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Assessment and management of Heart Failure in Patients with Chronic Kidney Disease

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Submitted:

14 April 2023

Posted:

17 April 2023

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Abstract
CKD in HF patients is very common condition, their dysfunction is closely linked and influence each other, so their management required multidisciplinary and personalized approaches. The diagnosis of HF and CDK relies on signs and symptoms. Several tools, such as blood-based biomarkers and echography help us to clarify and discriminate the main characteristics of these patients. Evidence in improving survival due to new drug-employment in HF, has increasingly challenged physicians to manage patients with multiple diseases, especially in patients with CKD. The difficulty is in the safe administration of these drugs in patients with HF and CKD. Knowing up to which values ​​of creatinine or renal clearance any drug can be administered is fundamental. We wanted to summarize, on this sizable and complex topic, the experiences of various prior study to get clearer ideas and a more precise reference about the assessment and management of HF and CKD.
Keywords: 
heart failure
;  
kidney disease
;  
multidisciplinary assessment
;  
personalized treatment
Subject: 
Medicine and Pharmacology  -   Cardiac and Cardiovascular Systems

1. Introduction

The management of Heart Failure (HF) has greatly improved in recent years; however, the prognosis remains poor for several reasons. Among others, population aging and an increased survival after myocardial infarction are two factors that have changed patients’ profiles [1]. HF is often a concurrent condition in elderly patients with many prognosis-relevant comorbidities, i.e., diabetes, lung diseases, vascular diseases, myocardial infarction, among which, one of the most frequent is kidney damage. Furthermore, HF and Chronic Kidney Disease (CDK), share the same risk factors such as atherosclerosis, hypertension, obesity, tobacco use, dyslipidaemia, amyloidosis, vasculitis, negatively affecting both functions. They also have in common the same pathophysiological bidirectional pathways, such as endothelial dysfunction, sympathetic neurohormonal activation, inflammation, and oxidative stress. These processes converge and promote, over time, the dysfunction of both organs [2]. Therefore, the management of this subset of patients is particularly challenging and requires multidisciplinary and personalized approaches to maximize safety and minimize disease progression.

2. Epidemiology

Different meta-analyses of randomized controlled studies have shown that 49% of patients with HF suffered from CKD, with eGFR reduction below 60 mL/min/1.73 m2 [3]. In the Atherosclerosis Risk In Communities (ARIC) study, the incidence of HF was 3-fold higher in people with an eGFR <60 mL/min/1.73 m2 compared with those with eGFR >90 mL/min/1.73 m2 [4]. The Acute Decompensated Heart Failure National Registry (ADHERE) has shown that approximately 30% of patients admitted to hospital for acute decompensated HF have acute or chronic renal disease [5,6]. The prevalence of CKD was observed to be higher in acute HF patients (53%) compared with chronic HF patients (42%). Renal impairment is a predictor of a poor prognosis in patients with HF and has a strong association with worse outcomes [7]. In fact, CKD is related to a higher mortality risk in patient with HF [hazard ratio (HR) 2.34 - 95% confidence interval (CI) 2.20–2.50] [8].

