European Journal of Heart Failure (2017) 19, 615–623 RESEARCH ARTICLE

doi:10.1002/ejhf.778

The association of chronic kidney disease

and microalbuminuria with heart failure with
preserved vs. reduced ejection fraction
Matthew Nayor1,2, Martin G. Larson1,3, Na Wang4, Rajalakshmi Santhanakrishnan5,
Douglas S. Lee6,7, Connie W. Tsao1,8, Susan Cheng1,2, Emelia J. Benjamin1,9,
Ramachandran S. Vasan1,9, Daniel Levy1,10, Caroline S. Fox1,10,11, and
Jennifer E. Ho1,12*
1 NationalHeart, Lung, and Blood Institute’s and Boston University’s Framingham Heart Study, Framingham, MA, USA; 2 Division of Cardiovascular Medicine, Brigham and
Women’s Hospital, Boston, MA, USA; 3 Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; 4 Data Coordinating Center, Boston University
School of Public Health, Boston, MA, USA; 5 Section of Cardiovascular Medicine, Department of Medicine, Boston University, Boston, MA, USA; 6 Institute for Clinical Evaluative
Sciences, University of Toronto, Toronto, Canada; 7 Peter Munk Cardiac Centre, University Health Network, Toronto, Canada; 8 Cardiovascular Division, Beth Israel Deaconess
Medical Center, Boston, MA, USA; 9 Sections of Preventive Medicine & Epidemiology, and Cardiology, Department of Medicine, Boston University School of Medicine, and
Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA; 10 Center for Population Studies of the National Heart, Lung, and Blood Institute,
Bethesda, MD, USA; 11 Division of Endocrinology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; and 12 Cardiology Division and Cardiovascular
Research Center, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

Received 18 August 2016; revised 31 October 2016; accepted 30 November 2016 ; online publish-ahead-of-print 20 February 2017

Aims Chronic kidney disease (CKD) and microalbuminuria are associated with incident heart failure (HF), but their relative
contributions to HF with preserved vs. reduced EF (HFpEF and HFrEF) are unknown. We sought to evaluate the
associations of CKD and microalbuminuria with incident HF subtypes in the community-based Framingham Heart
Study (FHS).
.....................................................................................................................................................................
Methods We defined CKD as glomerular filtration rate <60 mL/min/1.73 m2 , and microalbuminuria as a urine albumin to
and results creatinine ratio (UACR) ≥17 mg/g in men and ≥25 mg/g in women. We observed 754 HF events (324 HFpEF/326
HFrEF/104 unclassified) among 9889 FHS participants with serum creatinine measured (follow-up 13 ± 4 years).
In Cox models adjusted for clinical risk factors, CKD (prevalence = 9%) was associated with overall HF [hazard
ratio (HR) 1.24, 95% confidence interval (CI) 1.01–1.51], but was not significantly associated with individual HF
subtypes. Among 2912 individuals with available UACR (follow-up 15 ± 4 years), 192 HF events (91 HFpEF/93 HFrEF/8
unclassified) occurred. Microalbuminuria (prevalence = 17%) was associated with a higher risk of overall HF (HR
1.71, 95% CI 1.25–2.34) and HFrEF (HR 2.10, 95% CI 1.35–3.26), but not HFpEF (HR 1.26, 95% CI 0.78–2.03).
In cross-sectional analyses, microalbuminuria was associated with LV systolic dysfunction (odds ratio 3.19, 95% CI
1.67–6.09).
.....................................................................................................................................................................
Conclusions Microalbuminuria was associated with incident HFrEF prospectively, and with LV systolic dysfunction cross-sectionally
in a community-based sample. In contrast, CKD was modestly associated with overall HF but not differentially
associated with HFpEF vs. HFrEF. The mechanisms responsible for the relationship of microalbuminuria to future
development of HFrEF warrant further investigation.
..........................................................................................................
Keywords Heart failure • Epidemiology • Prevention • Kidney disease • Microalbuminuria •
Cardiorenal syndrome

*Corresponding author. Massachusetts General Hospital, CPZN 185 Cambridge Street, #3224, Boston, MA 02114, USA. Tel: +1 617 724 6411, Fax: +1 617 643 3451, Email:
[email protected]
© 2017 The Authors
European Journal of Heart Failure © 2017 European Society of Cardiology
616 M. Nayor et al.

