Rationale and design of the KP ENRICH trial: A food is medicine intervention in low-income high-risk adults with diabetes within Kaiser Permanente.

BACKGROUND: Food insecurity is associated with poor glycemic control and increased risk for diabetes-related complications. The clinical benefit of addressing these challenges through a medically supportive grocery prescription (GRx) program in patients with type 2 diabetes mellitus (T2D) remains unclear. We report the aims and design of a randomized clinical trial to evaluate the effectiveness of a 6-month GRx intervention on hemoglobin A1c (HbA1c) levels among low-income adults with T2D. METHODS: The Kaiser Permanente Evaluating Nutritional Interventions in Food-Insecure High-Risk Adults (KP ENRICH) Study is a pragmatic randomized trial enrolling 1100 participants within Kaiser Permanente Northern California and Southern California, two integrated health care delivery systems serving >9 million members. Medicaid-insured adults with T2D and baseline HbA1c ≥7.5% will be randomized at a 1:1 ratio to either GRx, delivered as $100 per month for select items from among a curated list of healthful food groups in an online grocery ordering and home-delivery platform along with biweekly digital nutrition educational materials, or control, consisting of free membership and deliveries from the online grocery platform but without curated food groups or purchasing dollars. The primary outcome is 6-month change in HbA1c. Secondary outcomes include 12-month change in HbA1c, and 6- and 12-month change in medical resource utilization, food security, nutrition security, dietary habits, diabetes-related quality of life, and dietary self-efficacy. CONCLUSIONS: The results of this large randomized clinical trial of GRx will help inform future policy and health system-based initiatives to improve food and nutrition security, disease management, and health equity among patients with T2D.

Sex-Based Differences in the Epidemiology, Clinical Characteristics, and Outcomes Associated with Worsening Heart Failure Events in a Learning Health System.

BACKGROUND: Differences in demographics, risk factors, and clinical characteristics may contribute to variations in men and women in terms of the prevalence, clinical setting, and outcomes associated with worsening heart failure (WHF) events. We sought to describe sex-based differences in the epidemiology, clinical characteristics, and outcomes associated with WHF events across clinical settings. METHODS AND RESULTS: We examined adults diagnosed with HF from 2010 to 2019 within a large, integrated health care delivery system. Electronic health record data were accessed for hospitalizations, emergency department (ED) visits and observation stays, and outpatient encounters. WHF was identified using validated natural language processing algorithms and defined as ≥1 symptom, ≥2 objective findings (including ≥1 sign), and ≥1 change in HF-related therapy. Incidence rates and associated outcomes for WHF were compared across care setting by sex. We identified 1,122,368 unique clinical encounters with a diagnosis code for HF, with 124,479 meeting WHF criteria. These WHF encounters existed among 102,116 patients, of whom 48,543 (47.5%) were women and 53,573 (52.5%) were men. Women experiencing WHF were older and more likely to have HF with preserved ejection fraction compared with men. The clinical settings of WHF were similar among women and men: hospitalizations (36.8% vs 37.7%), ED visits or observation stays (11.8% vs 13.4%), and outpatient encounters (4.4% vs 4.9%). Women had lower odds of 30-day mortality after an index hospitalization (adjusted odds ratio 0.88, 95% confidence interval 0.83-0.93) or ED visit or observation stay (adjusted odds ratio 0.86, 95% confidence interval 0.75-0.98) for WHF. CONCLUSIONS: Women and men contribute similarly to WHF events across diverse clinical settings despite marked differences in age and left ventricular ejection fraction.

Applying natural language processing to identify emergency department and observation encounters for worsening heart failure.

AIMS: Worsening heart failure (WHF) events occurring in non-inpatient settings are becoming increasingly recognized, with implications for prognostication. We evaluate the performance of a natural language processing (NLP)-based approach compared with traditional diagnostic coding for non-inpatient clinical encounters and left ventricular ejection fraction (LVEF). METHODS AND RESULTS: We compared characteristics for encounters that did vs. did not meet WHF criteria, stratified by care setting [i.e. emergency department (ED) and observation stay]. Overall, 8407 (22%) encounters met NLP-based criteria for WHF (3909 ED visits and 4498 observation stays). The use of an NLP-derived definition adjudicated 3983 (12%) of non-primary HF diagnoses as meeting consensus definitions for WHF. The most common diagnosis indicated in these encounters was dyspnoea. Results were primarily driven by observation stays, in which 2205 (23%) encounters with a secondary HF diagnosis met the WHF definition by NLP. CONCLUSIONS: The use of standard claims-based adjudication for primary diagnosis in the non-inpatient setting may lead to misclassification of WHF events in the ED and overestimate observation stays. Primary diagnoses alone may underestimate the burden of WHF in non-hospitalized settings.

