1 - The Edematous Patient - Cardiac Failure, Cirrhosis, and Nephrotic Syndrome | Manual of Nephrology. Diagnosis and Therapy 6e

Editors: Schrier, Robert W.

Title: Manual of Nephrology, 6th Edition

> Table of Contents > 1 - The Edematous Patient: Cardiac Failure, Cirrhosis, and Nephrotic Syndrome

The Edematous Patient: Cardiac Failure, Cirrhosis, and Nephrotic Syndrome

David H. Ellison

Robert W. Schrier

Body fluid distribution. Of the total fluids in the human body two-thirds reside inside the cell (i.e., intracellular fluid) and one-third resides outside cells (i.e., extracellular fluid [ECF]). The patient with generalized edema has an excess of ECF. The ECF resides in two locations: in the vascular compartment (plasma fluid) and between the cells of the body, but outside of the vascular compartment (interstitial fluid). In the vascular compartment, approximately 85% of the fluid resides on the venous side of the circulation and 15% on the arterial side (Table 1-1). An excess of interstitial fluid constitutes edema. On applying digital pressure, the interstitial fluid can generally be moved from the area of pressure, leaving and an indentation; this is described as pitting. This demonstrates that the excess interstitial fluid can move freely within its space between the body's cells. If digital pressure does not cause pitting in the edematous patient, then interstitial fluid cannot move freely. Such nonpitting edema can occur with lymphatic obstruction (i.e., lymphedema) or regional fibrosis of subcutaneous tissue, which may occur with chronic venous stasis.

Table 1-1. Body Fluid Distribution


Compartment	Amount	Volume (L) in 70 kg man

Total body fluid	60% of body weight	42
Intracellular fluid (ICF)	40% of body weight	28
Extracellular fluid (ECF)	20% of body weight	14
Interstitial fluid	Two-thirds of ECF	9.4
Plasma fluid	One-third of ECF	4.6
Venous fluid	85% of plasma fluid	3.9
Arterial fluid	15% of plasma fluid	0.7

Although generalized edema always signifies an excess of ECF, specifically in the interstitial compartment, the intravascular volume may be decreased, normal, or increased. Because two-thirds of ECF resides in the interstitial space and only one-third in the intravascular compartment, a rise in total ECF volume may occur as a consequence of excess interstitial fluid (i.e., generalized edema) even though intravascular volume is decreased.

Starling's Law states that the rate of fluid movement across a capillary wall is proportional to the hydraulic permeability of the capillary, the transcapillary hydrostatic pressure difference, and the transcapillary oncotic pressure difference. As shown in Figure 1-1, under normal conditions, fluid leaves the capillary at the arterial end because the transcapillary hydrostatic pressure difference favoring transudation exceeds the transcapillary oncotic pressure difference, which favors fluid resorption. In contrast, fluid returns to the capillary at the venous end because the transcapillary oncotic pressure difference exceeds the hydrostatic pressure difference. Because serum albumin is the major determinant of capillary oncotic pressure, which acts to maintain fluid in the capillary, hypoalbuminemia can lead to excess transudation of fluid from the vascular to interstitial compartment. Although hypoalbuminemia might be expected to lead commonly to edema, several factors act to buffer the effects of hypoalbuminemia on fluid transudation. First, an increase in transudation tends to dilute interstitial fluid, thus reducing the interstitial protein concentration. Second, increases in interstitial fluid volume increase interstitial hydrostatic pressure. Third, the lymphatic flow into the jugular veins, which returns transudated fluid to the circulation, increases. In fact, in cirrhosis, where hepatic fibrosis causes high capillary hydrostatic pressures in association with hypoalbuminemia, the lymphatic flow can increase 20-fold to 20 L per day, attenuating the tendency to accumulate interstitial fluid. When these safety factors are overwhelmed, interstitial fluid accumulation can lead to edema. Another factor that must be borne in mind as a cause of edema is an increase in the fluid permeability of the capillary wall (an increase in hydraulic conductivity). This increase is the cause of edema associated with
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hypersensitivity reactions and angioneurotic edema, and it may be a factor in edema associated with diabetes mellitus and idiopathic cyclic edema.

Figure 1-1. Effect of Starling forces on fluid movement across capillary wall. (ISF, interstitial fluid.)
These comments refer to generalized edema (i.e., an increase in total body interstitial fluid), but it should be noted that such edema may have a predilection for specific areas of the body for various reasons. The formation of ascites because of portal hypertension has already been mentioned. With the normal hours of upright posture, an accumulation of the edema fluid in the dependent parts of the body should be expected, whereas excessive hours at bed rest in the supine position predispose to edema accumulation in the sacral and periorbital areas of the body. The physician must also be aware of the potential presence of localized edema, which must be differentiated from generalized edema.
Although generalized edema may have a predilection for certain body sites, it is nevertheless a total-body phenomenon of excessive interstitial fluid. Localized edema, on the other hand, is caused by local factors and therefore is not a total-body phenomenon. Venous obstruction, as can occur with thrombophlebitis, may cause localized edema of one lower extremity. Lymphatic obstruction (e.g., from malignancy) can also cause an excessive accumulation of interstitial fluid and, thus, edema. The physical
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examination of a patient with ankle edema should, therefore, include a search for venous incompetence (e.g., varicose veins) and for evidence of lymphatic disease. It should be recognized, however, that deep venous disease may not be detectable on physical examination and therefore may necessitate other diagnostic approaches (e.g., noninvasive). Thus, if the venous disease is bilateral, the physician may mistakenly search for causes of generalized edema (e.g., cardiac failure and cirrhosis), when indeed the bilateral ankle edema is due to local factors. Pelvic lymphatic obstruction (e.g., malignancy) can also cause bilateral lower-extremity edema and thereby mimic generalized edema. Trauma, burns, inflammation, and cellulitis are other causes of localized edema.

Body fluid volume regulation. The edematous patient has long presented a challenge in the understanding of body fluid volume regulation. In the normal subject, if ECF is expanded by the administration of isotonic saline, the kidney will excrete the excessive amount of sodium and water, thus returning ECF volume to normal. Such an important role of the kidney in volume regulation has been recognized for many years. What has not been understood, however, is why the kidneys continue to retain sodium and water in the edematous patient. It is understandable that when kidney disease is present and renal function is markedly impaired (i.e., acute or chronic renal failure), the kidney continues to retain sodium and water even to a degree causing hypertension and pulmonary edema. Much more perplexing are those circumstances in which the kidneys are known to be normal and yet continue to retain sodium and water in spite of the expansion of ECF and edema formation (e.g., cirrhosis, congestive heart failure). For example, if the kidneys from a cirrhotic patient are transplanted to a patient without liver disease, excessive renal sodium and water retention no longer occur. The conclusion has emerged, therefore, that neither total ECF nor its interstitial component, both of which are expanded in the patient with generalized edema, is the modulator of renal sodium and water excretion. Rather, as Peters suggested in the 1950s, some body fluid compartment other than total ECF or interstitial fluid volume must be the regulator of renal sodium and water excretion.

