Current Heart Failure Reports (2022) 19:223–235

https://doi.org/10.1007/s11897-022-00557-y

BIOMARKERS OF HEART FAILURE (J. GRODIN AND W.H.W. TANG, SECTION EDITOR)

Novel Biomarkers of Kidney Disease in Advanced Heart Failure:

Beyond GFR and Proteinuria
Bethany Roehm1   · Meredith McAdams1 · S. Susan Hedayati1

Accepted: 25 April 2022 / Published online: 28 May 2022

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022

Abstract
Purpose  Kidney disease is a common finding in patients with heart failure and can significantly impact treatment
decisions and outcomes. Abnormal kidney function is currently determined in clinical practice using filtration mark-
ers in the blood to estimate glomerular filtration rate, but the manifestations of kidney disease in the setting of heart
failure are much more complex than this. In this manuscript, we review novel biomarkers that may provide a more
well-rounded assessment of kidney disease in patients with heart failure.
Recent Findings  Galectin-3, ST2, FGF-23, suPAR, miRNA, GDF-15, and NAG may be prognostic of kidney disease
progression. L-FABP and suPAR may help predict acute kidney injury (AKI). ST2 and NAG may be helpful in diu-
retic resistance.
Summary  Several biomarkers may be useful in determining prognosis of long-term kidney disease progression, pre-
diction of AKI, and development of diuretic resistance. Further research into the mechanisms of kidney disease in
heart failure utilizing many of these biomarkers may lead to the identification of therapeutic targets.

Keywords  Biomarkers · Heart failure · Kidney disease · Cardiorenal · Kidney function

Introduction in the setting of heart failure, and encompasses mecha-

Kidney disease is extremely prevalent in patients with
heart failure. Fifty-four percent of patients with heart
failure with reduced ejection fraction (HFrEF) have an
estimated glomerular filtration rate (eGFR) < 60  ml/
min/1.73  ­m 2, corresponding to chronic kidney disease
(CKD), defined as either a reduced eGFR < 60  ml/
min/1.73 ­m2 for ≥ 3 months or evidence of kidney dam-
age, such as albuminuria, abnormal urine sediment, or
structural abnormalities found on kidney biopsy or ultra-
sonography if the eGFR is ≥ 60 ml/min/1.73 ­m 2 [1, 2].
However, the pathophysiology of kidney damage and
reduced kidney function is more complex, especially
This article is part of the Topical Collection on Biomarkers of Heart
Failure
* Bethany Roehm
Bethany.roehm@utsouthwestern.edu
1
Division of Nephrology, Department of Internal Medicine,
University of Texas Southwestern Medical Center, 6201
Harry Hines Boulevard, Dallas, TX 75390, USA
nisms that may not be merely reflected by eGFR meas-
urements or urinary abnormalities alone. Other aspects
include kidney tubular damage and function, blood pres-
sure regulation, and endocrine pathways. Unfortunately,
measuring these aspects of kidney function is often not
practical or even possible in clinical practice due to the
lack of readily available assays.
Relying solely on eGFR, which is most frequently esti-
mated using serum creatinine, may also be problematic
in patients with advanced HFrEF. Incorrect estimation of
GFR may result in underutilization of certain evidence-
based treatments in advanced HFrEF, such as treatment
with sodium-glucose cotransporter-2 (SGLT2) inhibitors or
advanced heart failure therapies [3, 4]. In such instances,
other biomarkers of kidney function could prove useful in
determining candidacy for these beneficial treatments.
In this review, we will first discuss currently clini-
cally available assays for measuring kidney disease and
function, followed by a review of novel biomarkers not
currently used in routine clinical practice, but that may
be useful in the identification, prognostication, and man-
agement of kidney disease in patients with heart failure.

