Cyclosporine, Hypertension, and the Kidney

  • D. Diederich
  • Dai Fu-Xiang
  • M. Jameson
Conference paper


Cyclosporine has dramatically improved the success of organ transplantation [18, 19, 24]. The clinical usefulness of cyclosporine is compromised, however, by adverse effects of the agent, most important of which are reversible impairment in kidney function, hypertension, and nephrotoxicity [10, 11, 18, 19, 22, 28, 37, 70, 76, 80, 86]. The impairment in kidney function arises from direct effects of cyclosporine upon the renal vasculature and upon tubular cells. Cyclosporine induces renal vasoconstriction, which leads to a decrease in glomerular filtration rate in virtually every patient receiving the agent [5, 28]. The decrease in glomerular filtration rate is prompt and reversible. Injury to the tubular cells leads to magnesium wasting, renal hyperkalemia, and tubular acidosis [2, 7, 8. 100]. In addition, cyclosporine stimulates sodium and water reabsorption in the proximal tubules, leading to volume expansion. Renal and systemic vasoconstriction in the setting of volume expansion predispose to the development of hypertension. Indeed, hypertension is noted in the majority of patients treated with cyclosporine [10, 22, 31, 70]. Nephrotoxic effects of cyclosporine comprise a spectrum of abnormalities ranging from episodes of reversible and acute renal failure to chronic irreversible damage to the kidneys [38, 80, 86, 87, 106]. Recent studies which demonstrate alterations in vasoactive function of endothelial and mesangial cells induced by cyclosporine provide important new insight into mechanisms responsible for the major adverse effects of this agent. Indeed, endothelial dysfunction induced by cyclosporine provides a unifying, initiating mechanism to explain the impairment in kidney function and hypertension, as well as the acute nephrotoxicity related to the use of this agent. Chronic cyclosporine nephrotoxicity may also result in part from the same mechanism, but information is less clear in this regard.


Glomerular Filtration Rate Acute Renal Failure Acute Rejection Renal Transplant Recipient Calcium Channel Antagonist 
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.
    Abouna CM, Samhan MS, Kumar MSA, White AC, Silva OSG (1987) Limiting factors in successful preservation of cadaveric kidneys with ischemic times exceeding 50 hours. Transplant Proc 19: 2051 - 2055PubMedGoogle Scholar
  2. 2.
    Adu D, Michael J, Turney J, McMaster P (1983) Hyperkalemia in cyclosporine-treated renal allograft recipients. Lancet 2: 370 - 372PubMedGoogle Scholar
  3. 3.
    Bantle JP, Nath KA, Sutherland DER, Najarían JS, Ferris TD (1985) Effects of cyclosporine on the renin-angiotensin-aldosterone system and potassium excretion in renal transplant recipients. Arch Intern Med 145: 505 - 508PubMedGoogle Scholar
  4. 4.
    Bantle JP, Boudreau RJ, Ferris TF (1987) Suppression of plasma renin activity by cyclos-porine. Am J Med 83: 59 - 65PubMedGoogle Scholar
  5. 5.
    Bantle JP, Paller MS, Boudreau RJ, Olivari MT, Ferris TF (1990) Long-term effects of cyclosporine on renal function in organ transplant recipients. J Lab Clin Med 115: 233 - 240PubMedGoogle Scholar
  6. 6.
    Barros EJG, Boim MA, Ajzen H, Ramoa OL, Schor N (1987) Glomerular hemodynamics and hormonal participation on cyclosporine nephrotoxicity. Kidney Int 32: 19 - 25PubMedGoogle Scholar
  7. 7.
    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- 699Google Scholar
  8. 7a.
    Barton CH, Vaziri ND, Mina-Araghi S, Crosby S, Seo MI (1989) Effects of cyclosporine on magnesium metabolism in rats. J Lab Clin Med 114: 232 - 236PubMedGoogle Scholar
  9. 8.
    Battle DC, Gutterman C, Tarka J, Prasad R (1986) Effect of short-term cyclosporine A administration on urinary acidification. Clin Nephrol 25 [Suppl 1]: S62 - S69Google Scholar
  10. 9.
    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 Med 56: 927 - 931Google Scholar
  11. 10.
    Bennett WM, Porter GA (1988) Cyclosporine-associated hypertension. Am J Med 85:131- 133Google Scholar
  12. 11.
    Bennett W, Pulliam JP (1983) Cyclosporine nephrotoxicity. Ann Int Med 99: 851 - 854PubMedGoogle Scholar
  13. 12.