The term effective blood volume was coined to describe this undefined, enigmatic body fluid compartment that signals the kidney, through unknown pathways, to retain sodium and water in spite of an expansion of total ECF. That the kidney must be responding to cardiac output was suggested, providing an explanation for sodium and water retention in low-output cardiac failure. This idea, however, did not provide a universal explanation for generalized edema because many patients with decompensated cirrhosis, who were avidly retaining sodium and water, were found to have normal or elevated cardiac outputs.
Total plasma or blood volume was then considered as a possible candidate for the effective blood volume modulating renal sodium and water excretion. However, it was soon apparent that expanded plasma and blood volumes were frequently present in the renal sodium and water-retaining states, such as congestive heart failure and cirrhosis. The venous component of the plasma in the circulation has also been proposed as the modulator of renal sodium and water excretion and thus of volume regulation, because a rise in the left atrial pressure is known to cause a water diuresis and natriuresis, mediated in part by a suppression of vasopressin and a decrease in neurally mediated renal vascular resistance. A rise in right and left atrial pressure also has been found to cause a rise in atrial natriuretic peptide. However, despite these effects on the low-pressure venous side of the circulation, renal sodium and water retention are hallmarks of congestive heart failure, a situation in which pressures in the atria and venous component of the circulation are routinely increased.

The arterial portion of body fluids (Table 1-1) is the remaining component that may be pivotal in the regulation of renal sodium and water excretion. More recently, the relationship between cardiac output and peripheral

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arterial resistance [the effective arterial blood volume (EABV)] has been proposed as a regulator of renal sodium and water reabsorption. This relationship establishes the fullness of the arterial vascular tree. In this context, a primary decrease in cardiac output or peripheral arterial vasodilation, or a combination thereof, may cause arterial underfilling and thereby initiate and sustain a sodium and water-retaining state, which leads to edema. The sodium- and water-retaining states that are initiated by a decline in cardiac output are shown in Figure 1-2 and include (a) ECF volume depletion (e.g., diarrhea, vomiting, hemorrhage); (b) low-output cardiac failure, pericardial tamponade, and constrictive pericarditis; and (c) intravascular volume depletion secondary to protein loss and hypoalbuminemia (e.g., nephrotic syndrome, burns or other protein-losing dermopathies, protein-losing enteropathy); and (d) increased capillary permeability (capillary leak syndrome). The causes of increased renal sodium and water retention leading to edema that are initiated by primary peripheral arterial vasodilation are equally numerous and are shown in Figure 1-3. Severe anemia, beri-beri, Paget's disease, and thyrotoxicosis are causes of high-output cardiac failure that may lead to sodium and water retention. A wide-open arteriovenous fistula, hepatic cirrhosis, sepsis, pregnancy, and vasodilating drugs (e.g., minoxidil or hydralazine) are other causes of peripheral arterial vasodilation that decrease renal sodium and water excretion.

Figure 1-2. Decreased cardiac output as the initiator of arterial underfilling. (From Schrier RW. A unifying hypothesis of body fluid volume regulation. J R Coll Physicians Lond 1992;26:296. Reprinted with permission.)

Figure 1-3. Peripheral arterial vasodilation as the initiator of arterial underfilling. (From Schrier RW. A unifying hypothesis of body fluid volume regulation. J R Coll Physicians Lond 1992;26:296. Reprinted with permission.)

Two major compensatory processes protect against arterial underfilling, as defined by the interrelationship of cardiac output and peripheral arterial vascular resistance. One compensatory process is very rapid and consists of a neurohumoral and systemic hemodynamic response. The other is slower and involves renal sodium and water retention. In the edematous patient, these compensatory responses have occurred to varying degrees depending on the point when the patient is seen during the clinical course. Because of the occurrence of these compensatory processes, mean arterial pressure is a poor index of the integrity of the arterial circulation. Whether a primary fall in cardiac output or peripheral arterial vasodilation is the initiator of
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arterial underfilling, the compensatory responses are quite similar. As depicted in Figures 1-2 and 1-3, the common neurohumoral response to a decreased EABV involves the stimulation of three vasoconstrictor pathways, namely the sympathetic nervous system, angiotensin, and vasopressin. In addition to direct effects, the sympathetic nervous system also increases angiotensin and vasopressin because increases in central sympathetic hypothalamic input and beta-adrenergic stimulation via the renal nerves are important components of the increased nonosmotic vasopressin release and stimulation of renin secretion, respectively. With a primary fall in cardiac output or primary peripheral arterial vasodilation, secondary increases in peripheral arterial vascular resistance or cardiac output occur, respectively, to acutely maintain arterial pressure. This rapid compensation allows time for the slower renal sodium and water retention to occur and further restore arterial circulatory integrity. With a decrease in ECF volume, such as occurs with acute gastrointestinal losses, sufficient sodium and water retention can occur to restore cardiac output to normal and thus terminate renal sodium and water retention before edema forms. Such may not be the case with low-output cardiac failure, because even these compensatory responses may not restore cardiac output to normal.
- Thus, the neurohumoral and renal sodium- and water-retaining mechanisms persist as important compensatory processes in maintaining EABV. Specifically, neither the acute nor the chronic compensatory mechanisms are successful in restoring cardiac contractility, or reversing cardiac tamponade or constrictive pericardial tamponade. Compensatory renal sodium and water retention occurs with an expansion of the venous side of the circulation as arterial vascular filling improves but does not return to normal. The resultant rise in venous pressure enhances capillary hydrostatic pressure and thus transudation of
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  fluid into the interstitial fluid, with resultant edema formation. In hypoalbuminemia and the capillary leak syndrome, excessive transudation of fluid occurs across the capillary bed and also prevents the restoration of cardiac output; thus continuous renal sodium and water retention occurs and causes edema formation.
- Peripheral arterial vasodilation, the other major initiator of arterial underfilling, also generally cannot be totally reversed by the compensatory mechanisms and thus may lead to edema formation. Peripheral arterial vasodilation results in dilatation of precapillary arteriolar sphincters, thus increasing capillary hydrostatic pressure and probably capillary surface area. A larger proportion of retained sodium and water thus is transudated across the capillary bed into the interstitium in these edematous disorders (see Fig. 1-3).

