Clinical Kidney Journal, 2023, vol. 16, no.

10, 1587–1599

https:/doi.org/10.1093/ckj/sfad031
Advance Access Publication Date: 20 February 2023
CKJ Review

CKJ REVIEW

Kidney function changes in acute heart failure: a

Downloaded from https://academic.oup.com/ckj/article/16/10/1587/7049133 by guest on 26 February 2024

practical approach to interpretation and management
Laura Fuertes Kenneally1,2 , Miguel Lorenzo 3 ,
Gregorio Romero-González 4 , Marta Cobo 5,6 , Gonzalo Núñez3 ,
Jose Luis Górriz 7 , Ana Garcia Barrios1,2 , Marat Fudim8,9 , Rafael de la
Espriella3 and Julio Núñez 3,5
1
Cardiology Department, General Hospital of Alicante, Dr Balmis. Alicante, Spain, 2 Instituto de Investigación
Sanitaria y Biomédica de Alicante (ISABIAL). Alicante, Spain, 3 Cardiology Department, Hospital Clínico
Universitario de Valencia, Universitat de Valencia, INCLIVA, Valencia, Spain, 4 Nephrology Department,
University Hospital Germans Trias I Pujol, Badalona, Spain, International Renal Research Institute of Vicenza
(IRRIV), Vicenza, Italy, 5 CIBER Cardiovascular, 6 Cardiology Department, Hospital Universitario Puerta de Hierro
Majadahonda (IDIPHISA), Madrid, Spain, 7 Nephrology Department, Hospital Clínico Universitario de Valencia,
Universitat de Valencia, Valencia, Spain, 8 Cardiology Department, Duke University Medical Center. Durham,
NC, USA and 9 Duke Clinical Research Institute, Durham, NC, USA
Correspondence to: Julio Núñez; E-mail: yulnunez@gmail.com or juenuvi@uv.es

ABSTRACT
Worsening kidney function (WKF) is common in patients with acute heart failure (AHF) syndromes. Although WKF has
traditionally been associated with worse outcomes on a population level, serum creatinine concentrations vary greatly
during episodes of worsening heart failure, with substantial individual heterogeneity in terms of their clinical meaning.
Consequently, interpreting such changes within the appropriate clinical context is essential to unravel the
pathophysiology of kidney function changes and appropriately interpret their clinical meaning. This article aims to
provide a critical overview of WKF in AHF, aiming to provide physicians with some tips and tricks to appropriately
interpret kidney function changes in the context of AHF.

LAY SUMMARY
In this article we thoroughly review the literature on a debatable topic in cardiorenal medicine. We aimed to provide
physicians with some tips and tricks for interpreting kidney function changes in patients with acute heart failure
syndromes.

Keywords: decongestion, diuretic therapy, heart failure, intrarenal venous flow pattern, kidney venous congestion

Received: 29.12.2022; Editorial decision: 15.2.2023

© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA. This is an Open Access article distributed under the terms of the Creative
Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution,
and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

1587
 1588 L. F. Kenneally et al.

INTRODUCTION

For AKI criteria, if UO and SCr stage do not correspond to the same stage, patients are classified in the worse stage. Adapted from Mullens et al. Evaluation of kidney function throughout the heart failure trajectory—a position
Cr ≥3 times baseline or an increase above ≥4 mg/dl
Cr to ≥1.5 times within 7 days sustained for 24 h
Few organs in the body are as intricately linked to each other

(with an absolute increase >0.5 mg/dl) or RRT

in their function as the heart and kidneys. Chronic kidney dis-
ease (CKD) and heart failure (HF) frequently coexist and share
common risk factors [1]. Additionally, the dysfunction of one
organ can accelerate the progression of the other. In the acute
heart failure (AHF) setting, changes in kidney function are com-

RIFLE
mon [2–4]. While some of these changes merely reflect decon-
gestion or a healthy kidney’s response to decongestive therapy,
others could signify true kidney injury [5]. Distinguishing be-

Cr ≥2 times baseline
tween the two remains challenging, with crucial management
implications. Physicians are often reluctant to prescribe aggres-
sive diuretic therapy in patients with AHF and concomitant kid-

Downloaded from https://academic.oup.com/ckj/article/16/10/1587/7049133 by guest on 26 February 2024

ney impairment and usually withdraw or reduce the dose of di-
uretics and guideline-directed medical therapy in the presence
of an acute increase in serum creatinine, when in reality, some of
these patients might benefit from just the opposite. Many clini-

● ≥0.3 mg/dl increase and >25% increase from baseline

cians attribute worsening kidney function (WKF) to hypoperfu-
sion, neglecting that, in many cases, it is a proxy of an appropri-

Cr ≥3 times baseline or an increase above Cr ≥3 times baseline or an increase above ≥4 mg/dl

Cr to 1.5–1.9 times baseline over 7 days or Cr to 1.5–2 times baseline or an absolute increase
ate response to therapy or, conversely, of an insufficient diuretic

(with an absolute increase >0.5 mg/dl) or RRT

intensity [1]. Thus misinterpreting kidney function changes

Creatinine component
could promote ongoing tubular damage, inappropriate discon-
tinuation or insufficient titration of decongestive or disease-
modifying HF therapies [6–8]. The underlying mechanisms of

● ≥0.3 mg/dl increase from baseline

● ≥0.5 mg/dl increase from baseline

kidney dysfunction in patients with AHF are still not fully under-

AKIN
stood. The existing literature is difficult to interpret due to differ-

● ≥25% increase + >2.0 mg/dl

ent definitions of WKF and the heterogeneity of AHF syndromes.
In the current article, we review the terminology, pathophys-

Cr ≥2–3 times baseline

● ≥1.5 times baseline
iology and prognosis of kidney function changes in this clinical

≥0.3 mg/dl over 48 h

context. Additionally, we provide tips and tricks to interpret kid-
ney function changes in patients with AHF.
WKF

AKI

statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2020;22:584–603.
Creatinine

EPIDEMIOLOGY
CKD is one of the most prevalent comorbidities in patients with
HF, ranging from 20 to 57% in chronic HF and 30 to 67% in AHF

absolute increase > 0.3 mg/dl over 48 h

registries [2–4]. In the Heart Failure Pilot Survey, CKD was the
● >0.3 mg/dl increase from baseline

most prevalent comorbidity in patients with chronic HF (41%) [9].

It was independently related to increased mortality and HF hos-
pitalizations. In addition to prior CKD, changes in kidney func-
tion are commonly observed in hospitalized patients with AHF,
Cr ≥2–2.9 times baseline
KDIGO

ranging from 10 to 40% of patients [10, 11]. This wide variability

can be attributed, at least partly, to different parameters and cut-
off values used to define changes in kidney function (Table 1).
≥4 mg/dl or RRT
Table 1: Definition of changes in kidney function in AHF.

Cystatin C

DEFINITIONS
Changes in kidney function in patients with AHF are com-
monly defined in the literature by the terms ‘worsening kidney
<0.3 ml/kg/h for ≥24 h or anuria for ≥12 h

function’ (WKF) and ‘acute kidney injury’ (AKI). WKF has been
Cr: creatinine; RRT: renal replacement therapy.
● >5% per year decrease from baseline

broadly defined as an increase in serum creatinine (SCr) rang-

ing from ≥0.3 to 0.5 mg/dl from baseline [10, 12]. However, defi-
nitions vary greatly depending on the type of marker used [SCr,
● ≥20% decrease from baseline
● ≥25% decrease from baseline

cystatin C or estimated glomerular filtration rate (eGFR)] and the

degree of change (absolute versus relative). For instance, some
<0.5 ml/kg/h for 6–12 h

investigators use increases in SCr above a threshold (e.g. SCr

<0.5 ml/kg/h for ≥12 h

>1.5 mg/dl) to define WKF [13]. However, these definitions lack

universal consensus [6, 14]. In turn, there are three different def-
UO component

initions of AKI: the Risk, Injury, Failure, Loss, End-Stage (RIFLE),

Acute Kidney Injury Network (AKIN) and Kidney Disease: Im-
proving Global Outcomes (KDIGO) criteria [14]. Urine output (UO)
Grade 1

Grade 2

Grade 3
eGFR

is also used as a criterion to define AKI. However, only a small

number of studies in AHF have measured UO and evaluated how
 Kidney function changes in acute heart failure 1589

Downloaded from https://academic.oup.com/ckj/article/16/10/1587/7049133 by guest on 26 February 2024

