The development of new drugs and device therapies has led to remarkable advancements in heart failure (HF) treatment in the past couple of decades. However, it becomes increasingly evident that guideline-directed medical therapy cannot be one-size-fits-all across a wide range of ejection fractions (EFs) and various aetiologies. Therefore, classifications solely relying on EF and natriuretic peptide make optimization of treatment challenging, and there is a growing exploration of new indicators that enable efficient risk stratification of HF patients. Particularly when considering HF as a multi-organ interaction syndrome, the cardiorenal interaction plays a central role in its pathophysiology, and albuminuria has gained great prominence as its biomarker, independent from glomerular filtration rate. Albuminuria has been shown to exhibit a linear correlation with cardiovascular disease and HF prognosis in multiple epidemiological studies, ranging from normal (<30 mg/g) to high levels (>300 mg/g). However, on the other hand, it is only recently that the details of the pathological mechanisms that give rise to albuminuria have begun to be elucidated, including the efficient compaction/tightening of the glomerular basement membrane by podocytes and mesangial cells. Interestingly, renal disease, diabetes, and HF damage these components associated with albuminuria, and experimental models have demonstrated that recently developed HF drugs reduce albuminuria by ameliorating these pathological phenotypes. In this review, facing the rapid expansion of horizons in HF treatment, we aim to clarify the current understanding of the pathophysiology of albuminuria and explore the comprehensive understanding of albuminuria by examining the clinically established evidence to date, the pathophysiological mechanisms leading to its occurrence, and the outcomes of clinical studies utilizing various drug classes committed to specific pathological mechanisms to put albuminuria as a novel axis to depict the pathophysiology of HF.

Albuminuria is common in patients with heart failure and associated with worse outcomes. The underlying pathophysiological mechanism of albuminuria in heart failure is still incompletely understood. The association of clinical characteristics and biomarker profile with albuminuria in patients with heart failure with both reduced and preserved ejection fractions were evaluated.
Two thousand three hundred and fifteen patients included in the index cohort of BIOSTAT-CHF were evaluated and findings were validated in the independent BIOSTAT-CHF validation cohort (1431 patients). Micro-albuminuria and macro-albuminuria were defined as urinary albumincreatinine ratio (UACR) 30 mg/gCr and 300 mg/gCr in spot urines, respectively. The prevalence of micro- and macro-albuminuria was 35.4 and 10.0, respectively. Patients with albuminuria had more severe heart failure, as indicated by inclusion during admission, higher New York Heart Association functional class, more clinical signs and symptoms of congestion, and higher concentrations of biomarkers related to congestion, such as biologically active adrenomedullin, cancer antigen 125, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (all P 0.001). The presence of albuminuria was associated with increased risk of mortality and heart failure (re)hospitalization in both cohorts. The strongest independent association with log UACR was found for log NT-proBNP (standardized regression coefficient 0.438, 95 confidence interval 0.350.53, P 0.001). Hierarchical clustering analysis demonstrated that UACR clusters with markers of congestion and less with indices of renal function. The validation cohort yielded similar findings.
In patients with new-onset or worsening heart failure, albuminuria is consistently associated with clinical, echocardiographic, and circulating biomarkers of congestion.

Renal dysfunction is one of the strongest predictors of outcome in heart failure. Several studies have revealed that both reduced perfusion and increased congestion (and central venous pressure) contribute to worsening renal function in heart failure. This paper proposes a novel factor in the link between cardiac and renal dysfunction: \"renal tamponade\" or compression of renal structures caused by the limited space for expansion. This space can be limited either by the rigid renal capsule that encloses the renal interstitial tissue or by the layer of fat around the kidneys or by the peritoneal space exerting pressure on the retroperitoneal kidneys. Renal decapsulation in animal models of heart failure and acute renal ischemia has been shown effective in alleviating pressure-related injury within the kidney itself, thus supporting this concept and making it a potentially interesting novel treatment in heart failure.

Congestive heart failure (CHF) and impaired renal function are two often co-existing medical conditions and associated with adverse cardiovascular outcome. The aim of the current study was to assess renal and intraglomerular haemodynamics by constant infusion input clearance technique in subjects with CHF.
The group of subjects with CHF consisted of 27 individuals with HFpEF and 27 individuals with HFrEF and were compared with 31 healthy controls. Subjects underwent renal clearance examination to measure glomerular filtration rate (GFR) and renal blood and plasma flow (RBF and RPF) and to calculate intraglomerular haemodynamics such as resistances of the afferent (RA ) and efferent arterioles (RE ) as well as intraglomerular pressure (Pglom ). Measured GFR was lower in CHF subjects (68.1 ± 10.1 mL/min/1.73 m2 ) compared with controls (83.6 ± 13.4 mL/min/1.73 m2 , Padj  < 0.001) as was Pglom (Padj  < 0.001). Total renal vascular resistance (RVR) was higher in CHF subjects (87.3 ± 20.1 vs. 73.8 ± 17.1 dyn × s/cm5 , Padj  < 0.001) mediated by an increased resistance at the afferent site (3201 ± 1084 vs. 2181 ± 796 dyn × s/cm5 , Padj  < 0.001). Comparing HFpEF and HFrEF subjects, RA was higher in HFrEF subjects. The severity of CHF assessed by NT-proBNP revealed an inverse association with renal perfusion (RPF r = -0.421, P = 0.002, RBF r = -0.414, P = 0.002) and a positive relation with RVR (r = 0.346, P = 0.012) at the post-glomerular site (RE : r = 0.318, P = 0.022).
Renal function assessed by measured GFR is reduced and renal vascular resistance at the preglomerular, afferent site is increased in HFpEF and, to greater extent, in HFrEF. Our data indicate a close cardiorenal interaction in CHF.

