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The pathophysiology of Sandimmune (cyclosporine) in man and animals

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Abstract

Part I: The side-effects of Sandimmune that have been of most significance clinically are renal dysfunction, renal vascular damage and arterial hypertension. To examine the nature and the origin of such effects, the actions of Sandimmune on the renal tubule, the renal vessels and systemic vessels have been analyzed. To evaluate whether common vasoconstrictory systems may be involved, changes in the renin-angiotensin-aldosterone system and prostaglandin-thromboxane system have been assessed. Comparison between animal and human data obtained in vivo and in vitro shows the actions of Sandimmune on the renal tubule to be modest and involve only a few specific effects. The major action of Sandimmune is on the vessels, vasoconstriction being the major cause of renal dysfunction and also the cause of arterial hypertension. Neither the circulating renin-angiotension-aldosterone system nor the prostaglandin-thromboxane system is clearly responsible for vasoconstriction. Although not itself a vasoconstrictor, Sandimmune seems to modulate the constrictory and dilatory response to other agents in several vascular beds.

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References

  1. Farthing MJG, Clark ML, Pendry A, Sloane J, Alexander P (1981) Nature of the toxicity of cyclosporin A in the rat. Biochem Pharmacol 30: 3311–3316

    PubMed  Google Scholar 

  2. Blair JT, Thomson AW, Whiting PH, Davidson RJL, Simpson JG (1982) Toxicity of the immune suppressant cyclosporin A in the rat. J Pathol 138: 163–178

    PubMed  Google Scholar 

  3. Bertani T, Perico N, Abbate M, Battaglia C, Remuzzi G (1987) Renal injury induced by long-term administration of cyclosporin A to rats. Am J Pathol 127: 569–579

    PubMed  Google Scholar 

  4. Gillum DM, Truong L, Tasby J, Migliore P, Suki WN (1988) Chronic cyclosporine nephrotoxicity. A rodent model. Transplantation 46: 285–292

    PubMed  Google Scholar 

  5. Mihatsch MJ, Ryffel B, Hermle M, Brunner FP, Thiel G (1986) Morphology of cyclosporine nephrotoxicity in the rat. Clin Nephrol 25 [Suppl 1]: S2-S8

    PubMed  Google Scholar 

  6. Whiting PH, Propper DJ, Simpson JG, McKay J, Jones MC, Catto GRD (1988) The use of lithium clearance measurements to assess renal tubular function in experimental and clinical cyclosporine nephrotoxicity. Transplant Proc 20 [Suppl 3]: 675–680

    Google Scholar 

  7. Tejani A, Lancman I, Pomrantz, A, Khawar M, Chen C (1988) Nephrotoxicity of cyclosporine A and cyclosporine G in a rat model. Transplantation 45: 184–187

    PubMed  Google Scholar 

  8. Teraoka S, Sanaka T, Takahashi K, Toma H, Yamaguchi Y, Yagisawa T, Tanabe K, Sato H, Matsumura O, Nakajima I, Kawai T, Honda H, Fuchinoue S, Agishi T, Ota K (1988) Stimulation of intrinsic prostacyclin synthesis and inhibition of thromboxane production to minimize cyclosporine nephrotoxicity. Transplant Proc 20 [Suppl 3]: 638–645

    PubMed  Google Scholar 

  9. English J, Evan A, Houghton DC, Bennett WM (1987) Cyclosporine-induced acute renal dysfunction in the rat. Evidence of arteriolar vasoconstriction with preservation of tubular function. Transplantation 44: 135–141

    PubMed  Google Scholar 

  10. Whiting PH, Simpson JG (1988) Lithium clearance measurements as an indication of cyclosporin A nephrotoxicity in the rat. Clin Sci 74:173–178

    PubMed  Google Scholar 

  11. Whiting PH, Cunningham C, Thomson AW, Simpson JG (1984) Enhancement of high dose cyclosporin A toxicity by frusemide. Biochem Pharmacol 33: 1075–1079

    PubMed  Google Scholar 

  12. McAuley FT, Simpson JG, Thomson AW, Whiting PH (1987) Cyclosporin A-induced nephrotoxicity in the rat: relationship to increased plasma renin activity. Agents Actions. 21:209–216

    PubMed  Google Scholar 

  13. Jackson NM, Hsu CH, Visscher GE, Venkatachalam MA, Humes HD (1987) Alterations in renal structure and function in a rat model of cyclosporine nephrotoxicity. J Pharmacol Exp Ther 242:749–756

    PubMed  Google Scholar 

  14. Simpson JG, Saunders NJ, Thomson KJ, Whiting PH (1988) Chronic renal damage caused by cyclosporine. Transplant Proc 20 [Suppl 3]: 792–799

    PubMed  Google Scholar 

  15. Dieperink H, Leyssac PP, Starklint H, Kemp E (1988) Long-term cyclosporin nephrotoxicity in the rat: effects on renal function and morphology. Nephrol Dial Transplant 3:317–326

    PubMed  Google Scholar 

  16. Wong NLM, Dirks JH (1988) Cyclosporine-induced hypomagnesaemia and renal magnesium wasting in rats. Clin Sci 75: 509–514

    PubMed  Google Scholar 

  17. Mason J, Donatsch P, Rickenbacher U (1989) Tubular function with Sandimmune® (cyclosporine A) Kidney Int 35:413

    Google Scholar 

  18. Barton CH, Vaziri ND, Mina-Araghi S, Grosby S, Seo MI (1989) Effects of cyclosporine on magnesium metabolism in rats. J Lab Clin Med 114:232–236

    PubMed  Google Scholar 

  19. Faraci M, Vigeant, C, Yale JF (1988) Toxic effects of cyclosporine A and G in Wistar rats. Transplant Proc 20 [Suppl 3]:963–968

    PubMed  Google Scholar 

  20. Evans GO (1988) Hypomagnesaemia, hypoalbuminaemia and plasma lipid changes in rats following the oral administration of cyclosporin. Comp Biochem Physiol 89C:375–376

    Google Scholar 

  21. Batlle DC, Gutterman C, Tarka J, Prasad R (1986) Effect of shortterm cyclosporin A administration on urinary acidification. Clin Nephrol 25 [Suppl 1]: S62-S69

    PubMed  Google Scholar 

  22. Erman A, Chen-Gal B, Rosenfeld J (1989) The role of eicosanoids in cyclosporine nephrotoxicity in the rat. Biochem Pharmacol 38: 2153–2157

    PubMed  Google Scholar 

  23. Petric R, Freeman D, Walace C, McDonald J Stiller C, Keown P (1988) Effect of cyclosporine on urinary prostanoid excretion, renal blood flow and glomerulotubular function. Transplantation 45: 883–889

    PubMed  Google Scholar 

  24. Dieperink H, Leyssac PP, Starklint H, Jorgensen KA Kemp E (1986) Antagonist capacities of nifedipine, captoprill phenoxybenzamine, prostacyclin and indomethacin on cyclosporin A induced impairment of rat renal function. Eur J Clin Invest 16:540–548

    PubMed  Google Scholar 

  25. Kaskel FJ, Devarajan P, Arbeit LA, Partin JS, Moore LC (1987) Cyclosporine nephrotoxicity: sodium excretion, autoregulation and angiotensin II. Am J Physiol 252:F733-F42

    PubMed  Google Scholar 

  26. Brunner LJ, Vadiei K, Iyer LV, Luke DR (1989) Prevention of cyclosporine-induced nephrotoxicity with pentoxifylline. Ren Fail 11:97–104

    PubMed  Google Scholar 

  27. Sullivan BA, Hak LF, Finn WF (1985) Changes in renal vascular resistance associated with cyclosporin toxicity in the rat. Clin Res 33: 499A

    Google Scholar 

  28. Whiting PH, Thomson AW, Simpson JG (1986) Cyclosporine and renal enzyme excretion. Clin Nephrol 25 [Suppl 1]: S100-S104

    PubMed  Google Scholar 

  29. Berty R, Adler S (1989) Cyclosporin (CsA) induced renal dysfunction and enzymuria in the rat. Kidney Int 35:401

    Google Scholar 

  30. Mihatsch MJ, Thiel G, Spichtin HP, Oberholzer M, Brunner FP, Harder F, Olivieri V, Bremer R, Ryffel B, Stöcklin E, Torhorst J, Gudat F Zollinger HU, Loertscher R (1983) Morphological findings in kidney transplants after treatment with cyclosporine. Transplant Proc 15 [Suppl 1/2]: 2821–2835

