Academic Editors: Claudio Ronco and Giuseppe Coppolino
A wide range of comorbidities play a pivotal role in worsening outcomes and increasing mortality risk in patients with heart failure (HF). Among them, renal dysfunction has been recognized as a highly prevalent prognostic variable, with a strong impact on prognosis, length of hospital stay and need for intensive care. In this context, recent evidence has pointed out the relevance of both systemic hypoperfusion and venous congestion on the imbalance of renal function as well as on the conditioning the pathophysiological crosstalk between heart and kidneys through a wide range of haemodynamic and biochemical pathways. This narrative review aims to investigate the intricate interplay between impaired systemic perfusion and venous congestion in cardiorenal syndrome, as well as their haemodynamic and biochemical implications for renal damage in HF.
Despite the new insights concerning the therapeutic strategies for heart failure (HF), its prognostic outcomes remain unfavourable, with a high mortality and considerable impact on the quality of life [1]. A wide range of clinical comorbidities play an important role associated with poorer outcomes and increased risk of mortality in HF patients. Among them, renal dysfunction has been recognized as highly prevalent prognostic variable, affecting nearly 60% of patients hospitalized for acute decompensated HF, and whose impact on prognosis, length of hospital stay and need for intensive care, increases in proportion to the degree of baseline renal failure [2]. In this context, the bidirectional pathophysiological cross-talk between kidneys and heart leads to the definition of cardiorenal syndrome (CRS), whose classification has been proposed at the Consensus Conference of the Acute Dialysis Quality Initiative [3] (Table 1). Recent evidence has suggested that both impaired cardiac output and increased central venous pressure may actively contribute to renal deterioration in HF, although their respective contribution are currently a matter of extensive debate [4, 5]. This review aims to investigate the intricate relationship between impaired systemic perfusion and venous congestion in CRS, as well as their haemodynamic and biochemical implications on renal damage in HF.
Type | Denomination | Description |
CRS type 1 | Acute cardiorenal | HF leading to AKI |
CRS type 2 | Chronic cardiorenal | Chronic HF leading to CKD |
CRS type 3 | Acute renocardiac | AKI leading to acute HF |
CRS type 4 | Chronic renocardiac | CKD leading to chronic HF |
CRS type 5 | Secondary | Systemic disease leading to heart and kidney failure |
AKI, acute kidney injury; CKD, chronic kidney disease; CRS, cardiorenal syndrome; HF, heart failure. |
In the last decades, renal deterioration in HF has been attributed solely to renal hypoperfusion as a primary pathophysiologic trigger, caused by cardiac failure in generating adequate forward flow, as a result of reduced cardiac output with consequent progressive deterioration of renal function. In this pathophysiological context, several neurohormonal pathways, such as the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, play a key role in driving systemic vasoconstriction, in order to maintain an adequate glomerular filtration rate (GFR) and preserve renal function [6, 7]. This pathophysiological paradigm has been recently challenged by several investigations that have shown no correlation or even paradoxical correlation between pump failure and renal dysfunction. Data from ADHERE (Acute Decompensated Heart Failure National Registry) highlighted an overlapping incidence of renal derangement in patients with reduced or preserved ejection fraction, thus resizing the pathogenic role of systemic hypoperfusion in this clinical setting [8]. Furthermore, a post-hoc analysis of the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) randomized trial by Nohria et al. [9] showed a lack of correlation between baseline renal function and cardiac index in patients hospitalized for advanced decompensated HF, thus suggesting that reduced systemic perfusion might not be the sole cause of renal impairment in HF. These data were reinforced by the analysis of Hanberg and colleagues [10], in which no association between renal failure and low systemic perfusion was reported across multiple subgroups of subjects, with different metrics of renal function and spectrum of cardiac index. On the other hand, venous congestion has been largely detected in HF patients. However, its hypothetical role in worsening renal function has always been considered a secondary haemodynamic determinant consequent to the decreased stroke volume, despite experimental animal data collected since 1930s revealed a direct renal impairment induced by the backward transmission of increased central venous pressure [11, 12]. Even earlier, in 1861, Ludwing had reported slow urinary flow associated with progressive increase in right atrial pressure, that he attributed to kidney congestion [13]. However, in recent years human data focusing on the interrelation between kidney congestion and renal dysfunction have revalued this topic. Examining a cohort of subjects with advanced decompensated HF, Mullens and co-workers showed that venous congestion was the strongest driver for renal impairment, while little contribution was given by systemic hypoperfusion [14]. Similar evidence was found by Guglin et al. [15] in a different subset population, who underwent haemodynamic evaluation as part of their routine HF diagnostic work-up. Overall, these data show how both the haemodynamic variables of cardiac preload and those of renal perfusion seem to play a role at various levels of renal impairment in patients with HF.
