Burden and Outcomes of Heart Failure Hospitalizations in Adults with Chronic Kidney Disease

Abstract

Background:

Data on rates of heart failure (HF) hospitalizations, recurrent hospitalizations and outcomes related to HF hospitalizations in CKD are limited.

Objective:

We examined rates of HF hospitalizations and re-hospitalizations within a large, CKD population and evaluated the burden of HF hospitalizations with risk of subsequent CKD progression and death.

Methods:

Evaluating the prospective Chronic Renal Insufficiency Cohort (CRIC) Study, we estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR) were measured at baseline. We calculated crude rates and rate ratios of HF hospitalizations and 30-day HF re-hospitalizations using Poisson regression models. Cox regression was used to assess the association of the frequency of HF hospitalizations within the first 2 years of follow-up with risk of subsequent CKD progression and death.

Results:

Among 3,791 participants, the crude rate of HF admissions was 5.8 per 100 person-years (with higher rates of preserved vs. reduced ejection fraction HF). The adjusted rate of HF was higher with lower eGFR (vs. eGFR >45 ml/min/1.73m²): rate ratio 1.7 and 2.2 for eGFR 30-44 and <30 ml/min/1.73m² (vs. >45 ml/min/1.73 m²), respectively. Similarly, the adjusted rates of HF hospitalization were significantly higher in those with higher urine ACR (vs. urine ACR <30 mg/g): rate ratios of 1.9 and 2.6 for urine ACR 30-299, and ≥300 mg/g, respectively. Overall, 20.6% of participants had a subsequent HF re-admission within 30 days. HF hospitalization within 2 years of study entry was associated with greater adjusted risks for CKD progression (1 hospitalization: HR 1.93, 95%CI: 1.40, 2.67; 2+ hospitalizations: HR 2.14, 95%CI: 1.30, 3.54) and all-cause death (1 hospitalization: HR 2.20 (1.71, 2.84; 2+ hospitalizations: HR 3.06, 95%CI: 2.23, 4.18).

Conclusions:

Within a large U.S. CKD population, the rates of HF hospitalizations and rehospitalization were very high, with even higher rates across categories of lower eGFR and higher urine ACR. CKD patients hospitalized with HF had greater risks of CKD progression and death. HF prevention and treatment should be a public health priority to improve CKD outcomes.

CONDENSED ABSTRACT:

This study examined rates of heart failure hospitalizations within a large, U.S. population of chronic kidney disease participants. The study found that the rates of heart failure hospitalizations and 30-day heart failure re-hospitalizations were high in this population and the rates increased across categories of lower kidney function and higher urinary protein. Furthermore, chronic kidney disease participants hospitalized with heart failure had greater risks of kidney disease progression and death. Prevention and treatment of heart failure should be a public health priority to improve outcomes in chronic kidney disease.

Introduction

Heart failure (HF) is one of the leading causes of morbidity and mortality in the U.S. HF is the primary diagnosis in >1 million hospitalizations annually and the rates of hospitalizations for HF continue to increase (1,2). The total cost of HF care in the U.S. exceeds $30 billion annually (1). Hospitalization for HF represents a sentinel prognostic event in the course of many patients, with a high risk for recurrent hospitalization (e.g., 50% at 6 months), and a 1-year mortality rate of approximately 30% (3,4).

The risk of HF is even greater in patients with chronic kidney disease (CKD) (5-10). Prior studies have estimated that patients with CKD have threefold increased risk of incident HF (6). It is also well known that patients with CKD, in particular those with end-stage-renal-disease (ESRD) requiring dialysis, have higher rates of hospitalizations. Data from the U.S. Renal Data System (USRDS) indicate that, on average, ESRD patients are hospitalized twice a year and about 30% have an unplanned re-hospitalization within 30 days (11). However, there are limited published data on rates of HF hospitalizations, recurrent hospitalizations and outcomes related to HF hospitalizations specifically in patients with CKD, which may help prioritize research and health care policy initiatives. Therefore, we examined rates of HF hospitalizations and rehospitalizations within a large, multi-center CKD population, as well as evaluated the association between burden of HF hospitalizations and subsequent progression of CKD and all-cause death.