    Google Scholar 

  31. Mihatsch MJ, Thiel G, Basler V, Ryffel B, Landmann J, Overbeck J von, Zollinger HU (1985) Morphological patterns in cyclosporinetreated renal transplant recipients. Transplantation Proc 17 [Suppl 1] 101–116

    Google Scholar 

  32. Myers BD, Ross J, Newton L, Luetscher I, Perlroth M (1984) Cyclosporine-associated chronic nephropathy. N Engl J Med 311: 699–705

    PubMed  Google Scholar 

  33. Mihatsch MJ, Bach JF, Coovadia HM, Forre O, Moutsopoulos HM, Drosos AA, Siamopoulos KC, Nöel LH, Ramsaroop R, Hällgren R, Svenson K, Bohman SO (1988) Cyclosporin-associated nephropathy in patients with autoimmune diseases. Klin Wochenschr 66:43–47

    PubMed  Google Scholar 

  34. Svenson K, Bohman SO, Hällgren R (1986) Renal interstitial fibrosis and vascular changes. Occurrence in patients with autoimmune diseases treated with cyclosporine. Arch Inter Med 146:2007–2010

    Google Scholar 

  35. Klintmalm G, Bohman SO, Sundelin B, Wilczek H (1984) Interstitial fibrosis in renal allografts after 12 to 46 months of cyclosporin treatment: beneficial effect of low doses in early post-transplantation period. Lancet II:950–954

    Google Scholar 

  36. Myers, BD, Sibley R, Newton L, Tomlanovich SJ, Boshkos C, Stinson E, Luetscher JA, Whitney DJ, Krasny D, Coplon NS, Perlroth MG (1988) The long-term course of cyclosporine-associated chronic nephropathy Kidney Int 33:590–600

    PubMed  Google Scholar 

  37. Nizze H, Mihatsch MJ, Zollinger, HU (1988) Cyclosporine-associated nephropathy in patients with heart and bone marrow transplants. Clin Nephrol 30:248–260

    PubMed  Google Scholar 

  38. Myers BD, Newton L, Boshkos C, Macoviak JA, Frist WH, Derby GC, Perlroth MG, Sibley RK (1988) Chronic injury of human renal microvessels with low-dose cyclosporine therapy. Transplantation 46:694–703

    PubMed  Google Scholar 

  39. Palestine AG, Austin HA, Balow JE, Antonovych TT, Sabnis SG, Preuss HG, Nussenblatt RB (1986) Renal histopathologic alterations in patients treated with cyclosporine for uveitis. N Engl J Med 314: 1293–1298

    PubMed  Google Scholar 

  40. Miescher PA, Favre H, Chatelanat F, Mihatsch MJ (1987) Combined steroid-cyclosporin treatment of chronic autoimmune diseases. Klin Wochenschr 65:727–736

    PubMed  Google Scholar 

  41. Barton CH, Vaziri ND, Martin DC, Choi S, Alikhani S (1987) Hypomagnesemia and renal magnesium wasting in renal transplant recipients receiving cyclosporine. Am J Med 83:693–699

    PubMed  Google Scholar 

  42. Palestine AG, Austin HA, Nussenblatt RB (1986) Renal tubular function in cyclosporine-treated patients. Am J Med 81:419–424

    PubMed  Google Scholar 

  43. Ellis CN, Gorsulowsky DC, Hamilton TA, Billings JK, Brown MD, Headington JT, Cooper KD, Baadsgaard O, Duell EA, Annesley TM, Turcotte JG, Voorhees JJ (1986) Cyclosporine improves psoriasis in a double-blind study. JAMA 256:3110–3116

    PubMed  Google Scholar 

  44. European Multicentre Trial Group (1983) Cyclosporin in cadaveric renal transplantation: one-year follow-up of a multicentre trial. Lancet II:986–989

    Google Scholar 

  45. Kore BC, Whelton A, Santos G, Saral R, Watson AJ (1988) Hypertension and renal dysfunction in bone marrow transplant recipients. QJ Med 69:985–995

    Google Scholar 

  46. Lin HY, Rocher LL, McQuillan MA, Schmaltz S, Palella TD, Fox IH (1989) Cyclosporine-induced hyperuricemia and gout. N Engl J Med 321:287–292

    PubMed  Google Scholar 

  47. Chapman JR, Harding NGL, Griffiths D, Morris PJ (1985) Reversibility of cyclosporin nephrotoxicity after 3 months treatment. Lancet I:128–130

    Google Scholar 

  48. Noordzij TC, Leunissen KML, Van Hooff JP (1989) A very high incidence of gout when chronic cyclosporin therapy is combined with diuretics. Nephrol Dial Transplant 4:515

    Google Scholar 

  49. Tiller DJ, Hall BM, Horvath JS, Duggin GG, Thompson JF, Sheil AGR (1985) Gout and hyperuricaemia in patients on cyclosporin and diuretics. Lance I:453

    Google Scholar 

  50. Calne RY, Wood AJ (1985) Cyclosporin in cadaveric renal transplantation: 3-year follow-up of a European Multicentre Trial. Lancet II:549

    Google Scholar 

  51. Kahan BD, Flechner SM, Lorber MI, Golen D, Conley, S, Buren CT van (1987) Complications of cyclosporine-predinisone immunosuppression in 402 renal allograft recipients exclusively followed at a single center for from one to five years. Transplantation 43: 197–204

    PubMed  Google Scholar 

  52. Cohen SL, Boner G, Rosenfeld JB, Shmueli D, Sperling O, Yusim A, Todd-Pokropek A, Shapira Z (1987) The mechanism of hyperuricaemia in cyclosporine-treated renal transplant recipients. Transplant Proc 19:1829–1830

    PubMed  Google Scholar 

  53. Hoyer PF, Lee IJ, Oemar BS, Krohn HP, Offner G, Brodehl J (1988) Renal handling of uric acid under cyclosporin A treatment. Pediatr Nephrol 2:18–21

    PubMed  Google Scholar 

  54. Versluis DJ, Wenting GJ, Jeekel J, Weimar W (1988) The influence of cyclosporine A on proximal tubular function in renal allografts. Transplant Proc 20 [Suppl 3]: 686–690

    PubMed  Google Scholar 

  55. Tegzess AM, Son WJ van, Beelen JM, Sluiter WJ, Meijer S, Slooff MJH (1987) Improvement of renal function after conversion from cyclosporine only to predinisolone-azathioprine followed by lateonset graft failure in renal transplant patients. Transplant Proc 19: 2000–2004

    PubMed  Google Scholar 

  56. Bachem MG, Köhler B, Bauer H, Zanker B, Franz HE, Pfeiffer EF (1987) Cyclosporin A-bedingter Magnesiummangel nach Nierentransplantation. Nieren Hochdruckkr 16:279–284

    Google Scholar 

  57. Kaiser W, Biesenbach G, Kramer E, Zazgornik J (1988) Magnesium nach Nierentransplantation unter Cyclosporin A and Azathioprin/Prednisolon. Nieren Hochdruckkr 17:219–223

    Google Scholar 

  58. Allen RD, Hunnisett AG, Morris PJ (1985) Cyclosporin and magnesium. Lancet I:1283

    Google Scholar 

  59. Thompson CB, June CH, Sullivan KM, Thomas ED (1984) Association between cyclosporin neurotoxicity and hypomagnesaemia. Lancet II:1116–1120

    Google Scholar 

  60. June CH, Thompson CB, Kennedy MS, Nims J, Thomas ED (1985) Profound hypomagnesemia and renal magnesisum wasting associated with the use of cyclosporine for marrow transplantation. Transplantation 39:620–624

    PubMed  Google Scholar 

  61. June CH, Thompson CB, Kennedy MS, Loughran TP, Deeg HJ (1986) Correlation of hypomagnesemia with the onset of cyclosporine-associated hypertension in marrow transplant patients. Transplantation 41:47–51

