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Aims: The objective of the present study is to assess the prognostic value of acute kidney injury (AKI) in the evolution of patients with heart failure (HF) using real-world data. Methods and results: Patients with a diagnosis of HF and with serial measurements of renal function collected throughout the study period were included. Estimated glomerular filtration rate (GFR) was calculated with the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). AKI was defined when a sudden drop in creatinine with posterior recovery was recorded. According to the Risk, Injury, Failure, Loss, and End-Stage Renal Disease (RIFLE) scale, AKI severity was graded in three categories: risk [1.5-fold increase in serum creatinine (sCr)], injury (2.0-fold increase in sCr), and failure (3.0-fold increase in sCr or sCr > 4.0 mg/dL). AKI incidence and risk of hospitalization and mortality after the first episode were calculated by adjusting for potential confounders. A total of 30 529 patients with HF were included. During an average follow-up of 3.2 years, 5294 AKI episodes in 3970 patients (13.0%) and incidence of 3.3/100 HF patients/year were recorded. One episode was observed in 3161 (10.4%), two in 537 (1.8%), and three or more in 272 (0.9%). They were more frequent in women with diabetes and hypertension. The incidence increases across the GFR levels (Stages 1 to 4: risk 7.6%, 6.8%, 11.3%, and 12.5%; injury 2.1%, 2.0%, 3.3%, and 5.5%; and failure 0.9%, 0.6%. 1.4%, and 8.0%). A total of 3817 patients with acute HF admission were recorded during the follow-up, with incidence of 38.4/100 HF patients/year, 3101 (81.2%) patients without AKI, 545 (14.3%) patients with one episode, and 171 (4.5%) patients with two or more. The number of AKI episodes [one hazard ratio (HR) 1.05 (0.98-1.13); two or more HR 2.01 (1.79-2.25)] and severity [risk HR 1.05 (0.97-1.04); injury HR 1.41 (1.24-1.60); and failure HR 1.90 (1.64-2.20)] increases the risk of hospitalization. A total of 10 560 deaths were recorded, with incidence of 9.3/100 HF patients/year, 8951 (33.7%) of subjects without AKI episodes, 1180 (11.17%) of subjects with one episode, and 429 (4.06%) with two or more episodes. The number of episodes [one HR 1.05 (0.98-1.13); two or more HR 2.01 (1.79-2.25)] and severity [risk 1.05 confidence interval (CI) (0.97-1.14), injury 1.41 (CI 1.24-1.60), and failure 1.90 (CI 1.64-2.20)] increases mortality risk. Conclusions: The study demonstrated the worse prognostic value of sudden renal function decline in HF patients and pointed to those with more future risk who require review of treatment and closer follow-up.
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Acute kidney injury in heart failure: a population study
Jose Luis Holgado
1
, Cristina Lopez
1
, Antonio Fernandez
1
, Inmaculada Sauri
1
, Ruth Uso
1
, Jose Luis Trillo
1
, Sara
Vela
2
, Julio Nuñez
3
, Josep Redon
1,2,4
*and Adrian Ruiz
2
1
Cardiovascular and Renal Research Group, INCLIVA Research Institute, University of Valencia, Avda Blasco Ibañez,
17
,
46010
, Valencia, Spain;
2
Internal Medicine Hospital,
Clínico de Valencia, Valencia, Spain;
3
Cardiology Hospital, Clínico de Valencia, Valencia, Spain;
4
CIBERObn, Carlos III Health Institute, Madrid, Spain
Abstract
Aims The objective of the present study is to assess the prognostic value of acute kidney injury (AKI) in the evolution of
patients with heart failure (HF) using real-world data.
Methods and results Patients with a diagnosis of HF and with serial measurements of renal function collected throughout
the study period were included. Estimated glomerular ltration rate (GFR) was calculated with the CKD-EPI (Chronic Kidney
Disease Epidemiology Collaboration). AKI was dened when a sudden drop in creatinine with posterior recovery was recorded.
According to the Risk, Injury, Failure, Loss, and End-Stage Renal Disease (RIFLE) scale, AKI severity was graded in three cate-
gories: risk [1.5-fold increase in serum creatinine (sCr)], injury (2.0-fold increase in sCr), and failure (3.0-fold increase in sCr
or sCr >4.0mg/dL). AKI incidence and risk of hospitalization and mortality after the rst episode were calculated by adjusting
for potential confounders. A total of 30 529 patients with HF were included. During an average follow-up of 3.2years, 5294 AKI
episodes in 3970 patients (13.0%) and incidence of 3.3/100 HF patients/year were recorded. One episode was observed in
3161 (10.4%), two in 537 (1.8%), and three or more in 272 (0.9%). They were more frequent in women with diabetes and hy-
pertension. The incidence increases across the GFR levels (Stages 1to 4:risk 7.6%, 6.8%, 11.3%, and 12.5%; injury 2.1%, 2.0%,
3.3%, and 5.5%; and failure 0.9%, 0.6%. 1.4%, and 8.0%). A total of 3817 patients with acute HF admission were recorded dur-
ing the follow-up, with incidence of 38.4/100 HF patients/year, 3101 (81.2%) patients without AKI, 545 (14.3%) patients with
one episode, and 171 (4.5%) patients with two or more. The number of AKI episodes [one hazard ratio (HR) 1.05 (0.981.13);
two or more HR 2.01 (1.792.25)] and severity [risk HR 1.05 (0.971.04); injury HR 1.41 (1.241.60); and failure HR 1.90 (1.64
2.20)] increases the risk of hospitalization. A total of 10 560 deaths were recorded, with incidence of 9.3/100 HF patients/year,
8951 (33.7%) of subjects without AKI episodes, 1180 (11.17%) of subjects with one episode, and 429 (4.06%) with two or more
episodes. The number of episodes [one HR 1.05 (0.981.13); two or more HR 2.01 (1.792.25)] and severity [risk 1.05 con-
dence interval (CI) (0.971.14), injury 1.41 (CI 1.241.60), and failure 1.90 (CI 1.642.20)] increases mortality risk.
