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Decreased Effective Volume in Edematous Disorders: What Does This Mean?

Robert W. Schrier

University of Colorado School of Medicine, Denver, Colorado

ABSTRACT Edematous patients with renal sodium and water retention, particularly cardiac failure and cirrhosis. The afferent failure and cirrhosis, have been suggested to have a decreased “effective blood signal for renal sodium and water re- volume.” This enigmatic and undefined term was coined because edematous tention in edematous disorders contin- patients were found to have increased, rather than the earlier proposed de- ued to be perplexing. A term, therefore, creased, blood volumes. This article discusses the advances that have occurred in emerged and became ensconced in the understanding the pathophysiology of edema as occurs in conditions such as cardiac clinical vocabulary; specifically, so- failure, cirrhosis, and pregnancy. The regulatory mechanisms that lead to increased dium and water retention in edema- sodium and water retention by the normal are related to arterial underfilling, as tous disorders was proposed to be due a result of a decrease in , arterial , or both. to a decrease in “effective blood vol- ume” rather than total blood volume.5 J Am Soc Nephrol 18: 2028–2031, 2007. doi: 10.1681/ASN.2006111302 For many years, however, this enig- matic term, which was used to explain sodium and water retention in patients Early observations in patients with car- failure or cirrhosis is reversed, the af- with or cirrhosis, was diac failure demonstrated renal so- ferent signal for renal sodium and wa- never defined. dium and water retention that resulted ter retention in heart failure and cir- Cardiac output was initially proposed in an increase in extracellular fluid vol- rhosis was sought. Because these by Borst et al.6 as the mediator of the “ef- ume (ECFV) and edema. This degree of patients exhibit edema secondary to in- fective blood volume.” This possibility sodium and water retention in normal creased ECFV, a decrease in total ECFV was attractive, because a diminished car- individuals would lead to an increase in or interstitial volume could not be the diac output was a frequent finding in renal sodium and water excretion, yet signal for the normal kidney to retain edematous patients with cardiac failure. the reverse occurs in patients with sodium and water.3,4 However, if the normal kidney is uni- heart failure. A similar sequence of The focus then turned to a decrease formly responding to a decrease in car- events occurs in patients with cirrhosis. in total blood volume as the potential diac output in edematous disorders, then In these edematous disorders, the kid- signal for sodium and water retention a problem arises because sodium and wa- ney per se, however, was not found to in heart failure and cirrhosis. This ex- ter retention occurs in patients with cir- be directly responsible for the edema planation was plausible, because a de- rhosis, high-output cardiac failure, and formation. Specifically, the kidneys crease in blood volume (e.g., gastroin- normal pregnancy in the presence of an from patients with end-stage liver dis- testinal hemorrhage, diarrhea) was increase in cardiac output. ease no longer retained sodium and known to be associated with renal so- On this background, a unifying hy- water when transplanted into patients dium and water retention. In earlier pothesis for renal sodium and water re- with normal liver function but with years, this possibility actually led to tention that addressed most of these di- ESRD.1 Moreover, renal sodium and volume expansion as a treatment for lemmas was proposed.3,4,7,8 Estimates water retention is reversed after liver the edematous patient with heart fail- transplantation in patients with cir- ure or cirrhosis. Surprising, however, Published online ahead of print. Publication date rhosis. Heart transplantation has also when accurate measurements became available at www.jasn.org. been shown to reverse renal sodium available to assess total blood volume Correspondence: Dr Robert W. Schrier, University of and water retention in patients with in patients with heart failure or cirrho- Colorado School of Medicine, 4200 E. Ninth Ave., B173, Denver, CO 80262. Phone: 303-315-8059; Fax: 2 cardiac failure. Given the evidence sis, a decrease in blood volume was not 303-315-2685; E-mail: [email protected] that the kidney can normally regulate found. In fact, blood volume was fre- Copyright © 2007 by the American Society of sodium and water excretion, if heart quently increased in patients with Nephrology

2028 ISSN : 1046-6673/1807-2028 J Am Soc Nephrol 18: 2028–2031, 2007 www.jasn.org SCIENCE IN RENAL MEDICINE of blood volume distribution indicate A Low output cardiac failure, Oncotic pressure Extracellular that 85% of blood circulates on the Pericardial tamponade, and/or fluid volume low-pressure, venous side of the circu- Constrictive pericarditis permeability lation, whereas an estimated 15% of blood is circulating in the high-pres- sure, arterial circulation. Thus, an in- CARDIAC OUTPUT crease in total blood volume could oc- cur, even as there is an underfilling of Activation of ventricular and arterial receptors the arterial circulation, if the increase Non-osmotic Activation of the in total blood volume is primarily due vasopression Renin-angiolensin- stimulation aidosterone system to expansion of the venous compart- Stimulation of sympathetic nervous system ment. Underfilling of the arterial circu- lation could occur secondary either to a decrease in cardiac output, as occurs in RENAL WATER SYSTEMIC AND RENAL ARTERIAL RENAL SODIUM low-output cardiac failure, or to sys- RETENTION RETENTION temic arterial vasodilation, which oc- curs early in cirrhosis as a result of di- MAINTENANCE OF ARTERIAL minished vascular resistance in the CIRCULATORY INTEGRITY splanchnic circulation.9,10 With this hypothesis, the events that are trig- gered by arterial underfilling, as a re- B High-output Arteriovenous Arterial Sepsis Cirrhosis Pregnancy sult of either a decrease in cardiac out- cardiac failure fistula vasodilators put (Figure 1A) or systemic arterial vasodilation (Figure 1B), are compen- satory responses to restore arterial cir- SYSTEMIC ARTERIAL VASODILATION culatory integrity. Because adequate arterial of vital organs is mandatory for survival, a mechanism Activation of arterial for body fluid volume regulation by the baroreceptors kidney that focuses on the absolute (cardiac output) or relative (arterial Non-osmotic SNS Activation vasodilation) fullness of the arterial AVP stimulation stimulation of RAAS circulation is attractive from a teleo- logic point of view. CARDIAC WATER SYSTEMIC ARTERIAL SODIUM In sodium- and water-retaining dis- OUTPUT RETENTION VASCULAR AND RETENTION RENAL RESISTANCE orders that occur secondary to sys- temic arterial vasodilation, the com- pensatory hemodynamic response is an increase in cardiac output that occurs MAINTENANCE OF ARTERIAL secondary to the reduced cardiac after- CIRCULATORY INTEGRITY load. In both circumstances of arterial underfilling in edematous disorders, Figure 1. Clinical conditions in which a decrease in cardiac output (A) and systemic whether as a result of a decrease in car- arterial vasodilation (B) causes arterial underfilling with resultant neurohumoral activation diac output or arterial vasodilation, the and renal sodium and water retention. In addition to activating the neurohumoral axis, neurohumoral axis is stimulated and adrenergic stimulation causes renal and enhances sodium and fluid renal sodium and water retention oc- transport by the proximal tubule epithelium. Reprinted from Schrier,7 with permission. curs as a compensatory mechanism to maintain arterial perfusion. This in- rhosis.12 Similarly, oral active, nonpep- vasodilation occurs in cirrhosis or sepsis, cludes activation of the sympathetic tide V2 receptor antago- because an accompanying increase in cir- system and the renin-angiotensin-al- nists have been shown to correct culating TNF-␣ decreases myocardial con- dosterone system (RAAS) as well as hyponatremia in cardiac failure and cir- tractibility.14 nonosmotic vasopressin release (Fig- rhosis.13 In some circumstances, a decrease With the primacy of the integrity of ure 1). Reversal of sodium retention in both cardiac output and arterial vasodi- the arterial circulation in renal sodium with antagonist has lation may be involved in arterial underfill- and water regulation, sensitive arterial been shown in cardiac failure11 and cir- ing. Such is the case when primary arterial receptors that respond to arterial under-

J Am Soc Nephrol 18: 2028–2031, 2007 Edema and Arterial Underfilling 2029 SCIENCE IN RENAL MEDICINE www.jasn.org filling must exist. In this regard, there are stolic dysfunction and a normal car- the term “decreased effective blood sensitive stretch receptors in the carotid diac output. There are, however, ven- volume” can be considered outdated artery, aortic arch, and the glomerular af- tricular receptors that may be involved and be replaced by “arterial underfill- ferent arteriole that respond to a decrease with sodium and water retention in pa- ing.” However, if the use of the term in arterial pressure. Because of the im- tients with diastolic dysfunction.18 persists in clinical medicine, then it portance of arterial perfusion, the com- Similar reflexes may be involved in should be “decreased effective arterial pensatory responses to arterial under- right ventricular failure that occurs blood volume.” filling occur rapidly. With arterial under- with pulmonary in asso- filling, as a result of a decrease in cardiac ciation with renal sodium and water re- output, arterial vasodilation, or both, a tention. This possibility, however, is in ACKNOWLEDGMENTS decrease in glossopharyngeal and vagal need of investigation. tone from the carotid and aortic recep- Monitoring arterial underfilling in The author’s research cited in this article was tors leads to a rapid increase in sympa- edematous patients by measuring the supported by National Institutes of Health thetic activity with associated activation hormones that are associated with acti- grant P01 DK19928 and General Clinical Re- of the RAAS and nonosmotic release of vation of the neurohumoral axis is obvi- search Center grant M01 RR000051. vasopressin. The resultant increase in ously neither timely nor cost-effective in The assistance of Jan Darling in prepara- systemic vascular resistance and renal so- the clinical setting. However, in edema- tion of the manuscript is appreciated. dium and water retention attenuates the tous patients who are on a normal so- arterial underfilling and associated di- dium intake and in the absence of diuret- minished arterial perfusion. ics, a low fractional excretion of sodium DISCLOSURES There are low-pressure receptors in indicates clinically important arterial un- None. the cardiac atria that suppress vaso- derfilling and should initiate a search for pressin release, decrease renal vascular an associated decrease in cardiac output resistance, and increase sodium and and/or systemic arterial vasodilation, water excretion in response to an in- which are potentially reversible. REFERENCES creased transmural atrial pressure.15 In A unifying pathway for body fluid cardiac failure, however, atrial pres- volume regulation by the kidney should 1. 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