Methods

Study population

We studied 3,939 individuals with mild to severe CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. The CRIC study recruited participants with mild to severe CKD, defined as an eGFR 20-70 ml/min/1.73m2, between June 2003 and August 2008 at 7 clinical centers across the U.S. (Ann Arbor/Detroit, MI; Baltimore, MD; Chicago, IL; Cleveland, OH; New Orleans, LA; Philadelphia, PA; and Oakland, CA) (12,13). All study participants provided written informed consent, and the study protocol was approved by institutional review boards at each of the participating sites. Detailed inclusion and exclusion criteria have been previously described (12). Participants on maintenance dialysis or with a kidney transplant were not included at cohort entry. CRIC also excluded participants with advanced HF, defined as New York Heart Association Class III or IV, on cohort entry. All participants enrolled in the study had annual in-person study visits where detailed interviews were conducted, brief physical examination performed, laboratory measures done, and cardiovascular testing performed. In addition to the annual study visits, all CRIC participants were contacted every 6 months to obtain updated information on medication use and interim updates to medical history/hospitalizations.

For the present study, we excluded 148 participants who were missing urine albumin to creatinine ratio at the baseline study visit, leaving us with a final analytical cohort of 3,791 participants.

Measures of kidney function and definition of CKD progression

We evaluated two measures of kidney function: estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (urine ACR), which were measured via standardized methods at annual research study visits Serum creatinine was measured using an enzymatic method on an Ortho Vitros 950 at the CRIC central laboratory and standardized to isotope dilution mass spectrometry-traceable values (14,15). Estimated GFR was calculated using serum creatinine and the CKD-EPI equation (16) and categorized as ≥45, 30-44, and <30 ml/min/1.73 m² (17). Urine ACR was quantified from 24-hour urine samples and categorized as <30, 30-299 or >300 mg/g (17).

CKD progression was defined as either 50% decline in eGFR or progression to ESRD. All eGFR measures were calculated from serum creatinine obtained at annual study visits. ESRD was defined as receipt of chronic dialysis or a kidney transplant and was identified through participant self-report, medical records review and data from the USRDS.

Heart failure hospitalizations

Hospitalizations for HF were adjudicated from study entry through May 2014. Hospitalizations for HF were identified by asking study participants semi-annually if they were hospitalized and electronic health records from selected hospitals or health care systems were also queried for qualifying encounters. The first 30 discharge codes were identified for all hospitalizations, and codes relevant to HF resulted in retrieval of medical records by study personnel for centralized adjudicated review. At least 2 study physicians reviewed all possible HF events and deaths using medical records and adjudicated for clinical HF based on clinical symptoms, radiographic evidence of pulmonary congestion, physical examination of the heart and lungs and, when available, central venous hemodynamic monitoring data, and echocardiographic imaging. HF was confirmed when both reviewers agreed upon a “probable” or “definite” occurrence of HF based on modified clinical Framingham criteria.(18)

In addition to quantifying the number of HF hospitalizations, we also evaluated the number of HF readmissions within 30 days during all available CRIC follow-up. Additionally, we evaluated the total number of HF hospitalization days during CRIC follow-up. This was calculated from length of stay data available for each HF hospitalization.

In secondary analyses, we stratified the outcome of HF by preserved and reduced ejection fraction HF (HFpEF and HFrEF). HFpEF was defined as ejection fraction ≥40% and HFrEF was defined as ejection fraction <40%. Ejection fraction was ascertained from echocardiograms performed during the index hospitalization for clinical purposes. If an echocardiogram was not performed during the index hospitalization, we utilized the ejection fraction quantified from an ambulatory CRIC research echocardiogram ≤1 year before or after the index HF hospitalization. Research echocardiograms in CRIC were performed at multiple time-points including years 1, 4, 7, as well as when the participant progressed to eGFR<20 ml/min/1.73m² Our previous work has shown that ejection fraction in CRIC is generally stable over time.(19,20) Among a total of 1774 first (during CRIC follow-up) or recurrent HF hospitalizations, 1127 (64%) had ejection fraction available through either a clinical echocardiogram during the index hospitalization or a CRIC research echocardiogram.

All-cause mortality

Death status was ascertained from study entry through May 2014. Deaths were identified from report from next of kin, retrieval of death certificates or obituaries, review of hospital or outpatient records, and searching Social Security Death vital status and state death certificate files, if available.

Covariates

At the baseline study visit, participants provided information on their sociodemographic characteristics, medical history, medication usage, and lifestyle behaviors. Race/ethnicity was categorized as non-Hispanic white, non-Hispanic black, Hispanic, and other. History of cardiovascular disease was determined by self-report and included history of HF, myocardial infarction, coronary revascularization or stroke. Anthropometric measurements and blood pressure (BP) were assessed using standard protocols.(21) Body mass index (BMI) was calculated as weight in kg divided by height in meters squared. Diabetes mellitus was defined as a fasting glucose >126 mg/dL, a non-fasting glucose >200 mg/dL, or use of insulin or other antidiabetic medication. Cardiovascular medications including diuretics, angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), and β-blockers and were ascertained by detailed review with participants at baseline.

