Personal Practice Management of Edema in of edema is, however, cumbersome in those Nephrotic Syndrome with severe relapses and in those with resistance to corticosteroid therapy. Treat- ment with diuretics is indicated in patients Anil Vasudevan with significant edema or symptomatic fluid Mukta Mantan overload. Intravenous infusions of albumin Arvind Bagga may be required in certain situations. Current concepts on the pathogenesis and management of edema are reviewed in this Nephrotic syndrome is a recurrent or chronic article. disorder characterized by heavy proteinuria, hypoalbuminemia and edema. In most patients, the Pathophysiology of Formation of Edema edema can be managed satisfactorily with judicious Fluid movement across capillaries is oral administration of loop diuretics, most often frusemide. The treatment of patients with intractable normally the result of a balance between edema is more difficult and comprises a series of filtration and reabsorption due to changes in measures including salt restriction, treatment with capillary and tissue hydrostatic and oncotic intravenous frusemide, additional use of thiazide and pressures. Any disturbance in this balance, potassium sparing diuretics, and intravenous favoring increased filtration and/or decreased albumin. Ultrafiltration and head out water reabsorption results in edema. immersion are beneficial for treatment of patients with edema, which is unresponsive to the above While the pathogenesis of edema in measures. nephrotic syndrome is not well understood, it Key words: Albumin, Diuretics, Frusemide, is usually attributed to an expansion of the Nephrotic syndrome. interstitial compartment secondary to increased fluid transfer across capillary walls, Nephrotic syndrome, characterized by or accumulation of sodium secondary to an heavy proteinuria and hypoalbuminemia, is an intrarenal defect. Major sites involved in important chronic disorder in children. Edema edema formation are (i) capillaries - where is the chief clinical manifestation, which may there is disruption of Starling equilibria, and vary from mild periorbital puffiness to (ii) the kidney - where there is primary salt anasarca. In most patients, the edema is mild retention. According to the classical view, and transient, and resolves following therapy vascular underfill is responsible for the with corticosteroids (steroid sensitive formation of edema(1,2). Proteinuria results nephrotic syndrome) alone. The management in hypoalbuminemia and lowers plasma From the Division of Nephrology, Department of oncotic pressure. This alters Starling forces, Pediatrics, All India Institute of Medical Sciences, determining the distribution of fluid between Ansari Nagar, New Delhi-110029, India. plasma and interstitium, and results in an Correspondence to: Dr. Arvind Bagga, Department of increase in interstitial fluid and edema. The Pediatrics, All India Institute of Medical Sciences, resultant hypovolemia activates the renin- New Delhi. angiotensin-aldosterone axis, the sympathetic E-mail: [email protected] nervous system and vasopressin secretion INDIAN PEDIATRICS 787 VOLUME 41__ AUGUST 17, 2004 PERSONAL PRACTICE leading to renal salt and water retention, Management of Edema which further aggravates the edema. Therapy for edema is necessary since fluid However, a normal plasma volume, and retention predisposes to infections and normal blood levels of renin and aldosterone can exacerbate preexisting hypertension. in some patients with nephrotic syndrome Anasarca with ascites and pleural effusions does not support this mechanism(3,4). may cause respiratory embarrassment. Edema According to the overfill hypothesis a of intestinal walls may result in diarrhea. primary intrarenal defect in sodium handling Children with edema have restricted activity is responsible for the occurrence of edema(5). and low self-esteem. This results in decreased filtration per nephron, increased tubular reabsorption, and Assessment of Fluid Status decreased sensitivity to atrial natriuretic Determination of fluid status is important peptide, leading to fluid retention. Studies in in the initial evaluation. Assessment of animals with experimentally induced intravascular volume is achieved by clinical nephrotic syndrome, suggest that stimulation and biochemical features, and radiological of tubular sodium reabsorption occurs in the investigations. Hypovolemia is characterized collecting duct(6). Resistance to the action of by tachycardia, low normal or low blood atrial natriuretic peptide, due to enhanced pressure, features of dehydration and elevated activity of cyclic-GMP phosphodiesterase and blood levels of urea disproportionate to increased activity of Na+-K+ ATPase might creatinine. Measurement of urinary con- contribute