Conclusions The study demonstrated the worse prognostic value of sudden renal function decline in HF patients and pointed
to those with more future risk who require review of treatment and closer follow-up.
Keywords Heart failure; Acute kidney injury; Renal function; Risk of hospitalization; Risk of mortality
Received:
23
July
2019
; Revised:
8
November
2019
; Accepted:
25
November
2019
*Correspondence to: Josep Redon, Cardiovascular and Renal Research Group, INCLIVA Research Institute, University of Valencia, Avda Blasco Ibañez,
17
,
46010
Valencia,
Spain. Email: josep.redon@uv.es
Introduction
Heart failure (HF) is a mounting condition with huge impact in
health care burden. Prevalence is still increasing mainly
driven for the aging population in which renal dysfunction is
also frequent.
1
The association between HF and renal dys-
function is well known; while HF increases the risk of renal in-
sufciency, chronic kidney disease (CKD) increases the risk of
hospitalization and mortality.
2
Thus, the term cardiorenal
syndromewith various subtypes has been introduced.
3
One of the cardiorenal syndromes is acute kidney injury
(AKI), a syndrome of multiple aetiologies associated with in-
creased risk of hospitalization and high mortality.
4,5
It has
been recognized that even patients who have complete or
near-complete kidney function recovery after AKI are at in-
creased risk of progressive CKD, and that superimposition of
ORIGINAL RESEARCH ARTICLE
©2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.
ESC HEART FAILURE
ESC Heart Failure (2020)
Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.12595
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the
original work is properly cited.
AKI on CKD is associated with acceleration in the rate of pro-
gression to end-stage renal disease.
6
In patients with HF, the
incidence and impact of AKI have been reported mainly in
subjects hospitalized with acute HF (AHF), in which the prev-
alence of AKI is ~20%, and it has been recognized that AKI is a
strong independent predictor of both in-hospital and 1-year
mortality.
7,8
A meta-analysis of cohorts, registries, and post-
hoc studies concluded that CKD and worsening of renal func-
tion (WRF),
9
a term that has been used instead of AKI in HF
patients,
10
are frequently observed in patients with HF. How-
ever, the authors acknowledge heterogeneity due to differ-
ent inclusion criteria, selection bias, and different denitions
and criteria used to qualify AKI.
9
Indeed, the incidence, prev-
alence, and consequences of AKI in patients with HF are not
well established.
The objective of the present study is to assess the prognos-
tic value of AKI in the evolution of patients with HF using real-
world data. This study reects the view that electronic health
record (EHR)-based studies from general practice are a repre-
sentative setting to evaluate burden of disease associated
with health conditions such as AKI in HF.
Subjects and methods
Study population and baseline data collection
The sample was recruited from beneciaries of the Valencian
Health Agencys universal health care system. The Valencian
Community is a Mediterranean region located on the east
coast of Spain, with a population of 3 799 885 people older
than 18 years in 2012. Every patient has a unique personal
identication number for the health system, so there is one
unique electronic centralized clinical record per patient. The
total population data were extracted using the health infor-
mation exchange function of ABUCASIS for the period of time
between 1January 2012 and 31 December 2015. ABUCASIS
includes information on patient demographics, medications,
vital status, past medical history, and laboratory data,
among others. Patientsdata collected from the system dur-
ing the study were documented by a process of pseudo-
anonymization, making it impossible to use this information
to identify the patients because the only link between the
data and the patient is a code not available to the re-
searchers. The data generated during the study were handled
according to the Spanish Law 3/2008 of Data Protection and
Guaranty of Digital Rights the and corresponding European
norms.
11
The study was reviewed and approved by the
Committee for Ethics and Clinical Trials of the Hospital Clinico
of Valencia.
In the general population, 132 065 subjects were men and
women with a diagnosis of HF (ICD
398
.
91
,
402
.
01
,
402
.
11
,
402
.
91
,
404
.
01
,
404
.
11
,
404
.
91
,
404
.
03
,
404
.
13
,
404
.
93
,and
all
428
), and the eligible patients for the present study were
those with serial measurements of renal function collected
throughout the study period. Participants were included in
the study from 1January 2012 if they fullled the eligibility
condition of an HF diagnosis before this time. Subsequently,
participants newly diagnosed of HF during the study period
until 31 December 2015 were also included. Finally, 30 529
subjects of both sexes aged 18 years or older who attended
routine health examinations and fullled eligibility criteria
were initially selected from the total population database.
The observational study was undertaken as part of routine
clinical practice.
Glomerular ltration rate and acute kidney injury
Serum creatinine was measured using a kinetic rate Jaffé
method in a Hitachi Model 704 multichannel analyser
(Boehringer Mannheim Diagnostics). Serum creatinine was
calibrated to account for laboratory differences across time
and to standardize to creatinine measures with isotope
dilution mass spectrometry. Estimated glomerular ltration
rate (eGFR) was calculated from calibrated creatinine, age,
and sex by using the CKD-EPI (Chronic Kidney Disease Epide-
miology Collaboration)
12,13
and the KDIGO (Kidney Disease
Improving Global Outcomes) stratication of eGFR
14
at the
baseline of the study in stable conditions, dened as no
changes in creatinine levels in the previous 6months. During
the follow-up, AKI was dened when a sudden drop in creat-
inine with posterior recovery at previous levels was recorded.
According to the RIFLE scale,
15
AKI severity was graded in
three categories: risk [1.5-fold increase in serum creatinine
(sCr)], injury (2.0-fold increase in sCr), and failure (3.0-fold in-
crease in sCr or sCr >4.0mg/dL). The number of episodes for
each patient has been quantied and graded.
Cardiovascular risk factor denition
Body mass index (BMI) was calculated by dividing measured
weight in kilograms by square of height in metres. Obesity
was dened as a BMI 30 kg/m
2
. Blood pressure was mea-
sured up to three times on the same day in a sitting position,
and hypertension was dened as an ofce mean systolic
blood pressure 140 mmHg, a mean diastolic blood pressure
90 mmHg, a recorded physician diagnosis, or medication
use. Diabetes was dened as a non-fasting glucose 200
mg/dL, a recorded physician diagnosis, medication use or an
HbA1c6.5%. Serum total cholesterol was measured enzy-
matically using the Cholesterol High Performance reagent
(Roche Diagnostics). High-density lipoprotein (HDL) choles-
terol was measured using a direct HDL reagent (Roche Diag-
nostics). Low-density lipoprotein cholesterol was calculated
by using the Friedewald formula. Dyslipidaemia was dened
2J.L. Holgado et al.
ESC Heart Failure (2020)
DOI: 10.1002/ehf2.12595
by total cholesterol >200 mg/dL and/or treatment with lipid-
lowering drugs.
Mortality and hospitalization follow-up
Participants were followed up for hospitalization for AHF
and for all-cause mortality until 31 December 2015. Causes
of hospitalization were recorded using codes of the Interna-
tional Classication of Diseases,
9
th Revision. Vital status
was determined by matching records and death certicates
from the Spanish National Death Index. Mortality included
all causes of death. Time to event was calculated for each
individual as the difference between the date of the
inclusion into the study and the date of the hospital admis-
sion, the date of death, or 31 December 2015, whichever oc-
curred rst.
Statistical analysis
The cumulative survival rates and HF events in each of the
groups (presence of CKD or AKI and the degree of AKI) were
analysed using KaplanMeier curves, and the log-rank test
was used to calculate the statistical signicance of the differ-
ences. The prognostic value of the eGFR groups or AKI was
assessed using a Cox regression hazard model to determine
the hazard ratio (HR) for risk of hospitalization and mortality.
Clinically relevant factors affecting the prognosis, including
age (continuous modelled as restricted cubic splines with 5
knots), sex (men or women), BMI (continuous), hypertension
(no or yes), diabetes (no or yes), angiotensin AT1receptor
blockers (ARBs), angiotensin-converting-enzyme inhibitors
(ACEi), anti-aldosterone drugs, and diuretics (Henle loop and
thiazides), were selected for inclusion in the multivariate
analysis. Multivariate Cox regression hazard model was per-
formed by using the backward stepwise selection.
Results
General characteristics of the study population
A total of 30 529 patients with HF were included. Mean age
was 75 years, and 58% were female. Hypertension was pres-
ent in 89.4%, dyslipidaemia in 65.0%, and diabetes in 48.3%
of the participants. A total of 12 809 (42.0%) patients had
eGFR <60 mL/min/1.73 m
2
, among them 35.4% eGFR be-
tween 30 and 60 mL/min/1.73 m
2
and 6.5% between 15 and
30 mL/min/1.73 m
2
. The number of subjects with one episode
of AKI was 3161 (10.4%) and two or more in 809 (2.6%). The
main characteristics of the study population grouped by the
number of AKI episodes are shown in Table
1
. Patients with
AKI episodes were more frequently female with diabetes
and hypertension. Likewise, signicant lower eGFR values
were observed across the AKI severity groups. The treatments
are also shown in Table
1
. Patients with AKI were receiving
more diuretics, beta-blockers, and reninangiotensin aldoste-
rone system blockers (ARB, ACEi, and anti-aldosterone drugs).