Introduction incident HF, 3075 participants for cross-sectional analyses of eGFR

........................................................................................................................................................................
and echocardiographic traits, and 2652 for cross-sectional analyses
Kidney disease is associated with poor heart failure (HF)-related of albuminuria and echocardiographic traits (details of inclusion and
outcomes regardless of disease severity. In patients with estab- exclusion criteria are given in Supplementary material online, Figures
lished HF, reduced estimated glomerular filtration rate (eGFR) and S1 and S2). All study protocols were approved by the Boston Uni-
albuminuria are independent predictors of HF progression and versity Medical Center Institutional Review Board, and all participants
provided written informed consent.
mortality.1 – 6 Similarly, in community-based investigations, albu-
minuria and lower eGFR are associated with new-onset HF.7 – 13
The mechanisms responsible for cardiorenal interactions in HF are
incompletely understood and are likely to vary by underlying dis- Laboratory measures
ease process and HF syndrome.14,15 Fasting plasma samples were collected from FHS participants at each
Heart failure with preserved ejection fraction (HFpEF) and examination cycle, centrifuged, and stored at −80 ∘ C. Serum creatinine
HF with reduced ejection fraction (HFrEF) represent separate levels were assayed using the modified Jaffé method on a Roche
Hitachi 911 (Roche Diagnostics), and eGFR was calculated using
clinical subtypes, each accounting for approximately half of HF
the CKD-EPI equation.30 Chronic kidney disease (CKD) was defined
diagnoses.16 – 20 Although controversy exists regarding whether
as eGFR <60 mL/min/1.73 m2 . Spot urine samples were collected at
HFpEF and HFrEF represent overlapping or distinct pathophys-
the sixth offspring examination cycle and stored at −20 ∘ C. Urine
iological entities,21,22 substantial evidence supports distinct risk albumin concentration was assayed using immunoturbimetry (Tina
factor profiles23 – 25 and treatment responses26 for each subtype. Quant Albumin Assay, Roche Diagnostics) and urine creatinine was
Therefore, understanding how specific risk factors relate to the assayed using the modified Jaffé method (Colorimetric Assay, Roche,
development of HFpEF vs. HFrEF may allow for improved methods Diagnostics). Microalbuminuria was defined as a urine albumin to
to predict, and potentially prevent, the occurrence of HF. creatinine ratio (UACR) ≥17 mg/g in men and ≥25 mg/g in women.31
The relative contribution of kidney dysfunction to the devel-
opment of HFpEF vs. HFrEF is not well elucidated. Incident HF
subtypes have been adjudicated among participants of the Fram- Clinical assessment
ingham Heart Study (FHS), where kidney function has also been Systolic blood pressure was measured with a mercury sphygmo-
systematically assessed. We sought to evaluate the associations of manometer on seated participants, and the mean of two readings
albuminuria and reduced glomerular filtration with incident HFpEF was recorded for each individual. Weight in kilograms was divided by
and HFrEF prospectively. To understand further the mechanisms the square of height in metres to determine body mass index (BMI).
underlying these associations, we investigated the cross-sectional Valvular heart disease was defined as a systolic murmur ≥3/6 in inten-
relationships of albuminuria and reduced glomerular filtration with sity or any diastolic murmur. We defined diabetes as fasting glucose
echocardiographic measures of cardiac structure and function. ≥126 mg/dL, non-fasting glucose ≥200 mg/dL, or taking medications
for the treatment of elevated glucose. Total and HDL-cholesterol were
measured using standardized assays. Current smoking, antihypertensive
treatment status, and history of myocardial infarction were ascertained
Methods by review of relevant medical records and patient questionnaires.
Study samples
The design and enrolment of the FHS Original and Offspring cohorts
have been detailed previously.27,28 Participants underwent comprehen- Echocardiography
sive evaluation at the FHS clinic every 2 years (Original cohort) or Comprehensive two-dimensional transthoracic echocardiography with
4 years (Offspring cohort). At each examination cycle, a comprehen- Doppler colour flow imaging was performed on all attendees of the
sive medical history, anthropometry, a cardiovascular-targeted physical sixth examination cycle of the Framingham Offspring study. Echocar-
examination, and ECG were performed. diograms were read by a cardiologist or sonographer blinded to
To evaluate the associations of reduced eGFR and incident HF, participants’ clinical information. Measurements were made on dig-
we included Original cohort participants who attended examinations itized M-mode images using the leading edge-to-leading edge tech-
15 (1977–1979) or 24 (1995–1998), or Offspring cohort partici- nique and were averaged over at least three cardiac cycles. This
pants who attended examinations 2 (1979–1983) or 6 (1995–1998). technique was used to measure left atrial dimension (LAD), LV sep-
Follow-up was censored at 15 years or the date of the next exam- tal wall thickness, LV posterior wall thickness, LV diameter at the
ination, depending on which was the shorter follow-up time period. end of diastole (LVEDD), and the LV diameter at the end of sys-
Participants in each cohort were eligible for inclusion at both exam- tole (LVESD). Fractional shortening (FS) was then calculated using
ination cycles if no interim HF event occurred.29 Of 10 858 eligible the formula: [(LVEDD – LVESD)/LVEDD] × 100, and LV mass (LVM)
person-observations, we excluded 1 for missing follow-up time, 257 was calculated as: 0.8{1.04[(LVEDD + posterior wall thickness + septal
for off-site visits, 548 for missing clinical covariates, 108 for prevalent wall thickness)3 – (LVEDD)3 ]} + 0.6, based on American Society of
HF, and 55 for eGFR <15 mL/min/1.73 m2 or for being on haemodial- Echocardiography guidelines.32 Mild or greater reduction in LVEF based
ysis, yielding a final sample of 9889 person-observations. on qualitative assessment or FS <29% was used to define LV systolic
Urinary albumin and creatinine measures, and transthoracic dysfunction. LV hypertrophy (LVH) was determined by indexing LVM
echocardiography were performed at Offspring examination 6. Of to body surface area, and values >115 g/m2 for men and >95 g/m2 for
3532 participants who attended this examination cycle, we included women were considered abnormal.32 Left atrial enlargement (LAE) was
2912 participants for prospective analyses examining albuminuria and defined as LAD >4.0 cm in men and >3.8 cm in women.32

