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European Journal of Heart Failure 2004 6(7):877-882; doi:10.1016/j.ejheart.2004.03.017
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© 2004 European Society of Cardiology

Soluble TNF-{alpha} and interleukin-6 receptors in the urine of heart failure patients. Their clinical value and relationship with plasma levels

Miguel Riveraa,*, Raquel Taléns-Viscontia, Rafael Sireraa, Vicente Bertomeub, Antonio Salvadorc, Raquel Cortésa, Fernando García de Burgosd, Vicente Climente, Rafael Payáf, Luis Martinez-Dolzg, Maria Jose Sancho-Tellog and Andrés González-Molinaa

a Research Center La Fe Hospital, José María Haro 59, Puerta 59, 46022 Valencia, Spain
b San Juan Hospital Alicante, Spain
c Dr. Peset Hospital Valencia, Spain
d Elche Hospital Elche, Spain
e General Hospital Alicante, Spain
f General Hospital Valencia, Spain
g La Fe Hospital Valencia, Spain

* Corresponding author. Tel.: +34-96-371-61-98; Fax: +34-96-1973018. E-mail address: rivera_jmi{at}gva.es


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Proinflammatory cytokines are important mediators in heart failure (HF). Recently, urinary levels of tumor necrosis factor-{alpha} (TNF-{alpha}) and interleukin-6 (IL-6) have been determined.

Aims: The purpose of this study was to measure the urinary levels of TNF-{alpha} and IL-6 receptors, sTNF-RI, sTNF-RII, sIL-6R, and the relationship with plasma levels and NYHA classes in HF.

Methods: Plasma and urine were collected from 114 HF patients and sTNF-RI, sTNF-RII and sIL-6R (ng/ml) were analyzed.

Results: For the whole population, plasma levels of sTNF-RI were 2.1±0.1, of sTNF-RII were 5.0±0.3 and of sIL-6R were 49.8±2.5. Urinary levels were: sTNF-RI, 2.8±0.5, r=0.5, p<0.001; sTNF-RII, 12.6±2.1, r=0.4, p<0.001; and sIL-6R, 4.2±0.4, NS. In NYHA III subjects, we found sTNF-RI, r=0.6, p<0.01, sTNF-RII, r=0.5, p<0.05, and sILR-6, r=0.5, p<0.05. Both plasma TNF receptors and urinary levels of sTNF-RII were higher in patients in a more severe NYHA class (p<0.05).

Conclusions: Urine is a good environment to study sTNF-RI and sTNF-RII, and this fact has diagnostic and prognostic implications. Plasma and urinary levels of TNF receptors showed a fair correlation, which was increased in higher NYHA classes. Plasma and urinary levels of sIL6R showed a good correlation in NYHA III. The TNF receptor levels in urine increased in patients with more severe HF.

Key Words: Cytokine receptors • Heart failure • Urine

Received November 26, 2003; Revised February 4, 2004; Accepted March 10, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Heart failure (HF) is a complex syndrome, mediated by neurohumoral and inflammatory factors, among others. In this context, recent studies have shown that proinflammatory cytokines play a significant contributory role in the pathogenesis of cardiac depression and therefore in chronic HF [1]. Cytokines are extremely pleiotropic proteins, synthesized and secreted after stimulation of different cell types, that exert their biological function through a specific cell membrane receptors' interaction in an autocrine or paracrine way.