    PubMed  Google Scholar 

  62. Krull F, Hoyer PF, Offner G, Brodehl J (1988) Renal handling of magnesium in transplanted children under cyclosporin A treatment. Eur J Pediatr 148:148–151

    PubMed  Google Scholar 

  63. Heering P, Westhoff A, Bach D, Sprenger KBG, Passlick J, Helmchen U, Grabensee B (1988) Renin-Aldosterone system and renal function under cyclosporine A. Transplant Proc 20 [Suppl 3]: 556–562

    PubMed  Google Scholar 

  64. Adu D, Turney J, Michael J, McMaster P (1983) Hyperkalaemia in cyclosporin-treated renal allograft recipients. Lancet II:370–371

    Google Scholar 

  65. Foley RJ, Hamner RW, Weimman EJ (1985) Serum potassium concentrations in cyclosporine-and azathioprine-treated renal transplant patients. Nephron 40:280–285

    PubMed  Google Scholar 

  66. Stahl RAK, Kanz L, Kudelka S, Maier B, Schollmeyer P (1985) Der Einfluss von Cyclosporin A (CyA) auf die renale Prostaglandin-E2 (PGE2)-Produktion und das Renin-Angiotensin-Aldosteron-System bei Patienten nach Nierentransplantation. Nieren Hochdruckkr 14: 417

    Google Scholar 

  67. Vincent HH, Wenting GT, Versluis DJ, Weimar W, Schalekamp MADH (1988) Impaired fractional excretion of lithium: an early marker of cyclosporine-induced changes in renal hemodynamics. Transplant Proc 20 [Suppl 3]: 681–685

    Google Scholar 

  68. Hamilton DV, Evans DB, Henderson RG, Thiru S, Calne RY, White DJG (1982) Long-term nephrotoxicity of cyclosporin A in transplantation. dia. Transplant 11: 146 159–160

    Google Scholar 

  69. Deray G, Le Hoang P, Cacoub P, Aupetit B, Mertani A, Martinez F, Rottembourg J (1988) Renal function and blood pressure in patients treated with cyclosporin A for uveitis. Eur J Clin Pharmacol 34: 601–604

    PubMed  Google Scholar 

  70. Bantle JP, Nath KA, Sutherland DER, Najarian JS, Ferris TF (1985) Effects of cyclosporine on the renin-angiotensin-aldosterone system and potassium excretion in renal transplant recipients. Arch Inter Med 145:505–508

    Google Scholar 

  71. Morales JM, Andres A, Alcazar JM, Prieto C, Diaz de Tueste I, Ruilope LM, Rodicio JL (1988) Usefulness of fractional excretion of sodium as index of cyclosporine nephrotoxicity in renal transplantation. Transplant Proc 20 [Suppl 3]: 691–699

    PubMed  Google Scholar 

  72. Dieperink H, Leyssac PP, Kemp E, Starklint H, Frandsen NE, Tvede N, Moller J, Buchler-Frederiksen P, Tossing N (1987) Nephrotoxicity of cyclosporin A in humans: effects on glomerular filtration and tubular reabsorption rates. Eur J Clin Invest 17:493–496

    PubMed  Google Scholar 

  73. Chan MK, Wong KK, Cheng KP, Li MK (1988) Clinical prevalence and significance of electrolyte disorders in cyclosporine A-treated patients. Transplant Proc 20 [Suppl 3]:705–708

    PubMed  Google Scholar 

  74. Hannedouche T, Natov S, Garev L, Marquez LP, Boitard C Bach JF, Grünfeld JP (1990) Prospective one-year follow-up study of renal function in insulin-dependent diabetics (IDD) treated by cyclosporine A (CsA). Kidney Int 37:483

    Google Scholar 

  75. Hoyer PF, Krohn HP, Offner G, Byrd DJ, Brodehl J, Wonigeit K, Pichlmayr R (1987) Renal function after kidney transplantation in children: A comparison of conventional immunosuppression with cyclosporine. Transplantation 43:489–493

    PubMed  Google Scholar 

  76. Hoyer PF, Brodehl J, Bryd DJ, Krohn HP, Oemar BS, Offner G (1988) Effect of cyclosporine on the renal tubular amino acid handling after kidney transplantation. Transplantation 46:73–78

    PubMed  Google Scholar 

  77. Greenberg A, Egel JW, Thompson ME, Hardesty, RL, Griffith BP, Bahnson HT, Bernstein RL, Hastillo A, Hess ML, Puschett J (1987) Early and late forms of cyclosporine nephrotoxiccity: studies in cardiac transplant recipients. Am J. Kidney Dis 9:12–22

    PubMed  Google Scholar 

  78. Prischl F, Gremmel F, Schwabe M, Schindler J, Balcke P, Kopsa H, Pinter G, Schwarzmeier J, Zazgornik J (1989) Beta-2-microglobulin for differentiation between ciclosporin A nephrotoxicity and graft rejection in renal transplant recipients. Nephron 51:330–337

    PubMed  Google Scholar 

  79. Berg KJ, Forre O, Bjerkhoel F, Amundsen E, Djoseland O Rugstad HE, Westre B (1986) Side effects of cyclosporin A treatment in patients with rheumatoid arthritis. Kidney Int 29:1180–1187

    PubMed  Google Scholar 

  80. Berg KJ, Forre O, Djoseland O, Mikkelsen M, Narverud J, Rugstad HE (1989) Renal side effects of high and low cyclosporin A doses in patients with rheumatoid arthritis. Clin Nephrol 31:232–238

    PubMed  Google Scholar 

  81. Heering P, Grabensee B (1989) Evaluation of tubular function after renal transplantation under application of cyclosporin A. Nephrol Dial Transplant 4:514–515

    Google Scholar 

  82. Dawnay A, Lucey MR, Thornley C, Beetham R, Neuberger JM, Cattell WR, Williams R (1988) The effects of long-term low-dose cyclosporine A on renal tubular function in humans. Transplant Proc 20 [Suppl 3]: 725–731

    Google Scholar 

  83. Spragg J, Weinblatt ME, Coblyn J, Fraser P, Austen KF (1988) Effect of cyclosporine on urinary kallikrein excretion in patients with rheumatoid arthritis (RA). J Lab Clin Med 112:324–332

    PubMed  Google Scholar 

  84. Gajraj M, Campbell SK, Albano JDM, Venkat Raman G (1989) Urinary kallikrein excretion in cyclosporin-treated renal allograft recipients. Clin Sci 77 [Suppl 21]: 30P

    Google Scholar 

  85. Hillis AN, Knowlden J, Avis P, Horton J, Wiliams JD (1987) Cyclosporin A-induced distal tubular dysfunction is reflected by impaired generation of Tamm-Horsfall glycoprotein. Nephrol Dial Transplant 2:458–459

    Google Scholar 

  86. Versluis DJ, Wenting GJ, Jeekel J, Weimar W (1987), Cyclosporine A-related proximal tubular dysfunction: impaired handling of uric acid. Transplantation Proc 19:4029–4030

    Google Scholar 

  87. West C, Carpenter BJ, Hakala TR (1987) The incidence of gout in renal transplant recipients. Am J Kidney Dis 10:369–372

    PubMed  Google Scholar 

  88. Tomlanovich S, Golbetz H, Perlroth M, Stinson E, Myers BD (1986) Limitations of creatinine in quantifying the severity of cyclosporine-induced chronic nephropathy. Am J Kidney Dis 8:332–337

    PubMed  Google Scholar 

  89. Fcutren G (1988) Functional consequences and risk factors of chronic cyclosporine nephrotoxicity in type 1 diabetes trials. Transplant Proc 20 [Suppl 4]:356–366

    Google Scholar 

  90. Perico N, Zoja C, Benigni A, Ghilardi F, Gualandris L, Remuzzi G (1986) Effect of short-term cyclosporine administration in rats on renin-angiotensin and thromboxane A2: possible relevance to the reduction in glomerular filtration rate. J Pharmacol Exp Ther 239: 229–235

    PubMed  Google Scholar 

  91. Perico N, Benigni A, Zoja C, Delaini F, Remuzzi G (1986) Functional significance of exaggerated renal thromboxane A2 synthesis induced by cyclosporin A. Am J Physiol 251:F581-F587

