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Effect of Immunosuppressive Agents on Long-Term Survival of Renal Transplant Recipients

Focus on the Cardiovascular Risk

  • Review Article
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Abstract

In the control of acute rejection, attention is being focused more and more on the long-term adverse effects of the immunosuppressive agents used. Since cardiovascular disease is the main cause of death in renal transplant recipients, optimal control of cardiovascular risk factors is essential in the long-term management of these patients. Unfortunately, several commonly used immunosuppressive drugs interfere with the cardiovascular system. In this review, the cardiovascular adverse effects of the immunosuppressive agents currently used for maintenance immunosuppression are thoroughly discussed.

Optimising immunosuppression means finding a balance between efficacy and safety. Corticosteroids induce endothelial dysfunction, hypertension, hyperlipidaemia and diabetes mellitus, and impair fibrinolysis. The use of corticosteroids in transplant recipients is undesirable, not only because of their cardiovascular effects, but also because they induce such adverse effects as osteoporosis, obesity, and atrophy of the skin and vessel wall. Calcineurin inhibitors are the most powerful agents for maintenance immunosuppression. The calcineurin inhibitor ciclosporin (cyclosporine) not only induces these same adverse effects as corticosteroids but is also nephrotoxic. Tacrolimus has a more favourable cardiovascular risk profile than ciclosporin and is also less nephrotoxic. It has little or no effect on blood pressure and serum lipids; however, its diabetogenic effect is more prominent in the period immediately following transplantation, although at maintenance dosages, the diabetogenic effect appears to be comparable to that of ciclosporin. The diabetogenic effect of tacrolimus can be managed by reducing the dose of tacrolimus and early corticosteroid withdrawal. The effect of tacrolimus on endothelial function has not been completely elucidated. The proliferation inhibitors azathioprine and mycophenolate mofetil (MMF) have little effect on the cardiovascular system. Yet, indirectly, by inducing anaemia, they may lead to left ventricular hypertrophy. MMF is an attractive alternative to azathioprine because of its higher potency and possibly lower risk of malignancies. Sirolimus also induces anaemia, but may be promising because of its antiproliferative features. Whether the hyperlipidaemia induced by sirolimus counteracts its beneficial effects is, as yet, unknown. It may be combined with MMF, however, initial attempts resulted in severe mouth ulcers.

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  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999; 341: 1725–30

    Article  PubMed  CAS  Google Scholar 

  2. Schnuelle P, Lorenz D, Trede M, et al. Impact of renal cadaveric transplantation on survival in end-stage renal failure: evidence for reduced mortality risk compared with hemodialysis during long-term follow-up. J Am Soc Nephrol 1998; 9: 2135–41

    PubMed  CAS  Google Scholar 

  3. Ojo AO, Hanson JA, Meier-Kriesche H-U, et al. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates. J Am Soc Nephrol 2001; 12: 589–97

    PubMed  CAS  Google Scholar 

  4. Howard RJ, Patton PR, Reed AI, et al. The changing causes of graft loss and death after kidney transplantation. Transplantation 2002; 73: 1923–8

    Article  PubMed  Google Scholar 

  5. Ojo AO, Hanson JA, Wolfe RA, et al. Long-term survival in renal transplant recipients with graft function. Kidney Int 2000; 57: 307–13

    Article  PubMed  CAS  Google Scholar 

  6. Amemiya H, Itoh H. Mizoribine (Bredinin®): mode of action and effects on graft rejection. In: Thomson AW, Starzl TE, editors. Immunosuppressive drugs: developments in anti-rejection therapy. London: Edward Arnold, 1993: 161–76

    Google Scholar 

  7. Meier-Kriesche H-U, Arndorfer JA, Kaplan B. Association of antibody induction with short- and long-term cause specific mortality in renal transplantation. J Am Soc Nephrol 2002; 13: 769–72

    PubMed  Google Scholar 

  8. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999; 340: 115–26

    Article  PubMed  CAS  Google Scholar 

  9. Frohlich J, Dobiasova M, Lear S, et al. The role of risk factors in the development of atherosclerosis. Crit Rev Clin Lab Sci 2001; 38: 401–40

    Article  PubMed  CAS  Google Scholar 

  10. Keaney Jr JF. Atherosclerosis: from lesion formation to plaque activation and endothelial dysfunction. Mol Aspects Med 2000; 21: 99–166

    Article  PubMed  CAS  Google Scholar 

  11. Gimbrone Jr MA, Topper JN, Nagel T, et al. Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann N Y Acad Sci 2000; 902: 230–9

    Article  PubMed  CAS  Google Scholar 

  12. Poredos P. Endothelial dysfunction in the pathogenesis of atherosclerosis. Int Angiol 2002; 21: 109–16

    PubMed  CAS  Google Scholar 

  13. Glagov S, Zarins C, Giddens DP, et al. Hemodynamics and atherosclerosis: insights and perspectives gained from the studies of human arteries. Arch Pathol Lab Med 1988; 112: 1018–33

    PubMed  CAS  Google Scholar 

  14. Schächinger V, Zeiher AM. Atherogenesis: recent insights into basic mechanisms and their clinical impact. Nephrol Dial Transplant 2002; 17: 2055–64

    Article  PubMed  Google Scholar 

  15. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327: 524–6

    Article  PubMed  CAS  Google Scholar 

  16. Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 1988; 329: 664–6

    Article  Google Scholar 

  17. John S, Schmieder RE. Impaired endothelial function in arterial hypertension and hypercholesterolemia: potential mechanisms and differences. J Hypertens 2000; 18: 363–74

    Article  PubMed  CAS  Google Scholar 

  18. Cybulsky MI, Gimbrone Jr MA. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 1991; 251: 788–91

    Article  PubMed  CAS  Google Scholar 

  19. Cushing SD, Berliner JA, Valente AJ, et al. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci U S A 1990; 87: 5134–8

    Article  PubMed  CAS  Google Scholar 

  20. Jonasson L, Holm J, Skalli O, et al. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 1986; 6: 131–8

    Article  PubMed  CAS  Google Scholar 

  21. van der Wal AC, Das PK, Bentz van de Berg D, et al. Atherosclerotic lesions in humans: in situ immunophenotypic analysis suggesting an immune mediated response. Lab Invest 1989; 61: 166–70

    PubMed  Google Scholar 

  22. Napoli C, D’Armiento FP, Mancini FP, et al. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia: intimai accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest 1997; 100: 2680–90

    Article  PubMed  CAS  Google Scholar 

  23. Stary HC, Chandler AB, Glagov S, et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis: a report from the Comittee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1994; 89: 2462–78

    Article  PubMed  CAS  Google Scholar 

  24. Quinn MT, Parthasarathy S, Fong LG, et al. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocytes/macrophages during atherogenesis. Proc Natl Acad Sci U S A 1987; 84: 2995–8

    Article  PubMed  CAS  Google Scholar 

  25. McMurray HF, Parthasarathy S, Steinberg D. Oxidatively modified low density lipoprotein is a chemoattractant for human T lymphocytes. J Clin Invest 1993; 92: 1004–8