Statistical analyses

All analyses were performed using R 3.4.0 (R Foundation for Computing, Vienna, Austria). We first described characteristics of study participants, across categories based on number of HF hospitalizations per year. We then calculated the crude rates (per 100 person-years) of HF hospitalizations and 30-day HF re-hospitalizations, overall and by categories of eGFR and urine ACR individually and collectively; 95% confidence intervals were obtained using bootstrap methods. Participants were censored at death, loss to follow-up, study withdrawal or end of study follow-up (through May 2014). Rate ratios for HF hospitalizations and 30-day re-hospitalizations were calculated using Poisson regression models with Huber-White robust standard errors. We serially adjusted for age, sex, race/ethnicity in Model 1; additionally adjusted for diabetes, history of cardiovascular disease, use of statins, current smoking, systolic blood pressure and BMI in Model 2; and additionally adjusted for use of cardiovascular medications (diuretics, ACEi/ARBs and β-blockers) in the final Model 3. In secondary analyses, we repeated these analyses examining rates and rate ratios for HFrEF and HFpEF among participants who had available data on ejection fraction.

Cox regression was used to model the association of the number of HF hospitalizations within the first 2 years of study follow-up with subsequent risk of CKD progression (defined as eGFR decline by 50% or progression to ESRD) and all-cause mortality. Participants were censored at death, loss to follow-up, study withdrawal or at the end of study follow-up (through May 2014), whichever came first. For these analyses, time to follow-up started at year 2 and only included participants who did not experience the event within the first two years of the study or were not censored during this time (N = 2978 for CKD progression, N = 3582 for mortality). These models were adjusted for the same covariates as described above.

In a secondary analysis, we examined the total number of HF hospital days as a predictor. We calculated crude rates and rate ratios of HF hospital days across eGFR and urine ACR categories (similar to the primary analysis). We then used Cox models to examine the association of number of HF hospital days within the first 2 years of study follow-up with subsequent risks of CKD progression and all-cause mortality.

Results

Study population

A total of 1,774 HF hospitalizations during the follow-up period were observed among 3791 participants (range 0-17 per participant per year), of which 702 episodes were incident HF and 1072 were among participants with known HF. Among study participants, 607 participants had an annual HF hospitalization rate of >0 – 1 HF hospitalizations per year while 69 had an annual HF hospitalization rate of > 1 HF hospitalizations per year. Compared with participants who remained HF free during CRIC follow-up (N=3115), those who had a HF hospitalization were more likely to be older, men, black, have lower baseline eGFR and higher proteinuria, more likely to have diabetes, prevalent HF and a history of CVD (including atrial fibrillation), have higher blood pressure, and were more likely to be taking cardiovascular medications (Table 1).

Table 1:

Baseline characteristics, by annual heart failure hospitalization rate among participants with chronic kidney disease.

