Postgraduate Medical Journal (1985) 61, 1057-1062 Postgrad Med J: first published as 10.1136/pgmj.61.722.1057 on 1 December 1985. Downloaded from Mechanisms of Disease The nephrotic syndrome Edwina A. Brown Department ofMedicine, Charing Cross & Westminster Medical School, Fulham Palace Road, London W6 8RF, UK. Introduction The definition of nephrotic syndrome is proteinuria reduced binding of cationic stains to anionic sites of accompanied by hypoalbuminaemia and oedema. the glomerular capillary wall in aminonucleoside- This, however, is not a direct chain of events. In the treated rats (Michael et al., 1970). presence of normal liver albumin synthesis, nephrotic In man, there is also evidence of depleted range of proteinuria (> 3.5 g/24 h) should not cause glomerular polyanion in almost all glomerular dis- hypoalbuminaemia, and a low plasma albumin con- eases associated with proteinuria (Blau & Haas, 1973). centration itself does not result in oedema formation This loss of glomerular electrostatic barrier function except in the presence of sodium retention. The cause would allow the leak of the negatively charged Protected by copyright. of this sodium retention remains unknown, but is albumin into the urine. There is also increasing probably due to some intrarenal mechanism. evidence that the different protein selectivity found in different causes of nephrotic syndrome can be ex- plained by the fact that in minimal change Mechanisms of proteinuria glomerulonephritis there remains an intact size-selec- tive barrier, while in other glomerular lesions this By measuring the clearances of charged and neutral barrier becomes leaky (Deen et al., 1982). dextrans of known molecular weights and comparing them to inulin it is possible to study glomerular capillary permeability. Such studies show that in Hypoalbuminaemia and proteinuria normal animals both molecular charge and size in- fluence the transglomerular passage of circulating The liver of a normal 70 kg person can synthesize macromolecules. Thus, the filtration of the negatively albumin at the rate of 8-14 g/d (Rothschild et al., charged albumin is restricted to a much greater extent 1972), yet in nephrotic syndrome, hypoalbuminaemia http://pmj.bmj.com/ than is that of a neutral macromolecule of the same occurs with considerably lower urinary protein excre- size (Chang et al., 1975). This is due to the existence of tion rates. Nephrotic range proteinuria is usually fixed negative charges on the glomerular capillary wall defined as greater than 5 g/d and nephrotic syndrome as demonstrated by the use of cationic 'stains' such as can occur with a urinary protein excretion as low as colloidal iron and ruthenium red (Latta et al., 1975; 3.5 g/d. Although in some patients urinary protein Kanwar & Farquhar, 1979). losses may exceed the normal rate of synthesis of Studies in rats with nephrotoxic serum nephritis or albumin by the liver, it is not clear why hypoalbumin- aminonucleoside-induced nephrosis have shown that, aemia should occur in those patients with lesser on September 26, 2021 by guest. at any given molecular size, negatively charged dex- degrees of proteinuria. There are three possible ex- tran sulphate fractional clearances are greater than planations: (1) albumin synthesis could be diminished; those in normal rats (Bennett et al., 1976; Bohrer et al., (2) non-renal losses of albumin could occur; or (3) 1977). This suggests that albuminuria in these disor- albumin catabolism could be enhanced. ders is due to a reduction in the fixed negative charges There is no evidence ofdecreased albumin synthesis on the diseased glomerular capillary wall. Further in patients with nephrotic syndrome. Studies using support for this theory comes from the finding of radioiodinated albumin have shown that albumin synthesis in patients with nephrotic syndrome is either Correspondence: E.A. Brown, D.M., M.R.C.P. normal or slightly increased (Gitlin et al., 1956; Jensen Accepted: 1 May 1985 et al., 1967). Non-renal losses of albumin may occur, ) The Fellowship of Postgraduate Medicine, 1985 1058 E.A. BROWN Postgrad Med J: first published as 10.1136/pgmj.61.722.1057 on 1 December 1985. Downloaded from probably through the gastrointestinal tract, though plasma albumin concentration, however, is not always the evidence is conflicting. Jensen et al. (1967) and accompanied by oedema formation. Even patients Yssing et al. (1969) in their studies found no evidence with analbuminaemia are not oedematous and, in fact, ofincreased gastrointestinal losses but a later study by can have an exaggerated natriuresis in response to a Schultze et al. (1980) using 51Cr-albumin did show small saline load (Bennhold et al., 1960). Similarly, moderate to severe gastrointestinal protein losses in severe