Another reason why low cardiac output or peripheral arterial vasodilation may lead to edema formation is the inability of patients with these disorders, as compared with normal subjects, to escape from the sodium-retaining effect of aldosterone (Fig. 1-4). In the normal subject receiving large exogenous doses of aldosterone or another mineralocorticoid hormone, a rise in the glomerular filtration rate and a decrease in proximal tubular sodium and water reabsorption lead to an increase in sodium and water delivery to the distal nephron site of aldosterone action. This increase in distal sodium delivery is the major mediator of escape from the sodium-retaining effect of mineralocorticoids in normal subjects, thus avoiding edema formation. In contrast, the renal vasoconstriction that accompanies the

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compensatory neurohumoral response to arterial underfilling is associated with a decrease in distal sodium and water delivery to the distal nephron site of aldosterone action. This diminution in distal delivery, which occurs primarily because of a fall in the glomerular filtration rate and an increase in proximal tubular sodium reabsorption, results in a failure to escape from aldosterone and, therefore, causes edema formation. The importance of renal hemodynamics, particularly the glomerular filtration rate, in the aldosterone escape phenomena is emphasized by the observation that in pregnancy, a state of primary arterial vasodilation, aldosterone escape occurs despite arterial under-filling because of an associated 30% to 50% increase in the glomerular filtration rate. It still remains to be determined why pregnancy is associated with this large increase in the glomerular filtration rate, which occurs within 2 to 4 weeks of conception. The increase in the filtration rate cannot be due to plasma volume expansion, because this does not occur until several weeks after conception. The higher filtered load of sodium, and thus distal sodium load in pregnancy, no doubt allows the escape from the sodium-retaining effect of aldosterone. The occurrence of aldosterone escape in pregnancy attenuates edema formation when compared to other edematous disorders.

Figure 1-4. Aldosterone escape in a normal subject (left side) and failure of aldosterone escape in patients with arterial underfilling (right side). (EABS, effective arterial blood volume; ECF, extracellular fluid; GFR, glomerular filtration rate.) (From Schrier RW. Body fluid regulation in health and disease: a unifying hypothesis. Ann Intern Med 1990;113:155 59. Adapted with permission.)

Dietary and diuretic treatment of edema: general principles. The daily sodium intake in this country is typically 4 to 6 g (1 g of sodium contains 43 mEq; 1 g of sodium chloride [NaCl] contains 17 mEq of sodium). By not using added salt at meals, the daily sodium intake can be reduced to 4 g (172 mEq), whereas a typical low-salt diet contains 2 g (86 mEq). Diets that are lower in NaCl content can be prescribed, but many individuals find them unpalatable. If salt substitutes are used, it is important to remember that these contain potassium chloride; therefore potassium-sparing diuretics (i.e., spironolactone, eplerenone, triamterene, amiloride) should not be used with salt substitutes. Other drugs that increase serum potassium concentration must also be used with caution in the presence of salt substitute intake [e.g., converting enzyme inhibitors, beta blockers, and nonsteroidal anti-inflammatory drugs (NSAIDs)]. When prescribing dietary therapy for an edematous patient, it is important to emphasize that sodium chloride restriction is required, even if diuretic drugs are employed. The therapeutic potency of diuretic drugs varies inversely with dietary salt intake.

All commonly used diuretic drugs act by increasing urinary sodium excretion. They can be divided into five classes, based on their predominant site of action along the nephron (Table 1-2). Osmotic diuretics (e.g., mannitol) and proximal diuretics (e.g., acetazolamide) are not employed as primary agents to treat edematous disorders. Loop diuretics (e.g., furosemide), distal convoluted tubule diuretics (DCT; e.g., hydrochlorothiazide), and collecting duct diuretics (e.g., spironolactone), however, all play important but distinct roles in treating edematous patients. The goal of the diuretic treatment of edema is to reduce extracellular fluid volume and to maintain the extracellular fluid volume at the reduced level. This requires an initial natriuresis, but, at steady-state, urinary sodium chloride excretion returns close to baseline despite continued diuretic administration. Importantly, an increase in sodium and water excretion does not prove therapeutic efficacy if extracellular fluid volume does not decline. Conversely, a return to basal levels of urinary sodium chloride excretion does not indicate diuretic resistance. The continued efficacy of a diuretic is documented by the rapid return to ECF volume expansion that occurs if the diuretic is discontinued.

Table 1-2. Physiologic Classification of Diuretic Drugs

Osmotic diuretics

Proximal diuretics

Carbonic anhydrase inhibitors

Acetazolamide

Loop diuretics (maximal FE_Na = 30%)

Na-K-2Cl inhibitors

Furosemide

Bumetanide

Torsemide

Ethacrynic Acid

DCT diuretics (maximal FE_Na = 9%)

Na-Cl inhibitors

Chlorothiazide

Hydrochlorothiazide

Metolazone

Chlorthalidone

Indapamide

Many others

Collecting-duct diuretics (maximal FE_Na = 3%)

Na channel blockers

Amiloride

Triameterene

Aldosterone antagonists

Spironolactone

Eplerenone

Indapamide may have other actions as well. DCT, Distal Convoluted Tubule; CD, Collecting Duct.

When starting a loop diuretic as treatment for edema, it is important to establish a therapeutic goal, usually a target weight. If a low dose does not lead to natriuresis, it can be doubled repeatedly until the maximum recommended dose is reached (Table 1-3). When a diuretic drug is administered by mouth, the magnitude of the natriuretic response is determined by the intrinsic potency of the drug, the dose, the bioavailability, the amount delivered to the kidney, the amount that enters the tubule fluid (most diuretics

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act from the luminal side), and the physiologic state of the individual. Except for proximal diuretics, the maximal natriuretic potency of a diuretic can be predicted from its site of action. Table 1-2 shows that loop diuretics can increase fractional sodium (Na) excretion to 30%, distal convoluted tubule (DCT) diuretics can increase it to 9%, and sodium channel blockers can increase it to 3% of the filtered load. The intrinsic diuretic potency of a diuretic is defined by its dose response curve, which is generally sigmoid. The steep sigmoid relation is the reason that loop diuretic drugs are often described as threshold drugs. When starting loop diuretic treatment,

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ensuring that each dose reaches the steep part of the dose-response curve before the dose frequency is adjusted is important. Because loop diuretics are rapid-acting, many patients note an increase in urine output within several hours of taking the drug; this can be helpful in establishing that an adequate dose has been reached. Because loop diuretics are short-acting, any increase in urine output more than 6 hours after a dose is unrelated to drug effects. Therefore, most loop diuretic drugs should be administered at least twice daily, when given by mouth.