3. Clinical assessment and cardiorenal syndromes

The cardiorenal syndromes (CRS) are usually defined as “disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other.” CRS have been categorized into 5 types based on the organ primarily affected by the disease and on the progression course (acute or chronic) [2]. The goals of this consensus classification were to give a consistent definition of clinical presentation of the patient with cardiorenal dysregulation for both diagnostic and therapeutic applications supporting the management of the patient with CRS.
However, in clinical practice, identifying the initial insult can be difficult. In the last years, the historical definition of CRS and its categorizing has been reconsidered by proposing a single, new concept of cardiorenal syndrome. Hatamizadeh et al. proposed an alternative classification of CRS based on the various clinical manifestations of CRS, regardless of the initial organ of the injury including concomitant cardiovascular and renal diseases, resulting from systemic processes and the related neuro-hormonal, inflammatory, toxic, immunological consequences also enclosing uremic impairment, anaemia, alterations in the mineral metabolism of iron and bones [9]. This new concept is expressed through a variety of heart diseases [i.e., diastolic dysfunction, HF with preserved ejection fraction (HFpEF), HF with mildly reduced ejection fraction (HFmrEF), HF with reduced ejection fraction (HFrEF), left ventricular hypertrophy] and in the kidney diseases [Acute kidney Injury (AKI) or CKD]. It is a classification of the patient based on the prevailing pathophysiological mechanism, identifiable with the biomarkers, and consequently the available therapy could be optimized.
Heart and kidney dysfunction are closely linked and influence each other: on the one hand, the impossibility of excreting salt and water and the subsequent increase in renin secretion by a diseased kidney increases cardiac preload and afterload getting worse HF; on the other hand, the decreased cardiac output and increased venous congestion causes the decrease of renal perfusion pressure. The renal venous congestion leading to many intrarenal mechanisms such as variations in the vascular tone of afferent and efferent arterioles, glomerular feedback that can keep, for a limited period, constant eGFR within a wide range of hemodynamic abnormalities, thus contrasting the decreased renal perfusion. If this situation does not resolve, it arise in renal interstitial hypertension, with necrosis of tubular epithelium, tubular hypertrophy, fibrosis, and permanent tubular injury [10]. In addition to the abnormalities in the haemodynamic state, in patients with HF and CKD, the activation of the neurohormonal system is a constant, it is the first response to the drop in blood pressure. Consequently, to maintain the perfusion of the noble organs a redistribution of the blood volume occurs and vasoconstriction, mediated by the sympathetic nervous system, plays a central role. Although it is a short-term adaptive mechanism, their prolongation exerts deleterious effects on both the heart and the kidneys [11].
It causes an increase in circulating catecholamines, leading to an increase in contractility, heart rate and vasoconstriction. This situation leads to peripheral systemic resistance, an increase in filling pressures and ventricular hypertrophy secondary to cardiomyocyte proliferation. Nevertheless, the increased level of norepinephrine is a factor associated with poor prognosis. Angiotensin II and aldosterone, produced as result of activation of the Renin-Angiotensin Aldosterone System (RAAS), due to reduced renal perfusion, induces water and sodium retention, with renal and systemic vasoconstriction, increased venous pressure and venous return of the end-diastolic right ventricle, increased oxidative stress, increased production of proinflammatory cytokines and cell-mediated phenotypic alterations, exacerbate renal and cardiac remodelling through profibrotic mechanisms [12].