    PubMed  Google Scholar 

  92. Kaskel FJ, Devarajan P, Arbeit LA, Moore LC (1988) Effects of cyclosporine on renal hemodynamics and autoregulation in rats. Transplant Proc 20 [Suppl 3]:603–609

    Google Scholar 

  93. Devarajan, P, Kaskel FJ, Arbeit LA, Moore LC (1989) Cyclosporine nephrotoxicity: blood volume, sodium conservation, and renal hemodynamics. Am J Physiol. 256:F71-F78

    PubMed  Google Scholar 

  94. Rarros EJG, Boim MA, Moura LAR, Ramos OL, Schor N (1989) Effect of acute and chronic cyclosporine administration on glomerular haemodynamics in rats. In: Bach PH, Lock EA (eds) Nephrotoxicity: in vitro to in vivo, animals to man. Plenum Press, New York, London, pp 315–323

    Google Scholar 

  95. Murray BM, Paller MS, Ferris TF (1985) Effect of cyclosporine administration on renal hemodynamics in conscious rats. Kidney Int 28:767–774

    PubMed  Google Scholar 

  96. Sullivan BA, Hak LJ, Finn WF (1985) Cyclosporine nephrotoxicity: studies in laboratory animals. Transplant Proc 17 [Suppl 1]: 145–154

    PubMed  Google Scholar 

  97. Thomson SC, Tucker BJ, Gabbai F Blantz RC (1989) Functional effects on glomerular hemodynamics of short-term chronic cyclosporine in male rats. J Clin Invest 83:960–969

    PubMed  Google Scholar 

  98. Sabbatini M, Nicola L de, Uccello F, Romano G, Veniero P, Esposito C, Sepe V, Fuiano G, Dal Canton A, Andreucci VE (1989) Effects of chronic cyclosporine treatment on glomerular dynamics. Nephrol Dial Transplant 4:516

    Google Scholar 

  99. Sabbatini M, Esposito C, Uccello F, Nicola L de, Alba M, Conte G, Dal Canton A, Andreucci VE (1988) Acute effects of cyclosporine on glomerular dynamics-micropuncture study in the rat. Transplant Proc 20 [Suppl 3]:544–548

    PubMed  Google Scholar 

  100. Barros EJG, Boim MA, Ajzen H, Ramos OL, Schor N (1987) Glomerular hemodynamics and hormonal participation on cyclosporine nephrotoxicity. Kidney Int 32:19–25

    PubMed  Google Scholar 

  101. Kon V, Sugiura M, Inagami T, Hoover RL, Fogo A, Harvie BR, Ichikawa I (1990) Cyclosporine (Cy) causes endothelin-dependent acute renal failure. Kidney Int 37:486

    Google Scholar 

  102. Schwass DE, Sasaki AW, Houghton DC, Benner KE, Bennett WM (1986) Effect of phenobarbital and cimetidine on experimental cyclosporine nephrotoxicity: preliminary observations. Clin Nephrol 25 [Suppl 1]:S117-S120

    PubMed  Google Scholar 

  103. Yagisawa T, Takahashi K, Teraoka S, Yamaguchi Y, Toma H, Agishi T, Ota K (1986) Cyclosporine tissue levels and morphological and functional changes in organs of cyclosporine-treated rats. Transplant Proc 18:1272–1277

    Google Scholar 

  104. Ryffel B, Mihatsch MJ (1986) Cyclosporine nephrotoxicity. Toxicol Pathol 14:73–82

    PubMed  Google Scholar 

  105. Gerkens JF, Smith AJ (1985) Effect of captopril and therophylline treatment on cyclosporine-induced nephrotoxicity in rats. Transplantation 40:213–214

    PubMed  Google Scholar 

  106. Bunke M, Wilder L (1988) Effect of verapamil on glomerular prostaglandin production and glomerular filtration rate during cyclosporine administration. Kidney Int 33:355

    Google Scholar 

  107. Murray BM, Paller MS (1986) Beneficial effects of renal denervation and prazosin on GFR and renal blood flow after cyclosporine in rats. Clin Nephrol 25 [Suppl 1]:S37-S39

    PubMed  Google Scholar 

  108. Whiting PH, Barnard N, Neilsch A, Simpson JG, Burke MD (1987) Interactions between cyclosporin A, indomethacin and 16,16-dimethyl prostaglandin E2; effects on renal, hepatic and gastrointestinal toxicity in the rat. Br J Exp Pathol 68:777–786

    PubMed  Google Scholar 

  109. Makowka L, Lopatin W, Gilas T, Falk J, Phillips MJ, Falk R (1986) Prevention of cyclosporine (CyA) nephrotoxicity by synthetic prostaglandins. Clin Nephrol 25 [Suppl 1]:S89-S94

    PubMed  Google Scholar 

  110. Gnutzmann KH, Hering K, Gutsche HU (1986) Effect of cyclosporine on the diluting capacity of the rat kidney. Clin Nephrol 25 [Suppl 1]:S51-S56

    PubMed  Google Scholar 

  111. Dieperink H, Leyssac PP, Starklint H, Kemp E (1986) Nephrotoxicity of cyclosporin A.A lithium clearance and micropuncture study in rats. Eur J Clin Invest 16:69–77

    PubMed  Google Scholar 

  112. Dieperink H, Starklin H, Leyssac PP (1983) Nephrotoxicity of cyclosporine — an animal model: study of the nephrotoxic effect of cyclosporine on overal renal and tubular function in conscious rats. Transplant Proc 15 [Suppl 1]: 2736–2741

    Google Scholar 

  113. Gerkens JF, Bhagwandeen SB, Dosen PJ, Smith AJ (1984) The effect of salt intake on cyclosporine-induced impairment of renal function in rats. Transplantation 38: 412–417

    PubMed  Google Scholar 

  114. Brunkhorst R, Meding J, Koch KM, Wonigeit K, Kühn K,(1986) Renal functional impairment after cyclosporin treatment in hyperreninaemic rats. Nephrol Dial Transplant 1: 141

    Google Scholar 

  115. Yamaguchi Y, Teraoka S, Yagisawa T, Takahashi K, Toma H, Ota K (1989) Ultrastructural study of cyclosporine-associated arteriolopathy in renal allografts. Transplant Proc 21: 1517–1522

    PubMed  Google Scholar 

  116. Bantle JP, Boudreau RJ, Ferris TJ (1987) Suppression of plasma renin activity by cyclosporine. Am J Med 83: 59–64

    PubMed  Google Scholar 

  117. Bowles CA, Gabriel S, Bunch TW, Handwerger BS (1987) Cyclosporine (CyA) treatment for rheumatoid arthritis (RA). Arthritis Rheum 30 [Suppl]: S58

    Google Scholar 

  118. Tegzess AM, Doorenbos BM, Minderhoud JM, Donker AJM (1988) Prospective serial renal function studies in patients with non-renal disease treated with cyclosporine A. Transplant Proc 20 [Suppl 3]: 530–533

    PubMed  Google Scholar 

  119. Myers BD (1989) What is cyclosporine nephrotoxicity? Transplant Proc 21: 1430–1432

    PubMed  Google Scholar 

  120. Palestine AG, Nussenblatt RB, Chan CC (1984) Side effects of systemic cyclosporine in patients not undergoing transplantation. Am J Med 77: 652–656

    PubMed  Google Scholar 

  121. Conte G, Sabbatini M, Napodano P, Nicola L de, Gigliotti G, Fuiano G, Testa A, Russo D, Esposito C, Libetta C, Dal Canton A, Andreucci VE (1988) Dopamine counteracts the acute renal effects of cyclosporine in normal subjects. Transplant Proc 20 [Suppl 3]: 563–567

    PubMed  Google Scholar 

  122. Kho TL, Teule J, Leunissen KML, Heidendal GAK, Lijnen PJ, Amery AK, Hooff JP van (1987) Nephrotoxic effect of cyclosporin A can be reversed by dopamine. Transplant Proc 19: 1749–1753

    PubMed  Google Scholar 

  123. Feehally J, Walls J, Mistry N, Horsburgh T, Taylor J, Veitch PS, Bell PRF (1987) Does nifedipine ameliorate cyclosporin A nephrotoxicity? Br Med J 295: 310