The intricate interplay between venous congestion, reduced systemic perfusion
and renal impairment is a challenging pathogenic framework, in which multiple
haemodynamic variables play a critical role [5]. Among the main determinants of
renal circulatory function, renal blood flow (RBF) is defined as the volume of
blood delivered to the kidneys per unit of time. It normally reaches roughly 20%
of the total cardiac output, amounting to approximately 1 L/min in a 70 kg adult
male, and it is closely related to the renal plasma flow, defined as the volume
of blood plasma per unit of time. RBF is proportional to the difference between
renal arteries and veins al and venous pressure, while it is inversely related to
renal vascular resistances. Another crucial parameter of renal function is
related to the estimated GFR, which describes the fluid rate of blood flow
filtered through the kidneys [16]. GFR is linked to RBF, as with Starling forces
between the glomerular capillaries and the Bowman space. Finally, filtration
fraction is defined as the fraction of renal plasma flow filtered across the
glomerular capillaries which reaches the renal tubules. Its normal value is
nearly 20%. However, it has to be a dynamic variable on the basis of changes in
renal perfusion, in order to maintain the physiologic functions of the kidney
[17, 18]. Although the paradigm that a reduction in systemic perfusion will
trigger a decrease in the estimated GFR apparently seems to be extremely
rational, it appears oversimplified. Renal perfusion is normally preserved under
strict local control, within a certain range of renal arterial perfusion
pressure, between 80 and 180 mmHg, by two intrinsic and interdependent mechanisms
of autoregulation: a fast component related to myogenic vasoconstriction, and a
slow component derived from the tubuloglomerular feedback (Fig. 1) [19]. In case
of low renal perfusion, a fall in renal arterial pressure will reduce fluid and
Na
Schematic view of autoregulation of renal perfusion, which is preserved between 80 and 180 mmHg of renal arterial perfusion pressure. GFR, glomerular filtration rate; RBF, renal blood flow.
Different pathogenic mechanisms play a role in developing CRS, with regard to
prevailing left or right ventricular derangement. A decreased RBF and an
increased backward renal venous pressure are the mainstream mechanisms leading to
kidney deterioration in left ventricular HF [31, 32]. Lower renal arterial
perfusion pressures are detected both in HF with reduced ejection fraction (due
to decreased stroke volume and to systemic hypoperfusion) and in HF with
preserved ejection fraction (mainly related to increased afterload). This, in
turn, triggers renal and systemic vasoconstriction through neurohormonal
activation, with consequent Na
Several and multifactorial mechanisms are involved in the pathogenesis of CRS, including haemodynamic imbalance as well as neurohormonal activation and inflammatory response (Fig. 2, Ref. [37]).
Pathogenic mechanisms of worsening renal function in cardiorenal syndrome. Adapted from Fu K. et al. [37]. AHF, acute heart failure; AVP, arginine-vasopressin; CVP, central venous pressure; GFR, glomerular filtration rate; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system; WRF, worsening renal function.