© 2017 The Authors

European Journal of Heart Failure © 2017 European Society of Cardiology
Kidney disease and heart failure subtypes 617

Clinical assessment and outcome In cross-sectional analyses, we evaluated the associations between

........................................................................................................................................................................
the same predictors [CKD, log(eGFR), microalbuminuria, and
definitions log(UACR)] and echocardiographic traits using multivariable-adjusted
Participants in the FHS are under surveillance for cardiovascular linear and logistic regression models. These models adjusted for age,
outcomes, including hospitalized HF, which are ascertained after review sex, smoking, BMI, diabetes, valvular heart disease, systolic blood
of all medical records including physician visits and hospitalizations pressure, and hypertension treatment status.
related to cardiovascular disease. Outcome events were adjudicated We evaluated the association of two kidney function traits (CKD
by a committee of three FHS physicians using the FHS criteria,33 which and microalbuminuria) with two main outcomes (HFpEF and HFrEF),
define HF based on the presence of two major or one major and two and accordingly a Bonferroni corrected P-value of 0.0125 (0.05 divided
minor criteria. Major criteria are paroxysmal nocturnal dyspnoea or by 4) was used to determine statistical significance for our prospec-
orthopnoea, increased venous pressure, distended neck veins, rales, tive analyses, with a P-value of 0.0125–0.05 considered ‘suggestive’ of
cardiomegaly by radiograph, pulmonary oedema, a third heart sound, an association. For the echocardiographic analyses, we evaluated the
hepatojugular reflux, and weight loss on diuretic therapy. Minor criteria association of the two kidney function traits with three main echocar-
include the presence of ankle oedema, nocturnal cough, hepatomegaly, diographic variables (systolic function, LVM/LVH, and left atrial size)
dyspnoea on exertion, pleural effusion, decrease in vital capacity, and we therefore used a P-value of 0.008 to assess statistical signifi-
and tachycardia. The FHS HF criteria are used in a wide variety of cance. Analyses were performed using SAS Software version 9.3 (Cary,
study settings and have been shown to have adequate sensitivity and NC, USA).
specificity for the diagnosis of HF.34,35 Incident HF events occurring
after 1980 (after imaging was more widely used) were adjudicated into
HF subtypes using EF assessments by echocardiography, radionuclide Power calculations
angiography, or ventriculography during the index hospitalization or
within 1 year prior to the onset of HF if no myocardial infarction With the observed event rates, and assuming that covariates
occurred during the intervening period, as previously described.24 explain 25% of the variance of our outcomes, the present inves-
Thus, LVEF assessment for adjudication of HF subtypes was based tigation had 80% power to detect a hazard ratio (HR) of >1.24
on imaging reports and medical records obtained at the time of HF and >1.81 for the associations of HF subtypes with contin-
hospitalization. These assessments of LV function were distinct from uous eGFR and CKD, respectively. The power was 80% to
the echocardiograms systematically obtained at FHS study visits, which detect a HR of >1.50 for continuous UACR and >2.16 for
were used for cross-sectional analyses to examine cardiac structure microalbuminuria.
and function in relation to kidney function measures prior to HF onset.
HF events were classified as HFpEF if LVEF was >45%, and as HFrEF if
LVEF was ≤45%. Results
Baseline characteristics of the study samples by CKD and
microalbuminuria status are displayed in Table 1. The individ-
Statistical analysis uals with CKD were older, more likely to be women, had
Baseline characteristics for the samples were displayed according to the higher BMI and total cholesterol, and were more likely to have
presence of CKD or microalbuminuria. Age- and sex-standardized inci- hypertension and diabetes, when compared with those without
dence rates (by 10-year age strata) for HF and each HF subtype were
CKD. Among the 2912 participants included in the microal-
calculated according to the presence of CKD or microalbuminuria with
buminuria analyses, 499 (17%) had microalbuminuria. When
direct standardization using the internal study sample. To estimate the
cumulative incidence of HFpEF and HFrEF, we used a Kaplan–Meier-like compared with participants without, individuals with microalbu-
approach to account for competing risks of death, other HF subtype, minuria were older and more likely to have hypertension and
and unclassified HF.36 diabetes.
We used Cox proportional hazards regression models to assess
the associations of eGFR and albuminuria with incident HF and HF
subtypes after ensuring that the proportionality assumption was met. Chronic kidney disease is associated
To account for correlated observations within individuals, we used
robust sandwich covariance estimators.37 The predictors included
with incident overall heart failure
CKD (yes/no), eGFR (continuous, natural log-transformed), microal- Over a mean observation time of 13 ± 4 years, 598 (6.6%) individu-
buminuria (yes/no), and UACR (continuous, natural log-transformed). als without CKD and 156 (17.2%) individuals with CKD developed
Models were adjusted for age and sex, and then additionally for incident HF. The age- and sex-standardized incidence rate of HF
smoking, BMI, total/HDL-cholesterol, diabetes, valvular heart dis- was nearly three-fold higher for those with CKD compared with
ease, systolic blood pressure, hypertension treatment status, and those without CKD (17.4 vs. 5.9 events per 1000 person-years).
history of myocardial infarction. For modelling the associations of
Of 754 HF events, 324 (43%) were HFpEF, 326 (43%) HFrEF,
the predictors with each HF subtype, we used the cause-specific
and 104 (14%) were unclassified (baseline characteristics by HF
method to account for the competing risks of death, other HF sub-
type, and of unclassified HF. In secondary analyses, we evaluated
subtype are shown in Supplementary material online, Table S1).
whether the associations of CKD and albuminuria with HF sub- Incidence rates of both HFpEF and HFrEF were higher among
types were modified by systolic blood pressure or diabetes status individuals with CKD compared with those without CKD, although
by introducing multiplicative interaction terms into the multivariable rates of HFpEF and HFrEF appeared similar within the two groups
models. (Table 2; Figure 1A).

© 2017 The Authors

European Journal of Heart Failure © 2017 European Society of Cardiology
618 M. Nayor et al.

Table 1 Baseline clinical characteristics of the study samples

Characteristic No CKD CKD

(n = 8983) (n = 906)
...........................................................................................................................................
Age, years 56 ± 14 69 ± 10
Women, n (%) 4816 (54) 588 (65)
Body mass index, kg/m2 26.6 ± 4.7 27.0 ± 4.8
Systolic blood pressure, mmHg 128 ± 19 138 ± 21
Hypertension treatment, n (%) 1970 (22) 407 (45)
Current smoker, n (%) 2267 (25) 136 (15)
Diabetes mellitus, n (%) 501 (6) 102 (11)
Valvular heart disease, n (%) 231 (3) 55 (6)
History of myocardial infarction, n (%) 322 (4) 83 (9)
Total cholesterol, mg/dL 211 ± 41 220 ± 44
HDL-cholesterol, mg/dL 50 ± 16 50 ± 16
eGFR, mL/min/1.73 m2 94 ± 20 51 ± 8
...........................................................................................................................................
No microalbuminuria Microalbuminuria
(n = 2413) (n = 499)
...........................................................................................................................................
Age, years 58 ± 9 63 ± 10
Women, n (%) 1294 (54) 260 (52)
Body mass index, kg/m2 27.9 ± 5.1 27.9 ± 5.6
Systolic blood pressure, mmHg 127 ± 18 134 ± 21
Hypertension treatment, n (%) 595 (25) 197 (39)
Current smoker, n (%) 347 (14) 97 (19)
Diabetes mellitus, n (%) 163 (7) 103 (21)
Valvular heart disease, n (%) 58 (2) 22 (4)
History of myocardial infarction, n (%) 81 (3) 31 (6)
Chronic kidney disease, n (%) 156 (7) 78 (18)
Total cholesterol, mg/dL 206 ± 38 220 ± 44
HDL-cholesterol, mg/dL 51 ± 16 49 ± 17
eGFR, mL/min/1.73 m2 87 ± 18 81 ± 20
UACR, mg/g 4.98 (2.26, 9.33) 39.84 (27.40, 68.73)

Values represent the mean ± SD for continuous variables, except UACR, which is represented as median (25%, 75%), and number (%) for categorical variables.
CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; UACR, urinary albumin to creatinine ratio.

