Role for "uremic toxin" in the progressive loss of intact nephrons in chronic renal failure

Abstract

We studied the effect on the progression of glomerular sclerosis of two different experimental maneuvers, peritoneal dialysis and oral adsorbent, which remove circulating substances in different fashions. Munich-Wistar rats with established glomerular sclerosis, verified by renal biopsy analysis at seven weeks after subtotal nephrectomy, were treated for four weeks with either peritoneal dialysis (PD) or oral charcoal adsorbent (AST-120). Treatment was initiated at eight weeks. Rats were paired in treatment and control groups according to the similarity in the degree of sclerosis determined ai biopsy with a minimum of 50 glomeruli analyzed. Systolic blood pressure and BUN and creatinine clearance, measured at seven to eight weeks, were not different among groups. In Group 2 rats, PD was performed with 1.5% dextrose for eight one-hour cycles, six days per week, while Group 1 control rats had zero indwelling time of the dialysate. Group 4 rats received AST-120, an oral adsorbent charcoal, mixed 5% by weight with standard rat chow and given ad libitum from 8 to 12 weeks after subtotal nephrectomy, while control Group 3 rats received only rat chow. Whole kidney GFR at 12 weeks was significantly higher in Group 2 PD versus Group 1 control (0.50 ± 0.08 vs. 0.30 ± 0.05 ml/min, P < 0.05). There was no statistical difference for BUN and whole kidney creatinine or inulin clearance in Group 4 AST-120 treated versus Group 3 control rats. Light microscopic studies in autopsy specimens revealed that both PD and AST-120 attenuated progression of glomerular sclerosis. Thus, at autopsy, the sclerosis index averaged 1.78 ± 0.21 versus 1.30 ± 0.19 in Group 1 control and Group 2 PD, respectively (P < 0.05), and 1.42 ± 0.16 versus 0.99 ± 0.13 in Group 3 control and Group 4 AST-120 treated rats, respectively (P < 0.05). Since the dialysis replaces primarily the filtration function of the nephrons removed at the onset of the study, the present observations support the possibility that the biologically-active circulating substances, or so-called "uremic toxins", are involved in the advancement of glomerular sclerosis and are ultrafiltrable in nature.