Background: Cardiorenal syndrome (CRS) refers to the bidirectional interactions between the acutely or chronically dysfunctioning heart and kidney that lead to poor outcomes. Due to the evolving literature on renal impairment and heart failure with preserved ejection fraction (HFpEF), this review aimed to highlight the pathophysiological pathways, diagnosis using imaging and biomarkers, and management of CRS in patients with HFpEF. Summary: The mechanism of CRS in HFpEF can be hypothesized due to the interplay of elevated central venous pressure, renin-angiotensin-aldosterone system (RAAS) activation, oxidative stress, endothelial dysfunction, coronary microvascular dysfunction, and chronotropic incompetence. The correlation between HFpEF and worsening renal function seen in both long-term trials and observational data points to the evidence for these mechanisms. Upcoming biomarkers such as cystatin C, NGAL, NAG, KIM-1, ST-2, and galectin-3, along with conventional ones, are promising for early diagnosis, risk stratification, or response to therapy. Despite the lack of specific treatment for CRS in HFpEF, the management can be discussed with similar medications used in goal-directed medical therapy for heart failure with reduced ejection fraction (HFrEF). Additionally, there is increasing evidence for the role of vasodilators, inotropes, assist devices, and renal denervation, although long-term studies are necessary. Key Message: The management of CRS in HFpEF is an evolving field that currently shows promise for using diagnostic and prognostic biomarkers, conventional heart failure medications, and novel therapies such as renal denervation, interatrial shunt, and renal assist devices. Further studies are needed to understand the pathophysiological pathways, validate the use of novel biomarkers, especially for early diagnosis and prognostication, and institute new management strategies for CRS in patients with HFpEF.

As per recent data, the prevalence of all subtypes of heart failure (HF) in the USA is 6 million [1] and continues to rise, and that of heart failure with preserved ejection fraction (HFpEF) is estimated to exceed heart failure with reduced ejection fraction (HFrEF) soon [2, 3]. The national inpatient sample estimates show an exponential increase in HFpEF hospitalizations from 2008 to 2018, contributing significantly to the healthcare burden [4]. Impaired renal functions, including acute kidney injury (AKI) and chronic kidney disease (CKD), are significant predictors of mortality, cardiovascular death, and HF hospitalization in patients with HFpEF [5‒7]. Additionally, baseline glomerular filtration rate (GFR) was found to be a more significant predictor of mortality in HF than the NYHA class or LVEF [7]. Of note, impaired renal function was also projected as a risk factor for HFpEF [8]. Interestingly, reversing kidney dysfunction can improve cardiovascular function [9], hinting at the interactions between the cardiovascular and renal systems.

The National Heart, Lung, and Blood Institute initially defined cardiorenal syndrome (CRS) as a clinical entity resulting from interactions between the kidney and other circulatory compartments that increase the circulatory volume and exacerbate the symptoms of HF and disease progression [10]. However, this definition had significant limitations and focused mainly on the CRS subtype seen in acute heart failure (AHF). As research on renal dysfunction leading to cardiac damage was published, the Acute Dialysis Quality Initiative (ADQI) came up with a new definition of CRS. It defined CRS as “disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ can induce acute or chronic dysfunction in the other” [11] (Table 1).

Table 1.

Phenotypes of CRS

PhenotypeNomenclatureDescriptionExample
Type 1 Acute CRS AHF resulting in AKI AHF/cardiogenic shock causing AKI 
Type 2 Chronic CRS CHF resulting in CKD CHF 
Type 3 Acute renocardiac AKI resulting in AHF Acute uremia causing cardiac injury/volume overload 
Type 4 Chronic renocardiac CKD resulting in CHF CKD causing LVH, diastolic dysfunction, cardiomyopathy 
Type 5 Secondary CRS Systemic factors causing both heart and kidney dysfunction Diabetes, hypertension, amyloidosis 
PhenotypeNomenclatureDescriptionExample
Type 1 Acute CRS AHF resulting in AKI AHF/cardiogenic shock causing AKI 
Type 2 Chronic CRS CHF resulting in CKD CHF 
Type 3 Acute renocardiac AKI resulting in AHF Acute uremia causing cardiac injury/volume overload 
Type 4 Chronic renocardiac CKD resulting in CHF CKD causing LVH, diastolic dysfunction, cardiomyopathy 
Type 5 Secondary CRS Systemic factors causing both heart and kidney dysfunction Diabetes, hypertension, amyloidosis 

CRS, cardiorenal syndrome; AHF, acute heart failure; CHF, chronic heart failure; AKI, acute kidney injury; CKD, chronic kidney disease; LVH, left ventricular hypertrophy.

Almost half of the patients with HFpEF have CKD. In the two large trials, PARAGON HF [12] and EMPEROR Preserved [13], 47% and 50% cases, respectively, had an eGFR of <60 mL/min/1.73 m2. Similarly, baseline CKD is an established risk factor for incident HFpEF [14]. In addition, CKD is associated with systemic inflammation and endothelial dysfunction, which are also implicated in myocardial hypertrophy, stiffening, and fibrosis, eventually leading to HFpEF [15]. Increased filling pressures in HFpEF lead to neurohumoral activation, causing renal damage. Given the shared pathophysiological processes between HFpEF and CKD, it can be hypothesized that worsening cardiac function can alter renal milieu and vice versa, which is, by definition, CRS. Given that worsening renal function (WRF) increases mortality in HFpEF [16], the development of CRS in HFpEF is prognostically significant. This review aims to highlight the epidemiology, pathophysiology, diagnosis, and management of CRS in HFpEF, including recent therapeutic advances.

Older age, hypertension, diabetes mellitus, coronary artery disease, and obesity are well-established risk factors for HFpEF [17].

  • Age

With advancing age, there are increased arterial stiffness, myocardial stiffness, decreased diastolic relaxation, and increased LV mass [18].

  • Hypertension

Systemic hypertension leads to left ventricular hypertrophy, diastolic dysfunction, and abnormal ventriculoatrial coupling [19]. In the kidneys, it causes vascular lesions that lead to hyaline arteriosclerosis and glomerular injury [20].