    Google Scholar 

  124. Curtis II, Laskow DA, Julian BA, Luke RG, Jones P, Diethelm AG (1989) Nifedipine is a more effective renal vasodilator than captopril in cyclosporine (CsA) transplant (TX) hypertension. Kidney Int 35: 512

    Google Scholar 

  125. Paller MS, Bantle JP, Boudreau RJ, Olivari MT, Ferris TF (1990) Long-term effects of cyclosporine on renal function in organ transplant recipients. Kidney Int 37: 610

    Google Scholar 

  126. Kiberd BA (1990) Effect of prazosin on cyclosporine (CsA) treated renal allograft recipients. Kidney Int 37: 610

    Google Scholar 

  127. Hannedouche T, Delgado A, Boitard C, Lacour B, Gnionsahe A, Grünfeld JP (1988) Renal hemodynamics (RH) in recent onset adult insulin-dependent diabetes (IDD): effects of captopril (Ca) and cyclosporine A (CyA). Kidney Int 33: 193

    Google Scholar 

  128. Laskow DA, Curtis J, Luke R, Jones P, Barber H, Deierhoi M, Diethelm A (1988) Cyclosporine impairs the renal response to volume depletion. Transplant Proc 20 [Suppl 3]: 568–571

    PubMed  Google Scholar 

  129. Peters AM, McKinnon S, Hows JM, Ballardie F (1987) Non-invasive measurement of microvascular permeability to Tc-99m DTPA. Clin Sci 73 [Suppl 17]: 47

    PubMed  Google Scholar 

  130. Hows JM, Yin JL, Marsh JCW, Gordon-Smith EC (1984) Capillary leak syndrome in BMT for aplastic anaemia. Exp Hematol 12 [Suppl 15]: 39

    PubMed  Google Scholar 

  131. Powell-jackson PR, Carmichael FJL, Calne RY, Williams R (1984) Adult respiratory distress syndrome and convulsions associated with administration of cyclosporine in liver transplant recipients. Transplantation 38: 341–343

    PubMed  Google Scholar 

  132. Barrett AJ, Kendra JR, Lucas CF, Joss DV, Joshi R, Pendharkar P, Hugh-Jones K (1982) Cyclosporin A as prophylaxis against graftversus-host disease in 36 patients. Br Med J 285: 162–166

    Google Scholar 

  133. Carbone L, Appel GB, Benvenisty AI, Cohen DJ, Kunis CL, Hardy MA (1987) Adult respiratory distress syndrome associated with oral cyclosporine. Transplantation 43: 767–768

    PubMed  Google Scholar 

  134. Besarab A, Jarrell BE, Burke JF, Francos J, Caro J, Mallon E (1988) “Erythrocytosis” in renal transplantation patients treated with cyclosporine. Transplant Proc 20 [Suppl 3]: 945–947

    PubMed  Google Scholar 

  135. Wickre CG, Norman DJ, Bennison A, Barry JM, Bennett WM (1983) Postrenal transplant erythrocytosis: a review of 53 patients. Kidney Int 23: 731–737

    Google Scholar 

  136. Obermiller LE, Tzamaloukas AH, Avasthi PS, Halpern JA, Sterlin WA (1985) Decreased plasma volume in post-transplant erythrocytosis. Clin Nephrol 23: 213–217

    PubMed  Google Scholar 

  137. Keusch G, Jungbluth H, Fehr J, Mühlethaler K, Binswanger U (1985) Erythrocytosis (E) after kidney allotransplantation (KT): hematological characterization and complications. Kidney Int 28: 377

    Google Scholar 

  138. Curtis JJ, Luke RG, Jones P, Diethelm AG (1988) Hypertension in cyclosporine-treated renal transplant recipients is sodium dependent. Am J Med 85: 134–138

    PubMed  Google Scholar 

  139. Bellet M, Cabrol C, Sassano P, Leger P, Corvol P, Menard J (1985) Systemic hypertension after cardiac transplantation: effect of cyclosporine on the renin-angiotensin-aldosterone system. Am J Cardiol 56: 927–931

    Google Scholar 

  140. Verpooten GA, Wybo I, Pattyn VM, Hendrix PG, Giuliano RA, Nouwen EJ, Roels F, Broe ME de (1986) Cyclosporine nephrotoxicity: comparative cytochemical study of rat kidney and human allograft biopsies. Clin Nephrol 25 [Suppl 1]: S18-S22

    PubMed  Google Scholar 

  141. Nitta K, Friedman AL, Nicastri AD, Paik S, Friedman EA (1987) Granular juxtaglomerular cell hyperplasia caused by cyclosporine. Transplantation 44: 417–421

    PubMed  Google Scholar 

  142. Rebuffat P, Kasprzak A, Andreis PG, Mazzocchi G, Gottardo G, Coi A, Nussdorfer GG (1989) Effects of prolonged cyclosporine A-treatment on the morphology and function of rat adrenal cortex. Endocrinology 125: 1407–1413

    PubMed  Google Scholar 

  143. Neumayer HH, Mihatsch MJ, Löpping A, Velten M, Wagner K (1988) Effect of cyclosporine A on post-ischemic acute renal failure in conscious dogs: role of vasoactive renal hormones. Transplant Proc 20 [Suppl 3]: 584–594

    Google Scholar 

  144. Siegl H, Ryffel B (1982) Effect of cyclosporin on renin-angiotensin-aldosterone system. Lancet II: 1274

    Google Scholar 

  145. Siegl H, Ryffel B, Petric R, Shoemaker P, Muller A, Donatsch P, Mihatsch M (1983) Cyclosporine, the renin-angiotensin-aldosterone system, and renal adverse reactions. Transplant Proc 15 [Suppl 1/2]: 2719–2725

    Google Scholar 

  146. Baxter CR, Duggin GG, Horvath JS, Hall BM, Tiller DJ (1984) Cyclosporin A and renal prostaglandin biosynthesis. Res Commun Chem Pathol Pharmacol 45: 69–80

    PubMed  Google Scholar 

  147. Baxter CR, Duggin GG, Willis NS, Hall BM, Horvath JS, Tiller DJ (1982) Cyclosporin A-induced increases in renin storage and release. Res commun Chem Pathol Pharmacol 37: 305–312

    PubMed  Google Scholar 

  148. Dieperink H, Leyssac PP, Kemp E, Steinbruchel D, Starklint H (1986) Glomerulotubular function in cyclosporine A treated rats. Clin Nephrol 25 [Suppl 1]: S70-S74

    PubMed  Google Scholar 

  149. Perico N, Benigni A, Bosco E, Rossini M, Orisio S, Ghilardi F, Piccinelli A, Remuzzi G (1986) Acute cyclosporine A nephrotoxicity in rats: which role for renin-angiotensin system and glomerular prostaglandins? Clin Nephrol 25 [Suppl 1]: S83-S88

    PubMed  Google Scholar 

  150. Lustig S, Stern N, Petrasek D, Eggena P, Lee DBN (1987) Cyclosporine-A hypertension: a unique form of hyperreninemic hypoaldosteronism. Kidney Int 31: 303

    Google Scholar 

  151. Lustig S, Stern N, Golub MS, Eggena P, Barrett J, Lee DBN (1989) Experimental cyclosporin hypertension: characterization of the rat model. Transplant Proc 21: 950–951

    PubMed  Google Scholar 

  152. McAuley FT, Whiting PH, Thomson AW, Simpson JG (1987) The influence of enalapril or spironolactone on experimental cyclosporin nephrotoxicity. Biochem Pharmacol 36: 699–703

    PubMed  Google Scholar 

  153. Baxter CR, Duggin GG, Hall BM, Horvath JS, Tiller DJ (1984) Stimulation of renin release from rat renal cortical slices by Cyclosporin A. Res commun Chem Pathol Pharmacol 43: 417–423

    PubMed  Google Scholar 

  154. Lustig S, Eggena P, Barrett J, Stern N, Lee DBN (1988) Further studies on cyclosporin A (CsA)-induced hyperreninemic hypoaldosteronism: evidence for a direct stimulatory action of CsA on renin release. Kidney Int 33: 274