4. Biomarkers

The diagnosis of HF and CDK relies on signs and symptoms, together with cardiac and renal anomalies either structural or functional. Several means, including blood-based biomarkers, help us to clarify and discriminate the main characteristics of these patients. These are useful to indicate early cardiac or kidney damage and can have a diagnostic, prognostic, and predictive role. In cardiology, biomarkers of myocardial stretch (BNP/NT-proBNP) are frequently used in clinical practice [13,14]. NT-proBNP may provide useful prognostic information in patients with HF and CKD, such as cardiovascular events, all-cause death, and quality of life [15]. The accuracy of NT-proBNP is higher than other biomarkers, even when used alone [16] (Table 1).
His superiority is also marked in patients with CKD stage 4-5 and end stage renal disease undergoing dialysis [17]. The correction for age is necessary to have a negative predictive value of this biomarker. Instead, its diagnostic cut-off must also be adjusted on eGFR, though a strong reference value is not yet known. BNP clearance is mainly pre-renal thus its concentration in CKD patients is less affected by eGFR, and there is no need to adjust the value in patients with CKD stages 1-2 [20]. In patients without symptoms of HF, increased atrial wall stretch increases BNP release which then reflects left ventricular overload, which may predict a high risk of evolving in HF. For patients with CKD and HF, a high BNP strongly predicts cardiovascular events and death from all causes. Patients with a reduction in BNP after treatment have a better prognosis than those with an increase or absence of variation in BNP [21].
Given the reduced renal excretion, patients with CKD accumulate toxins, which can cause specific damage to cardiomyocytes. P-cresyl sulfate, a cresol-derived protein-bound toxin, and asymmetric dimethylarginine, a product of protein catabolism in cells, were related to cardiovascular outcome and mortality in recent studies and were found to contribute to cardiac hypertrophy and endothelial dysfunction in in-vitro experiments [22,23]. Although promising, the role of these toxins as HF markers was not sufficiently specified and validated for their clinical use as markers of cardiovascular disease. These and other toxins could explain elevated biomarkers of myocyte damage as eGFR decreases. Myocyte damage biomarkers play an important role in the diagnostic and prognostic evaluation of patients with HF and CKD. The increase of high-sensitive Troponin T (HsTnT), the most important biomarker of myocyte injury, connects with the severity of HF and may correlate with poor prognosis for patients hospitalized with HF [21]. For patients with CKD and HF, the cut-off value of all-cause death should be adjusted by eGFR. HsTnT can predict death in CKD patients without cardiac symptoms and may predict the occurrence of HF. As the eGFR decreases, the prediction accuracy of HsTnT slightly decreases, particularly for CKD stages 5 [24] (Table 2).
Renal biomarkers are used as important additional tools in the diagnostic algorithm. Creatinine and eGFR have always been the reference biomarkers for acute and chronic kidney damage. Overt CKD is defined by eGFR <60 mL/min/1.73 m2 of body surface area, and/or by the presence of albuminuria (high 30–300 mg albumin/1 g of urine creatinine or very high >300 mg albumin/1 g of urine creatinine) (Figure 1). There are different criteria for the diagnosis of AKI, namely KDIGO, REFLE and AKIN. According to these, the acute kidney damage is staged based on the severity of the parameters considered, i.e., urinary output and serum creatinine value (Table 3).
Novel clinical biomarkers reflecting glomerular and tubular injury are currently available. In a subset of patients with HF, serum cystatin C (CysC), that along with albuminuria is a glomerular biomarker, has been shown to be a strong predictor of rehospitalization and short and long-term mortality. Plasma CysC can be used to estimate eGFR, which has been shown to be in good agreement with eGFR calculated from inulin clearance [25]. In patients with CKD and HF, several studies have shown that CysC can provide more prognostic information than creatinine and it can detect more correctly the risk groups of all causes of death and recurrent HF, although a clear cut-off value has not been proposed yet [26,27]. Its plasma concentrations are influenced by smoking habit, cancer, thyroid diseases, obesity, and it is not routinely used in clinical practice. Recent studies have also shown that excessive increase in plasma CysC can promote myocardial fibrosis through the accumulation of osteopontin and TIMP-1, and it can promote atrial dilatation and ventricular hypertrophy, resulting in diastolic dysfunction [28]. Neutrophil gelatinase-associated lipocalin (NGAL), in patient with CKD and AHF has diagnostic and prognostic value [29]; the combination of Tissue Inhibitor of MetalloProteinases-2 (TIMP-2) and Insulin-like Growth Factor Binding Protein 7 (IFGBP7) is a useful diagnostic and prognostic biomarker in AKI [30].
Clinical data in CKD patients identified circulating FGF23 as a marker for the diagnosis and prognosis of HF in CKD. FGF23 is a hormone produced by osteocytes that inhibits phosphate reabsorption and 1,25(OH)2D synthesis in the kidney. Multiple studies showed that FGF23 production progressively increases during CKD and its blood concentrations were associated with incident HF and cardiovascular events in general population and CKD patients [31,32,33]. Mechanisms supporting these clinical observations were explained by findings in in-vitro experiments showing that FGF23 may stimulate myocardial hypertrophy through a direct effect on cardiomyocytes [34,35] and fibroblasts leading to cardiac remodelling and fibrosis [36,37]. In addition, the activation of renin-angiotensin system and the administration of angiotensin II was able to increase FGF23 secretion by osteocytes in lab animals [36]; accordingly, patients with normal renal function showed an association of serum FGF23 with serum levels of BNP and cardiovascular adverse events that decreased in patients taking ACE-inhibitors [38]. Thus, FGF23 may be an independent predictor of cardiovascular risk in CKD patients [39] and the use of serum FGF23 determination in the clinical practice has been suggested, but not currently established, as its diagnostic and clinical value yet needs to be better detailed in prospective studies.
Canonical effects of FGF23 in the kidney may be modulated by Klotho, a membrane protein working as a cofactor of FGF23 receptor. The extracellular domain of Klotho may be cleaved and released in blood as soluble klotho that may have protective effects on heart and arteries [40,41]. Serum levels of soluble Klotho were associated with a lower risk of HF in a cross-sectional analysis of NHANES population [42]. Beneficial effects of Klotho are lost in CKD as its serum levels decrease with the decline of GFR. Therefore, soluble klotho could be considered to define the weight of serum FGF23 for the diagnosis of HF in CKD.
As mentioned above, clinical standards for the prognosis of HF depend on protein-based biomarkers. Recently, new opportunities for genetic analysis have emerged as a new approach to understanding the pathophysiology of HF and cardiovascular disease, paving the way for the development of gene-based biomarkers. "Omics" technology, which identifies gene variations at the genome and transcriptome levels, is a novel approach to identify DNA/RNA-based biomarkers [43,44]. In addition, omics analysis not only enables the identification of genetic variations that may contribute to the identification of HF risk, but also provides insight into the molecular mechanisms of the underlying disease. Although the application of new genetic biomarkers, such as genetic risk scores in disease prognosis, promises to improve disease risk estimation, unfortunately, only limited studies are available, and the efficacy of most new biomarker candidates has yet to be demonstrated [45]. However fascinating, the true value of these new biomarker candidates in the prognosis of HF remains unclear.

