Blood Purif 2014;37(suppl 2):14–19 DOI: 10.1159/000361060
Published online: July 31, 2014
Biomarkers in Cardiorenal Syndrome Lui G. Forni a, b Lakhmir S. Chawla c a
Department of Critical Care, Western Sussex Hospitals Foundation Trust, Worthing, and b Brighton and Sussex Medical Schools, Falmer, UK; c Division of Intensive Care Medicine and Division of Nephrology, Department of Medicine, Veterans Affairs Medical Center, Washington, D.C., USA
Abstract Cardiac and renal diseases often coexist. Treatment may prove difficult as early diagnosis and effective therapy may be hindered by a lack of robust markers of disease activity. However, several candidate molecules are now available which may help elucidate the complexities of organ crosstalk, enabling effective therapies. We discuss the available data on the commonly studied biomarkers of acute kidney injury with reference to the cardiorenal syndrome. Furthermore, we propose how the use of biomarkers as a panel may provide information which can guide therapy. Although this is a relatively new field, advances are rapid, and such options may well be available to the clinician soon. © 2014 S. Karger AG, Basel
Introduction
In patients with heart failure (HF) the presence of coexistent renal insufficiency portends a grave prognosis [1]. Where the primary problem is one of chronic kidney disease (CKD), it is well established that the highest cause © 2014 S. Karger AG, Basel 0253–5068/14/0376–0014$39.50/0 E-Mail [email protected] www.karger.com/bpu
of mortality in these patients is cardiovascular disease, and similarly in patients with HF, mortality increases as the glomerular filtration rate (GFR) falls [2, 3]. The potential interactions between the heart and kidneys have long been known and such organ ‘cross-talk’ is not a new concept. However, there is enhanced interest in this potential bidirectional interaction between both the heart and kidney with proposed mechanisms ranging from hemodynamic change, endothelial dysfunction, activation of the renin-aldosterone system, and the sympathetic nervous system, as well as dysregulation of salt and water balance [4, 5]. Furthermore, there is evidence from many patients that HF is not only associated with physiological changes, but also with structural change in both organs. For example, changes in tissue architecture including increased fibrosis and apoptosis leading to pathological cardiac remodeling occurs in response to both cardiac and renal stimuli. There is evidence that structural tubular damage is present in the HF population, which is associated with a worse prognosis [6, 7]. The presence of glomerular injury as evidenced by albuminuria is also prevalent and has been shown to be a strong predictor of cardiovascular outcomes [8, 9]. Therefore, either cardiac or renal dysfunction may lead to either an acute or a chronic deterioration in either or both organs. This concept has been codified into a new Lakhmir S. Chawla Department of Anesthesiology and Critical Care Medicine George Washington University Medical Center 900 23rd Street NW, Washington, DC 20037 (USA) E-Mail minkchawla @ gmail.com
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Key Words Cardiorenal syndrome · Acute kidney injury · Biomarkers
Biomarkers of AKI
Currently, biomarkers play a pivotal role in HF, unlike either acute or chronic renal failure. Several biomarkers of HF have direct clinical relevance in terms of diagnosis, risk stratification, and monitoring treatment. Perhaps the most well-known biomarkers are the natriuretic peptides, which are at the cornerstones of both diagnosis and treatment. As outlined above, the use of biomarkers to aid in the diagnosis of AKI is an area of increasing scientific interest, reflecting the fact that, until relatively recently, the predominantly employed biochemical markers of renal function were limited to serum creatinine and urea. These conventional measures are well established, and serum creatinine together with eGFR form the mainstay of CKD management. However, creatinine kinetics are such that AKI, as heralded by a rise in serum creatinine, is not diagnosed until 24–48 h after the initial insult. Furthermore, factors such as comparing creatinine measurements obtained from different laboratories, biological and nutritional variation, and enhanced tubular secretion of creatinine further confound the diagnosis. Hence, there has been much interest in the pursuit of a quantifiable indicator which will allow for the early detection of AKI. Recently identified biomarkers are low-molecularweight proteins associated with AKI and fall into three main categories [10–12]: (1) those present in the systemic circulation and undergo glomerular filtration, (2) those released into the urine after tubular cell injury, and (3) Biomarkers in CRS
Table 1. Classification of CRS
Type
Known as
Description
Type 1 Type 2
Acute Chronic
Type 3
Acute renocardiac
Type 4
Chronic renocardiac
Type 5
Secondary
Acute HF results in AKI Chronic cardiac dysfunction causes progressive CKD Abrupt and primary worsening of kidney function causes acute cardiac dysfunction which may present as cardiac failure Primary CKD contributes to cardiac dysfunction which may be manifested by coronary disease, cardiac failure, or arrhythmia Acute or chronic systemic disorders that cause both cardiac and renal dysfunction