  • Diabetes Mellitus

Almost 45% of patients with HFpEF have diabetes mellitus [21]. Patients with diabetes have neurohumoral activation and altered sodium handling. This leads to vascular congestion and decreased diuretic responsiveness [22], thus worsening HFpEF. Diabetes also affects kidneys in multiple ways, including intraglomerular hypertension, hyperfiltration, renin-angiotensin-aldosterone system (RAAS) activation, and inflammation [23].

  • Obesity

Obesity is implicated in atrial and ventricular remodeling and dysfunction, systemic inflammation, and plasma volume expansion in HFpEF [24]. Studies indicate that obesity is associated with chamber stiffness, prolonged myocardial relaxation, and reduced myocardial ATP availability [25, 26], leading to sustained pressure overload and progressive diastolic dysfunction that can lead to HFpEF [27].

In patients with CKD, obesity can directly cause glomerular injury via dilation of the afferent arteriole and an increase in salt reabsorption [28]. In patients with HFpEF, factors affecting renal function include hypertension, RAAS activation, endothelial dysfunction, elevated central venous pressure, microvascular dysfunction, inflammation, and chronotropic incompetence (CI). Figure 1 shows the pathophysiology of CRS.

Fig. 1.

Pathophysiology of CRS.

Fig. 1.

Pathophysiology of CRS.

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Increased Central Venous Pressure

CVP is a marker of venous congestion. An increased CVP is associated with a predisposition for the development of HF in patients with cardiac dysfunction and reduced survival [29]. The study by Damman et al. [29] showed that an increased CVP was a determinant of all-cause mortality, independent of cardiac function, and was most significant in patients with severely increased CVP. HFpEF is characterized by an elevated CVP that leads to renal venous hypertension, increased renal resistance, and decreased renal perfusion [29]. In conditions of poor cardiac output, the blood accumulates in the renal veins. This increases renal venous pressure and, subsequently, CVP.

The increase in CVP can also cause increased renal venous pressure, a reduction in renal blood flow, and an increase in interstitial pressure, which is transmitted to glomerular tubules, reducing the GFR. Mullens et al. [30] studied outcomes of acute decompensated HF (ADHF) patients when treatment was guided by pulmonary artery pressure. Patients with higher CVP on admission had WRF. The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial demonstrated a significant positive correlation between right atrial pressure (RAP) and serum creatinine [31]. This underlined the role of increased venous pressure and congestion in WRF in HF patients [31]. Similar correlations were also demonstrated by Iida et al. [32] and Nijst et al. [33], where renal hemodynamics worsened with central venous congestion and not with resistance index. The association of all-cause mortality and elevated CVP was additive to the observation that the same also lowers eGFR, which may influence survival by different mechanisms [29].

Renin-Angiotensin-Aldosterone System

The activation of RAAS in response to reduced renal blood flow in decompensation leads to vasoconstriction of the afferent arteriole [34]. Initially, these compensatory mechanisms increase filtration fraction and GFR, although chronic RAAS activation causes worsening of kidney function [34]. The hemodynamics of HFpEF are ambiguous as the ESCAPE trial did not show improvement in renal function with improved cardiac index [31]. The positive effects of RAAS inhibition (via ACEi) in patients with ejection fraction of more than 40%, no apparent HF, or substantial hypertension were demonstrated by three prospective trials, namely Heart Outcomes Prevention Evaluation (HOPE), European Trial of Reduction in Cardiac Events with Perindopril among patients with stable coronary artery disease (EUROPA), and Prevention of Events with ACE Inhibition (PEACE) trials [35‒37]. However, renal outcomes were not reported.

Coronary Microvascular Dysfunction

Coronary microvascular dysfunction (CMD) is postulated as an essential HFpEF mechanism. In the PROMIS-HFpEF trial, 75% of patients with HFpEF and nonobstructive coronary arteries had evidence of CMD (measured using coronary flow reserve) [38]. Reduced coronary flow reserve, in turn, was associated with statistically significant elevation in NT-proBNP and urine albumin-creatinine ratio [38, 39]. NT-proBNP, being an indicator of RV dysfunction, supports the association with elevated CVP. Elevated urine albumin-creatinine ratio supports the evidence for microvascular disease in the kidney [40]. CMD is important, especially in type 4 CRS. As per a study by Bajaj et al. [41], in patients with CKD and nonobstructive coronary artery disease, CMD is associated with impaired left ventricular mechanics and cardiovascular risk. Moreover, this chronic renal dysfunction is independently associated with a gradual reduction in coronary microvascular function and left ventricular function [41].

Oxidative Stress

Among the nonhemodynamic mechanisms for cardiac and renal dysfunction, reactive oxygen species (ROS) are essential [42]. The generation of ROS occurs via the nicotinamide adenine dinucleotide phosphate hydrogenase and nicotinamide adenine dinucleotide hydrogenase oxidase pathways, which are activated by the RAAS [42]. These ROS can cause oxidative injury to cardiomyocytes and renal tubular epithelial (RTE) cells. RAAS-induced ROS activation and subsequent organ damage can occur in all types of CRS. In renal cells, mitochondrial dysfunction is thought to play a role in CRS due to an increased release of mitochondrial ROS induced by hypoxia and chronic RAAS activation [43].

Recent studies have aimed to study the change in oxidative stress in response to various management strategies. Although the benefit of statins in HFpEF is not well established, an animal study showed that they were associated with improvement in diastolic function [44].

The SATELLITE trial using a novel selective myeloperoxidase inhibitor demonstrated the downregulation of biomarker pathways associated with clinical outcomes in patients with HFpEF [45]. The supplementation of ferric carboxymaltose in patients with HFpEF was also shown to have a significant reduction in serum malondialdehyde levels, along with an improvement in endothelial function [46]. With a trial of exercise training cardiac rehabilitation therapy, Corbi et al. [47] demonstrated a significant increase in antioxidant pathway molecules (sirtuin-1 and beta-hydroxybutyrate) in elderly NYHA II and III patients with HFpEF.