5. Imaging modalities

Echocardiography is always recommended in patients with suspected HF to identify any underlying anatomical and functional abnormalities and to classify it in HFpEF (> 50%), HFmrEF (41-49%) and HFrEF (<40%) to adjust the therapeutic approach. The calculation of the Ejection Fraction (EF) is also fundamental for evaluating the necessity for devices therapy i.e., Implantable Cardioverter- Defibrillator (ICD) or Cardiac Resynchronization Therapy- Defibrillator (CRT-D).
Echocardiography is also useful to find the causes of HF, through the estimation of left ventricular (LV) size, wall thickness and systolic function (global and regional qualitative assessment, quantitative volume estimation, EF), right ventricular (RV) systolic function, (qualitative assessment and systolic pressure in the pulmonary artery), size of the left atrium (LA) (Figure 1)[46,47,48,49].
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Figure 1. Echocardiographic evaluation of heart failure. Echocardiography plays a key role in the diagnostic algorithm in case of clinical suspicion and during the follow up. The bidimensional (a) and M-mode (b) assessment from multiple views are necessary to define the systolic function and the classification of HF according to the Left Ventricle Ejection Fraction (LVEF). The assessment of the diastolic function should be always performed by the measurement of the left atrium diameters and volumes, (c) the pulsed wave Doppler transmitral flow pattern and velocities (d) and the Tissue Doppler Imaging velocities on the septal (e) and lateral (f) mitral annulus. Moreover, echocardiography may allow an aetiological definition of heart failure.
Figure 1. Echocardiographic evaluation of heart failure. Echocardiography plays a key role in the diagnostic algorithm in case of clinical suspicion and during the follow up. The bidimensional (a) and M-mode (b) assessment from multiple views are necessary to define the systolic function and the classification of HF according to the Left Ventricle Ejection Fraction (LVEF). The assessment of the diastolic function should be always performed by the measurement of the left atrium diameters and volumes, (c) the pulsed wave Doppler transmitral flow pattern and velocities (d) and the Tissue Doppler Imaging velocities on the septal (e) and lateral (f) mitral annulus. Moreover, echocardiography may allow an aetiological definition of heart failure.
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Furthermore, the repetition of the echocardiogram is useful even when a change in the clinical picture suggests a change in ventricular function. Additional techniques such as Tissue Doppler Imaging (TDI) and Strain Rate (SR) should be incorporated into the protocol to identify patients who are at risk of HF or to identify early worsening of HF [50,51]. Hassanin N et al, showed that in patients with CKD, LV longitudinal systolic strain and early and late diastolic strain rates are significantly reduced despite preserved FE, identifying early patients at high risk of developing HF [52]. Krishnasamy et al, showed that global longitudinal strain predict mortality for all cause in CKD [53].
Echocardiography is also useful to estimate the volume status, trying to early identify patients with venous congestion and fluid overload through typical echocardiographic signs: right ventricular function calculated through some parameters such as the Fractional Area Change (FAC), the Tricuspid Annular Plane Systolic Excursion (TAPSE) and peak systolic velocity on Tissue Doppler (S′ wave) [54], tricuspid regurgitation [55], and inferior vena cava congestion [56] (Figure 2) and some haemodynamic parameters (esteem of central venous pressure, systolic pressure), lateral and septal longitudinal movement of the wall (E′), the mitral the inflow velocity (E) and their ratio E/E′, are parameters that relate to pulmonary capillary wedge pressure, (E/E′ >15 correspond approximately to >18 mmHg) [57,58].
Cardiac magnetic resonance (CMR) allows the morpho-functional study in patient with poor acoustic window or allows to evaluate the state of myocardial fibrosis and inflammation, useful for clarifying the progress of HF and assists echocardiography in identification the cause of HF [59,60,61].
In patients with HF, venous congestion causes a slowing renal flow before a significant increase in cardiac filling pressures associated with less diuretic efficacy. Renal ultrasound, furthermore, gives information on the chronicity of the disease by the kidney size, cortical echogenicity, abnormal cortical-medullary ratio, so it is useful in identifying the progression of CKD [62]. It has been shown that the mean right atrial pressure can be estimated through the Doppler measurement of intrarenal venous flow, and based on the result, the prognosis was different [63].