inflammatory mediators released by renal cells or infiltrating inflammatory cells. Building upon the work of animal studies, the search for AKI biomarkers has continued and involves candidate molecules in both plasma and urine. With respect to CRS, the main biomarkers investigated to date are neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), cystatin C, and N-acetyl-β-Dglucosaminidase (NAG). Unsurprisingly, many studies on the use of biomarkers in AKI have focused on the ability to diagnose AKI before a detectable serum creatinine rise, with many studies centered on ICU patients. For example, an early study measured plasma NGAL (pNGAL) and demonstrated the diagnosis of AKI up to 48 h earlier than AKI diagnosed according to classical creatinine criteria. However, a strong association between pNGAL and overall disease severity regardless of the presence of AKI was also seen [13]. A further study employing a single pNGAL measurement on admission to the ICU again predicted the onset of AKI 48 h before AKI as per RIFLE criteria with an impressive AUC of 0.92 although this study was small and excluded patients with CKD [14]. This was in contrast to work where an array of urinary biomarkers were analyzed prospectively and no one biomarker was found to have an AUC above 0.7 [15]. A further prospective study in ICU patients examining pNGAL and urine NGAL (uNGAL) to predict severe AKI prospectively in a cohort of 632 consecutive adult critically ill patients found a significant association between admission pNGAL and uNGAL levels and the final RIFLE class. However, approximately 30% of patients with sepsis had elevated uNGAL levels Blood Purif 2014;37(suppl 2):14–19 DOI: 10.1159/000361060
15
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nomenclature known as the cardiorenal syndrome(s) (CRS; table 1) [5]. Thus, in many patients with cardiac failure, CRS may be causative or contributory to any observed decline. Hence, when faced with a patient with CRS, it is of paramount importance to ascertain whether any functional decline is acute or chronic. With regard to renal function, this may be evidenced by CKD defined through estimated GFR (eGFR), or may be an acute deterioration now known as acute kidney injury (AKI). However, in the absence of any previous serum creatinine measurements, it may be difficult to ascertain whether any derangement in serum creatinine is acute or chronic. Furthermore, there may have been an acute insult to the kidneys, which is not manifest in terms of serum creatinine at presentation, but may be evident 24–48 h later. This lack of precision has led to numerous investigations to determine an early marker of AKI which may aid in both diagnosis and treatment.
Biomarkers of AKI and Outcomes in CRS
Acute HF is one of the dominant causes for hospital admission, particularly in the age group of 65 years and over. Treatment of these patients is complicated by both the presence of multiple comorbidities and involvement of other organs. As discussed, since the combination of renal dysfunction and HF results in a poor prognosis regardless of CRS type, there has been considerable interest in the role of biomarkers in CRS both in terms of early diagnosis as well as in providing insights into the pathophysiology. Results reported to date, however, are by no means conclusive. For example, in patients with acute HF the predictive potential of pNGAL for AKI, compared to serum creatinine, has been assessed in 207 consecutive patients presenting to the emergency department. After controlling for preexisting chronic cardiac or kidney disease in a multivariate regression analysis, serum creatinine, but not NGAL, remained an independent predictor of AKI. In this study, therefore, pNGAL levels did not adequately predict AKI in patients with acute HF, which has also been observed in other studies in hospitalized as well as outpatients with HF where changes in NGAL levels were not associated with hospital admission or eGFR [17–19]. Reports do vary. In some studies the ability of pNGAL to predict type 1 CRS is impressive but depends on the cutoff value used [20], whereas in a multicenter prospective study, elevated pNGAL at the time of discharge was a strong prognostic indicator of 30-day outcomes in patients admitted for acute HF [21]. In addition to NGAL, cystatin C has also attracted much attention in the early detection of AKI, and a recent meta-analysis found that the AUC of plasma cystatin C to predict AKI was between 0.86 and 0.96 depending on the inclusion criteria employed. In contrast, urinary cystatin C levels had only moderate diagnostic value. The conclusions of this metaanalysis, however, were limited by great heterogeneity of 16
Blood Purif 2014;37(suppl 2):14–19 DOI: 10.1159/000361060
pooled studies in terms of clinical setting, AKI definition, and the type and timing of the assay used [22]. A recent study examined predictors of CRS in patients admitted with acute coronary syndromes. Unsurprisingly, the patients who developed CRS were older, had more comorbidities, and needed greater intervention(s). Multivariate analysis on this group of 368 patients found that admission cystatin C was the best predictor of the development of CRS [23]. Further studies have examined the role of other biomarkers of AKI in HF. Jungbauer et al. [24] examined urinary KIM-1, NAG, and NGAL in 150 patients with stable, chronic HF as defined by echocardiographic appearances, clinical examination, and NT-proBNP levels. These were compared to 23 normal healthy individuals and despite this inclusion of a ‘normal’ control group there was no statistical difference in uNGAL or NAG between the two groups. KIM-1 levels, however, were significantly different. Furthermore, no correlation between NGAL and severity of HF could be found although KIM1 again showed a positive and significant correlation with clinical condition, as did NAG to a lesser degree. Of interest in this study is that KIM-1 was found to be a significant predictor for all-cause mortality and hospital readmission rates for congestive cardiac failure over a 1-year follow-up period. Besides evidence suggesting biomarkers may provide insight into the development of AKI complicating HF, there is also evidence that biomarkers may provide some insights into the underlying pathophysiology. This is evidenced by the fact that biomarkers may be elevated in patients with HF who appear to have normal renal function. Certainly there is some clinical evidence that tubular damage may be associated with chronic HF with urinary NAG correlating with both GFR and renal plasma flow [25]. This observation is further supported by other evidence gleaned from over 2,000 patients in the GISSI-HF trial, where an increase in tubular markers was associated with a poorer outcome even in patients with a normal eGFR [26].