Acute kidney injury episodes
During an average follow-up of 3.2years, 5294 episodes of
AKI in 3970 patients (13%), with incidence of 3.3/100
patients/year, were recorded. Only one episode was ob-
served in 3161 (10.4%), two in 537 (1.8%), and three or
more in 272 (0.9%). The odds ratio of a second episode after
the rst was 0.26 (95%CI0.240.28). According to the
severity, AKI risk was present in 2712 patients, injury in 821,
and failure in 437. The prevalence increases across the
reduction of GFR levels (Stages 1to 4:risk 7.6%, 6.8%,
11.3%, and 12.5%; injury 2.1%, 2.0%, 3.3%, and 5.5%; and
failure 0.9%, 0.6%. 1.4%, and 8.0%, respectively) and inci-
dence rate (Stages 1to 4:risk 2.0,1.8,3.2, and 3.7/100
patients/year; injury 0.5,0.5,0.9, and 1.6/100
patients/year; and failure 0.2,0.2,0.4, and 2.3/100
patients/year, respectively) (Figures
1
and
2
).
Acute kidney injury episodes and acute heart
failure hospitalization
A total of 3817 patients with AHF admission in the study pe-
riod were recorded, with incidence of 38.4/100 HF
patients/year. They were 3101 (81.2%) patients without AKI,
545 (14.3%) patients with one AKI episode, and 171 (4.5%)
patients with two or more episodes. According to the AKI se-
verity, AKI risk was present in 472 (12.4%), injury in 171
(4.5%), and failure in 73 (1.9%). The number of AKI episodes
[one HR 1.05 (0.981.13); two or more HR 2.01 (1.792.25)]
and severity [risk HR 1.05 (0.971.04); injury HR 1.41 (1.24
1.60); and failure HR 1.90 (1.642.20)] increases the risk of
hospitalization, when adjusted by age, sex, CKD stage, hyper-
tension, diabetes, ACEi/ARB, diuretics, number of visits to the
specialist, and number of admissions (Figure
3
).
Acute kidney injury episodes and mortality
During the study period, a total of 10 560 deaths were re-
corded, with incidence of 9.3/100 HF patients/year, with
8951 (33.7%, incidence of 9/100 patients/year) of subjects
without AKI episodes, 1180 (11.17%) of subjects with one ep-
isode, and 429 (4.06%) with two or more episodes. According
to the severity of AKI, risk episodes were present in 992
(36.6%), injury in 367 (44.7%), and failure in 250 (57.2%).
The number of episodes [one HR 1.05 (0.981.13); two or
AKI in acute heart failure 3
ESC Heart Failure (2020)
DOI: 10.1002/ehf2.12595
more HR 2.01 (1.792.25)] and severity [risk 1.05 (CI 0.97
1.14), injury 1.41 (CI 1.241.60), and failure 1.90 (CI 1.64
2.20)] increases mortality risk (Figure
4
). When the mortality
risk was assessed in each of the eGFR groups according to the
AKI severity, patients with eGFR of between 30 and 90
mL/min/1.73 m
2
are those in whom the risk was graded by
the severity of AKI episode. In patients with eGFR between
15 and 30 mL/min/1.73 m
2
, the risk of mortality is high in
all subjects, with and without AKI episodes.
Discussion
In a large cohort of acute and chronic HF patients, AKI is a fre-
quent condition in ~15% of patients with at least one epi-
sode, with an increasing incidence according to the eGFR
group. AKI incidence and both number and severity of epi-
sodes increase the risk of hospital admission by AHF and all-
cause mortality.
The present study was conducted in a population from
the Valencian Community territory, with an EHR associated
with the public general-practice setting that has a 92%
coverage of the population living in the area. Every patient
has a unique personal identication number, which guaran-
tees the interoperability of the EHRs. Thus, administrative
data, including all prescriptions and dispensation of subsi-
dized treatments and hospitalization events, are linked to
the database that integrates all the health care interven-
tions and procedures that the patients received. Therefore,
this study includes information on baseline risk factors and
follow-up for mortality and hospitalizations from adults with
HF who had their serum creatinine repeatedly measured by
the public health system during the study period.
Dening and classifying the sudden decrease in renal func-
tion are still a matter of debate with several criteria used,
such as RIFLE,
15
AKIN,
16
KDIGO,
17
and WRF.
18
One study com-
pared them in patients hospitalized due to acute heart de-
compensation to assess the benets of using one or two of
the AKI classication systems.
19
The authors concluded that
the potential advantages of the new classications, AKIN
and KDIGO, lie in the ability to identify those patients with
more severe degrees of AKI who will go on to experience ad-
verse events at 30 days and 1year. However, the differences
in terms of predictive abilities were only marginal.