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Current Biomarkers to Assess Kidney
Function
eGFR
Current biomarkers used to assess kidney function are
summarized in Table 1. The most common measure of
kidney function is the estimated GFR using serum creati-
nine. Creatinine is a product of muscle catabolism that is
freely filtered by the glomerulus, with additional minor
contribution to the urine ultrafiltrate by tubular secretion
[5]. It is cost-effective and easily obtained. While the use
of creatinine-based GFR estimates has been instrumental
in defining kidney disease as a global health problem, cre-
atinine is not always the ideal surrogate marker for GFR. It
is influenced by conditions that affect muscle mass, such
as advanced heart failure. Twenty-one percent of patients
with chronic heart failure have sarcopenia, which would
potentially lead to the overestimation of GFR if using
serum creatinine [6]. The creatinine-based equation to
estimate GFR was also updated in 2021 to remove the
coefficient for African American race due to concerns for
healthcare disparities introduced by inclusion of a race
coefficient [7 ••]. As this new equation is implemented
in clinical settings, GFR estimates may appear lower in
African Americans and higher in non-African Americans
when compared to values obtained using prior equations.
It is important that providers be aware of this change since
absolute eGFR cutoffs may be used to determine eligibility
for specific treatments.
Serum cystatin C is another filtration marker used to esti-
mate GFR. It is less influenced by muscle mass, as it is a
cysteine protease inhibitor produced by all nucleated cells and
is not thought to be a byproduct of muscle catabolism [8].
Table 1  Current biomarkers of kidney function used in clinical practice
Test Usage
Serum creatinine Estimate GFR
Serum cystatin C Estimate GFR
Iohexol plasma clearance Measure GFR
Iothalamate urinary clearance Measure GFR
24-h urine collection Measure creatinine clearance
GFR, glomerular filtration rate
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Current Heart Failure Reports (2022) 19:223–235
However, despite cystatin C being largely touted as unaffected
by muscle mass, a study of 293 patients admitted with acute
decompensated heart failure did show an association between
cystatin C and muscle mass, leading to the overestimation of
GFR by cystatin C [9•]. Cystatin C is also affected by a host
of other factors including obesity, thyroid diseases, smoking,
cancer, glucocorticoids, and inflammation [10]. Inflammation
may lead to underestimation of GFR by cystatin C. Given the
high prevalence of sarcopenia in advanced heart failure and
chronic myocardial inflammation as a factor in the pathogen-
esis of heart failure, the use of cystatin C in patients with heart
failure may yield both under- and overestimates of GFR [11].
In summary, while serum creatinine and cystatin C pro-
vide relatively inexpensive and convenient means of estimat-
ing GFR, there are several pitfalls to their uses in advanced
heart failure. Until more accurate endogenous filtration
markers that are not affected by muscle mass and inflamma-
tion become available, we suggest using cystatin C-based
eGFR in sarcopenic patients with heart failure, or the com-
bination of the two which is suggested to be more accurate
in the general population [12].
Direct Measurements
When there is equipoise surrounding GFR estimates and
clinical decision-making is imperative, 24-h urinary creati-
nine clearance or, better yet, direct methods of measured
GFR may be used. Direct measurement of GFR can be per-
formed using plasma or urinary clearance of an exogenous
marker. Urinary clearance may be the preferred method in
heart failure patients where the presence of edema may affect
the volume of distribution of the exogenous marker leading
to overestimation of GFR if a plasma marker was used [10].
Iothalamate is traditionally the gold standard marker used
for urinary clearance. Measurements can be prone to error
Pitfalls
• Influenced by muscle mass
• Influenced by protein intake
• Influenced by inflammation
• Some influence by muscle mass
• Assay not standardized
• May not be covered by insurance
• Cumbersome for patients
• Requires clinician who can interpret results
• May be less accurate in heart failure
• Cumbersome for patients
• Requires clinician who can interpret results
• Error if incomplete urine collection and/or bladder emptying
• Cumbersome for patients
• Error if incomplete urine collection and/or bladder emptying
Current Heart Failure Reports (2022) 19:223–235 225

if urine collections or bladder emptying is incomplete [13].
Many institutions may not have the infrastructure to perform
urinary iothalamate clearance, in which case, 24-h urine
creatinine clearance can be useful. However, these are also
often prone to inaccuracies due to errors in urine collection,
especially under collection.
Current Biomarkers to Assess Kidney
Damage
Urine Dipstick and Urinalysis with Microscopic
Examination
Examination of urine sediment under the microscope is
another crucial means of evaluating for kidney damage. There
may be evidence of glomerulonephritis in the form of dysmor-
phic red blood cells (RBCs), white blood cells (WBCs), and
RBC or WBC casts [20]. WBCs and WBC casts can also be
indicative of pyelonephritis or acute interstitial nephritis [21]. In
nephrotic syndromes where there is heavy proteinuria, lipiduria
may also be present in the form of lipid droplets or lipid-laden
casts [22]. Cholesterol crystals may also be seen. In acute kid-
ney injury (AKI), there may be dense, granular casts suggestive
of acute tubular necrosis, hyaline casts—though a non-specific
finding—in pre-renal AKI, or drug crystals in some instances
of drug-induced AKI [20].

Urinalysis via urine dipstick is one of the simplest and most
cost-effective tests to evaluate for kidney damage. It can detect
abnormalities such as hematuria, leukocyturia, glucosuria, and
proteinuria in the form of albumin (Table 2) [14, 15]. Hematuria
and leukocyturia, in the right clinical context, can be indicative
of various inflammatory diseases in the kidney. Proteinuria is
a marker of kidney damage and is often present before GFR
falls. It can be predictive of future kidney failure and adverse
cardiovascular events [16, 17]. Patients with heart failure who
have clinically significant proteinuria have greater risk of mor-
tality [18]. Proteinuria may be either glomerular or tubular in
origin. Measurement of albuminuria, indicative of glomerular
damage, can help distinguish between the two. Proteinuria of
glomerular etiology would be expected to be composed of at
least 40% albumin [19].
Quantitative Measures of Proteinuria
Urine protein-to-creatinine ratio (UPCR) > 150 mg/g and
urine albumin-to-creatinine ratio (UACR) > 30 mg/g on spot
urine collection are the primary quantitative measures of
clinically significant proteinuria, with UACR being the pre-
ferred initial test [2, 19]. The presence of protein on urinaly-
sis primarily indicates albuminuria which may miss other
proteinuria such as light-chain proteins that can be detected
on UPCR, if clinical suspicion exists. If urinalysis tests
positive for protein, confirmatory testing is recommended
using the UACR or the UPCR. Morning urine specimens are
preferred since there are diurnal variations in urine protein
and albumin excretion. Since creatinine is in the denomi-
nator, extremes of muscle mass or medications that affect