Tumor necrosis factor-{alpha} (TNF-{alpha}) is a proinflammatory cytokine. Activated cells present in cardiac tissue, such as macrophages, endothelial cells and myocytes which are producers of TNF-{alpha}, and TNF-{alpha} receptors of types 1 (TNF-RI) and 2 (TNF-RII), have been identified in cardiac myocytes [2], suggesting that overexpression of cytokines may be one of several different maladaptive mechanisms responsible for progressive cardiac decompensation in HF [3]. The extracellular domain fragments of both receptors shed from cell surfaces can be detected as soluble forms sTNF-RI and sTNF-RII, and their blood levels in patients with severe HF are elevated [4,5]. On the other hand, interleukin-6 (IL-6) is a multifunctional protein that mediates both immune and inflammatory responses. In contrast to the homodimeric TNF receptors, the biological activities of IL-6 are initiated by the binding of cytokines to a high-affinity heterodimeric receptor, consisting of two membrane glycoproteins: a component receptor that binds IL-6 with low affinity (IL-6R or {alpha}-receptor) and a signal-trasducing component (gp130 or β-receptor) that does not bind IL-6 by itself but requires a high-affinity binding of IL-6 by the complex [6,7]. The IL-6R protein has been shown to be present in membrane-bound and soluble form [8].

Since the original observation that circulating levels of TNF were elevated in patients with HF, there have been countless reports in which elevated levels of proinflammatory cytokines and/or their cytokine receptors have been observed in this kind of patients [9]. Thus far, prior studies have shown that circulating levels of TNF and IL-6 are elevated in direct relation to deteriorating functional classes of HF [10–12]. Moreover, previous reports have suggested that elevated levels of cytokines and cytokine receptors predict a worse clinical outcome [4,5,10,13], being independent predictors of mortality in patients with advanced HF [14]. In this context, drugs that act directly against cytokines, as TNF-{alpha} receptor analogues, have been tested in clinical trials without any success [15,16].

Nothing is known about cytokine receptor levels in the urine of patients with HF, despite the increasing interest in the elucidation of mechanisms by which proinflammatory cytokines exert their effects in the heart. In fact, urine may be a good environment to study TNF-{alpha} and IL-6 and may have diagnostic, prognostic and therapeutic implications for patients with HF, as has been published previously [17]. Thus, determination of cytokine receptor presence in urine offers a noninvasive approach to the monitoring of the immune and inflammatory responses to HF. Therefore, the purpose of this study was to determine the urinary excretion of sTNF-RI, sTNF-RII and IL-6R in patients with HF and to compare this with the plasma levels in order to explore whether the observed plasma alterations of these cytokine receptors are also evident in urine. Furthermore, we calculated the cytokine receptor levels (plasma and urine) according to NYHA functional class.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients
We studied 114 consecutive HF patients, diagnosis of HF was performed based on basic medical history data, electrocardiogram, chest X-ray and echo-Doppler study [18]. A modified Naughton protocol was also performed on these patients. The cause of heart failure was dilated cardiomyopathy (41%), ischemic cardiomyopathy (43%), hypertensive cardiomyopathy (13%) and valvular heart disease (3%). The patients were functionally defined as New York Heart Association classes I (7.9%), II (74.6%) or III (17.5%) and were receiving standard medical treatment following the guidelines of the American Heart Association [19] and the European Society of Cardiology [20]. There were 82 males and 32 females and the mean age was 64±13 years. Subjects in atrial fibrillation, with acute coronary syndromes and those with acute and chronic liver disease, rheumatoid arthritis, chronic infections, pulmonary diseases, malignancy or urinary tract pathologies were excluded. All patients were on stable medical therapy for at least 1 month before study enrollment in order to avoid the possible effects of changing cardiovascular interventions, and none were receiving antiinflammatory drugs. Patients were receiving treatment with ACE inhibitors 66%, calcium-channel blockers 13%, diuretics 71%, aldosterone antagonists 42%, beta blockers 44%, ARBs 14% and digitalis 27%. Eleven age- and sex-matched healthy subjects served as a control group. The procedure was approved by the appropriate institutional review boards or ethics review committees of each study center, and the study was conducted in accordance with the guidelines of good clinical practice and with ethical standards for human experimentation established by the Declaration of Helsinki. The patients signed a written informed consent for their inclusion in the study.

2.2. Blood and urine samples
The procedure for sample collection and preparation of plasma and urine has been previously published in detail [17].

