European Heart Journal Advance Access originally published online on November 5, 2007
European Heart Journal 2007 28(24):2960-2961; doi:10.1093/eurheartj/ehl399
When renal and cardiac insufficiencies intersect: is there a role for natriuretic peptide testing in the ‘cardio-renal syndrome’?
1 Department of Cardiology, University Hospital Maastricht, The Netherlands
2 Division of Cardiology, Massachusetts General Hospital, Yawkey 5800, 55 Fruit Street, Boston, MA 02114, USA
* Corresponding author. Tel: +1 617 726 3443; fax: +1 617 643 1620. E-mail address: jjanuzzi{at}partners.org
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. 
This editorial refers to ‘Renal dysfunction, as measured by the modification of diet in renal disease equations, and outcome in patients with advanced heart failure’ by R.S. Gardner et al., on page 3027
Gardner et al.,1 report that NT-proBNP maintains strong prognosis in heart failure (HF) patients with renal impairment. This is an interesting contribution to the debate about the utility of NT-proBNP in renal impairment; chronic kidney disease is an important complication in patients suffering from HF, while there is often heated discussion about the usefulness of BNP and NT-proBNP measurement in patients with renal insufficiency.
Because of considerable overlap of risk factors and a myriad of pathophysiologic mechanisms, insufficiencies of the renal and cardiac system are tightly related.2 Furthermore, when HF is complicated by renal impairment, the prognosis of the patient worsens dramatically.3 Vice versa, patients with worse renal function are more likely to have heart disease, and those patients combining heart disease and renal dysfunction are more likely to suffer greater rates of adverse cardiovascular events. An objective measure of risk for patients with concomitant cardiac and renal disease would therefore be quite welcome.
An obvious choice for this application would be natriuretic peptides, such as BNP or NT-proBNP. Overall, the usefulness of natriuretic peptides in HF is undisputed: both indicate the presence and also severity of HF, and in HF patients with poor prognosis, higher concentrations of these markers are most often noted. Thus, a potential role for natriuretic peptides in risk assessment in those patients with cardiac and renal disease (those at highest risk for adverse outcomes) is worth discussing. Tempering the enthusiasm to use BNP or NT-proBNP for risk stratification of patients with combined cardiac and renal insufficiencies is the fact that both peptides are partially dependent on renal function for their clearance, thus kidney disease may lead to passive accumulations of either marker, at the risk of reducing their usefulness. Indeed, early observational studies demonstrated significant effects of renal function on levels of BNP and NT-proBNP, which led many to decry the use of these peptides in patients with renal disease.
In retrospect, rather than assuming that natriuretic peptide elevations in patients with HF complicated by renal dysfunction were nothing more than a faint signal, awash in a symphony of noise, the real question that we should have been asking ourselves was or whether these elevations were worth taking seriously and made efforts to figure out the answers. The results of the analysis by Gardner et al., in this issue of the European Heart Journal are a useful step forwards in developing clarity about application of NT-proBNP in patients with kidney disease.
Knowing that NT-proBNP may be useful to identify risk in those with kidney insufficiency and HF, the question is what this marker may add. Consider the magnitude of the problem: worsening of renal function happens in up to 45% of the patients suffering from HF,4 often with dire consequences. For that reason, the concept of combined cardiac and renal insufficiency has led physicians to baptize HF complicated with renal impairment the ‘Cardio-Renal Syndrome’ (CRS). The introduction of the concept of CRS has led to some interesting discussions. Should we interpret the CRS as a true syndrome that fundamentally differs from ‘ordinary’ HF, or should we interpret it as an indicator for decreased cardiac output, which is to be expected in the progression to end-stage HF? Should a patient with CRS be treated any differently than one without? More fundamentally, how should the CRS be defined?
One answer which seems clear is that the CRS is at least a different expression of disease within the broader entity of HF. Patients who are diagnosed with the CRS do not necessarily have a lower left ventricular ejection fraction, and do not necessarily have more complaints of fatigue or lower blood pressures on admission, both surrogates for decreased cardiac output.5 It seems that these patients, rather than having necessarily reached the end-stage of HF, are suffering from a different, perhaps more aggressive manifestation of the disease. Although studies with hypertonic saline infusions6 or newly developed drugs with both cardiac and renal preserving effects7 seem promising for this high-risk population of patients with HF, we still lack at this time a defined strategy for management of patients with CRS, and the definition of the syndrome remains disappointingly broad.