Table 2  Current biomarkers of kidney damage used in clinical practice

Marker Test Usage

Reduced eGFR, rising serum creatinine • Serum creatinine • AKI or CKD progression depending on chronicity
Urinalysis • Urine Dipstick • Initial screening assessment for damage
• Provides information on hematuria, leukocyturia, proteinuria
Proteinuria • UPCR • Marker of glomerular or tubular damage
• 24-h urine • Quantitates proteinuria
Albuminuria • UACR​ • Marker of glomerular damage
• 24-h urine • Quantitates albuminuria
Dysmorphic RBCs/RBC casts • Urine microscopy • Glomerulonephritis
• Rarely acute interstitial nephritis
WBCs/WBC casts • Urine microscopy • Glomerulonephritis
• Acute or chronic interstitial nephritis
• Pyelonephritis
Oval fat bodies, lipid droplets, cholesterol crystals • Urine microscopy • Nephrotic syndrome
Hyaline casts • Urine microscopy • Non-specific, can be normal
• Pre-renal AKI
Granular casts, renal tubular epithelial cell casts • Urine microscopy • Acute tubular necrosis
Crystals • Urine microscopy • Can be normal depending on crystal
• Drug-induced AKI
• Oxalate nephropathy

AKI, acute kidney injury; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; RBC, red blood cells; UACR​, urine albumin-
to-creatinine ratio; UPCR, urine protein-to-creatinine ratio; WBC, white blood cells

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creatinine secretion into the urine may lead to inaccurate
estimates of proteinuria with UPCR and UACR. When more
accurate quantification of proteinuria is needed, a 24-h urine
collection for protein and/or albumin can be performed, if
the amount of urine is accurately collected.
Tubular Dysfunction and Diuretic Resistance
Tubular dysfunction is another important aspect of kidney dam-
age. Kidney tubules are responsible for much of the homeo-
static functions the kidney performs, such as fine-tuning of
electrolyte concentrations and acid–base balance [23]. Tubular
dysfunction plays a role in loop diuretic resistance in heart fail-
ure independent of changes in eGFR. In a study of 50 patients
with acute decompensated heart failure receiving intravenous
bumetanide for diuresis, renal tubular resistance, rather than
GFR, was the driving factor in diuretic resistance [24]. On mul-
tivariable linear regression, renal tubular resistance, measured
by increase in fractional excretion of sodium per doubling of
excreted bumetanide, accounted for 71% of the variance of
global diuretic response across the whole kidney. Although urine
sodium < 50 mmol 1–2 h after diuretic administration may be
indicative of diuretic resistance, no other routine means of meas-
uring tubular function are available in current clinical practice
[25]. Some of the novel biomarkers described below may be
useful for assessing tubular damage.
Novel Biomarkers of Kidney Disease
Galectin‑3
Pathophysiologic Mechanism
Galectin-3 is a β-galactoside-binding lectin that seems to
have effects on cell–cell adhesion during inflammation and
fibrosis [26]. It has been associated with fibrosis in a variety
of tissues. Galectin-3 may also have a role in intracellular
protein sorting and receptor trafficking.
Role in Heart Failure
Galectin-3 has been implicated in cardiac fibrosis and
greater mortality in heart failure, such that it garnered a
class II-B recommendation in the 2017 ACC/AHA/HFSA
guidelines for heart failure management for measurement in
addition to BNP for prognostic purposes [27].
Role in Heart Failure‑Related Kidney Disease
Galectin-3 was shown to be associated with kidney fibrosis in rat
models and with CKD progression, but not mortality, in general
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Current Heart Failure Reports (2022) 19:223–235
CKD cohorts [28, 29]. Galectin-3 also has promising utility in
kidney disease in the setting of heart failure (Table 3). Rats
treated with aldosterone-salt developed cardiac dysfunction,
glomerular hypertrophy, glomerular hyperfiltration, and albu-
minuria [30]. Treatment with a galectin-3 inhibitor or genetic
knockout for galectin-3 prevented cardiac fibrosis and albuminu-
ria but not glomerular hypertrophy or hyperfiltration. Similarly,
in a rat model of cardiorenal syndrome, galectin-3 expression
was upregulated in both the heart and kidney, and rats experi-
enced higher albuminuria, though findings were attenuated with
valsartan [31].
In humans, galectin-3 may not be useful in predicting AKI
during acute decompensated heart failure [32] and may be more
useful in heart failure-associated CKD. In patients with chronic
HFrEF, higher galectin-3 has been associated with lower eGFR
[33] and declines in eGFR after 2–3 years of follow-up [34•].
Additionally, higher galectin-3 was associated with neurohormo-
nal markers suggesting a possible role in neurohormonal activa-
tion of heart failure. In this study, galectin-3 was not associated
with albuminuria. However, in another study of chronic heart
failure, galectin-3 was associated with albuminuria on stepwise
multivariable logistic regression [35].
Summary
Galectin-3 is associated with both heart failure and kidney dis-
ease and may be a useful biomarker to prognosticate progression
of kidney disease in the setting of heart failure. Galectin-3 may
also represent a potential future therapeutic target.
ST2
Pathophysiologic Mechanism
Soluble suppression of tumorigenicity 2 (ST2) is a member
of the interleukin-1 (IL-1) receptor family. It appears to play
a role in cardiac fibrosis and atherosclerosis.
Role in Heart Failure
ST2 is associated with worse outcomes in heart failure. Much
like galectin-3, ST2 has been shown to be of prognostic utility
in heart failure and was added to the 2017 ACC/AHA/HFSA
update on the 2013 guidelines for heart failure management as
a class II-B recommendation [27]. Moreover, ST2 seems to be
predictive of death independent of eGFR in the setting of heart
failure [36]. ST2 also appears to be predictive of incident heart
failure in patients with CKD. An analysis of the chronic renal
insufficiency cohort (CRIC) followed over a median of 7.9 years
showed on multivariable analysis that CKD patients in the two
highest quartiles of ST2 had a higher risk of developing heart
failure, with no interaction with eGFR [37].
Current Heart Failure Reports (2022) 19:223–235 227