Table 2 Age- and sex-standardized incidence of heart failure subtype by baseline chronic kidney disease and
microalbuminuria status

No CKD (n at risk = 8983) CKD (n at risk = 906)

...................................................... .....................................................
Outcome No. of events Incidence rate (95% CI) No. of events Incidence rate (95% CI)
...........................................................................................................................................
Overall HF 598 5.9 (5.4–6.4) 156 17.4 (14.5–20.2)
HFpEF 264 2.6 (2.3–3.0) 60 6.6 (4.9–8.3)
HFrEF 263 2.5 (2.2–2.8) 63 6.9 (5.1–8.6)
Unclassified HF 71 0.8 (0.6–0.9) 33 3.9 (2.5–5.3)
...........................................................................................................................................
No microalbuminuria (n at risk = 2413) Microalbuminuria (n at risk = 499)
...........................................................................................................................................
Overall HF 122 3.6 (3.0–4.3) 70 12.7 (9.6–15.8)
HFpEF 64 2.0 (1.5–2.4) 27 4.4 (2.7–6.0)
HFrEF 54 1.6 (1.2–2.0) 39 7.5 (5.0–9.9)
Unclassified HF 4 0.1 (0.0–0.2) 4 0.9 (0.0–1.8)

Incidence rate is per 1000 person-years.

CI, confience interval; CKD, chronic kidney disease; HF, heart failure; HFpEF, HF with preserved ejection fraction; HFrEF, HF with reduced ejection fraction.

© 2017 The Authors

European Journal of Heart Failure © 2017 European Society of Cardiology
Kidney disease and heart failure subtypes 619

HFpEF was not significantly associated with eGFR in age- and

........................................................................................................................................................................
A sex-adjusted or multivariable-adjusted models (Table 3).
8%
CKD HFrEF
CKD HFpEF
Cumulative incidence of HF

6%
No CKD HFrEF Microalbuminuria was associated
No CKD HFpEF
with the incidence of overall heart failure
4% and heart failure with reduced ejection
fracion but not heart failure
2% with preserved ejection fraction
Of the 2912 individuals with available UACR, there were 122
0% (5.0%) HF events among individuals without microalbuminuria
0 2 4 6 8 10 12
Number at risk and 70 (14.0%) events among those with microalbuminuria
Years
No CKD 8983 8845 8596 8318 7994 7644 7281 during 15 ± 4 years of follow-up. Participants with microalbumin-
CKD 906 854 783 711 648 596 511 uria had a 3.5-fold higher age- and sex-standardized incidence
rate of overall HF compared with those without microalbu-
B 8%
minuria (12.7 vs. 3.6 events per 1000 person-years). Of 192
MALB HFREF
Microalbuminuria HFrEF
HF events, 91 (47.3%) were classified as HFpEF, 93 (48.4%)
Cumulative incidence of HF

MALB HFPEF
Microalbuminuria HFpEF
6% No MALB HFREF
microalbuminuria HFrEF as HFrEF, and 8 (4.2%) were unclassified. Microalbuminuria
microalbuminuria
No MALB HFPEF HFpEF
was associated with a nearly five-fold higher incidence rate of
4% HFrEF and an over two-fold higher incidence rate of HFpEF
(Table 2; Figure 1B).
2% In multivariable-adjusted Cox models, we observed a more
than two-fold higher risk of overall HF with microalbuminuria
0%
in age- and sex-adjusted analyses (HR 2.22, 95% CI 1.64–2.99,
0 2 4 6 8 10 12 P < 0.0001). Microalbuminuria remained significantly associated
Years
Number at risk with risk of overall HF after accounting for potential clinical
No microalbuminuria 2413 2394 2351 2305 2240 2169 2072
confounders, including smoking, BMI, total/HDL-cholesterol, dia-
Microalbuminuria 499 486 460 438 414 390 342
betes, valvular heart disease, systolic blood pressure, hyper-
Figure 1 Cumulative incidence of heart failure (HF) subtype by tension treatment, and history of myocardial infarction (HR
(A) chronic kidney disease (CKD) status and (B) microalbuminuria 1.71, 95% CI 1.25–2.34, P < 0.0001) (Table 3). When examin-
status. HFpEF, HF with preserved ejection fraction; HFrEF, HF ing HF subtypes, microalbuminuria was associated with incident
with reduced ejection fraction. HFpEF in age- and sex-adjusted (HR 1.62, 95% CI 1.02–2.55,
P = 0.04) but not multivariable-adjusted models (HR 1.26, 95%
CI 0.78–2.03, P = 0.34). In contrast, microalbuminuria was asso-
ciated with an over two-fold increased risk of HFrEF in both
In Cox regression models, the presence of CKD was associated
age- and sex-adjusted (HR 2.89, 95% CI 1.89–4.41, P < 0.0001)
with a 52% increased risk for HF in age- and sex-adjusted analyses
and multivariable-adjusted (HR 2.10, 95% CI 1.35–3.26, P = 0.01)
[95% confidence interval (CI) 1.25–1.85, P < 0.0001], which was
analyses.
partially attenuated upon adjustment for clinical HF risk factors
When analysed as a continuous variable, UACR was associated
(HR 1.24, 95% CI 1.01–1.51, P = 0.04) (Table 3). CKD was not
with an increased risk of overall HF and both HF subtypes in age-
associated with incident HFpEF, but was associated with a 66%
and sex-adjusted and multivariable-adjusted analyses (Table 3).
increased risk of HFrEF (95% CI 1.22–2.26, P = 0.001) in age- and
sex-adjusted analyses, which did not reach statistical significance
upon additional adjustment for clinical HF risk factors (HR 1.36, Associations of chronic kidney disease
95% CI 0.99–1.86, P = 0.06).
When examining eGFR as a continuous variable, we found simi-
and microalbuminuria
lar associations. Each 1 SD higher log(eGFR) was associated with a with echocardiographic traits
14% reduction in the risk of overall HF in age- and sex-adjusted We examined the cross-sectional associations of CKD with
analyses (95% CI 0.79–0.93, P = 0.006), but the association did echocardiographic traits for 3075 participants with available eGFR
not reach statistical significance after multivariable adjustment (HR and echocardiographic data (see Supplementary material online,
0.93, 95% CI 0.86–1.01, P = 0.08). Estimated GFR was inversely Table S2 for baseline characteristics). CKD and reduced eGFR were
associated with the incidence of HFrEF [HR 0.83 for each 1 not associated with LVM, LV systolic function, LVH, or LAE. A statis-
SD higher log(eGFR), 95% CI 0.73–0.95, P = 0.005] in age- and tically significant association of higher eGFR with larger LAD (beta
sex-adjusted analyses, which was not statistically significant upon estimate for each 1 SD higher eGFR: 0.03 ± 0.01 cm, P = 0.005) was
multivariable adjustment (HR 0.90, 95% CI 0.80–1.02, P = 0.10). observed.