Figure 1: Pathophysiology of worsening kidney function in AHF.

it correlates with SCr or eGFR changes [15]. Furthermore, if a di- lence of WKF compared with HFrEF patients [22, 23]. In a post hoc
uretic is being used as the primary treatment, the utility of as- analysis of the ESCAPE trial, there was no correlation between
sessing UO is arguable. As a result, the UO definition of AKI is WKF and cardiac index (CI; cardiac output corrected for the pa-
not routinely used in clinical practice. Table 1 summarises the tient’s body surface area) [24]. Accordingly, haemodynamic op-
different criteria used to define WKF and AKI. timization with pulmonary artery catheter-guided therapy did
not reduce the incidence of WKF compared with clinical assess-
ment. Along the same line, Mullens et al. [25], in a cohort of
PATHOPHYSIOLOGY 145 subjects with AHF, showed that the mean baseline CI was
Nowadays, AKI is recognized as a syndrome in which one or significantly higher in patients who developed WKF (2.0 ± 0.8
more mechanisms of kidney damage may be present [16]. The versus 1.8 ± 0.4 L/min/m2 ). Likewise, Hanberg et al. [26] found
prognosis depends on the underlying cause. Thus a thorough that a higher CI was paradoxically associated with worse eGFR
analysis of the pathophysiological mechanisms responsible for in a multicentre population of decompensated HF. It is impor-
kidney function changes during AHF is essential for their correct tant to note that the kidney microcirculation has autoregula-
interpretation. These complex and multifactorial mechanisms tory properties that maintain eGFR within narrow limits in re-
include both haemodynamic and non-haemodynamic factors, sponse to kidney pressure or flow fluctuations [27]. Therefore,
such as septic AKI or contrast-associated AKI [17, 18]. Fig. 1 sum- high-magnitude blood pressure drops are necessary to surpass
marises the pathophysiology of WKF in AHF. this compensatory mechanism. A post hoc analysis of the pre-
RELAX-AHF study showed that only large drops in systolic blood
pressure (usually >20 mmHg) during the first 48 hours of hos-
Haemodynamic factors pitalization predicted WKF [28]. In summary, current evidence
Kidney hypoperfusion suggests low CO might not be the primary determinant of WKF
in patients with AHF.
Classically, WKF has been attributed to kidney hypoperfusion
caused by low cardiac output (CO) or intravascular depletion sec-
Kidney venous congestion
ondary to diuretic use (deemed the ‘pre-renal aetiology’) [19]. Re-
duced CO decreases kidney perfusion, which activates compen- Recent studies suggest that an increase in central venous pres-
satory mechanisms such as the sympathetic nervous system, sure (CVP) has a more pronounced impact on eGFR than a de-
renin–angiotensin–aldosterone system (RAAS) and vasopressin crease in CO [25, 29]. Early experimental research demonstrated
secretion to preserve eGFR. These mechanisms help to main- that elevated CVP (>20 mmHg) reduced diuresis in an isolated
tain kidney perfusion in the short term by stimulating water and canine kidney [30]. Similarly, elevated intra-abdominal pressure
sodium reabsorption, but are deleterious in the long-term, pro- (IAP; >8 mmHg), found in up to 60% of hospitalized patients with
moting fibrosis, apoptosis and adverse ventricular remodelling. HF, is also associated with greater impairment of kidney func-
Persistent hypoperfusion could also lead to kidney ischaemia tion [31]. In turn, a reduction in IAP with different treatments
[20]. (diuretics, peritoneal dialysis, paracentesis or ultrafiltration) has
Several studies have recently challenged this traditional been shown to improve kidney function [32, 33]. Therefore, many
paradigm, demonstrating a lack of correlation between CO and studies support the association between high CVP and WKF,
kidney function. Indeed, only a minority of patients with HF with which seems to be superior to the effect of arterial blood pres-
reduced ejection fraction (HFrEF) present hypotension on admis- sure, CI or pulmonary capillary wedge pressure to predict WKF.
sion [4, 21]. In fact, most patients have normal or elevated blood Nonetheless, venous congestion and hypotension may act as
pressure and no evidence of hypoperfusion. Also, patients with complementary mechanisms of WKF. For example, CVP is an in-
HF and preserved ejection fraction (HFpEF) have an equal preva- dependent predictor of WKF, especially when there is low CO
 1590 L. F. Kenneally et al.

Downloaded from https://academic.oup.com/ckj/article/16/10/1587/7049133 by guest on 26 February 2024

Figure 2: Mechanisms of renal tamponade.

[25, 34]. In an animal model of kidney venous hypertension, venous Doppler (IRD) ultrasonography has emerged as a non-
only when CO was compromised did eGFR decline [35]. Overall, invasive tool to assess intrarenal venous flow (IRVF). A contin-
patients with congestion plus hypoperfusion have worse eGFR uous IRVF pattern is associated with low kidney venous pres-
and outcomes than patients with either one [36, 37]. These re- sures. Conversely, a discontinuous IRVF pattern (monophasic or
sults highlight the importance of preserving adequate perfusion biphasic) indicates elevated venous pressures and thus might
pressure during decongestive therapy. identify patients with the CN phenotype [42]. Fig. 3 shows dif-
The exact mechanisms by which increased CVP contributes ferent IRVF patterns in patients with HF. IRD could also help
to WKF are not totally elucidated, but possible explana- guide decongestive therapy, evaluating treatment response and
tions include a reduction of the net pressure gradient across identifying patients at risk for adverse outcomes [43]. IRVF pat-
the glomerulus, increased intrarenal pressure (intracapsular terns have shown stronger independent associations with ad-
or interstitial space) causing tubular compression and hy- verse outcomes than invasive haemodynamic measurements
poxia and/or increased extrarenal pressure (perirenal or intra- [43–45]. A discontinuous IRVF pattern in response to volume
abdominal space) compressing kidney veins and parenchyma expansion is associated with a reduced diuretic response and
[1]. Boorsma et al. [38] recently coined the term ‘renal tampon- a worse prognosis [43]. However, confirmation studies evalu-
ade’ to explain the compression of kidney structures that occurs ating the clinical meaning of IRVF are warranted (e.g. corre-
by the combination of increased kidney venous pressure and lating invasive measurements of kidney venous pressure with
the inability of the kidneys to expand as they are surrounded IRVF). It should be noted that a discontinuous flow pattern is not
by a rigid capsule. The mechanisms of renal tamponade are il- specific and has also been described in obstructive nephropa-
lustrated in Fig. 2. thy, diabetic nephropathy, pre-eclampsia and tricuspid regurgi-
These findings support the role of kidney congestion as a tation without right-sided HF [46–48]. Lastly, echocardiography
novel treatment target, renewing the interest in kidney decap- has demonstrated its utility in providing non-invasive measure-
sulation as a potential therapeutic strategy for patients with HF ments to identify the pathophysiological mechanisms of WKF
and kidney congestion. This technique is not new and has been in AHF. First, it can estimate the patient’s CO and subsequently
used to treat various diseases (kidney abscesses, pre-eclampsia help to diagnose a hypoperfusion state. Second, it can evaluate
and oliguria) [39]. Studies in animal models of HF or ischaemia- systemic venous congestion by estimating haemodynamic pa-
induced AKI have shown promising results [40, 41]. However, to rameters such as the CVP, systolic pulmonary artery pressure
date, there is no evidence in humans with HF. or pulmonary capillary wedge pressure and by measuring the
Contemporary studies have proposed the term ‘congestive size and collapsibility of the inferior vena cava [49]. A dilated
nephropathy’ (CN) as an independent haemodynamic pheno- inferior vena cava (defined as a diameter >2.1 cm) with <50%
type of kidney dysfunction that could be reversible with decon- collapsibility during inspiration estimates a right atrial pressure
gestion. There is no gold standard for diagnosing CN. Intrarenal of 15 mmHg [50, 51].
 Kidney function changes in acute heart failure 1591

Downloaded from https://academic.oup.com/ckj/article/16/10/1587/7049133 by guest on 26 February 2024

Figure 3: Different intrarenal venous flow patterns in patients with heart failure.