Table 3  Novel biomarkers of kidney disease in heart failure

Biomarker Mechanism Potential Uses

Galectin-3 (plasma) Affects cell–cell adhesion during inflammation/fibrosis • Mortality in heart failure
• CKD progression
ST2 (plasma) Member of IL-1-R family, plays a rose in cardiac fibrosis and atherosclerosis • Mortality in heart failure
• Risk of incident heart failure
• Development of AKI
• CKD progression
• Diuretic resistance
NGAL (urine or plasma) Marker of kidney tubular damage • AKI in acute heart failure
FGF-23/klotho (plasma) Regulates phosphorus excretion by the kidney; FGF-23 expressed in kidney • Cardiac fibrosis
and heart during physiologic stress • Kidney fibrosis/CKD progression
suPAR (plasma) Cell adhesion and chemotaxis in acute inflammation • Mortality in heart failure
• AKI
• CKD progression
miRNA (tissue or plasma) Regulate post-transcription gene expression • Risk of incident heart failure
• Incident CKD due to heart failure
• CKD progression
L-FABP (urine) Fatty acid metabolism, cell growth, cell proliferation • AKI
GDF-15 (plasma) Pro- and anti-inflammatory activity • Mortality in heart failure
• Incident heart failure
• Incident CKD
• CKD progression
NAG (urine) Marker of kidney tubular damage • Mortality in heart failure
• Heart failure hospitalization
• CKD progression
• Diuretic resistance

AKI, acute kidney injury; CKD, chronic kidney disease; FGF-23, fibroblast growth factor 23; GDF-15, growth differentiation factor 15; IL-1-R,
interleukin-1 receptor. L-FABP, liver fatty acid binding protein; miRNA, micro ribonucleic acid; NAG, N-acetyl-β-D-glucosaminidase; NGAL,
neutrophil gelatinase associated lipocalin; ST2, soluble suppression of tumorigenicity 2; suPAR, soluble urokinase plasminogen activator recep-
tor

