Pathogenesis and Treatment of Edema

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Pediatric Nephrology

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Pathogenesis and Treatment of Edem~

Radhakrishna Baliga, MD,* and John E. Lewy, MDt

Edema is defined operationally as an excess accumulation of interstitial fluid. This may result either from retention of excess salt and water or from increased transfer of fluid across capillary membranes. The pathogenesis of edema and its management is best appreciated by understanding the physiologic regulation of interstitial fluid volume and the manner by which the kidney regulates salt and water homeostasis. The management of edema should include an attempt to correct the primary disorder whenever possible. The general therapeutic goal is to reverse the physiologic aberrations and to promote natriuresis and diuresis. PATHOGENESIS Changes occur in the total body water and its major subdivisions with age. The total body water in the newborn comprises approximately 75 per cent of body weight,7 the extracellular fluid compartment 45 per cent, and the intracellular fluid 35 per cent. By the end of the first year, the extracellular fluid compartment has contracted to 30 per cent of body weight and the intracellular compartment expanded to 40 per cent. Throughout childhood the extracellular fluid compartment continues to decrease until the total body water reaches 60 to 65 per cent of body weight, with the extracellular fluid compartment comprising 20 to 25 per cent of body weight. In 1896, Starling described interstitial fluid formation and absorption in relation to pressure gradients acting across the capillary endothelium, the surface area availability for fluid transfer, and the permeability of the capillary membrane to protein. 20 Under physiologic conditions, the summation of forces at the arterial end of a capillary cause a net filtration pressure of approximately 8.3 mm Hg. This results in movement of fluid *Assistant Professor, Department of Pediatrics, Tulane University School of Medicine; Department of Pediatrics, Louisiana State University, New Orleans, Louisiana tReily Professor and Chairman, Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana

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out of the capillary into the interstitial space. At the venous portion of a capillary, the hydrostatic pressure is much lower than at the arterial side. The summation of forces at that site results in a net negative pressure of 6.7 mm Hg, causing movement of fluid from interstitial space back into the capillary. The net forces along the entire capillary favor filtration over resorption. The fluid filtered in excess of that absorbed does not accummulate in the interstitial space but is returned to the circulation via the lymphatics. Thus, edema results when there is increased capillary pressure, as found in congestive cardiac failure, decreased plasma protein concentration as the result ofloss of protein through the kidney (e. g., the nephrotic syndrome) or through capillary beds (e.g., burns), and as occurs in protein malnutrition, impaired lymphatic flow as that which may be present in lymphomas, Milroy's disease and filariasis, and increased permeability of the capillaries as a consequence of allergic reactions, bacterial toxins, burns or vitamin E deficiency. Renal Control of Sodium Balance All states of generalized edema are characterized by retention of salt and water. The control of sodium balance is determined according to the relationship between sodium intake, extrarenal sodium loss, and renal sodium excretion. The kidneys playa key role in the regulation of salt and water metabolism. Under normal circumstances, an increase in the intake of sodium results in the retention of salt along with water, causing an increase in body weight without changes in the osmolality of blood. This is followed by an increase in the excretion of salt and water, resulting in the regulation of sodium balance. Under such circumstances, alterations in the effective circulating blood volume are sensed by the receptors located in the atria or the arterial vascular tree, which in turn regulate ADH release and water excretion. Additionally receptors in the CNS are more sensitive to changes in blood osmolality and sodium concentration. ANATOMY The bulk of sodium reabsorption occurs in the proximal tubule and loop of Henle. The distal tubule and the collecting duct are responsible for the final adjustment that determines the amount of urinary sodium and water excretion. The proximal tubule plays an important role in the maintenance of fluid and electrolyte balance. Fifty to seventy per cent of the glomerular filtrate is reabsorbed isosmotically from this part of the nephron. The proximal tubule is also an active participant in the phenomenon of glomerulotubular balance since alterations in GFR are associated with parallel changes in proximal tubular reabsorption. The thick ascending limb of the loop of Henle has been found in some studies to transport chloride actively with sodium following passively along the electrical gradient. 3 This portion of the loop is water impermeable and the movement of sodium chloride out of the lumen helps to achieve a