PROGNOSIS status (wet, dry, pale), baseline kidney function, the magnitude
and chronology of kidney function changes, concomitant treat-
Classically, WKF in the setting of HF has been associated with
ment and kinetics with other biomarkers (Table 2). A proposed
a longer hospital stay, higher costs and worse outcomes [3]. A
algorithm is presented in Fig. 4. This algorithm is an attempt
meta-analysis of 28 studies of patients with AFH reported that
to synthesize all available information on the subject and of-
23% of patients had WKF, which was related to an increased
fer a simplified approach for a complicated problem; however,
risk of long-term mortality [10]. Nonetheless, the authors point
we hope it will assist medical professionals in their clinical
out there was evidence of publication bias, which might over-
practice.
estimate the real relationship between WKF and prognosis. Fur-
thermore, more recent findings have revealed divergent results
[52–54]. Applying the same logic, improving kidney function (IKF)
and kidney recovery should be expected to translate into better Baseline fluid overload status
outcomes. However, IKF has also been associated with a greater High-dose diuretics are beneficial in patients with total blood
risk of mortality and HF readmissions [55]. This might be ex- volume expansion but can be harmful in patients with mild
plained by the fact that most of these patients had kidney im- fluid overload (FO) or those with volume redistribution [59, 60].
pairment before hospitalization [56]. Beldhuis et al. [57] hypothe- In this latter scenario, aggressive diuretic therapy may produce
sized that this paradoxical finding was because previous studies intravascular depletion, leading to kidney hypoperfusion [54]. In
were population-based and did not consider the interindividual contrast, in patients with overt FO, aggressive diuretic therapy
differences in kidney function. To prove their hypothesis, Beld- may improve organ function (including the kidneys) [61]. In clin-
huis et al. identified individual trajectories of kidney function ical practice, the main challenge remains to identify and opti-
during hospitalization and found similar mortality rates, ques- mally define a patient’s degree of FO [61, 62]. Núñez et al. [63]
tioning the prognostic importance of kidney function changes in sought to assess whether SCr changes induced by diuretic ther-
AHF. Overall, these heterogeneous findings could be partially ex- apy differed depending on FO status (as measured by CA125) in
plained by the discrepancy in the diagnostic criteria of WKF, the AHF. They found that patients with higher CA125 levels (greater
diversity of underlying mechanisms causing AKI and the com- FO and higher risk of CN) displayed a decrease in SCr in re-
plexity of AHF syndromes [58]. sponse to aggressive diuretic therapy, compared with patients
with low CA125 values in whom SCr increased. Along the same
TIPS AND TRICKS TO INTERPRET KIDNEY line, in 1389 patients discharged for AHF, subjects with elevated
CA125 and blood urea nitrogen levels (≥24.8 mg/dl) treated with
FUNCTION CHANGES IN AHF
high doses of loop diuretics (≥120 mg/day) had a lower risk of
Distinguishing true WKF (accompanied by underlying kidney long-term mortality compared with the rest of the population
damage) from pseudo-WKF (decongestion, which does not imply [64]. The property of this biomarker to define the intensity of di-
tubular damage or a worse prognosis) remains one of the most uretic therapy was tested in a randomized clinical trial that allo-
important challenges physicians face when evaluating patients cated 160 patients with worsening HF and kidney dysfunction at
with AHF. To aid physicians in this task, we propose taking into presentation (mean 33.7 ± 11.3 ml/min/1.73 m2 ) to a conven-
consideration circumstances/parameters such as the clinical tional diuretic strategy (clinically guided) versus CA125-guided
response to therapy and decongestion status, haemodynamic therapy (intensive in cases of high CA125 and more conservative
 1592 L. F. Kenneally et al.

Table 2: Differential diagnosis of worsening kidney function in AHF.

Characteristic True WKF Pseudo-WKF

Fluid overload Mild congestion/fluid redistribution, Severe congestion (based on a multiparametric

hypoperfusion evaluation)
Clinical course and decongestion Persistent or worsening congestion Resolution of congestion (multiparametric
evaluation)
Baseline renal function and Large increase in creatinine or decrease in GFR, Small changes in patients with normal or mildly
magnitude of changes especially in subjects with baseline renal impaired renal function
dysfunction.
Caution if increasing creatinine >50% of
baseline or >3 mg/dl and decreasing GFR >10%
of baseline if eGFR is <25 ml/min
Onset and time course ≥5 days after admission, persistent ≤4 days after admission, transient

Downloaded from https://academic.oup.com/ckj/article/16/10/1587/7049133 by guest on 26 February 2024

Aetiology Hypoperfusion, nephrotoxic agents Venous congestion, diuretic therapy, RAAS
inhibitor, ARNI, SGLT2i initiation or up-titration
Prognosis Worse Does not necessarily mean a worse prognosis if
adequate decongestion is attained

when CA125 was low) [65]. The CA125-guided therapy led to bet- post hoc analysis of the DOSE-AHF and CARESS-HF trials, only
ter kidney function at 72 hours and a statistical trend to lower half of the patients were free from signs of congestion at dis-
30-day adverse outcomes. Thus, defining the congestion pheno- charge, and they had lower rates of death and rehospitalization
type of each patient is crucial to choose the intensity of diuretic [75].
therapy and interpreting WKF.

Baseline kidney function and magnitude of creatinine

Clinical course and decongestion changes
When evaluating kidney function changes, we recommend When interpreting the clinical implications of kidney func-
considering the patient’s clinical context and risk factors for tion changes in the AHF setting, it is essential to consider the
developing AKI (pretest probability) as well as a multipara- patient’s baseline kidney function and the magnitude of the
metric evaluation of decongestion ideally based on clinical as- change. In a meta-analysis of eight studies with 18 000 patients
sessment (signs and symptoms, weight change, vital signs and with HF the odds ratio (OR) was 1.03 (not significant) when
urinary output), biomarkers (haematocrit/haemoglobin or natri- the SCr rose by 0.2–0.3 mg/dl or the eGFR decreased by <5–
uretic changes) and imaging techniques such as ultrasonogra- 10 ml/min/1.73 m2 . Conversely, the OR rose to 3.22 when
phy [66]. WKF in patients with adequate urinary output and clin- the SCr increased >0.5 mg/dl or the eGFR decreased by
ical improvement does not necessarily portend a worse progno- >15 ml/min/1.73 m2 [78]. These results suggest that kidney func-
sis [5, 54, 67–73]. Numerous studies have shown that WKF re- tion changes should be viewed as a continuous variable consid-
sults in a worse prognosis when accompanied by residual con- ering the magnitude of changes. This complicates efforts to find
gestion [5, 54, 69–73]. For instance, Wettersten et al. [69] and Mc- a clinically meaningful elevation of SCr to define WKF [12, 58].
Callum et al. [73] demonstrated that WKF during AHF hospi- Furthermore, the clinical importance of the magnitude of
talization was associated with a higher risk of mortality only kidney function changes depends on the patient’s baseline kid-
when N-terminal pro b-type natriuretic peptide (NT-proBNP) lev- ney function. Sánchez-Serna et al. [56] found that the presence
els did not decrease with diuretic therapy. Metra et al. [5] also ob- of WKF at admission was associated with a higher risk of death
served that, in the absence of congestion, an increase in serum and HF readmissions, even in the mild stages of AKI. In a study
SCr levels had no prognostic value. Similarly, an analysis of the of 705 patients with AHF, the risk of 1-year mortality varied de-
ESCAPE trial showed that haemoconcentration (a surrogate of pending on the presence of kidney insufficiency on admission.
decongestion) was associated with WKF and better outcomes In patients with impaired kidney function on admission (SCr
[54]. Emmens et al. [72] investigated the interaction between di- >1.4 mg/dl), even small increases in SCr levels were indepen-
uretic response and WKF on clinical outcomes in patients with dently associated with a greater risk of 1-year mortality. In con-
AHF using the PROTECT and RELAX-AHF-2 cohorts. They con- trast, in patients with normal or mildly impaired kidney function
cluded that WKF was associated with a higher risk of cardiovas- on admission, only important SCr increases (>1 mg) were re-
cular death or hospitalization except for patients with a good di- lated to worse outcomes [79]. Unfortunately, there is no accepted
uretic response. Comparable results were observed with IKF [70]. method for establishing baseline kidney function due to the in-
In summary, it seems like decongestion, and not changes herent fluctuations in SCr. The Acute Disease Quality Initiative
in kidney function, is the key determinant of prognosis in AHF (ADQI) work group suggests that if one or more premorbid SCr
patients. Indeed, cumulative evidence endorses that surrogates values are available, the mean SCr measured 7–365 days before
of decongestion such as NT-proBNP, haemoconcentration and admission is the value that best represents a patient’s baseline
weight loss outweigh WKF/IKF as a prognostic parameter kidney function [80].
[54, 69, 73]. In fact, residual congestion at discharge is one of the Based on these studies, we postulate that small changes
main predictors of readmission, and adequate decongestion is in patients without established kidney failure may represent
often not achieved during hospitalization [74–77]. In a recent haemoconcentration rather than kidney damage. In contrast,
 Kidney function changes in acute heart failure 1593