    Article  PubMed  CAS  Google Scholar 

  26. Parums DV, Brown DL, Mitchinson MJ. Serum antibodies to oxidized low-density lipoprotein and ceroid in chronic periaortitis. Arch Pathol Lab Med 1990; 114: 383–7

    PubMed  CAS  Google Scholar 

  27. Salonen JT, Ylä-Herttuala S, Yamamoto R, et al. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet 1992; 339: 883–7

    Article  PubMed  CAS  Google Scholar 

  28. Klimov AN, Denisenko AD, Popov AV, et al. Lipoprotein-antibody immune complexes: their catabolism and role in foam cell formation. Atherosclerosis 1985; 58: 1–15

    Article  PubMed  CAS  Google Scholar 

  29. Griffith RL, Virella GT, Stevenson HC, et al. Low density lipoprotein metabolism by human macrophages activated with low density lipoprotein immune complexes: a possible mechanism of foam cell formation. J Exp Med 1988; 168: 1041–59

    Article  PubMed  CAS  Google Scholar 

  30. Glagov S, Weisenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987; 316: 1371–5

    Article  PubMed  CAS  Google Scholar 

  31. Kiechl S, Willeit J. The natural course of atherosclerosis. Part I: incidence and progression. The Bruneck Study Group. Arterioscler Thromb Vasc Biol 1999; 19: 1484–90

    CAS  Google Scholar 

  32. London GM, Drüeke TB. Atherosclerosis and arteriosclerosis in chronic renal failure. Kidney Int 1997; 51: 1678–95

    Article  PubMed  CAS  Google Scholar 

  33. Hodis HN, Mack WJ, LaBree L, et al. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med 1998; 128: 262–9

    PubMed  CAS  Google Scholar 

  34. Blacher J, Guerin AP, Pannier B, et al. Impact of aortic stiffness on survival in end-stage renal disease. Circulation 1999; 99: 2434–9

    Article  PubMed  CAS  Google Scholar 

  35. Blacher J, Safar ME, Guerin AP, et al. Aortic pulse wave velocity index and mortality in end-stage renal disease. Kidney Int 2003; 63: 1852–60

    Article  PubMed  Google Scholar 

  36. Roman MJ, Saba PS, Pini R, et al. Parallel cardiac and vascular adaptation in hypertension. Circulation 1992; 86: 1909–18

    Article  PubMed  CAS  Google Scholar 

  37. London GM. The concept of ventricular/vascular coupling: functional and structural alterations of the heart and arterial vessels go in parallel. Nephrol Dial Transplant 1998; 13: 250–3

    Article  PubMed  CAS  Google Scholar 

  38. O’Rourke M. Mechanical principles in arterial disease. Hypertension 1995; 26: 2–9

    Article  PubMed  Google Scholar 

  39. Panza JA, Quyyumi AA, Brush JE, et al. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990; 323: 22–7

    Article  PubMed  CAS  Google Scholar 

  40. Higashi Y, Sasaki S, Nakagawa K, et al. Endothelial function and oxidative stress in renovascular hypertension. N Engl J Med 2002; 346: 1954–62

    Article  PubMed  CAS  Google Scholar 

  41. Chowienczyk PJ, Watts GF, Cockcroft JR, et al. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet 1992; 340: 1430–2

    Article  PubMed  CAS  Google Scholar 

  42. Johnstone MT, Creager SJ, Scales KM, et al. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993; 88: 2510–6

    Article  PubMed  CAS  Google Scholar 

  43. Celermajer DS, Sorensen KE, Georgakopoulos D, et al. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation 1993; 88: 2149–55

    Article  PubMed  CAS  Google Scholar 

  44. Pannier B, Guerin AP, Marchais SJ, et al. Postischemic vasodilation, endothelial activation, and cardiovascular remodeling in end-stage renal disease. Kidney Int 2000; 57: 1091–9

    Article  PubMed  CAS  Google Scholar 

  45. Bolton CH, Downs LG, Victory JGG, et al. Endothelial dysfunction in chronic renal failure: roles of lipoprotein oxidation and pro-inflammatory cytokines. Nephrol Dial Transplant 2001; 16: 1189–97

    Article  PubMed  CAS  Google Scholar 

  46. Annuk M, Lind L, Linde T, et al. Impaired endothelium-dependent vasodilatation in renal failure in humans. Nephrol Dial Transplant 2001; 16: 302–6

    Article  PubMed  CAS  Google Scholar 

  47. Celermajer DS, Sorensen K, Ryalls M, et al. Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents. J Am Coll Cardiol 1993; 22: 854–8

    Article  PubMed  CAS  Google Scholar 

  48. Stühlinger MC, Oka RK, Graf EE, et al. Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine. Circulation 2003; 108: 933–8

    Article  PubMed  CAS  Google Scholar 

  49. Graham A, Hogg N, Kalyanaraman B, et al. Peroxynitrite modification of low-density lipoprotein leads to recognition by the macrophage scavenger receptor. FEBS Lett 1993; 330: 181–5

    Article  PubMed  CAS  Google Scholar 

  50. Chambers JC, Ueland PM, Wright M, et al. Investigation of relationship between reduced, oxidized, and protein-bound homocysteine and vascular endothelial function in healthy human subjects. Circ Res 2001; 89: 187–92

    Article  PubMed  CAS  Google Scholar 

  51. Dawber TR, Kannel WB. The Framingham Study: an epidemiological approach to coronary heart disease. Circulation 1966; 34: 553–5

    Article  PubMed  CAS  Google Scholar 

  52. Kasiske BL. Risk factors for accelerated atherosclerosis in renal transplant recipients. Am J Med 1988; 84: 985–92

    Article  PubMed  CAS  Google Scholar 

  53. Kasiske BL, Chakkera HA, Roel J. Explained and unexplained ischemic heart disease risk after renal transplantation. J Am Soc Nephrol 2000; 11: 1735–43

    PubMed  CAS  Google Scholar 

  54. Manske CL, Wang Y, Rector T, et al. Coronary revascularisation in insulin-dependent diabetic patients with chronic renal failure. Lancet 1992; 340: 998–1002

    Article  PubMed  CAS  Google Scholar 

  55. Kasiske BL, Guijarro C, Massy ZA. Cardiovascular disease after renal transplantation. J Am Soc Nephrol 1996; 7: 158–65

    PubMed  CAS  Google Scholar 

  56. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998; 32 (5 Suppl. 3): S112–S9

    Article  PubMed  CAS  Google Scholar 

  57. Hollander AA, van Saase JL, Kootte AM, et al. Beneficial effects of conversion from cyclosporin to azathioprine after kidney transplantation. Lancet 1995; 345: 610–4

    Article  PubMed  CAS  Google Scholar 

  58. Bakker RC, Hollander AAMJ, Mallat MJK, et al. Conversion from cyclosporine to azathioprine at three months reduces the incidence of chronic allograft nephropathy. Kidney Int 2003; 64: 1027–34

    Article  PubMed  CAS  Google Scholar 

  59. Pirsch JD, Miller J, Deierhoi MH, et al. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation: the FK506 Kidney Transplant Study Group. Transplantation 1997; 63: 977–83

    Article  PubMed  CAS  Google Scholar 

  60. Mayer AD, Dmitrewski J, Squifflet J-P, et al. Multicenter randomized trial comparing tacrolimus (FK 506) and cyclosporin in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group. Transplantation 1997; 64: 436–43