Endothelial Dysfunction

Chronic inflammation from comorbidities such as obesity, diabetes mellitus, hypertension, COPD, and CKD in patients with HFpEF leads to a systemic inflammatory state and microvascular endothelial inflammation, thereby reducing nitric oxide (NO) levels [42]. This leads to reduced NO-cyclic guanosine monophosphate signaling, causing LV remodeling and HFpEF [42]. NO regulates renal hemodynamics, and reduced signaling worsens renal function [42]. CKD is also associated with inflammation and endothelial dysfunction and can contribute to HFpEF (CRS types 3 and 4). NO also regulates renal hemodynamics, and reduced signaling leads to WRF, sodium, and water retention, leading to HFpEF [42, 48, 49]. A trial of praliciguat, a selective upregulator of NO-cyclic guanosine monophosphate, was conducted in patients with HFpEF, although no significant changes were seen in levels of NT-proBNP and eGFR [50]. The findings from small and short-term trials with N-acetyl cysteine and L-citrulline show an improvement in peripheral vessel blood flow, and long-term and large-scale evidence is necessary to derive associations [51, 52].

Chronotropic Incompetence

The mechanism of reduced exercise capacity in patients with HFpEF is potentially explained by CI [53]. It is speculated that the underlying autonomic dysfunction associated with CI in HFpEF leads to increased renal sympathetic activity, causing reduced renal plasma flow [53]. Klein et al. [54] showed the prevalence of CI in HFpEF to be 75%, and it was significantly associated with low GFR and high BNP, with an independent association with GFR as well. In contrast, in the PRESERVE-HR trial, a withdrawal of beta blockers from therapy in patients with HFpEF showed no change in NT-proBNP, although the withdrawal crossover period was 2 weeks [53]. Additionally, renal dysfunction is associated with autonomic dysfunction, leading to CI and HFpEF.

Biomarkers can identify early renal or cardiac injury, risk stratification, and response to therapy. Troponin (biomarker for myocardial injury) and NT-proBNP (biomarker for wall stretch) are commonly used in clinical practice and correlate well with cardiac injury. In contrast, biomarkers of renal injury (creatinine) have numerous caveats, especially in CRS. Ahmad et al. [55] showed that tubular injury (quantified by cystatin C) was not associated with WRF (measured using serum creatinine) in patients with AHF undergoing diuresis. Thus, differentiating between functional changes in eGFR and true AKI is essential in CRS. Most of the current biomarkers are used for prognostication. However, the aim is to identify patients most likely to benefit from CRS-specific therapies [56]. Thus, the use of novel biomarkers to indicate actual cardiac and renal damage and guide therapy is essential (Table 2) [57‒70].

Table 2.

Biomarkers in CRS

BiomarkerValuePrognostic valueStudySample sizeConclusionDiagnostic valueStudySample sizeConclusion
Cystatin C Glomerular filtration and integrity CRS Brouwers et al. [578,592 Higher cystatin C levels are strong risk factors for new-onset HFpEF CRS Soto et al. [58616 Serum cystatin C is an early, predictive biomarker of AKI 
Albuminuria Glomerular filtration and integrity CRS CHARM [597,599 Albuminuria had a strong prognostic value for all-cause mortality, cardiovascular death, and readmission in patients with HF CRS Gori [60217 The patients with HFpEF, low eGFR, and albuminuria were associated with the presence of mixed structural and functional abnormalities, as shown by higher LV wall thickness, NT-proBNP, and lower MWFS 
GISSI-HF [612,131 
Val-HeFT [625,010 
Serum NGAL Tubular kidney injury CRS Hasse et al. [632,538 NGAL level appears to be of diagnostic and prognostic value for AKI AKI Hasse et al. [632,538 NGAL level appears to be of diagnostic and prognostic values for AKI 
NAG Tubular kidney injury CRS Damman et al. [64655 Higher NAG levels showed the strongest association with the combined endpoint of all-cause mortality and HF hospitalizations CRS, AKI Jungbauer et al. [66173 NAG is potential marker of CRS 
KIM 1 Tubular kidney injury CRS Damman et al. [64655 Higher KIM-1 levels were associated with increased combined endpoint of all-cause mortality and HF hospitalizations AKI Grodin et al. [65874 Increased plasma KIM-1 at baseline is associated with a greater incidence of renal dysfunction 
IL 18 Tubular kidney injury CRS Chen et al. [67732 Urinary IL-18 measurement at the time of AKI diagnosis predicted AKI progression and worsening of AKI with death in ADHF AKI Liu et al. [694,512 Urinary IL-18 is a useful biomarker of AKI with a moderate predictive value across all clinical settings. 
Galectin 3 Tissue fibrosis HF, CRS Lok et al. [68240 Plasma galectin-3 has a prognostic value independent of severity of HF, as assessed by NT-proBNP levels 
Carbohydrate antigen 125 (CA125) Glycoprotein synthesized by epithelial serosal cells HF Menghoum et al. [70139 CA 125 levels were a strong and independent predictor of HF hospitalization in HFpEF patients 
CRS Espriella et al. [714,595 In patients with AHF and severely reduced eGFR, CA125 outperforms NT-proBNP in predicting 1-year mortality     
BiomarkerValuePrognostic valueStudySample sizeConclusionDiagnostic valueStudySample sizeConclusion
Cystatin C Glomerular filtration and integrity CRS Brouwers et al. [578,592 Higher cystatin C levels are strong risk factors for new-onset HFpEF CRS Soto et al. [58616 Serum cystatin C is an early, predictive biomarker of AKI 
Albuminuria Glomerular filtration and integrity CRS CHARM [597,599 Albuminuria had a strong prognostic value for all-cause mortality, cardiovascular death, and readmission in patients with HF CRS Gori [60217 The patients with HFpEF, low eGFR, and albuminuria were associated with the presence of mixed structural and functional abnormalities, as shown by higher LV wall thickness, NT-proBNP, and lower MWFS 
GISSI-HF [612,131 
Val-HeFT [625,010 
Serum NGAL Tubular kidney injury CRS Hasse et al. [632,538 NGAL level appears to be of diagnostic and prognostic value for AKI AKI Hasse et al. [632,538 NGAL level appears to be of diagnostic and prognostic values for AKI 
NAG Tubular kidney injury CRS Damman et al. [64655 Higher NAG levels showed the strongest association with the combined endpoint of all-cause mortality and HF hospitalizations CRS, AKI Jungbauer et al. [66173 NAG is potential marker of CRS 
KIM 1 Tubular kidney injury CRS Damman et al. [64655 Higher KIM-1 levels were associated with increased combined endpoint of all-cause mortality and HF hospitalizations AKI Grodin et al. [65874 Increased plasma KIM-1 at baseline is associated with a greater incidence of renal dysfunction 
IL 18 Tubular kidney injury CRS Chen et al. [67732 Urinary IL-18 measurement at the time of AKI diagnosis predicted AKI progression and worsening of AKI with death in ADHF AKI Liu et al. [694,512 Urinary IL-18 is a useful biomarker of AKI with a moderate predictive value across all clinical settings. 
Galectin 3 Tissue fibrosis HF, CRS Lok et al. [68240 Plasma galectin-3 has a prognostic value independent of severity of HF, as assessed by NT-proBNP levels 
Carbohydrate antigen 125 (CA125) Glycoprotein synthesized by epithelial serosal cells HF Menghoum et al. [70139 CA 125 levels were a strong and independent predictor of HF hospitalization in HFpEF patients 
CRS Espriella et al. [714,595 In patients with AHF and severely reduced eGFR, CA125 outperforms NT-proBNP in predicting 1-year mortality     