2.3. Cytokine receptor measurement
Plasma and urine concentrations of sTNF-RI, sTNF-RII and sIL-6R were measured in duplicated by specific commercial sandwich enzyme-linked immunosorbent assay (ELISA) following manufacturer's recommendations (Quantikine R&D Systems, Minneapolis, MN). The tests were quantified at 450 nm in a dual wavelength microplate reader (Sunrise, TECAN, Austria) using Magellan software (version 2.5 TECAN, Austria). The ELISAs were suitable for the quantitative determination of cytokines in both the plasma and urine, and analyzed concentrations found in samples were in the range for linearity of each assay. Results were expressed as ng/ml in plasma and ng/mg creatinine in urine, as the urinary cytokine receptor was normalized by the urinary creatinine levels (mg/ml).

2.4. Echo-Doppler study
The study was performed using the standard echocardiographic systems of the hospitals involved in the study using 2.5-MHz transducers. The echocardiographic examinations were performed using the standard apical and parasternal long axis views. Doppler echocardiogram images were stored on videotape and analyses of recordings were all performed in a central laboratory.

2.5. Statistical analysis
All data are presented as mean±S.E.M. (mean standard error). Because the cytokine receptor data were not normally distributed, data were subjected to logarithmic transformation before all statistical analyses. However, to allow comparison with results from other studies, the cytokine data are presented as the mean±S.E.M. of the nontransformed data. Plasma correlation with urine cytokine receptor levels was performed using Pearson's product-moment correlation of the log-normalized data. One-way analysis of variance (ANOVA) was used, after proving the agreement of this model hypothesis, to test mean differences in all cytokine receptor levels in functional classes I to III. Significant differences were said to exist at p<0.05 for all parameters.

All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS/PC 10.1) statistical software (SPSS Chicago, IL).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
For control subjects, the plasma levels of sTNF-RI were 0.7±0.05, of sTNF-RII were 2.0±0.2 and of sIL-6R were 30.1±2.3. The urinary levels of sTNF-RI were 1.5±0.2, of sTNF-RII were 5.2±0.9 and of sIL-6R were 5.1±1.0.

As shown in Table 1, a significant positive correlation was found between sTNF-RI and sTNF-RII plasma and urinary levels (p<0.001) for all functional classes combined. Correlation for sIL-6 was not significant. However, for patients in NYHA III, we found r=0.6, p<0.01 for sTNF-RI; r=0.5, p<0.05 for sTNF-RII; and r=0.5, p<0.05 for sILR-6. Furthermore, as shown in Table 2, both plasma and urinary levels of sTNFR-II were higher in patients in class III when compared with classes II and I HF subjects (p<0.05). We also found that plasma levels of sTNF-RI in patients in class III were higher than for patients in classes II and I (p<0.05).


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  		Table 1 Pearson's product-moment correlation between cytokine receptor plasma and urine levels

 


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  		Table 2 Levels of cytokine receptors in HF patients according to NYHA functional class

 
Fig. 1 illustrates the distribution of sTNF-RI plasma and urine levels as a function of NYHA functional class, although the mean urinary level was not significantly elevated in higher NYHA classes, we found a statistical trend (p=0.1). In Fig. 2, we show the distribution of sTNF-RII plasma and urinary levels which were elevated in direct proportion to the patients' functional classes (p<0.05).


Figure 1
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  		Fig. 1 Levels of sTNF-RI in patients with New York Heart Association functional classes I to III HF. Both plasma (solid bar, ng/ml) and urinary levels (open bar ng/mg) were elevated in direct proportion to the patients' functional classes (p<0.05 by ANOVA in plasma, NS in urine).

 


Figure 2
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  		Fig. 2 Levels of sTNF-RII in patients with New York Heart Association functional classes I to III HF. Both plasma (solid bar, ng/ml) and urinary levels (open bar, ng/mg) were elevated in direct proportion to the patients' functional classes (p<0.05 by ANOVA).