Downloaded from https://academic.oup.com/ckj/article/16/10/1587/7049133 by guest on 26 February 2024

Figure 4: Approach to worsening kidney function in AHF.

extreme changes in SCr, especially when moving in the range pitalization for AHF) was independently linked to higher mor-
of severe kidney dysfunction and/or accompanied by other tality and blood urea nitrogen levels, whereas early-onset AKI
metabolic alterations (e.g. hyperkalaemia or acidosis) should (≤4 days after admission) was not related to mortality but had
make physicians suspect true WKF. In light of these findings, higher SCr levels at admission and a greater decrease in body
the cut-off point for WKF has evolved from an SCr increase weight. These results suggest different mechanisms may play a
≥0.3 mg/dl [71] to a more demanding definition such as dou- role depending on the time course during hospitalization. Acute
bling of SCr levels from baseline or a ≥50% sustained decrease declines in kidney function are usually the result of haemody-
in eGFR in the ADVOR trial or sustained reduction of ≥40% in the namic alterations present before hospitalization and/or decon-
EMPULSE trial [81, 82]. gestion or initiation/up-titration of neurohumoral blockade. In
turn, later changes may be brought on by severe haemodynamic
abnormalities, as hinted by a higher blood urea nitrogen level (a
surrogate of neurohormonal activation). Timing is also crucial
Onset and time course
when selecting the baseline kidney function value used to define
In relation to the onset of kidney function changes, Takaya et al. WKF. Sánchez-Serna et al. [56], in an observational, single-centre
[83] reported that late-onset AKI (occurring ≥5 days after hos- study of 458 patients hospitalized for AHF, investigated the
 1594 L. F. Kenneally et al.

occurrence of AKI using two different definitions depending on kidney stress’ [100] suggest that tubular injury is already present
the SCr value used as baseline: the most recent outpatient mea- before SCr increases. In an attempt to overcome the shortcom-
surement prior to admission or the first at admission. The preva- ings of traditional biomarkers, different markers have emerged
lence of AKI almost doubled, from 20.1% to 33.8%, when pre- [101–111]. Neutrophil gelatinase-associated lipocalin (NGAL) is
hospital kidney function was used as a reference. Regardless of rapidly released (within 2 hours) [101] in response to AKI and
the definition, AKI was associated with a longer hospital stay was strongly related to adverse outcomes 30 days after discharge
and greater in-hospital mortality. However, only AKI based on in AHF patients in the GALLANT trial [102]. However, these re-
pre-hospital kidney function was associated with adverse clini- sults were not supported by the AKINESIS trial that concluded
cal events after discharge. As for the progression of kidney func- NGAL was not superior to SCr for predicting WKF, use of kid-
tion changes, transient WKF due to intensive diuretic treatment ney replacement therapies and adverse outcomes [103]. Still,
may not be associated with a worse prognosis, in contrast to per- two of the most promising biomarkers are urinary insulin-like
sistent WKF [52]. growth factor-binding protein (IGFBP-7) and tissue inhibitor of
metalloproteinase (TIMP-2), which have proven their utility for
early detection of AKI even in patients with chronic conditions
The role of non-traditional diuretic agents

Downloaded from https://academic.oup.com/ckj/article/16/10/1587/7049133 by guest on 26 February 2024

(diabetes, HF and CKD) [107–109]. TIMP-2 and IGFBP7 are pro-
A careful review of the patient’s prior medications and those teins that cause cell-cycle arrest of tubular cells in response
initiated during hospitalization is imperative. Certain nephro- to injury, acting as a protective mechanism to allow them to
toxic agents can cause WKF [84], and HF patients may be more shut down and repair the damage [107]. The US Food and Drug
prone to develop tubular injury after exposure to iodine con- Administration approved the immunoassay test NephroCheck
trast, antibiotics (e.g. aminoglycosides, vancomycin, etc.) or non- (Astute Medical, San Diego, CA, USA) in 2014 for early detection
steroidal anti-inflammatory drugs [85–88]. Similar to the in- of moderate–severe AKI in critically ill patients, which measures
crease in SCr that can occur after diuretic therapy, initiation the urinary concentrations of TIMP-2 and IGFBP7 and combines
of RAAS inhibitors, angiotensin receptor–neprilysin inhibitors them into a formula that is the product of their concentrations
(ARNIs) or sodium–glucose cotransporter-2 inhibitors (SGLT2is) {[(TIMP-2) × (IGFBP-7)]/1000, in (ng/ml)2 /1000)}. A high sensitivity
is usually accompanied by an initial and transient decrease in cut-off of 0.3 has been proposed [110]. In critically ill patients,
eGFR that is not associated with worse outcomes in the long TIMP-2 and IGFBP7 together showed an area under the curve
term. In the EMPA-RESPONSE-AHF trial, the authors found an (AUC) of 0.80, which was significantly superior (P < .002) to other
early decline in eGFR of 8 ml/min/1.73 m2 within 24 hours of biomarkers such as NGAL or kidney injury molecule-1 for pre-
initiation of SGLT2i in AHF patients compared with placebo, dicting AKI [108]. With the routine adoption of these biomark-
which attenuated 30 days after admission. These findings were ers, the ADQI group suggests a new definition of AKI based on
consistent with a post hoc analysis of the EMPULSE trial, in phenotypes regarding functional and damage criteria, in which
which empagliflozin caused an initial decrease in eGFR of some patients will have elevated SCr with no increase in dam-
2 ml/min/1.73 m2 at day 15 compared with placebo (P = .08), age biomarkers (e.g. initiation of SGLT2i or decongestive therapy)
having resolved by day 90 (mean difference 0.9 ml/min/1.73 m2 ; and other patients will have elevated damage biomarkers with-
P = .57) [82]. It is likely that this early decrease in kidney func- out increased SCr (acute kidney stress) and a higher risk of de-
tion is followed by a lower slope of eGFR decline and HF re- veloping AKI [111].
hospitalizations as observed in chronic HF studies with SGLT2i Lastly, we must not undermine the utility of older and widely
[89–91]. In the PARADIGM-HF trial, patients treated with sacubi- available biomarkers to interpret kidney function changes and
tril/valsartan had a slower decline in kidney function despite a guide decongestion, such as haemoconcentration and UACR. As
greater increase in the urinary albumin:creatinine ratio (UACR) mentioned before, haemoconcentration represents an inexpen-
compared with the enalapril group [92]. In the AHF setting of sive and easily accessible surrogate of decongestion and is asso-
the PIONEER trial, however, there was no difference regarding ciated with lower mortality [112, 113]. A possible goal could be to
WKF between the sacubitril/valsartan group and the enalapril achieve late and persistent haemoconcentration (>4 days after
group [relative risk 0.93% (95% confidence interval 0.67–1.28)] admission) that probably represents adequate intravascular fill-
[93]. These findings suggest that WKF could be a manifestation ing. Nonetheless, haematocrit changes are often small and non-
of the agent’s mechanism of action (efferent arteriolar vasocon- specific [112]. In contrast, albuminuria has recently emerged as
striction with RAAS inhibitors or reduced glomerular hyperfiltra- a risk marker in HF. Boorsma et al. [114] measured UACR in two
tion with SGLT2i). As a result, the 2021 European HF guidelines cohorts of patients from the BIOSTAT-CHF study. Albuminuria
consider an increase in SCr of <50% above baseline (as long as it was present in 40% of patients and was independently associ-
is <3 mg/dl or 266 μmol/L) or a decrease in eGFR of <10% from ated with an increased risk of mortality and HF hospitalization
baseline (as long as eGFR is >25 ml/min/1.73 m2 ) as acceptable (P < .001). Moreover, UACR was correlated with biomarkers of
and expected changes after initiation of RAAS inhibitors, ARNIs congestion [NT-proBNP, biologically active adrenomedullin and
or SGLT2is [6]. CA125 (P < .0001)], independent of the EF, even after adjusting
for several kidney markers, including NGAL [114].

