Highlights
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Reduced estimated glomerular filtration rate (eGFR) and the presence of albuminuria are independent risk factors for the development of heart failure.
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Lower eGFR and higher levels of proteinuria are associated with a higher incidence of worsening heart failure (WHF) events.
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Nearly 50% of WHF events take place in outpatient clinics or emergency department settings, rather than during hospitalizations.
ABSTRACT
Background
Chronic kidney disease (CKD) is a major risk factor for heart failure (HF). However, the burden of worsening HF (WHF) events among adults with mild-to-moderate CKD has not been well described.
Objectives
This study assessed the burden of WHF in a contemporary cohort of adults with mild-to-moderate CKD.
Methods
We identified adults with mild-to-moderate CKD (eGFR 30-59 mL/min/1.73m² or eGFR ≥60 mL/min/1.73m² with albuminuria) within a large, integrated healthcare delivery system from 2012 to 2021. Outcomes included hospitalizations, emergency department visits, and outpatient encounters for WHF, stratified by HF status and level of CKD.
Results
Among 375,495 adults with mild-to-moderate CKD, mean age was 64 ± 16 years, 54% were women, mean eGFR was 76 ± 26 mL/min/1.73m², and 6.5% had prior known HF. CKD stages G1A2 (31.6%), G2A2 (24.9%), and G3aA1 (25.1%) were most prevalent. Rates (95% CI) per 100 person-years for WHF events were 1.85 (1.83-1.87) for hospitalizations, 0.85 (0.84-0.86) for emergency department visits, and 0.83 (0.81-0.84) for outpatient encounters, resulting in a cumulative rate of 2.42 (2.40-2.44). Event rates were higher at lower eGFR and higher albuminuria levels.
Conclusions
WHF is a common source of morbidity in adults with earlier stage CKD, and particularly high in those with lower eGFR and greater albuminuria. These findings underscore the importance of implementing available and emerging cardioprotective and renoprotective therapies in this high-risk population.
Background
Chronic kidney disease (CKD) affects an estimated 37 million people in the United States and is a major risk factor for heart failure (HF). Cardiovascular and kidney physiology is intricately linked and drives the co-occurrence of HF and CKD, with approximately half of HF patients experiencing some degree of renal dysfunction. Similarly, in patients with kidney dysfunction, HF remains the most common source of morbidity and mortality. ,
In general, proteinuria and reduced estimated glomerular filtration rate (eGFR), both indications of kidney dysfunction, increase risk of HF. Of patients with CKD stages 4 and 5, up to 50% have concomitant diagnosed HF. However, there is often a risk-treatment mismatch in the subset of HF patients with CKD, whereby these patients are both at increased risk of HF-related morbidity and mortality and less likely to receive optimal guideline-directed medical therapy. ,, Despite the strong evidence linking cardiovascular and kidney dysfunction and the increasing recognition of cardiovascular-kidney-metabolic (CKM) syndrome, little is known about the specific burden of HF outcomes in earlier stages of CKD. Understanding the distribution of worsening HF (WHF) events in patients with earlier stage CKD could enable early preventative or therapeutic measures. Slowing or halting the progression of one or both conditions at an earlier stage may minimize clinical complications and reduce the overall burden.
In this study, we aimed to characterize the epidemiology of outpatient encounters, emergency department (ED) visits, observation stays, and hospitalizations for WHF in a contemporary, demographically diverse population with a broad range of CKD severity.
Methods
Setting and source population
Kaiser Permanente Northern California (KPNC) is a large integrated healthcare delivery system that currently offers comprehensive care (ie, inpatient, ED, and outpatient) to more than 4.5 million members via 21 hospitals and >260 clinics. KPNC membership is highly representative of local and statewide populations in terms of age, sex, race and ethnicity and socioeconomic status. ,, This study was approved by the KPNC Institutional Review Board (IRB), and a waiver of consent was obtained due to the retrospective nature of this study.
Study overview and cohort assembly
The study cohort included all adult (age ≥18 years) KPNC members with evidence of mild-to-moderate CKD between January 1st, 2012 and December 31st, 2021. Mild-to-moderate CKD was defined as having an outpatient, nonemergency department eGFR between 30 and 59 mL/min/1.73m2 (using the 2021 CKD-Epi race-free equation) for a period of >3 months OR an outpatient, nonemergency department eGFR ≥60 mL/min/1.73m2 with laboratory evidence of proteinuria, defined as a urine albumin-to-creatinine ratio ≥30 mg/ g. , A minimum of 6 months of continuous health plan membership and pharmacy benefit was required prior to index date. Patients with left ventricular assist device or solid organ transplant prior to index date, death on the index date or no evidence of health plan membership after index date, were excluded.