6. Towards personalized treatment

Therapeutic goals include both control of symptoms with improved quality of life and prevention of renal disease progression. A known issue is that most studies on the treatment of HF often exclude patients with kidney damage, so the evidence of treatment in this area is limited. The treatment strategy must be multidisciplinary with a close monitoring. When managing patients with HF and renal damage, altered drugs pharmacokinetics and pharmacodynamics and electrolyte abnormalities are main hindrance.
Diuretic therapy is a mainstay for cardiac congestion. However, the efficacy decreases as the kidney function declines, thus it is difficult to optimize the treatment in these patients. High doses of intravenous loop diuretic, oral metolazone, oral loop diuretic and oral thiazide diuretic (though often ineffective in stages 4 and 5 of CKD) can be used [64]. The best strategy is to use different types of diuretics, acting in different segments of the nephron, to control symptoms and improve survival. In selected cases, despite the increase in creatinine, aggressive diuresis can be helpful in terms of clinical benefit [65]. Several studies have demonstrated that a reduced diuretic response (DR) is associated with an increased risk of death [66]. Other studies, have tried to calculate the DR as the ratio of the change in body weight and the amount of furosemide administered, proving the association with patient severity and outcomes [67].
Further disease-modifying drugs that may be used include Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin Receptor Blockers (ARB), Mineralocorticoid receptor antagonists (MRAs). They are recommended to reduce cardiovascular and total mortality in patients with HFrEF [68]. In patients with HFrEF and CKD stage 1-3 ACEIs, ARB and MRAs should be used while monitoring creatinine and potassium. In patients with HFrEF and CKD stage 4-5, they may be used with caution and adjusting the dose if necessary. There is limited evidence of their clinical efficacy in patients on dialysis. A post hoc analysis of the Study of Left Ventricular Dysfunction (SOLVD) in patients with HF and CKD has shown that the use of ACEIs reduces mortality even in patients with higher degrees of CKD [69]. Though an impairment of renal function can occur after starting ACEIs, there are long term advantages. In fact, the reduced hospitalization rate and benefit on survival justify the continuation of therapy to an increase up to 35% of creatinine [70]. Hyperkalaemia is not infrequent as a side effect, prompting many physicians to stop the therapy, or reducing the optimal doses. In addition, in patients with HF serum potassium levels may change due to dietary changes and not appropriate use of some diuretics. This concern is often addressed with a combined use of different diuretics and correction of acidosis. Oral potassium binders such as patiromer or sodium zirconium cyclosilicate could are valid alternative, they can be used without throw again or decrease other treatments [71]. Patiromer has also been demonstrated in a randomized, double-blind, placebo-controlled study to prevent hyperkalaemia in normokalaemic patients with HF with or without CKD in treatment with spironolactone [72].
Finally, the development of new MRAs molecules, such as finerenone and eplerenone, with less affinity to other steroid receptors, should reveal fewer both hyperkalaemic effect, and systemic adverse effects like gynaecomastia, low libido, and impotence that often lead patients to discontinue therapy [73,74].
MRAs when added to an ACEI/ARB, can provide additional suppression of Renin Angiotensin Aldosterone System (RAAS) with potential long-term cardiorenal benefits. The reduction in mortality, hospitalization, and cardiovascular events in HFrEF was shown in several studies such as, Randomized Aldactone Evaluation Study (RALES) [75], and Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EPHASIS-HF) [76]. These studies included patients with CKD (GFR 30-60 ml/min per 1.73 m2) with safe and effective outcome. Data on the safety and efficacy of MRAs in HFrEF with advanced CKD (stage 4 and 5) are limited [77].
