Renin-angiotensin-aldosterone system and kidney interactions in heart failure

Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). The interplay between the renin-angiotensin-aldosterone system (RAAS) and kidneys in patients with heart failure (HF) can lead to highly complex and challenging clinical scenarios. Among these scenarios, worsening renal function (WRF) and/or hydro-electrolytic alterations (hyperkalemia in particular) often raise clinicians’ awareness leading to downstream decisions (e.g. change in medications and/or its dosages), which can have consequences for the patients.1 It should, nonetheless, be noted that WRF (a major determinant of adverse outcomes in HF patients) may be of multifactorial origin and the RAAS inhibitors (RAASi) are one of its multiple causes. This is thought to occur because RAAS activation in HF leads to glomerular efferent arteriolar vasoconstriction that preserves glomerular filtration (in the face of a fall in glomerular perfusion pressure caused by HF). By reducing this neurohormonal activation, RAAS blockers can reduce the glomerular perfusion pressure (reducing systemic arterial and glomerular afferent arteriolar pressure while also preventing the compensatory efferent arteriolar constriction) and cause WRF.2 However, used chronically, RAASi treatment may attenuate renal function deterioration, suggesting an initial creatinine rise may not be clinically relevant in certain populations.3 Increment in serum creatinine/WRF occurring in the setting of decongestion or titration of neurohormonal antagonists is also commonly encountered, primarily as a result of the effects of loop diuretics and/or of RAASi on renal hemodynamics. Recent data showed that when HF medications (i.e. angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, mineralocorticoid receptor antagonists (MRAs), β-blockers and diuretics) were held for 48 hours, serum creatinine decreased but natriuretic peptides and cardiac volumes increased.4 These data support the concept that serum creatinine increases and WRF should not be evaluated in isolation but rather considered in the context of the whole clinical scenario: not all increases in serum creatinine adversely affect prognosis. For example, a meta-analysis showed that WRF in patients with HF with reduced ejection fraction (HFrEF) randomized to an RAASi therapy was associated with lower mortality than WRF on placebo.5 It should be emphasized that RAASi have convincing evidence of benefit on prolonging survival and reducing morbidity in patients with HFrEF, and both United States and European guidelines give a Class I, Level of Evidence A recommendation for their use. In contrast, WRF in patients with HF with preserved ejection fraction (HFpEF) was associated in increased events regardless of the use of RAASi. This is because, to date, the HFpEF trials failed to demonstrate a clear morbidity and mortality improvement.5 Despite this, a particularity should be noted with spironolactone in the TOPCAT (Spironolactone for Heart Failure with Preserved Ejection Fraction) trial.6 In TOPCAT only patients from the Americas had characteristics compatible with HFpEF and adequate blood levels of the drug metabolites.7,8 Hence, when considering this HFpEF population, spironolactone improved outcomes regardless of the baseline estimated glomerular filtration rate; however, more adverse events, including WRF, were observed in patients with impaired renal function in whom close laboratory monitoring is recommended.9 In concordance, the updated American Renin-angiotensin-aldosterone system and kidney interactions in heart failure