Table 1-3. Ceiling Doses of Loop Diuretics


	Furosemide (mg)		Bumetanide (mg)		Torsemide (mg)
	IV	PO	IV	PO	IV	PO

Renal insufficiency
GFR 20 50 mL/min	80	80 160	2 3	2 3	50	50
GFR < 20 mL/min	200	240	8 10	8 10	100	100
Severe acute renal failure	500	NA	12	NA
Nephrotic syndrome	120	240	3	3	50	50
Cirrhosis	40 80	80 160	1	1 2	10 20	10 20
Congestive heart failure	40 80	160 240	2 3	2 3	20 50	50

GFR, glomerular filtration rate.
Note: Ceiling dose indicates the dose that produces the maximal increase in fractional sodium excretion. Larger doses may increase net daily natriuresis by increasing the duration of natriuresis without increasing the maximal rate.

The bioavailability of diuretic drugs varies widely among classes of drugs, among different drugs of the same class, and even within the same drug. The bioavailability of loop diuretics ranges from 10% to 100% (mean, 50% for furosemide; 80% to 100% for bumetanide and torsemide). Limited bioavailability can usually be overcome by appropriate dosing, but some drugs, such as furosemide, are variably absorbed by the same patient on different days, making precise titration difficult. Doubling the furosemide dose when changing from intravenous to oral therapy is customary, but the relation between intravenous and oral dose may vary. For example, the amount of sodium excreted during 24 hours is similar whether furosemide is administered to a normal individual by mouth or by vein, despite its 50% bioavailability. This paradox results from the fact that oral furosemide absorption is slower than its clearance, leading to absorption-limited kinetics. Thus, effective serum furosemide concentrations persist longer when the drug is given by mouth, because a reservoir in the gastrointestinal tract continues to supply furosemide to the body. This relation holds for a normal individual. Predicting the precise relation between oral and intravenous doses, therefore, is difficult.

Diuretic resistance. Patients are considered to be diuretic resistant when an inadequate reduction in ECF volume is observed despite near maximal doses of loop diuretics. Several causes of resistance can be determined by considering factors that affect diuretic efficacy, as discussed above.

Causes of diuretic resistance
- Excessive dietary NaCl intake is one cause of diuretic resistance. When NaCl intake is high, renal NaCl retention can occur between natriuretic periods, thus maintaining the ECF volume expansion. Measuring the sodium excreted during 24 hours can be useful in diagnosing excessive intake. If the patient is at steady state (the weight is stable), then the urinary sodium excreted during 24 hours is equal to dietary NaCl intake. If sodium excretion exceeds 100 to 120 mM (approximately 2 3 g sodium per day), then dietary NaCl consumption is too high and dietary counseling should be undertaken.
- Impaired diuretic delivery to its active site in the kidney tubule is another cause of diuretic resistance. Most diuretics, including the loop diuretics, DCT diuretics, and amiloride, act from the luminal surface. Although diuretics are small molecules, most circulate while tightly bound to protein and reach tubule fluid primarily by tubular secretion. Loop and DCT diuretics are organic anions that circulate bound to albumin and reach tubule fluid primarily via the organic anion secretory pathway in the proximal tubule. Although experimental data suggest that diuretic resistance results when serum albumin concentrations are very low, because the volume of diuretic distribution increases, most studies suggest that this effect is only marginally significant clinically and is observed only when serum albumin concentration declines below 2 g/L. A variety of endogenous and exogenous substances that compete with diuretics for secretion into tubule fluid are more probable causes of diuretic resistance. Uremic anions, NSAIDS, probenecid, and penicillins all inhibit loop and DCT diuretic secretion into tubule fluid. Under some conditions, this may predispose to diuretic resistance, because the concentration of drug achieved in tubule fluid does not exceed the diuretic threshold. For example, chronic renal failure shifts the loop diuretic
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  dose-response curve to the right, therefore requiring a higher dose to achieve maximal effect.
- Diuretic binding to protein in tubule fluid is another factor that may influence diuretic effectiveness. Diuretic drugs are normally bound to proteins in the plasma, but not once they are secreted into tubule fluid. This reflects the normally low protein concentrations in tubule fluid. In contrast, when serum proteins, such as albumin, are filtered in appreciable quantities, as in nephrotic syndrome, diuretic drugs interact with them and lose effectiveness. Despite experimental support, recent clinical studies have indicated that this phenomenon does not contribute significantly to diuretic resistance in nephrotic syndrome.

Treatment of diuretic resistance. Several strategies are available to achieve the effective control of ECF volume in patients who do not respond to full doses of effective loop diuretics.

A diuretic of another class may be added to a regimen that includes a loop diuretic (Combination Diuretic Therapy Table 1-4). This strategy produces true synergy; the combination of agents is more effective than the sum of the responses to each agent alone. DCT diuretics are most commonly combined with loop diuretics. DCT diuretics inhibit the adaptive changes in the distal nephron that increase the reabsorptive capacity of the tubule and limit the potency of loop diuretics. Because, DCT diuretics have longer half-lives than loop diuretics, they prevent or attenuate NaCl retention during the periods between doses of loop diuretics, thereby increasing their net effect. When two diuretics are combined, the DCT diuretic is generally administered some time before the loop diuretic (1 hour is reasonable) to ensure that NaCl transport in the distal nephron is blocked when it is flooded with solute. When intravenous therapy is indicated, chlorothiazide (500 1000 mg) may be employed. Metolazone is the DCT diuretic most frequently combined with loop diuretics, because its half-life is relatively long (as formulated in Zaroxylin) and because it has been reported to be effective even when renal failure is present. Other thiazide and thiazide-like diuretics, however, appear to be equally effective, even in severe renal failure. The dramatic effectiveness of combination diuretic therapy is accompanied by complications in a significant number of patients. Massive fluid and electrolyte losses have led to circulatory collapse during combination therapy, and patients must be followed carefully. The lowest effective dose of DCT diuretic should be added to the loop diuretic regimen; patients can frequently be treated with combination therapy for only a few days and then must be placed back on a single drug regimen. When continuous combination therapy is needed, low doses of DCT diuretic (2.5 mg metolazone or 25 mg hydrochlorothiazide) administered only 2 or 3 times per week may be sufficient.

Table 1-4. Combination Diuretic Therapy (to Add to a Ceiling Dose of a Loop Diuretic)

Distal convoluted tubule diuretics:

Metolazone 2.5 10 mg P.O. daily*

Hydrochlorothiazide (or equivalent) 25 100 mg P.O. daily

Chlorothiazide 500 1,000 mg intravenously

Proximal tubule diuretics:

Acetazolamide 250 375 mg daily or up to 500 mg intravenously

Collecting-duct diuretics:

Spironolactone 100 200 mg daily

Amiloride 5 10 mg daily

*Metolazone is generally best given for a limited period (3 5 days) or should be reduced in frequency to 3 times per week once extracellular fluid volume has declined to the target level. Only in patients who remain volume expanded should full doses be continued indefinitely, based on the target weight.