    Article  PubMed  CAS  Google Scholar 

  61. Schnitzler MA, Craig KE, Hardinger KE, et al. Mycophenolate mofetil is associated with less death with function than azathioprine in cadaveric renal transplantation. Nephrol Dial Transplant 2003; 18: 1197–200

    Article  PubMed  CAS  Google Scholar 

  62. Passauer J, Büssemaker E, Lassig G, et al. Kidney transplantation improves endothelium-dependent vasodilation in patients with endstage renal disease. Transplantation 2003; 75: 1907–10

    Article  PubMed  Google Scholar 

  63. Oflaz H, Pusuroglu H, Genchallac H, et al. Endothelial function is more impaired in hemodialysis patients than renal transplant recipients. Clin Transplant 2003; 17: 528–33

    Article  PubMed  Google Scholar 

  64. Iuchi T, Akaike M, Mitsui T, et al. Glucocorticoid excess induces Superoxide production in vascular endothelial cells and elicits vascular endothelial dysfunction. Circ Res 2003; 92: 81–7

    Article  PubMed  CAS  Google Scholar 

  65. Morris STW, McMurray JJV, Rodger RSC, et al. Endothelial dysfunction in renal transplant recipients maintained on cyclosporin. Kidney Int 2000; 57: 1100–6

    Article  PubMed  CAS  Google Scholar 

  66. van den Dorpel MA, van den Meiracker AH, Lameris TW, et al. Forearm vasorelaxation in hypertensive renal transplant patients: the impact of withdrawal of cyclosporine. J Hypertens 1998; 16: 331–7

    Article  PubMed  Google Scholar 

  67. Galle J, Lehman-Bodem C, Hübner U, et al. CyA and OxLDL cause endothelial dysfunction in isolated arteries through endothelin-mediated stimulation of O2-formation. Nephrol Dial Transplant 2000; 15: 339–46

    Article  PubMed  CAS  Google Scholar 

  68. Ovuworie CA, Fox ER, Chow C-M, et al. Vascular endothelial function in cyclosporine and tacrolimus treated renal transplant recipients. Transplantation 2001; 72: 1385–8

    Article  PubMed  CAS  Google Scholar 

  69. Oflaz H, Turkmen A, Kazancioglu R, et al. The effect of calcineurin inhibitors on endothelial function in renal transplant recipients. Clin Transplant 2003; 17: 212–6

    Article  PubMed  Google Scholar 

  70. Wilasrusmee C, Da Silva M, Singh B, et al. Morphological and biochemical effects of immunosuppressive drugs in a capillary tube assay for endothelial dysfunction. Clin Transplant 2003; 17: 6–12

    Article  PubMed  Google Scholar 

  71. Wilasrusmee C, Da Silva M, Siddiqui J, et al. Role of endothelin-1 in microvascular dysfunction caused by cyclosporin A. J Am Coll Surg 2003; 196: 584–91

    Article  PubMed  Google Scholar 

  72. Wilson PWF, D’Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97: 1837–47

    Article  PubMed  CAS  Google Scholar 

  73. Mange KC, Cizman B, Joffe M, et al. Arterial hypertension and renal allograft survival. JAMA 2000; 283: 633–8

    Article  PubMed  CAS  Google Scholar 

  74. Opelz G, Wujciak T, Ritz E. Association of chronic kidney graft failure with recipient blood pressure: the Collaborative Transplant Study. Kidney Int 1998; 53: 217–22

    Article  PubMed  CAS  Google Scholar 

  75. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials: the Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet 2000; 356: 1955–64

    Article  PubMed  CAS  Google Scholar 

  76. Hoes AW, Grobbee DE, Lubsen J. Does drug treatment improve survival? Reconciling the trials in mild-to-moderate hypertension. J Hypertens 1995; 13: 805–11

    PubMed  CAS  Google Scholar 

  77. Kasiske BL, Vazquez MA, Harmon WE, et al. Recommendations for the outpatient surveillance of renal transplant recipients. J Am Soc Nephrol 2000; 11: S1–S86

    PubMed  Google Scholar 

  78. Pérez Fontán M, Rodriguez-Carmona A, Garcia Falcón T, et al. Early immunologic and nonimmunologic predictors of arterial hypertension after renal transplantation. Am J Kidney Dis 1999; 33: 21–8

    Article  PubMed  Google Scholar 

  79. Peschke B, Scheuermann EH, Geiger H, et al. Hypertension is associated with hyperlipidemia, coronary heart disease and chronic graft failure in kidney transplant recipients. Clin Nephrol 1999; 51: 290–5

    PubMed  CAS  Google Scholar 

  80. Kasiske BL. Ischemic heart disease after renal transplantation. Kidney Int 2002; 61: 356–69

    Article  PubMed  Google Scholar 

  81. Midtvedt K, Hartmann A. Hypertension after kidney transplantation: are treatment guidelines emerging? Nephrol Dial Transplant 2002; 17: 166–1169

    Article  Google Scholar 

  82. Warholm C, Wilczek H, Petterson E. Hypertension two years after renal transplantation: causes and consequences. Transpl Int 1995; 8: 286–92

    Article  PubMed  CAS  Google Scholar 

  83. Huysmans FT, Hoitsma AJ, Koene RA. Factors determining the prevalence of hypertension after renal transplantation. Nephrol Dial Transplant 1987; 2: 34–8

    PubMed  CAS  Google Scholar 

  84. Whitworth JA, Mangos GJ, Kelly JJ. Cushing, Cortisol, and cardiovascular disease. Hypertension 2000; 36: 912–6

    Article  PubMed  CAS  Google Scholar 

  85. van de Borne P, Gelin M, van de Stadt J, et al. Circadian rhythms of blood pressure after liver transplantation. Hypertension 1993; 21: 398–405

    Article  PubMed  Google Scholar 

  86. Fallo F, Paoletta A, Tona F, et al. Response of hypertension to conventional antihypertensive treatment and/or steroidogenesis inhibitors in Cushing’s syndrome. J Intern Med 1993; 234: 595–8

    Article  PubMed  CAS  Google Scholar 

  87. Brinker KR, Dickerman RM, Gonwa TA, et al. A randomized trial comparing double-drug and triple drug therapy in primary cadaveric renal transplants. Transplantation 1990; 50: 43–9

    Article  PubMed  CAS  Google Scholar 

  88. Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients: the U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1995; 60: 225–32

    CAS  Google Scholar 

  89. Schnuelle P, van der Heide JH, Tegzess A, et al. Open randomized trial comparing early withdrawal of either cyclosporine or mycophenolate mofetil in stable renal transplant recipients initially treated with a triple drug regimen. J Am Soc Nephrol 2002; 13: 536–43

    PubMed  CAS  Google Scholar 

  90. Chapman JR, Marcen R, Arias M, et al. Hypertension after renal transplantation. Transplantation 1987; 43: 860–4

    PubMed  CAS  Google Scholar 

  91. Sutherland DE, Fryd DS, Strand MH, et al. Results of the Minnesota randomized prospective trial of cyclosporine versus azathioprine-antilymphocyte globulin for immunosuppression in renal allograft recipients. Am J Kidney Dis 1985; 5: 318–27

