% change per year; 95% CI -8.6 to 2.3%; P = 0.24). After multivariable adjustment, characteristics independently associated with AKI included black race [hazard ratio (HR) 2.44; 95% CI 1.42-4.20], hypertension (HR 1.62; 95% CI 1.09-2.38), dipstick proteinuria > 1 (HR 1.86; 95% CI 1.07-3.23), a history of AIDS (HR 1.82; 95% CI 1.29-2.56), CD4 count < 200 cells/µL (HR 1.46; 95% CI 1.02-2.07), and lower serum albumin (HR 1.73 per 1 g/dL decrease; 95% CI 1.02-2.07). CONCLUSIONS: In this contemporary cohort of PLWH, the annual incidence of first AKI fluctuated during the study period. Attention to modifiable AKI risk factors and social determinants of health may further reduce AKI incidence among PLWH.

Association of Intra-individual Differences in Estimated GFR by Creatinine Versus Cystatin C With Incident Heart Failure.

RATIONALE & OBJECTIVE: Lower estimated glomerular filtration rate (eGFR) is associated with heart failure (HF) risk. However, eGFR based on cystatin C (eGFRcys) and creatinine (eGFRcr) may differ substantially within an individual. The clinical implications of these differences for risk of HF among persons with chronic kidney disease (CKD) are unknown. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 4,512 adults with CKD and without prevalent HF who enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURE: Difference in GFR estimates (eGFRdiff; ie, eGFRcys minus eGFRcr). OUTCOME: Incident HF hospitalization. ANALYTICAL APPROACH: Fine-Gray proportional subhazards regression was used to investigate the associations of baseline, time-updated, and slope of eGFRdiff with incident HF. RESULTS: Of 4,512 participants, one-third had eGFRcys and eGFRcr values that differed by over 15 mL/min/1.73 m2. In multivariable-adjusted models, each 15 mL/min/1.73 m2 lower baseline eGFRdiff was associated with higher risk of incident HF hospitalization (hazard ratio [HR], 1.20 [95% CI, 1.07-1.34]). In time-updated analyses, those with eGFRdiff less than -15 mL/min/1.73 m2 had higher risk of incident HF hospitalization (HR, 1.99 [95% CI, 1.39-2.86]), and those with eGFRdiff ≥15 mL/min/1.73 m2 had lower risk of incident HF hospitalization (HR, 0.67 [95% CI, 0.49-0.91]) compared with participants with similar eGFRcys and eGFRcr. Participants with faster declines in eGFRcys relative to eGFRcr had higher risk of incident HF (HR, 1.49 [95% CI, 1.19-1.85]) compared with those in whom eGFRcys and eGFRcr declined in parallel. LIMITATIONS: Entry into the CRIC Study was determined by eGFRcr, which constrained the range of baseline eGFRcr-but not eGFRcys-values. CONCLUSIONS: Among persons with CKD who have large differences between eGFRcys and eGFRcr, risk for incident HF is more strongly associated with eGFRcys. Diverging slopes between eGFRcys and eGFRcr over time are also independently associated with risk of incident HF.

Black and White Adults With CKD Hospitalized With Acute Kidney Injury: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Few studies have investigated racial disparities in acute kidney injury (AKI), in contrast to the extensive literature on racial differences in the risk of kidney failure. We sought to study potential differences in risk in the setting of chronic kidney disease (CKD). STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We studied 2,720 self-identified Black or White participants with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study from July 1, 2013, to December 31, 2017. EXPOSURE: Self-reported race (Black vs White). OUTCOME: Hospitalized AKI (≥50% increase from nadir to peak serum creatinine). ANALYTICAL APPROACH: Cox regression models adjusting for demographics (age and sex), prehospitalization clinical risk factors (diabetes, blood pressure, cardiovascular disease, estimated glomerular filtration rate, proteinuria, receipt of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers), and socioeconomic status (insurance status and education level). In a subset of participants with genotype data, we adjusted for apolipoprotein L1 gene (APOL1) high-risk status and sickle cell trait. RESULTS: Black participants (n = 1,266) were younger but had a higher burden of prehospitalization clinical risk factors. The incidence rate of first AKI hospitalization among Black participants was 6.3 (95% CI, 5.5-7.2) per 100 person-years versus 5.3 (95% CI, 4.6-6.1) per 100 person-years among White participants. In an unadjusted Cox regression model, Black participants were at a modestly increased risk of incident AKI (HR, 1.22 [95% CI, 1.01-1.48]) compared with White participants. However, this risk was attenuated and no longer significant after adjusting for prehospitalization clinical risk factors (adjusted HR, 1.02 [95% CI, 0.83-1.25]). There were only 11 AKI hospitalizations among individuals with high-risk APOL1 risk status and 14 AKI hospitalizations among individuals with sickle cell trait. LIMITATIONS: Participants were limited to research volunteers and potentially not fully representative of all CKD patients. CONCLUSIONS: In this multicenter prospective cohort of CKD patients, racial disparities in AKI incidence were modest and were explained by differences in prehospitalization clinical risk factors.