Role in Heart Failure‑Related Kidney Disease
Although observational studies of the association of ST2 with
CKD progression in general CKD cohorts have been conflict-
ing, ST2 may have prognostic value for both AKI and CKD
progression in the setting of heart failure. In patients with acute
STEMI or undergoing CABG, ST2 was shown to be associated
with higher risk of subsequent AKI [38, 39]. A pooled study of
two longitudinal cohorts—Clinical Phenotyping and Resource
Biobank Study (C-PROBE) and Seattle Kidney Study (SKS)—
with a total of 841 patients found no association between ST2 and
composite primary endpoint of development of eGFR < 15 ml/
min/1.73 ­m2 or end stage kidney disease (ESKD) [29]. Notably
patients had a mean number of only three eGFR measurements
and a median follow-up of only 3.1 years. Interestingly, ST2 lev-
els did correlate with UACR which, as previously stated, may
precede declines in GFR. Conversely, another observational
study of 342 participants with CKD found that higher ST2 was
associated with CKD progression, defined as > 50% reduction
in eGFR from baseline or need for kidney replacement therapy
(KRT) over a mean follow-up of 3.6 years [28].
In a cross-sectional post-hoc analysis of the Registry to
Improve the Use of Evidence-Based Heart Failure Therapies in
the Outpatient Setting (IMPROVE-HF), data from 160 patients
with acute heart failure and an eGFR < 60 ml/min/1.73 ­m2 were
analyzed to test the association between ST2 and diuretic effi-
ciency, defined as the net fluid output produced per 40 mg of
furosemide equivalents [40]. Higher ST2 level was associated
with lower diuretic efficiency using multivariable analysis.
Summary
Just as ST2 is prognostic in heart failure, it has the potential
for clinical utility in identifying patients at risk for AKI, kid-
ney disease progression, and diuretic resistance in the setting
of heart failure, but its role needs to be further validated.
NGAL
Pathophysiologic Mechanism
Neutrophil gelatinase-associated lipocalin (NGAL) is a
lipocalin protein initially found in the azurophilic granules
of neutrophils [41]. It may be synthesized in the kidney dur-
ing injury and complex with iron as a scavenging protective
response [42]. Furthermore, it seems to be found readily