    PubMed  CAS  Google Scholar 

  92. Jarowenko MV, Flechner SM, van Buren CT, et al. Influence of cyclosporine on posttransplant blood pressure response. Am J Kidney Dis 1987; 10: 98–103

    PubMed  CAS  Google Scholar 

  93. Hueso M, Bover J, Serón D, et al. Low-dose cyclosporine and mycophenolate mofetil in renal allograft recipients with suboptimal renal function. Transplantation 1998; 66: 1727–31

    Article  PubMed  CAS  Google Scholar 

  94. Versluis DJ, Wenting GJ, Derkx FHM, et al. Who should be converted from cyclosporine to conventional immunosuppression in kidney transplantation, and why. Transplantation 1987; 44: 387–9

    Article  PubMed  CAS  Google Scholar 

  95. van den Dorpel MA, van den Meiracker AH, Lameris TW, et al. Cyclosporine A impairs the nocturnal blood pressure fall in renal transplant recipients. Hypertension 1996; 28: 304–7

    Article  PubMed  Google Scholar 

  96. Hilbrands LB, Hoitsma AJ, Koene RAP. Randomized, prospective trial of cyclosporin monotherapy versus azathioprine-prednisone from three months after renal transplantation. Transplantation 1996; 61: 1038–46

    Article  PubMed  CAS  Google Scholar 

  97. Schrama YC, Joles JA, van Tol A, et al. Conversion to mycophenolate mofetil in conjunction with stepwise withdrawal of cyclosporine in stable renal transplant recipients. Transplantation 2000; 69: 376–83

    Article  PubMed  CAS  Google Scholar 

  98. Johnson RW, Kreis H, Oberbauer R, et al. Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. Transplantation 2001; 72: 777–86

    Article  PubMed  CAS  Google Scholar 

  99. Oberbauer R, Kreis H, Johnson RWG, et al. Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study. Transplantation 2003; 76: 364–70

    Article  PubMed  CAS  Google Scholar 

  100. Ruggenenti P, Perico N, Mosconi L, et al. Calcium channel blockers protect transplant patients from cyclosporine-induced daily renal hypoperfusion. Kidney Int 1993; 43: 706–11

    Article  PubMed  CAS  Google Scholar 

  101. Kivlighn SD, Gabel RA, Siegl PKS. Effects of BQ-123 on renal function and acute cyclosporine-induced renal dysfunction. Kidney Int 1994; 45: 131–6

    Article  PubMed  CAS  Google Scholar 

  102. Kirk AD, Jacobson LM, Heisey DM, et al. Posttransplant diastolic hypertension: associations with intragraft transforming growth factor-β, endothelin and renin transcription. Transplantation 1997; 64: 1716–20

    Article  PubMed  CAS  Google Scholar 

  103. Sturrock NDC, Struthers AD. Hormonal and other mechanisms involved in the pathogenesis of cyclosporin-induced nephrotoxicity and hypertension in man. Clin Sci 1994; 86: 1–9

    PubMed  CAS  Google Scholar 

  104. Galiatsou E, Morris ST, Jardine AG, et al. Cardiac and vascular abnormalities in renal transplant patients: differential effects of cyclosporin and azathioprine. J Nephrol 2000; 13: 185–92

    PubMed  CAS  Google Scholar 

  105. Textor SC, Wiesner R, Wilson DJ, et al. Systemic and renal hemodynamic differences between FK506 and cyclosporine in liver transplant recipients. Transplantation 1993; 55: 1332–9

    Article  PubMed  CAS  Google Scholar 

  106. Taler SJ, Textor SC, Canzanello VJ, et al. Role of steroid dose in hypertension early after liver transplantation with tacrolimus (FK506) and cyclosporine. Transplantation 1996; 62: 1588–92

    Article  PubMed  CAS  Google Scholar 

  107. Radermacher J, Meiners M, Bramlage C, et al. Pronounced renal vasoconstriction and systemic hypertension in renal transplant recipients treated with cyclosporin A versus FK 506. Transpl Int 1998; 11: 3–10

    Article  PubMed  CAS  Google Scholar 

  108. Hohage H, Bruckner D, Arlt M, et al. Influence of cyclosporin A and FK506 on 24h blood pressure monitoring in kidney transplant recipients. Clin Nephrol 1996; 45: 342–4

    PubMed  Google Scholar 

  109. Margreiter R. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomised multicentre study: the European Tacrolimus vs Ciclosporin Microemulsion Renal Transplantation Study Group. Lancet 2002; 359: 741–6

    Article  PubMed  CAS  Google Scholar 

  110. Kohnle M, Zimmermann U, Lütkes P, et al. Conversion from cyclosporin A to tacrolimus after kidney transplantation due to hyperlipidemia. Transpl Int 2000; 13 Suppl. 1: S345–58

    Article  PubMed  Google Scholar 

  111. Ligtenberg G, Hené RJ, Blankestijn PJ, et al. Cardiovascular risk factors in renal transplant patients: cyclosporin a versus tacrolimus. J Am Soc Nephrol 2001; 12: 368–73

    PubMed  CAS  Google Scholar 

  112. Klein IH, Abrahams A, van Ede T, et al. Different effects of tacrolimus and cyclosporine on renal hemodynamics and blood pressure in healthy subjects. Transplantation 2002; 73: 732–6

    Article  PubMed  CAS  Google Scholar 

  113. Artz MA, Boots JMM, Ligtenberg G, et al. Improved cardiovascular risk profile and renal function in renal transplant patients after randomized conversion from cyclosporine to tacrolimus. J Am Soc Nephrol 2003; 14: 1880–8

    Article  PubMed  CAS  Google Scholar 

  114. Artz MA, Boots JMM, Ligtenberg G, et al. Conversion from cyclosporine to tacrolimus improves quality-of-life indices, renal graft function, and cardiovascular risk profile. Am J Transplant 2004; 4: 937–45

    Article  PubMed  CAS  Google Scholar 

  115. Martinez Castelao A, Ramos R, Seron D, et al. Effect of cyclosporin and tacrolimus on lipoprotein oxidation after renal transplantation. Nefrologia 2002; 22: 364–9

    PubMed  CAS  Google Scholar 

  116. Kahan BD, Julian BA, Pescovitz MD, et al. Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in Caucasian recipients of mismatched primary renal allografts: a phase II trial. The Rapamune Study Group. Transplantation 1999; 68: 1526–32

    CAS  Google Scholar 

  117. Groth CG, Bäckman L, Morales J-M, et al. Sirolimus (rapamycin)-based therapy in human renal transplantation. Transplantation 1999; 67: 1036–42

    Article  PubMed  CAS  Google Scholar 

  118. Gonwa T, Mendez R, Yang HC, et al. Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months. Transplantation 2003; 75: 1213–20

    Article  PubMed  CAS  Google Scholar 

  119. Levin A, Singer J, Thompson CR, et al. Prevalent left ventricular hypertrophy in the predialysis population: identifying opportunities for intervention. Am J Kidney Dis 1996; 27: 347–54