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hypertonic medullary interstitium. Diuretics acting in this portion of the nephron interfere with both the diluting and concentrating processes. The loop of Henle also participates in the phenomenon of glomerulotubular balance. Increased delivery of sodium chloride from the proximal tubule causes increased reabsorption of sodium chloride in the loop of Henle and vice versa. The distal nephron plays an important role in the final adjustment of urinary sodium concentration and excretion. Comparable degrees of inhibition of reabsorption at the level of the proximal tubule may result in variable degrees of natriuresis, suggesting independently controlled changes in distal reabsorption. Movement of water is controlled ih large part by antidiuretic hormone (ADH). ADH increases the permeability of the collecting tubule to water, enabling net water absorption to occur by osmosis into the hypertonic interstitium. Aldosterone is the main hormone that regulates distal renal sodium balance. It enhances distal sodium reabsorption and potassium excretion. Aldostetone is secreted in response to volume depletion and suppressed with volume expansion. Other factors that trigger aldosterone secretion are elevation of plasma potassium concentration and elevated renin and angiotensin levels. Several additional factors affect salt and water reabsorption by the kidney. An acute reduction in glomerular filtration rate can lead to retention of salt and water. Changes in hydrostatic and oncotic pressure in the peritubular capillaries can alter proximal tubular reabsorption of salt and water. 19 Renal retention of solute and water is enhanced by maneuvers that reduce blood flow to the kidneys. This has been observed during prolonged standing, after occlusion of peripheral veins by tourniquet or thrombosis, and following hemorrhage and other processes that compromise renal blood flow. Redistribution of blood flow within the kidney between superficial and juxtamedullary nephrons alters renal sodium excretion. Renal nerve stimuiation decreases sodium excretion and renal denervation leads to increased sodium excretion. Recently the atria has been considered an "endocrine organ," being the site of synthesis of vasoactive and natriuretic polypeptides. 4, 6 These atrial natriuretic factors inhibit salt and water reabsorption and promote vasodilatation. There is also evidence that they suppress renin and aldosterone release. 15, 16 A number of humoral agents including prostaglandins, kallikrein-kinins, prolactin, and estrogen are also known to effect sodium balance either directly or indirectly. CLINICAL CONDITIONS Generalized edema is usually the manifestation of a primary disorder such as cardiac failure, hepatic cirrhosis, or the nephrotic syndrome. Clinical conditions associated with generalized edema are listed in Table 1. NEPHROTIC SYNDROME

An increase in glomerular permeability to proteins l2 , 17 causes massive proteinuria and hypoproteinemia. Plasma oncotic pressure is diminished,

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Table 1. Conditions Leading to Generalized Edema DISEASES OF THE KIDNEY

Acute glomerulonephritis Nephrotic syndrome Acute renal failure Chronic renal failure HEART FAILURE

Numerous conditions of the heart, pericardium, or lungs leading to low-output congestive heart failure Noncardiovascular diseases leading to high-output heart failure (e.g., anemia, thyrotoxicosis, beriberi, sepsis, etc.) DISEASES OF THE UVER

Arteriovenous fistulas* Obstruction to the great veins of the thorax Inferior vena cava Superior vena cava ENDOCRINE DISORDERS

Hypothyroidism Mineralocorticoid excess IATROGENIC CAUSES

Drug administration Estrogens; oral contraceptives Antihypertensive agents MISCELLANEOUS

Chronic hypokalemia Ghronic anemia (especially myelofibrosis) Nutritional edema (especially on re-feeding) Capillary leak syndrome *Usuaily associated with high-output heart failure.