Biomarkers of AKI and Management of CRS
Clearly, baseline renal function as defined by GFR is predictive of outcome; however, in terms of acute management, the relationship between changes in GFR and prognosis is of interest. This is somewhat complex given the available interventions, but perhaps the most compelling argument comes from a random-effects meta-analyForni /Chawla
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without AKI [16]. Thus, the diagnostic utility of NGAL or other biomarkers to diagnose AKI prior to elevations in creatinine varies between different patient populations and is affected by comorbidity, timing of the measurements, and, importantly, the chosen cutoff values. A more recent study investigating novel biomarkers of cell cycle arrest (IGFBP7 and TIMP-2) also showed more promise in diagnosing AKI early, but again this was in a critical care setting [12].
The Use of Biomarkers in CRS
Using biomarkers in CRS is an area of increasing interest as it may herald a change in the potential management strategies for acute HF complicated by renal dysfunction. Part of the problem in treating acute decompensation in CRS is the limitations imposed by impaired renal function on the ability to correct volume overload. Biomarkers in CRS
Therefore, effective treatment of CRS could improve patient outcomes particularly where decompensation does not reflect a more severe cardiac disease. Under such conditions, the use of biomarkers may point to worsening HF through elevated BNP, for example, whereas markers of AKI may be normal or elevated. Efforts could then be concentrated on improving cardiac output and hence GFR. Therefore in types 1 and 2 CRS, any reversible component can be treated aggressively. Indeed, evidence does suggest that improvement in cardiac function through the use of cardiac resynchronization as well as left ventricular assist devices leads to improvements in GFR [29, 30]. This could theoretically be monitored by an improvement in biomarker profiles for both cardiac and renal function. However, first-line treatment tends to be of diuretic use rather than such aggressive strategies. One could argue that on commencing diuretic therapy, monitoring biomarkers of AKI may provide additional information guiding treatment. Under certain conditions, for example, vigorous diuresis may lead to a decline in cardiac output through reduced cardiac filling pressures and consequent reduction in GFR. While this may translate into a rise in serum creatinine acutely, treatment could be continued if biomarker levels do not increase; hence, the application of the biomarker would be a marker of hemoconcentration. However, if the fall in renal perfusion leads to tissue injury, a rise in biomarker levels may suggest AKI and hence treatment could be reduced or withheld. In other cases, diuretic therapy may lead to no change in either creatinine or biomarkers where changes in left ventricular end-diastolic pressure have little effect on cardiac performance. Also, reduced right ventricular filling may improve left ventricular performance as well as reduce renal venous pressure, leading to improved renal function. The application of biomarkers to the treatment of decompensated HF with diuretics may dramatically change current practice. There is much evidence supporting the view that hemoconcentration leads to an improved outcome. The ability of AKI biomarkers to delineate between true hemoconcentration and AKI is exciting as this will enable accurate tailored treatment to this patient group in that they may differentiate between reduction in GFR and renal injury. At present, the latter is implied by an increase in creatinine, which may not be the case in this patient group. Similarly, a role for AKI biomarkers could be considered when other agents are used to treat acute decompensation, including ACE inhibition, vasodilators, and inotropes. Blood Purif 2014;37(suppl 2):14–19 DOI: 10.1159/000361060
17
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sis of some 18,634 patients with HF [27]. This examined the mortality risk associated with worsening renal function (WRF), defined as an increase in serum creatinine ≥0.2 mg/dl or a corresponding decrease in eGFR ≥5 ml/ min/1.73 m2. WRF developed in 25% of the patients and was associated with a higher risk for mortality (OR = 1.62, 95% CI: 1.45–1.82, p < 0.001) and hospitalization (OR = 1.30, 95% CI: 1.04–1.62, p = 0.022). Unsurprisingly, the severity of WRF was associated with increased mortality, and patients with less renal reserve as indicated by impaired renal function at baseline were more prone to progressive renal function loss. Therefore, ameliorating WRF during the management of HF may translate into improved outcomes. The use of some AKI biomarkers has been used to determine whether the response to treatment is able to be predicted. For example, a prospective evaluation of 93 patients with acute decompensated HF examining both plasma and urinary NGAL found that uNGAL correlated with a reduced response to diuretics whereas pNGAL correlated with the GFR [28]. Both markers also predicted the development of AKI and the authors postulated that uNGAL corresponds to distal tubular injury while pNGAL is indicative of reduced glomerular function. An additional study confirmed that changes in measured biomarker profiles may add to patients’ management. KIM-1, NAG, and plasma and urine NGAL in stable patients with HF were measured. Diuretic therapy was withdrawn, which was associated with increases in KIM1 and NAG as well as natriuretic peptides, whereas NGAL was unaffected. Reinstating the diuretic led to an improvement in biomarker profile [29]. However, a similar study on some 141 consecutive patients examining the uNGAL (expressed in terms of urinary creatinine) failed to demonstrate a difference in response to diuretics and only a minor rise in uNGAL preceeded development of AKI as defined by a rise in serum creatinine >0.3 mg/dl [30]. Therefore, under certain conditions an intervention may lead to a decrease in biomarker level, but it is unclear as to what this translates to under clinical conditions.