    Article  PubMed  CAS  Google Scholar 

  120. Foley RN, Parfrey PS, Harnett JD, et al. Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int 1995; 47: 186–92

    Article  PubMed  CAS  Google Scholar 

  121. Levy D, Garrison RJ, Savage DD, et al. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990; 322: 1561–6

    Article  PubMed  CAS  Google Scholar 

  122. Middleton RJ, Parfrey PS, Foley RN. Left ventricular hypertrophy in the renal patient. J Am Soc Nephrol 2001; 12: 1079–84

    PubMed  CAS  Google Scholar 

  123. McGregor E, Jardine AG, Murray LS, et al. Pre-operative echocardiographic abnormalities and adverse outcome following renal transplantation. Nephrol Dial Transplant 1998; 13: 1499–505

    Article  PubMed  CAS  Google Scholar 

  124. Rigatto C, Foley RN, Kent GM, et al. Long-term changes in left ventricular hypertrophy after renal transplantation. Transplantation 2000; 70: 570–5

    Article  PubMed  CAS  Google Scholar 

  125. Peteiro J, Alvarez N, Calviño R, et al. Changes in left ventricular mass and filling after renal transplantation are related to changes in blood pressure: an echocardiographic and pulsed Doppler study. Cardiology 1994; 85: 273–83

    Article  PubMed  CAS  Google Scholar 

  126. Ritter O, Hack S, Schuh K, et al. Calcineurin in human heart hypertrophy. Circulation 2002; 105: 2265–9

    Article  PubMed  CAS  Google Scholar 

  127. Molkentin JD, Lu J-R, Antos CL, et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 1998; 93: 215–28

    Article  PubMed  CAS  Google Scholar 

  128. Sussman MA, Lim HW, Gude N, et al. Prevention of cardiac hypertrophy in mice by calcineurin inhibition. Science 1998; 281: 1690–3

    Article  PubMed  CAS  Google Scholar 

  129. Shimoyama M, Hayashi D, Takimoto E, et al. Calcineurin plays a critical role in pressure overload-induced cardiac hypertrophy. Circulation 1999; 100: 2449–54

    Article  PubMed  CAS  Google Scholar 

  130. Shimoyama M, Hayashi D, Zou Y, et al. Calcineurin inhibitor attenuates the development and induces the regression of cardiac hypertrophy in rats with salt-sensitive hypertension. Circulation 2000; 102: 1996–2004

    Article  PubMed  CAS  Google Scholar 

  131. Atkinson P, Joubert G, Barron A, et al. Hypertrophic cardiomyopathy associated with tacrolimus in paediatric transplant patients. Lancet 1995; 345: 894–6

    Article  Google Scholar 

  132. Nakata Y, Yoshibayashi M, Yonemura T, et al. Tacrolimus and myocardial hypertrophy. Transplantation 2000; 69: 1960–2

    Article  PubMed  CAS  Google Scholar 

  133. Espino G, Denney J, Furlong T, et al. Graft-versus-host disease: assessment of myocardial hypertrophy by echocardiography in adult patients receiving tacrolimus or cyclosporine therapy for prevention of acute GVHD. Bone Marrow Transplant 2001; 28: 1097–103

    Article  PubMed  CAS  Google Scholar 

  134. Schwitter J, De Marco T, Globits S, et al. Influence of felodipine on left ventricular hypertrophy and systolic function in orthotopic heart transplant recipients: possible interaction with cyclosporin medication. J Heart Lung Transplant 1999; 18: 1003–13

    Article  PubMed  CAS  Google Scholar 

  135. van Besouw NM, van der Mast BJ, Smak Gregoor PJH, et al. Effect of mycophenolate mofetil on erythropoiesis in stable renal transplant patients is correlated with mycophenolic acid trough levels. Nephrol Dial Transplant 1999; 14: 2710–3

    Article  PubMed  Google Scholar 

  136. Pascual J, Ortuño J. Simple tacrolimus-based immunosuppressive regimens following renal transplantation: a large multi-center comparison between double and triple therapy. The Spanish and Italian Tacrolimus Study Group. Transplant Proc 2002; 34: 89–91

    Article  PubMed  CAS  Google Scholar 

  137. Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. The Rapamune US Study Group. Lancet 2000; 356: 194–202

    CAS  Google Scholar 

  138. Mihatsch MJ, Kyo M, Morozumi K, et al. The side effects of ciclosporin-A and tacrolimus. Clin Nephrol 1998; 49: 356–63

    PubMed  CAS  Google Scholar 

  139. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 1999; 282: 2340–6

    Article  PubMed  CAS  Google Scholar 

  140. Pedersen TR, Olsson AG, Færgeman O, et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 1998; 97: 1453–60

    Article  PubMed  CAS  Google Scholar 

  141. Aakhus S, Dahl K, Widerøe TE. Cardiovascular morbidity and risk factors in renal transplant patients. Nephrol Dial Transplant 1999; 14: 648–54

    Article  PubMed  CAS  Google Scholar 

  142. Roodnat JI, Mulder PGH, Zietse R, et al. Cholesterol as an independent predictor of outcome after renal transplantation. Transplantation 2000; 69: 1704–10

    Article  PubMed  CAS  Google Scholar 

  143. Booth JC, Joseph JT, Jindal RM. Influence of hypercholesterolemia on patient and graft survival in recipients of kidney transplants. Clin Transplant 2003; 17: 101–7

    Article  PubMed  Google Scholar 

  144. Cosio FG, Pesavento TE, Pelletier RP, et al. Patient survival after renal transplantation III: the effect of statins. Am J Kidney Dis 2002; 40: 638–43

    Article  PubMed  CAS  Google Scholar 

  145. Dimény E, Wahlberg J, Lithell H, et al. Hyperlipidaemia in renal transplantation: risk factor for long-term graft outcome. Eur J Clin Invest 1995; 25: 574–83

    Article  PubMed  Google Scholar 

  146. Wissing KM, Abramowicz D, Breeders N, et al. Hypercholesterolemia is associated with increased kidney graft loss caused by chronic rejection in male patients with previous acute rejection. Transplantation 2000; 70: 464–72

    Article  PubMed  CAS  Google Scholar 

  147. Holdaas H, Fellström B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003; 361: 2024–31

    Article  PubMed  CAS  Google Scholar 

  148. Sever PS, Dahlöf B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial — Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361: 1149–58

    Article  PubMed  CAS  Google Scholar 

  149. Aguilar-Salinas CA, Diaz-Polanco A, Quintana E, et al. Genetic factors play an important role in the pathogenesis of hyperlipidemia post-transplantation. Am J Kidney Dis 2002; 40: 169–77

    Article  PubMed  Google Scholar 

  150. Hricik DE, Schulak JA. Metabolic effects of steroid withdrawal in adult renal transplant recipients. Kidney Int 1993; 44 Suppl. 43: S26–S9

    Google Scholar 

  151. Sévaux RGL de, Hilbrands LB, Tiggeler RGWL, et al. A randomised, prospective study on the conversion from cyclosporine-prednisone to cyclosporine-azathioprine at 6 months after renal transplantation. Transpl Int 1998; 11 Suppl. 1: S322–4

    Article  PubMed  Google Scholar 

  152. Squifflet J-P, Vanrenterghem Y, van Hooff JP, et al. Safe withdrawal of corticosteroids or mycophenolate mofetil: results of a large, prospective, multicenter, randomized study. The European Tacrolimus/MMF Transplantation Study Group. Transplant Proc 2002; 34: 1584–6