OTHER RENAL BIOMARKERS

CONCLUSION
The evolving conceptual model of AKI included searching for
new biomarkers to better predict AKI [94, 95]. Although SCr is a In this review we have debunked two old paradigms. First, the
criterion for AKI, its reliability is limited because it is both filtered main driver of worsening kidney function in AHF is not hypoper-
by the glomerulus and secreted by the tubules, and numerous fusion, but venous congestion. Second, worsening kidney func-
factors influence its values [96]. Also, SCr elevation is a late find- tion does not necessarily entail a worse prognosis. In order to
ing in AKI. SCr concentrations may not change until there is a correctly interpret kidney function changes in AHF, we must
loss of up to 50% of eGFR and the damage is established [97]. Con- consider the patient’s clinical context, a multiparametric assess-
cepts such as ‘renal angina’ [98], ‘subclinical AKI’ [99] and ‘acute ment of initial fluid status and decongestion status. Additionally,
 Kidney function changes in acute heart failure 1595

we should account for baseline kidney function, magnitude, tim- heart failure: developed by the Task Force for the diagno-
ing and duration of changes. Small and transient decreases in sis and treatment of acute and chronic heart failure of the
kidney function during aggressive diuretic treatment, especially European Society of Cardiology (ESC) with the special con-
in patients with overt fluid overload (congestive nephropathy tribution of the Heart Failure Association (HFA) of the ESC.
phenotype) are not associated with worse prognosis if accompa- Eur Heart J 2021;42:3599–726. https://pubmed.ncbi.nlm.nih.
nied by adequate decongestion. Therefore, diuretic therapy and gov/34447992/
disease-modifying heart failure treatments should not be dis- 7. Beltrami M, Milli M, Dei LL et al. The treatment of heart
continued in light of minor kidney function changes. Instead, failure in patients with chronic kidney disease: doubts and
the focus should be centred on achieving decongestion instead new developments from the last ESC guidelines. J Clin Med
of transient changes in kidney function during therapy. 2022;11:2243. https://doi.org/10.3390/jcm11082243
8. Gilstrap LG, Stevenson LW, Small R et al. Reasons for
guideline nonadherence at heart failure discharge. J Am
FUNDING Heart Assoc 2018;7:e008789. https://doi.org/10.1161/JAHA.
This work was supported by grants from FIS PI20/00392 and 118.008789

Downloaded from https://academic.oup.com/ckj/article/16/10/1587/7049133 by guest on 26 February 2024

CIBER Cardiovascular (grant 16/11/00420). 9. van Deursen VM, Urso R, Laroche C et al. Co-morbidities
in patients with heart failure: an analysis of the European
Heart Failure Pilot Survey. Eur J Heart Fail 2014;16:103–11.
AUTHORS’ CONTRIBUTIONS https://doi.org/10.1002/ejhf.30
10. Damman K, Valente MA, Voors AA et al. Renal impair-
L.F.K. and M.L. contributed equally to this work. All authors have
ment, worsening renal function, and outcome in patients
participated in the work and have reviewed and agree with the
with heart failure: an updated meta-analysis. Eur Heart J
content of the article.
2014;35:455–69. https://doi.org/10.1093/eurheartj/eht386
11. Butler J, Chirovsky D, Phatak H et al. Renal function, health
outcomes, and resource utilization in acute heart failure.
DATA AVAILABILITY STATEMENT
Circ Heart Fail 2010;3:726–45. https://pubmed.ncbi.nlm.nih.
The data underlying this article will be shared upon reasonable gov/21081740/
request to the corresponding author. 12. Gottlieb SS, Abraham W, Butler J et al. The prognostic im-
portance of different definitions of worsening renal func-
tion in congestive heart failure. J Card Fail 2002;8:136–41.
CONFLICT OF INTEREST STATEMENT https://doi.org/10.1054/jcaf.2002.125289
J.N. is member of the CKJ editorial board. The other authors 13. Damman K, Tang WH, Testani JM et al. Terminology and
declare no conflicts of interest. definition of changes renal function in heart failure. Eur
Heart J 2014;35:3413–6. https://doi.org/10.1093/eurheartj/
ehu320
14. Khwaja A. KDIGO clinical practice guidelines for acute kid-
REFERENCES ney injury. Nephron Clin Pract 2012;120:c179–84. https://doi.
1. Núñez J, Miñana G, Santas E et al. Cardiorenal syndrome org/10.1159/000339789
in acute heart failure: revisiting paradigms. Rev Esp Cardiol 15. Damman K, Tang WHW, Testani JM et al. Terminology and
(Engl Ed) 2015;68:426–35. https://pubmed.ncbi.nlm.nih.gov/ definition of changes renal function in heart failure. Eur
25758162/ Heart J 2014;35:3413–6. https://doi.org/10.1093/eurheartj/
2. Heywood JT, Fonarow GC, Costanzo MR et al. High preva- ehu320
lence of renal dysfunction and its impact on outcome in 16. Ronco C, Bellomo R, Kellum JA. Acute kidney injury. Lancet
118,465 patients hospitalized with acute decompensated 2019;394:1949–64. https://doi.org/10.1016/S0140-6736(19)
heart failure: a report from the ADHERE database. J Card 32563-2
Fail 2007;13:422–30. https://doi.org/10.1016/j.cardfail.2007. 17. Peerapornratana S, Manrique-Caballero CL, Gómez H et al.
03.011 Acute kidney injury from sepsis: current concepts, epi-
3. Cleland JGF, Carubelli V, Castiello T et al. Renal dys- demiology, pathophysiology, prevention and treatment.
function in acute and chronic heart failure: prevalence, Kidney Int 2019;96:1083–99. https://doi.org/10.1016/j.kint.
incidence and prognosis. Heart Fail Rev 2012;17:133–49. 2019.05.026
https://doi.org/10.1007/s10741-012-9306-2 18. Mehran R, Dangas GD, Weisbord SD. Contrast-associated
4. Adams KF, Jr, Fonarow GC, Emerman CL et al. Characteris- acute kidney injury. N Engl J Med 2019;380:2146–55.
tics and outcomes of patients hospitalized for heart failure https://pubmed.ncbi.nlm.nih.gov/31141635/
in the United States: rationale, design, and preliminary ob- 19. Forman DE, Butler J, Wang Y et al. Incidence, predictors at
servations from the first 100,000 cases in the Acute Decom- admission, and impact of worsening renal function among
pensated Heart Failure National Registry (ADHERE). Am patients hospitalized with heart failure. J Am Coll Cardiol
Heart J 2005;149:209–16. https://doi.org/10.1016/j.ahj.2004. 2004;43:61–7. https://doi.org/10.1016/j.jacc.2003.07.031
08.005 20. Bock JS, Gottlieb SS. Cardiorenal syndrome: new per-
5. Metra M, Davison B, Bettari L et al. Is worsening renal func- spectives. Circulation 2010;121:2592–600. https://doi.org/10.
tion an ominous prognostic sign in patients with acute 1161/CIRCULATIONAHA.109.886473
heart failure? The role of congestion and its interaction 21. Núñez J, Núñez E, Fonarow GC et al. Differential prognos-
with renal function. Circ Heart Fail 2012;5:54–62. https://doi. tic effect of systolic blood pressure on mortality accord-
org/10.1161/CIRCHEARTFAILURE.111.963413 ing to left-ventricular function in patients with acute heart
6. McDonagh TA, Metra M, Adamo M et al. 2021 ESC guide- failure. Eur J Heart Fail 2010;12:38–44. https://pubmed.ncbi.
lines for the diagnosis and treatment of acute and chronic nlm.nih.gov/20023043/
 1596 L. F. Kenneally et al.

