A Study of the Plasma Kinin-generating System in Children with the Minimal Lesion, Idiopathic Nephrotic Syndrome

Extract: Although the precise etiologic incitant of the minimal lesion idiopathic nephrotic syndrome of childhood is not known, it is likely that a host mechanism mediates the permeability alterations of the glomerular capillary wall resulting in massive proteinuria. As a first step in examining the possibility that local kinin release may account for the proteinuria in this disorder, two parameters of the plasma kinin-generating system, plasma prekallikrein and kallikrein inhibitor, were assayed during 27 nephrotic episodes in 21 corticosteroid-responsive children. Plasma kallikrein was assayed by means of its esterase activity on a synthetic arginine ester substrate, N-α-tosyl-L-arginine methyl ester (TAMe), after activation of Hageman factor by kaolin. This activity, after subtraction of spontaneous arginine esterase activity (i.e., TAMe esterase activity measured in plasma not exposed to kaolin) is derived from prekallikrein. Plasma prekallikrein activity in 11 normal children was 99.6 ± 2.9 pnol TAMe hydrolyzed/ml plasma/hr (mean ± SEM). Kallikrein inhibitor was quantified in arbitrary units. Kallikrein inhibitor activity in 11 normal children was 0.94 ± 0.04 units. During the overt nephrotic syndrome, before initiation of intensive daily corticosteroid treatment, mean values were: prekallikrein, 58.5 ± 7.24 μmol/ml/hr; and kallikrein inhibitor, 0.35 ± 0.06 units. After corticosteroid-induced remission occurred, mean values were: plasma prekallikrein, 118.6 ± 3.2 μmol/ml/hr; and kallikrein inhibitor, 0.78 ± 0.03 μmol/ml/hr. Both parameters were again assayed in 14 of the 21 children after complete cessation of corticosteroid treatment. Plasma prekallikrein was normal, 99.6 ± 4.8 μmol/ml/hr; but kallikrein inhibitor was still somewhat depressed, 0.84 ± 0.03 units. A subset of 9 patients had marked depression of plasma prekallikrein to levels less than 20 μmol/ml/hr and essentially undetectable inhibitor activity. Serum α-2 macroglobulin was elevated in nephrotic patients: mean value during relapse, 862 ± 29 mg/100 ml; during corticosteroid-maintaining remission, 615 ± 29 mg/100 ml. After cessation of corticosteroids, mean serum level was 481 ± 20 mg/100 ml. The proportional reduction of plasma prekallikrein and kallikrein inhibitor suggested that an enzyme-inhibitor complex formed in vivo, perhaps at a local site of activation in proximity to the glomerular basement membrane. These data suggest that the plasma kinin-generating system may be the host effector mechanism subserving the increased glomerular capillary permeability in the minimal lesion nephrotic syndrome of childhood. Speculation: Local activation of the plasma kinin-generating system in close proximity to the glomerular capillary wall may mediate the proteinuria of the minimal lesion nephrotic syndrome. Inhibitors of the kinin-generating sequence may provide effective and rational treatment for children with frequent relapses of the nephrotic syndrome or those corticosteroid-resistant children destined to have a recurrence of the minimal lesion nephrotic syndrome in a renal allograft.