    Article  PubMed  CAS  Google Scholar 

  153. Hilbrands LB, Demacker PNM, Hoitsma AJ, et al. The effects of cyclosporine and prednisone on serum lipid and (apo)lipoprotein levels in renal transplant recipients. J Am Soc Nephrol 1995; 5: 2073–81

    PubMed  CAS  Google Scholar 

  154. Chan MK, Varghese Z, Persaud JW, et al. The role of multiple pharmaco-therapy in the pathogenesis of hyperlipidemia after renal transplantation. Clin Nephrol 1981; 15: 309–13

    PubMed  CAS  Google Scholar 

  155. Ibels LS, Alfrey AC, Subryan V, et al. Hyperlipidemia following renal transplantation. Trans Am Soc Artif Intern Organs 1976; 22: 46–53

    PubMed  CAS  Google Scholar 

  156. Ibels LS, Simons LA, King JO, et al. Studies on the nature and causes of hyperlipidaemia in uraemia, maintenance dialysis and renal transplantation. Q J Med 1975; 44: 601–14

    PubMed  CAS  Google Scholar 

  157. Ponticelli C, Barbi GL, Cantaluppi A, et al. Lipid disorders in renal transplant recipients. Nephron 1978; 20: 189–95

    Article  PubMed  CAS  Google Scholar 

  158. Diamant S, Shafrir E. Modulation of the activity of insulin-dependent enzymes of lipogenesis by glucocorticoids. Eur J Biochem 1975; 53: 541–6

    Article  PubMed  CAS  Google Scholar 

  159. Carpentier A, Patterson BW, Leung N, et al. Sensitivity to acute insulin-mediated suppression of plasma free fatty acids is not a determinant of fasting VLDL triglyceride secretion in healthy humans. Diabetes 2002; 51: 1867–75

    Article  PubMed  CAS  Google Scholar 

  160. Chan MK, Persaud JW, Varghese Z, et al. Fat clearances and hyperlipidaemia in renal allograft recipients: the role of insulin resistance. Clin Chim Acta 1981; 114: 61–7

    Article  PubMed  CAS  Google Scholar 

  161. Quiñones-Galvan A, Sironi AM, Baldi S, et al. Evidence that acute insulin administration enhances LDL cholesterol susceptibility to oxidation in healthy humans. Arterioscler Thromb Vasc Biol 1999; 19: 2928–32

    Article  PubMed  Google Scholar 

  162. Chan MK, Varghese Z, Moorhead JF. Lipid abnormalities in uremia, dialysis, and transplantation. Kidney Int 1981; 19: 625–37

    Article  PubMed  CAS  Google Scholar 

  163. Henze K, Chait A, Albers JJ, et al. Hydrocortisone decreases the internalization of low density lipoprotein in cultured human fibroblasts and arterial smooth muscle cells. Eur J Clin Invest 1983; 13: 171–7

    Article  PubMed  CAS  Google Scholar 

  164. Rayyes OA, Wallmark A, Florén C-H. Additive inhibitory effect of hydrocortisone and cyclosporine on low-density lipoprotein receptor activity in cultured HepG2 cells. Hepatology 1997; 26: 967–71

    Article  PubMed  Google Scholar 

  165. Kancha RK, Hussain MM. Up-regulation of the low density lipoprotein receptor-related protein by dexamethasone in HepG2 cells. Biochim Biophys Acta 1996; 1301: 213–20

    Article  PubMed  Google Scholar 

  166. Moulin P, Appel GB, Ginsberg HN, et al. Increased concentration of plasma cholesteryl ester transfer protein in nephrotic syndrome: role in dyslipidemia. J Lipid Res 1992; 33: 1817–22

    PubMed  CAS  Google Scholar 

  167. Agellon LB, Walsh A, Hayek T, et al. Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer protein transgenic mice. J Biol Chem 1991; 266: 10796–801

    PubMed  CAS  Google Scholar 

  168. Hayek T, Chajek-Shaul T, Walsh A, et al. An interaction between the human cholesteryl ester transfer protein (CETP) and apolipoprotein A-1 genes in transgenic mice results in a profound CETP-mediated depression of high density lipoprotein cholesterol levels. J Clin Invest 1992; 90: 505–10

    Article  PubMed  CAS  Google Scholar 

  169. Kuster GM, Drexel H, Bleisch JA, et al. Relation of cyclosporin blood levels to adverse effects on lipoproteins. Transplantation 1994; 57: 1479–83

    PubMed  CAS  Google Scholar 

  170. Ballantyne CM, Podet EJ, Patsch WP, et al. Effects of cyclosporine therapy on plasma lipoprotein levels. JAMA 1989; 262: 53–6

    Article  PubMed  CAS  Google Scholar 

  171. Raine AE, Carter R, Mann JI, et al. Adverse effects of cyclosporin on plasma cholesterol in renal transplant recipients. Ne phrol Dial Transplant 1988; 3: 458–63

    CAS  Google Scholar 

  172. van den Dorpel MA, Ghanem H, Rischen-Vos J, et al. Conversion from cyclosporin A to azathioprine treatment improves LDL oxidation in kidney transplant recipients. Kidney Int 1997; 51: 1608–12

    Article  PubMed  Google Scholar 

  173. Harris KP, Russell GI, Parvin SD, et al. Alterations in lipid and carbohydrate metabolism attributable to cyclosporin A in renal transplant recipients. BMJ 1986; 292: 16–9

    Article  PubMed  CAS  Google Scholar 

  174. Abramowicz D, Manas D, Lao M, et al. Cyclosporine withdrawal from a mycophenolate mofetil-containing immunosuppressive regimen in stable kidney transplant recipients: a randomized, controlled study. Transplantation 2002; 74: 1725–34

    Article  PubMed  CAS  Google Scholar 

  175. Espino A, Lopez-Miranda J, Blanco-Cerrada J, et al. The effect of cyclosporine and methylprednisolone on plasma lipoprotein levels in rats. J Lab Clin Med 1995; 125: 222–7

    PubMed  CAS  Google Scholar 

  176. Vathsala A, Weinberg RB, Schoenberg L, et al. Lipid abnormalities in cyclosporine-prednisone-treated renal transplant recipients. Transplantation 1989; 48: 37–43

    Article  PubMed  CAS  Google Scholar 

  177. Quaschning T, Mainka T, Nauck M, et al. Immunosuppression enhances atherogenicity of lipid profile after transplantation. Kidney Int 1999; 56: S235–S7

    Article  Google Scholar 

  178. Vaziri ND, Liang K, Azad H. Effect of cyclopsorine on HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LDL receptor, HDL receptor, VLDL receptor, and lipoprotein lipase expressions. J Pharmacol Exp Ther 2000; 294: 778–83

    PubMed  CAS  Google Scholar 

  179. Lopez-Miranda J, Vilella E, Pérez-Jiménez F, et al. Lowdensity lipoprotein metabolism in rats treated with cyclosporine. Metabolism 1993; 42: 678–83