CKD stage-specific utility of two equations for predicting 1-year risk of ESKD.

BACKGROUND: The Kidney Failure Risk Equation (KFRE) and Kaiser Permanente Northwest (KPNW) models have been proposed to predict progression to ESKD among adults with CKD within 2 and 5 years. We evaluated the utility of these equations to predict the 1-year risk of ESKD in a contemporary, ethnically diverse CKD population. METHODS: We conducted a retrospective cohort study of adult members of Kaiser Permanente Northern California (KPNC) with CKD Stages 3-5 from January 2008-September 2015. We ascertained the onset of ESKD through September 2016, and calculated stage-specific estimates of model discrimination and calibration for the KFRE and KPNW equations. RESULTS: We identified 108,091 eligible adults with CKD (98,757 CKD Stage 3; 8,384 CKD Stage 4; and 950 CKD Stage 5 not yet receiving kidney replacement therapy), with mean age of 75 years, 55% women, and 37% being non-white. The overall 1-year risk of ESKD was 0.8% (95%CI: 0.8-0.9%). The KFRE displayed only moderate discrimination for CKD 3 and 5 (c = 0.76) but excellent discrimination for CKD 4 (c = 0.86), with good calibration for CKD 3-4 patients but suboptimal calibration for CKD 5. Calibration by CKD stage was similar to KFRE for the KPNW equation but displayed worse calibration across CKD stages for 1-year ESKD prediction. CONCLUSIONS: In a large, ethnically diverse, community-based CKD 3-5 population, both the KFRE and KPNW equation were suboptimal in accurately predicting the 1-year risk of ESKD within CKD stage 3 and 5, but more accurate for stage 4. Our findings suggest these equations can be used in1-year prediction for CKD 4 patients, but also highlight the need for more personalized, stage-specific equations that predicted various short- and long-term adverse outcomes to better inform overall decision-making.

Developing Clinical Risk Prediction Models for Worsening Heart Failure Events and Death by Left Ventricular Ejection Fraction.

Background There is a need to develop electronic health record-based predictive models for worsening heart failure (WHF) events across clinical settings and across the spectrum of left ventricular ejection fraction (LVEF). Methods and Results We studied adults with heart failure (HF) from 2011 to 2019 within an integrated health care delivery system. WHF encounters were ascertained using natural language processing and structured data. We conducted boosted decision tree ensemble models to predict 1-year hospitalizations, emergency department visits/observation stays, and outpatient encounters for WHF and all-cause death within each LVEF category: HF with reduced ejection fraction (EF) (LVEF <40%), HF with mildly reduced EF (LVEF 40%-49%), and HF with preserved EF (LVEF ≥50%). Model discrimination was evaluated using area under the curve and calibration using mean squared error. We identified 338 426 adults with HF: 61 045 (18.0%) had HF with reduced EF, 49 618 (14.7%) had HF with mildly reduced EF, and 227 763 (67.3%) had HF with preserved EF. The 1-year risks of any WHF event and death were, respectively, 22.3% and 13.0% for HF with reduced EF, 17.0% and 10.1% for HF with mildly reduced EF, and 16.3% and 10.3% for HF with preserved EF. The WHF model displayed an area under the curve of 0.76 and mean squared error of 0.13, whereas the model for death displayed an area under the curve of 0.83 and mean squared error of 0.076. Performance and predictors were similar across WHF encounter types and LVEF categories. Conclusions We developed risk prediction models for 1-year WHF events and death across the LVEF spectrum using structured and unstructured electronic health record data and observed no substantial differences in model performance or predictors except for death, despite differences in underlying HF cause.

Association Between Participation in a Heart Failure Telemonitoring Program and Health Care Utilization and Death Within an Integrated Health Care Delivery System.