High-sensitivity cardiac troponins serve as well-established indicators for both diagnosis and prognosis in acute myocardial infarction. Beyond their diagnostic utility, these biomarkers carry significant prognostic implications when heightened in cases of ADHF, irrespective of the presence of myocardial ischemia or underlying coronary artery disease. Elevated levels of cardiac troponins correlate with an elevated risk of mortality. Moreover, the prevalence of heightened cardiac troponins escalates with a deteriorating GFR, and a persistent elevation is linked to an increased risk of mortality [72].

The “2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure” provides a strong recommendation for using BNP and proBNP in the diagnosis, assessing severity and prognostication of both AHF and chronic heart failure (CHF) [73]. Increases in BNP levels during episodes of acutely decompensated HF and acute coronary syndromes are linked to a heightened risk of AKI [73]. Patients with CKD exhibit elevated levels of BNP compared to individuals of similar age and sex with normal renal function. BNP levels are also significantly elevated in patients with evidence of CRS compared with patients with AHF without renal impairment [73]. This elevation likely stems from a combination of heightened cardiac BNP production due to pressure-volume overload and reduced renal clearance, particularly notable with NT-proBNP compared to BNP [74]. It is imperative to reassess our interpretation of natriuretic peptides in patients using ARNI therapy, especially in patients with CRS.

Cystatin C

Cystatin C is a low molecular weight cysteine proteinase in all nucleated cells and is synthesized at a constant rate, freely filtered, completely reabsorbed, and not secreted in renal tubules [34]. It is an early biomarker of AKI, and multiple studies have proven cystatin C to outperform serum creatinine in detecting AKI [58, 75]. Higher levels of cystatin C in patients (age >65 years) with CHF are associated with a higher mortality risk, and the sequentially increasing risk doubles at a cystatin C value >1.55 mg/dL [76]. Independent of eGFR, a higher serum concentration of cystatin C was associated with a worse NYHA class and diastolic dysfunction in elderly patients with HFpEF in cohort studies in China and Spain [77, 78]. Although extensive prospective studies are required, it can be hypothesized that cystatin C can be a marker of renal dysfunction and cardiac functional status in HFpEF independent of eGFR.

Soluble Suppressor of Tumorigenicity 2

Soluble suppressor of tumorigenicity 2 (sST2) is produced by LV and LVOT endothelial cells in response to mechanical strain [34]. sST2 signaling is implicated in myocardial inflammation, hypertrophy, and interstitial fibrosis [34, 79]. A meta-analysis of 16 studies on the association of HFpEF and sST2 showed sST as a prognostic marker [79]. It was strongly associated with all-cause mortality and hospitalization in patients with HFpEF [79]. ST2 has a prognostic value in risk stratification for HF, presumably CKD, and is not adversely influenced by age and impaired renal function [80].

Galectin-3

Galectin-3 is a lectin that is involved in various processes, such as cell-cell or cell-ECM interactions through beta-glucoside, inflammation, fibrosis, apoptosis, cell cycle control, and macrophage activation [81]. It is secreted in the serum and urine during pathological processes and can act as a prognostic or diagnostic marker, particularly in heart disease [81]. Galectin 3 has been approved by the US FDA to detect myocardial fibrosis in HF [81]. It is an independent predictor of mortality in NYHA III and IV patients adjusted for NT-proBNP and eGFR levels [68]. A study by Gopal et al. [82] showed that galectin-3 levels were independently associated with the severity of renal dysfunction regardless of the severity of HF in HFpEF, HFrEF, or CKD patients without HF. The association was exponential in patients with GFR <20 mL/min/1.73 m2 [82].

Neutrophil Gelatinase-Associated Lipocalin

Neutrophil gelatinase-associated lipocalin (NGAL) is a protein found in the neutrophil granules and transcribed in the kidney [56]. The steady-state concentrations of NGAL in the serum and urine are less than 20 ng/mL [56]. It is almost completely absorbed in the PCT and hence acts as a marker for tubular damage, particularly urinary NGAL, which is synthesized in the kidneys [56]. Higher NGAL levels were associated with AKI and mortality in hospitalized patients with ADHF [83]. The predictive value of urinary NGAL for AKI has increased with the rise of NGAL in patients with AHF [84]. In a recent cohort study comparing urinary markers between HFpEF and HFrEF, higher levels of the proximal tubular damage markers urinary KIM-1 and urinary NGAL were seen in HFpEF. In patients with an eGFR <45 mL/min/1.73 m2, urinary NGAL levels were higher in HFpEF. The difference in tubular markers was mainly present in patients with a preserved eGFR and HFpEF, implying that renal dysfunction might already be present, even when glomerular function is still preserved [85].

Tissue Inhibitor of Metalloproteinase-2 and Insulin-Like Growth Factor-Binding Protein 7

Tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 are tubular markers and have been studied in cohort studies in patients with ADHF as indicators for AKI [86‒88]. All studies demonstrated tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 as sensitive markers for AKI and CRS in ADHF.

Kidney Injury Molecule-1

Kidney injury molecule-1 (KIM-1) is a transmembrane receptor glycoprotein secreted in renal tubular injury due to ischemia or hypoxia as urine KIM-1 [89]. In the analysis of the ROSE-AHF registry, the levels of KIM-1 were not associated with WRF in patients with AHF under aggressive loop diuretics [55]. Meanwhile, in the analysis of the ASCEND-HF study group, day 30 plasma levels of KIM-1 were independently associated with 180-day mortality [65]. The same study supported the diagnostic utility of baseline KIM-1, which was associated with a lesser 24-h urine volume (p = 0.019), greater creatinine increase at 24 h (p = 0.048), more dynamic renal function at 48 h (defined as either an increase or decrease in serum creatinine of ≥0.3 mg/dL; p = 0.0008), and a greater incidence of WRF (Δcystatin C >0.3 mg/L) by 48–72 h (p < 0.0001) [65].