    Bonser RS, Adu D, Franklin L, McMaster P (1984) Cyclosporine induced haemolytic uraemic syndrome in liver allograft recipient. Lancet 2: 1337PubMedGoogle Scholar
  14. 13.
    Bossaler C, Forstermann, Hertel R, Olbrict C, Reschke V, Fleck E (1989) Cyclosporin A inhibits endothelium-dependent vasodilatation and vascular prostacyclin production. Eur J Pharmacol 165: 165 - 169Google Scholar
  15. 14.
    Boulanger C, Lüscher TF (1990) Release of endothelin from the porcine aorta: inhibition by endothelium-derived nitric oxide. J Clin Invest 85: 567 - 590Google Scholar
  16. 15.
    Brooks DP, Drutz DJ, Ruffolo RR (1990) Prevention and complete reversal of cyclosporine A-induced renal vasoconstriction and nephrotoxicity in the rat by fenoldopam. J Pharmacol Exp Therapeutics 254: 375 - 379Google Scholar
  17. 16.
    Bunchman TE, Brookshire CA (1990) Cyclosporine stimulated synthesis of endothelin by human endothelial cells in tissue culture. Kidney Int 37: 177AGoogle Scholar
  18. 17.
    Burke TJ, Arnold PE, Gordon JA, Bulger RE, Dobyan DC, Schrier RW (1984) Protective effect of intrarenal calcium membrane blockers before and after renal ischemia: functional, morphological, and mitochondrial studies. J Clin Invest 74: 1830 - 1841PubMedGoogle Scholar
  19. 18.
    Calne RY, White DJG, Thiru S, Evans DB, McMaster P, Dunn DC (1978) Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 2: 1323 - 1327PubMedGoogle Scholar
  20. 19.
    Canadian Multicentre Transplant Study Group (1986) A randomized clinical trial of cyclosporine in cadaveric renal transplantation: analysis at three years. N Engl J Med 314: 1219–1225Google Scholar
  21. 20.
    Cantarovich F, Bizollon C, Cantarovich D, Lefrancois N, Dubernard JM, Traeger J (1988) Cyclosporine plasma levels six hours after oral administration: a useful tool for monitoring therapy. Transplantation 45: 389 - 394PubMedGoogle Scholar
  22. 21.
    Caramelo C, López F, Gallego MJ, Grandes S, Riesco A, Bosch R, Casado S, Hernando L, Fundación JD (1990) Cyclosporine A (CSA) inhibits the endothelium-dependent, cGMP- mediated natriuretic, diuretic and vasodilatory responses. Reversibility by L-arginine. J Am Soc Nephrol 1: 608AGoogle Scholar
  23. 22.
    Chapman JR, Mareen R, Arias M, Raine AEG, Dunnill MS, Morris PJ (1987) Hypertension after renal transplantation: a comparison of cyclosporine and conventional immunosuppres¬sion. Transplantation 43: 860 - 864PubMedGoogle Scholar
  24. 23.
    Coffman TM, Carr DR, Yarger WE, Klotman PA (1987) Evidence that renal prostaglandin and thromboxane production is stimulated in chronic cyclosporine nephrotoxicity. Transplantation 43: 282 - 285PubMedGoogle Scholar
  25. 24.
    Cohen DJ, Loertscher R, Rubin MD, Tilney NL, Carpenter CB, Strom TB (1984) Cyclos-porine: a new immunosuppressive agent for organ transplantation. Ann Intern Med 101: 667–682PubMedGoogle Scholar
  26. 25.
    Cohen RA, Weisbrod RM (1988) Endothelium inhibits norepinephrine release from adrenergic nerves of rabbit carotid artery. Am J Physiol 254: H871 - H878PubMedGoogle Scholar
  27. 26.
    Conte G, Canton AD, Sabbatini M, Napodano P, De Nicola L, Gigliotti G, Fuiano G, Testa A, Esposito C, Russo D, Andreucci VE (1989) Acute cyclosporine renal dysfunctio reversed by dopamine infusion in healthy subjects. Kidney Int 36: 1086 - 1092PubMedGoogle Scholar
  28. 27.
    Creager MA, Cooke JP, Mendelsohn ME, Gallagher S J, Coleman SM, Loscalzo J, Dzau VJ (1990) Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest 86: 228 - 234PubMedGoogle Scholar
  29. 28.
    Curtis JJ, Dubovsky E, Whelchel JD, Like RG, Diethelm AG, Jones P (1986) Cyclosporine in therapeutic doses increases renal allograft vascular resistance. Lancet 2: 477 - 479PubMedGoogle Scholar
  30. 29.