	No HF events/year	>0 – 1 event/year	> 1 event/year
N	3115	607	69
Mean (SD) age, years	57.2 (11.1)	60.2 (9.5)	61.6 (9.2)
Women	1425 (46)	265 (44)	25 (36)
Race/ethnicity
Non-Hispanic white	1383 (44)	207 (34)	14 (20)
Non-Hispanic black	1230 (39)	305 (50)	45 (65)
Hispanic	374 (12)	78 (13)	8 (12)
Other	128 (4)	17 (3)	2 (3)
Mean (SD) eGFR, mL/min/1.73m2	45.6 (15.1)	38.4 (13.0)	38.4 (13.4)
Median (interquartile range) urine albumin to creatinine ratio (μg/mg),	37.3 (7.3-335.4)	309.6 (33.4-1405.1)	210.6 (42.6-944.9)
Diabetes mellitus	1348 (43)	434 (71)	48 (70)
Prior cardiovascular disease	872 (28)	346 (57)	51 (74)
Prior heart failure	191 (6)	140 (23)	38 (55)
Prior atrial fibrillation	433 (14)	177 (29)	32 (46)
Current smoker	399 (13)	83 (14)	13 (19)
Mean (SD) body mass index, kg/m2	31.6 (7.6)	34.3 (8.4)	32.9 (7.1)
Mean (SD) systolic blood pressure, mmHg	126.7 (21.4)	136.0 (23.3)	133.7 (24.4)
Mean (SD) diastolic blood pressure, mmHg	71.7 (12.4)	70.0 (13.8)	69.8 (15.6)
Mean (SD) hemoglobin, g/dL	12.8 (1.7)	12.0 (1.8)	11.9 (1.7)
Mean (SD) LDL cholesterol, mg/dL	103.4 (34.8)	98.7 (36.5)	96.2 (40.3)
Mean (SD) HDL cholesterol, mg/dL	48.0 (15.7)	45.4 (14.3)	44.2 (13.2)
ACEi/ARBs	2076 (67)	463 (76)	49 (71)
Diuretics	1710 (55)	478 (79)	57 (83)
Loop diuretics	1001 (32)	374 (62)	55 (80)
Thiazide diuretics	905 (29)	155 (26)	8 (12)
Beta blockers	1387 (45)	412 (68)	52 (75)
Calcium channel blockers	1173 (38)	320 (53)	33 (48)
Aldosterone receptor antagonists	105 (3)	33 (5)	16 (23)
Statins	1621 (52)	412 (68)	47 (68)
Median (interquartile range) FGF-23 (RU/mL)	134.2 (90.9-212.6)	207.7 (133.9-346.5)	289.6 (148.4-456.2)
Mean (SD) serum phosphorus, mg/dL	3.7 (0.6)	3.9 (0.8)	3.9 (0.6)
Median (interquartile range) total parathyroid hormone, pg/mL	50.1 (33.0-82.6)	72.9 (45.8-120.0)	87.7 (47.5-120.5)
Mean (SD) left ventricular ejection fraction, %	55.2 (7.5)	50.2 (11.0)	43.9 (14.2)
Mean (SD) left ventricular mass index, g/m2	49.0 (12.5)	61.4 (15.0)	68.9 (16.7)
Median (interquartile range) NTpro-BNP, (pg/mL	109.1 (39.3-285.7)	432.2 (175.5-972.8)	808.1 (428.9-2675.6)
Median (interquartile range) high sensitive troponin T, pg/mL	13.1 (8.0-22.7)	25.4 (15.7-41.4)	35.0 (18.1-50.2)

Rates of HF admissions overall and by eGFR and urine ACR categories

Median follow-up for participants who experience at least one HF hospitalization was 7.8 [Interquartile Range (IQR) 5.6, 9.2] years. The overall crude rate of HF admissions was 5.8 (95% CI:5.2-6.4) per 100 person-years, with higher rates with lower baseline eGFR and higher urine ACR (Central Illustration). After adjustment for demographic characteristics, the rate of HF was 2.1 and 2.9-fold higher for participants with eGFR 30-44 and <30 ml/min/1.73m², respectively (Table 2). These associations remained robust with adjustment for cardiovascular risk factors and medication use: rate ratio 1.7 (95% CI 1.3, 2.2) and 2.2 (95% CI: 1.7, 2.9) for participants with eGFR 30-44 and <30 ml/min/1.73m² (vs. >45 ml/min/1.73 m²), respectively.

Central Illustration. Heart Failure in Chronic Kidney Disease.

Unadjusted rates of heart failure admissions across by level of kidney function among participants with chronic kidney disease

Table 2.

Rates and rate ratios of heart failure admissions across levels of kidney function among participants with chronic kidney disease

		Rate Ratio (95% CI)
	Number at risk (Total number of events)	Crude rate, per 100 pys (95% bootstrapped CIs)	Model 1	Model 2	Model 3
Overall	3791 (1706)	5.8 (5.2, 6.4)
eGFR stage
eGFR ≥ 45	1714 (437)	3.1 (2.5, 3.7)	1.0 (Ref.)	1.0 (Ref.)	1.0 (Ref.)
eGFR 30-44	1379 (766)	7.4 (6.2, 8.6)	2.1 (1.7, 2.7)	1.9 (1.5, 2.4)	1.7 (1.3, 2.2)
eGFR < 30	698 (503)	10.3 (8.4, 12.2)	2.9 (2.2, 3.8)	2.5 (1.9, 3.3)	2.2 (1.7, 2.9)
Albuminuria
uACR < 30	1629 (383)	2.9 (2.3, 3.5)	1.0 (Ref.)	1.0 (Ref.)	1.0 (Ref.)
uACR 30 - < 300	1001 (510)	6.6 (5.3, 8.0)	2.3 (1.8, 3.1)	1.9 (1.4, 2.6)	1.9 (1.5, 2.6)
uACR ≥ 300	1161 (813)	9.7 (8.3, 11.2)	3.8 (3.0, 4.9)	2.6 (2.0, 3.5)	2.6 (1.9, 3.5)
CKD category
eGFR ≥ 45, uACR < 300	1401 (253)	2.2 (1.7, 2.7)	1.0 (Ref.)	1.0 (Ref.)	1.0 (Ref.)
eGFR < 45, uACR < 300	1229 (640)	6.9 (5.7, 8.1)	2.7 (2.0, 3.6)	2.5 (1.9, 3.4)	2.3 (1.7, 3.0)
eGFR ≥ 45, uACR > 300	313 (184)	7.7 (5.4, 10.1)	4.1 (2.8, 6.1)	2.9 (1.9, 4.4)	2.9 (1.9, 4.4)
eGFR < 45, uACR > 300	848 (629)	10.6 (8.8, 12.3)	4.6 (3.5, 6.2)	3.2 (2.3, 4.4)	3.0 (2.2, 4.1)