    Google Scholar 

  155. Kurtz A, Bruna R Della, Kühn K (1988) Cyclosporine A enhances renin secretion and production in isolated juxtaglomerular cells. Kidney Int 33: 947–953

    PubMed  Google Scholar 

  156. Curtis JJ, Luke RG, Jones P, Diethelm AG (1987) Cyclosporin induced hypoaldosteronism in man despite normal plasma renin activity (PRA). Kidney Int 31: 266

    Google Scholar 

  157. Jorkasky D, Audet P, Williams S, Grossman R, Conrad M (1987) Cyclosporine-induced nephrotoxicity: role of prostaglandins. Transplant Proc 19: 1742–1744

    PubMed  Google Scholar 

  158. Hannedouche T, Delgado A, Boitard C, Lacour B, Bach JF, Grünfeld JP (1989) Renal hemodynamics effect of short-term cyclosporin A administration in insulin-dependent diabetes. Nephrol Dial Transplant 4: 514

    Google Scholar 

  159. Held P, Yusuf S, Mathias C, Dhalla N, Theodoropoulos S, Yacoub M (1989) Renin response to sympathetic stimulation in cyclosporin-treated heart transplant patients. Am J Cardiol 63: 1142–1144

    PubMed  Google Scholar 

  160. Deray G, Hoang P le, Cacoub P, Hornych A, Legrand S, Aupetit B, Zogbi F, Landault C, Carayon A, Baumelou A, Jacobs C (1988) Effects of Ciclosporin on plasma renin activity, catecholamines and prostaglandins in patients with idiopathic uveitis. Am J Nephrol 8: 298–304

    PubMed  Google Scholar 

  161. Stanek B, Kovarik J, Rasoul-Rockenschaub S, Silberbauer K (1987) Renin angiotensin-aldosterone system and vasopressin in cyclosporine-treated renal allograft recipients. Clin Nephrol 28: 186–189

    PubMed  Google Scholar 

  162. Casas A, Fernandez-Cruz L, Puig-Parellada P, Rosello J, Hotter G, Sanchez J, Targarona E, Gelpi E (1988) The effect of cyclosporine alone and with steroids on arachidonic acid metabolites. Transplant Proc 20 [Suppl 3]: 670–674

    Google Scholar 

  163. Knauss TC (1986) Cyclosporin nephrotoxicity in the rat associated with increased urinary thromboxane. Kidney Int 29: 304

    Google Scholar 

  164. Persan L, Kaskel F, Barnett R, Wilson T, Moore L, Arbeit L, Schlondorff D (1989) Altered renal prostaglandin (PG) and thromboxane (Tx) production in cyclosporine nephrotoxicity. Kidney Int 35: 508

    Google Scholar 

  165. Cooper P, Mason J, Donatsch P, Rickenbacher U (1990) Proststanoid excretion in rats treated with Sandimmune®. Kidney Int 37: 594

    Google Scholar 

  166. Benigni A, Chiabrando C, Piccinelli A, Perico N, Gavinelli M, Furci L, Patino O, Abbate M, Bertani T, Remuzzi G (1988) Increased urinary excretion of thromboxane B2 and 2,3-dinor-TxB2 in cyclosporin A nephrotoxicity. Kidney Int 34: 164–174

    PubMed  Google Scholar 

  167. Kawaguchi A, Goldman MH, Shapiro R, Foegh ML, Ramwell PW, Lower RR (1985) Increase in urinary thromboxane B2 in rats caused by cyclosporine. Transplantation 40: 214–216

    PubMed  Google Scholar 

  168. Grieve EM, Hawksworth GM, Whiting PH (1989) Protection mediated by inhibition of thromboxane synthesis is not enhanced by ACE inhibition in cyclosporin A treated animals. Br J Pharmacol 96 [Suppl] 173P

  169. Whiting PH, Burke MD, Thomson AW (1986) Drug interactions with cyclosporine: implications from animal studies. Transplant Proc 18 [Suppl 5]: 56–70

    PubMed  Google Scholar 

  170. Rogers TS, Elzinga L, Bennett WM, Kelley VE (1988) Selective enhancement of thromboxane in macrophages and kidneys in cyclosporine-induced nephrotoxicity. Dietary protection by fish oil. Transplantation 45: 153–156

    PubMed  Google Scholar 

  171. Elzinga L, Kelley VE, Houghton DC, Bennett WM (1987) Fish oil vehicle for cyclosporine lowers renal thromboxanes and reduces experimental nephrotoxicity. Transplant Proc 19: 1403–1406

    PubMed  Google Scholar 

  172. Jevnikar AM, Petric R, Holub BJ, Philbrick DJ, Clark WF (1988) Effect of cyclosporine on plasma lipids and modification with dietary fish oil. Transplantation 46: 722–725

    PubMed  Google Scholar 

  173. Bunke M, Wilder L (1989) Protection of glomerular filtration rate by the thromboxane receptor antagonist L655,240 during cyclosporin A administration. Clin Res 37: 486A

    Google Scholar 

  174. Bunke M, Wilder L, McLeish K (1988) Effect of cyclosporine on glomerular prostaglandin production. Transplant Proc 20 [Suppl 3]: 646–649

    Google Scholar 

  175. Stahl RAK, Kudelka S (1986) Chronic cyclosporine A treatment reduces prostaglandin E2 formation in isolated glomeruli and papilla of rat kidneys. Clin Nephrol 25 [Suppl 1]: S78-S82

    PubMed  Google Scholar 

  176. Jacobs A, Bunke M, Wilder L (1989) Effect of cyclosporine (CyA) on angiotensin II and norepinephrine stimulated glomerular prostaglandin production. Kidney Int 35: 409

    Google Scholar 

  177. Neild GH, Rocchi G, Imberti L, Fumagalli F, Brown Z, Remuzzi G, Williams DG (1983) Effect of cyclosporine on prostacyclin synthesis by vascular tissue in rabbits. Transplant Proc 15 [Suppl 1/2]: 2398–2400

    Google Scholar 

  178. Jones DB, Schroeder ET, Hueber P, Patchin DS, Elliott WC (1986) Cyclosporine (CSA) nephrotoxicity (NTX) in rats: effects on GFR, tubular function and prostacyclin (PGI) production. Kidney Int 29: 303

    Google Scholar 

  179. Bossaller C, Förstermann U, Hertel R, Olbricht C, Reschke V, Fleck E (1989) Cyclosporin A inhibits endothelium-dependent vasodilatation and vascular prostacyclin production. Eur J Pharmacol 165: 165–169

    PubMed  Google Scholar 

  180. Lindsey JA, Morisaki N, Stitts JM, Zager RA, Cornwell DG (1983) Fatty acid metabolism and cell proliferation. IV. Effect of prostanoid biosynthesis from endogenous fatty acid release with cyclosporin-A. Lipids 18: 566–569

    PubMed  Google Scholar 

  181. Zhang H, Kaseki H, Davis WB, Whisler RL, Cornwell DG (1989) Mechanisms for the stimulation of prostanoid synthesis by cyclosporine and bacterial lipopolysaccharide. Transplantation 47: 864–871

    PubMed  Google Scholar 

  182. Zoja C, Furci L, Ghilardi F, Zilio P, Benigni A, Remuzzi G (1986) Cyclosporin-induced endothelial cell injury. Lab Invest 55: 455–462

    PubMed  Google Scholar 

  183. Lau DCW, Wong KL (1987) Effect of cyclosporine on microvascular endothelial cell growth in culture. Transplant Proc 19: 3496–3498

    PubMed  Google Scholar 

  184. Fan TPD, Lewis GP (1985) Mechanism of cyclosporin A-induced inhibition of prostacyclin synthesis by macrophages. Prostaglandins 30: 735–747

    PubMed  Google Scholar 

  185. Hattori Y, Kasai K, Emoto T, Hiraiwa M, Shimoda S (1989) The inhibitory effect of cyclosporine on prostacyclin production by cultured endothelial cells from porcine aorta. Transplant Proc 21: 3461–3463

    PubMed  Google Scholar 

  186. Kurtz A, Pfeilschifter J, Kühn K, Koch KM (1987) Cyclosporin A inhibits PGE2 release from vascular smooth muscle cells. Biochem Biophys Res Commun 147: 542–549