BACKGROUND: The clinical usefulness of remote telemonitoring to reduce postdischarge health care use and death in adults with heart failure (HF) remains controversial. METHODS AND RESULTS: Within a large integrated health care delivery system, we matched patients enrolled in a postdischarge telemonitoring intervention from 2015 to 2019 to patients not receiving telemonitoring at up to a 1:4 ratio on age, sex, and calipers of a propensity score. Primary outcomes were readmissions for worsening HF and all-cause death within 30, 90, and 365 days of the index discharge; secondary outcomes were all-cause readmissions and any outpatient diuretic dose adjustments. We matched 726 patients receiving telemonitoring to 1985 controls not receiving telemonitoring, with a mean age of 75 ± 11 years and 45% female. Patients receiving telemonitoring did not have a significant reduction in worsening HF hospitalizations (adjusted rate ratio [aRR] 0.95, 95% confidence interval [CI] 0.68-1.33), all-cause death (adjusted hazard ratio 0.60, 95% CI 0.33-1.08), or all-cause hospitalization (aRR 0.82, 95% CI 0.65-1.05) at 30 days, but did have an increase in outpatient diuretic dose adjustments (aRR 1.84, 95% CI 1.44-2.36). All associations were similar at 90 and 365 days postdischarge. CONCLUSIONS: A postdischarge HF telemonitoring intervention was associated with more diuretic dose adjustments but was not significantly associated with HF-related morbidity and mortality.

The association between changes in echocardiography and risk of heart failure hospitalizations and death in adults with chronic kidney disease.

Adults with chronic kidney disease (CKD) are at increased risk for developing heart failure (HF). However, longitudinal cardiac remodeling in CKD has not been well-characterized and its association with HF outcomes remains unknown. We evaluated the association between change in echocardiographic parameters between baseline and year 4 with the subsequent risk of HF hospitalization and death using Cox proportional hazard models in a landmark analysis of a prospective multicenter CKD cohort. Among 2673 participants, mean ± SD age was 61 ± 11 years, with 45% women, and 56% non-white. A total of 472 hospitalizations for HF and 776 deaths occurred during a median (interquartile range) follow-up duration of 8.0 (6.3-9.1) years. Patients hospitalized for HF experienced larger preceding absolute increases in left ventricular (LV) volumes and decreases in LV ejection fraction. Adverse changes in LV ejection fraction, LV cavity volume, LV mass index, and LV geometry were independently associated with an increased risk of HF hospitalization and death. Among adults with CKD, deleterious cardiac remodeling occurs over a relatively short timeframe and adverse remodeling is associated with increased risk of HF-related morbidity and mortality.

Breast arterial calcification is associated with incident atrial fibrillation among older but not younger post-menopausal women.

Aims: The goal of this study was to examine the association of breast arterial calcification (BAC) presence and quantity with incident atrial fibrillation (AF) in a large cohort of post-menopausal women. Methods and results: We conducted a longitudinal cohort study among women free of clinically overt cardiovascular disease and AF at baseline (between October 2012 and February 2015) when they attended mammography screening. Atrial fibrillation incidence was ascertained using diagnostic codes and natural language processing. Among 4908 women, 354 incident cases of AF (7%) were ascertained after a mean (standard deviation) of 7 (2) years of follow-up. In Cox regression adjusting for a propensity score for BAC, BAC presence vs. absence was not significantly associated with AF [hazard ratio (HR) = 1.12; 95% confidence interval (CI), 0.89-1.42; P = 0.34]. However, a significant (a priori hypothesized) age by BAC interaction was found (P = 0.02) such that BAC presence was not associated with incident AF in women aged 60-69 years (HR = 0.83; 95% CI, 0.63-1.15; P = 0.26) but was significantly associated with incident AF in women aged 70-79 years (HR = 1.75; 95% CI, 1.21-2.53; P = 0.003). No evidence of dose-response relationship between BAC gradation and AF was noted in the entire cohort or in age groups separately. Conclusion: Our results demonstrate, for the first time, an independent association between BAC and AF in women over age 70 years.

Effect of Medically Tailored Meals on Clinical Outcomes in Recently Hospitalized High-Risk Adults.