resulting in a shift of fluid from the vascular to the interstitial compartment and a contraction in plasma volume. 2 , 8 Renal blood flow and glomerular filtration rate are not uniformally diminished and in some instances GFR may be above normal. The increased filtration rate is related to hypoalbuminemia, which decreases glomerular capillary oncotic pressure and hence increases net glomerular filtration pressure. With profound hypovolemia, however, GFR is diminished because of a decreased RPF and increased afferent arteriolar constriction, which diminishes glomerular capillary hydrostatic pressure. When GFR is reduced, solute and fluid retention occurs. Aldosterone secretion is elevated, which enhances distal solute reabsorption, although edema can also occur in the absence of the adrenals.

CONGESTIVE HEART FAILURE Sodium retention and resultant edema are cardinal features of cardiac failure. Two theories have been proposed to explain the renal response to failing circulation. The backward failure theory postulates that increased hydrostatic pressure due to the failing of the right side of the heart causes edema by excessive transudation of fluid from the intravascular to the interstitial compartment. It has been shown that chronic dilatation of the

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cardiac chambers may modify the sensitivity to the further stretching and tension of the mechanical receptors located within the walls. 9 The reduced intravascular volume causes retention of salt and water. According to the "forward failure" theory, a primary fall in cardiac output causes a decrease in peripheral perfusion, which results in renal sodium retention. 22 Priebe and co-workersl8 also showed that a reduction in cardiac output, rather than venous congestion, was primarily responsible for renal salt retention. The combined effects of decreased perfusion and increased aldosterone levels stimulate the kidney to retain salt and water. This causes a temporary restoration of venous return and cardiac output. As decompensation continues, venous pressure rises and fluid transudates into the interstitial compartment. The diminished intravascular volume perpetuates the tendency toward increased tubular salt and water reabsorption. In severe forms of heart failure, diminished GFR acts in combination with the above factors. CIRRHOSIS OF THE LIVER Sodium retention, resulting in edema and ascites, are hallmarks of cirrhosis. Two theories have been advocated for the pathogenesis of sodium retention in cirrhosis. According to the traditional or underfilling theory, decreased albumin synthesis by the diseased liver reduces oncotic pressure. The intrahepatic obstruction raises hydrostatic pressure in the splanchnic circulation. These changes alter Starling forces that favor transudation of fluid into the abdominal cavity. 1. 5 Lieberman and associates proposed the alternative or "overflow" theory since measured plasma volumes were invariably increased in cirrhosis with ascites. 13, 14 According to the researchers, renal sodium retention is the primary initiating factor in ascites formation and the presence of portal hypertension localizes the accumulation to the peritoneal cavity. The diseased liver probably releases or stimulates factors that cause tubular retention of salt and volume expansion. Altered renal vascular perfusion, particularly of the superficial cortex,1O and a decrease in GFR may playa role in the edema of cirrhosis. High levels of aldosterone secondary to decreased catabolism by the diseased liver may also contribute to the retention of salt and fluid.

EDEMA IN THE NEWBORN Physiologic edema may be noted to develop within 24 hours of birth and usually lasts for less than 7 days. Intrauterine hypoxia, accompanied by an increase in serum osmolality, might lead to water movement from maternal to fetal circulation, causing edema in the newborn. An increase in vascular permeability has also been noted to occur. Other causes of edema in the first year of life include congenital nephrotic syndrome, congenital syphilis or the nephrotic syndrome secondary to renal vein thrombosis, cytomegalic inclusion disease, toxoplasmosis, malignancy, and mercury toxicity.

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MANAGEMENT OF EDEMA General Measures

Dietary Management. Sodium and fluid intake should be restricted in edematous children, although salt restriction is the most critical requirement. It is advisable to limit salt intake to 2 gm of sodium (4 gm sodium chloride) per square meter body surface area per day in edematous children. Severe sodium restriction leads to poor caloric intake and hence is not advisable. Fluid balance can be maintained by giving the patient an amount of fluid equivalent to insensible fluid loss plus urine output. 11 Insensible water losses between the ages of 1 and 5 years are approximately 30 ml per kg per 24 hours. In children between 5 and 10 years of age they are about 20 ml per kg per 24 hours, whereas in older children the average number for insensible water loss is 10 to 15 ml per kg per 24 hours. In the presence of fever or hyperpnea, these figures should be increased. Restriction of fluid should aim to produce a gradual weight loss. This can be done by limiting the fluid intake to replacement of insensible water loss, plus urine output, minus a planned weight loss. The scale is the cheapest and most accurate (but often forgotten) tool in assessing accurate body fluid changes. Diuretics Diuretics cause an increase in urinary excretion of salt and water. They can be broadly classified depending on their site of action along the nephron. Diuretics That Act Primarily at the Proximal Tubule. These act principally to decrease proximal tubular reabsorption of sodium, and include osmotic diuretics such as mannitol and carbonic anhydrase inhibitors. Proximal tubular diuretics are not very effective and their effect may be reversed by sodium and water reabsorption at more distal nephron sites. Mannitol requires a fluid load to administer and carbonic anhydrase inhibitors may accentuate acidosis. Diuretics That Act PrincipaUy at the Loop of Henle. Furosemide and ethacrynic acid are among the most potent diuretic agents available. They are dissimilar chemically but have similar pharmacologic actions. These agents inhibit sodium chloride transport in the medullary ascending limb of the loop of Henle, where 25 to 30 per cent of filtered sodium and chloride are normally reabsorbed. This inhibition of solute resorption at the level of Henle's loop exceeds the resorptive capability of the distal tubule and collecting ducts and leads to diuresis and natriuresis. Both concentrating and diluting capacity are inhibited. Increased potassium and hydrogen ion secretion occurs owing to the relatively large load of sodium presented to the distal nephron. Thus, hypokalemia and metabolic alkalosis may result. These agents are effective in the presence of diminished GFRs (as low as 10 ml per minute). They may transiently increase renal plasma flow and glomerular filtration in acute glomerulonephritis. The usual oral dosage of furosemide is 2 mg per kg per dose. The dosage may be gradually increased in increments of 1 mg per kg per dose

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to 5 mg per kg if an adequate response is not achieved and may be repeated at 6- to 8-hour intervals. An intravenous dose of 1 mg per kg of furosemide is generally effective in promoting natriuresis and diuresis. Larger amounts may be administered for resistant forms of edema, but with extreme caution. Both ethacrynic acid and furosemide may produce ototoxicity when given in large doses to patients with renal disease. Potassium supplementation or potassium-sparing diuretics are often indicated to prevent hypokalemia in patients with normal or near normal GFRs. Hyperuricemia and carbohydrate intolerance also have been described. Diuretics That Act PrincipaUy at the Distal Tubule. These diuretics can be classified into two groups, potassium-losing and potassium-retaining diuretics. The thiazide diuretics, chlorthalidone and metolazone, although chemically different, have similar modes of action. These distal tubule diuretics inhibit only the urinary-diluting capacity because they decrease sodium resorption in the cortical diluting segment of the early distal tubule. Inhibition . of sodium resorption in the distal tubule is accompanied by enhanced secretion of potassium. Hypokalemia may occur with continued administration and can be prevented by providing potassium chloride supplementation or potassium-sparing diuretics in patients with normal or minimally reduced renal function. Long-term administration of thiazides may produce reversible elevation of blood urea nitrogen, which is most likely due to a reduction in circulating blood volume. Hyponatremia may occur due to interference by thiazides with the diluting segment of the nephron, particularly in patients with congestive cardiac failure who are sodium restricted. This is best treated by appropriate fluid restriction. Hyperuricemia is produced from increased tubular resorption of uric acid. Carbohydrate intolerance has been noted. The usual oral dose of hydrochlorothiazide is 2 mg per kg per day given once or twice a day. They are relatively ineffective when the GFR is reduced to less than 50 per cent of normal. The potassium-conserving diuretics are triamterene and spironolactone. Triamterene directly inhibits electrolyte transport in the distal tubule; spironolactone competitively antagonizes aldosterone. These diuretics are not potent enough to achieve adequate diuresis. However, they may be used to avoid the potassium-losing effects of thiazides and loop diuretics. Dialysis Both hemodialysis (with hemofiltration) and peritoneal dialysis are effective in removing excess fluid in patients in whom the GFR is severely diminished.