Kidney tubule health, mineral metabolism and adverse events in persons with CKD in SPRINT.

BACKGROUND: Measures of kidney tubule health are risk markers for acute kidney injury (AKI) in persons with chronic kidney disease (CKD) during hypertension treatment, but their associations with other adverse events (AEs) are unknown. METHODS: Among 2377 Systolic Blood Pressure Intervention Trial (SPRINT) participants with CKD, we measured at baseline eight urine biomarkers of kidney tubule health and two serum biomarkers of mineral metabolism pathways that act on the kidney tubules. Cox proportional hazards models were used to evaluate biomarker associations with risk of a composite of pre-specified serious AEs (hypotension, syncope, electrolyte abnormalities, AKI, bradycardia and injurious falls) and outpatient AEs (hyperkalemia and hypokalemia). RESULTS: At baseline, the mean age was 73 ± 9 years and mean estimated glomerular filtration rate (eGFR) was 46 ± 11 mL/min/1.73 m2. During a median follow-up of 3.8 years, 716 (30%) participants experienced the composite AE. Higher urine interleukin-18, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin (NGAL) and monocyte chemoattractant protein-1 (MCP-1), lower urine uromodulin (UMOD) and higher serum fibroblast growth factor-23 were individually associated with higher risk of the composite AE outcome in multivariable-adjusted models including eGFR and albuminuria. When modeling biomarkers in combination, higher NGAL [hazard ratio (HR) = 1.08 per 2-fold higher biomarker level, 95% confidence interval (CI) 1.03-1.13], higher MCP-1 (HR = 1.11, 95% CI 1.03-1.19) and lower UMOD (HR = 0.91, 95% CI 0.85-0.97) were each associated with higher composite AE risk. Biomarker associations did not vary by intervention arm (P > 0.10 for all interactions). CONCLUSIONS: Among persons with CKD, several kidney tubule biomarkers are associated with higher risk of AEs during hypertension treatment, independent of eGFR and albuminuria.

Association of abnormal electrocardiograph metrics with prolonged recovery time in incident hemodialysis patients.

BACKGROUND: Patients receiving intermittent hemodialysis have variable times of recovery to feeling better after dialysis. QT prolongation, a precursor to clinical and subclinical cardiovascular events, may contribute to delayed recovery time. We hypothesized that abnormal electrocardiographic parameters indicating perturbations in ventricular action are associated with longer recovery times thus impacting a patient-centered quality of life. METHODS: Among 242 incident in-center hemodialysis participants from the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study, corrected QT interval (QTc), QRST angle and heart rate variance were measured on non-dialysis days using a standard 5-min electrocardiograph recording. Left ventricular hypertrophy (LVH) was defined using the Cornell voltage product. Recovery time was ascertained during a phone interview with a standardized validated questionnaire. Associations between QTc, QRST angle, heart rate variance, and LVH and natural log-transformed recovery time were examined using linear regression adjusted for participant characteristics and electrolytes. RESULTS: Mean age was 55 (standard deviation 13) years, 55% were male, 72% were African American. Longer QTc interval was associated with increased recovery time (per 10 ms increase in QTc, recovery time increased by 6.2%; 95% confidence interval: 0.0-10.5). QRST angle, heart rate, heart rate variability and LVH were not significantly associated with recovery time. CONCLUSION: Longer QTc intervals are associated with longer recovery time independent of serum electrolytes. This supports a relationship between a patient's underlying arrhythmic status and time to recovery after hemodialysis. Future studies will determine if maneuvers to reduce QTc improves recovery time and quality of life of patients on hemodialysis.

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.

Capitated versus fee-for-service reimbursement and quality of care for chronic disease: a US cross-sectional analysis.