to increased tubular sodium centration and fractional excretion of sodium resorption. Finally, the human body is (FENa) assist in the evaluation of fluid status. equipped with defense mechanisms that limit excessive capillary fluid filtration. These The normal urinary sodium concentration mechanisms include increased interstitial varies between 30-40 mEq/L; values below 20 hydrostatic pressure and lymph flow, mEq/L indicate sodium-conserving states, decreased interstitial oncotic pressure and e.g., hypovolemia, dehydration and pre-renal reduced permeability of the capillaries to ARF. FENa (percent), the ratio of sodium proteins. Edema results when these adaptive excreted to that filtered by the renal tubules, is mechanisms are inadequate(7). It is suggested below 1% in sodium retaining conditions. that while vascular underfill is responsible for (urinary Na+) × (serum creatinine) × 100 FENa% = ————————–––––———–—— most cases of edema in minimal change (serum Na+) × (urinary creatinine) disease, other mechanisms might be important The ratio of urinary concentrations of K+ in patients with non-minimal disease. to the sum of K+ and Na+ (urinary K+/ K+ + There is increasing evidence that Na+) is also a satisfactory index of activation hypoalbuminemia and the inability of the of the renin-angiotensin-aldosterone axis(9). renal distal tubule to excrete sodium are not A ratio of more than 0.6 or 60% suggests the only factors responsible for the occurrence activation of the axis and renal potassium of edema. Increased vascular capillary wasting. Patients with nephrotic syndrome permeability, related to the release of vascular and hypovolemia typically show low FENa permeability factor and other cytokines, may (often below 0.2%) and high urinary K+/K+ + also play an important role in the patho- Na+ (ratio greater than 60%)(9). Such patients physiology of nephrotic edema(8). should not receive oral or intravenous INDIAN PEDIATRICS 788 VOLUME 41__ AUGUST 17, 2004 PERSONAL PRACTICE diuretics, before correction of their should be ensured. No restriction on intake of intravascular volume with either crystalloids salt and water is necessary in most subjects. or colloids. Patients with edema and no Patients with edema should consume clinical or laboratory features of hypovolemia unprocessed foods like vegetables, fruit, fish, (normal levels of blood urea, FENa >1% and chicken and meat, all of which contain small urinary K+/ K+ + Na+ <60%) can safely be amounts of salt. Use of table salt and items treated with potent diuretics. It is however with high sodium content should be avoided. important to understand sodium wasting due Sodium content of some common foods is to prior therapy with diuretics often limits the listed in Table II. The replacement of common practical utility of these indices. salt by low sodium salts (e.g., LONA) is not recommended. A number of radiological investigations are proposed to be useful for assessing fluid Strict salt restriction, limiting sodium status in patients with nephrotic syndrome. intake to 1-2 mEq/kg/day is necessary only in Determination of the diameters of left atrium subjects with refractory edema (see below). and inferior vena cava and their change with Diuretic Therapy respiration, on ultrasonography, may provide an accurate assessment of intravascular Diuretics, the standard therapy for edema, volume(10). The precise role of these act by increasing urinary sodium excretion. measurements in the management of patients Based on their site of action on the renal is however not defined. tubule they are classified as highly potent loop diuretics, moderately efficacious thiazide In steroid responsive nephrotic syndrome, diuretics, potassium sparing diuretics, osmotic treatment with daily corticosteroids usually agents like mannitol and carbonic anhydrase leads to diuresis within 7-10 days. Treatment inhibitors (Fig. 1). for minimal periorbital puffiness or pedal edema is therefore not required. Patients Factors affecting response to diuretics showing moderate to severe edema need (a) Potency of diuretics is chiefly determined specific treatment for its control (Table I). Most such patients show reduction of edema by its site of action in the nephron (Fig. 1). Most filtered sodium is reabsorbed in the with modest restriction of sodium intake and oral administration of frusemide. Aggressive proximal tubule (55-60%) and loop of Henle (25-30%). However, the efficacy therapy for edema is required in less than 10% patients. of proximally acting diuretics (e.g., acetazolamide) is offset by compensatory Sodium Restriction increased distal resorption of sodium and The recommended dietary allowance for water in the ascending limb of Henle. calories and protein, appropriate for that age, Loop diuretics,