MANAGEMENT OF EDEMA IN SPECIFIC DISEASE STATES

Nephrotic Syndrome The nephrotic syndrome is characterized by diminished blood volume, unless GFR is severely compromised. Proximal tubular reabsorption is decreased or normal owing to the markedly decreased plasma oncotic

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pressure. Because of the already diminished plasma volume, overzealous use of diuretics may cause further diminution of plasma volume resulting in hypotension, and a fall in GFR. The edema of the nephrotic syndrome is treated by restricting salt and water intake, optimizing their excretion with diuretics, and increasing plasma volume if diuretics by themselves are not effective. Restriction of sodium is more important than fluid restriction; however, failure to restrict fluid may result in hyponatremia. Adequate potassium supplements may have to be provided if GFR is normal because potassium losses occur in the urine owing to a combination of secondary hyperaldosteronism and diuretic therapy. Hydrochlorothiazide is often effective in treating edema of the nephrotic syndrome unless the GFR is impaired. Spironolactone may be added if the GFR is normal to minimize potassium losses. Furosemide is generally effective in inducing diuresis and natriuresis in spite of moderately decreased GFR and hypoalbuminemia. Caution must be exercised in the use of furosemide, however, by starting with relatively small doses and monitoring the patient closely for volume depletion and electrolyte disturbances. Even furosemide may be relatively ineffective in children with severe hypoalbuminemia. In these children, volume expansion with albumin (0.5 gm per kg IV over 2 hours) followed by furosemide at 1 to 2 mg per kg usually results in a diuresis. This therapy may be repeated once or twice as needed. The infused albumin will be quantitatively excreted in patients with the nephrotic syndrome over 48 to 72 hours. Once adequate volume expansion has been achieved further therapy with oral furosemide alone may suffice. One needs to be certain that albumin infusions are given only in the presence of volume contraction. Patients should be closely monitored for evidence of volume expansion leading to congestive heart failure. Congestive Heart Failure The most effective form of therapy in congestive heart failure is to improve cardiac contractility by the use of inotropic drugs such as digitalis. Restriction of sodium intake is effective in producing some degree of volume contraction. Diuretic therapy diminishes the preload and alleviates some of the congestive symptoms of heart failure. Improved cardiac contractility often results in improved renal perfusion. Therapy with hydrochlorothiazide alone or in combination with spironolactone is usually effective; however, one should be aware of the diuretic-induced decrease in serum potassium that might predispose to digitalis toxicity. Acute Glomerulonephritis Edema of acute glomerulonephritis may be associated with pulmonary congestion and encephalopathy, especially in the presence of hypertension. This can usually be reversed by infusing furosemide at a dose of 1 mg per kg intravenously. The effect is seen within a 4-hour period in spite of little change in blood pressure, suggesting that CNS edema plays an important role. Chlorothiazide is particularly ineffective when GFR is reduced to less

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than 50 per cent of normal. Persistent edema can be effectively treated with furosemide at 2 mg per kg per dose given once or twice daily PO. Chronic Renal Failure The edema of chronic oliguric renal failure is due to marked reduction in GFR. Diuretic agents are usuaily ineffective because of the severely reduced GFR. The principal therapy consists of salt and water restriction until the edema is minimized. This can be done by replacement of insensible water loss plus urinary output minus a planned gradual weight loss of approximately 1 per cent body weight per day. Dialytic therapy may be required. REFERENCES 1. Atkirison M, Losowsky MS: Plasma colloid osmotic pressure in relation to the formation of ascites and edema in liver disease. Clin Sci 22:283, 1962 2. Brown EA et al: Evidence that some mechanism other than the renin system causes sodium retention in nephrotic syndrome. Lancet 2:1237, 1982 3. Burg MB, Green N: Function of the thick ascending limb of Henle's loop. Am J Physiol 224:659, 1973 4. Curry MG, Zeller DM, Cole BC et al: Bioactive cardiac substances: Potent vasorelaxant activity in mammalian atria. Science 221:71, ,1983 5. Drurnond AE, Mulholland JH: Hepatic lymph in cirrhosis. In Popper H, Shaffner F (eds): Progress in Liver Disease, Vol II. Orlando, Florida, Grune & Stratton, 1965, p 427 6. Flynn TG, deBold ML, deBold AJ: The amino acid sequence of an atrial peptide with patent diuretic and natriuretic properties. Biochem Biophys Res Commun 17:859, 1983 7. Friis-Hansen B: Body water compartments in children: Changes dUring growth and . related changes in body composition. Pediatrics 28:169, 1961 . 8. Garnett ES, Webber CE: Changes in blood volume produced by treatment in the nephrotic syndrome. Lancet 2:798, 1967 9. Greenberg IT, Richmond WH, Stoking RA et al: Impaired atrial recll~tor responses in dogs with heart failure due to tricuspid insufficiency and pulmonary artery stenosis. Cir Res 32:424, 1973 10. Kew MD, Varma RR, Williams HS et al: Renal and intrarenal blood flow in cirrhosis of the liver. Lancet 2:504, 1971 11. Lewy JE, Moel DI: Pathogenesis and management of edema in the newborn. Clin PerinatoI2:117, 1975 12. Lewy JE, Pesce A: Micropuncture study of proximal tubular albumin transfer in aminonucleoside nephrosis. Pediatr Res 7:553, 1973 13. Lieberman FL, Denison EK, Reynolds TB: The relationship of plasma volume, portal hypertension, ascites and renal sodium retention in cirrhosis: The overflow theory of ascites formation. Ann NY Acad Sci 170:202, 1970 14. Lieberman FL, Ito S, Reynolds TB: Effective plasma volume in cirrhosis and ascites: Evidence that a decreased volume does not account for renal sodium retention, a spontaneous reduction in glomerular filtration rate (GFR) and a fall in GFR during drug induced diuresis. J Clin Invest 48:975, 1969 15. Maack T et al: Atrial natriuretic factor: Structure and functional properties. Kidney Intern 27:607, 1985 16. Needleman P et al: Atriopeptins as cardiac hormones. Hypertension 7:469, 1985 17. Oken DE, Cotes SC, Mende CW: Micropuncture study of tubular transport of albumin in rats with aminonucleoside nephrosis. Kidney Intern 1:3, 1972 18. Priebe HJ, Heimann JC, Hedley-White J: Effects of renal and hepatic venous congestion on renal function in presence of low and normal cardiac output in dogs. Circ Res 47:883, 1980

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19. Spitzer A, Windhager EE: Effect of peritubular oncotic pressure changes on proximal tubular fluid reabsorption. Am J Physiol 218:1188, 1970 20. Starling EH: Physiological factors involved in the causation of dropsy. Lancet 2:1405, 1896 21. Surtshin A: Influence of adrenals on edema in nephrotic syndrome (abstr). Fed Proc 17:158,1958 22. Warren JV, Stead EA: Fluid dynamics in chronic congestive heart failure: An interpretation of the mechanisms producing edema, increased plasma volume and elevated venous pressure in certain patients with prolonged congestive heart failure. Arch Intern Med 73:138, 1944 Department of Pediatrics Tulane University School of Medicine 1430 Tulane Avenue New Orleans, Louisiana 70112