Medical Hypotheses 83 (2014) 401–403

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Medical Hypotheses

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Can the difference in serum concentration of urea and cystatin C be usedin diagnosis and prognosis of heart failure?

http://dx.doi.org/10.1016/j.mehy.2014.07.0050306-9877/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author. Address: I. Lupisa 13, HR 51000 Rijeka, Croatia. Tel.:+385 51 264 944; fax: +385 51 218 059.

E-mail address: ante.matana@gmail.com (A. Matana).1 Retired cardiologist, formerly worked at Department of Cardiovascular Disease,

Clinical Hospital Centre Rijeka, HR 51000 Rijeka, T. Strizica 3, Croatia.

Ante Matana a,⇑,1, Teodora Zaninovic Jurjevic a, Zrinka Matana Kaštelan b

a Department of Cardiovascular Disease, Clinical Hospital Centre Rijeka, HR 51000 Rijeka, T. Strizica 3, Croatiab Department of Radiology, Clinical Hospital Centre Rijeka, HR 51000 Rijeka, T. Strizica 3, Croatia

a r t i c l e i n f o

Article history:Received 29 January 2014Accepted 11 July 2014

a b s t r a c t

Changes in renal function are an important diagnostic and prognostic indicator in patients with heart fail-ure (HF). They are caused by decreased renal perfusion and consequently decreased glomerular filtrationrate (GFR), or by the effect of increased neurohormonal activity (sympathetic nervous system [SNS],rennin–angiotensin–aldosterone system [RAAS] and arginine vasopressin [AVP]). However, the increaseof serum concentration of urea, creatinine and other metabolites is not specific for HF. Therefore, it isnot possible to distinguish HF from renal diseases solely based on the increase of their concentration,since the increase of their concentration caused by the decrease of GFR cannot be differentiated fromthe increase due to neurohormonal activity. Urea and cystatin C (Cys C) have different mechanisms ofrenal elimination, so it can be assumed that in HF their concentrations will not be increased proportion-ally, what can be used for diagnostic and prognostic purposes. After glomerular filtration Cy C undergoesproximal tubular reabsorption and breakdown, without returning to the blood flow. Since it is notsecreted, its serum concentration depends only on GFR. In contrast to Cys C, urea is filtered in glomerulusand subsequently reabsorbed in proximal tubules and colleting duct. Reabsorption of urea is modified byeffects of SNS, RAAS and AVP. Therefore its serum concentration depends upon GFR and neurohormonaleffect on the tubular function. Since the increase of serum concentration of Cys C is caused only by theeffect of the decreased renal perfusion on GFR, while the increase of urea is a result from both decreasedGFR and tubular effects of increased neurohormonal activity, the paper hypothesis is that in HF theincrease of urea will be significantly higher than the increase of serum Cys C, while in the patients withrenal diseases their increase would be mostly proportional. It can be assumed that the disproportionbetween the increase of Cys C and urea would indicate an increased neurohormonal activity in patientswith HF and correlate with its activity. If this hypothesis is proved correct, this parameter could be usedin HF diagnosis and risk stratification of such patients.

� 2014 Elsevier Ltd. All rights reserved.

Introduction

Changes in renal function represent an important diagnosticand prognostic indicator in patients with heart failure (HF) [1–8].However, they are not specific for HF since they appear also inother conditions, above all in kidney diseases (KD). In HF theyare caused by hemodynamic reasons (fall of cardiac output,increase of vein pressure) on one side and by activation of neuro-hormonal system (sympathetic nervous system [SNS], rennin–angiotensin–aldosterone system [RAAS] and arginine vasopressin[AVP]) on the other side [9–15].

Change of renal perfusion and the degree of neurohormonalactivity correlate with the level of HF, but from increase of concen-tration of serum urea, creatinine and other metabolites it cannot beidentified in which level this increase is a consequence ofdecreased renal perfusion and in which level of increased neuro-hormonal activity. From the clinical point of view it would be use-ful to have a simple method which would enable differentiation ofdeterioration of the renal function due to nephron injury from thedeterioration due to increased neurohormonal activity, since theincrease of neurohormonal activity is more specific for HF thanthe decreased glomerular filtration rate (GFR). The level of neuro-hormonal activity may be assessed by direct measurement of hor-mones, but that is unsuitable in clinical practice. Indirectassessment of neurohormonal activity could be useful in differen-tiating cardiac from other causes of dyspnea and in prognosis ofpatients with HF. Two indicators are required for such purpose:

402 A. Matana et al. / Medical Hypotheses 83 (2014) 401–403

one whose concentration increases only due to the decrease of kid-ney perfusion (what is reflected in decrease of GFR) and the otherwhose increase is caused both due to decreased perfusion andincreased neurohormonal activity. The difference in increase ofconcentration between these two indicators will point towardchanges in neurohormonal activity.

Hypothesis

The hypothesis of this paper is that the difference of serum con-centration of cystatin C (Cys C) and urea reflects the level of neuro-hormonal activity in HF. We expect that in HF patientsconcentration of urea will increase significantly faster in compari-son to increase of concentration of Cys C, while in patients with KDthat increase would be mostly parallel. We also expect that thelevel of their disproportion will correlate with the severity of HF,what would enable better stratification of risk in these patients.If the hypothesis is correct, the difference in the rate of increasebetween Cys C and urea could be used for diagnostic purposes,but also for assessment of outcome in patients with HF.

The hypothesis is based on the difference in eliminationbetween Cys C and urea. Increase of concentration of Cys Cdepends on the decrease of GFR due to nephron injury anddecreased kidney perfusion, while the increase of urea is a conse-quence of cumulative effect of decreased GFR and increased neuro-hormonal activity [6,16]. Therefore in HF a higher increase ofconcentration of urea in relation to Cys C can be expected. Sinceconcentration of Cys C indicates the change in GFR, the differencebetween the increase of Cys C and urea would correlate withincreased neurohormonal activity, because the increase of urea isdefined both by the decrease of GFR and increase of neurohormo-nal activity.

If the increase of urea and the increase of Cys C is expressed as apercentage increase in relation to the highest levels of their normalvalues, it can be expected that in HF such percentage would be sig-nificantly higher for urea, while in KD the increase would be moreproportional. Another way to express the difference in increase ofCys C and urea could be by multiplication of CyS C with 10. In thiscase the difference between them (10 Cys C – urea) in relation tothe highest levels of their normal values will be positive andaround 1.2 (normal level of urea 2.6–8.3 mmol/L, normal level ofCys C 0.53–0.95 mg/L). Higher increase of urea in HF will lead todecrease of this difference, while in more severe HF the result willlead to negative values. The third possible approach would bedividing of 10 CysC with the value of urea, in which case theexpected result would be >1 when there is no HF. In patients withHF its decrease is expected, leading to values <1 in more severe dis-eases. In practice, most accurate method of these three suggestedshould be used.

Evaluation of hypothesis

Cys C is a sensitive indicator of GFR, superior in comparison tocreatinine, especially in the case of minor reduction of GFR [16,17].Serum concentration of Cys C shows good correlation with the riskof death in HF [16,17]. Urea is also a strong predictor of mortalityand rehospitalisation of patients with HF, even when its concentra-tion is only slightly to moderately increased [3–7]. Currently theirrelation in HF is not used in diagnostic and neither for prognosticpurposes. The idea of this paper is that the difference in theincrease of urea and Cys C is more specific for HF than each indivi-dual parameter alone.

The diagnostic accuracy of the described hypothesis should bechecked on a group of patients with HF in relation to a controlgroup of healthy and in relation to patients with KD. The prognos-

tic value of hypothesis should be tested in patients with HF com-paring the group of survived and diseased in a specified periodand conditions, for example in a group of patients treated in hospi-tal with acute decompensation of chronic HF. If proved correct, itshould be tested also in other forms of acute HF (hypertensiveHF, HF in acute coronary syndrome, pulmonary oedema, cardio-genic shock, right HF) and in patients with chronic HF. The methodmight be used not only for the assessment of risk of hospital mor-tality, but also in assessing probability of post-hospital events(early rehospitalization, post-hospital death). This would enablebetter selection of patients who require more intensive post-hospi-tal observation. Changes of initial results arising from applied ther-apy should also be considered, what could also have a prognosticvalue. Obtained results have to be compared with echocardio-graphic findings and values and changes of NT-proBNP. Finally,most reliable demonstration of the possible value of this methodwould be its direct correlation with the level of hormones. Thedefinition of criteria, sensitivity, specificity, positive and negativepredictive values would enable evaluation of its usefulness in rela-tion to existing methods.

Consequences of hypothesis and discussion

The diagnosis of HF can be difficult. In such situations ESCguidelines recommend determination of NT-proBNP and echocar-diography [1]. However, because of its non-specificity, the benefitof NT-proBNP is higher as a ‘‘rule-out test’’ than in confirmationof HF [1]. For urea it is proved that it is a sensitive marker in HFand that its prognostic value does not fall behind in relation toNT-proBNP [19,20]. However, its concentration may increase dueto other reasons, such as KD, increased input or excessive catabo-lism of proteins or gastrointestinal bleeding. Comparison ofincrease of serum urea with changes in the level of Cys C couldincrease its exactness in HF diagnostics and in assessment of riskin this population, since increased neurohormonal activity hashigher impact on the retention of urea, than on the retention ofCys C. Namely, the retention of Cys C increases as a result ofdecreased cardiac output, increased venous pressure and neuro-hormonal effects on renal perfusion. In contrast, the retention ofurea is increased due to the same reasons, but additionally alsodue to the direct neurohormonal effects on its reabsorption.

Cys C is produced by all nucleated cells. It is filtered in glomer-ulus and subsequently reabsorbed in proximal tubules, after whichit is catabolized. In such way it does not return to the blood flow,and since it is not secreted in tubules, its serum level is dependantonly on GFR [16–18,21,22]. That is why it is perceived as a goodindicator of GFR and the level of renal disfunction [23–27].

Urea is created as a by-product of protein metabolism and over90% is eliminated by kidneys [23]. Its excretion is more complexthan the excretion of Cys C. After glomerular filtration it is reab-sorbed in proximal tubules and in the collecting duct [28]. Thereabsorption of urea in proximal tubules is concentration depen-dent, while in collecting duct it is flow dependent [19,28]. Theincrease of urea concentration in primary urine increases its pas-sive reabsorption in accordance with the concentration gradient.SNS and RAAS stimulate reabsorption of water and sodium in prox-imal tubules, increasing the concentration of urea and consequen-tially its passive reabsorption, leading to 40–50% of filtered ureabeing reabsorbed in proximal tubules [29,30]. The second mechan-ism, dependent on the flow, proceeds in the collecting duct. Theless liquid comes to the distal nephron, the tubular flow is slowerand the reabsorption of urea higher [19,28]. Since due to increasedinfluence of SNS and RAAS more water and sodium are reabsorbedin proximal tubules, less liquid comes to the distal parts and theflow is slowed. The terminal part of collecting duct is well perme-

A. Matana et al. / Medical Hypotheses 83 (2014) 401–403 403

able for urea, and the permeability is significantly increased by theinfluence of AVP on urea transporters [29]. Additionally, AVP regu-lates the number of urea transporters [31]. In such a way theincrease of serum urea is linked to effects of SNS, RAAS and AVPand therefore represents an indirect indicator of neurohormonalactivity independently and beyond to GFR changes [28]. The recentpapers on determination of GFR by marked iothalamate showed ahigh correlation of GFR with renal blood flow, but its low relationwith neurohormonal activity in HF [32]. Since increase of Cys C islinked to the changes of GFR, Cys C level reflects the renal functionand the vascular effects of HF. On the other side the increase ofurea is not only a reflection of renal function and vascular effectsof HF, but also of tubular effects of neurohormonal activity[19,28]. That is why this additional increase of its concentration,i.e. the one above the increase caused by the decrease of GFR cor-responds to the increased neurohormonal activity in HF. Sinceincreased levels of noradrenaline [10,14,15], rennin [13,14] andAVP [14,33,34] are associated with the increased mortality risk,this additional increase of urea would lead to the same direction.

If the hypothesis is proved as correct, this method could be usedas a fast and simple way to indirectly assess the level of neurohor-monal activity in HF. That is why the method could be useful indiagnostics of HF. Additionally it could be used for stratificationof risk in patients with HF and possibly help in decision makingon hospitalization or treatment on an outpatient basis. Changesof relation between urea and Cys C may be useful in assessmentof posthospital mortality risk and early rehospitalisation andenable identification of patients which require earlier control ormore intensive observation. The method is very simple and fast,while additional cost would be only determination of Cys C, sinceurea is determined as a routine parameter in HF.

Sources of support in the form of grants

None.

Conflict of interest

None declared.

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