    PubMed  Google Scholar 

  187. Stahl RAK, Adler S, Baker PJ, Johnson RJ, chen YP, Pritzl P, Couser WG (1989) Cyclosporin A inhibits prostaglandin E2 formation by rat mesangial cells in culture. Kidney Int 35: 1161–1167

    PubMed  Google Scholar 

  188. Walker RJ, Lazzaro VA, Duggin GG, Horvath JS, Tiller DJ (1989) Dietary eicosapentaenoic acid does not modify cyclosporin-induced inhibition of angiotensin II-stimulated prostaglandin synthesis in mesangial cells. Ren Fail 11: 125–132

    PubMed  Google Scholar 

  189. Kremer S, Margolis B, Harper P, Skorecki K (1989) Cyclosporine induced alterations in vasopressin signalling in the glomerular mesangial cell. Clin Invest Med 12: 201–206

    PubMed  Google Scholar 

  190. Förstermann U, Kühn K, Vesterqvist O, Green K, Frei U, Brunk-horst R, Haas J, Koch KM, Frölich JC (1989) An increase in the ratio of thromboxane A2 to prostacyclin in association with increased blood pressure in patients on cyclosporine A. Prostaglandins 37: 567–575

    PubMed  Google Scholar 

  191. Koivisto VA, Leirisalorepo M, Pelkonen R, Turunen U, Viinikka L, Rapola J, Ylikorkala O (1988) Reduced renal prostanoid synthesis may contribute to the nephrotoxicity of cyclosporin (Cy) in type 1 diabetic patients. Diabetes 37 [Suppl 1]: 79A

    Google Scholar 

  192. Adu D, Lote CJ, Michael J, Turney JH, McMaster P (1985) Cyclosporine and prostaglandins. Ann Intern Med 103: 303

    Google Scholar 

  193. Coffman TM, Creech L, Bollinger RR, Klotman PE (1988) Conversion from cyclosporine (CyA) to azathioprine (Aza) results in improved renal function and reduced urinary thromboxane excretion. Clin Res 36: 28A

    Google Scholar 

  194. Tugwell P, Bombardier C, Gent M, Bennett K, Ludwin D, Grace E, Buchanan WW, Bensen WG, Bellamy N, Murphy GF, Graffenried B von (1987) Low dose cyclosporine in rheumatoid arthritis: a pilot study. J Rheumatol 14: 1108–1114

    PubMed  Google Scholar 

  195. Deray G, Hoang P le, Aupetit B, Achour A, Rottembourg J, Baumelou A (1987) Enhancement of cyclosporine A nephrotoxicity by diclofenac. Clin Nephrol 27: 213–214

    Google Scholar 

  196. Boers M, Rijthoven AWAM van, Goei Thè HS, Dijkmans BAC, Cats A (1988) Serum creatinine levels two years later: follow up of a placebo-controlled trial of cyclosporine in rheumatoid patients. Transplant Proc 20 [Suppl 4]: 371–375

    PubMed  Google Scholar 

  197. Harris KP, Jenkins D, Walls J (1988) Nonsteroidal antiinflammatory drugs and cyclosporine. A potentially serious adverse interaction. Transplantation 46: 598–599

    PubMed  Google Scholar 

  198. Wheeler DC, Lui SF, Varghese Z, Kingstone D, Persaud J, Sweny P, Fernando ON, Moorhead JF (1988) Omega-3 polyunsaturated fatty acids (PUFAs) improve lipid profile but not renal haemodynamics in renal transplant recipients (RTR). Kidney Int 33: 456

    Google Scholar 

  199. Homan van der Heide JJ, Bilo HJG, Tegzess AM, Donker AJM (1989) Omega-3 polyunsaturated fatty acids improve renal function in renal transplant recipients treated with cyclosporin-A. Kidney Int 35: 516

    Google Scholar 

  200. Bilo HJG, Stoof TJ, Korstanje MJ, Comans EFI, Donker AJM (1989) Fish-oil and renal function in cyclosporin-treated psoriasis patients. Kidney Int 36: 509

    Google Scholar 

  201. Whisler RL, Lindsey JA, Proctor KVW, Morisaki N, Cornwell DG (1984) Characteristics of cyclosporine induction of increased prostaglandin levels from human peripheral blood monocytes. Transplantation 38: 377–381

    PubMed  Google Scholar 

  202. Rosenthal RA, Chukwuogo NA, Ocasio VH, Kahng KU (1989) Cyclosporine inhibits endothelial cell prostacyclin production. J Surg Res 46: 593–596

    PubMed  Google Scholar 

  203. Brown Z, Neild GH (1987) Cyclosporine inhibits prostacyclin production by cultured human endothelial cells. Transplant Proc 19: 1178–1180

    PubMed  Google Scholar 

  204. Brown Z, Neild GH, Lewis GP (1988) Mechanism of inhibition of prostacyclin synthesis by cyclosporine in cultured human umbilical vein endothelial cells. Transplant Proc 20 [Suppl 3]: 654–657

    Google Scholar 

  205. Voss BL, Hamilton KK, Samara ENS, McKee PA (1988) Cyclosporine suppression of endothelial prostacyclin generation. A possible mechanism for nephrotoxicity. Transplantation 45: 793–796

    PubMed  Google Scholar 

  206. Gordon JA, Hadjiagapiou C, Spector AA (1987) Cyclosporine inhibits prostacyclin formation in cultured human endothelial cells. Kidney Int 31: 457

    Google Scholar 

  207. Hirsch S, Besarab A, Jarrell BE, Carabasi RA, Cressman MD, Green P (1987) Acute nephrotoxicity following intravenous cyclosporine. Transplant Proc 19: 1387–1390

    PubMed  Google Scholar 

  208. Luke DR, Kasiske BL, Matzke GR, Awni WM, Keane WF (1987) Effects of cyclosporine on the isolated perfused rat kidney. Transplantation 43: 795–799

    PubMed  Google Scholar 

  209. Walley GJ, Endre ZH, Ratcliffe PJ, Holt D, Ledingham JGG (1988) Renal handling and effects of cyclosporin A in filtering and non-filtering isolated perfused kidneys. Nephrol Dial Transplant 3: 575

    Google Scholar 

  210. Besarab A, Jarrell BE, Hirsch S, Carabasi RA, Cressman MD, Green P (1987) Use of the isolated perfused kidney model to assess the acute pharmacologic effects of cyclosporine and its vehicle, cremophor EL. Transplantation 44: 195–201

    PubMed  Google Scholar 

  211. Sumpio BE (1988) Cyclosporine toxicity in the isolated perfused rat kidney. Transplantation Proc 20 [Suppl 3]: 712–716

    Google Scholar 

  212. Racusen LC, Kone BC, Solez K (1987) Early renal pathophysiology in an acute model of cyclosporine nephrotoxicity in rats. Ren Fail 10: 29–37

    PubMed  Google Scholar 

  213. Thiel G, Hermle M, Brunner FP (1986) Acutely impaired renal function during intravenous administration of cyclosporine A: a cremophor side-effect. Clin Nephrol 25 [Suppl 1]: S40-S42

    PubMed  Google Scholar 

  214. Finn WF, McCormack AJ, Sullivan BA, Hak LJ, Clark RL (1989) Influence of the rate of infusion on cyclosporine nephrotoxicity in the rat. Ren Fail 11: 3–15

    PubMed  Google Scholar 

  215. Hak LJ, Finn WF (1987) Cyclosporin (CsA) induced renal vasoconstriction. Clin Pharmacol Ther 41: 173

    Google Scholar 

  216. Barros EJG, Boim MA, Figueiredo JF, Sigulem D, Ramos OL, Schor N (1987) Cyclosporine: glomerular hemodynamics. Transplantation Proc 19: 1754

    Google Scholar 

  217. Mason J (1989) Pathophysiology of cyclosporin therapy-associated renal function disturbance. In: Cyclosporin. Five years on. Medicine Group, Oxford pp 69–73

    Google Scholar 

  218. Xue H, Bukoski RD, McCarron DA, Bennett WM (1987) Induction of contraction in isolated rat aorta by cyclosporine. Transplantation 43: 715–718

    PubMed  Google Scholar 

  219. Lamb FS, Webb RC (1987) Cyclosporine augments reactivity of isolated blood vessels. Life Sci 40: 2571–2578

    PubMed  Google Scholar 

  220. Müller-Schweinitzer E, Mason J (1989) Effect of Sandimmune on isolated blood vessels. Kidney Int 35: 331

    Google Scholar 

  221. Golub MS, Berger ME (1987) Direct augmentation by cyclosporin A of the vascular contractile response to nerve stimulation. Hypertension 9 [Suppl 3]: 96–100

    PubMed  Google Scholar 

  222. Müller-Schweinitzer E, Mason J, Olea Baza I (1990) Action of Sandimmune on porcine renal arteries. Kidney Int 37: 598

    Google Scholar 

  223. Rego A, Vargas RL, Foegh ML, Ramwell PW (1988) Effect of cyclosporine A treatment on vascular reactivity of the rat thoracic aorta. Transplant Proc 20 [Suppl 3]: 572–577

    Google Scholar 

  224. Bossaller C, Olbricht CJ, Reschke V (1989) Effect of cyclosporin A on endothelium-dependent and endothelium-independent vascular relaxation. Kidney Int 35: 504

    Google Scholar 

  225. Lüscher TF, Weber E, Bühler FR (1988) Effects of cyclosporin A on endothelium-dependent relaxations in the rat renal artery. Kidney Int 33: 274

    Google Scholar 

  226. Yang Z, Diederich D, Bühler FR, Lüscher TF (1989) Cyclosporin therapy impairs endothelium-dependent relaxations in the renal circulation. Kidney Int 35: 511

    Google Scholar 

  227. Gerkens JF (1989) Cyclosporine treatment of normal rats produces a rise in blood pressure and decreased renal vascular response to nerve stimulation, vasoconstrictors and endothelium dependent dilators. J Pharmacol Exp Ther 250: 1105–1112

    PubMed  Google Scholar 

  228. Cairns HS, Fairbanks LD, Westwick J, Neild GH (1989) Cyclosporin therapy in vivo attenuates the response to vasodilators in the isolated perfused kidney of the rabbit. Brit J Pharmacol 98: 463–468

    Google Scholar 

  229. Schnabel FR, Wait RB, Aaronson P, Kahng KU (1989) Effect of cyclosporine administration on vascular reactivity in the rabbit. Transplantation Proc 21: 918–921

    Google Scholar 

  230. Monaco DO, Wait RB, Friedman AL, Kahng KU (1988) Effect of chronic cyclosporine therapy on renal vascular reactivity in the isolated perfused rabbit kidney. Transplant Proc 20 [Suppl 3]: 578–583

    Google Scholar 

  231. Dadan J, Perico N, Remuzzi G (1990) Role of endothelin (EN) in cyclosporine (CsA)-induced renal vasconstriction. Kidney Int 37: 479

    Google Scholar 

  232. Textor SC, Telles T, Smith-Powell L (1989) Blunted vascular reactivity during cyclosporine (CsA) administration in conscious rats. Kidney Int 35: 336

    Google Scholar 

  233. Müller-Schweinitzer E (1988) Changes in the venous compliance by bradykinin and angiotensin II and its significance for the vascular effects of cyclosporine A. Naunyn Schmiedebergs Arch Pharmacol 338: 699–703

    PubMed  Google Scholar 

  234. Müller-Schweinitzer E (1989) Interaction of cyclosporine-A with the renin-angiotensin system in canine veins. Naunyn Schmiedebergs Arch Pharmacol 340: 252–257

    PubMed  Google Scholar 

  235. Pfeilschifter J, Rüegg UT (1987) Cyclosporin A augments angiotensin II-stimulated rise in intracellular free calcium in vascular smooth muscle cells. Biochem J 248: 883–887

    PubMed  Google Scholar 

  236. Meyer-Lehnert H, Schrier RW (1989) Potential mechanism of cyclosporine A-induced vascular smooth muscle contraction. Hypertension 13: 352–360

    PubMed  Google Scholar 

  237. Pfeilschifter J (1988) Cyclosporin A augments vasoconstrictor induced rise in intracellular free calcium in rat renal mesangial cells. Biochem Pharmacol 37: 4205–4210

    PubMed  Google Scholar 

  238. Meyer-Lehnert H, Schrier RW (1988) Cyclosporin A enhances vasopressin-induced Ca2+ mobilization and contraction in mesangial cells. Kidney Int 34: 89–97

    PubMed  Google Scholar 

  239. Goldberg HJ, Wong PY, Cole EH, Levy GA, Skorecki KL (1989) Dissociation between the immunosuppressive activity of cyclosporine derivatives and their effects on intracellular calcium signalling in mesangial cells. Transplantation 47: 731–733

    PubMed  Google Scholar 

  240. Meyer-Lehnert H, Schrier RW (1988) Cyclosporine A (CyA) stimulates Ca uptake in vascular smooth muscle cells (VSMC) via non-voltage dependent channels. Eur J Clin Invest 18: A59

    Google Scholar 

  241. Powell-Jackson PR, Young B, Calne RY, Williams R (1983) Nephrotoxicity of parenterally administered cyclosporine after orthotopic liver transplanation. Transplantation 36: 505–508

    PubMed  Google Scholar 

  242. Blaauw AAM, Leunissen KML, Cheriex EC, Wolters J, Kootstra G, Hooff JP van (1987) Disappearance of pulmonary capillary leak syndrome when intravenous cyclosporine is replaced by oral cyclosporine. Transplantation 43: 758–759

    PubMed  Google Scholar 

  243. Powles RL, Morgenstern GR, Kay HEM, McElwain TJ, Clink HM, Dady PJ, Barret A, Jameson B, Depledge MH, Watson JG, Sloane J, Leigh M, Lumley H, Hedley D, Lawler S, Filshie J, Robinson B (1983) Mismatched family donors for bone-marrow transplantation as treatment for acute leukaemia. Lancet I: 612–615

    Google Scholar 

  244. Richards NT, Hilton PJ (1989) Cyclosporine A inhibits relaxation but does not induce vasoconstriction in subcutaneous resistance vessels J. Hypertens 7: 1–3

    PubMed  Google Scholar 

  245. Richards NT, Wolfson RG, Poston L, Hilton PJ (1990) Decreased prostanoid-mediated, endothelium dependent relaxation and increased sensitivity to norepinephrine in resistance vessels from cyclosporine treated transplant recipients. Kidney Int 37: 392

    Google Scholar 

  246. Fry WR, Dawidson I, Alway CC, Rooth P (1988) Cyclosporine A induces decreased blood flow in cadaveric kidney transplants. Transplant Proc 20 [Suppl 3]: 222–225

    PubMed  Google Scholar 

  247. Curtis JJ, Luke RG, Dubovsky E, Diethelm AG, Whelchel JD, Jones P (1986) Cyclosporin in therapeutic doses increases renal allograft vascular resistance. Lancet II: 477–479

    Google Scholar 

  248. Scott JP, Nunez D, Hay IFC, Higenbottam TW, Evans DB, Calne R (1987) Exercise-induced hypertension in normotensive renal transplant recipients receiving cyclosporine A. Transplant Proc 19: 4002

    PubMed  Google Scholar 

  249. Leunissen KML, Teule J, Degenaar CP, Kho TL, Frenken LAM, Hooff JP van (1987) Impairment of liver synthetic function and decreased liver flow during cyclosporin A therapy. Transplant Proc 19: 1822–1824

    PubMed  Google Scholar 

  250. Deray G, Le Hoang P, Achour L, Hornych A, Landault C, Caraillon A (1986) Cyclosporin and Raynaud phenomenon. Lancet II: 1092–1093

    Google Scholar 

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Authors and Affiliations

  1. Preclinical and Clinical Research, Sandoz Pharma Ltd, CH-4002, Basle, Switzerland

    June Mason

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  1. June Mason
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Sandimmune is the registered tradename for cyclosporine

Part II of this survey will be published in Pediatr Nephrol (1990) Volume 4, Issue 6

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Mason, J. The pathophysiology of Sandimmune (cyclosporine) in man and animals. Pediatr Nephrol 4, 554–574 (1990). https://doi.org/10.1007/BF00869843

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  • DOI: https://doi.org/10.1007/BF00869843

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