Nephrology Hypertension

Diseases of Volume Regulation: Volume Overload

Does this patient have volume overload?

Like volume depletion, the diagnosis of volume overload is made predominantly on clinical grounds. Laboratory tests are only supportive. Volume overload can result from primary renal salt retention, or the renal salt retention can be secondary to other processes. When the salt retention is primary, then the predominant manifestation of volume overload is hypertension and signs of volume expansion are typically absent (as in primary aldosteronism). When the salt retention is secondary (most typically to a reduction in the blood pressure below the set point), then the pedominant manifestations are signs of extracellular fluid volume expansion.

Hypertension is addressed in other chapters.

Symptoms of volume overload include peripheral edema (often worse at the end of the day), dyspnea (most commonly in the setting of heart failure, when it is typically worse during recumbency), abdominal distention, fatigue, and lassitude. Specific symptoms can point to a particular cause. These include paroxysmal nocturnal dyspnea, orthopnea and pedal edema in heart failure, abdominal distention, jaundice, dark urine, and confusion, in cirrhosis, and more puffiness around the eyes in nephrotic syndrome.

Signs of volume overload also help point to a cause. Patients with heart failure from systolic dysfunction often have low blood pressure. There are crackles in the lungs. The point of maximal impulse may be displaced leftward and there may be an S3 gallop. The edema is predominantly pedal and typically pits. In cirrhosis, the blood pressure is also typically low, although in this situation the circulation is hyperdynamic, as the blood pressure reduction results from systemic vasodilation. The fluid accumulation is typically most prominent in the abdomen, although pedal edema may be present, as well.

There are often stigmata of chronic liver disease, including icterus, spider angiomata, muscle wasting, and asterixis. Periorbital edema is especially common in association with minimal change nephrosis. Other causes of nephrotic syndrome, such as diabetes or amyloidosis have typical systemic manifestations, which should be sought.

What are disorders that lead to volume overload?

The term volume overload typically implies overall expansion of the extracellular fluid volume, and is not used to describe the consequences of local phenomena such as the upper extremity edema that can occur after breast cancer treatment. A possible exception is patients with obstruction to venous return from the lower extremities, which is most common in the massively obese. In these situations, substantial edema and venous stasis with secondary dermatopathy implies that the extracellular fluid (ECF) volume is substantially elevated.

Chronic heart failure, cirrhosis of the liver, and nephrotic syndrome are the most common causes of generalized expansion of the ECF volume, although patients in the intensive care unit, who are critically ill, often receive massive quantities of fluids, leading to iatrogenic volume overload.

In the case of heart failure, cardiac function is impaired, leading to reductions in tissue perfusion. This is compensated by salt and water retention, driven largely by activation of the renin/angiotensin/aldosterone system, increasing the preload to return cardiac output toward normal. This comes, however, at the expense of adverse symptoms and signs.

Cirrhosis of the liver can lead to splanchnic vasodilation. The resulting hyperdynamic circulation and relative hypotension predispose to renal NaCl and water retention, again triggered by activation of the renin/angiotensin/aldosterone system and arginine vasopressin, leading to edema and ascites.

Nephrotic syndrome is typically defined as proteinuria >3.5 grams daily, hypoalbuminemia, and edema, with hyperlipidemia and thrombosis as suportive features. Nephrotic syndrome can be part of a bland nephropathy (such as minimal change disease) or part of a sclerotic process (such as focal and segmental glomerulonephritis) or a nephritic process (such as post infectious glomerulonephritis).

In the former case, the plasma volume may be relatively low, and the renal salt retention may result largely from the reduced plasma oncotic pressure and reduced effective arterial blood volume. In the latter cases, a primary renal stimulus to NaCl retention is likely present, and combined with hypoproteinemia, keeps the blood volume and the blood pressure relatively normal; here, signs of plasma volume expansion are often present.

What are signs and symptoms of volume overload?

  • Breathlessness, dyspnea on exertion, orthopnea (breathlessness induced by recumbancy), paroxysmal nocturnal dyspnea (bouts of breathlessness at night), and troublesome edema are common symptoms of diffuse volume overload.

  • Localized edema often points to a specific cause. Periorbital edema or diffuse edema is most common with nephrotic syndrome, Ascites is most common with cirrhosis of the liver. Paroxysmal nocturnal dyspnea and orthopnea are most commonly seen in heart failure.

  • Other signs and symptoms may point to an underlying cause, such as dusky urine in nephritis, spider angiomata in cirrhosis, or jaundice with cirrhosis.