19
Diagnosis
and classication of AKI were performed based on the RIFLE
Table 1 General characteristics of the study population
All subjects No AKI AKI risk AKI injury AKI failure
Number 30 529 26 559 2712 821 437
Sex (M) 14 030 (46.0) 12 173 (45.8) 1232 (45.4)
a
379 (46.2)
a
246 (56.3)
a,b,c
Body mass index (kg/m
2
) 30.8 (5.8) 30.8 (5.8) 30.8 (5.6) 31.0 (5.7) 30.4 (6.5)
Age at diagnosis 75.1 (11.0) 75.1 (11.1) 75.4 (10.2) 75.9 (9.9) 74.6 (10.7)
eGFR (mL/min/1.73 m
2
) 65.0 (22.4) 66.0 (21.9) 59.8 (23.4)
a
58.2 (24.7)
a
46.5 (27.0)
a,b,c
CKD Stage 1, >90 13.4 13.8 11.4
a
10.6
a
8.2
a,b,c
CKD Stage 2, 9060 44.6 46.4 34.3 33.3 19.9
CKD Stage 3, 6030 35.4 34.2 45.1 42.9 35.5
CKD Stage 4, 3015 6.5 5.6 9.2 13.3 36.4
Average of visits
d
19.4 (19.1) 18.9 (18.2) 23.8 (23.1)
a
21.2 (24.6)
a
22.1 (26.1)
a
Acute HF hospitalization 3817 (12.5) 3101 (11.7) 472 (17.4)
a
171 (20.8)
a,b
73 (16.7)
a
Mortality 10 560 (34.6) 8951 (33.7) 992 (36.6) 367 (44.7)
a,b
250 (57.2)
a,b,c
Co-morbidities
Anaemia 16 145 (52.9) 13 534 (51.0) 1760 (64.9)
a
541 (65.9)
a
310 (70.9)
a
Diabetes 14 740 (48.3) 12 484 (47.0) 1536 (56.6)
a
475 (57.9)
a
245 (56.1)
a
Dyslipidaemia 19 831 (65.0) 17 135 (64.5) 1861 (68.6)
a
545 (66.4) 290 (66.4)
Hypertension 27 303 (89.4) 23 595 (88.8) 2526 (93.1)
a
767 (93.4)
a
415 (95.0)
a
Myocardial infarction 5569 (18.2) 4695 (17.7) 604 (22.3)
a
174 (21.2)
a
96 (22.0)
Atrial brillation 17 159 (56.2) 14 675 (55.3) 1689 (62.3)
a
541 (65.9)
a
254 (58.1)
c
Treatment
Diuretics 22 715 (74.4) 19 471 (73.3) 2232 (82.3)
a
663 (80.8)
a
349 (79.9)
a
Beta-blockers 13 131 (43.0) 11 199 (42.2) 1326 (48.9)
a
406 (49.5)
a
200 (45.8)
ACEi/ARB 19 859 (65.0) 17 053 (64.2) 1924 (70.9)
a
596 (72.6)
a
286 (65.4)
Calcium antagonists 7795 (25.5) 6569 (24.7) 797 (29.4)
a
258 (31.4)
a
171 (39.1)
a,b,c
NSAIDs 8660 (28.4) 7668 (28.9) 711 (26.2)
a
191 (23.3)
a
90 (20.6)
a
Anti-aldosterone 5477 (17.9) 4537 (17.1) 631 (23.3)
a
216 (26.3)
a
93 (21.3)
ACEi, angiotensin-converting-enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; CKD, chronic kidney disease;
eGFR, estimated glomerular ltration rate; NSAIDs, non-steroidal anti-inammatory drug.
Values are number (percentage).
a
Difference with no AKI group.
b
Difference with AKI risk group.
c
Difference with AKI injury group.
d
Visits to specialists and primary care physicians.
4J.L. Holgado et al.
ESC Heart Failure (2020)
DOI: 10.1002/ehf2.12595
scale on the changes in serum creatinine, without the criteria
that include urine output, owing to the characteristics of the
database that do not record specic data from the hospitali-
zation period or the ambulant control.
In patients with HF, AKI is a frequent event in which the
haemodynamic status, low cardiac output or congestive
status, and the impact of drugs, mainly diuretics and renin
angiotensin system blockade, are relevant factors. As it is ex-
pected, the incidence increases in patients with eGFR <60
mL/min/1.73 m
2
owing to the lower renal functional reserve
produced by the HF itself or owing to age and co-morbidities
that increase the risk of renal functional deterioration. The
Figure 1Risk to develop AKI episodes by CKD stage. Using as a reference the group in CKD Stage 1, the risk of risk (A) was HR 0.87 (95%CI0.760.99)
in Stage 2,HR1.48 (95%CI1.291.69) in Stage 3, and HR 1.95 (95%CI1.652.30) in Stage 4.Injury (B) was HR 0.97 (95%CI0.761.25) in Stage 2,HR
1.58 (95%CI1.222.05) in Stage 3, and HR 3.49 (95%CI2.614.66) in Stage 4.Failure (C) was HR 1.09 (95%CI0.721.63) in Stage 2,HR2.75 (95%CI
1.844.11) in Stage 3, and HR 16.36 (95%CI10.8424.69) in Stage 3. Lines: blue (Stage 1), orange (Stage 2), green (Stage 3), and red (Stage 4). AKI,
acute kidney injury; CI, condence interval; CKD, chronic kidney disease; HR, hazard ratio.