BACKGROUND: Inability to adhere to nutritional recommendations is common and linked to worse outcomes in patients with nutrition-sensitive conditions. OBJECTIVES: The purpose of this study is to evaluate whether medically tailored meals (MTMs) improve outcomes in recently discharged adults with nutrition-sensitive conditions compared with usual care. RESEARCH DESIGN: Remote pragmatic randomized trial. SUBJECTS: Adults with heart failure, diabetes, or chronic kidney disease being discharged home between April 27, 2020, and June 9, 2021, from 5 hospitals within an integrated health care delivery system. MEASURES: Participants were prerandomized to 10 weeks of MTMs (with or without virtual nutritional counseling) compared with usual care. The primary outcome was all-cause hospitalization within 90 days after discharge. Exploratory outcomes included all-cause and cause-specific health care utilization and all-cause death within 90 days after discharge. RESULTS: A total of 1977 participants (MTMs: n=993, with 497 assigned to also receive virtual nutritional counseling; usual care: n=984) were enrolled. Compared with usual care, MTMs did not reduce all-cause hospitalization at 90 days after discharge [adjusted hazard ratio, aHR: 1.02, 95% confidence interval (CI), 0.86-1.21]. In exploratory analyses, MTMs were associated with lower mortality (aHR: 0.65, 95% CI, 0.43-0.98) and fewer hospitalizations for heart failure (aHR: 0.53, 95% CI, 0.33-0.88), but not for any emergency department visits (aHR: 0.95, 95% CI, 0.78-1.15) or diabetes-related hospitalizations (aHR: 0.75, 95% CI, 0.31-1.82). No additional benefit was observed with virtual nutritional counseling. CONCLUSIONS: Provision of MTMs after discharge did not reduce risk of all-cause hospitalization in adults with nutrition-sensitive conditions. Additional large-scale randomized controlled trials are needed to definitively determine the impact of MTMs on survival and cause-specific health care utilization in at-risk individuals.

Analysis of Worsening Heart Failure Events in an Integrated Health Care System.

BACKGROUND: There is growing interest to disentangle worsening heart failure (WHF) from location of care and move away from hospitalization as a surrogate for acuity. OBJECTIVES: The purpose of this study was to describe the incidence of WHF events across the care continuum from ambulatory encounters to hospitalizations. METHODS: We studied calendar year cohorts of adults with diagnosed heart failure (HF) from 2010-2019 within a large, integrated health care delivery system. Electronic health record (EHR) data were accessed for outpatient encounters, emergency department (ED) visits/observation stays, and hospitalizations. WHF was defined as ≥1 symptom, ≥2 objective findings including ≥1 sign, and ≥1 change in HF-related therapy. Symptoms and signs were ascertained using natural language processing. RESULTS: We identified 103,138 eligible individuals with mean age 73.6 ± 13.7 years, 47.5% women, and mean left ventricular ejection fraction of 51.4% ± 13.7%. There were 1,136,750 unique encounters including 743,039 (65.4%) outpatient encounters, 224,670 (19.8%) ED visits/observation stays, and 169,041 (14.9%) hospitalizations. A total of 126,008 WHF episodes were identified, including 34,758 (27.6%) outpatient encounters, 28,301 (22.5%) ED visits/observation stays, and 62,949 (50.0%) hospitalizations. The annual incidence (events per 100 person-years) of WHF increased from 25 to 33 during the study period primarily caused by outpatient encounters (7 to 10) and ED visits/observation stays (4 to 7). The 30-day rate of hospitalizations for WHF ranged from 8.2% for outpatient encounters to 12.4% for hospitalizations. CONCLUSIONS: ED visits/observation stays and outpatient encounters account for approximately one-half of WHF events, are driving the underlying growth in HF morbidity, and portend a poor short-term prognosis.

Prognostic value of echocardiography for heart failure and death in adults with chronic kidney disease.

BACKGROUND: Adults with chronic kidney disease (CKD) are at increased risk of heart failure (HF) morbidity and mortality. Despite well-characterized abnormalities in cardiac structure in CKD, it remains unclear how to optimally leverage echocardiography to risk stratify CKD patients. METHODS: We evaluated associations between echocardiographic parameters and risk of HF hospitalization and death using Cox proportional hazard models and forward selection with integrated discrimination improvement (IDI). RESULTS: The study included 3,505 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. Mean age was 59 ± 11 years, HF prevalence was 10%, and mean left ventricular (LV) ejection fraction (LVEF) was 54 ± 9%. During median 11 (interquartile range: 8-12) years of follow-up, event rates per 100-person years for HF hospitalizations and death, respectively, were 9.4 (95% Confidence Interval [CI]: 7.9-11.3) and 8.9 (95% CI: 7.6-10.5) for participants with LVEF <40%, 3.5 (95% CI: 3.0-4.2) and 4.6 (95% CI: 4.0-5.2) for patients with LVEF 40% to 49%, and 1.9 (95% CI: 1.7-2.1) and 3.1 (95% CI: 2.9-3.3) for patients with LVEF >50%. The rate of HF hospitalizations and deaths increased with lower eGFR across all LVEF categories. LV mass index, LVEF, and LV geometry had the strongest association with outcomes but provided modest incremental prognostic value to a baseline clinical model (IDI = 0.14 and ΔAUC = 0.017 for HF hospitalization, IDI = 0.12 and ΔAUC = 0.008 for death). CONCLUSIONS: Baseline echocardiographic parameters are independently associated with increased risk of subsequent HF morbidity and mortality but provide only marginal incremental prognostic utility beyond clinical characteristics in the setting of CKD.