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For hospitalized patients who are resistant to diuretic therapy, the continuous infusion of loop diuretics is an alternative approach. Continuous diuretic infusions (Table 1-5) have several advantages over bolus diuretic administration. First, because they avoid peaks and troughs of diuretic concentration, continuous infusions prevent periods of positive NaCl balance (post-diuretic NaCl retention) from occurring. Second, continuous infusions are more efficient than bolus therapy (the amount of NaCl excreted per mg of drug administered is greater). Third, some patients who are resistant to large doses of diuretics given by bolus respond to continuous infusion. Fourth, diuretic response can be titrated; in the intensive care unit, where obligate fluid administration must be balanced by fluid excretion, excellent control of NaCl and water excretion can be obtained. Finally, complications associated with high doses of loop diuretics, such as ototoxicity, appear to be less common when large doses are administered as a continuous infusion. Total daily furosemide doses exceeding 1 g have been tolerated well when administered over 24 hours. One approach is to administer a loading dose of 20 mg furosemide followed by a continuous infusion at 4 to 60 mg per hr. In patients with preserved renal function, therapy at the lower dosage range should be sufficient. When renal failure is present, higher doses may be used, but patients should be monitored carefully for side effects, such as ECF volume depletion and ototoxicity.

Table 1-5. Continuous Infusion of Loop Diuretics


		Infusion rate, mg/hr
Diuretic	Starting bolus mg	GFR <25 mL/min	GFR 25 75 mL/min	GFR >75 mL/min

Furosemide	40	20 then 40	10 then 20	10
Bumetanide	1	1 then 2	0.5 then 1	05
Torsemide	20	10 then 20	5 then 10

When therapy with diuretic drugs fails, ultrafiltration using hemodialysis equipment or a specialized ultrafiltration apparatus has been used. Although this approach is not recommended for routine use, in one controlled study, the response to volume removal via ultrafiltration was better sustained than after an equivalent volume removal via diuretics. In that study, loop diuretics induced a large rise in renin and angiotensin secretion, probably by stimulating the macula densa mechanism directly. This may explain the unique beneficial results sometimes observed following nonpharmacologic volume removal.

Congestive heart failure

Early clinical symptoms of cardiac failure occur before overt physical findings of pedal edema and pulmonary congestion. These symptoms relate to the compensatory renal sodium and water retention that accompanies arterial underfilling. The patient may present with a history of weight gain, weakness, dyspnea on exertion, decreased exercise tolerance, paroxysmal nocturnal dyspnea, and orthopnea. Nocturia may occur because cardiac output, and therefore renal perfusion, may be enhanced by the supine position. Patients with congestive heart failure may lose considerable weight during the first few days of hospitalization, even without the administration of diuretics because of this nocturia. Although overt edema is not detectable early in the course of congestive heart failure, the patient may complain of swollen eyes on awakening and tight rings and shoes, particularly at the end of the day. With incipient edema, as much as 3 to 4 L of fluid can be retained prior to the occurrence of overt edema.

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The period of incipient edema is then followed by more overt symptoms and physical findings: basilar pulmonary rales, ankle edema, distended neck veins at 30 degrees, tachycardia, and a gallop rhythm with a third heart sound. Although the chest x-ray may only show cephalization of pulmonary markings early in cardiac failure, increased hilar markings, Kerley's B lines, and pleural effusions occur later, generally accompanied by an enlarged heart size.
Etiology. Two mechanisms that reduce cardiac output are recognized to cause congestive heart failure: systolic dysfunction and diastolic dysfunction. Because specific, life-saving therapy is available for systolic dysfunction, it is essential to determine whether systolic dysfunction is present when a patient presents with the symptoms and signs of heart failure. Although physical examination, chest x-ray, and electrocardiogram are useful in this regard, additional diagnostic tests are usually indicated. An echocardiogram provides information about systolic (the ejection fraction) and diastolic function, and about valvular disease, which may require surgery. Occult hypo- or hyperthyroidism and alcoholic cardiomyopathy may present as congestive heart failure; these are treatable. Uncontrolled hypertension may contribute to congestive heart failure, but disease of the coronary arteries is the most common cause. In one study, severe coronary artery disease was found in 9 of 38 patients undergoing cardiac transplantation for presumed idiopathic dilated cardiomyopathy, and in 3 of 4 patients with presumed alcoholic cardiomyopathy. These data suggest that cardiac catheterization may be indicated in virtually all patients who present with new-onset congestive heart failure. In patients with preexisting cardiac disease, a cardiac arrhythmia, pulmonary embolus, cessation of medicines, severe anemia or fever, dietary sodium indiscretion, and worsening of chronic obstructive lung disease with infection and resultant hypoxia are examples of potentially treatable precipitants of worsening of congestive heart failure. Drugs with a negative inotropic effect, such as verapamil, may worsen heart failure by decreasing cardiac output. A trial cessation of these drugs is the best means of determining their possible role in worsening congestive heart failure.

Treatment. When none of these specific primary or precipitating causes of congestive heart failure are detectable, then general principles of treatment must be considered.

Every patient with symptomatic systolic dysfunction or, if asymptomatic, an ejection fraction of less than 40% should be started on an angiotensin converting enzyme (ACE) inhibitor, unless a specific contraindication exists. ACE inhibitors (and angiotensin receptor inhibitors) are unique agents that reduce blood pressure (reduce afterload), shift the renal function curve to the left (promote continued sodium losses), and block maladaptive neuroregulatory hormones (Fig. 1-5). These agents should be started at low doses (enalapril 2.5 mg b.i.d. or captopril 6.25 mg t.i.d.), but increased if tolerated to 10 b.i.d. of enalapril or 50 t.i.d. of captopril, unless side effects occur. If cough or angioedema limits ACE inhibitor use, then an AT1 angiotensin receptor blocker should be used (although angioedema may develop with AT1 receptor blockers, the incidence is lower with this class of drugs). If neither class of drug can be employed safely, then therapy with hydralazine and isosorbide dihydrate or monohydrase should be used.

Figure 1-5. Relationship between cardiac output and left ventricular filling pressure under normal circumstances (upper curve) and low-output congestive heart failure (lower curve). Reduction of afterload (e.g., angiotensin-converting enzyme inhibitor or a vasodilator) or improved contractility (inotropic agents) may shift the lower curve to the middle curve. Diuretic-induced preload reduction or other causes of volume depletion may decrease cardiac output (e.g., shift from point A to point B on the lower curve). (From Schrier RW, ed. Renal and Electrolyte Disorders, 4th ed. Boston: Little, Brown, 1990. Reprinted with permission.)

Beta blockers have been shown to improve symptoms and mortality in patients with systolic dysfunction. Both selective beta blockers (metoprolol) and nonselective beta blockers with alpha blocking properties (carvedilol) are approved by the Food and Drug Administration (FDA) for the treatment of congestive heart failure. Because beta blockers can lead to symptomatic exacerbations of heart failure, these drugs are initiated only when patients are clinically stable and without expansion of the ECF volume.

The role of digitalis glycosides has been clarified by recent controlled studies. Digoxin significantly improves symptoms and reduces the

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incidence of hospitalization in patients with impaired left ventricular function, but it does not appear to prolong life. Thus, the drug is indicated for symptomatic treatment when combined with ACE inhibitors and diuretics. In certain clinical states of heart failure, however, cardiac glycosides have been shown to be of little therapeutic value, for example in association with thyrotoxicosis, chronic obstructive pulmonary disease, and cor pulmonale. Cardiac glycosides may actually worsen symptoms in patients with hypertrophic obstructive cardiomyopathy and subaortic stenosis, pericardial tamponade, and constrictive pericarditis. It should also be remembered that digoxin is excreted by the kidneys; therefore, the dosage interval should be increased in the patient with chronic renal disease (see Chapter 16). Also, the elderly patient should receive a decreased dose (e.g., 0.125 mg q.o.d.), even if the serum creatinine level is not increased. Because renal function deteriorates with age, serum creatinine levels may not rise because of a concomitant loss of muscle mass. Although potentially useful acute therapy, phosphodiesterase inhibitors, such as milrinone, which also increase

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cardiac output, have been shown to increase mortality when used chronically; these drugs should be avoided.

If symptomatic pulmonary congestion or periperal edema is present, diuretic therapy is indicated (Fig. 1-5). A loop diuretic is usually employed as first-line therapy, although some patients may be managed using a thiazide. In patients with congestive heart failure, diuretic therapy must be instituted with full knowledge of the Starling-Frank curve of myocardial contractility (Fig. 1-6). The patient with congestive heart failure who responds to a diuretic will exhibit improved symptomatology as end-diastolic volume and pulmonary congestion decrease. However, because the Starling-Frank curve is usually either flat or up-sloping even in failing hearts, an improvement in cardiac output may not occur. If, during the diuretic treatment of a patient with congestive heart failure, the serum creatinine and blood urea nitrogen levels begin to rise, it is likely that cardiac output has fallen. This situation is especially pronounced in patients who receive ACE inhibitor therapy. ACE inhibitors impair renal autoregulation and make patients prone to prerenal azotemia. When mild azotemia develops in a patient treated with diuretics and an ACE inhibitor, it is usually advisable to reduce the diuretic dose or liberalize dietary salt intake, provided that pulmonary congestion is not present simultaneously. This approach has been shown to permit the continued administration of ACE inhibitors in many patients. Some pedal edema may be preferable to a diuretic-induced decline

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in cardiac output as estimated by the occurrence or worsening of prerenal azotemia. Patients with congestive heart failure are especially sensitive to renal functional deterioration if NSAIDs are used together with diuretics and ACE inhibitors. Thus, NSAIDS should be diligently avoided in this patient population.

Figure 1-6. Comparison of diuretic, angiotensin converting enzyme (ACE) inhibitor, and vasodilator effects on mean arterial pressure and natriuresis. The normal renal function curve is shown (solid line). Adding a vasodilator reduces mean arterial pressure but also reduces natriuresis because blood pressure declines. A diuretic moves the individual to a new renal function curve (dashed line), thereby increasing natriuresis, but has little effect on blood pressure. An ACE inhibitor moves the individual to a new renal function curve, maintaining natriuresis at a lower blood pressure.

Both congestive heart failure itself and treatment with loop diuretics stimulate the renin-angiotensin-aldosterone axis. Two large studies have provided evidence that blocking mineralocorticoid (aldosterone) receptors can improve mortality of such patients. In one trial, adding spironolactone (25 to 50 mg per day) to a regimen that included an ACE inhibitor and a diuretic (with or without digoxin) reduced all cause mortality by 30% and reduced hospitalization for heart failure by 35%. Gynecomastia, which is a relatively common side effect of spironolactone owing to its estrogenic side effects, does not appear to occur with eplerenone, a newer more selective drug.

Hyperkalemia is of concern when aldosterone blockade is instituted. It is currently recommended that serum potassium be monitored 1 week after initiating therapy with an aldosterone blocker, after 1 month, and every 3 months thereafter. An increase in serum potassium greater than 5.5 mEq per L should prompt an evaluation for medications such as potassium supplements or NSAIDs that might be contributing to the hyperkalemia. If such factors are not detected, the dose of aldosterone blocker should be reduced 25 mg every other day. It is prudent to avoid the use of aldosterone blockers in patients with a creatinine clearance of less than 30 mL per min and to be cautious in those with a creatinine clearance of between 30 and 50 mL per min. These patients must be followed very closely.

Complications of diuretic therapy are shown in Table 1-6. Although hyponatremia may be a complication of diuretic treatment, furosemide, when combined with ACE inhibitors, may ameliorate hyponatremia in some patients with congestive heart failure, possibly by improving cardiac output. Hypokalemia and hypomagnesemia are frequent complications of diuretic treatment in heart failure patients because of secondary hyperaldosteronism, which increases sodium delivery to the distal sites at which aldosterone stimulates potassium and hydrogen ion secretion. Severe renal magnesium wasting may also occur in the setting of secondary hyperaldosteronism and loop diuretic administration. Because both magnesium and potassium depletion cause similar deleterious effects on the heart, and potassium repletion is very difficult in the presence of magnesium depletion, supplemental replacement of both these cations is frequently necessary in patients with cardiac failure.

Table 1-6. Complications of Diuretics

Contraction of the vascular volume

Orthostatic hypotension (from volume depletion)

Hypokalemia (loop and DCT diuretics)

Hyperkalemia (spironolactone, eplerenone, triamterene, and amiloride)

Gynecomastia (spironolactone)

Hyperuricemia

Hypercalcemia (thiazides)

Hypercholesterolemia

Hyponatremia (especially with DCT diuretics)

Metabolic alkalosis

Gastrointestinal upset

Hyperglycemia

Pancreatitis (DCT diuretics)

Allergic interstitial nephritis

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The treatment of patients with congestive heart failure and preserved systolic function, is less clearly defined. Hypertension control is clearly paramount in these patients, because hypertension is a frequent cause of cardiac hypertrophy. Diuretics are usually necessary to improve symptoms of dyspnea and orthopnea. Beta blockers, ACE inhibitors, angiotensin receptor blockers, or non-dihydropyridine calcium antagonists may be beneficial in some patients with diastolic dysfunction.