    Curtis JJ, Luke RG, Jones PA, Diethelm AG (1988) Hypertension in cyclosporine-treated renal transplant patients is sodium dependent. Am J Med 85: 134 - 138PubMedGoogle Scholar
  31. 30.
    Curtis JJ (1989) Hypertension after renal transplantation: cyclosporine increases in diagnostic and therapeutic considerations. Am J Kidney Dis 13 [Suppl 1]: 28 — 32PubMedGoogle Scholar
  32. 31.
    Curtis JJ (1990) Cyclosporine-induced hypertension. In: Laragh JH, Brenner BM (ed) Hypertension: pathophysiology, diagnosis, and management. Raven, New YorkGoogle Scholar
  33. 32.
    Dawidson I, Rooth P, Fry WR, Sandor Z, Willms C, Coorpender L, Alway C, Reisch (1989) Prevention of acute cyclosporine-induced renal blood flow inhibition and improved immu¬nosuppression with verapamil. Transplantation 48: 575 - 580Google Scholar
  34. 33.
    Dawidson I, Rooth P (1990) Effects of calcium antagonists in ameliorating cyclosporine A nephrotoxicity and post-transplant ATN. In: Epstein M, Loutzenhiser R (ed) Calcium antagonists and the kidney. Hanley and Belfus, Philadelphia, pp 233 - 256Google Scholar
  35. 34.
    Delmonico FL, Conti D, Auchincloss H Jr, Russell PS, Tolkoff-Rubin N, Fang LT, Cosimi AB (1990) Long-term, low-dose cyclosporine treatment of renal allograft recipients. Transplantation 49: 899 - 904PubMedGoogle Scholar
  36. 35.
    Deray G, Le Hoang P, Aupetit B, Martinez F, Rottembourg (1988) Renal function and blood pressure in patients treated with cyclosporin A for uveitis. Eur J Clin Pharmacol 34: 601 - 604Google Scholar
  37. 36.
    Diederich D, Jameson M, Fu-Xiang D, Skopec J, Diederich A (1990) Cyclosporine treatment impairs endothelial function in resistance arteries in rats. J Am Soc Nephrol 1: 609AGoogle Scholar
  38. 37.
    Dieperink H (1989) Cyclosporin A nephrotoxicity. Danish Med Bull 36: 235 - 248PubMedGoogle Scholar
  39. 38.
    Dieterle A, Gratwohl, Nizze H, Huser B, Mihatsch MJ, Thiel G, Tichelli A, Signer E, Nissen C, Speck B (1990) Chronic cyclosporine-associated nephrotoxicity in bone marrow transplant patients. Transplantation 49: 1093 - 1100PubMedGoogle Scholar
  40. 39.
    Dunn J, Golden D, Van Buren CT, Lewis RM, Lawen J, Kahan BD (1990) Causes of graft loss beyound two years in the cyclosporine era. Transplantation 49: 349 - 353PubMedGoogle Scholar
  41. 40.
    Dworkin LD (1990) Effects of calcium channel blockers on experimental glomerular injury. J Am Soc Nephrol 1 [Suppl 1]: S21 - S27PubMedGoogle Scholar
  42. 41.
    Dzik WH, Georgi BA, Khettry U, Jenkins RL (1987) Cyclosporine-associated thrombotic thrombocytopenic purpura following liver transplantation—successful treatment with plasma exchange. Transplantation 44: 570 - 572PubMedGoogle Scholar
  43. 42.
    English J, Evan A, Houghton DC, Bennett WM (1987) Cyclosporine-induced renal dysfunction in the rat: evidence for arteriolar vasoconstriction with preservation of tubular function. Transplantation 44: 135 - 141PubMedGoogle Scholar
  44. 43.
    Feehally J, Walls J, Horsburgh T, Taylor J, Veitch PS, Bell PRF (1987) Does nifedipine ameliorate cyclosporine A nephrotoxicity? Br Med J 295: 310Google Scholar
  45. 44.
    Firth JD, Raine AEG, Ratcliffe PJ, Ledingham JGG (1988) Endothelin: an important factor in acute renal failure? Lancet 2: 1179 - 1182PubMedGoogle Scholar
  46. 45.
    Fogo A, Hakim RC, Sugiura M, Inagami T, Kon V (1990) Severe endothelial injury in a renal transplant patient receiving cyclosporine. Transplantation 49: 1190 - 1192PubMedGoogle Scholar
  47. 46.
    Frei U, Margreiter R, Harms A, Bossmuller C, Neumann KH, Viebahn R, Gubenatis G, Wonigeit K, Pichlmayr R (1987) Preoperative graft reperfusion with calcium antagonist improves initial function: Preliminary results of a prospective randomized trial in 100 kidney recipients. Transplant Proc 19: 3539 - 3541PubMedGoogle Scholar
  48. 47.