Color version available online
120 BNP
NGAL
Biomarker level
100 80 60
the clinician (fig. 1). Therefore, the simultaneous measurement of biomarkers would enable maximum improvement in cardiac function while indicating where damage to the kidney would begin. Hence, a point may be reached where further improvement in cardiac function is limited but renal damage is likely. As a result, treatment could be ceased at this point.
40
Conclusions
20 0
1
2
3
4 5 6 Days of treatment
7
8
Fig. 1. Idealized response of cardiac and renal biomarkers on treat-
ment of CRS. Arrow: point of optimal diuresis without initiating AKI.
The HF patient who has become relatively diuretic resistant often proves to be a difficult management problem. However, ultrafiltration (isotonic fluid removal through an extracorporeal circuit) may be employed in these conditions and the use of biomarkers is potentially attractive. Again a role can be foreseen whereby serial measures of BNP and NGAL, for example, may inform
Much progress has been made regarding the role of biomarkers, particularly in the treatment of HF. However, CRS presents its own array of challenges which may be best met by employing our new armamentarium of biomarkers as a panel rather than individually. Much as we consider organ cross-talk vital, perhaps biomarkers, and their interdependence, may help in our understanding and ultimately guide treatment. This in turn may result in improved outcomes for our patients.
Disclosure Statement L.S.C. has links with Alere Medical, Astute Medical, Nxstage Medical, and Baxter Medical. L.G.F. received funding from Astute Medical.
References
18
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10 Ostermann M, Philips BJ, Forni LG: Clinical review: biomarkers of AKI: where are we now? Crit Care 2012;16:233. 11 Honore PM, Jacobs R, Joannes-Boyau O, et al: Biomarkers for early diagnosis of AKI in the ICU: ready for prime time use at the bedside? Ann Intensive Care 2012;2:24. 12 Kashani K, Al-Khafaji A, Ardiles T, et al: Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care 2013;17:R25. 13 Cruz DN, de Cal M, Garzotto F, Perazella MA, Lentini P, Corradi V, Piccinni P, Ronco C: Plasma neutrophil gelatinase-associated lipocalin is an early biomarker for acute kidney injury in an adult ICU population. Intensive Care Med 2010;36:444–451. 14 Constantin JM, Futier E, Perbet S, Roszyk L, Lautrette A, Gillart T, Guerin R, Jabaudon M, Souweine B, Bazin JE, Sapin V: Plasma neutrophil gelatinase associated lipocalin is an early marker of acute kidney injury in adult critically ill patients: a prospective study. J Crit Care 2010;25:176.e1–6.
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1 Damman K: Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis. Eur Heart J 2014;35:455–469. 2 Excerpts from the USRDS 2007 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Minneapolis, United States Renal Data System, 2007. 3 Coresh J, Astor BC, Greene T, et al: Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kid Dis 2003;41:1–12. 4 Bongartz LG, Cramer MJ, Doevendans PA, Joles JA, Braam B: The severe cardiorenal syndrome: ‘Guyton revisited’. Eur Heart J 2005; 26:11–17. 5 Ronco C, Haapio M, House AA, Anavekar N, Bellomo R: Cardiorenal syndrome. J Am Coll Cardiol 2008;52:1527–1539.
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20 Alvelos M, Pimentel R, Pinho E, Gomes A, Lourenco P, Teles MJ, Almeida P, Guimaraes JT, Bettencourt P: Neutrophil gelatinase-associated lipocalin in the diagnosis of type 1 cardio-renal syndrome in the general ward. Clin J Am Soc Nephrol 2011;6:476–481. 21 Maisel AS, Mueller C, Fitzgerald R, Brikhan R, Hiestand BC, Iqbal N, Clopton P, Van Veldhuisen DJ: 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. Eur J Heart Fail 2011;13:846–851. 22 Zhang Z, Lu B, Sheng X, Jin N: Cystatin C in prediction of acute kidney injury: a systemic review and meta-analysis. Am J Kidney Dis 2011;58:356–365. 23 Caetano AF, Almeida I, Silva J, Seca L, Botelho A, Mota P, Marques AL: The best predictor of cardiorenal syndrome in ischemic cardiomyopathy. Circulation 2012;125:e785–e786. 24 Jungbauer CG, Birner C, Jung B, Buchner S, Lubnow M, Von Bary C, Endemann D, Banas B, MacK M, Boger CA, Riegger G, Luchner A: Kidney injury molecule-1 and N-acetyl-β-Dglucosaminidase in chronic heart failure: possible biomarkers of cardiorenal syndrome. Eur J Heart Fail 2011;13:1104–1110.