Hepatic cirrhosis. The pathogenesis of renal sodium and water retention is similar in all varieties of cirrhosis, including alcoholic, viral, and biliary cirrhosis. Studies in both humans and animals indicate that renal sodium and water retention precedes the formation of ascites in cirrhosis. Thus, the classic underfill theory, which attributed the renal sodium and water retention of cirrhosis to ascites formation with resultant hypovolemia, seems untenable as a primary mechanism. Because plasma volume expansion secondary to renal sodium and water excretion occurs prior to ascites formation, the overflow theory of ascites formation was proposed. This postulated that an undefined process, triggered by the diseased liver (e.g., increased intrahepatic pressure), causes renal sodium and water retention that then overflows into the abdomen because of portal hypertension. This overflow theory, however, predicts that renal salt retention and ascites formation would be associated with decreased levels of vasopressin, renin, aldosterone, and norepinephrine. Because these hormones rise progressively as cirrhosis advances from the states of compensation (no ascites) to decompensation (ascites) to hepatorenal syndrome, the overflow hypothesis also does not seem to explain the renal sodium and water retention associated with advanced cirrhosis. More recently, the peripheral arterial vasodilation theory has been proposed. This theory, summarized in Figure 1-7, is compatible with virtually all known observations in

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patients during the various stages of cirrhosis. According to this theory, cirrhosis causes arterial vasodilation and a decline in blood pressure; hypotension stimulates renal NaCl retention. The cause of the primary arterial vasodilation in cirrhosis is not clear, but is known to occur early in the course of the disease before ascites formation, primarily in the splanchnic circulation. Although several mediators, including substance P, vasoactive intestinal peptide, endotoxin, and glucagon have been proposed to play a role in arterial vasodilation, recent information indicates that nitric oxide may be a crucial participant. The opening of existing splanchnic arteriovenous shunts may account for some early arterial vasodilation. Later, anatomically new portosystemic and arteriovenous shunting secondary to the portal hypertension may also occur.

Figure 1-7. Peripheral arterial vasodilation hypothesis. Stages of progression of cirrhosis. (AVP, arginine vasopressin; NE, norepinephrine.)

* Given the positive sodium and water balance that has occurred, these plasma hormones would be suppressed in normal subjects without liver disease.

** The progressive renal sodium and water retention increases extracellular fluid, interstitial fluid, and plasma volume. However, the concomitant occurrence of hypoalbuminemia in decompensated cirrhosis and hepatorenal syndrome may attenuate the degree of volume expansion.

Options for treating cirrhotic ascites and edema include dietary NaCl restriction, diuretic drugs, large-volume paracentesis, peritoneovenous shunting, portosystemic shunting [usually transjugular intrahepatic portosystemic shunting (TIPS)], and liver transplantation. Each of these approaches has a role in the treatment of cirrhotic ascites, but most patients can be treated successfully with dietary restriction, diuretics, and occasionally large-volume paracentesis.

The initial therapy of cirrhotic ascites is supportive, including dietary sodium restriction and cessation of alcohol. When these measures prove inadequate, diuretic treatment should begin with spironolactone. Spironolactone has several advantages. First, a controlled trial showed that spironolactone is more effective than furosemide alone in reducing ascites in cirrhotic patients. Second, spironolactone is a long-acting diuretic that can be given once per day in doses ranging from 25 mg to 400 mg per day. Third, unlike most other diuretics, hypokalemia does not occur when spironolactone is administered. Hypokalemia increases renal ammonia production and can precipitate encephalopathy. The most common side effect of spironolactone is painful gynecomastia. (Gynecomastia appears to be much less common with eplerenone, a newer, more selective antagonist, which may be substituted.) Although amiloride, another K-sparing diuretic, can be used as an alternative, spironolactone is more effective than amiloride in reducing ascites. In patients who do not respond to a low dose of spironolactone, spironolactone can be combined with furosemide, starting at 100 mg spironolactone and 40 mg furosemide (to a maximum of 400 mg spironolactone and 160 mg furosemide). This regimen has the advantages of once per day dosing and minimal hypokalemia.
The appropriate rate of diuresis depends on the presence or absence of peripheral edema. Because mobilizing ascitic fluid into the vascular compartment is slow (approximately 500 mL per day), the rate of daily diuresis should be limited to 0.5 kg per day if peripheral edema is absent. In the presence of peripheral edema, most patients can tolerate up to 1.0 kg per day of fluid removal. Because ascites in the decompensated cirrhotic patient is associated with substantial complications including (a) spontaneous bacterial peritonitis (50% to 80% mortality), which does not occur in the absence of ascites; (b) impaired ambulation, decreased appetite, and back and abdominal pain; (c) an elevated diaphragm with decreased ventilation predisposing to hypoventilation, atelectasis, and pulmonary infections; and (d) negative cosmetic and psychologic effects, the treatment of ascites with diuretics and sodium restriction is appropriate. This approach is successful in approximately 90% of patients, and complications are rare. Earlier studies of diuretic therapy complications often utilized more aggressive diuretic regimens.

An alternate approach to diuretics is large-volume paracentesis. Total paracentesis, occurring in increments over 3 days or, more commonly, at one setting has been shown to have few complications; in some studies paracentesis appears to have a lower incidence of complications than does diuretic treatment. When peripheral edema is absent, albumin (6 g for each L of
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ascitic fluid removed) may be infused to reduce hemodynamic compromise and the elaboration of vasoregulatory hormones. The use of albumin remains controversial in patients with concomitant peripheral edema. Patients often favor paracentesis because of the rapid improvement in symptoms; diuretics and salt restriction, however, continue to be the primary approach and are required between paracentesis, even in those patients who cannot be maintained on diuretics alone.

Portosystemic shunting is usually performed as TIPS. In two uncontrolled trials, TIPS led to an increase in urine output, a marked reduction in ascites, and a reduction in diuretic usage. Renal function also improved. Yet in a controlled trial, mortality increased in patients who received a TIPS as compared with controls, and TIPS can precipitate hepatic encephalopathy, especially in Child-Pugh Class C patients. A recent review of the literature confirmed that TIPS can effectively reduce or eliminate ascites, but carries a substantial complication rate. Therefore, it remains best reserved for truly refractory patients who will not receive a liver transplant. Similar considerations apply to peritoneovenous (LeVeen) shunting. In controlled trials, peritoneovenous shunting was shown to reduce ascites more effectively than paracentesis or diuretics, but this was associated with a high rate of complications (e.g., shunt clotting); the shunt carries no survival advantage. Despite reports that the high complication rate can be reduced, most centers reserve this therapy for patients who are truly refractory to more conventional approaches and who are not candidates for liver transplantation.