A Natural Language Processing-Based Approach for Identifying Hospitalizations for Worsening Heart Failure Within an Integrated Health Care Delivery System.

Importance: The current understanding of epidemiological mechanisms and temporal trends in hospitalizations for worsening heart failure (WHF) is based on claims and national reporting databases. However, these data sources are inherently limited by the accuracy and completeness of diagnostic coding and/or voluntary reporting. Objective: To assess the overall burden of and temporal trends in the rate of hospitalizations for WHF. Design, Setting, and Participants: This cohort study, performed from January 1, 2010, to December 31, 2019, used electronic health record (EHR) data from a large integrated health care delivery system. Exposures: Calendar year trends. Main Outcomes and Measures: Hospitalizations for WHF (ie, excluding observation stays) were defined as 1 symptom or more, 2 objective findings or more including 1 sign or more, and 2 doses or more of intravenous loop diuretics and/or new hemodialysis or continuous kidney replacement therapy. Symptoms and signs were identified using natural language processing (NLP) algorithms applied to EHR data. Results: The study population was composed of 118 002 eligible patients experiencing 287 992 unique hospitalizations (mean [SD] age, 75.6 [13.1] years; 147 203 [51.1%] male; 1655 [0.6%] American Indian or Alaska Native, 28 451 [9.9%] Asian or Pacific Islander, 34 903 [12.1%] Black, 23 452 [8.1%] multiracial, 175 840 [61.1%] White, and 23 691 [8.2%] unknown), including 65 357 with a principal discharge diagnosis and 222 635 with a secondary discharge diagnosis of HF. The study population included 59 868 patients (20.8%) with HF with a reduced ejection fraction (HFrEF) (<40%), 33 361 (11.6%) with HF with a midrange EF (HFmrEF) (40%-49%), 142 347 (49.4%) with HF with a preserved EF (HFpEF) (≥50%), and 52 416 (18.2%) with unknown EF. A total of 58 042 admissions (88.8%) with a primary discharge diagnosis of HF and 62 764 admissions (28.2%) with a secondary discharge diagnosis of HF met the prespecified diagnostic criteria for WHF. Overall, hospitalizations for WHF identified on NLP-based algorithms increased from 5.2 to 7.6 per 100 hospitalizations per year during the study period. Subgroup analyses found an increase in hospitalizations for WHF based on NLP from 1.5 to 1.9 per 100 hospitalizations for HFrEF, from 0.6 to 1.0 per 100 hospitalizations for HFmrEF, and from 2.6 to 3.9 per 100 hospitalizations for HFpEF. Conclusions and Relevance: The findings of this cohort study suggest that the burden of hospitalizations for WHF may be more than double that previously estimated using only principal discharge diagnosis. There has been a gradual increase in the rate of hospitalizations for WHF with a more noticeable increase observed for HFpEF.

Population-based identification and temporal trend of children with primary nephrotic syndrome: The Kaiser Permanente nephrotic syndrome study.

INTRODUCTION: Limited population-based data exist about children with primary nephrotic syndrome (NS). METHODS: We identified a cohort of children with primary NS receiving care in Kaiser Permanente Northern California, an integrated healthcare delivery system caring for >750,000 children. We identified all children <18 years between 1996 and 2012 who had nephrotic range proteinuria (urine ACR>3500 mg/g, urine PCR>3.5 mg/mg, 24-hour urine protein>3500 mg or urine dipstick>300 mg/dL) in laboratory databases or a diagnosis of NS in electronic health records. Nephrologists reviewed health records for clinical presentation and laboratory and biopsy results to confirm primary NS. RESULTS: Among 365 cases of confirmed NS, 179 had confirmed primary NS attributed to presumed minimal change disease (MCD) (72%), focal segmental glomerulosclerosis (FSGS) (23%) or membranous nephropathy (MN) (5%). The overall incidence of primary NS was 1.47 (95% Confidence Interval:1.27-1.70) per 100,000 person-years. Biopsy data were available in 40% of cases. Median age for patients with primary NS was 6.9 (interquartile range:3.7 to 12.9) years, 43% were female and 26% were white, 13% black, 17% Asian/Pacific Islander, and 32% Hispanic. CONCLUSION: This population-based identification of children with primary NS leveraging electronic health records can provide a unique approach and platform for describing the natural history of NS and identifying determinants of outcomes in children with primary NS.