25 Damman K, Van Veldhuisen DJ, Navis G, Vaidya VS, Smilde TDJ, Westenbrink BD, Bonventre JV, Voors AA, Hillege HL: Tubular damage in chronic systolic heart failure is associated with reduced survival independent of glomerular filtration rate. Heart 2010; 96: 1297–1302. 26 Damman K, Masson S, Hillege HL, Maggioni AP, Voors AA, Opasich C, Van Veldhuisen DJ, Montagna L, Cosmi F, Tognoni G, Tavazzi L, Latini R: Clinical outcome of renal tubular damage in chronic heart failure. Eur Heart J 2011;32:2705–2712. 27 Damman K, Navis G, Voors AA, Asselbergs FW, Smilde TD, Cleland JGF, Van Veldhuisen DJ, Hillege HL: Worsening renal function and prognosis in heart failure: systematic review and meta-analysis. J Cardiac Fail 2007; 13:599–608. 28 Shrestha K, Shao Z, Singh D, Dupont M, Tang WH: Relation of systemic and urinary neutrophil gelatinase-associated lipocalin levels to different aspects of impaired renal function in patients with acute decompensated heart failure. Am J Cardiology 2012;110:1329–1335. 29 Butler J, Geisberg C, Howser R, et al: Relationship between renal function and left ventricular assist devise use. Ann Thorac Surg 2006; 81:1745. 30 Adelstein EC, Shalaby A, Saba S: Response to cardiac resynchronisation therapy in patients with heart failure and renal insufficiency. Pacing Clin Electrophysiol 2010;33:850–859.
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15 Endre ZH, Pickering JW, Walker RJ, Devarajan P, Edelstein CL, Bonventre JV, Frampton CM, Bennett MR, Ma Q, Sabbisetti VS, Vaidya VS, Walcher AM, Shaw GM, Henderson SJ, Nejat M, Schollum JB, George PM: Improved performance of urinary biomarkers of acute kidney injury in the critically ill by stratification for injury duration and baseline renal function. Kidney Int 2011;79:1119–1130. 16 De Geus HR, Bakker J, Lesaffre EM, le Noble JL: Neutrophil gelatinase associated lipocalin at ICU admission predicts for acute kidney injury in adult patients. Am J Respir Crit Care Med 2011;183:907–914. 17 Breidthardt T, Socrates T, Drexler B, Noveanu M, Heinisch C, Arenja N, Klima T, Züsli C, Reichlin T, Potocki M, Twerenbold R, Steiger J, Mueller C: Plasma neutrophil gelatinase-associated lipocalin for the prediction of acute kidney injury in acute heart failure. Crit Care 2012;16:R2. 18 Nymo SH, Ueland T, Askevold ET, Flo TH, Kjekshus J, Hulthe J, Wikstrand J, McMurray J, Van Veldhuisen DJ, Gullestad L, Aukrust P, Yndestad A: The association between neutrophil gelatinase-associated lipocalin and clinical outcome in chronic heart failure: results from CORONA. J Int Med 2012;271:436–443. 19 Saeed M, Lim V, Tappia P, Cordova F, Malik A, Rigatto C, Shafer L, Sood M, Zieroth S: Urinary NGAL is not associated with renal function changes or hospitalization in ambulatory heart failure patients. Can J Cardiol 2012; 28:S280–S281.
Published online: July 31, 2014
Biomarkers in Cardiorenal Syndrome Lui G. Forni a, b Lakhmir S. Chawla c a
Department of Critical Care, Western Sussex Hospitals Foundation Trust, Worthing, and b Brighton and Sussex Medical Schools, Falmer, UK; c Division of Intensive Care Medicine and Division of Nephrology, Department of Medicine, Veterans Affairs Medical Center, Washington, D.C., USA
Abstract Cardiac and renal diseases often coexist. Treatment may prove difficult as early diagnosis and effective therapy may be hindered by a lack of robust markers of disease activity. However, several candidate molecules are now available which may help elucidate the complexities of organ crosstalk, enabling effective therapies. We discuss the available data on the commonly studied biomarkers of acute kidney injury with reference to the cardiorenal syndrome. Furthermore, we propose how the use of biomarkers as a panel may provide information which can guide therapy. Although this is a relatively new field, advances are rapid, and such options may well be available to the clinician soon. © 2014 S. Karger AG, Basel
Introduction
In patients with heart failure (HF) the presence of coexistent renal insufficiency portends a grave prognosis [1]. Where the primary problem is one of chronic kidney disease (CKD), it is well established that the highest cause © 2014 S. Karger AG, Basel 0253–5068/14/0376–0014$39.50/0 E-Mail [email protected] www.karger.com/bpu
of mortality in these patients is cardiovascular disease, and similarly in patients with HF, mortality increases as the glomerular filtration rate (GFR) falls [2, 3]. The potential interactions between the heart and kidneys have long been known and such organ ‘cross-talk’ is not a new concept. However, there is enhanced interest in this potential bidirectional interaction between both the heart and kidney with proposed mechanisms ranging from hemodynamic change, endothelial dysfunction, activation of the renin-aldosterone system, and the sympathetic nervous system, as well as dysregulation of salt and water balance [4, 5]. Furthermore, there is evidence from many patients that HF is not only associated with physiological changes, but also with structural change in both organs. For example, changes in tissue architecture including increased fibrosis and apoptosis leading to pathological cardiac remodeling occurs in response to both cardiac and renal stimuli. There is evidence that structural tubular damage is present in the HF population, which is associated with a worse prognosis [6, 7]. The presence of glomerular injury as evidenced by albuminuria is also prevalent and has been shown to be a strong predictor of cardiovascular outcomes [8, 9]. Therefore, either cardiac or renal dysfunction may lead to either an acute or a chronic deterioration in either or both organs. This concept has been codified into a new Lakhmir S. Chawla Department of Anesthesiology and Critical Care Medicine George Washington University Medical Center 900 23rd Street NW, Washington, DC 20037 (USA) E-Mail minkchawla @ gmail.com