    Furchgott RF, Zawadzke JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288: 373 - 376PubMedGoogle Scholar
  49. 48.
    Goldberg JP, Schrier RW (1984) Effects of calcium membrane blockers on in vivo vasocon¬strictor properties of norepinephrine, angiotensin II, and vasopressin. Mineral Electrolyte Metab 10: 178 - 183Google Scholar
  50. 49.
    Greenberg A, Thompson ME, Griffith BJ, Hardesty RL, Kormos RL, El-Shahawy MA, Janosky JE, Puschett JB (1990) Cyclosporine nephrotoxicity in cardiac allograft patients — a seven-year follow-up. Transplantation 50: 589 - 593PubMedGoogle Scholar
  51. 50.
    Gryglewski RJ, Botting RM, Vane JR (1988) Mediators produced by the endothelial cell. Hypertension 12: 530 - 548PubMedGoogle Scholar
  52. 51.
    Hall BM, Tiller DJ, Duggin G, Horvath JS, Fransworth A, May J, Johnson JR, Shell AGR (1985) Post-transplant acute renal failure in cadaver renal recipients treated with cyclosporine. Kidney Int 28: 178 - 186PubMedGoogle Scholar
  53. 52.
    Hannedouche TP, Delgado AG, Gnionsahe AD, Boitard C, Noel L-H, Grünfeld J-P (1990) Nephrotoxicity of cyclosporine in autoimmune disease. Adv Nephrol 19: 169 - 186Google Scholar
  54. 53.
    Harris KP, Jenkins D, Walls J (1988) Nonsteroidal antiinflammatory drugs and cyclosporine: a potentially serious adverse interaction. Transplantation 46: 598 - 599PubMedGoogle Scholar
  55. 54.
    Harrison DG, Armstrong ML, Freimann PC, Heistad DD (1987) Restoration of endothelium- dependent relaxation by dietary treatment of atherosclerosis. J Clin Invest 80: 1808 - 1811PubMedGoogle Scholar
  56. 55.
    Hunt Sa, Gamberg P, Stinson EB, Oyer PE, Shumway NE (1990) The Stanford experience: survival and renal function in the pre-Sandimmune era compared to the Sandimmune era. Transpl Proc 22: 1 - 5Google Scholar
  57. 56.
    June CH, Thompson CB, Kennedy MS, Nims J, Thomas ED (1985) Profound hypomagnene- mia and renal magnesium wasting associated with the use of cyclosporine for marrow transplantation. Transplantation 39: 620 - 624PubMedGoogle Scholar
  58. 57.
    June CH, Thompson CB, Kennedy MS, Loughran TP Jr, Deeg HJ (1986) Correlation of hypomagnesemia with the onset of cyclosporine-associated hypertension in marrow transplant patients. Transplantation 41: 47 - 51PubMedGoogle Scholar
  59. 58.
    Kahan BD (1985) Individualization of cyclosporine therapy using pharmacokinetic and pharmacodynamic parameters. Transplantation 40: 457–76PubMedGoogle Scholar
  60. 59.
    Kahan DB (1990) Summary on therapeutic drug monitoring for renal transplantation. Transplant Proc 22: 1348 - 1351PubMedGoogle Scholar
  61. 60.
    Kirk AJB, Omar I, Bateman DN, Dark JH (1989) Cyclosporine-associated hypertension in cardiopulmonary transplantation: the beneficial effect of nifedipine on renal function. Transplantation 48: 428 - 430PubMedGoogle Scholar
  62. 61.
    Kon V, Sugiura M, Inagami T, Harvie BR, Ichikawa I, Hoover RL (1990) Role of endothelin in cyclosporine-induced glomerular dysfunction. Kidney Int 37: 1467 - 1491Google Scholar
  63. 62.
    Kon V, Yoshioka T, Fogo A Ichikawa I (1989) Glomerular actions of endothelin in vivo. J Clin Invest 83: 1762 - 1767PubMedGoogle Scholar
  64. 63.
    Kopp JB, Klotzman PE (1990) Cellular and molecular mechanisms of cyclosporine nephrotoxicity. J Amer Soc Nephrol 1: 162 - 179Google Scholar
  65. 64.
    Lamb JS, Webb RC (1987) Cyclosporine augments reactivity of isolated blood vessels. Life Sci 40: 2571 - 2578PubMedGoogle Scholar
  66. 65.
