Renal failure commonly occurs in heart failure (HF), where it contributes adversely to major clinical outcomes.1–3 Indeed, a high proportion of patients admitted for acute heart failure (AHF) shows renal dysfunction on admission or develops worsening of renal function (WRF) during hospitalization.3 The coexistence of these 2 conditions has translated in longer hospital stays and worse short- and long-term prognosis.4,5 In the setting of AHF, the pathophysiology of renal dysfunction is complex and not fully understood.3 While traditionally attributed to the reduction in cardiac output and the consequent renal hypoperfusion, recent data have highlighted the role of renal congestion as an alternative pivotal mechanism.6–9 Building on these findings, we believe that it is crucial to identify those patients who might benefit from tight control of volume overload. Because the intensity of diuretic therapy usually relies on subjective evaluation and not on evidence-based guidance, it has become an unmet need the search for a tool that not only reflects the severity of fluid overload but is also useful for tailoring the intensity of diuretic therapy. Based on data showing that plasma levels of carbohydrate antigen 125 (CA125) are strongly correlated with clinical, hemodynamic, and echocardiographic surrogates of fluid overload,10–15 together with recent findings of a clinical trial endorsing the role of CA125 for guiding therapy in patients with a recent episode of AHF,16 we speculate that this biomarker may serve as a potential candidate for guiding diuretic therapy in patients with cardiorenal syndrome type 1. Under the proposed hypothesis, high diuretic doses would be especially beneficial in terms of renal function and clinical status in patients with increased CA125. In contrast, low CA25 would identify those patients who should undergo a more conservative diuretic strategy.

Renal dysfunction is a pervasive companion in patients with HF with higher figures reported during AHF decompensations.1–3 As a consequence, these patients have longer hospital stays and generally worse prognosis in the short- and long-term.4,5

An additional complicating factor is that at greater degrees of renal failure, well-evidenced therapies are lacking and current management remains mostly empirical.3,17,18

The pathophysiology of renal dysfunction in patients with AHF is complex, multifactorial, and not fully elucidated.3 Historically, WRF has been attributed to the reduction in cardiac output and consequently to renal hypoperfusion.3 However, recent data have failed to correlate surrogate parameters of low cardiac output with WRF in patients with HF.3,9 Indeed, a recent and elegant study of Hanberg et al.20 found no association between reduced cardiac index–assessed by pulmonary artery catheterization–and degree of renal dysfunction in 575 patients with advanced HF (New York Heart Association functional class III or IV, and mean left ventricular ejection fraction 23 ± 12%). Likewise, there are also recent data highlighting the role of renal congestion (venous, intra-abdominal, and hydrostatic pressure of the renal vein) as an important player in the pathogenesis of WRF complicating AHF.6–9 For example, Mullens et al.,8 found that the elevation of the central venous pressure on admission and the persistence of this elevation after treatment were the most important factors associated with WRF. In a related context, Damman et al.,21 showed, in 30 patients with chronic congestive HF, an increase in markers of renal tubular injury after the withdrawal of diuretics. Similar findings have been corroborated in other studies, emphasizing the role of venous congestion as a potential contributor in the pathophysiology of renal dysfunction, especially in patients with AHF.6–9

Currently, diuretics are the pharmacological therapy of choice for the treatment of congestion in AHF patients.17,18 However, its use is largely empirical and has traditionally been associated with significant deleterious effects, including WRF.3,17,18,22,23 Paradoxically, in some subsets of patients, diuretics have also been shown to be independently associated with improved renal function,3,19,21,23 a finding that, at least indirectly, reinforces the role of venous congestion as the main player in the deterioration of glomerular filtration rate in AHF. It seems that the effects of diuretics on renal function are determined by a delicate balance between renal perfusion pressure and renal venous congestion.3 Unfortunately, no consensus exists about the best way to guide diuretic therapy in these patients.17,18 Perhaps the absence of definitive evidence from randomized clinical trials together with the fact that no reliable method exists for quantification of systemic congestion explain the lack of a clinical tool for diuretic-guiding therapy.24,25 Indeed, common clinical parameters used for diagnosis and prognostic stratification have shown poor profitability for quantifying the degree and distribution of fluid overload.24 In addition, it is worth mentioning that natriuretic peptides levels have shown no correlation with the degree of congestion.24,26 Therefore, in the AHF setting, there is an unmet need for a clinical/biological tool that reflects the severity of the fluid overload while being sensitive enough to detect variations induced by diuretic therapy.