BACKGROUND: Upcoming alternative payment models Primary Care First (PCF) and Kidney Care Choices (KCC) incorporate capitated payments for chronic disease management. Prior research on the effect of capitated payments on chronic disease management has shown mixed results. We assessed the patient, physician, and practice characteristics of practices with capitation as the majority of revenue, and evaluated the association of capitated reimbursement with quality of chronic disease care. METHODS: We performed a cross-sectional analysis of visits in the United States' National Ambulatory Medical Care Survey (NAMCS) for patients with hypertension, diabetes, or chronic kidney disease (CKD). Our predictor was practice reimbursement type, classified as 1) majority capitation, 2) majority FFS, or 3) other reimbursement mix. Outcomes were quality indicators of hypertension control, diabetes control, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEi/ARB) use, and statin use. RESULTS: About 9% of visits were to practices with majority capitation revenue. Capitated practices, compared with FFS and other practices, had lower visit frequency (3.7 vs. 5.2 vs. 5.2, p = 0.006), were more likely to be located in the West Census Region (55% vs. 18% vs. 17%, p < 0.001), less likely to be solo practice (21% vs. 37% vs. 35%, p = 0.005), more likely to be owned by an insurance company, health plan or HMO (24% vs. 13% vs. 13%, p = 0.033), and more likely to have private insurance (43% vs. 25% vs. 19%, p = 0.004) and managed care payments (69% vs. 23% vs. 26%, p < 0.001) as the majority of revenue. The prevalence of controlled hypertension, controlled diabetes, ACEi/ARB use, and statin use was suboptimal across practice reimbursement types. Capitated reimbursement was not associated with differences in hypertension, diabetes, or CKD quality indicators, in multivariable models adjusting for patient, physician, and practice characteristics. CONCLUSIONS: Practices with majority capitation revenue differed substantially from FFS and other practices in patient, physician, and practice characteristics, but were not associated with consistent quality differences. Our findings establish baseline estimates of chronic disease quality of care performance by practice reimbursement composition, informing chronic disease care delivery within upcoming payment models.

Association of Race and Ethnicity With Prescription of SGLT2 Inhibitors and GLP1 Receptor Agonists Among Patients With Type 2 Diabetes in the Veterans Health Administration System.

Importance: Novel therapies for type 2 diabetes can reduce the risk of cardiovascular disease and chronic kidney disease progression. The equitability of these agents' prescription across racial and ethnic groups has not been well-evaluated. Objective: To investigate differences in the prescription of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) among adult patients with type 2 diabetes by racial and ethnic groups. Design, Setting, and Participants: Cross-sectional analysis of data from the US Veterans Health Administration's Corporate Data Warehouse. The sample included adult patients with type 2 diabetes and at least 2 primary care clinic visits from January 1, 2019, to December 31, 2020. Exposures: Self-identified race and self-identified ethnicity. Main Outcomes and Measures: The primary outcomes were prevalent SGLT2i or GLP-1 RA prescription, defined as any active prescription during the study period. Results: Among 1 197 914 patients (mean age, 68 years; 96% men; 1% American Indian or Alaska Native, 2% Asian, Native Hawaiian, or Other Pacific Islander, 20% Black or African American, 71% White, and 7% of Hispanic or Latino ethnicity), 10.7% and 7.7% were prescribed an SGLT2i or a GLP-1 RA, respectively. Prescription rates for SGLT2i and GLP-1 RA, respectively, were 11% and 8.4% among American Indian or Alaska Native patients; 11.8% and 8% among Asian, Native Hawaiian, or Other Pacific Islander patients; 8.8% and 6.1% among Black or African American patients; and 11.3% and 8.2% among White patients, respectively. Prescription rates for SGLT2i and GLP-1 RA, respectively, were 11% and 7.1% among Hispanic or Latino patients and 10.7% and 7.8% among non-Hispanic or Latino patients. After accounting for patient- and system-level factors, all racial groups had significantly lower odds of SGLT2i and GLP-1 RA prescription compared with White patients. Black patients had the lowest odds of prescription compared with White patients (adjusted odds ratio, 0.72 [95% CI, 0.71-0.74] for SGLT2i and 0.64 [95% CI, 0.63-0.66] for GLP-1 RA). Patients of Hispanic or Latino ethnicity had significantly lower odds of prescription (0.90 [95% CI, 0.88-0.93] for SGLT2i and 0.88 [95% CI, 0.85-0.91] for GLP-1 RA) compared with non-Hispanic or Latino patients. Conclusions and Relevance: Among patients with type 2 diabetes in the Veterans Health Administration system during 2019 and 2020, prescription rates of SGLT2i and GLP-1 RA medications were low, and individuals of several different racial groups and those of Hispanic ethnicity had statistically significantly lower odds of receiving prescriptions for these medications compared with individuals of White race and non-Hispanic ethnicity. Further research is needed to understand the mechanisms underlying these differences in rates of prescribing and the potential relationship with differences in clinical outcomes.

Biomarkers of Kidney Tubule Health, CKD Progression, and Acute Kidney Injury in SPRINT (Systolic Blood Pressure Intervention Trial) Participants.