Three trials, Inhibition of Metallo Protease by Omapatrilat in a Randomized Exercise and Symptoms Study of Heart Failure (IMPRESS), Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events trial (OVERTURE), and Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) compared Angiotensin Receptor and Neprilysin Inhibition (ARNI) with ACEI/ARB in HFrEF.
They showed that the cardiovascular mortality and all-cause mortality was reduced in patients receiving ARNI as compared with ACEI/ARB [78]. According to this study, the American College of Cardiology (ACC)/American Heart Association (AHA) and the European Society of Cardiology (ESC) have updated evidence-based guidelines for the treatment of HFrEF. ARNI is approved as first-line treatment of HFrEF if patients remain symptomatic despite optimal treatment with ACEI or ARB, having potential benefits on renal function even in chronic diseases (eGFR between 30 and 60 ml/min/1.73 m2), with a reduction in the decline in eGFR, as well as a reduced rate of hyperkalaemia [79].
β-Blockers, that have been shown to reduce mortality and morbidity in HF, include metoprolol, bisoprolol (β-1 receptor blockers), and carvedilol (α-1, β-1, and β-2 receptor blockers). They are recommended as Class 1A evidence for HFrEF. They are safe and beneficial in CKD patients and should always be used [80]. Carvedilol has been shown to be beneficial in patients with HF and CKD stage 5 and improves mortality in HFrEF patient on haemodialysis [81].
Studies on Ivabradine, approved for HFrEF therapy, included patients with creatinine, 2.5 mg/dL, CKD stage 3, and the benefits were the same in patients with or without CKD [82].
Sodium-glucose cotransporter inhibitor 2 (SGLT2i) is approved as a first-line treatment for HFrEF and recommended by the guidelines irrespective of diabetic status [68]. SGLT2i reduce cardiovascular mortality and hospitalisation (i.e., Dapagliflozin: HR 0,74 [95% Cl 0,65; 0,85], p < 0,0001). The Dapagliflozin in Patient with Chronic Kidney Disease (DAPA-CKD) trial was an international, multicentre, randomized, double-blind, placebo-controlled study in patients with CKD, (eGFR>25 ml/min per 1.73 m2 but < 75 ml/min per 1.73 m2 and proteinuria ≥ 200 e ≤ 5000 mg/g). Dapagliflozin was superior in preventing of a sustained ≥ 50% drop in eGFR, achievement of end-stage renal disease, cardiovascular or renal death. In patients with CDK, treatment with Dapagliflozin improved overall survival, with a significant reduction in all-cause mortality [83].
In the recent study EMPEROR-Reduced was shown that empagliflozin reduces by 25% cardiovascular death and HF hospitalization, including patients with eGFR as low as 20 ml/min per 1.73 m2. The eGFR decline was slower with empagliflozin compared with placebo [84].
Monitoring of renal function is not standardized as well as drug titration if eGFR decreases slightly (3-4 ml/min/1.73 m2), encountered very frequently in the first 2-3 weeks. Despite all drugs, including SGLT2i, cause an initial decrease in eGFR, do not require their interruption. An increase in serum creatinine of <50% above baseline, provided it is <266 μmol/L (3 mg/dL), or a decrease in eGFR of <10% of baseline provided eGFR is >25 mL/min/1.73 m2 , may be acceptable because long-term SGLT2i and other drugs have been shown to slow progression decline in eGFR, reduce proteinuria, and ultimately preserve renal function compared to placebo and should not be discontinued without good reason [85] (Table 4).
The recent study has also been shown that in a population of patients with a variety of causes of CKD, with varying levels of eGFR (even below 30 ml/min/1.73 m2), empagliflozin safely reduced the progression of renal disease and death from cardiovascular causes by about 28%. The risk of hospitalizations for any cause was reduced by 14%. Establishing to be a prognostically relevant drug also in patients with advanced renal disease [86].
The benefits of cardiac resynchronization therapy (CRT) in patients with eGFR < 60 ml/min per 1.73 m2 are comparable to individuals with normal kidney function [87]. Furthermore, Sudden Cardiac Death (SCD) rates are higher in patient with advanced CKD and HF [88].