For values of renal arterial perfusion pressure below 80 mmHg, renal autoregulatory mechanisms fail. In this pathophysiological context, the neurohormonal axis (including both sympathetic nervous system and RAAS) is upregulated, thus leading to increased levels of angiotensin II and catecholamines, which in turn lead to a disproportionate vasoconstrictive effect on the efferent glomerular arterioles [38]. This response is crucial in order to initially preserve GFR and the filtration fraction, despite the decreased renal plasma flow. However, long-term increased angiotensin II and catecholamines become maladaptive, leading to pre-glomerular vasoconstriction and reduction of GFR. Moreover, increased angiotensin II concentrations promote renal fibrosis, induce a blunted responsiveness to natriuretic peptides and affect GFR, either directly or by increasing the sympathetic nervous system activity [39, 40]. The consequent activation of proximal tubular sodium and water reabsorption leads to raised central venous pressure and backward transmission to the kidneys. The latter is responsible for increased interstitial renal pressure and tubular compression, which result in lower trans-glomerular pressure gradient and decreased GFR [41].
Both venous congestion and systemic hypoperfusion perpetuate kidney injury through the deregulation of the nitric oxide (NO) pathway. NO is an endothelium-derived vasodilator mediator which plays a key role in autoregulation mechanisms, through the modulation of vascular tone, the antagonization of smooth muscle cell hypertrophy and its involvement in tubuloglomerular feedback through afferent arteriolar dilatation [42]. Acute decompensated HF upregulates the renin-angiotensin-aldosterone axis and increases angiotensin II levels, which downregulate the NO pathway and lead to the vasoconstriction of efferent arterioles [43, 44]. Furthermore, the derangement of the NO pathway is also promoted by the increased oxidative stress occurring through the reduced activity of the superoxide dismutase enzyme and the raised levels of asymmetric dimethyl arginine. They both contribute to decrease NO plasmatic levels and to enhance the generation of ROS [45]. Finally, increased levels of angiotensin II promote the release of endothelin-1 from endothelial cells, which contributes to antagonize the NO pathway and predisposes to vasoconstriction, vascular remodelling and proliferation, as well as to worsening endothelial dysfunction [46, 47].
The arginine-vasopressin (AVP) system plays an active role in perpetuating a
pathophysiological vicious circle leading to CRS in HF patients. AVP is a
neuroendocrine peptide secreted by the paraventricular nucleus of the
hypothalamus and stored in the posterior pituitary gland before its secretion. It
exerts its actions by binding to its specific receptors: V
Congestive HF is often characterized by inadequate natriuresis, which
progressively leads to volume overload and systemic congestion. In this context,
splanchnic circulation plays a crucial role in preserving an euvolemic
circulatory system, with no detrimental systemic haemodynamic effects. Under
physiological conditions, splanchnic capacitance veins involve 25% of total
blood volume, which may increase as much as 65% of total volume, in order to
maintain a stable effective circulatory volume [52]. In congestive HF, the
occurrence of backward failure together with arteriolar vasoconstriction due to
systemic hypoperfusion lead to a progressive blood shift from the effective
circulatory volume to the splanchnic capacitance veins, which become maladaptive
[53]. Therefore, a progressive increase in intra-abdominal pressure (whose normal
values range below 5–7 mmHg), leads to intra-abdominal venous hypertension (in
case of intra-abdominal pressure
Impaired systemic perfusion and venous congestion play a pivotal role in
inflammatory response in CRS, with a strong impact on worsening renal function.
