Renal dysfunction is one of the most important comorbidities in patients with chronic heart failure (HF) and frequently accentuated in the setting of acute HF (AHF).1 In either context, renal dysfunction has important clinical implications that deserve to be highlighted: (A) the added increase in risk of adverse clinical outcomes2 and (B) at greater degrees of renal failure, well evidenced therapies are lacking and current management remains mostly empirical.1

The pathophysiology of renal dysfunction in AHF is complex, multifactorial and not completely understood, which may potentially explain why patients with worsening renal function (WRF) show mixed clinical response and outcomes.1 An imbalance between abnormal haemodynamic (arterial hypoperfusion and/or venous congestion), neurohormonal activation, inflammatory responses, intrinsic tubular damage and heterogeneous response to therapeutic interventions have been proposed as the most common pathogenic pathways.1

Serum creatinine and blood urea nitrogen (BUN) have been classically used as proxies for renal function assessment; nevertheless, there are several concerns regarding their performance.1 Serum is influenced by important extrarenal factors such as muscle mass, gender, age, nutrition and race. It is well established that serum creatinine underestimates renal function in highly prevalent subgroups of patients with HF such as the elderly, women and low-weight individuals. In contrast, creatinine overestimates renal damage when renal dysfunction is already present.1 Other additional shortcomings are: (A) creatinine is known to be a slow-release marker after acute kidney injury (increased following 24–48 hours after renal injury) and (B) an increase in creatinine may occur as a consequence of haemoconcentration, even in the absence of any true renal function deterioration, a fact that is particularly true in patients with AHF treated with intensive diuretic therapy.1 ,3

Similarly, BUN is not a specific marker for renal dysfunction. Indeed, the three main causes of a raised plasma urea concentration are: (A) decreased glomerular filtration rate, (B) an increased load of urea for excretion (from the diet or tissue metabolism) and (C) an increased tubular reabsorption of urea.1 Interestingly, activation of the renin-angiotensin-aldosterone system increases urea reabsorption in the proximal tubule, a process that is linked to sodium and water reabsorption, whereas vasopressin levels enhance reuptake in the collecting duct, through activation of urea transporters.1 Thus, BUN may reflect a persistent and inappropriate activation of the renin-angiotensin-aldosterone and vasopressin systems in HF, and not necessarily a marker of decrease glomerular filtration rate.1 The lack of specificity of these classic renal function markers have stimulated the search for other surrogates of renal dysfunction such as cystatin C, markers of tubular integrity and the creation of new formulas for estimation of glomerular filtration rates, among others.

In their Heart paper, Matsue et al,4 evaluate the prognostic implications of the BUN to creatinine ratio (BUN/Cr) in a cohort of patients with AHF, using the normal values previously determined in a general population cohort. Indeed, an age-specific and sex-specific normal range of BUN/Cr was determined in a cohort of 4484 subjects with a mean age of 44±11 years, 55% women and most of them Caucasians. Then, the authors evaluated the adequacy of such abnormal ranges on the incidence of WRF during hospitalisation, and short-term adverse clinical outcomes in 1956 patients with AHF from the PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) study.4 This latter cohort, with a higher than normal BUN/Cr—representing 24.7% of the patients—was not related with the risk of WRF but it was related with the risk of 180-day death and the composite of death or cardiovascular or renal rehospitalisations through day 60. Estimates of risk were independent of well established prognosticators, including both components of the ratio (BUN and creatinine) as main effects. The addition of this ratio over traditional covariates reclassified patients for the 180-day mortality and composite end point (up to 27%, p<0.001 and 15%, p=0.003, respectively).4

Since decades ago, and mostly based on theoretical considerations, we have learnt in internal medicine textbooks that the BUN/Cr ratio was a helpful tool to distinguish the aetiology of acute renal failure.5 According to these postulates, prerenal failure should be suspected when this ratio was >20 and intrarenal failure when this ratio was in between 10 and 15.5 Although some studies have questioned the value of this ratio for distinguishing prerenal azotaemia from acute tubular necrosis,6 the main advantage of this ratio constitutes the possibility of identifying a different phenotype of renal dysfunction seen in HF.7 ,8 In this regard, Brisco et al have suggested a differential prognostic effect associated to renal dysfunction according to BUN/Cr in AHF. In patients with elevated BUN/Cr, renal dysfunction (glomerular filtration rate <45) was significantly associated with a substantial increase in the risk of death, but in patients with normal BUN/Cr, the presence of renal dysfunction had no impact on mortality.8 Moreover, these and others researchers also found that elevated BUN/Cr identified a subgroup of patients with multiple signs of increased neurohormonal activation and labile renal function.7 ,8 Patients with elevated BUN/Cr were more prone to improve renal function during hospitalisation and to develop WRF after discharge.8 Intriguingly, in the work of Matsue et al4 BUN/Cr was not related to inhospital WRF, a finding that could be explained by differences among characteristics of patients and criteria used to define WRF among studies.7 ,8

Previous results rekindle the interest of this ratio as a widely available tool for improving diagnosis and risk stratification, and more importantly, for unravelling the core pathophysiological mechanisms behind this pervasive association between renal dysfunction and AHF. Even though this ratio may be helpful to identify patients with functional renal dysfunction from more established parenchymal dysfunction, its utility for identifying the precise role of renal venous congestion and arterial renal hypoperfusion in the pathogenesis of cardiorenal syndrome type I remains unknown1 and therefore, its usefulness as a biomarker for guiding therapy in this challenging scenario.

Despite these encouraging results presented by Matsue et al, further studies are needed to confirm the normal/abnormal threshold for defining high/normal values of this ratio especially in older subjects, to define the clinical utility role of trajectories of BUN/Cr over a single measurement, and to evaluate the prognostic utility in other subgroups of patients—underrepresented in this study—such as the elderly and patients with HF with preserved ejection fraction.

Finally, it is necessary to highlight that only through the integration of clinical information—fluid overload status, magnitude and chronology of renal function changes, and patient's respond to therapy—with information provided by biomarkers, will the clinical meaning of the different phenotypes of renal dysfunction in AHF be revealed.