Author + information
- Roland R.J. van Kimmenade, MD, PhDa,b,∗ (, )
- Tim J. ten Cate, MD, PhDa and
- Hans-Peter Brunner-La Rocca, MDb
- aDepartment of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands
- bDepartment of Cardiology, Maastricht University Medical Center, Maastricht, the Netherlands
- ↵∗Reprint requests and correspondence:
Dr. Roland R.J. van Kimmenade, Department of Cardiology, Route 616, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands.
Studies of renal function during attacks of heart failure have of course been numerous.
—H.J. Stewart and J.F. MacIntosh, Journal of Clinical Investigation, 1928 (1)
For more than a century, the interaction between renal and cardiac dysfunction has intrigued physicians treating “cardiorenal” or “renocardiac” patients. The paper in this issue of the Journal by Ng et al. (2) reporting the predictive role of proenkephalin (PENK) for outcome and development of renal dysfunction in heart failure perfectly fits this tradition of fascination with the so-called cardiorenal interaction. Although enkephalins are especially known as mediators in nociception, their role is not restricted merely to pain perception; enkephalins are also found in the myocardium, where they mediate paracrine effects via opioid receptors, while these receptors are abundantly expressed in the kidneys as well.
In the present paper, the investigators demonstrate that PENK, a member of this enkephalin family, may be of value in predicting an event in heart failure therapy that clinicians very much try to avoid: a decrease in glomerular filtration rate while the patient is still symptomatic or not clinically euvolemic at the least. The question is, however, whether PENK fulfills the criteria that a novel biomarker should meet to be of clinical relevance, which steps are required to (further) develop PENK in this direction (3), and of course how relevant prediction of worsening renal function (WRF) is in heart failure.
To appreciate a prognostic biomarker in WRF, it is worthwhile to reflect on the complete picture of cardiorenal interaction. In their 2008 landmark paper in the Journal concerning the cardiorenal interaction, Ronco et al. (4) introduced a classification for cardiorenal syndrome (CRS) that may not be perfect but finally provided a tool that discriminates 5 manifestations of the vicious cycle of cardiac and renal dysfunction, on the basis of the etiology of the negative cardiorenal interaction.
This classification introduced clarity in this matter and boosted research in this field, as patient populations were now better defined and study results became comparable. This is well demonstrated by the fact that a search for the term cardiorenal syndrome produces >900 hits on PubMed published after 2008, compared with <150 hits published between 1990 and 2008 (date of search October 15, 2016).
However, the CRS classification is a more static concept, based on the etiology (simplified: acute vs. chronic; primary causal mechanism being cardiac vs. renal vs. external). We still lack a better differentiation in WRF, which is by definition a dynamic occurrence. Although there is a large overlap with CRS type 1 (characterized by a “rapid worsening of cardiac function leading to acute kidney injury” ), it is a simplification to consider CRS type 1 equivalent to WRF.
WRF is reported mostly as a binary rather than a continuous variable, and the definitions we use seem to be chosen randomly, arbitrarily, or as best suitable for publication: relative and/or absolute increase in creatinine concentration or a decrease in glomerular filtration rate during hospitalization, while some consider refractoriness to diuretic agents or a decrease in diuresis to reflect WRF as well. This is illustrated in Table 1, which is not intended to be a complete overview but illustrates the diversity of definitions.
A logical first step would be a more (patho)physiological categorization of WRF describing why renal function decreases (caused by the renin-angiotensin-aldosterone system and pharmacotherapy that interferes with it, potentially direct nephrotoxicity of diuretic agents or other nephrotoxic drugs [e.g., nonsteroidal anti-inflammatory drugs], hypotension or hypovolemia, ongoing renal venous congestion, acute tubular necrosis, or diagnostic contrast agent). This is important because there is evidence that WRF sometimes may be less relevant as long as heart failure is sufficiently treated (5) and/or WRF is less severe (6). It may very well be that in some subcategories, the effect on prognosis might be different from the complete mixed bag of patients with WRF.
In addition, several therapies have been introduced in patients with CRS or WRF, but mostly with limited success: ultrafiltration, renal denervation, vasopressin antagonists, hypertonic saline, dobutamine or dopamine or other vasoactive medications, and even kidney transplantation. A better classification might identify patients who may instead benefit from a therapy specifically aimed at WRF rather than heart failure or vice versa.
As for PENK, new biomarkers should provide additional information for simple prognostication, as the clinical value of predicting outcome only is very limited, and the large number of such predictors have not yet led to any significant change in the management of patients with heart failure (3). The study by Ng et al. (2), however, goes further than predicting outcome: it describes a potentially direct pathophysiological pathway of the cardiorenal interaction, which may help us better understand this complex interaction in the future. However, the present study was not a classic observational study, and there are some imperfections that cannot be ignored. For instance, B-type natriuretic peptide or N-terminal pro–B-type natriuretic peptide was measured at the different centers, which makes interpretation of the pooled results statistically more complex. In addition, PENK was compared only with creatinine and plasma urea but not with other more novel markers of renal function or prognosis, (e.g., cystatin-c, ST-2), so it remains unknown if the predictive value of PENK for the development of WRF is still significant in the presence of these markers.
In conclusion, beyond the introduction of a thus far less acknowledged but fascinating (patho)physiological pathway in heart failure mediated by opioid receptors, which we challenge with the oldest element in our present heart failure armamentarium (i.e., morphine), Ng et al. (2) once again turn our attention to an old complication: WRF. Unfortunately, their study was not able (or intended) to distinguish whether enkephalins directly contribute to WRF in acute heart failure or are simple markers of underlying risk. Yet there are intriguing data, such as those published by Mutoh et al. (7), who showed that the opioid receptor antagonist naloxone attenuates WRF in acute experimental kidney injury due to ischemia. Thus, additional work is required both experimentally and clinically to further unravel a potential direct pathophysiological role of endorphins in CRS. Otherwise, PENK will merely remain just another new kid on the (biomarker) block.
To successfully cope with WRF in heart failure, we 1) need to better define WRF; and 2) better predict this phenomenon (e.g., by measuring PENK concentrations); so that we can 3) develop or optimize strategies that prevent “malignant” WRF or at the least improve prognosis in these patients. This is not something for cardiologists alone but should be done in cooperation with nephrologists, who can contribute greatly in the understanding of WRF in patients with heart failure. Besides, it takes at least 2 to untangle and to tango.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Brunner-La Rocca has received research grants from Roche Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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