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Managing patients with cardiorenal syndrome: time to look to the gut?

Chronic kidney disease (CKD) is an extremely common comorbidity in patients with chronic heart failure (CHF). Studies have consistently shown that it is an independent predictor of mortality and adverse cardiovascular events. Treating patients with CHF and advanced CKD presents a particular challenge. While the evidence base for treating patients with CHF is among the strongest for any disease, patients with severe renal impairment have generally been excluded from major studies. Fear that antagonists of the renin–angiotensin–aldosterone system will precipitate end-stage renal disease in such patients often leads to inappropriate underutilization. The potential adverse impact on each other’s function from an abnormality in either of these organ systems led to Ronco and colleagues proposing a classification for cardiorenal syndrome which included five subtypes. It is a logical classification for differentiating between acute and chronic interactions and identifying the responsible organ system driving pathophysiological abnormalities in each clinical scenario. It also highlights the associated risk. There are, however, major limitations of this classification; each subtype may co-exist with another and clinical presentations are commonly not so clearly delineated. For example, a patient with decompensated heart failure is more likely to develop acute kidney injury if they have underlying CKD and/or systemic illness such as diabetes or vascular disease. In many respects this classification highlights our limited understanding of the pathophysiological abnormalities that drive these interactions and therefore adds little, if any, value to defining the management of the patient sitting in front of you. Cardiologists and nephrologists must work together to coordinate quality research into this area and evaluate novel treatment strategies. Optimization of fluid balance for patients with CHF is crucial to relieve symptoms. Recent data suggest that congestion per se may also impact on disease progression. The presence of venous congestion, be it elevated jugular venous pressure, orthopnoea, oedema, or ascites, predicts worse outcome and is independently related to lower estimated glomerular filtration rate (eGFR). The detrimental effects of venous congestion on renal function are predominantly seen in the presence of pre-existing renal hypoperfusion, which in turn is driven by reduced cardiac output. Invariably optimization of fluid balance necessitates the use of diuretics. This itself may incur some cost, and for patients with advanced CHF and/or CKD is hugely challenging. Kidney function may deteriorate further (acute kidney injury, associated with adverse outcomes) and resistance to loop diuretics may supervene. There are a number of ways to counteract this. For example, the addition of mineralocorticoid receptor antagonists (MRAs, aldosterone blockers) and thiazide diuretics enhances renal sodium excretion by ‘progressive nephron blockade’. Recent data from the EMPHASIS-HF study have shown that MRAs (in this case eplerenone) have a major impact on prognosis even in patients with mildly symptomatic CHF. Prognostic benefit is likely to relate to beneficial antagonism of aldosterone-mediated cardiac and renal fibrosis. Current guidelines recognize an expanded indication for MRA use. Initiation and up-titration of MRAs may be limited by the development of severe hyperkalaemia. In ‘real life’ this may be more apparent than that seen in carefully monitored clinical trials. Juurlink et al. showed that following publication of the RALES study, the spironolactone prescription rate went up from 34 per 1000 patients (in 1994 pre-RALES) to 149 per 1000 patients by late 2001 (P , 0.001). The rate of hospitalization for hyperkalaemia also rose from 2.4 per 1000 patients in 1994 to 11.0 per 1000 patients in 2001 (P , 0.001), and the associated mortality rose from 0.3 per 1000 to 2.0 per 1000 patients (P , 0.001). In the EMPHASIS-HF study, potassium levels exceeding 5.5 mmol/L were seen in 11.8% of patients receiving eplerenone vs 7.2% of those in the placebo group (P , 0.001). In the subgroup of patients with eGFR ,60 mL/min/1.73 m, figures of