N-Acetyl-β-d-Glucosaminidase

N-Acetyl-β-d-glucosaminidase is a lysosomal protein seen in the urine as a marker of tubular injury [90]. It has been shown to be associated with an increased risk of hospitalizations and mortality in patients with HFrEF independent of GFR over a 5-year follow-up [64]. However, another study in patients admitted for AHF with HFpEF and CKD showed that high levels of N-acetyl-β-d-glucosaminidase (>14.2 U/gCr) were not associated with HF-related exacerbations or death [91].

In CRS, accurate diagnosis is crucial for appropriate management and improved patient outcomes. Given the complex interplay between cardiac and renal dysfunction, CRS diagnostic strategies aim to comprehensively assess cardiovascular and renal parameters [34]. Here are the key diagnostic approaches.

Clinical Evaluation

  • 1.

    A thorough clinical history and physical examination are essential to identify signs and symptoms suggestive of CRS, such as dyspnea, edema, fatigue, reduced exercise tolerance, and fluid overload.

  • 2.

    Assessing comorbidities, including hypertension, diabetes mellitus, coronary artery disease, and CKD, is vital to understanding the underlying pathophysiology and risk factors. Laboratory investigations involve the use of biomarkers (mentioned above).

Impaired kidney function in patients with HF is defined as a reduction in GFR. The most common test used to estimate GFR is the serum creatinine concentration. However, serum creatinine is variable based on age, sex, and body weight. Estimation equations provide a better estimate of GFR than the serum creatinine alone by including known variables that affect the serum creatinine independent of GFR. These equations require stable serum creatinine concentration; they cannot be used to estimate GFR in a patient with rising serum creatinine.

Markers of tubular renal injury have a diagnostic value in differentiating between prerenal and intrinsic renal causes of AKI. Urinary microscopy, a readily available tool, in patients with ATN classically is described as containing RTE cells, RTE cell casts, granular casts, or mixed cellular casts. In contrast, sediment in prerenal AKI patients is usually bland or contains occasional hyaline casts [92]. Several emerging urinary biomarkers exhibit potential in detecting tubular injury in AKI.

Especially in CRS, Ahmad et al. [55] showed that tubular injury (quantified by cystatin C) was not associated with WRF (measured using serum creatinine) in patients with AHF undergoing diuresis. Thus, differentiating between functional changes in eGFR and true AKI is essential in CRS. Most of the current biomarkers are used for prognostication. However, the aim is to identify patients most likely to benefit from CRS-specific therapies [56]. Thus, using novel biomarkers to indicate actual cardiac and renal damage and guide therapy is essential.

Imaging

Echocardiography

Based on the definition of HFpEF, echocardiography is essential to confirm a left ventricular ejection fraction (LVEF) >50% and to assess evidence of cardiac structural and functional abnormalities consistent with the presence of LV diastolic dysfunction/raised LV filling pressures (LV mass index, LV volume index, and E/e′ ratio) including raised levels of natriuretic peptides [93]. In a post hoc analysis of the PARAMOUNT trial, low eGFR in the absence of albuminuria had a higher prevalence of abnormal LV geometry (concentric hypertrophy, remodeling, or eccentric hypertrophy) and lower mid-wall fractional shortening as compared to reserved renal function [60]. The patients with low eGFR and albuminuria were associated with mixed structural and functional abnormalities, as shown by higher LV wall thickness, NT-proBNP, and lower mid-wall fractional shortening [60]. A retrospective study showed that reducing LVEF, increasing pulmonary artery pressure, and RV diameter were independently associated with the incidence of CRS [94].

Renal Ultrasonography

Renal ultrasonography offers valuable insights into the chronicity of disease by assessing factors such as renal size, echogenicity, cortical thickness, and abnormal corticomedullary ratios. These parameters aid in distinguishing progression from type 1 CRS to a more gradual type 2 CRS phenotype or determine whether AKI or CKD is the primary underlying condition in the clinical manifestation of CRS [95].

Intrarenal venous flow patterns are emerging tools for identifying CRS renal venous congestion. In a prospective study of 224 patients with HF, Lida et al. [96] showed that intrarenal venous flow patterns depended on RAP, suggesting a correlation with renal congestion. In addition, intrarenal venous flow patterns were shown to strongly correlate with clinical outcomes independent of RAP and other risk factors and may be a useful visual biomarker of renal congestion, providing additional information to stratify vulnerable HF patients.

The management of CRS in HFpEF is focused on controlling comorbidities such as hypertension and diabetes mellitus, avoiding tachycardia, and maintaining euvolemia. Prompt diagnosis is essential for disease attenuation and survival [11]. Figure 2 highlights the key strategies in the management of CRS in HFpEF.

Fig. 2.

Treatment approach for HFpEF and CRS.

Fig. 2.

Treatment approach for HFpEF and CRS.

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Volume Overload State

Diuretics

Diuretics are the mainstay in the acute decompensated phase of HFpEF, just like in HFrEF. However, the fluid volume, fluid distribution, and diuretic response patterns differ in HFpEF and HFrEF [97]. In response to diuretics, HFpEF patients lost more total body fluid compared to HFrEF and less intravascular volume compared to HFrEF. Another study on AHF assessing plasma volume reduction and renal function found that HFpEF patients were more susceptible to renal dysfunction compared to HFrEF in response to diuretics [98]. Therefore, the traditional approach used in HFrEF may not be applicable. Measuring accurate intravascular volume, although challenging, can help guide adequate diuretic therapy in these patients. In recent trials, bio-impedance vector analysis has shown promise in assessing intravascular volume [99, 100].