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in the urine though is not reabsorbed into blood, and uri-
nary NGAL may be superior to plasma NGAL in predict-
ing AKI [43]. Non-kidney-derived NGAL is reabsorbed in
the proximal tubules though this may be blunted by tubular
injury. NGAL has been shown to be an early marker of kid-
ney damage and predictive of AKI in several observational
human studies, as the levels rise before serum creatinine in
patients post-operatively after cardiac surgery, particularly in
the pediatric population [44–47]. Results in predicting AKI
in adult cohorts have not been as promising, and equipoise
remains with regard to its utility in prognostication of CKD
progression [48–50].
Role in Heart Failure
Studies examining the association of NGAL with mortal-
ity in chronic heart failure have yielded conflicting results
[51–53].
Role in Heart Failure‑Related Kidney Disease
The prognostic utility of NGAL with regard to both AKI and
CKD in the setting of heart failure is also unclear. Several
studies have demonstrated an association between elevated
plasma or serum NGAL at the time of hospitalization for
acute decompensated heart failure and a subsequent worsen-
ing in serum creatinine [54–56]. However, worsening serum
creatinine or AKI was often defined as an increase in serum
creatinine ≥ 0.3 mg/dl, and severity of AKI was typically
not described. While this is an appropriate classification for
early or stage 1 AKI according to most recent guidelines, it
may not represent a clinically meaningful increase in serum
creatinine, especially in patients with more advanced CKD
[57]. Indeed, a small increase in creatinine during diuresis
for acute decompensated heart failure may not be harm-
ful in the long term. For example, in a sub-study of 105
patients from the CARESS-HF trial with urinary biomark-
ers of kidney tubular injury measured, 53% had an increase
in serum creatinine of about 0.2 mg/dl during diuresis for
acute decompensated heart failure [58••]. They also found
that while an increase in urinary NGAL was associated with
an increase in serum creatinine, it was also associated with
greater hemoconcentration during diuresis and subsequent
recovery of serum creatinine at 60 days. Another study in
patients with acute decompensated heart failure found no
association between serum or urinary NGAL and the com-
posite endpoint of death, need for dialysis, heart failure
rehospitalization, and emergent outpatient visit for a heart
failure related issue at 60 days [59]. In chronic heart failure,
cross-sectional studies have suggested a possible association
between serum or urinary NGAL and kidney disease [60,
61]. However, longitudinal studies of NGAL and GFR in
chronic heart failure are lacking.
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Current Heart Failure Reports (2022) 19:223–235
Summary
NGAL may not be the ideal biomarker for AKI in the setting
of heart failure. In general CKD cohorts, it has not been a
promising biomarker for CKD progression. If NGAL is to
be studied in heart failure populations as a biomarker for
CKD progression, hard outcomes such as mortality or KRT
should be used.
FGF‑23 and Klotho
Pathophysiologic Mechanism
Fibroblast growth factor 23 (FGF-23) regulates phospho-
rus excretion by the kidney. It is secreted predominantly by
osteoblasts but may also be expressed in the kidney and the
heart during physiologic stress [62, 63]. From a compensa-
tory standpoint, FGF-23 levels increase in CKD to increase
phosphorus excretion by functional nephrons to prevent
hyperphosphatemia [64]. Yet FGF-23 cannot act in the kid-
ney without the help of a molecule called Klotho. Klotho
functions as a co-receptor with FGF receptors in the kidney
to allow FGF-23 binding [65].
Role in Heart Failure
Plasma or serum FGF-23 is associated with higher risk of
mortality and heart failure rehospitalization in patients with
acute heart failure [66–69]. In patients without heart failure,
higher plasma FGF-23 has been associated with higher left
ventricular mass, left ventricular hypertrophy, and heart fail-
ure hospitalizations later in life [70–72].
Role in Heart Failure‑Related Kidney Disease
A study in a mouse heart failure model of the Wnt/β-catenin
pathway, which is involved in inflammation and tissue repair,
showed that mice experienced both cardiac and kidney fibro-
sis [73]. Klotho expression was markedly reduced independ-
ent of the Wnt/β-catenin pathway, and Wnt/β-catenin activa-
tion in cardiac myocytes in vitro was halted by klotho. This
suggests that the lower klotho levels seen in kidney disease
may mediate further cardiac fibrosis in heart failure.
FGF-23 levels increase, while klotho levels decrease
in the general CKD population [74]. Serum FGF-23 and
klotho have also been found to correlate with albuminuria
[75]. Similarly, in a mouse model of cardiorenal syndrome,
FGF-23 expressions and FGF4, a receptor for FGF23, were
upregulated in the kidneys, whereas klotho expression was
lower [76]. Furthermore, inhibition of FGF-23 reduced
heart and kidney fibrosis.
In human studies, an analysis of 3747 participants from
CRIC showed that those with CKD and concomitant iron
Current Heart Failure Reports (2022) 19:223–235
deficiency had higher mortality risk. FGF-23 was inversely
associated with iron levels, and risk of heart failure was
attenuated in iron-deficient patients when adjusted for
FGF-23, suggesting a link between FGF-23, kidney dis-
ease, and heart failure [77]. However, a study of 199
patients with chronic heart failure showed no association
between FGF-23 and sodium avidity, diuretic response,
neurohormonal activation, or mortality [78]. Given that
other studies have shown an association with mortality, it
may be this study was underpowered.
Summary
Although these data indicate that FGF-23 may be an
intriguing biomarker to study in heart failure, larger stud-
ies are needed so that as the role of the FGF-23/klotho axis
is further defined to allow for identification of potential
therapeutic strategies and prognostic utility.
suPAR
Pathophysiologic Mechanism
Soluble urokinase plasminogen activator receptor (suPAR)
is the soluble, circulating, and therefore easily measurable
form of the glycosylphosphatidylinositol (GPI) anchor
protein urokinase plasminogen activator receptor (uPAR)
[79]. It is expressed on a variety of cells including immune
cells, endothelial cells, and kidney podocytes [80]. suPAR
and uPAR are involved at multiple points in the inflam-