© 2017 The Authors

European Journal of Heart Failure © 2017 European Society of Cardiology
620 M. Nayor et al.

Table 3 Associations of incident heart failure subtypes with kidney function

Predictor Outcome No. of events/no. at risk

Age- and sex-adjusted Multivariable adjusteda
..................................... ......................................
HR (95% CI) P-value HR (95% CI) P-value
...........................................................................................................................................
CKD Overall HF 754/9889 1.52 (1.25–1.85) <0.0001 1.24 (1.01–1.51) 0.04
HFpEF 324/9889 1.32 (0.97–1.79) 0.08 1.10 (0.81–1.51) 0.53
HFrEF 326/9889 1.66 (1.22–2.26) 0.001 1.36 (0.99–1.86) 0.06
eGFR Overall HF 754/9889 0.86 (0.79–0.93) 0.006 0.93 (0.86–1.01) 0.08
HFpEF 324/9889 0.91 (0.81–1.03) 0.13 0.08 (0.86–1.10) 0.69
HFrEF 326/9889 0.83 (0.73–0.95) 0.005 0.90 (0.80–1.02) 0.10
Microalbuminuria Overall HF 192/2912 2.22 (1.64–2.99) <0.0001 1.71 (1.25–2.34) <0.0001
HFpEF 91/2912 1.62 (1.02–2.55) 0.04 1.26 (0.78–2.03) 0.34
HFrEF 93/2912 2.89 (1.89–4.41) <0.0001 2.10 (1.35–3.26) 0.01
UACR Overall HF 192/2912 1.78 (1.53–2.08) <0.0001 1.47 (1.27–1.71) <0.0001
HFpEF 91/2912 1.60 (1.27–2.02) <0.0001 1.39 (1.11–1.74) 0.004
HFrEF 93/2912 1.92 (1.56–2.36) <0.0001 1.48 (1.21–1.81) 0.001

Hazard ratios represent the relative hazard associated with having CKD or microalbuminuria, and the relative hazard associated with each 1 SD higher log-transformed eGFR
and UACR.
CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HF, heart failure; HFpEF, HF with preserved ejection fraction; HFrEF, HF with
reduced ejection fraction; HR, hazard ratio; UACR, urinary albumin to creatinine ratio.
a Multivariable model is adjusted for age, sex, smoking, body mass index, total/HDL-cholesterol, diabetes, valvular heart disease, systolic blood pressure, hypertension treatment,

and history of myocardial infarction.

In contrast, in the 2652 individuals with available echocardio- albuminuria may specifically be linked to systolic dysfunction and
................................................................................................