In this line of thought, plasma CA125 levels have emerged as a potential candidate for guiding depletive therapy.15 Carbohydrate antigen 125 is a glycoprotein synthesized by epithelial serous cells that has been widely used for monitoring ovarian cancer therapy. However, high plasma levels have also been reported in other diseases such as HF, nephrotic syndrome, liver cirrhosis, or pelvic inflammatory disease, among others.15 In the HF setting, several studies have shown that CA125 strongly correlated with clinical, echocardiographic, and hemodynamic parameters indicative of severity of systemic congestion and/or organ water redistribution.10–15 In addition, elevated levels of this glycoprotein are present in most patients hospitalized for AHF and are associated with an increased risk of death and readmission for AHF.10–15 Moreover, this biomarker has proved to be sensitive enough to follow the patient's clinical course; as such, it has been tested as a potential tool for monitoring and guiding depletive treatment in HF.27–31 In fact, in a recent randomized study performed in 380 patients with a recent episode of AHF, a CA125-guided therapy, driven mainly on modifications of frequency of monitoring and the intensity of diuretic therapy, was associated with a significant reduction in 1-year risk of subsequent AHF-readmissions compared with standard of care.16 In this trial, the authors suggested an intensification of the frequency of monitoring and up-titration of diuretics when CA125 was elevated (CA125 > 35 U/mL) while following a more relaxed schedule of ambulatory visits and down-titration of diuretic therapy if CA125 was ≤ 35 U/mL.16 Along the same line, but in the AHF setting, we found that, in 526 patients hospitalized for AHF, early changes in renal function following intravenous administration of furosemide were largely dependent on renal function and plasma levels of CA125 on admission. In fact, increasing doses of furosemide were associated with an increase in serum Cr at 48 to 72hours in patients with Cr ≥ 1.4mg/dL on admission and CA125 < 35 U/mL.19 In contrast, increasing doses of furosemide were associated with a significant decrease of Cr in subjects with Cr ≥ 1.4mg/dL on admission and CA125 > 35 U/mL. Similar findings for blood urea nitrogen values and estimated glomerular filtration rate were observed.19 Moreover, in 1389 patients admitted for AHF, our group observed that the mortality risk associated with the dose of loop diuretics at discharge was intense and differentially associated with plasma levels of blood urea nitrogen and CA125.32 Thus, high doses of loop diuretics were associated with an increased risk of death during follow-up, especially in patients with normal CA125 values and high levels of blood urea nitrogen, while in those who had elevated levels of blood urea nitrogen and CA125, high doses of loop diuretics were associated with a 27% decrease in the risk of death.32

Other characteristics such as its wide availability, low cost, standarized measurement, prolonged half-life, and the fact that CA125 levels are not subtantiallly influenced by age and renal dysfunction are important advantages that deserve to be highlighted.15

In summary, a substantial body of evidence suggests the usefulness of this biomarker for monitoring and guiding diuretic therapy in patients with cardiorenal syndrome type 1. A randomized clinical trial is a necessary step forward to evaluate this hypothesis.

There is enough evidence to support the notion that, in patients hospitalized for AHF, early changes in renal function induced by the administration of diuretics are influenced by the degree of venous congestion. Under these premises, we postulated that the use of high doses of diuretics would be especially beneficial–in terms of improvement of renal function–in patients with WRF and increased plasma levels of CA125 on admission. In contrast, high doses of diuretics would be associated with greater renal deterioration in patients with WRF and serum levels of CA125 within normal limits on admission.

Project PI13/01519 in collaboration with “Plataforma de Unidades de Investigación Clínica y Ensayos Clínicos” (SCReN [Spanish Clinical Research Network]) (PT13/0002/0031). Cofinanciated by ERDF (European Regional Development Fund). Unrestricted grant: “Proyectos de Investigación de Insuficiencia Cardiaca de la Sección de Insuficiencia Cardiaca 2015” from “Sección de Insuficiencia Cardíaca de la Sociedad Española de Cardiología”. Unrestricted grant: “Beca Mutual Médica 2014”. Instituto de Salud Carlos III and co-funded by ERDF [grant number PIE15/00013]. Red de Investigación Cardiovascular; Programa 7 (RD12/0042/0010)

None declared.