Pathophysiology and treatment of edema in patients with the nephrotic syndrome
- Jai Radhakrishnan, MD, MS
Jai Radhakrishnan, MD, MS
- Professor of Medicine
- Columbia University Medical Center
- Section Editors
- Richard J Glassock, MD, MACP
Richard J Glassock, MD, MACP
- Editor-in-Chief — Nephrology
- Section Editor — Glomerular Diseases
- Emeritus Professor
- The David Geffen School of Medicine at UCLA
- Fernando C Fervenza, MD, PhD
Fernando C Fervenza, MD, PhD
- Section Editor — Glomerular Diseases
- Professor of Medicine
- Mayo Clinic College of Medicine
Edema is one of the major clinical manifestations of the nephrotic syndrome. The pathophysiology and treatment of edema in patients with the nephrotic syndrome will be reviewed here. More general issues such as the clinical manifestations, diagnosis, and general principles of the treatment of edema are discussed elsewhere as is the mechanism of hypoalbuminemia in the nephrotic syndrome. (See "Clinical manifestations and diagnosis of edema in adults" and "General principles of the treatment of edema in adults" and "Overview of heavy proteinuria and the nephrotic syndrome", section on 'Hypoalbuminemia'.)
UNDERFILLING VERSUS RENAL SODIUM RETENTION
Two major factors, both of which lead to retention, have been thought to be responsible the development of edema in patients with the nephrotic syndrome; it is likely that both contribute to a variable degree in individual patients [1,2]:
●Primary sodium retention that is directly induced by the renal disease (overfill hypothesis)
●Secondary sodium retention in which the low plasma oncotic pressure due to hypoalbuminemia promotes the movement of fluid from the vascular space into the interstitium, leading to underfilling of the vasculature and activation of the renin-angiotensin-aldosterone system (underfill hypothesis)
The clinical importance of distinguishing between these mechanisms is the ability to tolerate diuretic therapy. Diuretics are well tolerated in patients with renal sodium retention but, if underfilling is the primary mechanism, can lead to worsening hypovolemia as evidenced clinically by an elevation in serum creatinine. As will be described below, most patients tolerate diuretic therapy at least initially.
- Perico N, Remuzzi G. Edema of the nephrotic syndrome: the role of the atrial peptide system. Am J Kidney Dis 1993; 22:355.
- Humphreys MH. Mechanisms and management of nephrotic edema. Kidney Int 1994; 45:266.
- Noddeland H, Riisnes SM, Fadnes HO. Interstitial fluid colloid osmotic and hydrostatic pressures in subcutaneous tissue of patients with nephrotic syndrome. Scand J Clin Lab Invest 1982; 42:139.
- Koomans HA, Kortlandt W, Geers AB, Dorhout Mees EJ. Lowered protein content of tissue fluid in patients with the nephrotic syndrome: observations during disease and recovery. Nephron 1985; 40:391.
- Aukland K, Nicolaysen G. Interstitial fluid volume: local regulatory mechanisms. Physiol Rev 1981; 61:556.
- Geers AB, Koomans HA, Roos JC, et al. Functional relationships in the nephrotic syndrome. Kidney Int 1984; 26:324.
- Geers AB, Koomans HA, Roos JC, Dorhout Mees EJ. Preservation of blood volume during edema removal in nephrotic subjects. Kidney Int 1985; 28:652.
- Dzau VJ, Colucci WS, Hollenberg NK, Williams GH. Relation of the renin-angiotensin-aldosterone system to clinical state in congestive heart failure. Circulation 1981; 63:645.
- Watkins L Jr, Burton JA, Haber E, et al. The renin-angiotensin-aldosterone system in congestive failure in conscious dogs. J Clin Invest 1976; 57:1606.
- EISENBERG S. Blood volume in patients with acute glomerulonephritis as determined by radioactive chromium tagged red cells. Am J Med 1959; 27:241.
- Meltzer JI, Keim HJ, Laragh JH, et al. Nephrotic syndrome: vasoconstriction and hypervolemic types indicated by renin-sodium profiling. Ann Intern Med 1979; 91:688.
- Vande Walle JG, Donckerwolcke RA, van Isselt JW, et al. Volume regulation in children with early relapse of minimal-change nephrosis with or without hypovolaemic symptoms. Lancet 1995; 346:148.
- Manning RD Jr, Guyton AC. Effects of hypoproteinemia on fluid volumes and arterial pressure. Am J Physiol 1983; 245:H284.
- Manning RD Jr. Effects of hypoproteinemia on renal hemodynamics, arterial pressure, and fluid volume. Am J Physiol 1987; 252:F91.
- Vande Walle JG, Donckerwolcke RA, Koomans HA. Pathophysiology of edema formation in children with nephrotic syndrome not due to minimal change disease. J Am Soc Nephrol 1999; 10:323.
- EDER HA, LAUSON HD, CHINARD FP, et al. A study of the mechanisms of edema formation in patients with the nephrotic syndrome. J Clin Invest 1954; 33:636.
- LUETSCHER JA Jr, HALL AD, KREMER VL. Treatment of nephrosis with concentrated human serum albumin. II. Effects on renal function and on excretion of water and some electrolytes. J Clin Invest 1950; 29:896.
- Ichikawa I, Rennke HG, Hoyer JR, et al. Role for intrarenal mechanisms in the impaired salt excretion of experimental nephrotic syndrome. J Clin Invest 1983; 71:91.