  • Peripheral edema is the most common sign of volume overload. It is typically softly pitting and most common in dependent areas, expecially late in the day.

  • Mild ascites can be detected as shifting dullness of the abdomen, or as a fluid wave.

  • Pulmonary crackles, especially in dependent areas of the lung are common in heart failure. A laterally displaced cardiac apex and an S3 gallop are commonly present in heart failure.

  • An elevated jugular pulse suggests expansion of the plasma volume and an elevated right sided filling pressure, although there are concerns about the accuracy of this test.

What tests to perform?

  • It is essential to identify the cause of the volume overload. When the diagnosis of heart failure is considered, an electrocardiogram and a chest x ray are useful, as are routine electrolytes, a blood urea nitrogen (BUN) and creatinine, and a complete blood count (CBC). An echocardiogram is essential for determining the ejection fraction, as the approach to treatment depends on the presence or absence of systolic dysfunction. It can also provide information about filling pressures in the heart. A more thorough discussion of the diagnosis of heart failure is found in other sections.

  • When the diagnosis of cirrhosis of the liver is entertained, an analysis of liver enzymes, bilirubin, the international normalized ratio (INR), the creatinine and electrolytes, and a CBC are useful. Serology to seek evidence for viral hepatitis is also useful. None of the results, however, is diagnostic on its own. An ultrasound of the liver may also show cirrhosis and a liver biopsy is sometimes performed. The complete workup of cirrhosis of the liver is beyond the scope of this discussion.In nephrotic patients, the urine protein excretion can be analyzed using a 'dipstik'. While this test is not definitive, heavy proteinuria is often evident.

  • In patients at steady state, a quantitative estimate of urinary protein excretion can be obtained by determining the ratio of protein/creatinine in the urine.

  • When the urine protein concentration and creatinine concentration are measured on a single sample of urine (typically a single void, or 'spot' sample), and in the same units, then their ratio (a unitless number) can be taken as an estimate of the protein excretion in grams during 24 hours.

  • Some laboratories report the results in units of milligrams of protein per gram of creatinine. In this case, because daily creatinine excretion approximates 1 gram, the result is an estimate of the urine protein excretion in milligrams per day.

  • In evaluating potential nephrotic patients, serum electrolytes, BUN and creatinine, and serum albumin are essential tests. The cholesterol is often elevated, sometimes markedly, and should be masured. The differential diagnosis of nephrotic syndrome is beyond the scope of this discussion and the reader is referred to other chapters for more information.

  • Other supplementary tests are often helpful. A b-type natiuretic peptide (BNP) can help differentiate between heart failure and other causes of breathlessness. It is especially useful when it is very high or normal, or when a prior value is known. An analysis of the inferior vena cava, and its collapse, can be useful, when the volume status is difficult to determine. The width of the pulmonary vascular pedicle as detected on portable chest x ray has been shown to correlate with volume status when determined by invasive means.

  • The central venous pressure can be measured using an indwelling catheter. A pulmonary artery catheter can provide information about left sided pressures, but the use os these catheters has declined, as controlled studies have rarely suggested that they improve outcomes.

How should volume overload be managed?

How is volume overload treated and how are diuretics classified?

When possible, the underlying disorder should be treated. As noted above, specific treatments for heart failure, cirrhosis of the liver, and nephrotic syndrome are beyond the scope of this chapter. The information below is focused on treating the volume overload itself.

As NaCl and water input and excretion determine the extracellular fluid volume, dietary NaCl intake should always be restricted, when chronic volume expansion is present. All patients should be encouraged to limit their Na intake to 2 grams per day. Lower levels provide further volume reductions, but often difficult to adhere to.

Diuretics are potent and useful drugs, which often provide substantial symptomatic relief. Because most diuretics were developed during the 1950's and 1960's, few randomized trials of their use available. It is likely, however, that they prolong life when used appropriately. They can be dangerous drugs, however, and must be used carefully.

The rate at which NaCl is excreted in the urine is dependent on the rate of NaCl filtration at the glomerulus and the rate of NaCl reabsorption along the tubules.

Tubular NaCl rebasorption is highly regulated, and can be inhibited by diuretic drugs, to enhance urinary NaCl excretion up to 25% of the filtered load.

Diuretics are typically classified according to the site along the nephron at which they inhibit Na reabsorption (Table 1).

Table 1.