Loops diuretics are the preferred diuretics, and they have a steep dose-response curve highlighting the importance of diuretic threshold and ceiling effects [101]. In patients not responding adequately to initial doses, doubling the dose is reasonable. Minor creatinine increases after initiating diuretics reflect hemodynamic changes rather than renal injury. The ROSE-AHF trial studied kidney injury biomarkers in AHF patients taking high-dose diuretics [102]. They found that the tubular kidney injury diagnosed with biomarkers did not correlate with WRF associated with high-dose diuretics. Studies have also shown that temporary cessation of ACEi/ARB to improve renal function worsens diuretic response in hemodynamically stable patients. Use of ACEi/ARB with intravenous diuretics is associated with increased natriuresis and diuresis without worsening kidney function [103, 104]. This suggests that a mild increase in creatinine should not be a factor in discontinuing diuretics, reducing the dose of diuretics in a congested patient, or holding essential therapy such as ACEi/ARB. If no response is seen after increasing dose and frequency, diuretic resistance, defined as an inadequate rate or quantity of natriuresis despite an adequate diuretic regimen [105], should be considered (Table 3).

Table 3.

Approach to diuretic resistance

MechanismExamplesSolution
Prerenal Venous congestion, increased intra-abdominal pressure, reduced cardiac output, hypoalbuminemia, increased salt intake Address hypotension, low cardiac output 
Limit sodium intake 
Possible use of hypertonic saline in addition to diuretics 
Pre-loop of Henle Increased PCT sodium absorption, reduced GFR, increased organic anions, albuminuria  
Loop of Henle Loop diuretic dose, response at the level of loop of Henle, hypokalemic alkalosis Increase dose/frequency 
Post-loop of Henle Compensatory DCT sodium reabsorption Add thiazide/metolazone for sequential nephron blockade 
MechanismExamplesSolution
Prerenal Venous congestion, increased intra-abdominal pressure, reduced cardiac output, hypoalbuminemia, increased salt intake Address hypotension, low cardiac output 
Limit sodium intake 
Possible use of hypertonic saline in addition to diuretics 
Pre-loop of Henle Increased PCT sodium absorption, reduced GFR, increased organic anions, albuminuria  
Loop of Henle Loop diuretic dose, response at the level of loop of Henle, hypokalemic alkalosis Increase dose/frequency 
Post-loop of Henle Compensatory DCT sodium reabsorption Add thiazide/metolazone for sequential nephron blockade 

Ultrafiltration

Ultrafiltration (UF) can be used for the management of ADHF in patients with volume overload who do not respond to diuretics. However, the safety and efficacy of UF in patients with HFpEF need further clarification. Thus, the optimal mode of decongestion in AHF using diuresis versus UF has been the subject of clinical trials. The UNLOAD trial (Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure) studied 200 randomized patients within 24 h of hospitalization for AHF to either loop diuretics or UF [106]. The UF group achieved a more significant weight loss at the 48-h mark. However, the dyspnea score did not differ significantly between both groups, and no correlation was observed between the weight reduction and dyspnea scores [106]. There was no difference in episodes of hypotension within the first 48 h or changes in serum creatinine at 90 days between the two groups [106]. However, fewer readmissions at the 90-day mark were observed in the UF group [106]. About 70% of patients in both groups had an ejection fraction <40%, underlying the importance of studying UF in the HFpEF cohort [106].

While the UNLOAD trial highlights the advantages of using UF as a decongestion strategy, the results from the CARRESS-HF trial, a landmark study on AHF and WRF, comparing UF with stepped diuretics therapy, exhibited contrasting results. The change in weight and creatinine at 96 h after randomization showed no significant differences in weight loss between the two groups (5.5 ± 5.1 kg in the diuretic group versus 5.7 ± 3.9 kg in the UF group; p = 0.58) [107]. The UF group had an increase in serum creatinine of 0.23 mg/dL versus a decrease of 0.04 ± 0.53 mg/dL in the diuretic group (p = 0.003). The patients in the UF. group experienced a higher rate of adverse events (72% versus 53%; p = 0.03) [107]. However, it is essential to note that in this trial, the mean EF was 30–35%, i.e., HFrEF. Fudim et al. [108] further analyzed the data from the CARRESS-HF trial and found that in patients with HFpEF, UF was associated with WRF irrespective of fluid removal rate. We need further research to determine if UF can provide clinically and economically significant benefits for high-risk populations with functional diuretic resistance and frequent readmission for AHF.

RAAS Inhibition

Angiotensin-Converting Enzyme Inhibitors/Angiotensin II Receptor Blockers (ACEi/ARBs)

Unlike HFrEF, RAAS inhibitors have not been shown to improve outcomes in HFpEF [109]. A meta-analysis conducted by Belduis et al. [110] showed that in patients with HFrEF who were randomly assigned to RAAS inhibitors, WRF was linked to slightly poorer outcomes than those without WRF. Nevertheless, the increase in mortality risk attributed to WRF in patients with HFrEF receiving a placebo was more pronounced. Similarly, among patients with HFpEF who were randomized to RAAS inhibitors, WRF was strongly associated with adverse outcomes compared to those without WRF. However, unlike HFrEF, HFpEF patients experiencing WRF while on placebo showed a lesser additional mortality risk compared to those on RAAS inhibition and experiencing WRF.

A study conducted by Schwatchenberg et al. [111] on the effects of vasodilation in HF patients can explain the lack of efficacy/deleterious effect of RAAS inhibitors in HFpEF. Compared to HFrEF, HFpEF patients had a greater blood pressure reduction, less cardiac output augmentation, and a higher drop in stroke volume. This suggests that HFpEF patients are more susceptible to vasodilator effects and can have excessive reductions in cardiac output with ACEi/ARBs.

ACEi/ARBs are not routinely used as a primary treatment for HFpEF. However, many patients with HFpEF may have an indication for treatment with an ACEi/ARB (e.g., diabetes, acute myocardial infarction, CKD) [112, 113]. In such cases, clinicians should exercise heightened caution when initiating, adjusting, or maintaining RAAS inhibitor therapy in response to declining eGFR levels.

Angiotensin Receptor/Neprilysin Inhibitor

Sacubitril/valsartan, also known as angiotensin receptor neprilysin inhibitor (ARNI), is widely used in treating HFrEF. However, for HFpEF, it carries a class 2B recommendation [114]. The PARAGON-HF trial compared clinical outcomes with sacubitril/valsartan versus valsartan in 4,796 patients with NYHA class II to IV HF, LVEF ≥45 percent (median 57 percent), and elevated natriuretic peptide levels [115]. At a median follow-up of 35 months, patients in the sacubitril/valsartan group were less likely to have increases in creatinine and potassium levels than those in the valsartan group. Similarly, in the PARAMOUNT trial, the decline in eGFR was less in the intervention group compared to the valsartan group. The incidence of WRF was also lower in the intervention group [116].