All rate ratios with p-value<0.05

eGFR= estimated glomerular filtration rate; uACR= urine albumin-to-creatinine-ratio

Model 1: age, sex, and race/ethnicity

Model 2: model 1 + diabetes, history of cardiovascular disease, use of lipid-lowering medications, smoking, systolic blood pressure, and body mass index

Model 3: model 2 + use of diuretics, angiotensin-converting-enzyme inhibitors/aldosterone receptor blockers, β-blockers

The crude rate of HF hospitalizations was also higher across categories of higher urine ACR with a rate of 9.7 (95% CI: 8.3, 11.2) among participants with a urine ACR≥300 mg/g (Figure 1). In models adjusted for demographic characteristics, the rate of HF hospitalizations was significantly higher among participants with urine ACR 30-299 or ≥300 mg/g vs. urine ACR <30 mg/g (Table 2). Even after additional adjustment for cardiovascular risk factors and medication use, the rates of HF hospitalization remained significantly higher in those with higher baseline urine ACR (vs. urine ACR<30 mg/g): rate ratios of 1.9 (95% CI: 1.5, 2.6) and 2.6 (95% CI: 1.9, 3.5) for urine ACR 30-299 and ≥300 mg/g, respectively.

Rates of HFrEF and HFpEF hospitalizations overall and by categories of eGFR and urine ACR

There were 1,127 participants for whom HF subtype could be determined. The rate of the first HF hospitalization during CRIC follow-up was 8.3 (95%CI: 7.1, 9.5) per 1,000 person years (213 events) for HFrEF and 11.2 (95%CI: 9.9, 12.5) per 1,000 person years for HFpEF (288 events). The rates of all (first and recurrent) HFrEF hospitalization was 19.4 (95%CI: 16.3, 22.5) per 1,000 person years (568 events) and for HFpEF was 17.8 (95%CI: 15.6, 20) per 1,000 person years (522 events).

After accounting for differences in demographic characteristics, cardiovascular risk factors and medication use, there were graded, higher adjusted rates of both HFrEF and HFpEF hospitalizations with lower eGFR and higher urine ACR, with similar rate ratios to the primary analysis (Online Tables 1 and 2).

30-day readmissions for HF

Among 702 participants with incident HF during CRIC follow-up, 67 (9.5%) were readmitted for HF within 30 days, compared with 179 (16.7%) of 1072 participants with prevalent HF. Rates of recurrent HF hospitalizations increased across categories of lower eGFR and higher urine ACR (Online Figure 1, Table 3). In models that adjusted for demographic characteristics, cardiovascular risk factors and medication use, the rate ratio for re-hospitalization within 30 days was 2-3 fold in participants with the lowest eGFR and highest urine ACR: rate ratio 2.6 (95% CI: 1.4, 4.7) for eGFR<30 ml/min/1.73m2 and 3.6 (95%CI: 1.8, 7.3) for urine ACR ≥300 mg/g.

Table 3.

Rates of total number of 30-day heart failure re-hospitalizations across level of kidney function among participants with chronic kidney disease