    Laskow DA, Curtis JJ, Luke RG, Julian BA, Jones P, Deierhoi MH, Barber H, Diethelm AG (1990) Cyclosporine-induced changes in glomerular filtration rate and urea excretion. Am J Med 88: 497 - 502PubMedGoogle Scholar
  67. 66.
    Lewis RM, Janney RP, Golden DL, Kerr NB, Van Buren CT, Kerman RH, Kahan Bd (1989) Stability of renal allograft function associate with long-term cyclosporine immunosuppressive therapy-five year follow-up. Transplantation 47: 266 - 272PubMedGoogle Scholar
  68. 67.
    Lin H-Y, Rocher LL, McQuillan MA, Schmaltz S, Palella TD, Fox IH (1989) Cyclosporine- induced hyperuricemia and gout. N Engl J Med 321: 287 - 292PubMedGoogle Scholar
  69. 68.
    Loutzenhiser R, Epstein M, Hayashi K, Horton C (1990) Direct visualization of effects of endothelin on the renal microcirculation. Am J Physiol 258: F61 - F68PubMedGoogle Scholar
  70. 69.
    Loutzenhiser R, Epstein M (1990) Renal microvascular actions of calcium antagonists. J Am Soc Nephrol 1 [Suppl 1]: S3 - S12PubMedGoogle Scholar
  71. 70.
    Luke RG (1987) Hypertension in renal transplant recipients. Kidney Int 31: 1024 - 1037PubMedGoogle Scholar
  72. 71.
    Lüscher TF ( 1990 The endothelium: target and promoter of hypertension? Hypertension 15: 482 - 485PubMedGoogle Scholar
  73. 72.
    Lüscher TF ( 1990 The endothelium: target and promoter of hypertension? Hypertension 15: 482 - 485PubMedGoogle Scholar
  74. 73.
    Lustig S, Stern N, Eggena P, Tuck ML, Lee DBN (1987) Effect of cyclosporin on blood pressure and renin-aldosterone axis in the rat. Am J Physiol 2531596-H1600Google Scholar
  75. 74.
    Macris MP, Frazier OH, Van Buren CT, Lammermeier DE, Kahan DB ( 1989 Improved immunosuppression for heart transplant patients using intravenous doses of cyclosporine. Transplantation 47: 311 - 314PubMedGoogle Scholar
  76. 75.
    Mayhan WG (1989) Impairment of endothelium-dependent dilation of cerebral arterioles during diabetes mellitus. Am J Physiol 256: H621 - H625PubMedGoogle Scholar
  77. 76.
    Mark AL (1990) Cyclosporine, sympathetic activity, and hypertension. N Engl J Med 323: 748 - 750PubMedGoogle Scholar
  78. 77.
    Mason J (1990) Renal side-effects of cyclosporine. Transplant Proc 22: 1280 - 1283PubMedGoogle Scholar
  79. 78.
    McDiarmid SW, Ettenger RB, Hawkins RA, Senguttvan P, Busuttil RW, Vargas J, Berquist WE, Ament ME (1990) The impairment of true glomerular filtration rate in long-term cyclosporine-treated pediatric allograft recipients. Transplantation 49: 81 - 85PubMedGoogle Scholar
  80. 79.
    McNally PG, Baker F, Walls J, Feehally J (1990) Effect of nifedipine on renal haemodynamics in an animal model of cyclosporine A nephrotoxicity. Clin Sci 79: 259 - 266PubMedGoogle Scholar
  81. 80.
    Mihatsch MJ, Thiel G, Ryffel B (1988) Cyclosporine nephrotoxicity. Adv Nephrol 17:303- 320Google Scholar
  82. 81.
    Miller LW, Pennington DG, McBride LR (1990) Long-term effects of cyclosporine in cardiac transplantation. Transplant Proc 22: 15 - 20PubMedGoogle Scholar
  83. 82.
    Moncada S, Palmer RMJ, Higgs EA (1988) The discovery of nitric oxide as the endogenous nitrovasodilator. Hypertension 12: 365 - 372PubMedGoogle Scholar
  84. 83.
    Moran M, Mozes MF, Daddux MS, Veremis S, Bartkus C, Ketel B, Pollak R, Wallemark C, Jonasson O (1990) Prevention of acute graft rejection by the prostaglandin analogue misoprostol in renal transplant recipients treated with cyclosporine and prednisone. N Engl J Med 322: 1183 - 1188PubMedGoogle Scholar
  85. 84.
    Moss NG, Powell SL, Falk WF (1985) Intravenous cyclosporine activates afferent and efferent renal nerves and causes sodium retention in innervated kidneys in rats. Proc Natl Acad Sci USA 82: 8222 - 8226PubMedGoogle Scholar
  86. 85.