graphic data and UACR measured, UACR [odds ratio (OR) 1.48 future HFrEF.
for each 1 SD increase in UACR, 95% CI 1.14–1.90, P = 0.003] Multiple studies have demonstrated that albuminuria predicts
and microalbuminuria (OR 3.19, 95% CI 1.67–6.09, P = 0.0004) incident HF.12,13,39,40 In contrast, specific associations with HFrEF
were associated with higher odds of having LV systolic dysfunction vs. HFpEF remain less clear. We observed a statistically significant
(Tables 4 and 5). association between baseline microalbuminuria and incident HFrEF
but not HFpEF. In contrast to our findings, investigators from the
PREVEND (Prevention of Renal and Vascular End-stage Disease)
Secondary analyses cohort showed that higher urinary albumin excretion was more
In secondary analyses, we tested for statistical interactions with strongly associated with incident HFpEF compared with HFrEF.23
systolic blood pressure and diabetes in the primary analyses. We Several differences in study cohorts and design might account for
found no evidence that the effect of CKD or microalbuminuria the discrepant results between the PREVEND study and ours. In
on either HF subtype was modified by diabetes or systolic blood the present investigation, HFpEF and HFrEF each accounted for
pressure (P > 0.05 for all interactions). ∼50% of HF events; in PREVEND, 34% of events were charac-
In exploratory analyses, we formally tested for equality of the terized as HFpEF and 66% were HFrEF. The varying distribution
associations of CKD and microalbuminuria with incident HFrEF in HF types might reflect inherent differences between the two
using the Lunn–McNeil technique.38 The P-value for this test study samples, including older mean age in PREVEND. Further-
was 0.07 for the age- and sex-adjusted models and 0.13 for the more, the PREVEND cohort was designed to overselect individuals
multivariable model, and therefore the null hypothesis of equality with elevated urinary albumin excretion, and, although statistical
was not rejected. techniques were used to account for the probability of selection,
this overselection might contribute to our discordant findings.
The association of albuminuria with incident HFrEF was substan-
Discussion tiated in our study by the association with LV systolic dysfunction
In our community-based investigation, both CKD and microalbu- cross-sectionally. Indeed, numerous previous studies have demon-
minuria were associated with an increased risk of incident overall strated associations of albuminuria with changes to cardiac struc-
HF in adjusted analyses. When HF subtypes were examined ture and function including LV systolic dysfunction, higher LVM, and
separately, microalbuminuria was associated with a greater than LVH.41,42
two-fold increased risk of incident HFrEF but not HFpEF. Sup- The mechanisms linking albuminuria with HF are not well
porting our observation, we found that microalbuminuria (but not elucidated.41 However, because albuminuria is thought to reflect
CKD) was associated with LV systolic dysfunction cross-sectionally. endothelial dysfunction and inflammation,43 we may have expected
In contrast, CKD was not associated with either HF subtype stronger associations of albuminuria with HFpEF, which has been
in multivariable-adjusted models. Our findings suggest that postulated to result from these conditions.44 Our findings suggest

© 2017 The Authors

European Journal of Heart Failure © 2017 European Society of Cardiology
Kidney disease and heart failure subtypes 621

Table 4 Multivariable-adjusted associations of kidney function measurements with binary echocardiographic traits

Predictor Left ventricular systolic dysfunction Left ventricular hypertrophy Left atrial enlargement
............................................
..................................... ...............................
OR (95% CI) P-value OR (95% CI) P-value OR (95% CI) P-value
...........................................................................................................................................
CKD 1.87 (0.86–4.06) 0.11 0.99 (0.69–1.40) 0.94 0.82 (0.61–1.10) 0.19
eGFR 0.86 (0.66–1.12) 0.27 1.07 (0.96–1.20) 0.22 1.09 (1.00–1.20) 0.06
Microalbuminuria 3.19 (1.67–6.09) 0.0004 1.25 (0.94–1.68) 0.13 0.92 (0.73–1.16) 0.47
UACR 1.48 (1.14–1.90) 0.003 1.06 (0.96–1.17) 0.22 0.98 (0.92–1.06) 0.68

Odds ratios represent the odds of having each binary echocardiographic trait for each 1 SD higher log-transformed eGFR and UACR, and for the presence of CKD and
microalbuminuria vs. their absence.
Analyses are adjusted for age, sex, smoking, body mass index, diabetes, valvular heart disease, systolic blood pressure, and hypertension treatment status.
CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; OR, odds ratio; UACR, urinary albumin to creatinine ratio.

Table 5 Multivariable-adjusted associations of kidney function measurements with continuous echocardiographic

traits

Predictor Fractional shortening (%) Left ventricular mass (g) Left atrial dimension (cm)
................................... .................................. ....................................
Est 𝜷 ± SE P-value Est 𝜷 ± SE P-value Est 𝜷 ± SE P-value
...........................................................................................................................................
CKD −0.04 ± 0.43 0.92 1.93 ± 2.73 0.48 −0.07 ± 0.03 0.04
eGFR −0.10 ± 0.13 0.43 0.17 ± 0.84 0.84 0.03 ± 0.01 0.005
Microalbuminuria −0.52 ± 0.34 0.12 3.02 ± 2.13 0.16 −0.02 ± 0.03 0.53
UACR −0.22 ± 0.10 0.03 0.83 ± 0.66 0.21 0.00 ± 0.01 0.92

Beta estimates represent the mean change in echocardiographic trait for the presence of CKD and microalbuminuria vs. their absence, or for each 1 SD higher log-transformed
eGFR and UACR.
CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; SE, standard error; UACR, urinary albumin to creatinine ratio.

that additional mechanisms may contribute to the increased Previous reports of associations of CKD with echocardio-
...............................................................................

