Graphical Abstract
The complex relationship between systemic and renal congestion in heart failure. ARNI: angiotensin receptor–neprilysin inhibitor; CVP: central venous pressure; RAASi: renin–angiotensin–aldosterone system inhibitor; SGLT2i: sodium–glucose co-transporter 2 inhibitor.
The presence of albuminuria in patients with heart failure (HF) portends adverse prognosis even after correction for the typical extra-cardiac comorbidities associated with an increased urinary albumin–creatinine ratio (UACR; e.g. diabetes, hypertension, and concomitant renal disease).[1,2] While its prognostic value is well recognized, the underlying mechanisms of albuminuria in HF are incompletely understood. This is due to the complex pathophysiology underlying HF, characterized by renin–angiotensin–aldosterone (RAAS) system hyperactivation, endothelial dysfunction, systemic congestion (including increased renal venous pressure), and a wide spectrum of non-cardiac comorbidities.[3] All these features can lead to micro- and macroalbuminuria, making it challenging to promote albuminuria from risk marker to risk factor for HF.
In this issue of the European Heart Journal, Boorsma et al. present exciting data about the role of albuminuria as a marker of systemic congestion in patients with HF.[4] These findings derive from a multicentre study, the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF). Briefly, the study included 2516 patients with HF on suboptimal medical treatment from 11 European countries, while another 1738 patients from Scotland were included in a validation cohort. Most patients were hospitalized for acute HF, and the remainder presented with worsening signs and/or symptoms of HF at outpatient clinics. The recruitment period was 24 months, from December 2010 to December 2012. Up-titration to guideline-recommended doses was encouraged during a median follow-up of 21 months. The investigators incorporated demographics, biomarkers, genome-wide analysis, and proteomics to characterize biological pathways better and promote a more individualized therapy for patients with HF. In >90% of the patients from the primary cohort and 82% of those in the validation cohort, urinary samples were available: microalbuminuria and macroalbuminuria were defined as a UACR >30 mg/gCr and >300 mg/gCr, respectively. As previously reported,[1] a third of the population had microalbuminuria while macroalbuminuria was observed in <10.0%. The authors also confirmed the independent prognostic value of albuminuria in predicting the risk of mortality and HF (re)hospitalization in HF patients with both reduced (HFrEF) and preserved ejection fraction (HFpEF).[1,2] Since the underlying pathophysiology of albuminuria in HF is still debated, the present findings provide an intriguing explanation, linking albuminuria more to congestion than to an intrinsic renal disease (Graphical Abstract). Indeed, this multicentre study elegantly shows that the UACR has a strong and independent correlation with N-terminal probrain natriuretic petide (NT-proBNP) after adjustment for several kidney markers, such as glomerular filtration rate (GFR), urinary neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury marker-1 (KIM-1). The goodness of the association was confirmed across all New York Heart Association (NYHA) functional classes and with other markers of congestion, such as bio-ADM (biologically active adrenomedullin) and the presence of peripheral oedema. Patients with albuminuria were also on higher doses of loop diuretics, further evidence that clinical congestion was more advanced in these subjects. Likewise, the available echo parameters showed that pulmonary pressures were higher in patients with albuminuria, along with a more prevalent dilated inferior vena cava. It is conceivable that the prevalence of subclinical congestion, altered haemodynamics, and more sensitive markers of cardiac dysfunction (e.g. evaluated by ultrasound at rest or during exercise[5–9]) may be even higher in subjects with albuminuria. Since conventional regression modelling fails to classify a mixed population into a more homogeneous one, the authors used hierarchical clustering analysis to identify novel homogenous groups based on available features. Interestingly, the UACR clustered with clinical, echocardiographic, and circulating biomarkers of congestion, but failed to cluster with glomerular and tubular markers such as creatinine, NGAL, and KIM-1. To establish the generalizability of the findings, the authors tested the model in the external validation cohort of the BIOSTAT-CHF study and this yielded similar findings. Taken all together, the data convincingly support the association of albuminuria with congestion, especially in the presence of increased right-sided pressures (Graphical Abstract). This is particularly true for patients with HFrEF, as <10% and only a third of subjects of the index and validation cohort had a diagnosis of HFpEF, respectively. More data will be necessary to evaluate the role of albuminuria in HFpEF, as it is a more heterogeneous syndrome than HFrEF[10] and can significantly increase right-sided pressures to even higher levels than HFrEF despite similar disease severity.[11] HFpEF is also more closely associated with increased inflammatory activity than HFrEF, and the development of venous congestion activates the innate immune system and the secretion of proinflammatory cytokines.[10] Indeed, increased activity of inflammatory cytokines determines systemic and glomerular endothelial dysfunction, resulting in one of the pathophysiological mechanisms that link persistent congestion and renal dysfunction with poor prognosis in patients hospitalized for acute HF.[12] Another important finding of the present research worthy of future investigations is the association between albuminuria and congestion, irrespective of the presence of diabetes. Since diabetes alone is a cause of intrinsic renal disease, the relationship between albuminuria and congestion in this subgroup is more tricky and challenging to grasp.
Overall, wider use of UACR in the HF setting is desirable to gain more knowledge, also because early change both in albuminuria and in GFR fulfil criteria for surrogacy for use as endpoints in clinical trials for chronic kidney disease progression.[13] However, estimated GFR is a routine assessment, while spot urine analysis is hardly performed in clinical practice by HF specialists.[14]
After assessing albuminuria (and congestion), how should the clinicians tailor HF therapy to each patient? We already have drugs acting on the RAAS that can lower albuminuria and are associated with preventing the onset and worsening of HF and other cardiovascular disorders.[3] Interestingly, those with any albuminuria in the BIOSTAT-CHF population were less likely to be on RAAS inhibitors. Also, the enrolled patients did not have access to sacubitril/valsartan and sodium–glucose co-transporter 2 inhibitors, which were consistently demonstrated to positively affect GFR and NT-proBNP in dedicated HF trials, albeit the impact of these novel drugs on micro-/macroalbuminuria is less clear and should be further investigated in the HF setting.[15] Nevertheless, we still must demonstrate the causality and the direction of the relationship between albuminuria and congestion in HF. Indeed, before considering albuminuria the next target in HF, we should remember that even a strategy of NT-proBNP-guided therapy did not prove to be more effective than a usual care strategy in improving outcomes.[16] Likewise, there is no guideline recommendation for markers of congestion to guide HF treatment, albeit a recent meta-analysis of current evidence suggests that lung ultrasound-guided treatment might reduce the risk of hospitalization of HF outpatients.[17]
In conclusion, there is convincing evidence that albuminuria is a solid risk marker in HF, but we need more data to better appreciate its role, especially in HFpEF. We must also look for causality before considering albuminuria a risk factor and a target for therapy in HF.
Eur Heart J. 2023;44(5):381-382. © 2023 Oxford University Press
Copyright 2007 European Society of Cardiology. Published by Oxford University Press. All rights reserved.