A pooled analysis of PARAGLIDE HF [117] and PARAGON HF [115] trials showed a reduction in poor renal outcomes in the sacubitril-valsartan group compared to the valsartan group [118]. While ARNI is not recommended as a primary therapy, it can be used in patients with persistent HF symptoms. Cost is a factor that needs to be taken into consideration. Before starting treatment with an ARNI, potassium levels should be <4.7 mEq/L and eGFR >30 mL/min/1.73 m2, and renal function and electrolytes should be closely monitored.

Mineralocorticoid Receptor Antagonist

The benefit of mineralocorticoid receptor antagonists (MRAs) in patients with HFrEF has already been established [119]. In trials that included patients with HFpEF, MRAs reduced the risk of HF hospitalization but did not reduce mortality risk [120]. Regarding renal function, a recent study investigating MRA therapy in CKD patients showed that MRA use was significantly associated with a lower risk of renal replacement therapy initiation. This association was consistently observed in patients with and without diabetes and those with advanced CKD. The slowing of the decline in renal function may have potential benefits in patients with CRSs and needs further investigation. The benefit of MRA therapy must also be weighed against the risk of hyperkalemia.

Finerenone is a novel nonsteroidal MRA that has recently received regulatory approval to indicate cardiorenal protection in patients with CKD associated with diabetes mellitus. Two landmark phase 3 clinical trials, FIDELIO-DKD and FIGARO-DKD, demonstrated that among patients with diabetes and a broad spectrum of CKD, finerenone reduced the risk of “hard” cardiovascular and kidney failure outcomes as compared with placebo, with a minimal risk of hyperkalemia [121‒123].

A prespecified subgroup analysis of the FIDELIO-DKD trial provided preliminary data that the effect of finerenone on cardiorenal outcomes in patients with CKD and diabetes was not modified by a baseline history of HF [124]. Since symptomatic HFrEF was an exclusion criterion, patients reporting a history of HF in FIDELIO-DKD had either HFmrEF or HFpEF. Similarly, the benefit of finerenone on the composite kidney failure outcome was irrespective of a history of HF at baseline [124]. Owing to these subgroup analyses’ post hoc nature and limited statistical power, the results are only hypothesis-generating [123]. More conclusive evidence on the safety and efficacy of finerenone in patients with HFpEF is anticipated from the ongoing FINEARTS-HF (Finerenone Trial to Investigate Efficacy And Safety Superior to Placebo in Patients With Heart Failure) trial [125].

Since the evidence for MRA efficacy in patients with HFpEF is weaker than the evidence for MRA efficacy in patients with HFrEF, it should be dosed more cautiously in patients with HFpEF. Hyperkalemia commonly limits the dose, while the effect on systolic blood pressure is mild (e.g., a mean decrease of 3 mm Hg in TOPCAT). Factors that may cause hyperkalemia should be avoided, mainly if the serum potassium level is >4.5 mEq/L. If the serum potassium level is >5.0 mEq/L, the dose of MRA should be reduced or even discontinued.

Sodium-Glucose Transporter 2 Inhibitors

Sodium-glucose transporter 2 inhibitors (SGLT2i) have been found to have a protective effect on the heart and kidney [126]. The cardiac benefits are postulated to stem from their ability to cause natriuresis and glycosuria, thereby reducing plasma volume and preload. Afterload reduction also occurs due to a reduction in arterial pressure and stiffness [126].

It is theorized that one mechanism through which SGLT2i exert renoprotective effects is by diminishing tubular sodium reabsorption and reinstating tubule-glomerular feedback (TGF) [127]. Restoration of TGF mitigates the UF within nephrons, thereby alleviating kidney congestion. In the long run, this ability to relieve congestion is crucial for delaying the onset of type 2 CRS. Figure 3 summarizes the beneficial effects of SGLT 2 inhibitors.

Fig. 3.

Beneficial effects of SGLT2i.

Fig. 3.

Beneficial effects of SGLT2i.

Close modal

In addition to restoring renal hemodynamics by TGF regulation, SGLT2i protect the renal tubular cells through various mechanisms. It reduces inflammation in the renal tubular cells by inhibiting NF-kB pathways [128], reduces oxidative stress by suppression of angiotensin II-mediated ROS generation by inhibiting angiotensin II-induced SGLT2 overexpression [128], improves energy metabolism of renal tubular cells by facilitating AMPK activation [129, 130], and delays tubular fibrosis by regulating fibrosis-related proteins [131, 132].

In a post hoc analysis of renal composite outcomes of the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus) trial, empagliflozin was associated with 35% reduction in HF hospitalization and 38% reduction in cardiovascular death [133]. In the EMPEROR-preserved trial, patients with an LVEF >40 percent, NYHA class II to IV HF symptoms, and an elevated NT-proBNP level, who were randomly assigned to treatment with Empagliflozin had a lower risk of HF hospitalization [13]. The risk of cardiovascular death was similar between the empagliflozin and placebo groups. The rate of decline in eGFR was lower in the empagliflozin group.

The CANVAS program (Canagliflozin Cardiovascular Assessment Study), comprising two sister trials, was designed to assess the cardiovascular safety and efficacy of canagliflozin and to evaluate the balance between any potential benefits of the drug and the risks associated with it, such as genitourinary infection, diabetic ketoacidosis, limb amputation, and fracture [134]. In regard to renal outcomes, the results showed a possible benefit of canagliflozin concerning the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67–0.79) and the composite outcome of a sustained 40% reduction in the estimated GFR, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47–0.77) [134]. A meta-analysis conducted by Neuen et al. [135] showed a significantly reduced risk of AKI, end-stage renal disease, and the risk of dialysis, transplantations, or death due to kidney diseases in the SGLT2i group compared to placebo. Improving kidney functions results in a decreased incidence of cardiovascular events and can improve established HF [136].

With studies showing beneficial cardiovascular and renal outcomes, SGLT2i are a potential therapeutic option for CRS. SGLT2i should not be used in patients with type 1 diabetes mellitus and type 2 diabetes with previous episodes of diabetic ketoacidosis. Caution should be exercised in patients with volume depletion, recurrent urinary tract infections, low eGFRs, and rapidly declining renal function.