7. Peritoneal dialysis in refractory congestive heart failure

Peritoneal dialysis (PD) may be considered a treatment option in patients with refractory volume overload unresponsive to diuretic treatment [68]. Residual kidney function influences the peritoneal dialysis prescription. In case of adequate residual renal function but need for fluid removal all low dose PD regimens (incremental PD) can be used to obtain adequate peritoneal ultrafiltration (PUF). Instead, patients with inadequate residual renal function and need for solute and fluid removal require full dose PD. Incremental PD regimens consist in a reduced number of dialysate exchanges and can be prescribed in manual PD (CAPD) with 1 or 2 dwell periods/day or in automated PD (APD) with 3-4 session/week [89].
In PD water and solute are removed over the peritoneal membrane by dwelling dialysate solution in the peritoneal cavity. Dialysate solution by an osmotic gradient drive peritoneal UF while convective and diffusive forces induce solute removal, including the removal of sodium and potassium [90]. Crystalloid and colloid dialysate solutions are currently available. Crystalloid solutions are dextrose or amino acid based and they induce solute-free water transport across the water channels of peritoneal membrane. Colloid osmosis, induced by a mixture of glucose polymers (maltodextrins) called Icodextrin, does not induce free water transport but UF with solutes. Icodextrin allows for more sodium removal compared to an equal UF volume induced with a dextrose-based solution [91].
Both CAPD and APD regimens have been proposed to treat fluid overload in heart failure. In patient with significant residual renal function, as first regimen a single manual night-time Icodextrin exchange, which is able to maintain slow and constant UF during long dwells, can be used. If clinically required, PUF can be increased with two exchanges/day using glucose, at concentrations that vary according to the UF obtained, plus a night-time exchange with Icodextrin. Alternatively, APD, that uses a machine for exchanges (cycler), can be used up to 3-4 sessions/week using different concentrations of glucose in night-time and Icodextrin in daytime. Patients with HF and advanced stage 5 kidney failure require full dose PD regimens that include CAPD with 3-5 dwell periods/day or daily APD [92].
Recent studies including patients with refractory HF suggest a positive effect of PD on the functional status, hospitalisation rate and quality of life while, at the moment, no advantage has been shown on survival rate. An improvement functional NYHA classification for patients treated with PUF was observed for patients surviving the first six months although a higher mortality rate was noted for patients starting with a NYHA class IV [93]. Several studies evaluating the clinical effects of PD in patients with diuretic resistant HF showed a significant reduction in hospitalisation rates for both the number of admission and days spent in hospital [94]. An improved quality of life according to Minnesota Living with Heart Failure Questionnaire (MLHQF) was found when compared with quality of life measured before starting of dialysis [95].
PUF allows for a restoration of sensitivity to diuretics and a rise of urine output connected to an improvement in cardiac performance [96]. Moreover, the drainage of ascites might decrease intraperitoneal pressure which has been demonstrated to improve renal function in HF [97].
There are insufficient data regarding which patient benefits the most from PUF. Patients eligible for PUF must have impaired renal function (eGFR < 50 ml/min/1.73 m2: stage 3 chronic kidney disease of the KDOQI classification) [98]. Potential candidates for PUF are those unresponsive to diuretic treatment, with frequent hospital admission for decompensated HF and not eligible for VAD/transplantation [68]. The main clinical contraindications for PUF include abdominal inflammatory process as ulcerative colitis and Crohn’s disease, end-stage liver diseases, the presence of ostomies and unrepaired hernias [99].

8. Conclusions

Many clinical studies have shown that most of drugs indicated as first line treatment by guidelines for HF are effective in improving patients prognosis and they can also be used in patients with mild to moderately impaired renal function. Many of these studies have mostly excluded patients with advanced chronic renal failure (eGFR <20-30ml/min/1.73m2) with less safety per treatment in this group. Therapy for HF in patients with CKD remains difficult, poorly demonstrated, poorly established and standardized, but nevertheless undergoing research. Future studies should address patients with advanced chronic renal failure and kidney replacement therapy to facilitate their management and support the clinician in therapeutic choices.

Author Contributions

Conceptualization, AIG, FP, GG; methodology, FS, GV; writing—original draft preparation, RR, PB, MS, GP, FF; writing—review and editing, AB, SM, LF, MS.; supervision, MMC, GV, AIG. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data Availability Statement