Figure 2Percentage of patients with AKI severity episodes by CKD stage. AKI, acute kidney injury; CKD, chronic kidney disease.
AKI in acute heart failure 5
ESC Heart Failure (2020)
DOI: 10.1002/ehf2.12595
more reduced eGFR increases not only the incidence but also
the severity and reduces the lag period of time free of AKI.
These data are in agreement with those of previous studies
performed in AHF subjects, but no information was available
on the total HF population. Whether or not the incidence was
higher in patients with HF with reduced ejection fraction than
in those with HF with preserved ejection fraction, it is not
possible to assess it in the present study because the left ven-
tricular function was not properly recorded in a great propor-
tion of patients.
The importance of co-morbidities in the evolution and
prognosis of HF has been emphasized,
20
and several studies
have tried to identify factors related with hospitalization
and prognosis.
21,22
Besides ischaemic heart disease, other
factors such as non-compliance to the prescribed treatments
or diet, infections, arrhythmias, uncontrolled hypertension,
anaemia, and renal dysfunction are among the most common
reasons for AHF, progression, and mortality. The relevance
and impact of AKI in terms of prognostic value for hospital ad-
mission by AHF or mortality have been investigated in the
present study. Hospital admissions were considered only for
those due to AHF avoiding total hospitalizations because pa-
tients with HF could have admission due to decompensation
or other deadly co-morbidities. AKI increases risk of hospital-
ization and mortality, indicating the more fragile status of the
patient.
The limitations and strengths of the present study should
be considered. First is with regards the denition of AKI.
While we recognized the utility of AKI denition in epidemi-
ology and clinical research arenas, it is not sufciently vali-
dated for use in the diagnosis and clinical management of
patients. The study does not identify the cause of mortality,
whether it is cardiovascular or not, although the AKI repre-
sents a status of fragility that can alert about the very high
risk of all-cause mortality. Moreover, the lack of assessment
of natriuretic peptides and left ventricular ejection fraction
precluded to better dissect the effect of AKI across the dif-
ferent phenotypes of HF. The large sample size and the av-
erage follow-up are useful to properly assess the
signicance of changes in renal function in terms of
prognosis.
In conclusion, the study described the prognostic value of
sudden renal function decline beyond the episode of AKI
and pointed to the patients with more future risk who re-
quire review of treatment and more careful follow-up. As
the problem of hospitalization for AHF is expected to
Figure 3Risk of AHF hospital admissions by AKI number (A), one-episode HR 1.19 (1.091.31), two or more episodes HR 1.84 (1.572.15). Line colours:
blue (no AKI), orange (one AKI), and red (two or more AKI). Severity (B) of AKI episodes risk 1.17 (1.061.3), injury 1.80 (1.542.1), and failure 1.38
(1.091.75). Line colours as in Figure
1
. AHF, acute heart failure; AKI, acute kidney injury; HR, hazard ratio.
6J.L. Holgado et al.
ESC Heart Failure (2020)
DOI: 10.1002/ehf2.12595
increase, we have to design strategies of management in the
future. Further research is needed to nd which is the best
plan or site of management for these patients, taking into ac-
count that this can vary according to the population or the or-
ganization of health systems.
Acknowledgement
We acknowledge the contribution of the Health Authorities
of the Conselleria de Salud UniversalGeneralitat Valenciana
for allowing to use their data.
Conicts of Interest
None declared.
Funding
This work was supported by the BigData@Heart (IMI2-
FPP116074-2), BigMedilytics (ICT-15-780495), and CIBERObn
Carlos III Health Institute (PI16/01402).
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... Heart failure as an independent risk for mortality in HD patients, whether incident or chronic, has been studied and confirmed. (32)(33)(34)(35)(36) Among HD patients, those who have cardiovascular disease have worse prognosis. Cardiovascular disease is the most common cause of death in HD patients. ...
... Several studies have also shown that patients with heart failure that develop acute or acute-on-chronic kidney disease with HD dependence have a poorer prognosis, with a median survival of less than 4 months. (36)(37) AKI requiring dialysis is associated with substantial morbidity, mortality, and progression to CKD. Patients are considered to have reached ESRD after 90 days of AKI with dialysis requirement. ...
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... The incidence of AKI in population is ~20%. [40][41][42] The significance of WRF among patients with AHF has been emphasized for years. 40,43 The presence of WRF, understood as an increase in SCr > 0.3 mg/dL in serum or a decrease in eGFR by >25% (expressed in mL/min/1.73 ...