As currently defined, the most accepted criterion nowadays for CRS is a rise in creatinine concentration of 0.3 mg/dL in patients clinically diagnosed with HF,8,9 a definition which we argue is disappointingly broad. The rise in serum creatinine concentration identifying patients with CRS was originally described in an elderly population of patients with mild systolic HF,10 but appears largely portable to other patient types with all forms of HF; limiting its usefulness, however, is the fact that it is a criterion which is only useful retrospectively, after serum creatinine has risen, and we have few guidelines as to how to properly identify those in whom worsening renal function may occur. As well, the ‘cardiac’ criterion for defining CRS remains surprisingly broad. Indeed, it seems overly simple to inject the simple diagnosis of HF as the ‘cardiac’ portion of the definition, as the overall appearance of patients with CRS is not one specific type of HF at all. Given this inability to most easily recognize the ‘typical’ profile of the patient with HF that is at risk for CRS, better tools are necessary to objectively identify those more likely to suffer consequences from the intersection between cardiac and renal insufficiencies.
Given their intimate relationship with the severity of HF, one surmises whether the natriuretic peptides could play the coveted role in defining the ‘cardiac’ part of the definition of the CRS. In order to do so, clear data would be necessary demonstrating that renal dependence for clearance not withstanding, that natriuretic peptides would need to provide strong, unmistakable prognostic data, irrespective of renal function.
In this edition of the European Heart Journal, Gardner et al.1 show that NT-proBNP is strongly prognostic for death and/or urgent cardiac transplantation even in the presence of renal impairment. Furthermore, not only was NT-proBNP powerfully prognostic in HF despite impaired renal function, but also the patients at highest risk for hazard in HF were those with the combination of an elevated NT-proBNP in the face of impaired renal function. These data are similar to recently published mortality data for 720 patients with acute destabilized HF in the International Collaborative of NT-proBNP (ICON) study. In ICON, both GFR <60 mL/min/1.73 m2 and elevated NT-proBNP were independent predictors of outcome,11 and in a similar analysis to that by Gardner et al., the majority of hazard in HF was seen in those with both an elevated NT-proBNP and impaired renal function. Furthermore, among patients with worsening renal function during treatment for HF, a worse prognosis was only seen in those with an elevated NT-proBNP. Thus, we now have compelling evidence in both outpatient HF1 and acute HF,11 that not only is NT-proBNP prognostically powerful despite kidney disease, but it may actually be more powerfully prognostic in those with impaired renal function.
The work by Gardner et al. represents an important step forward regarding the utility of NT-proBNP testing in patients with impaired renal function.
In analogy to prior arguments regarding the use of troponins and renal failure, we will most probably look back on many of the contentious debates regarding natriuretic peptide testing and renal function and wonder why we looked at the topic in such a one-dimensional fashion. Indeed, given the dramatic effects of kidney disease on patients with HF, it is time to ask ourselves if it is really so surprising that sensitive markers of the presence and severity of heart disease are so profoundly affected by renal disease.
Finally, though the early data are optimistic, it remains yet unclear at present if we have found a more logical description of CRS, incorporating NT-proBNP into the ‘cardiac’ portion of the definition. What is now needed are studies demonstrating that this new paradigm for CRS is not only able to identify those HF patients at highest risk, but also yield actionable information from a therapeutic perspective, particularly if a specifically cardiac/renal preserving therapy for patients with CRS was available. This would be a giant leap forward in the clinical and scientific approach of the treatment of HF, which is in 2006 still indoctrinated by a more or less one-size-fits-all attitude.
Conflict of interest: R.R.J.v.K., Y.P. and J.L.J. report naming received grant support and speaking fees from Roche Diagnostics.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehm480 References
- Gardner RS, Chong KS, O'Meara E, Jardine A, Ford I, McDonagh TA. Renal dysfunction, as measured by the modification of diet in renal disease (MDRD) equations, and outcome in patients with advanced heart failure. Eur Heart J (2007) 28:3027–3033. First Published on October 29, 2007. doi:10.1093/eurheartj/ehm480.
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[Abstract/Free Full Text]
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Related articles in EHJ:
- Renal dysfunction, as measured by the modification of diet in renal disease equations, and outcome in patients with advanced heart failure
- Roy S. Gardner, Kwok S. Chong, Eileen O’Meara, Alan Jardine, Ian Ford, and Theresa A. McDonagh
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