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. 1987 Sep;80(3):867–874. doi: 10.1172/JCI113145

Chronic glucocorticoid therapy amplifies glomerular injury in rats with renal ablation.

D L Garcia, H G Rennke, B M Brenner, S Anderson
PMCID: PMC442314  PMID: 3040810

Abstract

Functional and/or structural measurements were performed in eight groups of Munich-Wistar rats after five-sixths nephrectomy. Groups 1 and 5 received no therapy. Groups 2 and 6 received daily doses of methylprednisolone (MP). Groups 3 and 7 received MP plus the angiotensin I converting enzyme inhibitor (CEI), benzazepril. Groups 4 and 8 received CEI alone. Groups 1 through 4 underwent micropuncture study 2 wk after renal ablation. Untreated group 1 rats exhibited systemic hypertension and elevation of the single nephron glomerular filtration rate due to glomerular capillary hyperperfusion and hypertension. Administration of MP in group 2 resulted in comparable systemic hypertension, with further elevation of the single nephron glomerular filtration rate due to even higher values for glomerular perfusion and hydraulic pressure. Concurrent treatment with CEI in groups 3 and 4 controlled systemic and glomerular hypertension despite equivalent renal ablation and, in group 3, comparable doses of MP. Groups 5 through 8 were followed for 12 wk. Untreated group 1 rats demonstrated continued systemic hypertension, progressive proteinuria, and eventual glomerular sclerosis. Addition of MP in group 6 dramatically accelerated the development of proteinuria and glomerular sclerosis, while CEI (groups 7 and 8) afforded striking protection against disease progression. Thus, potent vasodilator glucocorticoids may amplify hemodynamically mediated glomerular injury, whereas control of systemic and glomerular hypertension prevents this undesirable consequence of chronic steroid therapy.