    Murray BM, Paller MS, Ferris TF (1985) Effect of cyclosporine administration on renal hemodynamics in conscious rats. Kidney Int 28: 767 - 774PubMedGoogle Scholar
  87. 86.
    Myers BD, Ross J, Newton L, Luetscher J, Perlroth M (1984) Cyclosporine-associated chronic nephropathy. N Engl J Med 311: 699 - 705PubMedGoogle Scholar
  88. 87.
    Myers BD (1986) Cyclosporine nephrotoxicity. Kidney Int 30: 964 - 974PubMedGoogle Scholar
  89. 88.
    Myers BD, Sibley R, Newton L, Tomlanovich SJ, Boshkos C, Stinson E, Luetscher JA, Whitney DJ, Krasny D, Colon NS, Perlroth MG (1988) The long-term course of cyclosporine- associated chronic nephropathy. Kidney Int 35: 590 - 600Google Scholar
  90. 89.
    Myer-Lehnert H, Schrier RW (1988) Cyclosporine A enhances vasopressin-induced CA2 mobilization and contraction in mesangial cells. Kidney Int 34: 89 - 97Google Scholar
  91. 90.
    Myer-Lehnert H, Schrier RW (1989) Potential mechanism for cyclosporine A-induced vascular smooth muscle contraction. Hypertension 13: 352 - 360Google Scholar
  92. 91.
    Nambi P, Pullen M, Contino LC, Brooks DP (1990) Upregulation of renal endothelin receptors in rats with cyclosporine A-induced nephrotoxicity. Eur J Pharmacol 187: 113 - 116PubMedGoogle Scholar
  93. 92.
    Nayler WG, Gu XH, Casley DJ, Panagiotopoulos S, Liu J, Mottram PL (1989) Cyclosporine increases endothelin-1 binding site density in cardiac cell membranes. Biochem Biophys Res Commun 163: 1270 - 1274PubMedGoogle Scholar
  94. 93.
    Neild GH, Reuben R, Hartley RB, Cameron JS (1985) Glomerular thrombi in renal allografts associated with cyclosporine treatment. J Clin Pathol 38: 253 - 258PubMedGoogle Scholar
  95. 94.
    Neumayer HH, Wagner K (1987) Prevention of delayed graft function in cadaver kidney transplants by diltiazem: Outcome of two prospective, randomized clinical trials. J Cardio-vasc Pharmacol 10: S170 - S177Google Scholar
  96. 95.
    Nicchitta CV, Kamoun M, Williamson JR (1985) Cyclosporine augments receptor-mediated cellular CA2 fluxes in isolated hepatocytes. J Biol Chem 260: 13613 - 13618PubMedGoogle Scholar
  97. 96.
    Novick AC, Hwei H-H, Steinmuller D, Streem SB, Cunningham RJ, Steinhilber D; Goor- mastic M, Buszta C (1986) Detrimental effect of cyclosporine on initial function of cadaver renal allografts following extended preservation: results of randomized prospective study. Transplantation 42: 154 - 158PubMedGoogle Scholar
  98. 97.
    Ohlstein EH, Nambi P, Contino LC, Storer B, Pullen M, Caltabiano M, Brooks DP (1990) Urinary endothelin excretion and renal endothelin receptor number in cyclosporine A- treated rats administered nifedipine. J Am Soc Nephrol 1: 616AGoogle Scholar
  99. 98.
    Paller MS (1988) Effects of the prostaglandin E1 analog misoprostol on cyclosporine nephrotoxicity. Transplantation 45: 1126 - 1131PubMedGoogle Scholar
  100. 99.
    Palmer RMJ, Ashton DS, Moneada S (1988) Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 333: 664 - 666PubMedGoogle Scholar
  101. 100.
    Palstine AG, Austin HA III, Nussenblatt RB (1986) Renal tubular function in cyclosporine- treated patients. Am J Med 81: 419 - 424Google Scholar
  102. 101.
    Panza JA, Quyyumi AA, Brush JE, Epstein SE (1990) Abnormal endothelium-dependent relaxation in patients with essential hypertension. N Engl J Med 323: 22 - 27PubMedGoogle Scholar
  103. 102.
    Perico N, Benigni A, Zoja C, Delaini F, Remuzzi G (1986) Functional significance of exaggerated renal thromboxane A2 synthesis induced by cyclosporine A. Am J Physiol 251:F581N587Google Scholar
  104. 103.
    Perico N, Dadan J, Remuzzi G (1990) Endothelin mediates the renal vasoconstriction induced by cyclosporine in the rat. J Am Soc Nephrol 1: 76 - 83PubMedGoogle Scholar
  105. 104.