    Article  PubMed  CAS  Google Scholar 

  180. Rayyes OA, Wallmark A, Florén C-H. Cyclosporine inhibits catabolism of low-density lipoproteins in HepG2 cells by about 25%. Hepatology 1996; 24: 613–9

    Article  PubMed  CAS  Google Scholar 

  181. Winegar DA, Salisbury JA, Sundseth SS, et al. Effects of cyclosporin on cholesterol 27-hydroxylation and LDL receptor activity in HepG2 cells. J Lipid Res 1996; 37: 179–91

    PubMed  CAS  Google Scholar 

  182. Azrolan N, Brown CD, Thomas L, et al. Cyclosporin A has divergent effects on plasma LDL cholesterol (LDL-C) and lipoprotein (a) [lp(a)] levels in renal transplant recipients. Arterioscler Thromb 1994; 14: 1393–8

    Article  PubMed  CAS  Google Scholar 

  183. Apanay DC, Neylan JF, Ragab MS, et al. Cyclosporin increases the oxidizability of low-density lipoproteins in renal transplant recipients. Transplantation 1994; 58: 663–9

    PubMed  CAS  Google Scholar 

  184. Venkiteswaran K, Sgoutas DS, Santanam N, et al. Tacrolimus, cyclosporine and plasma lipoproteins in renal transplant recipients. Transpl Int 2001; 14: 405–10

    Article  PubMed  CAS  Google Scholar 

  185. Devaraj S, Li DJ, Vazquez M, et al. Cyclosporin A does not increase the oxidative susceptibility of low density lipoprotein in vitro. Free Radic Biol Med 1999; 26: 1064–8

    Article  PubMed  CAS  Google Scholar 

  186. Claesson K, Mayer AD, Squifflet J-P, et al. Lipoprotein patterns in renal transplant patients: a comparison between FK 506 and cyclosporin A patients. Transplant Proc 1998; 30: 1292–4

    Article  PubMed  CAS  Google Scholar 

  187. Hohage H, Arlt M, Brückner D, et al. Effects of cyclosporin A and FK 506 on lipid metabolism and fibrinogen in kidney transplant recipients. Clin Transplant 1997; 11: 225–30

    PubMed  CAS  Google Scholar 

  188. McCune TR, Thacker II LR, Peters TG, et al. Effects of tacrolimus on hyperlipidemia after successful renal transplantation: a Southeastern Organ Procurement Foundation multi-center clinical study. Transplantation 1998; 65: 87–92

    Article  PubMed  CAS  Google Scholar 

  189. Artz MA, Boots JMM, Ligtenberg G, et al. Randomized conversion from cyclosporin to tacrolimus in renal transplant patients: improved lipid profile and unchanged plasma homocystein levels. Transplant Proc 2002; 34: 1793–4

    Article  PubMed  CAS  Google Scholar 

  190. Varghese Z, Fernando RL, Turakhia G, et al. Calcineurin inhibitors enhance low-density lipoprotein oxidation in transplant patients. Kidney Int 1999; 56: S137–S40

    Article  Google Scholar 

  191. Varghese Z, Fernando R, Turakhia G, et al. Oxidizability of low-density lipoproteins from neoral and tacrolimus-treated renal transplant patients. Transplant Proc 1998; 30: 2043–6

    Article  PubMed  CAS  Google Scholar 

  192. Morena M, Vela C, Garrigue V, et al. Low-density lipoprotein composition and oxidation are not influenced by calcineurin inhibitors in renal transplant patients. Transplant Proc 2000; 32: 2785–6

    Article  PubMed  CAS  Google Scholar 

  193. Murgia MG, Jordan S, Kahan BD. The side effect profile of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients. Kidney Int 1996; 49: 209–16

    Article  PubMed  CAS  Google Scholar 

  194. Kahan BD, Podbielski J, Napoli KL, et al. Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation. Transplantation 1998; 66: 1040–6

    Article  PubMed  CAS  Google Scholar 

  195. Kahan BD, Napoli KL, Kelly PA, et al. Therapeutic drug monitoring of sirolimus: correlations with efficacy and toxicity. Clin Transplant 2000; 14: 97–109

    Article  PubMed  CAS  Google Scholar 

  196. Morrisett JD, Abdel-Fattah G, Kahan BD. Sirolimus changes lipid concentrations and lipoprotein metabolism in kidney transplant recipients. Transplant Proc 2003; 35: 143S–50S

    Article  PubMed  CAS  Google Scholar 

  197. Morrisett JD, Abdel-Fattah G, Hoogeveen R, et al. Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. J Lipid Res 2002; 43: 1170–80

    PubMed  CAS  Google Scholar 

  198. Kreis H, Cisterne J-M, Land W, et al. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 2000; 69: 1252–60

    Article  PubMed  CAS  Google Scholar 

  199. van Hooff JP, Squifflet JP, Wlodarczyk Z, et al. A prospective randomized multicenter study of tacrolimus in combination with sirolimus in renal-transplant recipients. Transplantation 2003; 75: 1934–9

    Article  PubMed  CAS  Google Scholar 

  200. Hoogeveen RC, Ballantyne CM, Pownall HJ, et al. Effect of sirolimus on the metabolism of apoB100-containing lipoproteins in renal transplant patients. Transplantation 2001; 72: 1244–50

    Article  PubMed  CAS  Google Scholar 

  201. Shapiro R, Jordan ML, Scantlebury VP, et al. A prospective randomized trial of tacrolimus/prednisone versus tacrolimus/prednisone/mycophenolate mofetil in renal transplant recipients. Transplantation 1999; 67: 411–5

    Article  PubMed  CAS  Google Scholar 

  202. Isoniemi H, Tikkanen MJ, Ahonen J, et al. Comparison of lipid and lipoprotein profiles in blood using double and triple immunosuppressive drug combinations. Transpl Int 1991; 4: 130–5

    PubMed  CAS  Google Scholar 

  203. Boudreaux JP, McHugh L, Canafax DM, et al. The impact of cyclosporine and combination immunosuppression on the incidence of posttransplant diabetes in renal allograft recipients. Transplantation 1987; 44: 376–81

    Article  PubMed  CAS  Google Scholar 

  204. Roth D, Milgrom M, Esquenazi V, et al. Posttransplant hyper-glycemia: increased incidence in cyclosporine-treated renal allograft recipients. Transplantation 1989; 47: 278–81

    Article  PubMed  CAS  Google Scholar 

  205. Pagano G, Bruno A, Cavallo-Perin P, et al. Glucose intolerance after short-term administration of corticosteroids in healthy subjects: prednisone, deflazacort, and betamethasone. Arch Intern Med 1989; 149: 1098–101

    Article  PubMed  CAS  Google Scholar 

  206. Veenstra DL, Best JH, Hornberger J, et al. Incidence and long-term cost of steroid-related side effects after renal transplantation. Am J Kidney Dis 1999; 33: 829–39

    Article  PubMed  CAS  Google Scholar 

  207. Hricik DE, Bartucci MR, Moir EJ, et al. Effects of steroid withdrawal on posttransplant diabetes mellitus in cyclopsorine-treated renal transplant recipients. Transplantation 1991; 51: 374–7

    Article  PubMed  CAS  Google Scholar 

  208. Hollander AAMJ, Hené RJ, Hermans J, et al. Late prednisone withdrawal in cyclosporine-treated kidney transplant patients: a randomized study. J Am Soc Nephrol 1997; 8: 294–301

