Background/Aim: There is increasing evidence that hypoalbuminemia and the inability of the renal distal tubule to excrete salt are not the only factors responsible for nephrotic edema. We tested the possibility that vascular hyperpermeability also plays a role in the pathophysiology of nephrotic edema in human primary glomerulonephritis. Methods: We investigated the capillary permeability by means of a standardized test using albumin labelled with technetium (99mTc-albumin) in 20 healthy adults and in 101 nephrotic adult patients comprising 60 patients with idiopathic nephrotic syndrome (INS; minimal-change nephropathy and segmental glomerulosclerosis), 32 with idiopathic membranous nephropathy (IMN) and 9 patients with idiopathic type I membranoproliferative glomerulonephritis (MPGN). The patients and healthy controls were also compared with a group of women (n = 25) with idiopathic cyclic edema, a disease in which an increase in capillary permeability plays a pivotal role. The capillary permeability measured by the Landis isotope test is normal in edematous patients with cardiac and renal impairment unrelated to glomerular disease, cirrhosis, hypothyroidism, lymphatic obstruction and diuretic abuse. As values were not normally distributed, nonparametric analysis of variance was used (Kruskal-Wallis test), and patient groups were compared with healthy controls and with women with idiopathic cyclic edema by means of the two-tailed nonparametric Mann-Whitney test. The effects of high-dose steroids and Ginkgo biloba extract (Tanakan®; an agent able to improve capillary permeability) were analyzed by means of the two-tailed nonparametric Wilcoxon test. Results: The capillary permeability was significantly increased (Mann-Whitney test) in each glomerular disease group compared with the healthy controls. 99mTc-albumin extravasation values (%; median and range in parentheses were the following: healthy controls 0 (0–8.4); idiopathic cyclic edema patients 11.5 (8–24), p < 0.001; INS 20 (0–50), p < 0.0001; IMN 12.5 (0–40), p < 0.001, and MPGN 10 (0–40), p < 0.05. An increase in capillary permeability exceeding the upper limit of control values ( >8% of 99mTc-albumin extravasation) was observed in 88% of INS, in 53% of IMN and in 44% of MPGN patients. The increase in capillary permeability (%) was greater in idiopathic nephrotic patients than in idiopathic cyclic edema patients (p < 0.005, Mann-Whitney test) and was markedly reduced in nephrotic patients receiving high-dose steroids (n = 8) [before 25 (8–40); after 0 (0–25), p < 0.005 (Wilcoxon’s test)] and high doses of G. biloba extract (n = 16) [before 30 (8–50); after 2.5 (0–20, p < 0.0005 (Wilcoxon’s test)]. Conclusions: We conclude that capillary permeability is severely altered in most of the nephrotic patients with primary glomerulonephritis. These results strongly suggest that the capillary hyperpermeability plays a role in the pathophysiology of nephrotic edema in primary glomerular disease, especially in INS. We postulate that this widespread abnormality in capillary permeability is related to the release of vascular permeability factor and other cytokines by immune cells.

Keywords:
Vascular permeability, Nephrotic syndrome, Landis isotopic test, Nephrotic edema, Capillary hyperpermeability, Idiopathic nephrotic syndrome, Minimal change glomerulopathy, Idiopathic membranous nephropathy, Membranoproliferative glomerulonephritis, Cyclic edema
1.
Cameron S, Glassock R: The Nephrotic Syndrome. London, Churchill Livingstone, 1987.
2.
Bernard D: Extrarenal complications of the nephrotic syndrome. Kidney Int 1988;33:1184–1202.
3.
Palmer B, Alpern R: Pathogenesis of edema formation in the nephrotic syndrome. Kidney Int 1997;51(suppl 59):21–27.
4.
Van de Walle J, Donckerwolcke R, Van Isselt J, Derkx F, Joles J, Koomans H: Volume regulation in children with early relapse of minimal-change nephrosis with or without hypovolaemic symptoms. Lancet 1995;346:148–152.
5.
Perico N, Remuzzi G: Edema of the nephrotic syndrome: The role of the atrial peptide system. Am J Kidney Dis 1993;22:355–366.
6.
Taylor A: Capillary fluid filtration: Starling forces and lymph flow. Circ Res 1981;49:557–575.
7.
Behar A, Tournoux A, Baillet J, Lagrue G: Untersuchungen zur Bestimmung der kapillaren Durchlässigkeit mit markiertem menschlichem Albumin. Nuklearmedizin 1976;15:214–216.
8.