    Perico N, Genigni A, Ladny JR, Imberti O, Bellizzi L, Remuzzi G (1990) Chronic cyclosporine A administration to rats increases urinary excretion of big-endothelin and endothelin. J Am Soc Nephrol 1: 617AGoogle Scholar
  106. 105.
    Pfeilschifter J (1988) Cyclosporine A augments vasoconstrictor-induced rise in intracellular free calcium in rat renal mesangial cells. Biochem Pharmacol 37: 4205–4210PubMedGoogle Scholar
  107. 106.
    Puschett JB, Greenberg A, Holley J, McCauley J (1990) The spectrum of cyclosporine nephrotoxicity. Am J Nephrol 10: 296 - 309PubMedGoogle Scholar
  108. 107.
    Ramadan FM, Upchurch GR Jr, Blair BA, Johnson G Jr (1990) Endothelial cell thromboxane production and its inhibition by a calcium-channel blocker. Ann Thorac Surg 49: 916 - 919PubMedGoogle Scholar
  109. 108.
    Rego A, Vargas R, Suarea KR, Foegh ML, Ramwell P (1990) Mechanism of cyclosporine potentiation of vasoconstriction of the isolated rat mesenteric arterial bed: role of extracellu¬lar calcium. J Pharmacol Exp Therap 254: 799 - 808Google Scholar
  110. 109.
    Remuzzi G, Bertani T (1989) Renal vascular and thrombotic effects of cyclosporine. Am J Kidney Dis 13: 261 - 272PubMedGoogle Scholar
  111. 110.
    Richards NT, Poston L, Hilton PJ (1989) Cyclosporine A inhibits relaxation but does not induce vasoconstriction in human subcutaneous resistance vessels. J Hypertension 7: 1 - 2Google Scholar
  112. 111.
    Richards NT, Poston L, Hilton PJ (1990) Cyclosporine A inhibits endothelium-dependent, prostanoid-induced relaxation in human subcutaneous resistance vessels. J Hypertension 8: 159 - 163Google Scholar
  113. 112.
    Rocher LL, Milford EL, Kirkman RL, Carpenter CB, Strom TB, Tilney NL (1984) Conversion from cyclosporine to azathioprine in renal allograft recipients. Transplantation 38:669- 674Google Scholar
  114. 113.
    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 - 156PubMedGoogle Scholar
  115. 114.
    Rooth P, Dawidson I, Clothier N, Diller (1988) In vivo fluorescence microscopy of kidney subcapsular blood flow in mice: effects of cyclosporine, (Nva2)-cyclosporine, and isradipine, a new calcium antagonist. Transplantation 46: 566 - 569Google Scholar
  116. 115.
    Scherrer U, Vissing SF, Morgan BJ, Rollins JA, Tindall RSA, Ring S, Hanson P, Mohanty PK, Victor RG (1990) Cyclosporine-induced sympathetic activation and hypertension after heart transplantation. N Engl J Med 323: 693 - 699PubMedGoogle Scholar
  117. 116.
    Schrier RW, Arnold PE, Van Putten VJ, Burke TJ (1987) Cellular calcium in ischemic acute renal failure. Role of calcium entry blockers. Kidney Int 32: 313 - 321PubMedGoogle Scholar
  118. 117.
    Shaw LM, Audet PR, Fields L, Lensmeyer GL, Dafoe DC (1990) Adjustment of cyclosporin dosage in renal transplant patients based on concentration measured specifically in whole blood: clinical outcome results and diagnostic utility. Transplantation Proc 22: 1267 - 1273Google Scholar
  119. 118.
    Shulman H, Striker G, Deeg JH, Kennedy M, Shorb R, Thomas ED (1981) Nephrotoxicity of cyclosporine A after allogenic marrow transplantation: glomerular thrombosis and tubular injury. N Engl J Med 305: 1392 - 1395PubMedGoogle Scholar
  120. 119.
    Shultz PJ, Schorer AE, Raij L (1990) Effects of endothelium-derived relaxing factor and nitric oxide on rat mesangial cells. Am J Physiol 258: F162 - F167PubMedGoogle Scholar
  121. 120.
    Stahl RAK, Kanz L, Schollmeyer P (1986) Hyperchloremic metabolic acidosis with high serum potassium in renal transplant recipients: a cyclosporine A associated side effect. Clin Nephrol 25: 245 - 248PubMedGoogle Scholar
  122. 121.