The loop diuretics have the highest intrinsic potency. The distal convoluted tubule diuretics (thiazides and others) are intermediate in their potency, but they tend to have longer half lives. Both classes of diuretic predispose to potassium losses and alkalosis, in addition to contracting the extracellular fluid volume.

The drugs that act along the distal nephron in the connecting tubule and collecting duct are potassium sparing, instead of potassium wasting. The Na channel blocking drugs (amiloride and triamterene) are weakly natriuretic and act directly on the Na channel. The competitive aldosterone antagonists, spironolactone and eplerenone, block the effects of aldosterone to stimulate Na channel activity and activity of the Na/K ATPase pump.

When volume expansion is mild, drugs that act in the distal convoluted tubule may be employed, along with restrictions in dietary NaCl intake.

In most cases, however, loop diuretics are agents of choice to treat substantial volume overload.

How to use loop diuretics to treat volume overload

The goal of treatment with diuretics is not simply to increase urinary NaCl and water excretion, but rather to elicit a reduction in extracellular fluid volume and an improvement of symptoms. This typically requires a transient increase in urinary NaCl excretion, but such an increase is not necessarily sufficient (see below).

For outpatients, the best method to assess therapeutic success is with daily measurement of body weight, as a surrogate for ECF volume. Chose a target weight loss and time course.

Loop diuretics, other than ethacrynic acid, which is used only in highly selected circumstances, all have the same underlying mechanism of action.

They act from the lumen of the tubule to inhibit the Na-K-2Cl cotransporter, which reabsorbs up to 25% of the filtered salt load and plays an essential role in concentrating and diluting the urine. Therefore, these drugs impair both urinary concentration and dilution.

Loop diuretics are highly protein bound, so they are only minimally filtered at the glomerulus.

Instead, they are secreted along the proximal tubule by the organic anion transporter; to be active clinically, they must be secreted into the tubule lumen.

There are substantial pharmacokinetic differences in loop diuretics (see Table 1), which must be considered. Among the most important of these is the limited oral bioavailability of furosemide; furosemide's oral bioavailability is also highly variable from day to day. Another difference between the drugs is in their half lives.

Renal dysfunction impairs diuretic secretion into the tubule lumen, so higher doses should be selected when chronic kidney disease is present.

Chose a starting dose (Table 2), low if the patient has never been exposed to a diuretic, higher if he/she has been exposed, especially if there is concomitant chronic kidney disease.

Table 2.

The dose response curve for loop diuretics is sigmoidal, when plotted versus the logarithm of the dose (Figure 1); thus, these drugs are often characterized as having a 'threshold' effect. It is important to insure that the chosen dose is in the steep part of the curve.

Figure 1.

Dose response curve for a loop diuretic. Shown are the effects of chronic kidney disease (CKD) and edematous states, such as heart failure.

The initial efficacy can be ascertained either by measuring the urinary volume during the 6 hours following a diuretic dose, or when the patient is ambulatory, by asking the patient to note whether the urine output changes substantially.

If the initial dose is insufficient, the dose is typically doubled, until efficacy is reached or until a maximal safe dose is reached (see Table 1).

Most loop diuretics require twice daily dosing for full effectiveness.

Once an initially effective dose is reached, it is usually continued unless the underlying disease status improves enough to try reducing it.

It is important to assess therapeutic progress with frequent determination of symptoms and signs. The plasma electrolytes, BUN and creatinine should also be monitored several weeks after initiating treatment and occasionally thereafter.

What are complications of diuretic treatment?

The predominant complications of diuretic treatment (Table 3) are related to the natriuresis and chloriuresis. These include excessive depletion of the extracellular fluid volume.

Table 3.

Contraction of the vascular volumeHypokalemia (loop and DCT diuretics)Hyperkalemia (collecting duct diuretics)Gynecomastia (spironolactone)Hyperuricemia and goutHypercalcemia (distal convoluted tubule diuretics)Hyperlipidemia (distal convoluted tubule diuretics)Hyponatremia (especially with distal convoluted tubule diuretics)Metabolic alkalosis (loop and distal convoluted tubule diuretics)Hyperglycemia (distal convoluted tubule diuretics)Pancreatitis (distal convoluted tubule diuretics)Allergic processes, including interstitial nephritis

Renal insufficiency, resuiting from over-diuresis may occur, as can hypokalemia and alkalosis.

Other complications are often related to specific drugs

What to do if an outpatient is resistant to diuretic treatment?

  • Diuretic resistance is defined as the failure to achieve a therapeutically desired reduction in the extracellular fluid volume despite appropriate doses (see Table 1) of appropriate diuretics.

  • When patients are started on diuretics for the first time, they are rarely resistant.

  • It is always important to exclude correctable causes of resistance, before modifying the diuretic regimen. These include nonadherence, use of counteracting drugs, especially NSAIDs, inappropriate diagnosis, or excessive dietary NaCl intake.

  • As noted above, the maximum recommended dietary Na intake for edematous patients is 2 grams daily. When a patient appears diuretic resistant, and has a stable weight, then the dietary Na intake can be estimated by measuring the Na excretion during 24 hours. If it exceeds 120 mEq/day, then the patient is not diuretic resistant and is consuming too much salt. In this case, referral to a dietician is indicated. Many times, dietary salt consumption is in the form of processed foods, and not in the form of added or surface salt, and can be difficult for the patient to detect. Careful counselling can often overcome this problem.

  • In the setting of chronic kidney disease, the most common source of resistance is inadequate dosing, as renal failure increases the natriuretic threshold substantially.

  • If the patient is deemed diuretic resistant, and methods to improve the underlying disease process are not available, there are several useful options.

  • Combining diuretic drugs of different classes is extremely effective (Table 4).

  • A distal convoluted tubule diuretic, such as a thiazide, is often the first choice, as the combination of Distal Convoluted Tubule diuretics and Loop diuretics is synergistic.

Table 4.

Combination therapy often induces a substantial natriuresis rapidly, but it can lead to complications. These include substantial volume and electrolyte depletion. Thus, patients started on combination treatment must be monitored closely and serum electrolytes and BUN and creatinine must be measured soon after initiating the second drug.

It is often advisable to consider reducing the frequency of the Distal Convoluted Tubule diuretic, once therapeutic success has been obtained (for example, use full doses for 1 week, and then back off to three times weekly), as this reduces the risk of complications.

Although the combination of loop and distal convoluted tubule diuretics is typically the most effective natriuretic regimen, there are specific indications for other combinations. Both loop and distal convoluted tubule diuretics are kaliuretic and predispose to alkalosis. Diuretics acting in the collecting duct attenuate some of these complications. Thus, although the combination of loop with collecting duct diuretics is not as potent as loop with distal convoluted tubule diuretics, it can lead to a more gentle diuresis with fewer electrolyte complications.

It has been suggested that hypoalbuminemia and massive proteinuria contribute to diuretic resistance directly, by increasing the volume of diuretic distribution and by impairing diuretic actions along the nephron. In carefully performed studies in humans, however, these factors do not appear to be dominant contributors, at least as long at the plasma albumin concentration is 2 g/dl or higher. Thus, the use of albumin infusions with loop diuretics, or the use of drugs to inhibit diuretic binding to albumin in tubule fluid, are not generally recommended. In a patient with a serum albumin less than 2 from nephrotic syndrome, especially if the patient appears 'under filled', a trial of adjunctive albumin may be worthwhile.

What to do for diuretic resistance in seriously ill inpatients

  • Most of the same principles described above apply to seriously ill inpatients who are resistant to diuretic, but some special considerations apply.

  • In general, most resistant inpatients should receive diuretics intravenously (see Figure 1). This obviates any limitations on gastrointestinal absorption.

  • In a recent study of patients with heart failure, an intravenous bolus dose of furosemide equivalent to the total daily oral home dose (given every twelve hours) was nearly equivalent in performance to a dose 2.5 times the home daily dose. In the same study, a continuous infusion did not provide any benefit over bolus infusion, although it should be mentioned that these patients were not truly resistant.

  • Continuous infusions of loop diuretics are a safe and effective alternative (Table 5). Some data suggest that they are more efficient than bolus treatment, but this remains unclear. Nevertheless, they offer many practical advantages.

In hospitalized patients, especially those who are severely ill, intravenous diuretics are preferred. The only distal convoluted tubule diuretic available as an intravenous preparation is chlorothiazide. An alternative approach, especially if alkalosis is present, is to use acetazolamide (see Table 4). Acetazolamide can help correct alkalosis and thereby stimulate respiratory drive, without the need to administer NaCl, and perhaps improve the effectiveness of the loop diuretic.

Table 5.

In some cases, especially when renal failure supervenes, pure ultrafiltration, using either continuous venovenous hemofiltration with dialysis or a machine designed for aquapheresis, may be indicated. High quality studies indicating the best use of this approach are still lacking.