Downloaded by: Thammasat University 203.131.222.2 - 10/9/2014 9:45:57 PM
Key Words Cardiorenal syndrome · Acute kidney injury · Biomarkers
Biomarkers of AKI
Currently, biomarkers play a pivotal role in HF, unlike either acute or chronic renal failure. Several biomarkers of HF have direct clinical relevance in terms of diagnosis, risk stratification, and monitoring treatment. Perhaps the most well-known biomarkers are the natriuretic peptides, which are at the cornerstones of both diagnosis and treatment. As outlined above, the use of biomarkers to aid in the diagnosis of AKI is an area of increasing scientific interest, reflecting the fact that, until relatively recently, the predominantly employed biochemical markers of renal function were limited to serum creatinine and urea. These conventional measures are well established, and serum creatinine together with eGFR form the mainstay of CKD management. However, creatinine kinetics are such that AKI, as heralded by a rise in serum creatinine, is not diagnosed until 24–48 h after the initial insult. Furthermore, factors such as comparing creatinine measurements obtained from different laboratories, biological and nutritional variation, and enhanced tubular secretion of creatinine further confound the diagnosis. Hence, there has been much interest in the pursuit of a quantifiable indicator which will allow for the early detection of AKI. Recently identified biomarkers are low-molecularweight proteins associated with AKI and fall into three main categories [10–12]: (1) those present in the systemic circulation and undergo glomerular filtration, (2) those released into the urine after tubular cell injury, and (3) Biomarkers in CRS
Table 1. Classification of CRS
Type
Known as
Description
Type 1 Type 2
Acute Chronic
Type 3
Acute renocardiac
Type 4
Chronic renocardiac
Type 5
Secondary
Acute HF results in AKI Chronic cardiac dysfunction causes progressive CKD Abrupt and primary worsening of kidney function causes acute cardiac dysfunction which may present as cardiac failure Primary CKD contributes to cardiac dysfunction which may be manifested by coronary disease, cardiac failure, or arrhythmia Acute or chronic systemic disorders that cause both cardiac and renal dysfunction
inflammatory mediators released by renal cells or infiltrating inflammatory cells. Building upon the work of animal studies, the search for AKI biomarkers has continued and involves candidate molecules in both plasma and urine. With respect to CRS, the main biomarkers investigated to date are neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), cystatin C, and N-acetyl-β-Dglucosaminidase (NAG). Unsurprisingly, many studies on the use of biomarkers in AKI have focused on the ability to diagnose AKI before a detectable serum creatinine rise, with many studies centered on ICU patients. For example, an early study measured plasma NGAL (pNGAL) and demonstrated the diagnosis of AKI up to 48 h earlier than AKI diagnosed according to classical creatinine criteria. However, a strong association between pNGAL and overall disease severity regardless of the presence of AKI was also seen [13]. A further study employing a single pNGAL measurement on admission to the ICU again predicted the onset of AKI 48 h before AKI as per RIFLE criteria with an impressive AUC of 0.92 although this study was small and excluded patients with CKD [14]. This was in contrast to work where an array of urinary biomarkers were analyzed prospectively and no one biomarker was found to have an AUC above 0.7 [15]. A further prospective study in ICU patients examining pNGAL and urine NGAL (uNGAL) to predict severe AKI prospectively in a cohort of 632 consecutive adult critically ill patients found a significant association between admission pNGAL and uNGAL levels and the final RIFLE class. However, approximately 30% of patients with sepsis had elevated uNGAL levels Blood Purif 2014;37(suppl 2):14–19 DOI: 10.1159/000361060
15
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nomenclature known as the cardiorenal syndrome(s) (CRS; table 1) [5]. Thus, in many patients with cardiac failure, CRS may be causative or contributory to any observed decline. Hence, when faced with a patient with CRS, it is of paramount importance to ascertain whether any functional decline is acute or chronic. With regard to renal function, this may be evidenced by CKD defined through estimated GFR (eGFR), or may be an acute deterioration now known as acute kidney injury (AKI). However, in the absence of any previous serum creatinine measurements, it may be difficult to ascertain whether any derangement in serum creatinine is acute or chronic. Furthermore, there may have been an acute insult to the kidneys, which is not manifest in terms of serum creatinine at presentation, but may be evident 24–48 h later. This lack of precision has led to numerous investigations to determine an early marker of AKI which may aid in both diagnosis and treatment.