 
For the entire population, neither plasma nor urinary levels for sIL-6R were correlated with functional classes.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Soluble cytokine receptors are important regulators of the cytokine network and contribute not only to controlling cytokine activities during disease but also during normal homeostasis. These features have been ascribed to the composition of cytokine receptor complexes, which includes a signal-transducing receptor subunit used by all members of a cytokine family and a binding subunit that is specific for each cytokine [21].

TNF-{alpha} is a proinflammatory cytokine and has multiple physiological functions. Two distinct receptor types have been identified, the TNFR-II (Type A, Type {alpha}, Mw 75 kDa) [22] and the TNFR-I (Type B, Type β, Mw 55 kDa) [23,24]. Both are transmembrane glycoproteins showing similarities in each of their extracellular portions but are distinguishable immunologically [22]. Due to their proteolytic cleavage and posterior shedding, the soluble forms of both types of receptors have been isolated from the serum and urine of healthy persons and in patients with renal diseases [25,26]. In fact, these soluble receptors are able to neutralize the biological activities of TNF and may serve to modulate and localize its activity or may serve as a reservoir for the controlled release of TNF [4].

IL-6 exerts its biological activities through interaction with specific receptors expressed on the surface of target cells. IL-6 binds first to a low-affinity subunit, an 80-kDa glycoprotein also called gp80 or IL-6R alpha. The IL-6/IL-6R alpha complex recruits the signal-transducing b subunit, a 130-kDa glycoprotein called gp130. The association of gp130 with IL-6 and IL-6R alpha leads to the formation of the high-affinity IL-6 receptor complex to the linkage of two gp130 subunits and finally to signal transduction. The soluble form sIL-6R is a principal component in the regulation of IL-6 responses and forms a (sIL-6R/IL-6) complex capable of directly activating cells via membrane-bound gp130. Despite the fact that cells that do not express IL-6R are nonresponsive to IL-6 alone, they can be stimulated by the complex [27,28], creating a large new spectrum of IL-6 activities, ranging from the control of the immune response to the involvement in pathological states [29]. This pathway, termed "transsignaling" [30,31] (Fig. 3), may be a pathogenic factor in human disorders such as cardiovascular diseases [6]. In fact, recent work has demonstrated that gp130 activation in human cardiac cells leads to cardiomyocyte hypertrophy [32]. Thus, when thinking about the inflammatory potential of IL-6, it is essential to consider the effect that sIL-6R may have on cellular processes.


Figure 3
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  		Fig. 3 Transsignaling of receptors for IL-6. The sIL-6R generated by shedding or alternative splicing binds its ligand with comparable affinity to the membrane expressed IL-6R. The IL-6/sIL-6R complex associates with gp130 expressed on a cell with no IL-6R expression, induces dimerisation and initiates signaling.

 
In our study, we have determined for the first time the urinary levels of IL-6 and TNF-{alpha} soluble receptors in patients with HF, and we have demonstrated that there is a good correlation between plasma and urinary TNF receptor levels in these subjects. Renal glomeruli allow water and solute filtration, which is proportional to the plasma concentration and inversely proportional to the molecular weight of the solutes and dependant on specific permeability/selectivity coefficients. Actually, solutes with a molecular weight lower than 15 kDa diffuse freely, solutes of molecular weight higher than 70 kDa are not permeable in normal conditions and solutes of molecular weight between 15 and 70 kDa are filtered in variable amounts. Only in NYHA III was a good correlation observed for sIL6R, which may reflect a deterioration in renal function in these subjects. This would allow passage of sIL-6R, as the glomerular capillary wall normally restricts the transmural passage of plasma proteins, while showing little resistance to the filtration of water and small solutes.