Edwards O, Bayliss R: Idiopathic cyclic oedema of women: A clinical and investigative study. Q J Med 1976;45:125–144.
9.
Behar A, Baillet J, Lagrue G: Une nouvelle méthode de mesure de la perméabilité capillaire par méthode isotopique. J Mal Vasc 1977;2:101–104.
10.
Lagrue G, Behar A, Kazandjian M, Rahbar K: Œdèmes cycliques idiopathiques: Rôle de l’hyperperméabilité capillaire et correction par extrait de Ginkgo biloba. Presse Méd 1986;15:1550–1553.
11.
Behar A, Lagrue G, Cohen-Boulakia F, Baillet J: Capillary filtration in idiopathic cyclic edema: Effects of Daflon 500 mg. Nuclearmedizin 1988;27:105–107.
12.
Matthews DE, Farewell V: Using and Understanding Medical Statistics. Basel, Karger, 1985.
13.
Weil B, Lagrue G, Ménard J: Le syndrome d’œdèmes cycliques idiopathiques. III. Etudes biologiques, déductions physiopathologiques et thérapeutiques. J Urol Néphrol 1971;12:940–952.
14.
Hollander W, Reilly P, Burrows B: Lymphatic flow in human subjects as indicated by the disappearance of 131I labelled albumin from the subcutaneous tissue. J Clin Lab Invest 1960;40:222–223.
15.
Wraight E: Capillary permeability of protein as a factor in control of plasma volume. J Physiol (Lond) 1974;237:39.
16.
Hilsted J: Dual effect of insulin on plasma volume and transcapillary albumin transport. Diabetologia 1992;35:99–103.
17.
Cottran R, Pober J, Gimbrione M: Endothelial activation during interleukin 2 immunotherapy: A possible mechanism for the vascular leak syndrome. J Immunol 1987;139:1883–1888.
18.
Royall J, Berkow R, Beckman J, Cunningham M, Matalon S, Freeman B: Tumor necrosis factor and interleukin 1 alpha increase vascular endothelial permeability. Am J Physiol 1989;257:L399–L410.
19.
Lagrue G, Xheneumont S, Branellec A, Hirbec G, Weil B: A vascular permeability factor elaborated from lymphocytes. I. Demonstration in patients with nephrotic syndrome. Biomedicine 1975;23:37–40.
20.
Shalhoub R: Pathogenesis of lipoid nephrosis: A disorder of T-cell function. Lancet 1974;ii:556–560.
21.
Heslan JM, Branellec A, Laurent J, Lagrue G: The vascular permeability factor is a T lymphocyte product. Nephron 1986;42:187–188.
22.
Sobel A, Branellec A, Blanc C, Lagrue G: Physicochemical characterization of vascular permeability factor produced by ConA-stimulated human lymphocytes. J Immunol 1977;119:1230–1234.
23.
Heslan JM, Branellec A, Pilatte Y, Lang P, Lagrue G: Differentiation between vascular permeability factor and IL-2 in lymphocyte supernatants from patients with minimal-change nephrotic syndrome. Clin Exp Immunol 1991;86:157–162.
24.
Boulton-Jones JM, Tulloch I, Dore B, McClay A: Changes in the glomerular capillary wall induced by lymphocyte products and serum of nephrotic patients. Clin Nephrol 1983;20:72–77.
25.
Boulton-Jones JM, McWilliams G, Chandrachud L: Variation in charge on red cells of patients with different glomerulopathies. Lancet 1986;ii:186–189.
26.
Levin M, Smith C, Walters MDS, Gascoine P, Barrat TM: Steroid-responsive nephrotic syndrome: A generalised disorder of membrane negative charge. Lancet 1985;ii:239–242.
27.
Dantal J, Bigot E, Bogers W, Testa A, Kriaa F, Jacques Y, Hurault de Ligny B, Niaudet P, Charpentier B, Soulillou JP: Effect of plasma protein absorption on protein excretion in kidney transplant recipients with recurrent nephrotic syndrome. N Engl J Med 1994;330:7–14.
28.
Rostoker G, Rymer JC, Bagnard G, Griuncelli M, Petit-Phar M, Pilatte Y: Imbalances in serum proinflammatory cytokines and their soluble receptors: A putative role in the progression of idiopathic IgA nephropathy and Henoch-Schönlein purpura nephritis and a potential target of immunoglobulin therapy? Clin Exp Immunol 1998;114:468–476.
29.
Matsumoto K, Kanmatsuse K: Increased IL-12 release by monocytes in nephrotic patients. Clin Exp Immunol 1999;117:361–367.
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2000
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