risk of HF in those with albuminuria. As a marker of diffuse graphic traits have been similarly inconsistent. Increased LVM is
microvascular and endothelial injury, albuminuria may therefore present in up to 40% of individuals with CKD, but whether this
serve as an indicator of similar end-organ changes in the heart.45 association persists after accounting for shared risk factors is
Furthermore, albuminuria serves as a potent activator of the controversial.41 Whereas some studies have found independent
renin–angiotensin–aldosterone system, which is well known to associations between CKD and LVM,49,50 others have not.51 Inves-
contribute to the pathogenesis of HFrEF. The fact that inhibitors tigations evaluating the relationships between CKD and LVEF have
of the renin–angiotensin–aldosterone system (such as ACE consistently demonstrated no association,41,49,51,52 consistent with
inhibitors) both reduce albuminuria and improve HFrEF-related our findings. However, recent studies using more sensitive mark-
outcomes further supports a pathophysiological link. ers of LV systolic function, such as longitudinal strain imaging, have
Our observed associations between CKD and incident over- demonstrated more subtle abnormalities of LV systolic function to
all HF are consistent with numerous previous reports.7,9,10,46,47 be present in HFpEF patients with CKD.53 Although we did observe
Although several prior studies have examined the relationships of an association between eGFR and higher LAD (analysed as a contin-
CKD (or reduced eGFR) with HFpEF vs. HFrEF, results have been uous variable), no statistically significant association was observed
conflicting. A report from the FHS similarly concluded that eGFR between CKD (or eGFR) and LAE (analysed as a binary variable).
was not useful in predicting either HFpEF or HFrEF.25 However, The effect estimate for the observed association was small and the
using a different sample of participants from the FHS, Lam et al. clinical relevance is therefore uncertain. Furthermore, LAD is a rel-
reported that higher serum creatinine was associated with inci- atively crude measure of left atrial size, and future studies using left
dent HFrEF, but not HFpEF.8 Concordantly, a retrospective study atrial volumetric assessments or measurements of left atrial func-
of mostly male veterans with clinical HF found that CKD was more tion might be able to elucidate further relationships between CKD
common in patients with HFrEF than in those with HFpEF.48 Con- and left atrial size and function.
versely, using data from the PREVEND cohort, Brouwers et al. A number of mechanisms are likely to contribute to the
found higher cystatin C concentrations (another method of esti- observed association of CKD and incident HF. Cardiovascular and
mating glomerular filtration) to be associated with incident HFpEF, kidney disease share similar risk factors such as age, hypertension,
but not HFrEF.23 Therefore, although reduced glomerular filtration diabetes, and obesity, and their joint impact on the heart and kid-
(and CKD) was modestly associated with overall HF, whether it neys might partially explain the observed relationships. However, in
confers higher risk to either HF subtype remains unknown. our study, the associations between CKD and overall HF persisted

© 2017 The Authors

European Journal of Heart Failure © 2017 European Society of Cardiology
622 M. Nayor et al.

even after accounting for these clinical risk factors, suggesting that Funding

........................................................................................................................................................................
other pathways are likely to be involved. CKD leads to volume
This work was partially supported by the National Heart,
retention, altered calcium–phosphate metabolism, hyperparathy-
Lung and Blood Institute’s Framingham Heart Study (Contracts
roidism, vitamin D deficiency, anaemia, and the accumulation of
N01-HC-25195 and HHSN268201500001I). M.N. received
uraemic toxins. These and other mechanisms related to reduced
support from NIH grant T32-HL007604 and training grant
glomerular filtration may also contribute to the pathogenesis of
U10HL110337 from the National Heart, Lung, and Blood Insti-
overall HF, but the relative contributions to each HF subtype
tute. D.S.L. is supported by a clinician-scientist award from the
remain unknown.
Canadian Institutes of Health Research. C.W.T. is supported
Several limitations of the present investigation warrant men-
by NIH grant K23-HL118529. S.C. is supported in part by
tion. The adjudication of HFpEF and HFrEF was based on a single
R00-HL-107642 and a grant from the Ellison Foundation. J.H. is
assessment of EF, which might lead to misclassification as EF (and
supported by NIH grant K23-HL116780. The views expressed in
therefore HF subtype) may change over time. Given our restricted
this manuscript are those of the authors and do not necessarily
power, meaningful associations with lower effect sizes cannot be
represent the views of the National Heart, Lung, and Blood
definitively excluded. In particular, the formal testing of equality
Institute; the National Institutes of Health; or the US Department
between the associations of CKD and microalbuminuria with inci-
of Health and Human Services.
dent HFrEF should be interpreted in the context of limited power
Conflict of interest: none declared.
when examining separate HF subtypes. Albuminuria and eGFR are
commonly used but are relatively crude assessments of renal func-
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European Journal of Heart Failure © 2017 European Society of Cardiology