Follow-up and censoring
The index date was defined as the first date meeting either of the mild-to-moderate CKD criteria. Baseline data were collected up to 5 years before index date. Patients were followed from index date until December 31st, 2022 and were censored at KP membership end date, development of end-stage kidney disease (defined as receipt of chronic dialysis or kidney transplant), or death.
Outcome ascertainment
We used validated natural language processing (NLP)-based programs applied to structured and unstructured electronic health record (EHR) data to identify hospitalizations (ie, defined as admissions lasting >24 hours), ED visits (ie, including observation stays), and outpatient encounters (ie, defined as an urgent care visit or a clinical appointment with a primary care provider or a cardiologist) for WHF. Episodes of WHF were defined as including ≥1 qualifying clinical encounter, ≥1 symptom, ≥2 objective findings including ≥1 sign, and new administration of intravenous loop diuretics (ie, ≥2 doses if hospitalized or ≥1 dose if nonhospitalized) and/or new hemodialysis/continuous kidney replacement therapy. For outpatient encounters, we defined a change in HF-related therapy as either new initiation and/or augmentation of oral diuretics leveraging both structured (eg, pharmacy dispensing data) and unstructured (eg, written provider documentation) data. These diagnostic criteria are based on a standardized definition of WHF previously developed and validated by a consensus panel of trialists with expertise in clinical endpoint classification in collaboration with the U.S. Food and Drug Administration. Rule-based NLP queries were validated within KPNC compared to a “gold standard” consisting of manual records review and validation of >500 cases of suspected WHF across practice settings by 2 physicians, with final adjudication by a board-certified cardiologist if discrepancies existed. Overall, the NLP algorithm had outstanding accuracy ≥90% to 95% for hospitalizations, ED visits, and outpatient encounters for WHF.
Data sources and covariates
The KPNC Epic-based EHR system was the primary source of hospitalization data, provider progress notes, patient demographic information, and cardiac imaging reports. Data on inpatient medications, laboratory values, vital signs, and procedures were also obtained from EHR databases. To supplement these records, the KPNC Virtual Data Warehouse was also used to ascertain concurrent comorbidities, outpatient medications, and outpatient laboratory values.
Statistical analyses
All analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC) and R version 4.3.1 software (R Core Team, 2023). Baseline characteristics were presented as mean ± SD for continuous variables and as frequencies with percentages for categorical data. Any missing data were assigned to a missing or unknown category. Crude rates (per 100 person-years) with associated 95% confidence intervals were calculated for the composite of all WHF events and for each WHF encounter type. Direct age-standardized and sex-standardized rates of WHF were computed, and cumulative incidence functions for WHF events were also estimated, accounting for the competing risk of death The adjusted cumulative incidences were assessed using direct standardization methods to control for potential confounders. ,
Results
Cohort assembly and baseline characteristics
From January 1, 2012 to December 31, 2021, we identified 375,495 adults with mild-to-moderate CKD ( Figure 1 , Table 1 ). Mean (SD) age was 64 ± 16 years, 54% were women, and mean (SD) eGFR was 76 ± 26 mL/min/1.73m². Overall, 46.9% of patients identified as non-Hispanic White, 6.7% as non-Hispanic Black, 14.3% as Hispanic, and 14.1% as Asian. The majority of patients had underlying hypertension (73.9%) and dyslipidemia (75.6%). Diagnosed HF was present at baseline in 6.5% of patients. CKD stages G1A2 (31.6%), G2A2 (24.9%), and G3aA1 (25.1%) were the most prevalent.
Cohort assembly diagram.
Abbreviations: CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate.
Table 1
Baseline characteristics of adults with mild-to-moderate CKD between 2012 and 2021, overall and stratified by CKD stage.