Arterial underfilling, as well as renal congestion can induce vascular
dysfunction through endothelial cell activation, which is responsible for a
pro-oxidant, pro-inflammatory and vasoconstrictive state. Moreover, raised
filling pressures also induce circumferential elongation of the venous wall and
promote the release of pro-inflammatory cytokines (including endothelin-1, tumor
necrosis factor-
The haemodynamic contributions of both increased central venous pressure and reduced cardiac output on worsening renal function, may lead to several consequences in clinical practice. As previously reported by Stevenson and colleagues [59], the presence/absence of clinical signs of congestion (such as orthopnoea, paroxysmal nocturnal dyspnoea, jugular turgor, pulmonary or peripheral bilateral oedema, gut congestion and ascites) and/or impaired organ perfusion (such as the presence of cold sweaty extremities, oliguria, dizziness and narrow pulse pressure) also define four different haemodynamic profiles associated with different prognostic outcomes, which help to guide proper therapeutic strategies. Patients with a ‘wet’ haemodynamic profile show increased pulmonary or systemic congestion related to higher central venous pressure, which in turn impacts on renal venous pressure and renal perfusion pressure, leading to increased interstitial pressure and tubular collapse and predisposing to renal damage [60, 61]. Such more congested cardiac and renal profiles highly impact on both prognostic outcomes and mortality, as compared to more hypoperfused clinical profiles. Specifically, the ‘wet and warm’ patient profile (in which RBF is generally normal) has a direct impact on survival, with a 6-month mortality of 11%. This clinical profile has shown a minor impact on increased right atrial pressure and worsening renal function. As a consequence, treatments to reduce venous congestion and intra-cavitary filling pressures would have only a limited impact on improving GFR [62]. However, although in this subset of patients renal perfusion is largely preserved, its progressive impairment may lead to a fast worsening of renal function, shifting toward a more unfavourable ‘wet and cold’ profile, which is associated with a 6-month mortality of 40% and has a detrimental effect on survival [14, 63]. Therefore, the close relationship between cardiac output and central venous pressure challenges the first intuitive paradigm that fluid overload will invariably lead to a better renal perfusion [64]. In this kind of patients, inotropic treatment together with decongestive and vasodilator therapies have shown to be helpful in preventing acute loss of renal function. Consequently, the improved prognostic outcomes foster a shift toward a more favourable ‘dry and warm’ patient profile [22, 65]. On the other hand, euvolemic patient with systemic hypoperfusion, who have a ‘dry and cold’ haemodynamic profile, often require pharmacological inotropic support in order to improve the effective arterial filling volume and the cardiac output, with a consequent increase in renal arterial perfusion pressure and improvement of renal function [66, 67]. However, the long-term application of such a medical strategy often results in increased mortality. Therefore, for patients refractory to pharmacological treatment, the use of mechanical circulatory supports is often needed [68]. Taken into account the aforementioned findings, such a method of classification and risk stratification of HF patients should be considered as a prudent attempt to devise a suitable therapeutic strategy [69].
Several preventive measures and treatment options for the management of CRS have
been reported in clinical practice. Salt and water restriction in hyponatremic
patients have been reported to increase survival and quality of life, as well as
more effective strategies in reducing ventricular filling pressures, arterial
elastance and atrial remodelling [70, 71]. Intravenous loop diuretics are
commonly used as the first-line treatment of acute decompensated HF patients, as
they reduce fluid overload and soothe clinical signs and symptoms of pulmonary or
peripheral congestion [72]. Dosage and frequency of administration of loop
diuretics represent another challenging topic for debate in literature. An
initial intravenous dose of loop diuretics twice the domiciliary oral dose has
been commonly proposed in clinical practice, in order to overcome low intestinal
absorption related to splanchnic congestion [73]. To date, data from the
literature do not report continuous dosing of loop diuretics as being more
effective than optimally prescribed bolus regimen, as revealed by the DOSE
(Diuretic Optimization Strategy Evaluation) trial [74]. The prescription of
long-acting loop diuretics, such as torasemide, has been proposed to prevent
neurohormonal activation related to rebound Na
In conclusion, a conceptual shift is needed towards considering venous congestion and systemic hypoperfusion as both involved in the pathogenic mechanisms of CRS, like the two sides of the same coin. Their intricate interplay still represents a challenging pathophysiologic framework, knowledge of which appears to be necessary in clinical practice, in order to provide a comprehensive therapeutic approach and the best individualized clinical models.
RS–manuscript conception, design and writing. CB–critical review and final approval of the manuscript.
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This research received no external funding.
The authors declare no conflict of interest.