Immunopathology of Tubulo-Interstitial Nephritis in Man and in Experimental Animals

  • T. Sugisaki
  • G. Andres
Part of the Ettore Majorana International Science Series book series (EMISS, volume 9)


It is generally acknowledged that many forms of glomerular diseases are antibody-mediated, either as a result of deposition of circulating immune complexes or due to anti-glomerular basement membrane antibodies. Until recently little consideration was given to the possibility that there might be comparable forms of diseases involving other parts of the kidney. However, there is now clear evidence, obtained both in experimental models and human disease, that tubular and interstitial lesions can result from deposition or local formation of immune complexes or because of antibodies directed against tubular basement membranes or against the brush border of proximal convoluted tubules. Moreover, it appears that the renal interstitium is a site where cell-mediated reactions may occur, accounting for some forms of interstitial nephritis.

We shall discuss in sequence experimental models of immunologically-mediated tubular and interstitial renal diseases and the evidence concerning the occurrence and probable significance of corresponding lesions in man.


Immune Complex Interstitial Nephritis Proximal Convoluted Tubule Brown Norway Tubulointerstitial Nephritis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Andres, G. A., Accinni, L., Hsu, K.C., Penn, I., Porter, K.A., Randall, J.M., Seegal, B. C. and Starzl, T.E.: Human renal transplants. III. Immunopathologic studies. Lab. Invest. 22: 588–604, (1970).Google Scholar
  2. 2.
    Andres, G.A., Albini, B. and Ossi, E.: Pathogenesis, diagnosis, prognosis and treatment of immunologically mediated tubulo- interstitial nephritis. In: Prevention of Kidney and Urinary Tract Diseases, Fogarty International Center Series on Preventive Medicine., Coggins, C.H. and Cummings, W.B., eds. Vol. 5, pp. 251–262 (DHEW, NIH, Bethesda, 1978).Google Scholar
  3. 3.
    Andres, G.A., Brentjens, J. Kohli, R., Anthone, R., Anthone, S., Baliah, T., Montes, M., Mookerjee, B., Prezyna, A., Sepulveda, M., Venuto, T. and Elwood, C.: Histology of human tubulo- interstitial nephritis associated with antibodies to renal basement membranes. Kidney Int. 13: 480–491, (1978).CrossRefGoogle Scholar
  4. 4.
    Andres, G.A. and McCluskey, R.T.: Tubular and interstitial renal disease due to immunologic mechanisms. Kidney Int. 7: 271–289, (1975).CrossRefGoogle Scholar
  5. 5.
    Baldwin, D.S., Levine, B.B., McCluskey, R.T. and Gallo, G.R.: Renal failure and interstitial nephritis due to penicillin and methicillin. New Engl. J. Med. 279: 1245–1252, (1968).CrossRefGoogle Scholar
  6. 6.
    Bergstein, J. and Litman, N.: Interstitial nephritis with anti- tubular basement membrane antibody. New Eng. J. Med. 292: 875–878, (1975).CrossRefGoogle Scholar
  7. 7.
    Border, W., Lehman, D., Egan, J., Sass, H., Glode, J. and Wilson, C.B.: Antitubular basement membrane antibodies in methicillin-associated interstitial nephritis. New. Engl. J. Med. 291: 381–384, (1974).CrossRefGoogle Scholar
  8. 8.
    Brentjens, J., O’Connell, D., Pawloski, I. and Andres, G.A.: Extraglomerular lesions associated with depoöitibn of circulating antigen-antibody complexes in kidneys of rabbits with chronic serum sickness. Clin. Immunol. Immunopath. 3: 112–122, (1974).CrossRefGoogle Scholar
  9. 9.
    Brentjens, J., Sepulveda, M., Baliah, T., Bentzel, C., Erlanger, B., Elwood, C., Montes, M., Hsu, K. and Andres, G.A.: Interstitial immune complex nephritis in patients with systemic lupus erythematosus- Kidney Int. 7: 342–350, (1975).Google Scholar
  10. 10.
    Brod, J. and Benesova, D.: A comparative study of fuctional and morphological renal changes in glomerulonephritis. Acta Med. Scand. 157: 23–32, (1957).CrossRefGoogle Scholar
  11. 11.
    Case records of the Massachusetts General Hospital: Case 2 – 1976. New Engl. J. Med. 294: 100–105, (1976).Google Scholar
  12. 12.
    Chesvey, R., O’Regon, S., Guyda, H.Y. and Drummond, K.N.: Candida endocrinopathy syndrome with membranoproliferative glomerulonephritis: demonstration of glomerular Candida antigen. Clin. Nephrol. 5: 232–238, (1976).Google Scholar
  13. 13.
    Cochrane, C.G.: Mechanisms involved in deposition of immune complexes in tissue. J. Exp. Med. 134: (Pt. 2): 75s-89s, (1971).CrossRefGoogle Scholar
  14. 14.
    Colvin, R.B., Burton, N.E., Hyslop, N. E. Jr., Spitz, L, and Lichtenstein, N.S.: Penicillin-associated interstitial nephritis. Ann. Int. Med. 81: 404–405, (1974).Google Scholar
  15. 15.
    Cotran, R.S. and Peissens, W.F.: Pathogenesis 03 chronic pyelonephritis. Proc. Int. Congr. Nephrol., 6th, pp. 509–523 (Karger- Basel, 1976).Google Scholar
  16. 16.
    Couser, W. and Salant, G.: In situ immune complex formation and glomerular injury. Kidney Int. 17: 1–14, (1980).CrossRefGoogle Scholar
  17. 17.
    Faarup, P. and Cristensen, E.: IgE containing plasma cells in acute tubulo-interstitial nephropathy. Lancet 2: 718, (1974).CrossRefGoogle Scholar
  18. 18.
    Fleuren, G., Grond, J. and Hoedemacker, P.J.: In situ formation of subepithelial glomerular immune complexes in passive serum sickness. Kidney Int. 17: 631–637, (1980).CrossRefGoogle Scholar
  19. 19.
    Gelfand, M.C., Frank, M.M., Green, I, and Shin, M.L.: Binding sites of immune complexes containing IgG in the renal inter- stitium. Clin. Immunol. Immunopath. 13: 19–29, (1979).CrossRefGoogle Scholar
  20. 20.
    Grupe, W.E.: An “in vitro” demonstration of cellular sensitivity in experimental autoimmune nephrosis in rats. Proc. Soc. Exp. Biol. Med. 127: 1217–1222, (1968).Google Scholar
  21. 21.
    Harner, M.H., Nolte, M., Wilson, C.B., Talwalker, Y.B., Musgrave, J.E., Brooks, R.E. and Campbell, R.A.: Anti-tubular basement membrane antibody and nephrotic syndrome associated with milk hypersensitivity. Abstr. 3rd Int. Symp. Pediat. Nephrol., Washington, p. 8 (1974).Google Scholar
  22. 22.
    Heptinstall, R.H.: Interstitial nephritis; a brief review. Amer. J. Pathol. 83: 214–236, (1976).Google Scholar
  23. 23.
    Heymann, W., Hackel, D.B., Harwood, S., Wilson, S.G.F. and Hunter, J.L.P.: Production of nephrotic syndrome in rats by Freund’s adjuvant and rat kidney suspension. Proc. Soc. Exp. Biol. Med. 100: 660–664, (1959).Google Scholar
  24. 24.
    Hozer, J.R.: Tubulointerstitial immune complex nephritis in rats immunized with Tamm~Horsfall protein. Kidney Int. 17: 284–292, (1980).CrossRefGoogle Scholar
  25. 25.
    Hyman, L.R., Ballow, M. and Knieser, M.R.: Diphenylhydantoin nephropathy: Evidence for an autoimmune pathogenesis. Kidney Int. 8: 450, (1975) (Abstr.)Google Scholar
  26. 26.
    Hyman, L.R., Colvin, R.B. and Steinberg, A.D.: Immunopatho- genesis of autoimmune tubulointerstitial nephritis. I. Demonstration of differential susceptibility in strain II and strain XIII guinea pigs. J. Immunol. 116: 327–335, (1976).Google Scholar
  27. 27.
    Hyman, L.R., Steinberg, A.D., Colvin, R.B. and Bernard, E.F.: Immunopathogenesis of autoimmune tubulointerstitial nephritis. II. Role of an immune response gene linked to the major histocompatibility locus. J. Immunol. 117: 1894–1897, (1977).Google Scholar
  28. 28.
    Kawowski, S., McKay, D.G.: Howes, E. L. Jr., Csavossy, I. and Wolfson, M.: Multinucleated giant cells in antiglomerular basement membrane antibody-induced glomerulonephritis. Nephron 16: 415–426, (1976).CrossRefGoogle Scholar
  29. 29.
    Klassen, J., Andres, G., Brennen, J. and McCluskey, R.T.: An immunologic renal tubular lesion in man. Clin. Immunol. Immunopath. 1: 69–83, (1972).CrossRefGoogle Scholar
  30. 30.
    Klassen, J., Kano, K., Milgrom, F., Menno, A., Anthone, R., Sepulveda, M., Elwood, C. and Andres, G.A.: Tubular lesions produced by autoantibodies to tubular basement membranes in human renal allografts. Int. Arch. All. Appl. Immunol. 45: 675–689, (1973).CrossRefGoogle Scholar
  31. 31.
    Klassen, J., McCluskey, R.T. and Milgrom, F.: Nonglomerular renal disease produced in rabbits by immunization with homologous kidney. Amer. J. Pathol. 63: 333–350, (1971).Google Scholar
  32. 32.
    Klassen, J. and Milgrom, F.: Autoimmune concomitants of renal allografts. Transplant. Proc. 1: 605–608, (1969).Google Scholar
  33. 33.
    Klassen, J., Sugisaki, T., Milgrom, F. and McCluskey, R.T.: Studies on multiple renal lesions in Heymann nephritis. Lab. Invest. 25: 571–585, (1971).Google Scholar
  34. 34.
    Lehman, D.H., Lee, S., Wilson, C.B. and Dixon, F.J.: Induction of antitubular basement membrane antibodies in rats by renal transplantation. Transplantation 17: 429–431, (1976).CrossRefGoogle Scholar
  35. 35.
    Lehman, D.H.; Marquardt, H., Wilson, C.B. and Dixon, F.J.: Specificity of autoantibodies to tubular and glomerular basementmembranes induced in guinea pigs. J. Immunol. 112: 241–248, (1974).Google Scholar
  36. 36.
    Lehman, D.H. and Wilson, C.B.: Role of sensitized cells in antitubular basement membrane interstitial nephritis. Int. Arch. All. Appl. Immunol. 51: 168–176, (1976).CrossRefGoogle Scholar
  37. 37.
    Lehman, D.H., Wilson, C.B. and Dixon, F.J.: Interstitial nephritis in rats immunized with heterologous tubular basement membrane. Kidney Int. 5: 187–195, (1974).CrossRefGoogle Scholar
  38. 38.
    Lehman, D.H., Wilson, C.B. and Dixon, F.J.: Extraglomerular immunoglobulin deposits in human nephritis. Amer. J. Med. 58: 765:786, (1975).CrossRefGoogle Scholar
  39. 39.
    Levy, M., Gagnadoux, M.F., Beziall, A. and Habib, R.: Membranous glomerulonephritis associated with antitubular and antialveolar basement membrane antibodies. Clin. Nephrol. 10: 158–165, (1978).Google Scholar
  40. 40.
    Levy, M., Gagnadoux, M.F. and Habib, R.: An immunologic Fanconi syndrome. Int. Symp. Pediat. Nephrol., 3rd, Washington, D.C. (1974).Google Scholar
  41. 41.
    Lewis, E.J., Cavallo, J.A., Harrington, J.T. and Cotran, R.S.: An immunopathologic study on rapidly progressive glomerulonephritis in the adult. Human Pathol. 2: 185–208, (1971).CrossRefGoogle Scholar
  42. 42.
    Letwin, A., Adams, L.E., Levy, R., Cline, S. and Hess, E.B.: Cellular immunity in experimental glomerulonephritis of rats: I. Delayed hypersensitivity and lymphocyte stimulation studies with renal tubular antigen. Immunology 20: 755–766, (1971).Google Scholar
  43. 43.
    McCluskey, R.T. and Klassen, J.: Immunologically mediated glomerular tubular and interstitial renal disease. New. Engl. J. Med. 288: 564–570, (1973).CrossRefGoogle Scholar
  44. 44.
    McLeish, K. Senitzer, D. and Gohara, A.: Acute interstitial nephritis in a patient with aspirin hypersensitivity. Clin. Immunol. Immunopath. 14: 64–69, (1979).CrossRefGoogle Scholar
  45. 45.
    McPhaul, J.J. and Dixon, F.J.: Characterization of human anti- glomerular basement membrane antibodies eluated from glomerulo- nephritic kidneys. Clin. Invest. 49: 308–317, (1970).CrossRefGoogle Scholar
  46. 46.
    Morel-Maroger, L., Kourilsky, O. Mignon, F. and Richet, G.: Antitubular basement membrane antibodies in rapidly progressive poststreptococcal glomerulonephritis. Clin. Immunol. Immunopath. 2: 185–194, (1974).CrossRefGoogle Scholar
  47. 47.
    Muehrcke, C., Kark, R.M., Pirani, C.L. and Pollak, V.E.: Lupus nephritis, a clinical and pathologic study based on renal biopsies. Medicine (Baltimore) 36: 1–145, (1957).Google Scholar
  48. 48.
    Naruse, F., Kitamura, K., Miyakawa, Y. and Shibata, S.: Depo- sition of renal tubular antigen along the glomerular capillary walls of patients with membranous glomerulonephritis. J. Immunol. 110: 1163–1166, (1973).Google Scholar
  49. 49.
    Nicastri, A.D., Chen, C.K., Rao, T.K.S., Ginzler, E.M., Kaplan, D. and Friedman, E.A.: Renal disease with tubular immunofluorescence deposits. Kidney Int. 8: 452, (1975) (Abstr:).Google Scholar
  50. 50.
    Noble, B., Mendrick, D., Brentjens, J.R. and Andres, G.A.: Damage of renal proximal tubules by passive transfer of homologous brush border antibodies. Fed. Proc. 39, I: 815A, (1980).Google Scholar
  51. 51.
    Olsen, S. and Asklund, M.: Interstitial nephritis with acute renal failure following cardiac surgery and treatment with methicillin. Acta Med. Scand. 99: 305–310, (1976).Google Scholar
  52. 52.
    Ooi, B.S., First, M.R., Pesce, A.J., Pollak, V.E., Bernstein, I.L. and lag, W.: IgE levels in interstitial nephritis. Lancet 1: 1254–1256, (1974).CrossRefGoogle Scholar
  53. 53.
    Ozawa, T., Boedecker, E.A., Scharr, W., Guggenheim, S. and Mcintosh, R.M.: Immune-complex disease with unilateral renal vein thrombosis. Arch. Path. 100: 279–282, (1976).Google Scholar
  54. 54.
    Paul, L., Van Es, L., Stuffers-Heiman, M., Brutel,. Riviere, G. and Kalff, M. Antibodies directed against tubular basement membranes in human renal allograft recipients. Clin. Immunol. Immunopath. 14: 231–237, (1979).CrossRefGoogle Scholar
  55. 55.
    Proskey, A.J., Weatherbee, L., Esterling, R.E., Greene, J.A. and Weiler, J.M.: Goodpasture’s syndrome. A report of five cases and review of the literature. Amer. J. Med. 48: 162–173, (1970).CrossRefGoogle Scholar
  56. 56.
    Risdon, R.A., Sloper, J.C. and de Wardener, H.E.: Relationship between renal function and histological changes found in renal biopsy specimens from patients with persistent glomerular nephritis. Lancet. 2: 263–266, (1968).Google Scholar
  57. 57.
    Rudofsky, U.H., McMaster, P.R.B., Ma, W., Steblay, R.W. and Pollara, B.: Experimental autoimmune renal cortical tubulo- interstitial disease in guin a pigs lacking the fourth component of complement (C4). J. Immunol. 112: 1387–1393, (1974).Google Scholar
  58. 58.
    Rudofsky, U.H., Steblay, R.W. and Pollara, B.: Inhibition of experimental autoimmune renal tubulointerstitial disease in guinea pigs by depletion of complement with cobra venom factor. Clin. Immunol. Immunopath. 3: 396–402, (1975).CrossRefGoogle Scholar
  59. 59.
    Shwayder, M., Ozawa, T., Boedecker, E., Guggenheim, S. and Mcintosh, R.H.: Nephrotic syndrome associated with Fanconi syndrome. Immunopathogenic studies of tubulointerstitial nephritis with autologous immune-complex glomerulonephritis. Ann. Intern. Med. 84: 432–437, (1976).Google Scholar
  60. 60.
    Sloper, J.C., de Wardener, H. and Woodrow, D.F.: Relationship between renal structure and function deduced from renal biopsies. In: Renal Pathophysiology. Leaf, A, Giebisch, G., Bolis, L. and Gorini, S. eds. pp. 109–120 (Raven Press, New York, 1980).Google Scholar
  61. 61.
    Steblay, R.W. and Rudofsky, U.H.: Transfer of experimental autoimmune renal cortical tubular and interstitial disease in guinea pigs by serum. Science 180: 966–968, (1973).ADSCrossRefGoogle Scholar
  62. 62.
    Steblay, R.W. and Rudofsky, U.H.: Renal tubular disease and autoantibodies against tubular basement membrane induced in guinea pigs. J. Immunol. 107: 589–594, (1971).Google Scholar
  63. 63.
    Strauss, J., Pardo, V., Koss, M.N., Griswold, W. and Mcintosh, M.: Nephropathy associated with sickle cell anemia: An autologous immune complex nephritis. Amer. J. Med. 58: 382–387, (1975).CrossRefGoogle Scholar
  64. 64.
    Sugisaki, T., Klassen, J., Andres, G.A., Milgrom, F. and McCluskey, R.T.: Species specific renal lesions in different rat strains. VI Intern. Cong. Nephrol. (Abstr.), Firenze, Italy, p. 304, (1975).Google Scholar
  65. 65.
    Sugisaki, T., Klassen, J., Milgrom, G., Andres, G.A. and McCluskey, R.T.: Immunopathologic study of an autoimmune tubular and interstitial renal disease in Brown Norway rats. Lab. Invest. 28: 658–671, (1973).Google Scholar
  66. 66.
    Sugisaki, T., Yoshida, T., McCluskey, R.T., Andres, G.A. and Klassen, J.: Autoimmune cell-mediated tubulointerstitial nephritis induced in Lewis rats by renal antigens. Clin. Immunol, Immunopath. 15: 33–43, (1980).CrossRefGoogle Scholar
  67. 67.
    Sutton, J. and Weiss, L.: Transformation of monocytes in tissue culture into macrophages, epithelial cells and multinucleated giant cells. An electron microscopic study. J. Cell. Biol. 28: 303–332, (1966).CrossRefGoogle Scholar
  68. 68.
    Tung, K. and Black, W.: Association of renal glomerular and tubular immune complex disease and antitubular basement membrane antibody. Lab. Invest. 32: 696–700, (1975).Google Scholar
  69. 69.
    Van Zwieten, M.J., Bhan, A.K., McCluskey, R.T. and Collins, A.B.: Studies on the pathogenesis of experimental anti-tubular basement membrane nephritis in the guinea pig. Amer. J. Pathol. 83: 531–546, (1976).Google Scholar
  70. 70.
    Van Zwieten, M.J., Leber, P.D., Bhan, A.K, and McCluskey, R.T.: Experimental cell mediated interstitial nephritis induced with exogenous antigens. J. Immunol. 118: 589–593, (1977).Google Scholar
  71. 71.
    Wilson, C.B. and Dixon, F.L.: Antiglomerular basement membrane antibody-induced glomerulonephritis. Kidney Int. 3: 74–89, (1973).CrossRefGoogle Scholar
  72. 72.
    Wilson, C.B., Lehman, D., McCoy, R., Gunnels, J. and Stubel, D.: Antitubular basement membrane antibodies after renal transplantation. Transplantation, 18: 447–452, (1974).CrossRefGoogle Scholar
  73. 73.
    Wilson, C.B. and Dixon, F.J.: Diagnosis of immunopathologic renal disease. Editorial, Kidney Int. 5: 389–401, (1974).CrossRefGoogle Scholar
  74. 74.
    Wilson, C.B. and Dixon, F.J.: The renal response to immunological injury. In: The Kidney. Brenner, B.M. and Rector, F.C. Jr., eds. Vol. II, pp. 838–940 (W.B. Saunders Co., Philadelphia, 1976).Google Scholar
  75. 75.
    Wilson, C.B. and Dixon, F.J.: Renal injury from immune reactions involving antigens in or of the kidney. In: Immunologic Mechanisms of Renal Disease. Wilson, C.B., Brenner, B.M. and Stein, J.H., eds., pp. 35–66 (Churchill Livingstone, New York, 1979).Google Scholar

Copyright information

© Plenum Press, New York 1981

Authors and Affiliations

  • T. Sugisaki
    • 1
  • G. Andres
    • 1
  1. 1.Departments of Microbiology, Pathology and MedicineState University of New York at BuffaloBuffaloUSA

Personalised recommendations