RATIONALE & OBJECTIVE: The Systolic Blood Pressure Intervention Trial (SPRINT) compared the effect of intensive versus standard systolic blood pressure targets on cardiovascular morbidity and mortality. In this ancillary study, we evaluated the use of exploratory factor analysis (EFA) to combine biomarkers of kidney tubule health in urine and plasma and then study their role in longitudinal estimated glomerular filtration rate (eGFR) change and risk of acute kidney injury (AKI). STUDY DESIGN: Observational cohort nested in a clinical trial. SETTING & PARTICIPANTS: 2,351 SPRINT participants with eGFR < 60 mL/min/1.73 m2 at baseline. EXPOSURE: Levels of neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), chitinase-3-like protein (YKL-40), kidney injury molecule 1 (KIM-1), monocyte chemoattractant protein 1 (MCP-1), α1-microglobulin (A1M) and ß2-microglobulin (B2M), uromodulin (UMOD), fibroblast growth factor 23 (FGF-23), and intact parathyroid hormone (PTH). OUTCOME: Longitudinal changes in eGFR and risk of AKI. ANALYTICAL APPROACH: We performed EFA to capture different tubule pathophysiologic processes. We used linear mixed effects models to evaluate the association of each factor with longitudinal changes in eGFR. We evaluated the association of the tubular factors scores with AKI using Cox proportional hazards regression. RESULTS: From 10 biomarkers, EFA generated 4 factors reflecting tubule injury/repair (NGAL, IL-18, and YKL-40), tubule injury/fibrosis (KIM-1 and MCP-1), tubule reabsorption (A1M and B2M), and tubule reserve/mineral metabolism (UMOD, FGF-23, and PTH). Each 1-SD higher tubule reserve/mineral metabolism factor score was associated with a 0.58% (95% CI, 0.39%-0.67%) faster eGFR decline independent of baseline eGFR and albuminuria. Both the tubule injury/repair and tubule injury/fibrosis factors were independently associated with future risk of AKI (per 1 SD higher, HRs of 1.18 [95% CI, 1.10-1.37] and 1.23 [95% CI, 1.02-1.48], respectively). LIMITATIONS: The factors require validation in other settings. CONCLUSIONS: EFA allows parsimonious subgrouping of biomarkers into factors that are differentially associated with progressive eGFR decline and AKI. These subgroups may provide insights into the pathological processes driving adverse kidney outcomes.

Associations of Serum Calciprotein Particle Size and Transformation Time With Arterial Calcification, Arterial Stiffness, and Mortality in Incident Hemodialysis Patients.

RATIONALE & OBJECTIVE: Characteristics of the transformation of primary to secondary calciprotein particles (CPPs) in serum, including the size of secondary CPP (CPP2) aggregates and the time of transformation (T50), may be markers for arterial calcification in patients undergoing hemodialysis (HD). We examined the associations of CPP2 aggregate size and T50 with arterial calcification in incident HD patients. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Incident HD patients (n=402with available CPP2 measures and n=388with available T50 measures) from the Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease (PACE) Study PREDICTORS: Serum CPP2 size and T50 at baseline. OUTCOMES: Primary outcomes were baseline coronary artery and thoracic aorta calcifications. Exploratory outcomes included baseline arterial stiffness, measured by pulse wave velocity (PWV) and ankle brachial index, and longitudinally, repeat measures of PWV and all-cause mortality. ANALYTICAL APPROACH: Tobit regression, multiple linear regression, Poisson regression, linear mixed-effects regression, and Cox proportional hazards regression. RESULTS: Mean age was 55±13 years, 41% were women, 71% were Black, and 57% had diabetes mellitus. Baseline CPP2 size and T50 were correlated with baseline fetuin A level (r=-0.59 for CPP2 and 0.44 for T50; P<0.001 for both), but neither was associated with baseline measures of arterial calcification or arterial stiffness. Baseline CPP2 size and T50 were not associated with repeat measures of PWV. During a median follow-up of 3.5 (IQR, 1.7-6.2) years, larger CPP2 was associated with higher risk for mortality (HR, 1.17 [95% CI, 1.05-1.31] per 100nm larger CPP2 size) after adjusting for demographics and comorbid conditions, but there was no association between baseline T50 and risk for mortality. LIMITATIONS: Possible imprecision in assays, small sample size, limited generalizability to incident HD populations with different racial composition, and residual confounding. CONCLUSIONS: In incident HD patients, neither CPP2 size nor T50 was associated with prevalent arterial calcification and stiffness. Larger CPP2 was associated with risk for mortality, but this finding needs to be confirmed in future studies.