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Selected References

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  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. Anderson S., Rennke H. G., Brenner B. M. Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat. J Clin Invest. 1986 Jun;77(6):1993–2000. doi: 10.1172/JCI112528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arendshorst W. J., Beierwaltes W. H. Renal and nephron hemodynamics in spontaneously hypertensive rats. Am J Physiol. 1979 Mar;236(3):F246–F251. doi: 10.1152/ajprenal.1979.236.3.F246. [DOI] [PubMed] [Google Scholar]
  4. Austin H. A., 3rd, Klippel J. H., Balow J. E., le Riche N. G., Steinberg A. D., Plotz P. H., Decker J. L. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med. 1986 Mar 6;314(10):614–619. doi: 10.1056/NEJM198603063141004. [DOI] [PubMed] [Google Scholar]
  5. Balow J. E., Austin H. A., 3rd, Muenz L. R., Joyce K. M., Antonovych T. T., Klippel J. H., Steinberg A. D., Plotz P. H., Decker J. L. Effect of treatment on the evolution of renal abnormalities in lupus nephritis. N Engl J Med. 1984 Aug 23;311(8):491–495. doi: 10.1056/NEJM198408233110802. [DOI] [PubMed] [Google Scholar]
  6. Baylis C., Brenner B. M. Mechanism of the glucocorticoid-induced increase in glomerular filtration rate. Am J Physiol. 1978 Feb;234(2):F166–F170. doi: 10.1152/ajprenal.1978.234.2.F166. [DOI] [PubMed] [Google Scholar]
  7. Brenner B. M., Meyer T. W., Hostetter T. H. 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. 1982 Sep 9;307(11):652–659. doi: 10.1056/NEJM198209093071104. [DOI] [PubMed] [Google Scholar]
  8. Brunner F. P., Hermle M., Mihatsch M. J., Thiel G. Effect of cyclosporine in rats with reduced renal mass. Clin Nephrol. 1986;25 (Suppl 1):S148–S154. [PubMed] [Google Scholar]
  9. Carette S., Klippel J. H., Decker J. L., Austin H. A., Plotz P. H., Steinberg A. D., Balow J. E. Controlled studies of oral immunosuppressive drugs in lupus nephritis. A long-term follow-up. Ann Intern Med. 1983 Jul;99(1):1–8. doi: 10.7326/0003-4819-99-1-1. [DOI] [PubMed] [Google Scholar]
  10. Curtis J. J., Luke R. G., Dubovsky E., Diethelm A. G., Whelchel J. D., Jones P. Cyclosporin in therapeutic doses increases renal allograft vascular resistance. Lancet. 1986 Aug 30;2(8505):477–479. doi: 10.1016/s0140-6736(86)90355-7. [DOI] [PubMed] [Google Scholar]
  11. DAVIS J. O., HOWELL D. S. Comparative effect of ACTH, cortisone and DCA on renal function, electrolyte excretion and water exchange in normal dogs. Endocrinology. 1953 Mar;52(3):245–255. doi: 10.1210/endo-52-3-245. [DOI] [PubMed] [Google Scholar]
  12. DOWDLE E., SAUNDERS S. J. The acute effect of hydrocortisone sodium succinate on the proteinurea of the nephrotic syndrome. S Afr J Lab Clin Med. 1957 Mar;3(1):39–47. [PubMed] [Google Scholar]
  13. DeBermudez L., Hayslett J. P. Effect of methylprednisolone on renal function and the zonal distribution of blood flow in the rat. Circ Res. 1972 Jul;31(1):44–52. doi: 10.1161/01.res.31.1.44. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Dworkin L. D., Feiner H. D. Glomerular injury in uninephrectomized spontaneously hypertensive rats. A consequence of glomerular capillary hypertension. J Clin Invest. 1986 Mar;77(3):797–809. doi: 10.1172/JCI112377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Dworkin L. D., Hostetter T. H., Rennke H. G., Brenner B. M. Hemodynamic basis for glomerular injury in rats with desoxycorticosterone-salt hypertension. J Clin Invest. 1984 May;73(5):1448–1461. doi: 10.1172/JCI111349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. Gunn H. C., Ryffel B. Glomerulonephritis in NZB/W mice: therapeutic effect of cyclosporine. Clin Nephrol. 1986;25 (Suppl 1):S189–S192. [PubMed] [Google Scholar]
  19. Heymann W., Grupe W. E. Increase in proteinuria due to steroid medication in chronic renal disease. J Pediatr. 1969 Mar;74(3):356–363. doi: 10.1016/s0022-3476(69)80191-5. [DOI] [PubMed] [Google Scholar]
  20. Hostetter T. H., Meyer T. W., Rennke H. G., Brenner B. M. Chronic effects of dietary protein in the rat with intact and reduced renal mass. Kidney Int. 1986 Oct;30(4):509–517. doi: 10.1038/ki.1986.215. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Ichikawa I., Rennke H. G., Hoyer J. R., Badr K. F., Schor N., Troy J. L., Lechene C. P., Brenner B. M. Role for intrarenal mechanisms in the impaired salt excretion of experimental nephrotic syndrome. J Clin Invest. 1983 Jan;71(1):91–103. doi: 10.1172/JCI110756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. LEVITT M. F., BADER M. E. Effect of cortisone and ACTH on fluid and electrolyte distribution in man. Am J Med. 1951 Dec;11(6):715–723. doi: 10.1016/0002-9343(51)90022-8. [DOI] [PubMed] [Google Scholar]
  24. MORAN T. J., KURTZ S. M., VAZQUEZ J. J. Diabetic and cortisone-induced renal lesions. A morphologic and immunohistochemical study. Lab Invest. 1962 Mar;11:240–254. [PubMed] [Google Scholar]
  25. Maddox D. A., Price D. C., Rector F. C., Jr Effects of surgery on plasma volume and salt and water excretion in rats. Am J Physiol. 1977 Dec;233(6):F600–F606. doi: 10.1152/ajprenal.1977.233.6.F600. [DOI] [PubMed] [Google Scholar]
  26. Meyer T. W., Anderson S., Rennke H. G., Brenner B. M. Reversing glomerular hypertension stabilizes established glomerular injury. Kidney Int. 1987 Mar;31(3):752–759. doi: 10.1038/ki.1987.62. [DOI] [PubMed] [Google Scholar]
  27. Murray B. M., Paller M. S., Ferris T. F. Effect of cyclosporine administration on renal hemodynamics in conscious rats. Kidney Int. 1985 Nov;28(5):767–774. doi: 10.1038/ki.1985.196. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Neild G. H., Ivory K., Williams D. G. Effect of cyclosporine on proteinuria in chronic serum sickness in rats. Clin Nephrol. 1986;25 (Suppl 1):S186–S188. [PubMed] [Google Scholar]
  30. OPPENHEIMER E. H., ESTERLY J. R. GLOMERULAR LESIONS IN THE NEPHROTIC SYNDROME AND THEIR RELATION TO CORTISONE THERAPY. Bull Johns Hopkins Hosp. 1963 Sep;113:158–172. [PubMed] [Google Scholar]
  31. 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]
  32. Olson J. L., Wilson S. K., Heptinstall R. H. Relation of glomerular injury to preglomerular resistance in experimental hypertension. Kidney Int. 1986 Apr;29(4):849–857. doi: 10.1038/ki.1986.76. [DOI] [PubMed] [Google Scholar]
  33. PECHET M. M., BOWERS B., BARTTER F. C. Metabolic studies with a new series of 1, 4-diene steroids. II. Effects in normal subjects of prednisone, prednisolone, and 9 alpha-fluoroprednisolone. J Clin Invest. 1959 Apr;38(4):691–701. doi: 10.1172/JCI103848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. POLLAK V. E., PIRANI C. L., KARK R. M. Effect of large doses of prednisone on the renal lesions and life span of patients with lupus glomerulonephritis. J Lab Clin Med. 1961 Apr;57:495–511. [PubMed] [Google Scholar]
  35. Pfeffer J. M., Pfeffer M. A., Frohlich E. D. Validity of an indirect tail-cuff method for determining systolic arterial pressure in unanesthetized normotensive and spontaneously hypertensive rats. J Lab Clin Med. 1971 Dec;78(6):957–962. [PubMed] [Google Scholar]
  36. Raij L., Azar S., Keane W. F. Role of hypertension in progressive glomerular immune injury. Hypertension. 1985 May-Jun;7(3 Pt 1):398–404. [PubMed] [Google Scholar]
  37. Stein H. D., Sterzel R. B., Hunt J. D., Pabst R., Kashgarian M. No aggravation of the course of experimental glomerulonephritis in spontaneously hypertensive rats. Am J Pathol. 1986 Mar;122(3):520–530. [PMC free article] [PubMed] [Google Scholar]
  38. Steinberg A. D., Gelfand M. C., Hardin J. A., Lowenthal D. T. Therapeutic studies in NZB/W mice. III. Relationship between renal status and efficacy of immunosuppressive drug therapy. Arthritis Rheum. 1975 Jan-Feb;18(1):9–14. doi: 10.1002/art.1780180102. [DOI] [PubMed] [Google Scholar]
  39. Steinberg A. D. The treatment of lupus nephritis. Kidney Int. 1986 Nov;30(5):769–787. doi: 10.1038/ki.1986.254. [DOI] [PubMed] [Google Scholar]
  40. Steinberg E. B., Smith H. R., Steinberg A. D. Cyclophosphamide therapy in murine lupus: effect of combining multiple subsets into a single randomized study. Arthritis Rheum. 1983 Oct;26(10):1293–1294. doi: 10.1002/art.1780261024. [DOI] [PubMed] [Google Scholar]
  41. Striker G. E., Nagle R. B., Kohnen P. W., Smuckler E. A. Response to unilateral nephrectomy in old rats. Arch Pathol. 1969 Apr;87(4):439–442. [PubMed] [Google Scholar]
  42. Thaiss F., Mihatsch M. J., Batsford S., Vogt A., Schollmeyer P. Effect of cyclosporine on in situ immune complex glomerulonephritis. Clin Nephrol. 1986;25 (Suppl 1):S181–S185. [PubMed] [Google Scholar]
  43. 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]
  44. 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]
  45. Wetzels J. F., Gerlag P. G., Sluiter H. E., Hoitsma A. J., Koene R. A. Prednisone-induced fluctuations of proteinuria in patients with a nephrotic syndrome. Nephron. 1986;44(4):344–350. doi: 10.1159/000184017. [DOI] [PubMed] [Google Scholar]
  46. Zatz R., Dunn B. R., Meyer T. W., Anderson S., Rennke H. G., Brenner B. M. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest. 1986 Jun;77(6):1925–1930. doi: 10.1172/JCI112521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Zatz R., Meyer T. W., Rennke H. G., Brenner B. M. Predominance of hemodynamic rather than metabolic factors in the pathogenesis of diabetic glomerulopathy. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5963–5967. doi: 10.1073/pnas.82.17.5963. [DOI] [PMC free article] [PubMed] [Google Scholar]

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