Biomarkers of AKI and Outcomes in CRS
Acute HF is one of the dominant causes for hospital admission, particularly in the age group of 65 years and over. Treatment of these patients is complicated by both the presence of multiple comorbidities and involvement of other organs. As discussed, since the combination of renal dysfunction and HF results in a poor prognosis regardless of CRS type, there has been considerable interest in the role of biomarkers in CRS both in terms of early diagnosis as well as in providing insights into the pathophysiology. Results reported to date, however, are by no means conclusive. For example, in patients with acute HF the predictive potential of pNGAL for AKI, compared to serum creatinine, has been assessed in 207 consecutive patients presenting to the emergency department. After controlling for preexisting chronic cardiac or kidney disease in a multivariate regression analysis, serum creatinine, but not NGAL, remained an independent predictor of AKI. In this study, therefore, pNGAL levels did not adequately predict AKI in patients with acute HF, which has also been observed in other studies in hospitalized as well as outpatients with HF where changes in NGAL levels were not associated with hospital admission or eGFR [17–19]. Reports do vary. In some studies the ability of pNGAL to predict type 1 CRS is impressive but depends on the cutoff value used [20], whereas in a multicenter prospective study, elevated pNGAL at the time of discharge was a strong prognostic indicator of 30-day outcomes in patients admitted for acute HF [21]. In addition to NGAL, cystatin C has also attracted much attention in the early detection of AKI, and a recent meta-analysis found that the AUC of plasma cystatin C to predict AKI was between 0.86 and 0.96 depending on the inclusion criteria employed. In contrast, urinary cystatin C levels had only moderate diagnostic value. The conclusions of this metaanalysis, however, were limited by great heterogeneity of 16
Blood Purif 2014;37(suppl 2):14–19 DOI: 10.1159/000361060
pooled studies in terms of clinical setting, AKI definition, and the type and timing of the assay used [22]. A recent study examined predictors of CRS in patients admitted with acute coronary syndromes. Unsurprisingly, the patients who developed CRS were older, had more comorbidities, and needed greater intervention(s). Multivariate analysis on this group of 368 patients found that admission cystatin C was the best predictor of the development of CRS [23]. Further studies have examined the role of other biomarkers of AKI in HF. Jungbauer et al. [24] examined urinary KIM-1, NAG, and NGAL in 150 patients with stable, chronic HF as defined by echocardiographic appearances, clinical examination, and NT-proBNP levels. These were compared to 23 normal healthy individuals and despite this inclusion of a ‘normal’ control group there was no statistical difference in uNGAL or NAG between the two groups. KIM-1 levels, however, were significantly different. Furthermore, no correlation between NGAL and severity of HF could be found although KIM1 again showed a positive and significant correlation with clinical condition, as did NAG to a lesser degree. Of interest in this study is that KIM-1 was found to be a significant predictor for all-cause mortality and hospital readmission rates for congestive cardiac failure over a 1-year follow-up period. Besides evidence suggesting biomarkers may provide insight into the development of AKI complicating HF, there is also evidence that biomarkers may provide some insights into the underlying pathophysiology. This is evidenced by the fact that biomarkers may be elevated in patients with HF who appear to have normal renal function. Certainly there is some clinical evidence that tubular damage may be associated with chronic HF with urinary NAG correlating with both GFR and renal plasma flow [25]. This observation is further supported by other evidence gleaned from over 2,000 patients in the GISSI-HF trial, where an increase in tubular markers was associated with a poorer outcome even in patients with a normal eGFR [26].
Biomarkers of AKI and Management of CRS
Clearly, baseline renal function as defined by GFR is predictive of outcome; however, in terms of acute management, the relationship between changes in GFR and prognosis is of interest. This is somewhat complex given the available interventions, but perhaps the most compelling argument comes from a random-effects meta-analyForni /Chawla
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without AKI [16]. Thus, the diagnostic utility of NGAL or other biomarkers to diagnose AKI prior to elevations in creatinine varies between different patient populations and is affected by comorbidity, timing of the measurements, and, importantly, the chosen cutoff values. A more recent study investigating novel biomarkers of cell cycle arrest (IGFBP7 and TIMP-2) also showed more promise in diagnosing AKI early, but again this was in a critical care setting [12].