matory process. uPAR is believed to interact with integ-
rins to affect inflammatory cell adhesion and chemotaxis
[81]. suPAR also has chemoattractant properties and may
help recruit cells at sites of acute inflammation [79]. In
an animal model for AKI, mice treated with an uPAR
monoclonal antibody had less evidence of AKI on his-
topathologic examination compared to those not treated.
This study also provided insight into the mechanisms of
kidney injury mediated by suPAR. In vitro human kidney
proximal tubular cells exposed to suPAR had higher mark-
ers of increased oxidative stress [80].
Role in Heart Failure
Elevated plasma suPAR levels have been associated with
adverse outcomes such as mortality and hospital rehospitaliza-
tion in patients with heart failure. In 4530 subjects followed for
a median of 16.3 years, individuals with the highest tertile of
plasma suPAR at baseline had a higher risk of incident heart
failure at follow-up as compared to those with the lowest ter-
tile [82]. Among patients hospitalized for acute decompensated
229
heart failure, elevated suPAR was associated with higher mortal-
ity, although results regarding association with hospital rehospi-
talization for decompensated heart failure have been conflicting
[83, 84]. Elevated suPAR was also associated with higher mor-
tality in patients with chronic ambulatory heart failure [85]. In a
study of chronic heart failure patients followed for a median of
2.2 years with longitudinal measurements of suPAR measured
every 3 months, patients who experienced the primary com-
posite endpoint of cardiac death, heart transplantation, left ven-
tricular assist device implantation, and hospitalization for heart
failure had stable suPAR levels over time, whereas those who
did not experience an endpoint had decreasing suPAR levels
over time [86].
Role in Heart Failure‑Related Kidney Disease
There is no published data regarding the relationship
between suPAR and kidney disease in the setting of heart
failure. Elevated suPAR levels are associated with develop-
ment of both AKI and incident CKD, as well as CKD pro-
gression, in the general population [80, 87, 88]. In contrast
to some of the other biomarkers associated with AKI, which
have generally demonstrated associations after the proposed
insults have taken place, suPAR measured pre-procedurally
in patients undergoing coronary angiography or cardiac sur-
gery was shown to be predictive of post-procedure AKI [80].
Summary
Although suPAR is predictive of kidney disease in general
cohorts and predictive of mortality in heart failure, it remains
to be determined if suPAR is of utility in prognosis of kidney
disease in heart failure but appears to be a promising biomarker.
miRNA
Pathophysiologic Mechanism
MicroRNA (miRNA) are small pieces of non-coding RNA
that regulate post-transcription gene expression [89]. miRNA
may have utility in helping to understand the pathogenesis of
both cardiac and kidney fibrosis in heart failure. There are
countless miRNA, many of which may be yet to be discov-
ered. miRNA-21 has been most studied in kidney disease. In
a non-heart failure cohort of patients with IgA nephropathy
(IgAN), kidney biopsy specimens of 20 patients with IgAN
were compared to 10 controls [90]. Measuring expression of
the 84 most abundant miRNA sequences, miRNA-21 expres-
sion was greater in patients with IgAN in both kidney podo-
cytes and tubular cells and was correlated with the degree of
proteinuria and degree of scarring. Moreover, when podocytes
and tubular cells were placed in medium from cultured cells
treated with plasma IgA from patient with IgAN, they too
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developed an increase in miRNA-21 expression. Fibronectin
and collagen-1 (COL1) expression, which have been impli-
cated in fibrosis, were also higher, but expression was inhib-
ited by anti-miRNA-21 treatment.
Role in Heart Failure
miRNA-21 may be implicated in development of heart
failure in patients with CKD. A study in rats found higher
levels of the uremic toxin indoxyl sulfate and higher
expression of miRNA-21 after MI [91]. Rats treated with
an indoxyl sulfate inhibitor had lower miRNA-21 expres-
sion and less cardiac fibrosis compared to untreated rats.
Another study identified higher miRNA-21 expression in
the left ventricle of 5/6 nephrectomized rats [92]. Treat-
ment with anti-miRNA-21 prevented left ventricular dila-
tion and lower left ventricular ejection fraction.
Role in Heart Failure‑Related Kidney Disease
miRNA-21 has also been associated with the development
of CKD due to heart failure. A study of elderly patients
with NYHA class II-IV heart failure symptoms examined
the association between miRNA-21 and CKD [93•]. They
compared miRNA-21 levels in patients with heart failure
and no CKD with patients with CKD attributed to heart
failure. Higher miRNA-21 levels were associated with hav-
ing CKD due to heart failure. Several other miRNAs are
being studied as they relate to both CKD progression and
development of cardiovascular disease in CKD [94–96].
Summary
miRNA-21 and other types of miRNA warrant further
study in heart failure patients with kidney disease, particu-
larly with regard to mechanisms and potential therapeutic
targets for the treatment of kidney disease in heart failure.
L‑FABP
Pathophysiologic Mechanism
Fatty acid-binding proteins are involved in fatty acid metab-
olism, cell growth, and proliferation [97]. Heart-type fatty
acid-binding protein (H-FABP) is expressed in striated mus-
cle cells, released into the bloodstream during cardiac dam-
age, and associated with adverse outcomes such as acute
heart failure and death, though of less utility in kidney dis-
ease [98–100]. Conversely, liver fatty acid-binding protein
(L-FABP) may be of utility in AKI, particularly in patients
13
Current Heart Failure Reports (2022) 19:223–235
with heart failure or acute coronary syndromes. L-FABP
expression has been localized to kidney proximal tubules.
Higher expression of L-FABP is thought to be reflective of
stress or damage to the proximal tubules [101, 102].
A trial of interventional cardiologists using simulated
cases examined the utility of L-FABP in diagnosing and
preventing AKI due to contrast-induced nephropathy [103•].
Cardiologists were randomized to the intervention group
which utilized L-FABP levels prior to coronary procedure
or control group who did not receive L-FABP levels. Those
who received L-FABP results were more likely to correctly
