Impaired Plasma Protein Binding of Furosemide in the Nephrotic Syndrome and in Uremia

Abstract

Protein binding of 35S-Furosemide (FM) was measured by ultrafiltration technique in 8 normal subjects (C), 8 nephrotic patients (NS), 9 non-dialysis patients with chronic renal failure (CRF), 12 dialysis patients (HD) and 5 transplanted patients. The percent bound FM was 98.2±0.1% in C, 95.5±0.6% in NS, 95.8±0.5% in CRF and 94.0±0.5% in HD. FM binding was significantly reduced in. NS, CRF and HD (p<0.001). There was a linear relationship between albumin concentration and ratio of bound/unbound FM Therefore, it was considered that the reduced binding in NS was due to hypoalbuminemia. In contrast, it was considered that the reduced binding in uremia was not due to decreased albumin but due to abnormal metabolism in uremia. FM binding, however, was not influenced by pH (6.0-8.0), free fatty acids (0.3-3.0 mEq/L), urea, creatinine, methylguanidine and guanidinosuccinic acid. FM binding in uremic patients was increased slightly but significantly after hemodialysis and ultraf filtrate of uremic plasma contained a few substances which inhibited FM binding. Moreover, FM binding of uremic plasma was normalized by adsorption with synthetic polymers at pH3 After renal transplantation, FM binding was normalized after three to five weeks, whereas serum creatinine was restored to normal within a week. These findings indicated that the reduced binding in uremia was due to unknown substances, “binding inhibitors”, which accumulated in uremia. Since these inhibitors were strongly bound to albumin at physiologic pH, they were only partly dialyzed. Inhibitors were suggested to be excreted not by glomerular filtration but by tubular secretion of the transplanted kidney.