The Use of Biomarkers in CRS
Using biomarkers in CRS is an area of increasing interest as it may herald a change in the potential management strategies for acute HF complicated by renal dysfunction. Part of the problem in treating acute decompensation in CRS is the limitations imposed by impaired renal function on the ability to correct volume overload. Biomarkers in CRS
Therefore, effective treatment of CRS could improve patient outcomes particularly where decompensation does not reflect a more severe cardiac disease. Under such conditions, the use of biomarkers may point to worsening HF through elevated BNP, for example, whereas markers of AKI may be normal or elevated. Efforts could then be concentrated on improving cardiac output and hence GFR. Therefore in types 1 and 2 CRS, any reversible component can be treated aggressively. Indeed, evidence does suggest that improvement in cardiac function through the use of cardiac resynchronization as well as left ventricular assist devices leads to improvements in GFR [29, 30]. This could theoretically be monitored by an improvement in biomarker profiles for both cardiac and renal function. However, first-line treatment tends to be of diuretic use rather than such aggressive strategies. One could argue that on commencing diuretic therapy, monitoring biomarkers of AKI may provide additional information guiding treatment. Under certain conditions, for example, vigorous diuresis may lead to a decline in cardiac output through reduced cardiac filling pressures and consequent reduction in GFR. While this may translate into a rise in serum creatinine acutely, treatment could be continued if biomarker levels do not increase; hence, the application of the biomarker would be a marker of hemoconcentration. However, if the fall in renal perfusion leads to tissue injury, a rise in biomarker levels may suggest AKI and hence treatment could be reduced or withheld. In other cases, diuretic therapy may lead to no change in either creatinine or biomarkers where changes in left ventricular end-diastolic pressure have little effect on cardiac performance. Also, reduced right ventricular filling may improve left ventricular performance as well as reduce renal venous pressure, leading to improved renal function. The application of biomarkers to the treatment of decompensated HF with diuretics may dramatically change current practice. There is much evidence supporting the view that hemoconcentration leads to an improved outcome. The ability of AKI biomarkers to delineate between true hemoconcentration and AKI is exciting as this will enable accurate tailored treatment to this patient group in that they may differentiate between reduction in GFR and renal injury. At present, the latter is implied by an increase in creatinine, which may not be the case in this patient group. Similarly, a role for AKI biomarkers could be considered when other agents are used to treat acute decompensation, including ACE inhibition, vasodilators, and inotropes. Blood Purif 2014;37(suppl 2):14–19 DOI: 10.1159/000361060
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sis of some 18,634 patients with HF [27]. This examined the mortality risk associated with worsening renal function (WRF), defined as an increase in serum creatinine ≥0.2 mg/dl or a corresponding decrease in eGFR ≥5 ml/ min/1.73 m2. WRF developed in 25% of the patients and was associated with a higher risk for mortality (OR = 1.62, 95% CI: 1.45–1.82, p < 0.001) and hospitalization (OR = 1.30, 95% CI: 1.04–1.62, p = 0.022). Unsurprisingly, the severity of WRF was associated with increased mortality, and patients with less renal reserve as indicated by impaired renal function at baseline were more prone to progressive renal function loss. Therefore, ameliorating WRF during the management of HF may translate into improved outcomes. The use of some AKI biomarkers has been used to determine whether the response to treatment is able to be predicted. For example, a prospective evaluation of 93 patients with acute decompensated HF examining both plasma and urinary NGAL found that uNGAL correlated with a reduced response to diuretics whereas pNGAL correlated with the GFR [28]. Both markers also predicted the development of AKI and the authors postulated that uNGAL corresponds to distal tubular injury while pNGAL is indicative of reduced glomerular function. An additional study confirmed that changes in measured biomarker profiles may add to patients’ management. KIM-1, NAG, and plasma and urine NGAL in stable patients with HF were measured. Diuretic therapy was withdrawn, which was associated with increases in KIM1 and NAG as well as natriuretic peptides, whereas NGAL was unaffected. Reinstating the diuretic led to an improvement in biomarker profile [29]. However, a similar study on some 141 consecutive patients examining the uNGAL (expressed in terms of urinary creatinine) failed to demonstrate a difference in response to diuretics and only a minor rise in uNGAL preceeded development of AKI as defined by a rise in serum creatinine >0.3 mg/dl [30]. Therefore, under certain conditions an intervention may lead to a decrease in biomarker level, but it is unclear as to what this translates to under clinical conditions.
Color version available online
120 BNP
NGAL
Biomarker level
100 80 60
the clinician (fig. 1). Therefore, the simultaneous measurement of biomarkers would enable maximum improvement in cardiac function while indicating where damage to the kidney would begin. Hence, a point may be reached where further improvement in cardiac function is limited but renal damage is likely. As a result, treatment could be ceased at this point.
40
Conclusions
20 0
1
2
3
4 5 6 Days of treatment
7
8
Fig. 1. Idealized response of cardiac and renal biomarkers on treat-
ment of CRS. Arrow: point of optimal diuresis without initiating AKI.
The HF patient who has become relatively diuretic resistant often proves to be a difficult management problem. However, ultrafiltration (isotonic fluid removal through an extracorporeal circuit) may be employed in these conditions and the use of biomarkers is potentially attractive. Again a role can be foreseen whereby serial measures of BNP and NGAL, for example, may inform
Much progress has been made regarding the role of biomarkers, particularly in the treatment of HF. However, CRS presents its own array of challenges which may be best met by employing our new armamentarium of biomarkers as a panel rather than individually. Much as we consider organ cross-talk vital, perhaps biomarkers, and their interdependence, may help in our understanding and ultimately guide treatment. This in turn may result in improved outcomes for our patients.
Disclosure Statement L.S.C. has links with Alere Medical, Astute Medical, Nxstage Medical, and Baxter Medical. L.G.F. received funding from Astute Medical.
References
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