Neurohormonal Modulation and Vasodilator and Inotropic Therapy

The maladaptive neurohumoral responses in AHF resulting from type 1 CRS involve essential vasoactive peptides such as vasopressin, endothelin, and adenosine and a diminished response to endogenous natriuretic peptides. Although theoretically attractive, neurohormonal modulation in the AHF setting has failed to improve hard clinical and renal endpoints in large, randomized studies.

Arginine vasopressin is a nonapeptide hormone released by the posterior pituitary in conditions of elevated serum osmolarity, reduced cardiac index, or hypovolemia [137]. It interacts with the transmembrane receptors V1aR, V1bR, and V2R expressed by several cell types [138]. The EVEREST program (Efficacy of Vasopressin Antagonist in Heart Failure Outcome Study with Tolvaptan) evaluated the use of Tolvaptan, a selective V2 receptor antagonist, in AHF and LVEF <40% [139]. No benefits in reduction in death or the composite of cardiovascular death and hospitalizations for HF were noted in the long-term trial [139]. The TACTICS HF trial, which aimed to investigate the benefits of adding Tolvaptan to a standardized Furosemide regimen, failed to show an additional advantage [140].

Nesiritide, a recombinant BNP, aimed to exploit the vasodilator properties of BNP in venous, arterial, and coronary circulation [141]. The ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure) involved randomizing 7,141 patients with AHF to receive intravenous Nesiritide or placebo for 1–7 days [141]. The primary outcome, which included dyspnea improvement, rehospitalization, or death, did not show statistically significant differences between the two groups [141]. The Nesiritide group experienced more instances of hypotension, with no notable disparities in renal function [141]. The ROSE-AHF trial, which randomized 360 patients with AHF and CKD to low-dose Nesiritide or Dopamine, showed no notable impact observed on the co-primary endpoints regarding cumulative urine volume and the change in serum cystatin C at 72 h [102]. Additionally, no influence was detected on the secondary endpoints, which reflect decongestion, renal function, or clinical outcomes [102].

Inotropes promise to improve type 1 CRS by boosting cardiac output and alleviating venous congestion. Certain inotropes, like Dopamine, possess direct renal effects that could improve type 1 CRS outcomes, but the clinical evidence remains inconclusive. A recurring observation in studies on inotropic therapy for AHF and reduced EF is that despite achieving beneficial acute hemodynamic effects, long-term cardiovascular outcomes remain unaffected [142, 143].

Future Therapies

Implantable Hemodynamic Monitoring

Venous congestion is an important aspect of WRF in HFpEF patients. Thus, monitoring hemodynamics can help tailor diuretics, improve decongestion, and prevent decompensation. The CHAMPION trial used a pressure sensor implanted in a pulmonary artery branch to monitor right-sided pressures (the CardioMEMS HF System) [144]. There was a significant reduction in HF hospitalization in patients monitored with this system. Although patients with renal insufficiency were excluded, future trials might show benefits in improving renal congestion and outcomes [144].

Interatrial Shunt

Interatrial shunt devices offer a new paradigm of treatment for patients with HFpEF by targeting the end physiological manifestation of increased left atrial pressure. This obviates some of the complexity surrounding the pathophysiological pathways leading to its development. These devices may have a role in CRS if they can reduce the rates of HF decompensation.

  • 1.

    Corvia atrial shunt device has been studied in REDUCE LAP-HF I and II trials and has the largest volume of evidence [145]. Placement of the atrial shunt device did not reduce the total rate of HF events or improve health status in the overall population of patients with HF and ejection fraction of greater than or equal to 40% [145].

  • 2.

    Ventura shunt implantation in the RELIEVE-HF open-label roll-in cohort showed that shunting with the Ventura device was safe and resulted in favorable clinical effects in patients with HF, regardless of LVEF [146]. Left and right ventricular structure and function improvements were consistent with reverse myocardial remodeling [146]. Further large-scale trials are required.

  • 3.

    No-implant devices, such as NoYA, are under investigation as they theoretically reduce the risk of embolization and thrombus formation [147]. Further studies are required to determine their efficacy and long-term benefits.

Renal Assist Devices

The traditional view of CRS has long focused on low cardiac output with resultant renal arterial hypoperfusion as the central hemodynamic derangement. However, renal venous congestion is increasingly recognized as an important hemodynamic contributor to the development of CRS, resulting in diminished renal perfusion pressure [148]. Novel circulatory renal assist devices for the treatment of acute (type I) CRS are in development, which aims to improve renal arterial perfusion (pushers) and reduce renal venous congestion (pushers). The devices have reported encouraging early-stage clinical results, demonstrating that they are at least safe and capable of favorably altering hemodynamics and fluid balance in the short term [149]. It remains unknown whether the observed hemodynamic gains and decongestion will continue after device removal and if they translate to more meaningful improvements in clinical outcomes. The value of CRS device therapy will ultimately rest on safety and the ability of these devices to affect predictable, meaningful, and durable improvements in renal function.

Renal Denervation

Hypertension is a significant risk factor for the development of HFpEF and CKD. Studies have shown that it precedes the development of HF in almost 85% of cases [150, 151], especially those with CRS [34, 152]. Therefore, adequate control of hypertension is paramount in these patients. As discussed above, the sympathetic nervous system plays a huge role in CRS [34, 152] via regulating renal hemodynamics and blood pressure [153]. Renal denervation (RDN) therapy was developed to treat resistant hypertension and showed promising results [154]. Recent studies have also evaluated its role in HF and CRS [152, 155]. A recent study on transgenic rats showed that RDN has protective effects on the autoregulatory capacity of renal blood flow and GFR. RDN also improved the pressure natriuresis relationship in rats with CRS [156]. Further studies are required to establish RDN as a therapeutic option in CRS.

Given the growing prevalence of HFpEF, CKD, and CRS, along with the economic burden they place on the healthcare system, it is crucial to focus on early diagnosis and management. Although previous data indicate promising new biomarkers and therapies for diagnosis, larger randomized trials are necessary to authenticate their effectiveness.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

H.K. was responsible for conceptualization and preparation of the original draft. S.S.S. and N.K. contributed to the preparation of the original draft. V.B.B. carried out the supervisory role and suggested edits to the original draft.

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