Laboratory Investigation

Kidney International (1991) 40, 461–469; doi:10.1038/ki.1991.233

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

Masaru Motojima, Fuyuhiko Nishijima, Masaaki Ikoma, Tetsuya Kawamura, Toshimasa Yoshioka, Agnes B Fogo, Tadasu Sakai and Iekuni Ichikawa

Departments of Pediatrics and Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA and Kitasato University Kidney Center, Sagamihara, Japan

Correspondence: Iekuni Ichikawa MD, Department of Pediatrics, Vanderbilt University Medical Center, 21st and Garland Avenue, Nashville, Tennessee 37232, USA.

Received 29 October 1990; Revised 17 April 1991; Accepted 19 April 1991.

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Abstract

Role for "uremic toxin" in the progressive loss of intact nephrons in chronic renal failure. 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 at 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 plusminus 0.08 vs. 0.30 plusminus 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 plusminus 0.21 versus 1.30 plusminus 0.19 in Group 1 control and Group 2 PD, respectively (P < 0.05), and 1.42 plusminus 0.16 versus 0.99 plusminus 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.

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References

  1. Kurnick NB, Lindsey PA: Compensatory renal hypertrophy in parabiotic mice. Lab Invest 10:45–48, 1968
  2. Anderson S, Meyer TW, Rennke HG, Brenner BM: Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass. J Clin Invest 76:612–619, 1985 | PubMed | ISI | ChemPort |
  3. Hostetter TH, Meyer TW, Rennke HG, Brenner BM: Chronic effects of dietary protein in the rat with intact and reduced renal mass. Kidney Int 30:509–517, 1986 | PubMed | ISI | ChemPort |
  4. Shimamura T, Morrison AB: A progressive glomerulosclerosis occurring in partial five-sixths nephrectomized rats. Am J Pathol 79:95–101, 1975 | PubMed | ISI | ChemPort |
  5. Purkerson ML, Hoffsten PE, Klahr S: Pathogenesis of glomerulopathy associated with renal infarction in rats. Kidney Int 9:407–417, 1976 | PubMed | ISI | ChemPort |
  6. Brenner BM, Meyer TW, Hostetter TH: Dietary protein intake and the progressive nature of kidney disease: The role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Engl J Med 307:652–659, 1982 | PubMed | ISI | ChemPort |
  7. Pinto J, Lacerda G, Cameron JS, Turner DR, Bewiick M, Ogg CS: Recurrence of focal segmental glomerulosclerosis in renal allografts. Transplantation 32:83–89, 1981
  8. Adler S, Striker LJ, Striker GE, Perkinson DT, Hibbert J, Couser WG: Studies of progressive glomerular sclerosis in the rat. Am J Pathol 123:553–562, 1986 | PubMed | ISI | ChemPort |
  9. Ichikawa I, Purkerson ML, Klahr S, Troy JL, Martinez-Maldonado M, Brenner BM: Mechanism of reduced glomerular filtration rate in chronic malnutrition. J Clin Invest 65:982–988, 1980
  10. Pfeffer JM, Pfeffer MA, Frohlich ED: Validity of an indirect tail-cuff method for determining systolic arterial pressure in unanesthetized normotensive and spontaneously hypertensive rats. J Lab Clin Med 78:957–962, 1971 | PubMed | ISI | ChemPort |
  11. Sugiya Y, Aho Y, Kubo H, Sato H, Ise M, Uehara Y, Nishimura Y: Chronic (6-month) oral toxicity study, including a reversibility study, with AST-120 in rats. Basic Sci Clin Med 21:2179–2196, 1987
  12. Yoshida Y, Fogo A, Ichikawa I: Serial micropuncture analysis of single nephron function in the rat model of subtotal renal ablation. Kidney Int 33:855–867, 1988 | PubMed | ISI | ChemPort |
  13. Ichikawa I, Maddox DA, Cogan MG, Brenner BM: Dynamics of glomerular ultrafiltration in euvolemic Munich-Wistar rats. Renal Physiol (Basel) 1:121–131, 1978
  14. Rau L, Azar S, Keane W: Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats. Kidney Int 26:137–143, 1984
  15. Vurek GC, Pegram SE: Fluorometric method for the determination of nanogram quantities of inulin. Anal Biochem 16:409–419, 1966 | Article | ISI | ChemPort |
  16. Führ J, Kacmarczyk J, Kruttgen CD: Eine einfache colorimetrische Methode zur Inulinbestimmung fur Nieren-clearance-Unter-suchungen bei Stoffwechselgesunden und Diabetikern. Klin Wochenschr 33:729–730, 1955 | PubMed | ISI | ChemPort |
  17. Ikoma M, Kawamura T, Fogo A, Ichikawa I: Cause of variable therapeutic efficiency of angiotensin converting enzyme inhibitor on the glomerular mesangial lesion. Kidney Int 40:95–202, 1991
  18. Kanai F, Takahama T, Yamazaki Z, Idezuki Y, Koide K: Effect of oral adsorbent on experimental uremic rats. Jap J Nephrol 28:711–77, 1986
  19. Yoshida Y, Sakai T, Ise M, Sugano M, Asakura K: Effect of oral adsorbent (AST-120) in the rat model of chronic renal failure (CRF) induced by adriamycin (ADM). Xlth International Congress of Nephrology, Tokyo, 1990, (abstract) p. 456
  20. Harris RH, Best CF: Circulatory retention of urinary factors as a stimulus to renal growth. Kidney Int 12:305–312, 1977 | PubMed | ISI | ChemPort |
  21. Obertop H, Malt RA: Lost mass and excretion as stimuli to parabiotic compensatory renal hypertrophy. Am J Physiol 232:F405–F408, 1977 | PubMed | ISI | ChemPort |
  22. Fogo A, Ichikawa I: Evidence for the central role of glomerular growth promoters in the development of sclerosis. Semin Nephrol 9:329–342, 1989 | PubMed | ISI | ChemPort |
  23. Klahr S, Schreiner G, Ichikawa I: The progression of renal disease. N Engl J Med 318:1657–1666, 1988 | PubMed | ISI | ChemPort |
  24. Kasiske BL, O'Donnell MP, Schmitz PG, Kim Y, Keane WF: Renal injury of diet-induced hypercholesterolemia in rats. Kidney Int 37:880–891, 1990 | Article | PubMed | ISI | ChemPort |

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