| Characteristic | Overall N = 375,495 |
CKD
stage 1 N = 127,092 |
CKD
stage 2 N = 103,146 |
CKD
stage 3a N = 108,872 |
CKD
stage 3b N = 36,385 |
|---|---|---|---|---|---|
| Age, years, n (%) | |||||
| 18-49 | 72,836 (19.4) | 59,612 (46.9) | 9,402 (9.1) | 2,787 (2.6) | 1,035 (2.8) |
| 50-59 | 59,791 (15.9) | 30,892 (24.3) | 17,672 (17.1) | 8,949 (8.2) | 2,278 (6.3) |
| 60-69 | 91,491 (24.4) | 25,699 (20.2) | 32,107 (31.1) | 26,946 (24.8) | 6,739 (18.5) |
| 70-79 | 88,149 (23.5) | 10,171 (8.0) | 29,370 (28.5) | 37,403 (34.4) | 11,205 (30.8) |
| ≥80 | 63,228 (16.8) | 718 (0.6) | 14,595 (14.1) | 32,787 (30.1) | 15,128 (41.6) |
| Gender, n (%) | |||||
| Male | 171,956 (45.8) | 54,715 (43.1) | 56,012 (54.3) | 46,450 (42.7) | 14,779 (40.6) |
| Female | 203,539 (54.2) | 72,377 (56.9) | 47,134 (45.7) | 62,422 (57.3) | 21,606 (59.4) |
| Race/ethnicity, n (%) | |||||
| Non-Hispanic White | 176,124 (46.9) | 40,999 (32.3) | 46,331 (44.9) | 66,929 (61.5) | 21,865 (60.1) |
| Non-Hispanic Black | 25,331 (6.7) | 6,599 (5.2) | 7,818 (7.6) | 8,184 (7.5) | 2,730 (7.5) |
| Hispanic | 53,621 (14.3) | 31,369 (24.7) | 12,467 (12.1) | 7,088 (6.5) | 2,697 (7.4) |
| Asian | 52,869 (14.1) | 26,886 (21.2) | 15,696 (15.2) | 7,826 (7.2) | 2,461 (6.8) |
| Native Hawaiian or Pacific Islander | 2,974 (0.8) | 1,707 (1.3) | 874 (0.8) | 291 (0.3) | 102 (0.3) |
| American Indian or Alaska Native | 1,573 (0.4) | 722 (0.6) | 454 (0.4) | 298 (0.3) | 99 (0.3) |
| Multiracial | 59,215 (15.8) | 16,421 (12.9) | 18,556 (18.0) | 17,875 (16.4) | 6,363 (17.5) |
| Unknown | 3,788 (1.0) | 2,389 (1.9) | 950 (0.9) | 381 (0.3) | 68 (0.2) |
| Smoker, n (%) | |||||
| Current | 27,607 (7.4) | 11,441 (9.0) | 7,762 (7.5) | 6,390 (5.9) | 2,014 (5.5) |
| Former | 122,591 (32.6) | 30,551 (24.0) | 36,576 (35.5) | 40,883 (37.6) | 14,581 (40.1) |
| Never | 225,297 (60.0) | 85,100 (67.0) | 58,808 (57.0) | 61,599 (56.6) | 19,790 (54.4) |
| Medical history, n (%) | |||||
| Heart failure | 24,277 (6.5) | 2,276 (1.8) | 7,545 (7.3) | 8,808 (8.1) | 5,648 (15.5) |
| Atrial fibrillation or flutter | 32,639 (8.7) | 3,496 (2.8) | 10,966 (10.6) | 12,632 (11.6) | 5,545 (15.2) |
| Ventricular fibrillation or tachycardia | 1,407 (0.4) | 203 (0.2) | 446 (0.4) | 523 (0.5) | 235 (0.6) |
| Ischemic stroke or transient ischemic attack | 10,413 (2.8) | 1,559 (1.2) | 3,304 (3.2) | 3,855 (3.5) | 1,695 (4.7) |
| Acute myocardial infarction | 7,656 (2.0) | 1,134 (0.9) | 2,310 (2.2) | 2,808 (2.6) | 1,404 (3.9) |
| Mitral or aortic valvular disease | 15,425 (4.1) | 1,620 (1.3) | 4,845 (4.7) | 6,205 (5.7) | 2,755 (7.6) |
| Venous thromboembolism | 7,985 (2.1) | 1,774 (1.4) | 2,647 (2.6) | 2,486 (2.3) | 1,078 (3.0) |
| Diabetes mellitus | 91,133 (24.3) | 46,071 (36.3) | 29,178 (28.3) | 11,766 (10.8) | 4,118 (11.3) |
| Hypertension | 277,563 (73.9) | 69,582 (54.7) | 85,832 (83.2) | 89,030 (81.8) | 33,119 (91.0) |
| Dyslipidemia | 283,970 (75.6) | 81,936 (64.5) | 88,681 (86.0) | 83,666 (76.8) | 29,687 (81.6) |
| Hyperthyroidism | 13,834 (3.7) | 3,308 (2.6) | 3,465 (3.4) | 5,174 (4.8) | 1,887 (5.2) |
| Hypothyroidism | 55,730 (14.8) | 11,592 (9.1) | 15,093 (14.6) | 20,989 (19.3) | 8,056 (22.1) |
