Revisiting the cardio-renal hypothesis: the pivotal role of the kidney in congestive heart failure.

This editorial refers to ‘Prognostic utility of plasma neutrophil gelatinase-associated lipocalin in patients with acute heart failure: The NGAL EvaLuation Along with B-type NaTriuretic Peptide in acutely decompensated heart failure (GALLANT) trial’ by A.S. Maisel et al., published in this issue on pages 846–851. Our conceptual understanding of heart failure over the past century evolves over two common themes. First, the ability to demonstrate the existence of a pathogenic process by a measurement or a physiological finding allows the formulation of a testable hypothesis. Second, the ability to alter the natural history through treatment approaches that target such a process provides validation of the concept. Long before we had bedside haemodynamic and imaging techniques, ‘congestive failure’ was considered to be a heterogeneous condition but largely attributed to the failure of the kidneys to receive adequate blood flow (the so-called ‘cardio-renal hypothesis’). 1 Diuretic therapy was the primary approach, and continues to be highly effective at relieving signs and symptoms. With the development of tools to measure intra-cardiac pressures and estimate cardiac efficiencies with calculated output values or increasingly sophisticated imaging techniques, the cardio-centric views placed the word ‘heart’ into congestive heart failure (‘cardiocirculatory hypothesis’). 2 This led to the widespread adoption of ‘ejection fraction’ as an important criterion for determining an underlying impairment in cardiac function, and put forward the promise of vasodilators and inotropic drugs to facilitate circulatory efficiency in the 1970s to 1980s. Next, advances in laboratory measurements recognized high levels of hormonal activation occurring in the setting of congestion and cardiac insufficiency (‘neurohormonal hypothesis’). It has led to the development of drugs that counteract both the major regulatory homeostatic hormones (renin-angiotensin2aldosterone and adrenergic systems), and the conduct of large-scale clinical trials to demonstrate their abilities to reduce adverse outcomes beyond haemodynamic improvement in the 1980s and 1990s. Better understanding of how to avert arrhythmogenic death and the ability to visualize electrical and mechanical dyssynchrony catalyzed technological development in device therapy with implantable defibrillators and cardiac resynchronization therapy in the 2000s. Today, patients with heart failure survive longer but with more co-morbid conditions, and yet their recurrent admissions to the hospital with congestion remain the single largest challenge to healthcare providers and to societal costs. The cardio-renal interaction has regained attention in recent years because common aetiologies of heart failure and kidney disease cannot fully explain the co-occurrence of these pathologies. 3 During decongestive treatment of acute decompensated heart failure, this interaction is even more complex and poorly understood. The often-encountered scenario is worsening of renal function during diuretic treatment (conveniently defined as a ≥0.3 mg/dL rise in serum creatinine), 4,5 forcing clinicians to hold off on diuretics while the patient is incompletely decongested. However, the presence of significant congestion itself is more predictive of the development of worsening renal function than impaired cardiac output, 6,7 even though in some cases the treatment to relieve congestion may result in improving (or at the least neutral) outcomes despite a rise in serum creatinine. 8‐10 Clearly, our bedside insights into the adequacy of the failing heart and/or kidneys to maintain euvolaemia and relieve congestion remain far from precise, and treatment strategies are yet to alter the natural history of the condition. In this issue, Maisel et al. 11 present their findings from a prospective, multi-centre study looking at the prognostic value of a novel biomarker, neutrophil gelatinase-associated lipocalin (NGAL), alone and in combination with B-type natriuretic peptide (BNP) in 186 patients with acute on chronic heart failure confirmed by the presence of an elevated BNP (.100 pg/mL). The investigators report higher plasma levels of NGAL and BNP in patients with events (30-day re-hospitalization or all-cause mortality) compared to patients with no events. They also display an array of statistical findings in an attempt to show that NGAL provides incremental value to standard prognostic measures, despite their acknowledgement of a relatively small event rate (16% or 29 deaths) with short follow-up. The lack of comprehensive description of patient characteristics, their serial changes of plasma NGAL, and treatment regimens over the course of hospitalization precluded more detailed understanding of how to best utilize this biomarker at