					Model 1	Model 2	Model 3
	Number of participants	Number of HF hospitalizations	Total number of 30-day HF rehospitalizations	Crude rate, per 100 pys (95% CIs)
Overall	3791	1706	238	0.8 (0.6, 1.0)
eGFR stage
eGFR ≥ 45	1714	437	53	0.4 (0.2, 0.5)	1.0 (Ref.)	1.0 (Ref.)	1.0 (Ref.)
eGFR 30-44	1379	766	111	1.1 (0.7, 1.4)	2.5 (1.5, 4.1)	2.2 (1.3, 3.6)	1.9 (1.2, 3.1)
eGFR < 30	698	503	74	1.5 (0.8, 2.2)	3.4 (1.9, 6.2)	3.0 (1.6, 5.6)	2.6 (1.4, 4.7)
Albuminuria
uACR < 30	1629	383	43	0.3 (0.2, 0.4)	1.0 (Ref.)	1.0 (Ref.)	1.0 (Ref.)
uACR 30 - < 300	1001	510	80	1.0 (0.6, 1.5)	3.2 (1.8, 5.5)	2.7 (1.5, 4.7)	2.7 (1.5, 4.8)
uACR ≥ 300	1161	813	115	1.4 (0.9, 1.9)	4.6 (2.7, 7.7)	3.6 (1.8, 7.1)	3.6 (1.8, 7.3)
CKD category
eGFR ≥ 45, uACR < 300	1401	253	29	0.2 (0.1, 0.4)	1.0 (Ref.)	1.0 (Ref.)	1.0 (Ref.)
eGFR < 45, uACR < 300	1229	640	94	1.0 (0.7, 1.4)	3.4 (1.9, 6.1)	3.2 (1.8, 5.7)	2.8 (1.6, 4.9)
eGFR ≥ 45, uACR > 300	313	184	24	1.0 (0.4, 1.6)	4.5 (2.1, 9.7)	3.6 (1.6, 8.2)	3.8 (1.6, 8.7)
eGFR < 45, uACR > 300	848	629	91	1.5 (0.9, 2.2)	5.5 (3.0, 10.2)	4.2 (2.0, 8.8)	3.8 (1.8, 8.1)

All rate ratios with p-value<0.05

eGFR= estimated glomerular filtration rate; uACR= urine albumin-to-creatinine-ratio

Model 1: age, sex, and race/ethnicity

Model 2: model 1 + diabetes, history of cardiovascular disease, use of lipid-lowering medications, smoking, systolic blood pressure, and body mass index

Model 3: model 2 + use of diuretics, angiotensin-converting-enzyme inhibitors/aldosterone receptor blockers, β-blockers

Number of HF hospitalizations within 2 years and subsequent CKD progression

There were 884 participants who experienced a 50% decline in eGFR or developed ESRD during the follow-up period. In fully-adjusted models, participants who experienced a HF hospitalization within the first two years of follow-up had higher adjusted rates of subsequent CKD progression (1 hospitalization: HR 1.93, 95%CI:1.40-2.67; 2 or more hospitalizations: HR 2.14, 95%CI:1.30-3.54).

Number of HF hospitalizations within 2 years and subsequent all-cause mortality

A total of 819 participants died during follow-up. After adjustment for potential confounders, participants who experienced a HF hospitalization during the first 2 years of follow-up had a graded, higher risk of subsequent all-cause death. Participants with one HF hospitalization had a >2-fold increased adjusted rate of death (HR 2.20, 95%CI:1.71-2.84 and those with two or more HF hospitalizations had a threefold higher adjusted rate (HR 3.06, 95%CI:2.23-4.18).

Number of HF hospitalization days and clinical outcomes by eGFR and urine ACR

In secondary analyses, we evaluated burden of HF hospitalization (based on number of hospital days) and outcomes by level of kidney function and damage. The overall rate of HF hospital days was 36.9 (95%CI: 32.2, 41.7) per 100 person-years. Lower baseline eGFR and higher baseline urine ACR were associated with graded, increased rates of HF hospital days (Online Figure 2). The rate of HF hospital days was highest for participants with both low eGFR and higher urine ACR (60.6 per 100 person years, 95%CI:48.8-72.4). In models adjusted for demographics, there was a 2 to 4-fold increase in rate of HF hospital days across categories of lower eGFR and higher urine ACR (Online Table 3). These associations persisted after further adjustment for cardiovascular risk factors and medication use: rate ratio 1.7 (95%CI 1.2, 2.4) and 2.3 (95%CI: 1.6, 3.3) for participants with eGFR 30-44 and <30 ml/min/1.73m² (vs. >45 ml/min/1.73 m²), respectively. Similarly, the rates of HF hospital days remained significantly higher in those with higher urine ACR (vs. urine ACR<30 mg/g): rate ratios of 1.9 (95%CI: 1.4, 2.6) and 2.5 (95%CI: 1.8, 3.5) for urine ACR 30-299 and ≥300 mg/g, respectively (Online Table 3).

When we examined the total burden of HF hospitalization days in the first two years of follow-up with clinical outcomes, we found a strong association of a higher number of HF hospital days with higher subsequent risk of CKD progression and all-cause mortality (Online Table 4). Compared to participants with no HF hospital days in the first two years of follow-up, participants who had eight or more HF hospital days had a 90% higher rate (HR 1.90, 95%CI: 1.15-3.15) and nearly threefold higher rate (HR 2.91, 95%CI:2.17-3.90) of CKD progression and death, respectively, in fully-adjusted models (Online Table 4).