identify patients at higher risk for AKI, more likely to give
volume expansion for AKI prevention, and hold nephrotoxic
medications. These results demonstrate how urine L-FABP
could be used to prognosticate who will develop AKI in
order to implement interventions to potentially prevent AKI.
Role in Heart Failure‑Related Kidney Disease
L-FABP may also be useful in predicting AKI in acute heart
failure. In patients admitted for acute decompensated heart
failure, higher urine L-FABP was associated with greater
risk of AKI [104]. However, the authors did not report AKI
stages, so it is challenging to know if these were clinically
meaningful AKI events. While there may be some role for
L-FABP in AKI, its role in CKD progression seems less cer-
tain, with one study showing no association with worsening
kidney function at 2 years [105].
Summary
Overall, more studies are needed to determine if there is a
useful role for L-FABP in clinical practice in patients with
concomitant heart failure and kidney disease.
GDF‑15
Pathophysiologic Mechanism
Growth differentiation factor 15 (GDF-15) is a cytokine belong-
ing to the transforming growth factor beta (TGF-β) superfamily.
GDF-15 can have both pro- and anti-inflammatory actions in the
body depending on the clinical scenario [106]. Higher GDF-15
was associated with higher risk of incident CKD in 4318 sub-
jects followed over mean of 19 years [107]. GDF-15 has also
been associated with worsening albuminuria in patients with
diabetes or hypertension [108].
Role in Heart Failure
GDF-15 appears to be predictive of mortality in both
chronic and acute heart failure [109, 110]. In an analysis
of the aforementioned C-PROBE and SKS studies, higher
Current Heart Failure Reports (2022) 19:223–235
GDF-15 was associated with higher mortality and heart
failure diagnosis [111].
Role in Heart Failure‑Related Kidney Disease
In general CKD cohorts, GDF-15 has been associated with
both kidney and heart failure outcomes. A post-hoc analysis
of the randomized control trial, the Canagliflozin Cardio-
vascular Assessment Study (CANVAS), examined the asso-
ciation between kidney and heart failure outcomes [112••].
Kidney outcome was defined as a composite of sustained
40% decline in eGFR, ESKD, or renal death. Heart failure
outcome was defined as heart failure hospitalization. Dou-
bling of GDF-15 was associated with greater risk of both
heart failure and kidney outcomes.
Summary
The mechanisms and role of GDF-15 in heart failure and
kidney disease, as well as its relationship to SGLT2 inhibi-
tors like canagliflozin, warrant further study.
NAG
Pathophysiologic Mechanism
N-acetyl-β-D-glucosaminidase (NAG) is a lysosomal
enzyme found in kidney proximal tubular cells and a uri-
nary biomarker of tubular injury [113]. Its presence suggests
that damaged kidney tubule cells are leaking this enzyme
into the urine.
Role in Heart Failure
Higher urinary NAG levels may be associated with
higher mortality and heart failure hospitalization in heart
failure patients. Both higher urinary baseline NAG and
increasing NAG over time were associated with higher
risk of the primary composite outcome of cardiac death,
heart transplantation, LVAD implantation, and heart fail-
ure hospitalization in patients with chronic heart fail-
ure [114]. This risk was even greater in patients with
higher baseline NAG levels and concomitant CKD and
albuminuria. In a secondary analysis from GISSI-HF, a
randomized control trial examining the effects of polyun-
saturated fatty acids in patients with NYHA class II-IV
heart failure symptoms on all-cause mortality or heart
failure hospitalizations, there was an association between
higher urinary NAG levels and higher mortality [115].
Conversely, a study of 90 patients with chronic heart
failure found no association between urinary NAG levels
231
and the composite outcome of all-cause mortality and
heart failure hospitalization [116]. However, there was
an association on univariate analysis. Given the small
sample size, they may have been underpowered to detect
an association.
Role in Heart Failure‑Related Kidney Disease
NAG has been associated with kidney disease in heart fail-
ure patients. In another secondary analysis of the GISSI-HF
trial, higher urinary NAG levels were predictive of wors-
ening kidney function on univariate, but not multivariable,
analysis [117]. In 150 patients with chronic heart failure,
urinary NAG levels correlated with both eGFR and UACR
[118]. NAG levels were also significantly higher in patients
requiring furosemide doses > 80  mg/day compared to
patients requiring a lower diuretic dose, suggesting this bio-
marker may be of utility in the study of diuretic resistance.
Another study of patients with chronic heart failure, urinary
NAG was found to be an independent predictor of CKD pro-
gression, defined as a drop in CKD stage accompanied by a
25% drop in eGFR from baseline over a median follow-up
of 4.4 years (49).
Summary
As with the other biomarkers, further study is needed to
determine the usefulness of NAG in clinical practice. It may
have utility in not only AKI but also CKD progression and
diuretic resistance.
Conclusion
There are many promising biomarkers that may be useful in
the future for providers taking care of heart failure patients
with kidney disease. Biomarkers such as galectin-3, ST2,
FGF-23, suPAR, miRNA, GDF-15, and NAG may be prog-
nostic of CKD progression. ST2 and NAG may be promis-
ing in the diagnosis and pathogenesis of diuretic resistance.
Some biomarkers, like NGAL, may be of less reliable clini-
cal utility. miRNA is an exciting area of study that may lead
to the identification of therapeutic targets.
Funding Meredith McAdams is supported by training grant
5T32DK007257-38 from the National Institutes of Diabetes and Diges-
tive and Kidney Diseases. S. Susan Hedayati is supported by grant
1R38HL150214 from the National Health, Lung, and Blood Institute and
by grant AHA923721 from the American Heart Association. She is also
supported by the Yin Quan-Yuen Distinguished Professorship in Nephrol-
ogy at the University of Texas Southwestern Medical Center, Dallas, Texas.
13
232
Declarations  muscle mass and overestimated measured creatinine clear-
Conflict of Interest  Bethany Roehm, Meredith McAdams, and S. Su-
san Hedayati declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent  This article does not
contain any studies with human or animal subjects performed by any
of the authors.
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