BACKGROUND: Renal sodium-glucose cotransporter‑2 (SGLT2) inhibitors seem to have a cardioprotective effect beyond the antidiabetic effect. The underlying mechanisms are unclear.
METHODS: Selective search in PubMed with a focus on heart failure endpoints and possible mechanisms of action.
RESULTS: During treatment with three of the substances analyzed, there were fewer hospitalizations for heart failure compared with placebo; however, the numbers needed to treat within the primary analyses were relatively high (72-117). We found that loss of weight and lowering of blood pressure were more pronounced during treatment with verum than with placebo and an association of the preventive effect with more severely impaired renal function.
CONCLUSIONS: The SGLT2 inhibitors show a moderate heart failure protective effect in diabetic patients. It is likely that a nephroprotective effect with modulation of the cardiorenal interaction is an important part of the mechanism of action but this must be substantiated in further investigations.
UNASSIGNED: HINTERGRUND: Hemmstoffe des renalen Natrium-Glukose-Kotransporters 2 („sodium glucose-linked transporter 2“; SGLT2i) scheinen außer der antidiabetischen auch eine kardioprotektive Wirkung zu besitzen; deren Mechanismus ist jedoch unklar.
UNASSIGNED: Selektive Literaturrecherche in PubMed (Fokus Herzinsuffizienz und Wirkmechanismen).
UNASSIGNED: Unter Therapie mit 3 der untersuchten Substanzen kam es im Vergleich mit Placebo zu weniger herzinsuffizienzbedingten Krankenhausaufenthalten, allerdings mit einer relativ hohen Anzahl von Behandlungen pro verhindertes Ereignis (72–117). Außer einer stärkeren Gewichtsabnahme und Blutdrucksenkung unter dem Verum gegenüber Placebo fiel eine Zunahme des kardioprotektiven Effekts bei stärker eingeschränkter Nierenfunktion auf.
UNASSIGNED: Ein moderater herzinsuffizienzpräventiver Effekt von Hemmstoffen des renalen SGLT2 kann bei Diabetikern als gesichert gelten. Ein wesentlicher Wirkmechanismus beruht wahrscheinlich auf einem nephroprotektiven Effekt mit Modulation der kardiorenalen Interaktion, was jedoch weiterer Abklärung bedarf.

BACKGROUND: It is uncertain that chronic heart failure (CHF) patients are susceptible to renal tubular damage with that of worsening renal function (WRF) preceding clinical outcomes.
OBJECTIVE: Changes in tubular damage biomarkers are stronger predictors of subsequent clinical events than changes in creatinine (Cr), and both have different clinical determinants.
METHODS: During 2.2 years, we repeatedly simultaneously collected a median of 9 blood and 8 urine samples per patient in 263 CHF patients. We determined the slopes (rates of change) of the biomarker trajectories for plasma (Cr) and urinary tubular damage biomarkers N-acetyl-β-d-glucosaminidase (NAG), and kidney-injury-molecule (KIM)-1. The degree of tubular injury was ranked according to NAG and KIM-1 slopes: increase in neither, increase in either, or increase in both; WRF was defined as increasing Cr slope. The composite endpoint comprised HF-hospitalization, cardiac death, left ventricular assist device placement, and heart transplantation.
RESULTS: Higher baseline NT-proBNP and lower eGFR predicted more severe tubular damage (adjusted odds ratio, adj. OR [95%CI, 95% confidence interval] per doubling NT-proBNP: 1.26 [1.07-1.49]; per 10 mL/min/1.73 m2 eGFR decrease 1.16 [1.03-1.31]). Higher loop diuretic doses, lower aldosterone antagonist doses, and higher eGFR predicted WRF (furosemide per 40 mg increase: 1.32 [1.08-1.62]; spironolactone per 25 mg decrease: 1.76 [1.07-2.89]; per 10 mL/min/1.73 m2 eGFR increase: 1.40 [1.20-1.63]). WRF and higher rank of tubular injury individually entailed higher risk of the composite endpoint (adjusted hazard ratios, adj. HR [95%CI]: WRF 1.9 [1.1-3.4], tubular 8.4 [2.6-27.9]; when combined risk was highest 15.0 [2.0-111.0]).
CONCLUSIONS: Slopes of tubular damage and WRF biomarkers had different clinical determinants. Both predicted clinical outcome, but this association was stronger for tubular injury. Prognostic effects of both appeared independent and additive.

Heart and kidney are closely related in the clinical syndrome of heart failure (HF). It is now sufficiently clear that renal dysfunction occurs frequently in all phenotypes of HF, and when present, it is associated with higher mortality and morbidity. While the pathophysiology is multifactorial, the most important factors are a reduced renal perfusion and venous congestion. Recent interest has focused on worsening renal function (WRF), a situation strongly related to mortality, but seemingly only when HF status deteriorates. Unfortunately, to date clinicians are unable to identify specifically those patients with a grim prognosis following WRF. Although much has been learned on cardiorenal interaction in HF, still more questions have been left unanswered. The coming decade should provide us with more dedicated epidemiologic, mechanistic, and controlled trials in HF patients with reduced renal function. An updated classification of the cardiorenal syndrome that incorporates recent evidence and points towards areas of interest and uncertainties, and areas where progress is needed could facilitate this process. Ultimately, this should lead to preventive and treatment strategies that can preserve renal function and associated outcome in patients with HF.