Race, Genetic Ancestry, and Estimating Kidney Function in CKD.

BACKGROUND: The inclusion of race in equations to estimate the glomerular filtration rate (GFR) has become controversial. Alternative equations that can be used to achieve similar accuracy without the use of race are needed. METHODS: In a large national study involving adults with chronic kidney disease, we conducted cross-sectional analyses of baseline data from 1248 participants for whom data, including the following, had been collected: race as reported by the participant, genetic ancestry markers, and the serum creatinine, serum cystatin C, and 24-hour urinary creatinine levels. RESULTS: Using current formulations of GFR estimating equations, we found that in participants who identified as Black, a model that omitted race resulted in more underestimation of the GFR (median difference between measured and estimated GFR, 3.99 ml per minute per 1.73 m2 of body-surface area; 95% confidence interval [CI], 2.17 to 5.62) and lower accuracy (percent of estimated GFR within 10% of measured GFR [P10], 31%; 95% CI, 24 to 39) than models that included race (median difference, 1.11 ml per minute per 1.73 m2; 95% CI, -0.29 to 2.54; P10, 42%; 95% CI, 34 to 50). The incorporation of genetic ancestry data instead of race resulted in similar estimates of the GFR (median difference, 1.33 ml per minute per 1.73 m2; 95% CI, -0.12 to 2.33; P10, 42%; 95% CI, 34 to 50). The inclusion of non-GFR determinants of the serum creatinine level (e.g., body-composition metrics and urinary excretion of creatinine) that differed according to race reported by the participants and genetic ancestry did not eliminate the misclassification introduced by removing race (or ancestry) from serum creatinine-based GFR estimating equations. In contrast, the incorporation of race or ancestry was not necessary to achieve similarly statistically unbiased (median difference, 0.33 ml per minute per 1.73 m2; 95% CI, -1.43 to 1.92) and accurate (P10, 41%; 95% CI, 34 to 49) estimates in Black participants when GFR was estimated with the use of cystatin C. CONCLUSIONS: The use of the serum creatinine level to estimate the GFR without race (or genetic ancestry) introduced systematic misclassification that could not be eliminated even when numerous non-GFR determinants of the serum creatinine level were accounted for. The estimation of GFR with the use of cystatin C generated similar results while eliminating the negative consequences of the current race-based approaches. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Timing of AKI after urgent percutaneous coronary intervention and clinical outcomes: a high-dimensional propensity score analysis.

INTRODUCTION: Acute kidney injury is a common complication of percutaneous coronary intervention and has been associated with an increased risk of death and progressive chronic kidney disease. However, whether the timing of acute kidney injury after urgent percutaneous coronary intervention could be used to improve patient risk stratification is not known. METHODS: We conducted a retrospective cohort study in adults surviving an urgent percutaneous coronary intervention between 2008 and 2013 within Kaiser Permanente Northern California, a large integrated healthcare delivery system, to evaluate the impact of acute kidney injury during hospitalization at 12 (±6), 24 (±6) and 48 (±6) hours after urgent percutaneous coronary intervention and subsequent risks of adverse outcomes within the first year after discharge. We used multivariable Cox proportional hazards models with adjustment for a high-dimensional propensity score for developing acute kidney injury after percutaneous coronary intervention to examine the associations between acute kidney injury timing and all-cause death and worsening chronic kidney disease. RESULTS: Among 7250 eligible adults undergoing urgent percutaneous coronary intervention, 306 (4.2%) had acute kidney injury at one or more of the examined time periods after percutaneous coronary intervention. After adjustment, acute kidney injury at 12 (±6) hours was independently associated with higher risks of death (adjusted hazard ratio [aHR] 3.55, 95% confidence interval [CI] 2.19-5.75) and worsening kidney function (aHR 2.40, 95% CI:1.24-4.63). Similar results were observed for acute kidney injury at 24 (±6) hours and death (aHR 3.90, 95% CI:2.29-6.66) and worsening chronic kidney disease (aHR 4.77, 95% CI:2.46-9.23). Acute kidney injury at 48 (±6) hours was associated with excess mortality (aHR 1.97, 95% CI:1.19-3.26) but was not significantly associated with worsening kidney function (aHR 0.91, 95% CI:0.42-1.98). CONCLUSIONS: Timing of acute kidney injury after urgent percutaneous coronary intervention may be differentially associated with subsequent risk of worsening kidney function but not death.