Biomarkers of Immune Activation and Incident Kidney Failure With Replacement Therapy: Findings From the African American Study of Kidney Disease and Hypertension.

RATIONALE & OBJECTIVE: Immune activation is fundamental to the pathogenesis of many kidney diseases. Innate immune molecules such as soluble urokinase-type plasminogen activator receptor (suPAR) have been linked to the incidence and progression of chronic kidney disease (CKD). Whether other biomarkers of immune activation are associated with incident kidney failure with replacement therapy (KFRT) in African Americans with nondiabetic kidney disease is unclear. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: African American Study of Kidney Disease and Hypertension (AASK) participants with available baseline serum samples for biomarker measurement. PREDICTORS: Baseline serum levels of soluble tumor necrosis factor receptor 1 (sTNFR1), sTNFR2, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). OUTCOMES: Incident KFRT, all-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards models. RESULTS: Among 500 participants with available samples, mean glomerular filtration rate was 44.7mL/min/1.73m2, and median urinary protein-creatinine ratio was 0.09g/g at baseline. Over a median follow up of 9.6 years, there were 161 (32%) KFRT and 113 (23%) death events. In models adjusted for demographic and clinical factors and baseline kidney function, each 2-fold higher baseline level of sTNFR1, sTNFR2, and TNF-α was associated with 3.66-fold (95% CI, 2.31-5.80), 2.29-fold (95% CI, 1.60-3.29), and 1.35-fold (95% CI, 1.07-1.71) greater risks of KFRT, respectively; in comparison, each doubling of baseline suPAR concentration was associated with 1.39-fold (95% CI, 1.04-1.86) greater risk of KFRT. sTNFR1, sTNFR2, and TNF-α were also significantly associated with death (up to 2.2-fold higher risks per 2-fold higher baseline levels; P≤0.01). IFN-γ was not associated with either outcome. None of the biomarkers modified the association of APOL1 high-risk status (genetic risk factors for kidney disease among individuals of African ancestry) with KFRT (P>0.05 for interaction). LIMITATIONS: Limited generalizability to other ethnic groups or causes of CKD. CONCLUSIONS: Among African Americans with CKD attributed to hypertension, baseline levels of sTNFR1, sTNFR2, and TNF-α but not IFN-γ were associated with KFRT and mortality.

Urine Alpha-1-Microglobulin Levels and Acute Kidney Injury, Mortality, and Cardiovascular Events following Cardiac Surgery.

INTRODUCTION: Urine alpha-1-microglobulin (Uα1m) elevations signal proximal tubule dysfunction. In ambulatory settings, higher Uα1m is associated with acute kidney injury (AKI), progressive chronic kidney disease (CKD), cardiovascular (CV) events, and mortality. We investigated the associations of pre- and postoperative Uα1m concentrations with adverse outcomes after cardiac surgery. METHODS: In 1,464 adults undergoing cardiac surgery in the prospective multicenter Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury (TRIBE-AKI) cohort, we measured the pre-and postoperative Uα1m concentrations and calculated the changes from pre- to postoperative concentrations. Outcomes were postoperative AKI during index hospitalization and longitudinal risks for CKD incidence and progression, CV events, and all-cause mortality after discharge. We analyzed Uα1m continuously and categorically by tertiles using multivariable logistic regression and Cox proportional hazards regression adjusted for demographics, surgery characteristics, comorbidities, baseline estimated glomerular filtration rate, urine albumin, and urine creatinine. RESULTS: There were 230 AKI events during cardiac surgery hospitalization; during median 6.7 years of follow-up, there were 212 cases of incident CKD, 54 cases of CKD progression, 269 CV events, and 459 deaths. Each 2-fold higher concentration of preoperative Uα1m was independently associated with AKI (adjusted odds ratio [aOR] = 1.36, 95% confidence interval 1.14-1.62), CKD progression (adjusted hazard ratio [aHR] = 1.46, 1.04-2.05), and all-cause mortality (aHR = 1.19, 1.06-1.33) but not with incident CKD (aHR = 1.21, 0.96-1.51) or CV events (aHR = 1.01, 0.86-1.19). Postoperative Uα1m was not associated with AKI (aOR per 2-fold higher = 1.07, 0.93-1.22), CKD incidence (aHR = 0.90, 0.79-1.03) or progression (aHR = 0.79, 0.56-1.11), CV events (aHR = 1.06, 0.94-1.19), and mortality (aHR = 1.01, 0.92-1.11). CONCLUSION: Preoperative Uα1m concentrations may identify patients at high risk of AKI and other adverse events after cardiac surgery, but postoperative Uα1m concentrations do not appear to be informative.