... [40][41][42] The significance of WRF among patients with AHF has been emphasized for years. 40,43 The presence of WRF, understood as an increase in SCr > 0.3 mg/dL in serum or a decrease in eGFR by >25% (expressed in mL/min/1.73 m 2 , calculated according to the Modification of Diet in Renal Disease (MDRD) formula), together with worsening or lack of improvement in signs and symptoms of AHF, is known as the "true WRF". ...
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... The WRF and AKI in AHF are common complications associated with ominous outcomes [4]. The occurrence of AKI has been estimated at 9-13% of AHF patients [16,17]. The underlying causes of the WRF in AHF are complex and not fully understood; the most prominent hypotheses include the impact of, i.a., congestion [18]. ...
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... On the other hand, bolus-free levosimendan administration may have prevented significant hypotension reported in patients after administration of a bolus of the inodilatator levosimendan (19). These findings fit well into data reported here, showing stable kidney function after levosimendan in the context of acute heart failure, a condition known to affect kidney function normally negatively (37). ...
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Acute kidney injury (AKI) is a clinical syndrome that complicates the course and worsens the outcome in a signi cant number of hospitalised patients. Recent advances in clinical and basic research will help with a more accurate de nition of this syndrome and in the elucidation of its pathogenesis. With this knowledge we will be able to conduct more accurate epidemiologic studies in an effort to gain a better understanding of the impact of this syndrome. AKI is a syndrome that rarely has a sole and distinct pathophysiology. Recent evidence, in both basic science and clinical research, is beginning to change our view for AKI from a single organ failure syndrome to a syndrome where the kidney plays an active role in the progress of multi-organ dysfunction. Accurate and prompt recognition of AKI and better understanding of the pathophysiologic mechanisms underlying the various clinical phenotypes are of great importance to research for effective therapeutic interventions. In this review we provide the most recent updates in the de nition, epidemiology and pathophysiology of AKI.
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Background and objectives: AKI in the hospital is common and is associated with excess mortality. We examined whether AKI is also independently associated with a higher risk of different cardiovascular events in the first year after discharge. Design, setting, participants, & measurements: We conducted a retrospective analysis of a cohort between 2006 and 2013 with follow-up through 2014, within Kaiser Permanente Northern California. We identified all adults admitted to 21 hospitals who had one or more in-hospital serum creatinine test result and survived to discharge. Occurrence of AKI was on the basis of Kidney Disease: Improving Global Outcomes diagnostic criteria. Potential confounders were identified from comprehensive inpatient and outpatient, laboratory, and pharmacy electronic medical records. During the 365 days after discharge, we ascertained occurrence of heart failure, acute coronary syndromes, peripheral artery disease, and ischemic stroke events from electronic medical records. Results: Among a matched cohort of 146,941 hospitalized adults, 31,245 experienced AKI. At 365 days postdischarge, AKI was independently associated with higher rates of the composite outcome of hospitalization for heart failure and atherosclerotic events (adjusted hazard ratio [aHR], 1.18; 95% confidence interval [95% CI], 1.13 to 1.25) even after adjustment for demographics, comorbidities, preadmission eGFR and proteinuria, heart failure and sepsis complicating the hospitalization, intensive care unit (ICU) admission, length of stay, and predicted in-hospital mortality. This was driven by an excess risk of subsequent heart failure (aHR, 1.44; 95% CI, 1.33 to 1.56), whereas there was no significant association with follow-up atherosclerotic events (aHR, 1.05; 95% CI, 0.98 to 1.12). Conclusions: AKI is independently associated with a higher risk of cardiovascular events, especially heart failure, after hospital discharge.
Article
Background In-hospital worsening heart failure (WHF) occurs frequently in patients hospitalized for acute heart failure (AHF) and has strongly negative prognostic associations. It may be a useful endpoint in studies of AHF management but important questions remain regarding optimization of its definition and variability in its incidence. Methods Our objective was to survey the full extent of clinical interest in WHF and assess the impact of baseline variables and trial design on outcomes. PubMed, Embase, and BIOSIS were searched systematically for clinical studies that had in-hospital WHF as an endpoint. Differences in definitions of in-hospital WHF were reviewed for their potential impact on observed incidence of WHF and its associations with post-discharge outcomes. Results The search identified 35 publications representing 13 interventional trials, 3 observational studies, several different classes of therapeutic agent, and 78,752 patients overall. Incidence of in-hospital WHF varied greatly—from 4.2% to 37%. Concerning the impact of differences in the way in which WHF was defined, two important factors were physician determination of worsening and whether intensification of diuretic therapy alone was defined as a WHF event. Patients having in-hospital WHF were at substantially greater risk for death and longer length of stay during index hospitalizations, all-cause and heart-failure rehospitalization, cardiovascular complications, renal failure, all-cause death, cardiovascular death, and higher healthcare costs post-discharge. Conclusions There is diverse interest in selecting in-hospital WHF as an endpoint in clinical trials. Differences in reported incidence are complexly related to differences in the way in which WHF is defined.