The development of ascites in a previously compensated cirrhotic patient is an indication for liver transplantation. In view of the morbidity and mortality associated with diuretic-resistant decompensated cirrhosis, liver transplantation is an important treatment for the ECF volume expansion that accompanies cirrhotic ascites. Worsening of ascites in a previously stable individual is most often caused by progressive liver disease, but should also compel the search for hepatocellular carcinoma and portal vein thrombosis.
Treatment aimed at the peripheral arterial vasodilation of cirrhosis has only been used in the acute setting of the patient with portal hypertension and bleeding esophageal varices. Nitric oxide may play an important role in cirrhosis-associated vasodilation. In a rat model of cirrhosis, the blockade of nitric oxide synthesis corrected many of the hemodynamic and neurohumoral perturbations and dramatically improved sodium and water retention. In a short-term human trial, however, blocking nitric oxide synthesis increased blood pressure but did not lead to natriuresis. Definitive evidence for this approach awaits longer-term studies. Portal venous hypertension is caused not only by the intrahepatic capillary fibrosis that causes resistance to flow but also by increased splanchnic flow. Therefore, the administration of vasopressin, which selectively constricts the splanchnic vasculature, has been shown to decrease portal venous pressure and thereby diminish esophageal variceal bleeding. A chronic oral vasopressin analogue that has selective V₁ (vascular) agonist activity but not V₂ (antidiuretic) activity and a reasonably long duration of action (hours) could be of value in the chronic treatment of portal hypertension and the prevention of esophageal variceal bleeding. Such a compound, however, remains to be developed. Because there are fewer V₁ receptors on the renal than the splanchnic vascular bed, such an approach could also increase renal perfusion pressure without causing further renal vasoconstriction.

Nephrotic syndrome. Another major cause of edema is nephrotic syndrome, the clinical hallmarks of which include proteinuria (>3.5 gm per day), hypoalbuminemia, hypercholesterolemia, and edema. The degree of the edema may range from pedal edema to total body anasarca, including ascites and pleural effusions. The lower the plasma albumin concentration, the more likely the occurrence of anasarca; the degree of sodium intake is, however, also a determinant of the degree of edema. Nephrotic syndrome has many causes (see Chapter 8).
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Systemic causes include diabetes mellitus, lupus erythematosus, drugs (e.g., phenytoin, heavy metals, NSAIDs), carcinomas, and Hodgkin's disease, and primary renal diseases such as minimal change nephropathy, membranous nephropathy, focal glomerulosclerosis, and membranoproliferative glomerulonephritis.
- The pathogenesis of ECF volume expansion in nephrotic syndrome appears to be more variable than the pathogenesis of edema in congestive heart failure or cirrhotic ascites. Traditionally, ECF volume expansion in nephrotic syndrome was believed to depend on hypoalbuminemia and underfilling of the arterial circulation. Several observations have raised questions about this hypothesis. First, the interstitial oncotic pressure in normal individuals is higher than previously appreciated. Transudation of fluid during ECF volume expansion reduces the interstitial oncotic pressure, thus minimizing the change in transcapillary oncotic pressure. Second, patients recovering from minimal-change nephropathy frequently begin to excrete sodium before their serum albumin concentration rises. Third, the circulating concentrations of volume-regulatory hormones are not as high in nephrotic patients as in patients with severe cirrhosis or congestive heart failure. These and other observations have suggested a role for primary renal NaCl retention in the pathogenesis of nephrotic edema.
- Whereas primary renal NaCl retention may contribute to nephrotic edema in many patients, it is not often the only mechanism; some component of underfill often plays a role as well. Evidence for its role includes the observation that primary renal NaCl retention alone does not lead to edema. Chronic aldosterone infusion, for example, leads to hypertension and escape from sodium retention in the absence of edema formation. Furthermore, levels of vasoactive hormones, although below the levels commonly seen in cirrhosis and congestive heart failure, are often higher than would be expected based on the level of ECF expansion. It appears, therefore, that nephrotic syndrome reflects a combination of primary renal NaCl retention and relative arterial underfilling. A preponderance of one or the other mechanism may be observed in nephrosis from different causes. In general, a normal or near-normal glomerular filtration rate is associated with hypovolemic, vasoconstrictor nephrotic syndrome, whereas a diminution in glomerular filtration rate, primary renal sodium retention, and evidence of volume expansion (e.g., decreased plasma renin activity) are characteristic of hypervolemic nephrotic syndrome.
- Treatment. The initial focus of therapy must be aimed at those treatable, systemic causes of nephrotic syndrome such as systemic lupus erythematosus or drugs (e.g., phenytoin, NSAID). The treatment of the primary renal causes of nephrotic syndrome is described in Chapter 8.
  
  The treatment of edema in nephrotic patients involves dietary sodium restriction and diuretics. Because these patients may not be as underfilled as patients with cirrhosis or congestive heart failure, diuretic treatments are often tolerated well. In general, loop diuretics are used as initial therapy. For several reasons, however, nephrotic patients are relatively resistant to these drugs. Although low serum albumin concentrations may increase the volume of diuretic distribution, and filtered albumin may bind to diuretics in the tubule lumen, these factors do not appear to be the predominant causes of diuretic resistance. Rather, diuretic resistance likely reflects a combination of reduced glomerular filtration rate and intense renal NaCl retention. When the glomerular filtration rate is reduced, endogenous organic anions impair diuretic secretion into the tubule lumen, where these drugs act to inhibit NaCl transport. Thus, higher doses of loop diuretics are often required to achieve natriuresis.
  
  The administration of albumin to patients with nephrotic syndrome can be costly and may cause pulmonary edema. One report, however, suggested that mixing albumin with a loop diuretic (6.25 g albumin per 40 mg furosemide) may induce diuresis in severely hypoalbuminemic patients.
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  Recently, a double-blind, controlled study of nine nephrotic patients compared the effects of (a) 60 mg intravenous furosemide, (b) 60 mg intravenous furosemide plus 200 mL of a 20% solution of albumin, or (c) a sham infusion plus 200 mL of albumin. Co-administration of furosemide and albumin was significantly more effective than either albumin or furosemide alone. The authors noted that although adding albumin did increase natriuresis, the benefit was relatively small.