Discussion

In this large, prospective cohort of adults with CKD, the overall rate of HF hospitalizations was quite high at 5.8 hospitalizations per 100 person-years of follow-up and even higher among participants with either eGFR<30 ml/min/1.73m² or urine ACR ≥300 mg/g (Central Illustration). The rate of first hospitalization for HFpEF was higher than that of HFrEF but the rates of all hospitalizations were similar between HFpEF and HFrEF. Overall, >1 in 5 patients were readmitted for HF within 30 days. Greater burden of HF hospitalizations or HF hospital days in the first 2 years of follow-up was associated with a 2-to-3-fold increased risk of CKD progression and death. Collectively, these data provide unique and comprehensive evidence of the tremendous burden of HF in CKD and the independent association of HF with subsequent renal outcomes and survival.

In our study, participants with CKD experienced 3 to 10 HF hospitalizations per 100 person-years, depending on level of eGFR and urine ACR, which is substantially greater than seen in the general population. In the Nationwide Inpatient Sample, the rates of primary HF hospitalizations was 0.5 per 100 person-years and 1.5 per 100 person-years for secondary diagnosis of a HF hospitalization in 2009.(22) Among Medicare beneficiaries, the rate of HF hospitalizations were 0.4 per 100 person-years in 2004, which was a significant increase over the previous 25 years.(23) While data from USRDS reports that the rate of hospitalization for any cardiovascular cause was 46 per 100 person-years for ESRD patients,(11) limited data exist for HF-specific hospitalizations in those with CKD. Our study provides novel data on this important public health burden in CKD.

There are even fewer data on the rates of HF subtypes in patients with CKD. We found that the rates of first hospitalization during follow-up in CRIC participants was higher for HFpEF than HFrEF. However, the rates of all hospitalizations for HFpEF and HFrEF were similar, suggesting that while HFpEF may be more prevalent in CKD, HFrEF patients may be more likely to have recurrent HF hospitalizations. In the Framingham Heart Study of participants with and without CKD, microalbuminuria was only associated with HFrEF and low eGFR was associated with HF overall but not HFpEF or HFrEF (24). In a study of patients from multiple healthcare delivery systems participating in the Cardiovascular Research Network (CVRN), the association of eGFR with risk of a HF hospitalization or mortality was similar among patients with known HFpEF or HFrEF (25). Given the different pathophysiology of HFrEF vs. HFpEF and the lack of proven therapies for HFpEF, our findings support the need to identify more effective treatment strategies for both HFrEF and HFpEF in patients with CKD.

Rates of 30-day readmissions for HF were also high at 20.6% overall and 27% among participants with known HF. The observed rates seen in our CKD population were greater than those observed in the general population. In a study of the ARIC cohort, approximately 8% of participants with known HF were re-hospitalized for HF within 30 days.(26) Among Medicare fee-for-service beneficiaries aged 65 years or older, the median 30-day readmission rate for any cause (not specifically for HF as in our study) was 24.4% after HF admission.(27) Previous studies have tested strategies to decrease rates of recurrent hospitalizations such as earlier physician visits post discharge, target education about medication and diet adherence and support from an ambulatory HF care team (28-31). These strategies have not been specifically tested in patients with CKD and may be promising to reduce the excessive burden of recurrent HF hospitalizations in this high-risk population.

Our study also found that higher number of HF hospitalizations and HF hospital days was independently associated with a greater risk of CKD progression. Of participants hospitalized for HF, 52% experienced significant CKD progression. In a previous study of patients with CKD in Canada, rates of ESRD were 4-to-14-fold higher among patients with previous HF hospitalizations (32). In study of patients with normal kidney function, HF was associated with a 2-fold greater risk of incident CKD.(33) Our findings support and materially expand on these associations in a large U.S. population of patients with CKD. There are several possibilities to explain these findings. HF leads to hemodynamic changes, endothelial injury, inflammation and other processes which may further injure the kidneys (34-36). Thus, further studies are needed to explore therapies to help preserve kidney function after an acute HF hospitalization.

We found a graded, strong association between greater burden of HF with the risk of death. Among participants with 2 or more HF hospitalizations, the risk of all-cause death was 3-fold higher compared with participants who did not experience HF. Among participants in our study who experienced a HF hospitalization, 60% died during follow-up. A previous study using data from Medicare fee-for-service beneficiaries reported that all-cause mortality rates after a HF hospitalization was 11.7% overall (37). Another study from the same population found that reductions in rates of HF hospitalizations were associated with a reduction in post-discharge mortality (38). Given the even higher proportion of post-HF hospitalization deaths in patients with CKD, interventions to improve post-HF care should also be prioritized in this high-risk population.