Article
Aims: To analyse the characteristics of hospitalized patients for AHF, with special attention to the clustering of morbidities. Methods and results: Clinical records of patients, admitted in Internal Medicine due to AHF, during three years, were reviewed. The characteristics of patients-episodes were registered and key indicators of performance. Multiple correspondence analysis (MCA) was used to assess the distribution of morbidities. LR models were used to study clinical variables related with death or readmission. The median age was 80y, predominantly women and with multiple morbidities. As it was expected, CVRF were the main associated comorbidities followed by respiratory diseases, CKD and chronic anaemia. In the MCA, all the CVRF clustered around the origin so they explained little of the total inertia. Male sex, young age, IHD, obesity and lung disease were more common in reduced EF whereas female, older age and thyroid disease were more common in preserved EF. The confidence ellipses for death in hospitalization or during the follow-up or for readmissions overlapped, so it was not possible to identify clusters of morbidities to predict outcomes. The main causes for AHF were infections, anaemia and RVR in AF. Nearly 16% died during the hospitalization whereas 25.6% died and 56.3% were re-hospitalized during the following year after the discharge. Previous or repeated admissions to the hospital were the best single predictors for death or readmission. Conclusions: Strategies to control infections, anaemia and AF, in the outpatient settings, might help to reduce the burden of AHF, although this remains to be proven.
Article
Aim: To provide a robust estimates of mortality risk in acute coronary syndrome (ACS) associated acute kidney injury (AKI) to inform clinical practice and policy. Methods: A meta-analysis of cohort studies evaluating outcomes of ACS and which reported AKI and AKI associated mortality. Studies were excluded if they incorporated patients not admitted through the emergency department (i.e. for elective procedures), were limited to cardiogenic shock or cardiac arrest, or relied on registry data for outcomes without further adjudication. The predictor was ACS associated AKI and outcomes early (30-day or in-hospital) mortality and late-mortality (post-hospital discharge). Results: Thirty-six studies with 37 unique cohorts comprising 100,476 patients were included. The pooled rate of ACS-associated AKI was 15.8%. In 32 cohorts reporting early mortality the crude early mortality rate was 15.0% amongst those with AKI compared with 2.0% amongst those without AKI. The pooled estimate of the relative risk of AKI-associated early mortality was 4.1 (95% Confidence Interval: 3.3 to 5.0) with high heterogeneity between studies (I(2) = 84% [61% to 88%]). When heterogeneity was accounted for mathematically using credibility ceilings, the risk of mortality was lower, but still clinically significant (3.1 (2.6 to 3.6)). In 19 cohorts reporting late mortality (1 to 10 years), the relative risk of AKI-associated mortality was 2.6 (2.0 to 3.3) with moderate heterogeneity (I(2) = 65% [35% to 88%]). Following application of credibility ceiling relative risk estimate dropped to 2.2 (1.9 to 2.6). Conclusions: ACS-associated AKI is associated with more than a three-fold increase in early mortality and more than two-fold in long-term mortality. This article is protected by copyright. All rights reserved.
Article
Heart failure (HF) is a major health-care problem and the prognosis of affected patients is poor. HF often coexists with a number of comorbidities of which declining renal function is of particular importance. A loss of glomerular filtration rate, as in acute kidney injury (AKI) or chronic kidney disease (CKD), independently predicts mortality and accelerates the overall progression of cardiovascular disease and HF. Importantly, cardiac and renal diseases interact in a complex bidirectional and interdependent manner in both acute and chronic settings. From a pathophysiological perspective, cardiac and renal diseases share a number of common pathways, including inflammatory and direct, cellular immune-mediated mechanisms; stress-mediated and (neuro)hormonal responses; metabolic and nutritional changes including bone and mineral disorder, altered haemodynamic and acid-base or fluid status; and the development of anaemia. In an effort to better understand the important crosstalk between the two organs, classifications such as the cardio-renal syndromes were developed. This classification might lead to a more precise understanding of the complex interdependent pathophysiology of cardiac and renal diseases. In light of exceptionally high mortality associated with coexisting HF and kidney disease, this Review describes important crosstalk between the heart and kidney, with a focus on HF and kidney disease in the acute and chronic settings. Underlying molecular and cellular pathomechanisms in HF, AKI and CKD are discussed in addition to current and future therapeutic approaches.
Article
Acute heart failure (AHF) is a complex syndrome characterized by worsening heart failure (HF) symptoms that requires escalation of therapy. Intrinsic cardiac abnormalities and comorbid conditions, including lung and renal disease, and sleep-disordered breathing, can contribute to the development of AHF. In this Review, we summarize and discuss the literature on the clinical evaluation and underlying pathophysiology of AHF. Important features of AHF evaluation include identification of precipitating factors to the disease, and assessment of circulatory-renal limitations associated with use of HF medications, prior HF hospitalizations, congestion and perfusion profiles, and end-organ dysfunction. The pathophysiological contributions of endothelial dysfunction, neurohormonal activation, venous congestion, and myocardial injury to the development of AHF are also discussed. These potential causative mechanisms provide a framework for clinicians to evaluate and manage patients with AHF and highlight possible future targets for therapies designed to improve clinical outcomes.