What to do with patients with ascites

  • Ascites most frequently complicates cirrhosis of the liver.

  • It can cause abdominal discomfort, anorexia, dyspnea, and failure to thrive.

  • Volume expansion in the setting of liver disease is typically treated first with dietary salt restriction and diuretics.

  • In this setting, aldosterone blocking durgs, such as spironolactone, appear to be most effective.

  • Although the half life of spironolactone is relatively short, active metabolites exist giving a prolonged effective half life. Thus, once daily dosing if typically appropriate.

  • When ascites and edema fail to respond to spironolactone alone, furosemide can be added. The dose ratio should be 40 mg furosemide: 100 mg spironolactone, up to 160 mg furosemide and 400 mg spironolactone, if needed.

  • More rapid control of ascites can be achieved safely with large volume paracentesis.

  • Once non-cirrhotic causes of ascites have been excluded, 4-6 liters can be removed in one treatment. Often, albumin (25-50 grams) is given to attenuate post paracentesis neurohormonal surge syndrome.

  • This process can be repeated every other week, as necessary, although diuretic treatment should be continued. Most authorities, however, recommend diuretics as the principal treatment, with large volume paracentesis only for those truly resistant.

  • When ascites remains refractory, transjugular intrahepatic portosystemic shunting (TIPS) can be used. This procedure reduces ascites formation, but is complicated by many side effects. Please see other sections for more details.

What happens to patients with volume overload?


How to utilize team care?


Are there clinical practice guidelines to inform decision making?


Other considerations


What is the evidence?

Brater, DC. "Diuretic therapy". N Engl J Med. vol. 339. 1998. pp. 387-395.

(An authoratative review that is still relatively up to date).

Costanzo, MR, Guglin, ME, Saltzberg, MT, Jessup, ML, Bart, BA, Teerlink, JR, Jaski, BE, Fang, JC, Feller, ED, Haas, GJ, Anderson, AS, Schollmeyer, MP, Sobotka, PA, Investigators, UT. "Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure.[see comment]". J Am Coll Card. vol. 49. 2007. pp. 675-683.

(A reasonable trial of ultrafiltration, but this does not address the issue of its use as rescue therapy for diuretic resistance. Trials with this aim are in progress.)

Ellison, DH. "Diuretic therapy and resistance in congestive heart failure". Cardiology. vol. 96. 2001. pp. 132-143.

(A physiologically based approach to diuretic resistance.)

Ellison, DH, Wilcox, CS, Brenner, BM. "Diuretics". Brenner and Rector's The Kidney. vol. Vol 2. 2008. pp. 1646-1678.

Faris, R, Flather, MD, Purcell, H, Poole-Wilson, PA, Coats, AJ. "Diuretics for heart failure". Cochrane database of systematic reviews (Online). 2006. pp. CD003838.

Felker, GM, Lee, KL, Bull, DA, Redfield, MM, Stevenson, LW, Goldsmith, SR, LeWinter, MM, Deswal, A, Rouleau, JL, Ofili, EO, Anstrom, KJ, Hernandez, AF, McNulty, SE, Velazquez, EJ, Kfoury, AG, Chen, HH, Givertz, MM, Semigran, MJ, Bart, BA, Mascette, AM, Braunwald, E, O'Connor, CM. "Diuretic strategies in patients with acute decompensated heart failure". N Engl J Med,. vol. 364. 2011. pp. 797-805.

Greenberg, A. "Diuretic complications". Am J Med Sci. vol. 319. 2000. pp. 10-24.

Howard, PA, Dunn, MI. "Severe heart failure in the elderly: potential benefits of high-dose and continuous infusion diuretics". Drugs Aging. vol. 19. 2002. pp. 249-256.

Karalliedde, J, Buckingham, RE. "Thiazolidinediones and their fluid-related adverse effects: facts, fiction and putative management strategies". Drug Saf. vol. 30. 2007. pp. 741-753.

Rosner, MH, Gupta, R, Ellison, DH, Okusa, MD. "Management of cirrhotic ascites: Physiologic basis of diuretic action". Eur J Intern Med. 2005. pp. 16.

Salvador, DR, Rey, NR, Ramos, GC, Punzalan, FE. "Continuous infusion versus bolus injection of loop diuretics in congestive heart failure". Cochrane database of systematic reviews (Online). 2005. pp. CD003178.

Wilcox, CS. "New insights into diuretic use in patients with chronic renal disease". J Am Soc Nephrol. vol. 13. 2002. pp. 798-805.

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