    Sumrani N, Delaney V, Ding Z, Butt K, Hong J (1990) HLA-identical renal transplants: impact of cyclosporine on intermediate-term survival and renal function. Am J Kidney Dis 16: 417–422PubMedGoogle Scholar
  123. 122.
    Sweny P, Wheeler DC, Lui SF, Amin NS, Barradas MA, Jeremy JY, Mikhailidis DP, Varghese Z, Fernando ON, Moorhear JF (1989) Dietary fish oil supplements preserve renal function in renal transplant recipients with chronic vascular reaction. Nephrol Dial Transplant 4: 1070 - 1075PubMedGoogle Scholar
  124. 123.
    Tesfamariam B, Jakubowski JA, Cohen RA (1989) Contraction of diabetic rabbit aorta caused by endothelium-derived PGH2-TxA2. Am J Physiol 257: H1327 - H1333PubMedGoogle Scholar
  125. 124.
    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 - 337PubMedGoogle Scholar
  126. 125.
    Thompson CB, June CH, Sullivan KM, Thomas ED (1984) Association between cyclosporine neurotoxicity and hypomagnesaemia. Lancet 2: 116 - 1120Google Scholar
  127. 126.
    Thomson SC, Tucker BJ, Gabbai F, Blantz RC (1989) Functional effects of glomerular hemodynamics of short-term chronic cyclosporine in male rats. J Clin Invest 83: 960 - 969PubMedGoogle Scholar
  128. 127.
    Tolins JP, Palmer RMJ, Moncada S, Raij L (1990) Role of endothelium-derived relaxing factor in regulation of renal hemodynamic responses. Am J Physiol 258: H655 - H662PubMedGoogle Scholar
  129. 128.
    Van der Heide JJH, Bilo HJG, Tegzess AM, Donker AJM (1990) The effects of dietary supplementation with fish oil on renal function in cyclosporine-treated renal transplant recipients. Transplantation 49: 523 - 527Google Scholar
  130. 129.
    Vane JR, Anggard EE, Botting RM (1990) Regulatory functions of the vascular endothelium. N Engl J Med 323: 27 - 36PubMedGoogle Scholar
  131. 130.
    Vanhoutte PM, Rubanyi GM, Miller VM, Houston DA (1986) Modulation of vascular smooth muscle contraction by the endothelium. Ann Rev Physiol 48: 307 - 320Google Scholar
  132. 131.
    Voss BL, Hamilton KK, Scott Samara EN, McKee PA (1988) Cyclosporine suppression of endothelial prostacyclin generation. Transplantation 45: 793 - 796PubMedGoogle Scholar
  133. 132.
    Wagner K, Albrecht S, Neumayer HH (1987) Prevention of post-transplant acute tubular necrosis by the calcium antagonist diltiazem: a prospective randomized study. Am J Nephrol 7: 287 - 291PubMedGoogle Scholar
  134. 133.
    Weir MR, Klassen DK, Shen SY, Sullivan D, Buddemeyer EU, Handwerger BS (1990) Acute effects of intravenous cyclosporine on blood pressure, renal hemodynamics, and urine prostaglandin production of healthy humans. Transplantation 49: 41–47PubMedGoogle Scholar
  135. 134.
    Weir MR (1990) Calcium channel blockers in organ transplantation: import new therapeutic modalities. J Am Soc Nephrol 1 [Suppl 1]: S28 - S38PubMedGoogle Scholar
  136. 135.
    Whittle BJR, Moncada S (1990) The endothelin explosion: a pathophysiological reality or a biological curiosity. Circulation 81: 2022 - 2025PubMedGoogle Scholar
  137. 136.
    Wrenshall LE, Matas AJ, Canafax DM, Min DI, Sibley RJ, Dunn DL, Payne WD, Sutherland DER, Najarian JS (1990) An increased incidence of late acute rejection episodes in cadaver renal allograft recipients given azathioprine, cyclosporine, and prednisone. Transplantation 50: 233 - 237PubMedGoogle Scholar
  138. 137.
    Xue H, Bukoski RD, McCarron DA, Bennett WM (1987) Induction of contraction in isolated rat aorta by cyclosporine. Transplantation 43: 715 - 718PubMedGoogle Scholar
  139. 138.
    Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332: 411–415PubMedGoogle Scholar
  140. 139.
    Yee GC (1990) Pharmacokinetic interactions between cyclosporine and other drugs. Transplant Proc 22: 1203 - 1207PubMedGoogle Scholar

Copyright information

© Springer Verlag, Berlin Heidelberg 1992

Authors and Affiliations

  • D. Diederich
  • Dai Fu-Xiang
  • M. Jameson

There are no affiliations available

Personalised recommendations