These findings have important implications in the management of patients with CKD. Primary and secondary treatment of HF in CKD should be a public health priority. The high burden of HF hospitalizations in CKD likely contributes to the higher cost of care observed for the treatment of CKD and cardiovascular disease. Therefore, there is a need to improve treatment of HF in patients with known disease. Strategies would include better implementation of current therapies that may often be withheld in patients with CKD (e.g., RAAS inhibitors); development of novel therapies that may target CKD-specific HF risk factors; incentives to improve the transition between inpatient and outpatient HF care in CKD to reduce the risk of readmissions; and improve patient education around HF in CKD.

Our study had several strengths. We studied a large, multi-center, well-characterized, U.S.-based CKD population specifically designed to study cardiovascular complications with extensive longitudinal follow-up. All HF hospitalizations that occurred during CRIC follow-up were adjudicated using standardized criteria. We recognize a few limitations as well. We were not able to determine whether acute kidney injury occurred during the HF hospitalizations, which may have contributed to subsequent CKD progression. Ejection fraction data to determine HF subtype was not available in all participants. Kidney biopsy data on the cause of the CKD was not available in all participants; however, we did control for primary contributors of CKD, such as diabetes, in our statistical models. We did not have detailed data on whether certain medications (e.g. RAAS inhibitors or diuretics) were held or doses adjusted after the hospitalization since medication use was ascertained every six months per the CRIC study protocol. While the CRIC adjudication process is known to capture >90% of hospitalizations, it is possible that some HF hospitalizations were missed. This was a clinic-based population of research volunteers so it may not be generalizable to all CKD patients. In this observational study, we cannot determine causality and we cannot exclude reverse causality.

In conclusion, in a large U.S. CKD population, the rates of HF hospitalizations and 30-day re-hospitalization were very high, with even higher rates across categories of lower eGFR and higher urine ACR. HF hospitalizations were independently associated with 2-to-3-fold higher rates of CKD progression and death. Prevention and treatment of HF should be a major priority to improve clinical outcomes in patients with CKD.

Table 4:

Association of number of heart failure episodes in the first 2 years of follow-up with risk of chronic kidney disease progression and all-cause mortality among participants with chronic kidney disease

Decline in eGFR by 50% or progression to ESRD
			HR (95% CI)
Number of HF events, years 0 - 2	N at risk	N events	Unadjusted	Model 1	Model 2	Model 3
0	2868	827	1.0 (Ref.)	1.0 (Ref.)	1.0 (Ref.)	1.0 (Ref.)
1	80	41	3.27 (2.39, 4.48)	2.61 (1.90, 3.59)	1.98 (1.43, 2.73)	1.93 (1.40, 2.67)
≥ 2	30	16	3.77 (2.30, 6.19)	3.41 (2.08, 5.60)	2.32 (1.41, 3.83)	2.14 (1.30, 3.54)
All-cause mortality
0	3380	698	1.0 (Ref.)	1.0 (Ref.)	1.0 (Ref.)	1.0 (Ref.)
1	135	74	3.48 (2.74, 4.43)	3.41 (2.68, 4.35)	2.35 (1.83, 3.03)	2.20 (1.71, 2.84)
≥ 2	67	47	6.03 (4.48, 8.11)	5.81 (4.31, 7.83)	3.38 (2.48, 4.61)	3.06 (2.23, 4.18)

All HR with p-value <0.05

Model 1: age, sex, and race/ethnicity

Model 2: model 1 + diabetes, history of cardiovascular disease, use of lipid-lowering medications, smoking, systolic blood pressure, and body mass index

Model 3: model 2 + use of diuretics, angiotensin-converting-enzyme inhibitors/aldosterone receptor blockers, β-blockers

CLINICAL PERSPECTIVES.

Competency in Medical Knowledge:

Compared to patients with preserved renal function, those with chronic kidney disease (CKD; defined as eGFR<45 ml/min per 1.73m2 or microalbuminuria (uACR >30 mg/g) hospitalized with heart failure (HF) are at high risk of recurrent heart failure, re-admission for heart failure, and death within 2 years.

Translational Outlook:

Additional research is needed to improve outcomes of HF in patients with CKD.

ABBREVIATIONS

HF

heart failure

CKD

chronic kidney disease

ESRD

end-stage-renal-disease

CRIC

Chronic Renal Insufficiency Cohort

eGFR

estimated glomerular filtration rate

Urine ACR

urine albumin-to-creatinine-ratio

EF

ejection fraction

HFpEF

heart failure with preserved ejection fraction

HFrEF

heart failure with reduced ejection fraction