Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1988 Nov;82(5):1614–1623. doi: 10.1172/JCI113773

"Intact nephrons" as the primary origin of proteinuria in chronic renal disease. Study in the rat model of subtotal nephrectomy.

T Yoshioka 1, H Shiraga 1, Y Yoshida 1, A Fogo 1, A D Glick 1, W M Deen 1, J R Hoyer 1, I Ichikawa 1
PMCID: PMC442730  PMID: 3183057

Abstract

Single nephron filtration rate of albumin (SNGFRAlb) was measured in remnant nephrons of Munich-Wistar rats 4-6 wk after subtotal nephrectomy (NPX). Serial thin-section histological analysis was then conducted on the same glomeruli by light microscopy. SNGFRAlb ranged from 1 to 15 times normal. However, a direct relationship between abnormalities of structure and function was not seen, e.g. the glomeruli with the fewest structural abnormalities and marked hyperfiltration often had the highest SNGFRAlb. Moreover, the majority of glomeruli had minimal structural abnormalities. Normalization of the markedly elevated glomerular capillary pressure (PGC) in these glomeruli was accomplished by acute intravenous infusion of verapamil, which decreased SNGFRAlb by 9-83% without affecting the single nephron filtration rate of water (SNGFRH2O). 1-2 wk after subtotal NPX, all glomeruli were hyperfiltering and had elevated PGC. The fractional clearance of larger (greater than 36 A) dextrans was selectively increased in these glomeruli that lacked discernible damage by light microscopy. Verapamil normalized PGC, reduced proteinuria to 48 +/- 4% of baseline, and improved glomerular size selectivity without altering SNGFRH2O. Proteinuria after subtotal NPX thus originates largely from glomeruli with minimal structural abnormalities. The defect in size selectivity is largely attributed to the prevailing high PGC, producing large, nonselective channels on the glomerular capillary wall. The observations raise the possibility that in chronic renal diseases, the reduction in proteinuria often seen after therapeutic measures, including antihypertensive medication, may reflect their functional effect on the relatively intact glomeruli rather than their structure-sparing effect on severely damaged glomeruli, which contribute little to the proteinuria.

Full text

PDF
1614

Images in this article

1619Image
on p.1619
1619Image
on p.1619
1622Image
on p.1622
1622Image
on p.1622
1622Image
on p.1622
1622Image
on p.1622
1622Image
on p.1622