hypoalbuminaemia induced in animals by plas- many patients with nephrotic syndrome. mapheresis does not produce any change in urinary The most likely explanation of the hypoalbumin- sodium excretion (Vereerstraeten & Toussaint, 1969). aemia of nephrotic syndrome, however, is increased Volume receptors have not been detected in the catabolism of albumin, probably by the kidney. interstitial space, so control of the volume of the Studies in both animal models (Katz et al., 1963) and interstitial fluid compartment appears to be by the in patients with nephrotic syndrome (Jensen et al., interplay of a number of local automatic mechanisms 1967) have demonstrated an increase in fractional (Aukland & Nicolaysen, 1981). One of the primary albumin catabolism. The most likely site of this factors preventing oedema formation is structural increased albumin catabolism is the kidney since there resistance against volume changes making the inter- appears to be a direct relationship between renal stitial space relatively noncompliant. Guyton (1965) albumin catabolism and quantitative proteinuria found that at near normal interstitial volumes, small (Katz et al., 1963), and bilateral nephrectomy causes at increases in interstitial volume cause large increases in least a 50% fall in the rate of plasma albumin interstitial pressure which would oppose further tran- breakdown in rats with aminonucleoside or sudation of fluid into the interstitial space. However, nephrotoxic serum-induced nephrotic syndrome once interstitial pressure reaches a critical value, as the (Katz et al., 1964). interstitial volume increases further, the subsequent The site of this increased renal albumin catabolism increments in interstitial pressure are much smaller. is probably the proximal tubule. Radioiodinated The lymphatics also play a role in preventing oedemaProtected by copyright. albumin has been clearly demonstrated to be taken up formation. Lymph flow has been shown to increase by proximal tubule cells and perhaps then metabolized following oedema formation in many different by lysozomes (Maunsbach, 1966). Proximal tubule oedema states (Hollander et al., 1961; Zweifach, 1972). cells have been shown to be able to metabolize a Erdmann et al. (1975) showed that during steady state variety of plasma proteins (Waldmann et al., 1972). elevations of pulmonary micro-vascular hydrostatic Micropuncture studies, however, have failed to con- pressure, lymph flow increased while the lymph firm that significant albumin catabolism occurs at the protein concentration decreased, reflecting washout of proximal tubule. Studies in both aminonucleoside- interstitial protein. The consequent decrease in inter- induced (Oken et al., 1971, 1972; Lewy & Pesce, 1973) stitial oncotic pressure, by increasing the oncotic and nephrotoxic serum-induced nephrotic syndrome pressure gradient across the capillary wall would also (Landwehr et al., 1977) also gave no evidence that help to prevent further oedema formation. One further proximal tubular absorption plays a major role in mechanism which may protect against oedema forma- albumin catabolism. However, Cortney et al. (1970) tion is that the capillary wall appears to become less did find significant proximal tubular albumin absorp- permeable to albumin in the presence ofhypoalbumin- tion after injecting radioiodinated albumin into the aemia (Wraight, 1974; Aukland & Nicolaysen, 1981). http://pmj.bmj.com/ proximal tubule. This would tend to prevent a further fall in plasma Although the evidence is confficting it would appear oncotic pressure along the capillary and therefore that the most likely explanation for the discrepancy minimize oedema formation. between the hepatic capacity to synthesize albumin These control mechanisms preventing oedema for- and the degree of albuminuria in many patients with mation have also been observed in patients with nephrotic syndrome remains the increased albumin nephrotic syndrome. Increased lymphatic flow has catabolism by the kidney, plus, possibly in some been observed in patients with nephrotic syndrome patients, increased gastrointestinal protein losses. (Hollander et al., 1961; Zweifach, 1972). Furthermore, on September 26, 2021 by guest. using wick techniques, Noddeland et al. (1980) found that the interstitial oncotic pressure fell during oedema Hypoalbuminaemia and oedema formation formation in patients with nephrotic syndrome, presumably because of washout of the interstitial By Starling's law, the formation of interstitial fluid is protein by the increased lymphatic flow. From these dependent upon the balance between the hydrostatic observations, it is apparent that generalized oedema and the oncotic pressures in the intravascular and only occurs in the presence of hypoalbuminaemia