22. Yancy CW, Lopatin M, Stevenson LW et al. Clinical pre- classification on in-hospital and long-term outcomes; in-
sentation, management, and in-hospital outcomes of pa- sights from the ESC-EORP-HFA Heart Failure Long-Term
tients admitted with acute decompensated heart failure Registry. Eur J Heart Fail 2019;21:1338–52. https://doi.org/10.
with preserved systolic function: a report from the Acute 1002/ejhf.1492
Decompensated Heart Failure National Registry (ADHERE) 37. Damman K, Navis G, Smilde TD et al. Decreased cardiac out-
Database. J Am Coll Cardiol 2006;47:76–84. https://doi.org/10. put, venous congestion and the association with renal im-
1016/j.jacc.2005.09.022 pairment in patients with cardiac dysfunction. Eur J Heart
23. Verhaert D, Mullens W, Borowski A et al. Right ventric- Fail 2007;9:872–8. https://doi.org/10.1016/j.ejheart.2007.05.
ular response to intensive medical therapy in advanced 010
decompensated heart failure. Circ Heart Fail 2010;3:340–6. 38. Boorsma EM, ter Maaten, JM, Voors AA et al. Renal com-
https://doi.org/10.1161/CIRCHEARTFAILURE.109.900134 pression in heart failure: the renal tamponade hypothesis.
24. Nohria A, Hasselblad V, Stebbins A et al. Cardiorenal in- JACC Heart Fail 2022;10:175–83. https://pubmed.ncbi.nlm.
teractions: insights from the ESCAPE trial. J Am Coll Cardiol nih.gov/35241245/
2008;51:1268–74. https://doi.org/10.1016/j.jacc.2007.08.072 39. Fairchild DS. Decapsulation of the kidney. JAMA

Downloaded from https://academic.oup.com/ckj/article/16/10/1587/7049133 by guest on 26 February 2024

25. Mullens W, Abrahams Z, Francis GS et al. Importance 1912;LIX:2234–7. https://doi.org/10.1001/jama.1912.04270
of venous congestion for worsening of renal function in 140038012
advanced decompensated heart failure. J Am Coll Cardiol 40. Shimada S, Hirose T, Takahashi C et al. Pathophysiological
2009;53:589–96. https://doi.org/10.1016/j.jacc.2008.05.068 and molecular mechanisms involved in renal congestion
26. Hanberg JS, Sury K, Wilson FP et al. Reduced cardiac index in a novel rat model. Sci Rep 2018;8:16808. https://doi.org/
is not the dominant driver of renal dysfunction in heart 10.1038/s41598-018-35162-4
failure. J Am Coll Cardiol 2016;67:2199–208. https://doi.org/ 41. Cruces P, Lillo P, Salas C et al. Renal decapsulation prevents
10.1016/j.jacc.2016.02.058 intrinsic renal compartment syndrome in ischemia-
27. Mullens W, Verbrugge FH, Nijst P et al. Renal sodium avidity reperfusion–induced acute kidney injury: a physio-
in heart failure: from pathophysiology to treatment strate- logic approach. Crit Care Med 2018;46:216–22. https://
gies. Eur Heart J 2017;38:1872–82. https://doi.org/10.1093/ journals.lww.com/ccmjournal/Abstract/2018/02000/
eurheartj/ehx035 Renal_Decapsulation_Prevents_Intrinsic_Renal.6.aspx
28. Voors AA, Davison BA, Felker GM et al. Early drop in 42. Iida N, Seo Y, Sai S et al. Clinical implications of intrarenal
systolic blood pressure and worsening renal function in hemodynamic evaluation by Doppler ultrasonography in
acute heart failure: renal results of Pre-RELAX-AHF. Eur J heart failure. JACC Heart Fail 2016;4:674–82. https://doi.org/
Heart Fail 2011;13:961–7. https://pubmed.ncbi.nlm.nih.gov/ 10.1016/j.jchf.2016.03.016
21622980/ 43. Nijst P, Martens P, Dupont M et al. Intrarenal Flow alter-
29. Damman K, van Deursen VM, Navis G et al. Increased cen- ations during transition from euvolemia to intravascular
tral venous pressure is associated with impaired renal volume expansion in heart failure patients. JACC Heart Fail
function and mortality in a broad spectrum of patients 2017;5:672–81. https://doi.org/10.1016/j.jchf.2017.05.006
with cardiovascular disease. J Am Coll Cardiol 2009;53:582–8. 44. Husain-Syed F, Birk HW, Ronco C et al. Doppler-derived
https://doi.org/10.1016/j.jacc.2008.08.080 renal venous stasis index in the prognosis of right heart
30. Winton FR. The influence of venous pressure on the iso- failure. J Am Heart Assoc 2019;8:e013584. https://doi.org/10.
lated mammalian kidney. J Physiol 1931;72:49–61. https:// 1161/JAHA.119.013584
pubmed.ncbi.nlm.nih.gov/16994199/ 45. Núñez-Marín G, de la Espriella R, Santas E et al. CA125 but
31. Mullens W, Abrahams Z, Skouri HN et al. Elevated intra- not NT-proBNP predicts the presence of a congestive in-
abdominal pressure in acute decompensated heart fail- trarenal venous flow in patients with acute heart failure.
ure: a potential contributor to worsening renal function? Eur Heart J Acute Cardiovasc Care 2021;10:475–83. https://
J Am Coll Cardiol 2008;51:300–6. https://doi.org/10.1016/j. doi.org/10.1093/ehjacc/zuab022
jacc.2007.09.043 46. Bateman GA, Cuganesan R. Renal vein Doppler sonogra-
32. Mullens W, Abrahams Z, Francis GS et al. Prompt re- phy of obstructive uropathy. Am J Roentgenol 2002;178:921–
duction in intra-abdominal pressure following large- 5. https://doi.org/10.2214/ajr.178.4.1780921
volume mechanical fluid removal improves renal insuffi- 47. Vadana BMK, Pasumarthy A, Penumalli N et al. Renal ve-
ciency in refractory decompensated heart failure. J Card nous Doppler study in obstructive uropathy. J Clin Di-
Fail 2008;14:508–14. https://doi.org/10.1016/j.cardfail.2008. agn Res 2015;9:TC13–5. https://pubmed.ncbi.nlm.nih.gov/
02.010 26675709/
33. Lu R, Muciño-Bermejo MJ, Ribeiro LC et al. Peritoneal 48. Bateman GA, Giles W, England SL. Renal venous
dialysis in patients with refractory congestive heart fail- Doppler sonography in preeclampsia. J Ultrasound Med
ure: a systematic review. Cardiorenal Med 2015;5:145–56. 2004;23:1607–11. https://doi.org/10.7863/jum.2004.23.12.
https://doi.org/10.1159/000380915 1607
34. Uthoff H, Breidthardt T, Klima T et al. Central venous pres- 49. Cortesi C, Ibrahim M, Rivera FC et al. Cardiorenal syn-
sure and impaired renal function in patients with acute drome, hemodynamics, and noninvasive evaluation.
heart failure. Eur J Heart Fail 2011;13:432–9. https://pubmed. 2017;9:1179559X17742376. https://journals.sagepub.com/
ncbi.nlm.nih.gov/21097472/ doi/10.1177/1179559X17742376
35. Priebe HJ, Heimann JC, Hedley-Whyte J. Effects of renal and 50. Rudski LG, Lai WW, Afilalo J et al. Guidelines for the
hepatic venous congestion on renal function in the pres- echocardiographic assessment of the right heart in adults:
ence of low and normal cardiac output in dogs. Circ Res a report from the American Society of Echocardiography:
1980;47:883–90. https://doi.org/10.1161/01.RES.47.6.883 endorsed by the European Association of Echocardiogra-
36. Chioncel O, Mebazaa A, Maggioni AP et al. Acute heart fail- phy, a registered branch of the European Society of Cardi-
ure congestion and perfusion status - impact of the clinical ology, and the Canadian Society of Echocardiography. J Am
 Kidney function changes in acute heart failure 1597

Soc Echocardiogr 2010;23:685–713. https://pubmed.ncbi.nlm. 64. Núñez J, Núñez E, Miñana G et al. Differential mortal-
nih.gov/20620859/ ity association of loop diuretic dosage according to blood
51. Lee H-F, Hsu L-A, Chang C-J et al. Prognostic significance urea nitrogen and carbohydrate antigen 125 following a
of dilated inferior vena cava in advanced decompensated hospitalization for acute heart failure. Eur J Heart Fail
heart failure. Int J Cardiovasc Imaging 2014;30:1289–95. https: 2012;14:974–84. https://doi.org/10.1093/eurjhf/hfs090
//doi.org/10.1007/s10554-014-0468-y 65. Núñez J, Llàcer P, García-Blas S et al. CA125-guided diuretic
52. Aronson D, Burger AJ. The relationship between tran- treatment versus usual care in patients with acute heart
sient and persistent worsening renal function and mor- failure and renal dysfunction. Am J Med 2020;133:370–80.e4.
tality in patients with acute decompensated heart failure. https://doi.org/10.1016/j.amjmed.2019.07.041
J Card Fail 2010;16:541–7. https://doi.org/10.1016/j.cardfail. 66. Núñez J, Núñez E, Miñana G et al. Worsening renal function
2010.02.001 in acute decompensated heart failure: the puzzle is still
53. Cowie MR, Komajda M, Murray-Thomas T et al. Prevalence incomplete. JACC Heart Fail 2016;4:232–3. https://pubmed.
and impact of worsening renal function in patients hos- ncbi.nlm.nih.gov/26746376/
pitalized with decompensated heart failure: results of the 67. Ahmad T, Jackson K, Rao VS et al. Worsening renal

Downloaded from https://academic.oup.com/ckj/article/16/10/1587/7049133 by guest on 26 February 2024

Prospective Outcomes Study in Heart Failure (POSH). Eur function in patients with acute heart failure undergo-
Heart J 2006;27:1216–22. https://doi.org/10.1093/eurheartj/ ing aggressive diuresis is not associated with tubular in-
ehi859 jury. Circulation 2018;137:2016–28. https://doi.org/10.1161/
54. Testani JM, Chen J, McCauley BD et al. Potential effects CIRCULATIONAHA.117.030112
of aggressive decongestion during the treatment of de- 68. Brisco MA, Zile MR, Hanberg JS et al. Relevance of changes
compensated heart failure on renal function and sur- in serum creatinine during a heart failure trial of decon-
vival. Circulation 2010;122:265–72. https://doi.org/10.1161/ gestive strategies: insights from the DOSE Trial. J Card
CIRCULATIONAHA.109.933275 Fail 2016;22:753–60. https://doi.org/10.1016/j.cardfail.2016.
55. Testani JM, McCauley BD, Chen J et al. Clinical character- 06.423
istics and outcomes of patients with improvement in re- 69. Wettersten N, Horiuchi Y, van Veldhuisen DJ et al. B-
nal function during the treatment of decompensated heart type natriuretic peptide trend predicts clinical signifi-
failure. J Card Fail 2011;17:993–1000. https://doi.org/10.1016/ cance of worsening renal function in acute heart fail-
j.cardfail.2011.08.009 ure. Eur J Heart Fail 2019;21:1553–60. https://doi.org/10.1002/
56. Sanchez-Serna J, Hernandez-Vicente A, Garrido-Bravo IP ejhf.1627
et al. Impact of pre-hospital renal function on the detection 70. Wettersten N, Horiuchi Y, van Veldhuisen DJ et al. Decon-
of acute kidney injury in acute decompensated heart fail- gestion discriminates risk for one-year mortality in pa-
ure. Eur J Intern Med 2020;77:66–72. https://doi.org/10.1016/ tients with improving renal function in acute heart fail-
j.ejim.2020.02.028 ure. Eur J Heart Fail 2021;23:1122–30. https://doi.org/10.1002/
57. Beldhuis IE, Streng KW, van der Meer P et al. Trajectories ejhf.2179
of changes in renal function in patients with acute heart 71. Felker GM, Lee KL, Bull DA et al. Diuretic strategies in
failure. J Card Fail 2019;25:866–74. https://doi.org/10.1016/j. patients with acute decompensated heart failure. N Engl
cardfail.2019.07.004 J Med 2011;364:797–805. https://pubmed.ncbi.nlm.nih.gov/
58. Smith GL, Vaccarino V, Kosiborod M et al. Worsening renal 21366472/
function: what is a clinically meaningful change in creati- 72. Emmens JE, ter Maaten JM, Matsue Y et al. Worsening renal
nine during hospitalization with heart failure? J Card Fail function in acute heart failure in the context of diuretic
2003;9:13–25. https://doi.org/10.1054/jcaf.2003.3 response. Eur J Heart Fail 2022;24:365–74. https://pubmed.
59. Núñez J, Llàcer P, Núñez E et al. Antigen carbohydrate ncbi.nlm.nih.gov/34786794/
125 and creatinine on admission for prediction of re- 73. McCallum W, Tighiouart H, Kiernan MS et al. Relation of
nal function response following loop diuretic administra- kidney function decline and NT-proBNP with risk of mor-
tion in acute heart failure. Int J Cardiol 2014;174:516–23. tality and readmission in acute decompensated heart fail-
https://doi.org/10.1016/j.ijcard.2014.04.113 ure. Am J Med 2020;133:115–122.e2. https://doi.org/10.1016/
60. Damman K, Ng Kam Chuen MJ, MacFadyen RJ et al. Volume j.amjmed.2019.05.047
status and diuretic therapy in systolic heart failure and the 74. Ambrosy AP, Pang PS, Khan S et al. Clinical course and
detection of early abnormalities in renal and tubular func- predictive value of congestion during hospitalization in
tion. J Am Coll Cardiol 2011;57:2233–41. https://doi.org/10. patients admitted for worsening signs and symptoms of
1016/j.jacc.2010.10.065 heart failure with reduced ejection fraction: findings from
61. de la Espriella R, Cobo M, Santas E et al. Assessment of fill- the EVEREST trial. Eur Heart J 2013;34:835–43. https://doi.
ing pressures and fluid overload in heart failure: an up- org/10.1093/eurheartj/ehs444
dated perspective. Rev Esp Cardiol (English Ed) 2023;76:47–57. 75. Lala A, McNulty SE, Mentz RJ et al. Relief and recurrence
https://pubmed.ncbi.nlm.nih.gov/35934293/ of congestion during and after hospitalization for acute
62. Yaranov DM, Jefferies JL, Silver MA et al. Discordance of heart failure: insights from Diuretic Optimization Strategy
pressure and volume: potential implications for pressure- Evaluation in Acute Decompensated Heart Failure (DOSE-
guided remote monitoring in heart failure. J Card Fail AHF) and Cardiorenal Rescue Study in Acute Decompen-
2022;28:870–2. https://doi.org/10.1016/j.cardfail.2022.02. sated Heart Failure (CARESS-HF). Circ Heart Fail 2015;8:741–
003 8. https://pubmed.ncbi.nlm.nih.gov/26041600/
63. Núñez J, Llàcer P, Núñez E et al. Antigen carbohydrate 76. Rubio-Gracia J, Demissei BG, ter Maaten JM et al. Preva-
125 and creatinine on admission for prediction of renal lence, predictors and clinical outcome of residual con-
function response following loop diuretic administration gestion in acute decompensated heart failure. Int J Car-
in acute heart failure. Int J Cardiol 2014;174:516–23. https:// diol 2018;258:185–91. https://doi.org/10.1016/j.ijcard.2018.
doi.org/10.1016/j.ijcard.2014.04.113 01.067
 1598 L. F. Kenneally et al.

77. Mullens W, Damman K, Harjola VP et al. The use of di- 92. Damman K, Gori M, Claggett B et al. Renal effects and as-
uretics in heart failure with congestion – a position state- sociated outcomes during angiotensin-neprilysin inhibi-
ment from the Heart Failure Association of the Euro- tion in heart failure. JACC Heart Fail 2018;6:489–98. https://
pean Society of Cardiology. Eur J Heart Fail 2019;21:137–55. doi.org/10.1016/j.jchf.2018.02.004
https://doi.org/10.1002/ejhf.1369 93. Velazquez EJ, Morrow DA, DeVore AD et al. Angiotensin–
78. Damman K, Navis G, Voors AA et al. Worsening renal func- neprilysin inhibition in acute decompensated heart fail-
tion and prognosis in heart failure: systematic review and ure. N Engl J Med 2018;380:539–48. https://pubmed.ncbi.
meta-analysis. J Card Fail 2007;13:599–608. https://doi.org/ nlm.nih.gov/30415601/
10.1016/j.cardfail.2007.04.008 94. Ronco C, Rizo-Topete L, Serrano-Soto M et al. Pro: preven-
79. Núñez J, Garcia S, Núñez E et al. Early serum creatinine tion of acute kidney injury: time for teamwork and new
changes and outcomes in patients admitted for acute biomarkers. Nephrol Dial Transplant 2017;32:408–13. https://
heart failure: the cardio-renal syndrome revisited. Eur doi.org/10.1093/ndt/gfx016
Heart J Acute Cardiovasc Care 2017;6:430–40. https://doi.org/ 95. Vaara ST, Bhatraju PK, Stanski NL et al. Subphenotypes
10.1177/2048872614540094 in acute kidney injury: a narrative review. Crit Care

Downloaded from https://academic.oup.com/ckj/article/16/10/1587/7049133 by guest on 26 February 2024

80. Chawla LS, Bellomo R, Bihorac A et al. Acute kidney disease 2022;26:251. https://doi.org/10.1186/s13054-022-04121-x
and renal recovery: consensus report of the Acute Disease 96. Valente MAE, Hillege HL, Navis G et al. The Chronic Kidney
Quality Initiative (ADQI) 16 Workgroup. Nat Rev Nephrol Disease Epidemiology Collaboration equation outperforms
2017;13:241–57. https://doi.org/10.1038/nrneph.2017.2 the Modification of Diet in Renal Disease equation for esti-
81. Mullens W, Dauw J, Martens P et al. Acetazolamide in mating glomerular filtration rate in chronic systolic heart
acute decompensated heart failure with volume over- failure. Eur J Heart Fail 2014;16:86–94. https://pubmed.ncbi.
load. N Engl J Med 2022;387:1185–95. https://doi.org/10.1056/ nlm.nih.gov/23901055/
NEJMoa2203094 97. Kashani K, Rosner MH, Ostermann M. Creatinine: from
82. Voors AA, Damman K, Teerlink JR et al. Renal effects of em- physiology to clinical application. Eur J Intern Med
pagliflozin in patients hospitalized for acute heart failure: 2020;72:9–14. https://doi.org/10.1016/j.ejim.2019.10.025
from the EMPULSE trial. Eur J Heart Fail 2022;24:1844–52. 98. Goldstein SL, Chawla LS. Renal angina. Clin J Am Soc Nephrol
https://doi.org/10.1002/ejhf.2681 2010;5:943–9. https://pubmed.ncbi.nlm.nih.gov/20299370/
83. Takaya Y, Yoshihara F, Yokoyama H et al. Impact of on- 99. Ronco C, Kellum JA, Haase M. Subclinical AKI is still AKI.
set time of acute kidney injury on outcomes in patients Crit Care 2012;16:313. https://doi.org/10.1186/cc11240
with acute decompensated heart failure. Heart Vessels 100. Katz NM, Kellum JA, Ronco C. Acute kidney stress and pre-
2016;31:60–5. https://doi.org/10.1007/s00380-014-0572-x vention of acute kidney injury. Crit Care Med 2019;47:993–6.
84. Pierson-Marchandise M, Gras V, Moragny J et al. The https://doi.org/10.1097/CCM.0000000000003738
drugs that mostly frequently induce acute kidney injury: 101. Aimo A, Lupón J, Bayes-Genis A et al. Urinary NGAL in acute
a case-noncase study of a pharmacovigilance database. Br heart failure revisited: the game is not over yet. Int J Cardiol
J Clin Pharmacol 2017;83:1341–9. https://doi.org/10.1111/bcp. 2022;357:113–4. https://doi.org/10.1016/j.ijcard.2022.03.023
13216 102. Maisel AS, Mueller C, Fitzgerald R et al. Prognostic utility
85. Mehran R, Owen R, Chiarito M et al. A contemporary of plasma neutrophil gelatinase-associated lipocalin in pa-
simple risk score for prediction of contrast-associated tients with acute heart failure: the NGAL EvaLuation Along
acute kidney injury after percutaneous coronary inter- with B-type NaTriuretic Peptide in acutely decompensated
vention: derivation and validation from an observational heart failure (GALLANT) trial. Eur J Heart Fail 2011;13:846–
registry. Lancet 2021;398:1974–83. https://doi.org/10.1016/ 51. https://doi.org/10.1093/eurjhf/hfr087
S0140-6736(21)02326-6 103. Maisel AS, Wettersten N, van Veldhuisen DJ et al. Neu-
86. Lopez-Novoa JM, Quiros Y, Vicente L et al. New insights trophil gelatinase-associated lipocalin for acute kidney in-
into the mechanism of aminoglycoside nephrotoxicity: an jury during acute heart failure hospitalizations: the AKINE-
integrative point of view. Kidney Int 2011;79:33–45. https:// SIS Study. J Am Coll Cardiol 2016;68:1420–31. https://doi.org/
doi.org/10.1038/ki.2010.337 10.1016/j.jacc.2016.06.055
87. Filippone EJ, Kraft WK, Farber JL. The nephrotoxicity of van- 104. Harmankaya O, Oztürk Y, Bastürk T et al. Urinary excretion
comycin. Clin Pharmacol Ther 2017;102:459–69. https://doi. of N-acetyl-beta-D-glucosaminidase in newly diagnosed
org/10.1002/cpt.726 essential hypertensive patients and its changes with effec-
88. Klomjit N, Ungprasert P. Acute kidney injury associated tive antihypertensive therapy. Int Urol Nephrol 2001;32:583–
with non-steroidal anti-inflammatory drugs. Eur J Intern 4. https://doi.org/10.1023/A:1014443217611
Med 2022;101:21–8. https://doi.org/10.1016/j.ejim.2022.05. 105. Han WK, Bailly V, Abichandani R et al. Kidney injury
003 molecule-1 (KIM-1): a novel biomarker for human renal
89. Packer M, Anker SD, Butler J et al. Cardiovascular and renal proximal tubule injury. Kidney Int 2002;62:237–44. https://
outcomes with empagliflozin in heart failure. N Engl J Med doi.org/10.1046/j.1523-1755.2002.00433.x
2020;383:1413–24. https://doi.org/10.1056/NEJMoa2022190 106. Koyner JL, Vaidya VS, Bennett MR et al. Urinary biomark-
90. Zannad F, Ferreira JP, Pocock SJ et al. Cardiac and kid- ers in the clinical prognosis and early detection of
ney benefits of empagliflozin in heart failure across the acute kidney injury. Clin J Am Soc Nephrol 2010;5:2154–65.
spectrum of kidney function: insights from EMPEROR- https://doi.org/10.2215/CJN.00740110
Reduced. Circulation 2021;143:310–21. https://doi.org/10. 107. Fan W, Ankawi G, Zhang J et al. Current understanding and
1161/CIRCULATIONAHA.120.051685 future directions in the application of TIMP-2 and IGFBP7
91. McMurray JJV, Solomon SD, Inzucchi SE et al. Dapagliflozin in AKI clinical practice. Clin Chem Lab Med 2019;57:567–76.
in patients with heart failure and reduced ejection fraction. https://doi.org/10.1515/cclm-2018-0776
N Engl J Med 2019;381:1995–2008. https://pubmed.ncbi.nlm. 108. Kashani K, Al-Khafaji A, Ardiles T et al. Discovery and vali-
nih.gov/31535829/ dation of cell cycle arrest biomarkers in human acute kid-
 Kidney function changes in acute heart failure 1599

ney injury. Crit Care 2013;17:R25. https://doi.org/10.1186/ consensus statement. JAMA Netw Open 2020;3:e2019209.
cc12503 https://doi.org/10.1001/jamanetworkopen.2020.19209
109. Heung M, Ortega LM, Chawla LS et al. Common chronic 112. Breidthardt T, Weidmann ZM, Twerenbold R et al. Impact of
conditions do not affect performance of cell cycle arrest haemoconcentration during acute heart failure therapy on
biomarkers for risk stratification of acute kidney injury. mortality and its relationship with worsening renal func-
Nephrol Dial Transplant 2016;31:1633–40. https://doi.org/10. tion. Eur J Heart Fail 2017;19:226–36. https://doi.org/10.1002/
1093/ndt/gfw241 ejhf.667
110. Song Z, Ma Z, Qu K et al. Diagnostic prediction of uri- 113. Vaduganathan M, Greene SJ, Fonarow GC et al.
nary [TIMP-2] × [IGFBP7] for acute kidney injury: a meta- Hemoconcentration-guided diuresis in heart failure. Am
analysis exploring detection time and cutoff levels. Onco- J Med 2014;127:1154–9. https://doi.org/10.1016/j.amjmed.
target 2017;8:100631–9. https://doi.org/10.18632/oncotarget. 2014.06.009
21903 114. Boorsma EM, ter Maaten JM, Damman K et al. Albumin-
111. Ostermann M, Zarbock A, Goldstein S et al. Recommen- uria as a marker of systemic congestion in patients with
dations on acute kidney injury biomarkers from the heart failure. Eur Heart J 2023;44:368–80. https://pubmed.

Downloaded from https://academic.oup.com/ckj/article/16/10/1587/7049133 by guest on 26 February 2024

Acute Disease Quality Initiative Consensus Conference: a ncbi.nlm.nih.gov/36148485/