| Chronic liver disease | 22,523 (6.0) | 10,441 (8.2) | 7,590 (7.4) | 3,457 (3.2) | 1,035 (2.8) |
| Chronic lung disease | 98,386 (26.2) | 28,022 (22.0) | 28,815 (27.9) | 30,307 (27.8) | 11,242 (30.9) |
| Depression | 55,100 (14.7) | 15,836 (12.5) | 15,955 (15.5) | 17,408 (16.0) | 5,901 (16.2) |
| Dementia | 10,412 (2.8) | 778 (0.6) | 2,885 (2.8) | 4,563 (4.2) | 2,186 (6.0) |
| Vital signs | |||||
| BMI, kg/m 2, mean (SD) | 30.7 (7.3) | 32.1 (7.9) | 31.1 (7.2) | 29.2 (6.4) | 29.4 (6.7) |
| Missing | 13,252 (3.5) | 6,206 (4.9) | 4,053 (3.9) | 2,291 (2.1) | 702 (1.9) |
| Systolic blood pressure, mmHg, mean (SD) | 130.8 (17.1) | 129.6 (16.2) | 132.0 (17.2) | 130.8 (17.4) | 131.6 (18.7) |
| Missing | 6,928 (1.8) | 3,530 (2.8) | 2,041 (2.0) | 1,050 (1.0) | 307 (0.8) |
| Laboratory value s | |||||
| Hemoglobin, g/dL, mean (SD) | 13.5 (1.7) | 13.7 (1.7) | 13.6 (1.7) | 13.4 (1.6) | 12.7 (1.7) |
| Missing | 58,097 (15.5) | 22,705 (17.9) | 17,135 (16.6) | 14,589 (13.4) | 3,668 (10.1) |
| Estimated glomerular filtration rate, mL/min/1.73m 2, mean (SD) | 76.2 (26.1) | 107.2 (11.9) | 75.0 (8.8) | 53.8 (4.2) | 38.7 (4.3) |
| uACR, mg/g, mean (SD) | 142.0 (672.9) | 152.2 (641.9) | 191.6 (905.0) | 51.2 (204.8) | 109.3 (352.7) |
| Missing | 59,114 (15.7) | 0 (0.0) | 0 (0.0) | 47,081 (43.2) | 12,033 (33.1) |
| Medications, n (% ) | |||||
| Angiotensin-converting enzyme inhibitor | 136,245 (36.3) | 36,108 (28.4) | 42,063 (40.8) | 42,792 (39.3) | 15,282 (42.0) |
| Angiotensin II receptor blocker | 70,803 (18.9) | 18,553 (14.6) | 25,915 (25.1) | 19,422 (17.8) | 6,913 (19.0) |
| Angiotensin-neprilysin inhibitor | 259 (0.1) | 51 (0.0) | 161 (0.2) | 39 (0.0) | 8 (0.0) |
| Mineralocorticoid receptor antagonist | 7,240 (1.9) | 996 (0.8) | 2,297 (2.2) | 2,724 (2.5) | 1,223 (3.4) |
| Loop diuretics | 39,432 (10.5) | 4,566 (3.6) | 11,806 (11.4) | 14,019 (12.9) | 9,041 (24.8) |
| Thiazide diuretics | 103,569 (27.6) | 21,593 (17.0) | 29,236 (28.3) | 39,568 (36.3) | 13,172 (36.2) |
| β-Blocker | 132,950 (35.4) | 24,051 (18.9) | 41,336 (40.1) | 47,538 (43.7) | 20,025 (55.0) |
| Calcium channel blocker | 89,554 (23.8) | 18,705 (14.7) | 29,894 (29.0) | 27,856 (25.6) | 13,099 (36.0) |
| Antiarrhythmic drug | 6,724 (1.8) | 796 (0.6) | 1,856 (1.8) | 2,819 (2.6) | 1,253 (3.4) |
| Oral anticoagulant | 27,362 (7.3) | 3,770 (3.0) | 9,688 (9.4) | 9,776 (9.0) | 4,128 (11.3) |
| Antiplatelet drug | 13,851 (3.7) | 1,982 (1.6) | 4,337 (4.2) | 5,057 (4.6) | 2,475 (6.8) |
| Statins | 210,448 (56.0) | 56,577 (44.5) | 69,856 (67.7) | 60,880 (55.9) | 23,135 (63.6) |
| Other lipid-lowering drugs | 15,157 (4.0) | 3,354 (2.6) | 4,641 (4.5) | 4,836 (4.4) | 2,326 (6.4) |
| Nitrates | 13,647 (3.6) | 1,568 (1.2) | 4,116 (4.0) | 4,877 (4.5) | 3,086 (8.5) |
| Vasodilators | 22,029 (5.9) | 2,600 (2.0) | 6,930 (6.7) | 7,431 (6.8) | 5,068 (13.9) |
| Any diabetes therapy | 165,607 (44.1) | 69,482 (54.7) | 60,807 (59.0) | 24,255 (22.3) | 11,063 (30.4) |
| Sodium-glucose cotransporter 2 inhibitors | 1,808 (0.5) | 834 (0.7) | 892 (0.9) | 69 (0.1) | 13 (0.0) |
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