- Buerkert J, Martin DR, Trigg D, Simon EE. Sodium handling by deep nephrons and the terminal collecting duct in glomerulonephritis. Kidney Int 1991; 39:850.
- Féraille E, Vogt B, Rousselot M, et al. Mechanism of enhanced Na-K-ATPase activity in cortical collecting duct from rats with nephrotic syndrome. J Clin Invest 1993; 91:1295.
- Valentin JP, Ying WZ, Sechi LA, et al. Phosphodiesterase inhibitors correct resistance to natriuretic peptides in rats with Heymann Nephritis. J Am Soc Nephrol 1996; 7:582.
- Valentin JP, Qiu C, Muldowney WP, et al. Cellular basis for blunted volume expansion natriuresis in experimental nephrotic syndrome. J Clin Invest 1992; 90:1302.
- Lee EY, Humphreys MH. Phosphodiesterase activity as a mediator of renal resistance to ANP in pathological salt retention. Am J Physiol 1996; 271:F3.
- Svenningsen P, Bistrup C, Friis UG, et al. Plasmin in nephrotic urine activates the epithelial sodium channel. J Am Soc Nephrol 2009; 20:299.
- Passero CJ, Mueller GM, Rondon-Berrios H, et al. Plasmin activates epithelial Na+ channels by cleaving the gamma subunit. J Biol Chem 2008; 283:36586.
- Besse-Eschmann V, Klisic J, Nief V, et al. Regulation of the proximal tubular sodium/proton exchanger NHE3 in rats with puromycin aminonucleoside (PAN)-induced nephrotic syndrome. J Am Soc Nephrol 2002; 13:2199.
- Klisic J, Zhang J, Nief V, et al. Albumin regulates the Na+/H+ exchanger 3 in OKP cells. J Am Soc Nephrol 2003; 14:3008.
- Rodríguez-Iturbe B, Colic D, Parra G, Gutkowska J. Atrial natriuretic factor in the acute nephritic and nephrotic syndromes. Kidney Int 1990; 38:512.
- Usberti M, Federico S, Meccariello S, et al. Role of plasma vasopressin in the impairment of water excretion in nephrotic syndrome. Kidney Int 1984; 25:422.
- Pyo HJ, Summer SN, Niederberger M, et al. Arginine vasopressin gene expression in rats with puromycin-induced nephrotic syndrome. Am J Kidney Dis 1995; 25:58.
- Koomans HA, Boer WH, Dorhout Mees EJ. Renal function during recovery from minimal lesions nephrotic syndrome. Nephron 1987; 47:173.
- Mayatepek E, Becker K, Gana L, et al. Leukotrienes in the pathophysiology of kwashiorkor. Lancet 1993; 342:958.
- Schrier RW, Fassett RG. A critique of the overfill hypothesis of sodium and water retention in the nephrotic syndrome. Kidney Int 1998; 53:1111.
- Crew RJ, Radhakrishnan J, Appel G. Complications of the nephrotic syndrome and their treatment. Clin Nephrol 2004; 62:245.
- Smith DE, Hyneck ML, Berardi RR, Port FK. Urinary protein binding, kinetics, and dynamics of furosemide in nephrotic patients. J Pharm Sci 1985; 74:603.
- Keller E, Hoppe-Seyler G, Schollmeyer P. Disposition and diuretic effect of furosemide in the nephrotic syndrome. Clin Pharmacol Ther 1982; 32:442.
- Wilcox CS. New insights into diuretic use in patients with chronic renal disease. J Am Soc Nephrol 2002; 13:798.
- Kirchner KA, Voelker JR, Brater DC. Intratubular albumin blunts the response to furosemide-A mechanism for diuretic resistance in the nephrotic syndrome. J Pharmacol Exp Ther 1990; 252:1097.
- Kirchner KA, Voelker JR, Brater DC. Binding inhibitors restore furosemide potency in tubule fluid containing albumin. Kidney Int 1991; 40:418.
- Agarwal R, Gorski JC, Sundblad K, Brater DC. Urinary protein binding does not affect response to furosemide in patients with nephrotic syndrome. J Am Soc Nephrol 2000; 11:1100.
- Kirchner KA, Voelker JR, Brater DC. Tubular resistance to furosemide contributes to the attenuated diuretic response in nephrotic rats. J Am Soc Nephrol 1992; 2:1201.
- Chalasani N, Gorski JC, Horlander JC Sr, et al. Effects of albumin/furosemide mixtures on responses to furosemide in hypoalbuminemic patients. J Am Soc Nephrol 2001; 12:1010.
- Fliser D, Zurbrüggen I, Mutschler E, et al. Coadministration of albumin and furosemide in patients with the nephrotic syndrome. Kidney Int 1999; 55:629.
- Dharmaraj R, Hari P, Bagga A. Randomized cross-over trial comparing albumin and frusemide infusions in nephrotic syndrome. Pediatr Nephrol 2009; 24:775.
- Kapur G, Valentini RP, Imam AA, Mattoo TK. Treatment of severe edema in children with nephrotic syndrome with diuretics alone--a prospective study. Clin J Am Soc Nephrol 2009; 4:907.
- UNDERFILLING VERSUS RENAL SODIUM RETENTION
- Starling's law
- - Application to nephrotic syndrome
- Evidence supporting underfilling
- Evidence supporting primary renal sodium retention
- - Volume regulatory hormones
- - Response to glucocorticoids in minimal change disease
- Varying mechanisms in childhood minimal change disease
- Hypoalbuminemia in other edematous disorders
- Diuretics and sodium restriction
- Angiotensin inhibition
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS