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Heart failure and kidney dysfunction: epidemiology, mechanisms and management

Key Points

  • Heart failure (HF) interacts with kidney disease via numerous pathophysiological pathways in both the acute and chronic setting

  • Mounting data indicate that the complex interplay between the heart and the kidneys involves haemodynamic, (neuro)homonal and cardiovascular disease-associated mechanisms

  • Acceleration of HF or kidney dysfunction is driven by impairment of either the heart or kidneys via mechanisms including induction of inflammation, activation of the cellular immune system, metabolic disorders, anaemia and mineral and bone disorder

  • In an effort to differentiate respective underlying pathologies and to assess acute and/or chronic organ dysfunction over time, five subtypes of cardio-renal syndromes were proposed

  • The absence of a standardized terminology database and the lack of studies specific to cardio-renal syndrome has hampered efforts to develop novel treatments

Abstract

Heart failure (HF) is a major health-care problem and the prognosis of affected patients is poor. HF often coexists with a number of comorbidities of which declining renal function is of particular importance. A loss of glomerular filtration rate, as in acute kidney injury (AKI) or chronic kidney disease (CKD), independently predicts mortality and accelerates the overall progression of cardiovascular disease and HF. Importantly, cardiac and renal diseases interact in a complex bidirectional and interdependent manner in both acute and chronic settings. From a pathophysiological perspective, cardiac and renal diseases share a number of common pathways, including inflammatory and direct, cellular immune-mediated mechanisms; stress-mediated and (neuro)hormonal responses; metabolic and nutritional changes including bone and mineral disorder, altered haemodynamic and acid–base or fluid status; and the development of anaemia. In an effort to better understand the important crosstalk between the two organs, classifications such as the cardio-renal syndromes were developed. This classification might lead to a more precise understanding of the complex interdependent pathophysiology of cardiac and renal diseases. In light of exceptionally high mortality associated with coexisting HF and kidney disease, this Review describes important crosstalk between the heart and kidney, with a focus on HF and kidney disease in the acute and chronic settings. Underlying molecular and cellular pathomechanisms in HF, AKI and CKD are discussed in addition to current and future therapeutic approaches.

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Figure 1: Overview of key cardio-renal interactions.
Figure 2: Definitions of cardio-renal syndromes.
Figure 3: Haemodynamic mechanisms in cardio-renal interactions.
Figure 4: (Neuro)hormonal mechanisms in cardio-renal interactions.
Figure 5: Cardiovascular disease-associated mechanisms leading to the progression of heart failure, chronic kidney disease (CKD), and/or acute kidney injury (AKI).

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J.C.S. and S.v.H. wrote the article. All authors contributed to discussion and researching of the content and to review and/or editing of the manuscript before submission.

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Correspondence to Stefan D. Anker.

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Competing interests

The Department of Intensive Care Medicine, Bern University Hospital, Switzerland (J.C.S.) has received research and development and/or consulting contracts from Orion Corporation, Abbott Nutrition International, B. Braun Medical AG, CSEM SA, Edwards Lifesciences Services GmbH, Kenta Biotech Ltd, Maquet Critical Care AB, Omnicare Clinical Research AG, Edwards Lifesciences SA, and Nestlé, for which no personal financial gain was received; educational grants from Fresenius Kabi; GSK; MSD; Lilly; Baxter; Astellas; AstraZeneca; B. Braun Medical AG, CSL Behring, Maquet, Novartis, Covidien, Nycomed, Pierre Fabre Pharma (Roba Pharma); Pfizer, Orion Pharma; J.C.S. has received research funding, (travel) grants, or speaker fees from Bayer AG/Schering AG, Eli Lilly, Anagnostics Bionanalysis GmbH/ Cube DX GesmbH, and Nestlé. G.F. is a member of committees of heart failure trials and registries sponsored by Novartis, Servier, Cardiorentis, Medtronic and Vifor. G.H. has consulted for Servier, Impulse Dynamics, Novartis, CircuLite, and DC Devices and received honoraria from CVRx, Impulse Dynamics, AstraZeneca, Bayer, and Orion. S.D.A. has consulted or received honoraria from Vifor, Novartis, Cardiorentis, Brahms, Bayer, Relypsa, ZS Pharma and Stealth Peptides. S.v.H. has received consultant honoraria, travel support, and/or speaker's fees from Vifor, Thermo Fisher Scientific, Respicardia, Sorin, Novartis, Chugai Pharma, AstraZeneca, Pfizer, Professional Dietetics and Solartium Dietetics.

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Glossary

Left ventricular ejection fraction

The fraction of left intra-ventricular volume that is pumped from the left ventricle per contraction or heartbeat.

Renin–angiotensin–aldosterone system

A complex hormone system and a key regulator of salt and water homeostasis in humans. The renin–angiotensin–aldosterone system is considered to be one of the key blood pressure regulating hormonal systems. Activation of this system in heart failure and chronic kidney disease makes it particularly important in cardio-renal syndrome.

Forward failure

Term often used by physicians involved in the care of patients with acute heart failure to describe a clinical situation in which left ventricular output is substantially reduced leading to insufficient end-organ and/or peripheral perfusion and/or pulmonary oedema.

Cardiac index

Cardiac index (units: l per min per m2) is a global index of heart function and a quotient of cardiac output and body surface area. This index is important for the monitoring of heart function in critically ill patients in intensive care units.

Renal congestion

Central venous pressure is typically increased in heart failure and acts as the back pressure to venous return, resulting in diminished efferent renal blood flow and renal venous hypertension. Renal congestion is considered to be the result of right ventricular failure, (neuro)hormonal and sympathetic mechanisms resulting in hypervolaemia, inflammation, and reduced glomerular filtration rate.

Preload

The effective end-diastolic volume that stretches the ventricles of the heart before contraction. Ventricular end diastolic volume and/or pressure is used for assessment of preload; atrial pressure might serve as a surrogate marker.

Starling curve

Cardiac function curve showing the graphical relationship between cardiac output or venous return (y-axis) and end diastolic volume or right atrial pressure (x-axis). Frank Starling's law indicates that cardiac output increases in response to increased end diastolic volume (that is, filling) up to a certain maximum (given that all other influencing factors remain constant).

Increased venous return

Increased venous return can almost always be observed in heart failure and results from early activation of key compensatory mechanisms, including neurohormonal responses and activation of the sympathetic nervous system, resulting in increased circulating volume.

Obesity paradox

Epidemiological data show that obese patients with chronic diseases such as heart failure, coronary artery disease or chronic kidney disease requiring dialysis can have higher survival rates compared to those of non-obese individuals.

Orthodema

Key clinical symptoms at rest for congestion include orthopnoea and peripheral oedema. An orthodema congestion score based on these symptoms was previously used to grade congestion in clinical trials.

Aquaresis

Excretion of (free) water without loss of electrolytes via the renal system. Aquaresis is of particular interested in dilutional hyponatraemia. Vaptans (also referred to as aquaretics) are a new class of drugs used to promote aquaresis.

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Schefold, J., Filippatos, G., Hasenfuss, G. et al. Heart failure and kidney dysfunction: epidemiology, mechanisms and management. Nat Rev Nephrol 12, 610–623 (2016). https://doi.org/10.1038/nrneph.2016.113

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