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson S., Meyer T. W., Rennke H. G., Brenner B. M. Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass. J Clin Invest. 1985 Aug;76(2):612–619. doi: 10.1172/JCI112013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  3. Deen W. M., Bridges C. R., Brenner B. M., Myers B. D. Heteroporous model of glomerular size selectivity: application to normal and nephrotic humans. Am J Physiol. 1985 Sep;249(3 Pt 2):F374–F389. doi: 10.1152/ajprenal.1985.249.3.F374. [DOI] [PubMed] [Google Scholar]
  4. Deen W. M., Troy J. L., Robertson C. R., Brenner B. M. Dynamics of glomerular ultrafiltration in the rat. IV. Determination of the ultrafiltration coefficient. J Clin Invest. 1973 Jun;52(6):1500–1508. doi: 10.1172/JCI107324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. FUHR J., KACZMARCZYK J., KRUTTGEN C. D. Eine einfache colorimetrische Methode zur Inulinbestimmung für Nieren-Clearance-Untersuchungen bei Stoffwechselgesunden und Diabetikern. Klin Wochenschr. 1955 Aug 1;33(29-30):729–730. doi: 10.1007/BF01473295. [DOI] [PubMed] [Google Scholar]
  6. Feldt-Rasmussen B., Dinesen B., Deckert M. Enzyme immunoassay: an improved determination of urinary albumin in diabetics with incipient nephropathy. Scand J Clin Lab Invest. 1985 Oct;45(6):539–544. doi: 10.3109/00365518509155256. [DOI] [PubMed] [Google Scholar]
  7. Fielding B. A., Price D. A., Houlton C. A. Enzyme immunoassay for urinary albumin. Clin Chem. 1983 Feb;29(2):355–357. [PubMed] [Google Scholar]
  8. Goldszer R. C., Sweet J., Cotran R. S. Focal segmental glomerulosclerosis. Annu Rev Med. 1984;35:429–449. doi: 10.1146/annurev.me.35.020184.002241. [DOI] [PubMed] [Google Scholar]
  9. Heeg J. E., de Jong P. E., van der Hem G. K., de Zeeuw D. Reduction of proteinuria by angiotensin converting enzyme inhibition. Kidney Int. 1987 Jul;32(1):78–83. doi: 10.1038/ki.1987.174. [DOI] [PubMed] [Google Scholar]
  10. Hostetter T. H., Olson J. L., Rennke H. G., Venkatachalam M. A., Brenner B. M. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol. 1981 Jul;241(1):F85–F93. doi: 10.1152/ajprenal.1981.241.1.F85. [DOI] [PubMed] [Google Scholar]
  11. Ichikawa I., Pfeffer J. M., Pfeffer M. A., Hostetter T. H., Brenner B. M. Role of angiotensin II in the altered renal function of congestive heart failure. Circ Res. 1984 Nov;55(5):669–675. doi: 10.1161/01.res.55.5.669. [DOI] [PubMed] [Google Scholar]
  12. Lavender S., Bennett J., Morse P. F., Polak A. Albumin and creatinine clearances in renal disease. Clin Sci Mol Med. 1974 Jun;46(6):775–784. doi: 10.1042/cs0460775. [DOI] [PubMed] [Google Scholar]
  13. Mohamed A., Wilkin T., Leatherdale B., Davies R. A microenzyme-linked immunosorbent assay for urinary albumin, and its comparison with radioimmunoassay. J Immunol Methods. 1984 Nov 16;74(1):17–22. doi: 10.1016/0022-1759(84)90362-4. [DOI] [PubMed] [Google Scholar]
  14. Myers B. D., Okarma T. B., Friedman S., Bridges C., Ross J., Asseff S., Deen W. M. Mechanisms of proteinuria in human glomerulonephritis. J Clin Invest. 1982 Oct;70(4):732–746. doi: 10.1172/JCI110669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Nath K. A., Kren S. M., Hostetter T. H. Dietary protein restriction in established renal injury in the rat. Selective role of glomerular capillary pressure in progressive glomerular dysfunction. J Clin Invest. 1986 Nov;78(5):1199–1205. doi: 10.1172/JCI112703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Oken D. E., Flamenbaum W. Micropuncture studies of proximal tubule albumin concentrations in normal and nephrotic rats. J Clin Invest. 1971 Jul;50(7):1498–1505. doi: 10.1172/JCI106635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Olson J. L., Hostetter T. H., Rennke H. G., Brenner B. M., Venkatachalam M. A. Altered glomerular permselectivity and progressive sclerosis following extreme ablation of renal mass. Kidney Int. 1982 Aug;22(2):112–126. doi: 10.1038/ki.1982.143. [DOI] [PubMed] [Google Scholar]
  18. Purkerson M. L., Hoffsten P. E., Klahr S. Pathogenesis of the glomerulopathy associated with renal infarction in rats. Kidney Int. 1976 May;9(5):407–417. doi: 10.1038/ki.1976.50. [DOI] [PubMed] [Google Scholar]
  19. Raij L., Azar S., Keane W. Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats. Kidney Int. 1984 Aug;26(2):137–143. doi: 10.1038/ki.1984.147. [DOI] [PubMed] [Google Scholar]
  20. Schwerer B., Bach M., Bernheimer H. ELISA for determination of albumin in the nanogram range: assay in cerebrospinal fluid and comparison with radial immunodiffusion. Clin Chim Acta. 1987 Mar 30;163(3):237–244. doi: 10.1016/0009-8981(87)90242-7. [DOI] [PubMed] [Google Scholar]
  21. Shemesh O., Deen W. M., Brenner B. M., McNeely E., Myers B. D. Effect of colloid volume expansion on glomerular barrier size-selectivity in humans. Kidney Int. 1986 Apr;29(4):916–923. doi: 10.1038/ki.1986.86. [DOI] [PubMed] [Google Scholar]
  22. Shemesh O., Ross J. C., Deen W. M., Grant G. W., Myers B. D. Nature of the glomerular capillary injury in human membranous glomerulopathy. J Clin Invest. 1986 Mar;77(3):868–877. doi: 10.1172/JCI112384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Shimamura T., Morrison A. B. A progressive glomerulosclerosis occurring in partial five-sixths nephrectomized rats. Am J Pathol. 1975 Apr;79(1):95–106. [PMC free article] [PubMed] [Google Scholar]
  24. Viets J. W., Deen W. M., Troy J. L., Brenner B. M. Determination of serum protein concentration in nanoliter blood samples using fluorescamine or 9-phthalaldehyde. Anal Biochem. 1978 Aug 1;88(2):513–521. doi: 10.1016/0003-2697(78)90451-7. [DOI] [PubMed] [Google Scholar]
  25. Voller A., Bartlett A., Bidwell D. E. Enzyme immunoassays with special reference to ELISA techniques. J Clin Pathol. 1978 Jun;31(6):507–520. doi: 10.1136/jcp.31.6.507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Wallenstein S., Zucker C. L., Fleiss J. L. Some statistical methods useful in circulation research. Circ Res. 1980 Jul;47(1):1–9. doi: 10.1161/01.res.47.1.1. [DOI] [PubMed] [Google Scholar]
  27. Weening J. J., Rennke H. G. Glomerular permeability and polyanion in adriamycin nephrosis in the rat. Kidney Int. 1983 Aug;24(2):152–159. doi: 10.1038/ki.1983.139. [DOI] [PubMed] [Google Scholar]
  28. Yoshida Y., Fogo A., Shiraga H., Glick A. D., Ichikawa I. Serial micropuncture analysis of single nephron function in subtotal renal ablation. Kidney Int. 1988 Apr;33(4):855–867. doi: 10.1038/ki.1988.77. [DOI] [PubMed] [Google Scholar]
  29. Yoshioka T., Mitarai T., Kon V., Deen W. M., Rennke H. G., Ichikawa I. Role for angiotensin II in an overt functional proteinuria. Kidney Int. 1986 Oct;30(4):538–545. doi: 10.1038/ki.1986.219. [DOI] [PubMed] [Google Scholar]
  30. Yoshioka T., Rennke H. G., Salant D. J., Deen W. M., Ichikawa I. Role of abnormally high transmural pressure in the permselectivity defect of glomerular capillary wall: a study in early passive Heymann nephritis. Circ Res. 1987 Oct;61(4):531–538. doi: 10.1161/01.res.61.4.531. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES