Vascular Hyperpermeability in Nephrotic Edema

Abstract

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.