Primary Nephrotic Syndrome and Risks of ESKD, Cardiovascular Events, and Death: The Kaiser Permanente Nephrotic Syndrome Study.

BACKGROUND: Little population-based data exist about adults with primary nephrotic syndrome. METHODS: To evaluate kidney, cardiovascular, and mortality outcomes in adults with primary nephrotic syndrome, we identified adults within an integrated health care delivery system (Kaiser Permanente Northern California) with nephrotic-range proteinuria or diagnosed nephrotic syndrome between 1996 and 2012. Nephrologists reviewed medical records for clinical presentation, laboratory findings, and biopsy results to confirm primary nephrotic syndrome and assigned etiology. We identified a 1:100 time-matched cohort of adults without diabetes, diagnosed nephrotic syndrome, or proteinuria as controls to compare rates of ESKD, cardiovascular outcomes, and death through 2014, using multivariable Cox regression. RESULTS: We confirmed 907 patients with primary nephrotic syndrome (655 definite and 252 presumed patients with FSGS [40%], membranous nephropathy [40%], and minimal change disease [20%]). Mean age was 49 years; 43% were women. Adults with primary nephrotic syndrome had higher adjusted rates of ESKD (adjusted hazard ratio [aHR], 19.63; 95% confidence interval [95% CI], 12.76 to 30.20), acute coronary syndrome (aHR, 2.58; 95% CI, 1.89 to 3.52), heart failure (aHR, 3.01; 95% CI, 2.16 to 4.19), ischemic stroke (aHR, 1.80; 95% CI, 1.06 to 3.05), venous thromboembolism (aHR, 2.56; 95% CI, 1.35 to 4.85), and death (aHR, 1.34; 95% CI, 1.09 to 1.64) versus controls. Excess ESKD risk was significantly higher for FSGS and membranous nephropathy than for presumed minimal change disease. The three etiologies of primary nephrotic syndrome did not differ significantly in terms of cardiovascular outcomes and death. CONCLUSIONS: Adults with primary nephrotic syndrome experience higher adjusted rates of ESKD, cardiovascular outcomes, and death, with significant variation by underlying etiology in the risk for developing ESKD.

Rationale and design of the pragmatic randomized trial of icosapent ethyl for high cardiovascular risk adults (MITIGATE).

OBJECTIVE: The MITIGATE study aims to evaluate the real-world clinical effectiveness of pre-treatment with icosapent ethyl (IPE), compared with usual care, on laboratory-confirmed viral upper respiratory infection (URI)-related morbidity and mortality in adults with established atherosclerotic cardiovascular disease (ASCVD). BACKGROUND: IPE is a highly purified and stable omega-3 fatty acid prescription medication that is approved for cardiovascular risk reduction in high-risk adults on statin therapy with elevated triglycerides. Preclinical data and clinical observations suggest that IPE may have pleiotropic effects including antiviral and anti-inflammatory properties that may prevent or reduce the downstream sequelae and cardiopulmonary consequences of viral URIs. METHODS: MITIGATE is a virtual, electronic health record-based, open-label, randomized, pragmatic clinical trial enrolling ∼16,500 participants within Kaiser Permanente Northern California - a fully integrated and learning health care delivery system with 21 hospitals and >255 ambulatory clinics serving ∼4.5 million members. Adults ≥50 years with established ASCVD and no prior history of coronavirus disease 2019 (COVID-19) will be prospectively identified and pre-randomized in a 1:10 allocation ratio (∼ 1,500 IPE: ∼15,000 usual care) stratified by age and previous respiratory health status to the intervention (IPE 2 grams by mouth twice daily with meals) vs the control group (usual care) for a minimum follow-up duration of 6 months. The co-primary endpoints are moderate-to-severe laboratory-confirmed viral URI and worst clinical status due to a viral URI at any point in time. CONCLUSION: The MITIGATE study will inform clinical practice by providing evidence on the real-world clinical effectiveness of pretreatment with IPE to prevent and/or reduce the sequelae of laboratory-confirmed viral URIs in a high-risk cohort of patients with established ASCVD.

Implication of Trends in Timing of Dialysis Initiation for Incidence of End-stage Kidney Disease.

Importance: In the last 2 decades, there have been notable changes in the level of estimated glomerular filtration rate (eGFR) at which patients initiate long-term dialysis in the US and around the world. How changes over time in the likelihood of dialysis initiation at any given eGFR level in at-risk patients are associated with the population burden of end-stage kidney disease (ESKD) has not been not well defined. Objective: To examine temporal trends in long-term dialysis initiation by level of eGFR and to quantify how these patterns are associated with the number of patients with ESKD. Design, Setting, and Participants: Retrospective cohort study analyzing data obtained from a large, integrated health care delivery system in Northern California from 2001 to 2018 in successive 3-year intervals. Included individuals, ranging in number from as few as 983 122 (2001-2003) to as many as 1 844 317 (2016-2018), were adult members with 1 or more outpatient serum creatinine levels determined in the prior year. Main Outcomes and Measures: One-year risk of initiating long-term dialysis stratified by eGFR levels. Multivariable logistic regression was performed to assess temporal trends in each 3-year cohort with adjustment for age, sex, race, and diabetes status. The potential change in dialysis initiation in the final cohort (2016-2018) was estimated using the relative difference between the standardized risks in the initial cohort (2001-2003) and the final cohort. Results: In the initial 3-year cohort, the mean (SD) age was 55.4 (16.3) years, 55.0% were women, and the prevalence of diabetes was 14.9%. These characteristics, as well as the distribution of index eGFR, were stable across the study period. The likelihood of receiving dialysis at eGFR levels of 10 to 24 mL/min/1.73 m2 generally increased over time. For example, the 1-year odds of initiating dialysis increased for every 3-year interval by 5.2% (adjusted odds ratio, 1.052; 95% CI, 1.004-1.102) among adults with an index eGFR of 20 to 24 mL/min/1.73 m2, by 6.6% (adjusted odds ratio, 1.066; 95% CI, 1.007-1.130) among adults with an eGFR of 16 to 17 mL/min/1.73 m2, and by 5.3% (adjusted odds ratio, 1.053; 95% CI, 1.008-1.100) among adults with an eGFR of 10 to 13 mL/min/1.73 m2, adjusting for age, sex, race, and diabetes. The incidence of new cases of ESKD was estimated to have potentially been 16% (95% CI, 13%-18%) lower if there were no changes in system-level practice patterns or other factors besides timing of initiating long-term dialysis from the initial 3-year interval (2001-2003) to the final interval (2016-2018) assessed in this study. Conclusions and Relevance: The present results underscore the importance the timing of initiating long-term dialysis has on the size of the population of individuals with ESKD.

Kidney Function and Potassium Monitoring After Initiation of Renin-Angiotensin-Aldosterone System Blockade Therapy and Outcomes in 2 North American Populations.

BACKGROUND: Clinical practice guidelines recommend routine kidney function and serum potassium testing within 30 days of initiating ACE (angiotensin-converting enzyme) inhibitor or angiotensin II receptor blocker therapy. However, evidence is lacking about whether follow-up testing reduces therapy-related adverse outcomes. METHODS AND RESULTS: We conducted 2 population-based retrospective cohort studies in Kaiser Permanente Northern California and Ontario, Canada. Patients with outpatient serum creatinine and potassium tests in the 30 days after starting ACE inhibitor or angiotensin II receptor blocker therapy were matched 1:1 to patients without follow-up tests. We evaluated the association of follow-up testing with 30-day all-cause mortality and hospitalization with acute kidney injury or hyperkalemia using Cox regression. We also developed and externally validated a risk score to identify patients at risk of having abnormally high serum creatinine and potassium values in follow-up. We identified 75 251 matched pairs initiating ACE inhibitor or angiotensin II receptor blocker therapy between January 1, 2007, and December 31, 2017, in Kaiser Permanente Northern California. Follow-up testing was not significantly associated with 30-day all-cause mortality in Kaiser Permanente Northern California (hazard ratio, 0.75 [95% CI, 0.54-1.06]) and was associated with higher mortality in 84 905 matched pairs in Ontario (hazard ratio, 1.32 [95% CI, 1.07-1.62]). In Kaiser Permanente Northern California, follow-up testing was significantly associated with higher rates of hospitalization with acute kidney injury (hazard ratio, 1.66 [95% CI, 1.10-2.22]) and hyperkalemia (hazard ratio, 3.36 [95% CI, 1.08-10.41]), as was observed in Ontario. The risk score for abnormal potassium provided good discrimination (area under the curve [AUC], 0.75) and excellent calibration of predicted risks, while the risk score for abnormal serum creatinine provided moderate discrimination (AUC, 0.62) but excellent calibration. CONCLUSIONS: Routine laboratory monitoring after ACE inhibitor or angiotensin II receptor blocker initiation was not associated with a lower risk of 30-day mortality. We identified patient subgroups in which targeted testing may be effective in identifying therapy-related changes in serum potassium or kidney function.