No new data were created for the review.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 2. Echocardiographic evaluation of the volume status. (a) The bidimensional assessment in the four-chamber view shows a dilated right ventricle, with a severe tricuspid regurgitation and an enlarged right atrium. (b) The subcostal view displays a marked dilation of the inferior vena cava with a reduced inspiratory collapse. (c) The continuous wave Doppler on the tricuspid regurgitations may allow an estimation of pressures in the right heart chambers. (d) Peak systolic velocity on tricuspid annulus by Tissue Doppler Imaging (S′ wave) represents a useful tool to assess the systolic function of the right atrium. All these parameters may help clinicians in the recognition of fluid overload, inducing a prompt diuretic treatment.
Figure 2. Echocardiographic evaluation of the volume status. (a) The bidimensional assessment in the four-chamber view shows a dilated right ventricle, with a severe tricuspid regurgitation and an enlarged right atrium. (b) The subcostal view displays a marked dilation of the inferior vena cava with a reduced inspiratory collapse. (c) The continuous wave Doppler on the tricuspid regurgitations may allow an estimation of pressures in the right heart chambers. (d) Peak systolic velocity on tricuspid annulus by Tissue Doppler Imaging (S′ wave) represents a useful tool to assess the systolic function of the right atrium. All these parameters may help clinicians in the recognition of fluid overload, inducing a prompt diuretic treatment.
Preprints 71059 g002
Table 1. Biomarker of Myocardial stretch for CKD patients with HF. Abbreviations: AHF: Acute Heart Failure. CHF: Chronic Heart Failure.
Table 1. Biomarker of Myocardial stretch for CKD patients with HF. Abbreviations: AHF: Acute Heart Failure. CHF: Chronic Heart Failure.
Biomarker HF type Prognosis Cut-off Cut-off adjusted according to eGFR
NT-ProBNP AHF/CHF Short and long- term cardiovascular events and all-cause death AHF:300 pg/ml
CHF: 125 pg/ml		 As diagnostic value:
-AHF and CKD stage 3-5: 1200-6000 pg/ml.
As prognostic value: Only two studies have tried to give a cut-off:
-Horii et al, reported 259.7 pg/ml (eGFR >30 ml/min/1.73 m2) and 5111 pg/ml (eGFR <30 ml/min/1.73 m2) [17].
-Masson et al, reported 769 (eGFR >60 ml/min/1.73 m2) and 2023 pg/ml (eGFR <60 ml/min/1.73 m2) [18].
BNP AHF/CHF Short and long- term cardiovascular events, all-cause death, and quality of life. Diagnostic threshold:
AHF>400 pg/ml
CHF: >150 pg/ml		 As diagnostic value:
CHF: Only one study has tried to give a cut-off:
-McCullough et all reported for patient with CKD stage 3-5 (eGFR <60 ml/min/1.73m2) >200 pg/ml [19].
As prognostic value:
CHF: Only one study has tried to give a cut-off:
-Horii et al, reported 90.8 pg/ml (eGFR >30 ml/min/1.73 m2) and 157 pg/ml (eGFR <30 ml/min/1.73 m2) [17].
Table 2. Biomarkers of Myocardial injury for CKD patients with HF.
Table 2. Biomarkers of Myocardial injury for CKD patients with HF.
Biomarker Prognosis Prediction Cut-off adjusted according to eGFR
hsTnT Short- and long- term mortality HF occurrence and death in CKD without cardiac symptoms As prognostic value:
-13 ng/L CKD stage 1
-15 ng/L CKD stage 2
-22 ng/L CKD stage 3
-40 ng/L CKD stage 4-5
As prediction value in patient without HF:
<5 ng/L lower risk of HF within 12 years
Table 3. KDIGO: Kidney Disease Improving Global Outcomes. RIFLE: The Risk, Injury, Failure, Loss, End-Stage. AKIN: Acute Kidney Injury Network.
Table 3. KDIGO: Kidney Disease Improving Global Outcomes. RIFLE: The Risk, Injury, Failure, Loss, End-Stage. AKIN: Acute Kidney Injury Network.
Serum creatinine criteria Urine output
AKI Stage KDIGO RIFLE AKIN
1 (Risk) Increase ≥ 0.3 mg/dl within 48 h or ≥ 1.5 or 2-fold from baseline Increase x 1.5 baseline or eGFR decrease > 25% Increase 1.5- 1.9 times from baseline or ≥ 0.3 mg/dl increase within 48 h < 0.5 ml/Kg/h for 6-12 h
2 (Injury) 2.0 - 2.9 times from baseline Increase x 2 from baseline or eGFR decrease > 50% Increase > 2- to 3-fold from baseline < 0.5 ml/Kg/h for 2 h
3 (Failure) 3.0 times from baseline or increase to ≥ 4 mg/dl or initiation of renal replacement therapy or, in patient < 18 years decrease in eGFR to < 35 ml/min per 1.73 m2 Increase x 3 from baseline or eGFR decrease > 75%, or serum creatinine > 4 mg/dl with an acute rise > 0.5 mg/dl Increase > 300% (> 3-fold) from baseline, or ≥ 4 mg/dl with an acute rise ≥ 0.5 mg/dl or on renal replacement therapy < 0.3 ml/Kg/h for 24 h or anuria for 12 h.
Table 4. HF drug available adjusted for renal function.
Table 4. HF drug available adjusted for renal function.
DRUG AVAILABLE Recommended CREATININE or eGFR
Angiotensin-converting enzyme inhibitors (ACEI) <2.5 mg/dl or > 30 ml/min/1.73 m2
Angiotensin receptor blockers (ARB) <3 mg/dl
Mineralocorticoid receptor antagonists (MRAs) <2.5 mg/dl or > 30 ml/min/1.73 m2
B-blockers
 -Carvedilol
 -Metoprolol
 -Bisoprolol		 <2.8 mg/dl or > 30 ml/min/1.73 m2
>45 ml/min/1.73 m2
<3.5 mg/dl
Angiotensin receptor neprilysin inhibitor (ARNI) > 30 ml/min/1.73 m2
Ivabradine <2.5 mg/dl
SGLT2 inhibitor
 -Dapagliflozin
 -Empagliflozin		 > 30 ml/min/1.73 m2
> 20 ml/min/1.73 m2
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Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
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