Taking into account these considerations, it is possible that transmural passage of sIL-6R is restricted by the normal glomerular capillary, which means a poor release of sIL-6R that would increase sIL-6R plasma levels, thereby enhancing the inflammatory effects of IL-6. However, patients in NYHA III may have impaired urinary excretion [33] which could explain the significant correlation observed with sIL-6R plasma and urine in this functional class and also the improvement in TNF receptors' correlation. It is also possible that the high levels of sIL-6R detected in the plasma, compared with those in urine, are due to its physiological effect, as it can be bound to different molecules, whereas only the free sIL-6R could be detected in urine.

On the other hand, we have also found a significant increase in the plasma levels of TNF-{alpha} receptors with the NYHA functional class. These findings agree with other published reports [3–5,14], where other factors influencing plasma levels are also mentioned. Moreover, for the first time, we have found that the same results can be observed in the urine of these HF patients, but only the elevation of sTNF-RII with NYHA class attained statistical significance. No difference was detected in the plasma levels of sIL-R6 among functional classes, which is consistent with other work [5,34]. No differences were observed in urine either.

Independent of the site of production of cytokines in patients with HF, which is still poorly understood [3,5,12,35,36], elevated circulating levels of inflammatory cytokines have been reported in HF, but most studies have focused on only a few cytokine parameters. However, the activity of these cytokines is modulated by soluble cytokine receptors. Thus, sTNF-RI and sTNF-RII have been shown to neutralize the effect of TNF-{alpha}, whereas sIL-6 has been shown to increase the circulating IL-6 bioactivity. Therefore, if the soluble TNF receptors act as antagonists, the absolute levels of circulating TNF receptors increase in direct response to increased TNF-{alpha} levels (receptor shedding). In contrast, sIL-6R acts as an agonistic, making the situation more complex; consequently, the response of IL-6 receptors to increasing levels of IL-6 is quite variable and may increase, decrease or remain the same [9]. These considerations are in agreement with our results in the plasma; moreover, we have established that the same phenomenon is observed in urine. Actually, a good correlation is found between the plasma and urine with both TNF receptors but does not exist with sIL-6R. These findings show the diagnostic and prognostic implications of IL-6 and TNF-{alpha} receptors in the plasma, as stated previously [4,5,10,13,14] but also have been established for the first time in urine. Furthermore, urinary TNF receptor levels in subjects in NYHA III are more than double those in plasma, which would facilitate their measurement. Thus, the determination of cytokine receptor presence in urine offers a noninvasive approach to the monitoring of the immune and inflammatory responses to HF. On the other hand, it has been recently published that as soluble TNF receptors act as natural antagonists and have been shown to neutralize the effect of TNF-{alpha}, they could be used therapeutically [37].

4.1. Limitations of the study
A common limitation in this kind of study is that patients are receiving conventional therapy for their disease, and it is known that several drugs can reduce the plasma levels of proinflammatory cytokines and their receptors. However, this study confirms that a high degree of immune activation persists in HF patients even during standard therapy and can be detected in plasma and urine.

Another consideration is the fact that because better correlation with plasma and urine and also increase of receptor levels with NYHA class were more evident in NYHA III, it would have been very interesting to study patients in NYHA IV. More patients in NYHA III and IV would have been helpful.

4.2. Conclusion
In conclusion, this study expands on previous publications that have described elevated levels of cytokines in HF by demonstrating that urinary levels of sTNF-RI and sTNF-RII increase in patients in relation to HF. If we take into account that the activity of these cytokines is modulated by soluble cytokine receptors and that circulating levels of cytokine receptors were independent predictors of adverse outcome and mortality, understanding that they can be measured in urine offers us a new noninvasive approach. Therefore, urine may be a good way to study the cytokine receptor imbalance observed in HF patients and for monitoring of the immune and inflammatory responses to HF. These new data provide the basis for the development of a new methodology with diagnostic and prognostic implications.


   Acknowledgements
 
The research support source was from the National Institute of Health Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III, FIS 01/0943 Project, Spain.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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