    PubMed  CAS  Google Scholar 

  209. Boots JMM, Christiaans MHL, van Duijnhoven EM, et al. Early steroid withdrawal in renal transplantation with tacrolimus dual therapy: a pilot study. Transplantation 2002; 74: 1703–9

    Article  PubMed  CAS  Google Scholar 

  210. Fernandez LA, Lehmann R, Luzi L, et al. The effects of maintenance doses of FK506 versus cyclosporin A on glucose and lipid metabolism after orthotopic liver transplantation. Transplantation 1999; 68: 1532–41

    Article  PubMed  CAS  Google Scholar 

  211. Yamamoto H, Akazawa S, Yamaguchi Y, et al. Effects of cyclosporin A and low dosages of steroid on posttransplantation diabetes in kidney transplant recipients. Diabetes Care 1991; 14: 867–70

    Article  PubMed  CAS  Google Scholar 

  212. Nam JH, Mun JI, Kim SI, et al. β-Cell dysfunction rather than insulin resistance is the main contributing factor for the development of postrenal transplantation diabetes mellitus. Transplantation 2001; 71: 1417–23

    Article  PubMed  CAS  Google Scholar 

  213. Robertson RP. Cyclosporin-induced inhibition of insulin secretion in isolated rat islets and HIT cells. Diabetes 1986; 35: 1016–9

    Article  PubMed  CAS  Google Scholar 

  214. Gillison SL, Bartlett ST, Curry DL. Inhibition by cyclosporine of insulin secretion: a beta cell-specific alteration of islet tissue function. Transplantation 1991; 52: 890–5

    Article  PubMed  CAS  Google Scholar 

  215. Shapiro R, Jordan M, Scantlebury V, et al. FK 506 in clinical kidney transplantation. Transplant Proc 1991; 23: 3065–7

    PubMed  CAS  Google Scholar 

  216. Shapiro R, Jordan ML, Scantlebury VP, et al. A prospective randomized trial of FK506-based immunosuppression after renal transplantation. Transplantation 1995; 59: 485–90

    PubMed  CAS  Google Scholar 

  217. Boots JMM, Duijnhoven EM, Christiaans MHL, et al. Single center experience with tacrolimus versus cyclosporin-Neoral in renal transplant recipients. Transpl Int 2001; 14: 370–83

    Article  PubMed  CAS  Google Scholar 

  218. First MR, Gerber DA, Hariharan S, et al. Posttransplant diabetes mellitus in kidney allograft recipients: incidence, risk factors, and management. Transplantation 2002; 73: 379–86

    Article  PubMed  Google Scholar 

  219. van Duijnhoven EM, Boots JMM, Christiaans MHL, et al. Influence of tacrolimus on glucose metabolism before and after renal transplantation: a prospective study. J Am Soc Nephrol 2001; 12: 583–8

    PubMed  CAS  Google Scholar 

  220. van Duijnhoven EM, Christiaans MHL, Boots JMM, et al. Glucose metabolism in the first 3 years after renal transplantation in patients on tacrolimus versus cyclosporine-based immunosuppression. J Am Soc Nephrol 2002; 13: 213–20

    PubMed  Google Scholar 

  221. Strumph P, Kirsch D, Gooding W, et al. The effect of FK506 on glycemic response as assessed by the hyperglycemic clamp technique. Transplantation 1995; 60: 147–51

    PubMed  CAS  Google Scholar 

  222. Filler G, Neuschultz I, Vollmer I, et al. Tacrolimus reversibly reduces insulin secretion in paediatric renal transplant recipients. Nephrol Dial Transplant 2000; 15: 867–71

    Article  PubMed  CAS  Google Scholar 

  223. Dmitrewski J, Krentz AJ, Mayer AD, et al. Metabolic and hormonal effects of tacrolimus (FK506) or cyclosporin immunosuppression following renal transplantation. Diabetes Obes Metab 2001; 3: 287–92

    Article  PubMed  CAS  Google Scholar 

  224. Redmon JB, Olson LK, Armstrong MB, et al. Effects of tacrolimus (FK506) on human insulin gene expression, insulin mRNA levels, and insulin secretion in HIT-T15 cells. J Clin Invest 1996; 98: 2786–93

    Article  PubMed  CAS  Google Scholar 

  225. Tamura K, Fujimura T, Tsutsumi T, et al. Transcriptional inhibition of insulin by FK506 and positive involvement of FK506 binding protein-12 in pancreatic beta-cell. Transplantation 1995; 59: 1606–13

    PubMed  CAS  Google Scholar 

  226. Goto T, Kino T, Hatanaka H, et al. Discovery of FK-506, a novel immunosuppressant isolated from Streptomyces tsukubaensis. Transplant Proc 1987; 19: 4–8

    PubMed  CAS  Google Scholar 

  227. Meier-Kriesche H-U, Baliga R, Kaplan B. Decreased renal function is a strong risk factor for cardiovascular death after renal transplantation. Transplantation 2003; 75: 1291–5

    Article  PubMed  Google Scholar 

  228. Abbott KC, Yuan CM, Taylor AJ, et al. Early renal insufficiency and hospitalized heart disease after renal transplantation in the era of modern immunosuppression. J Am Soc Nephrol 2003; 14: 2358–65

    Article  PubMed  Google Scholar 

  229. Curtis JJ, Luke RG, Dubovsky E, et al. Cyclosporin in therapeutic doses increases renal allograft vascular resistance. Lancet 1986; II: 477–9

    Article  Google Scholar 

  230. Ishikawa A, Suzuki K, Fujita K. Mechanisms of cyclosporine-induced nephrotoxicity. Transplant Proc 1999; 31: 1127–8

    Article  PubMed  CAS  Google Scholar 

  231. Lanese DM, Conger JD. Effects of endothelin receptor antagonist on cyclosporine-induced vasoconstriction in isolated rat renal arterioles. J Clin Invest 1993; 91: 2144–9

    Article  PubMed  CAS  Google Scholar 

  232. Kurihara H, Yoshizumi M, Sugiyama T, et al. Transforming growth factor-β stimulates the expression of endothelin mRNA by vascular endothelial cells. Biochem Biophys Res Commun 1989; 159: 1435–40

    Article  PubMed  CAS  Google Scholar 

  233. Chareandee C, Herman WH, Hricik DE, et al. Elevated endothelin-1 in tubular epithelium is associated with renal allograft rejection. Am J Kidney Dis 2000; 36: 541–9

    Article  PubMed  CAS  Google Scholar 

  234. Simonson MS, Emancipator SN, Knauss T, et al. Elevated neointimal endothelin-1 in transplantation-associated arteriosclerosis of renal allograft recipients. Kidney Int 1998; 54: 960–71

    Article  PubMed  CAS  Google Scholar 

  235. Simonson MS, Herman WH, Robinson A, et al. Inhibition of endothelin-converting enzyme attenuates transplant vasculopathy and rejection in rat cardiac allografts. Transplantation 1999; 67: 1542–7

    Article  PubMed  CAS  Google Scholar 

  236. Waiser J, Dell K, Böhler T, et al. Cyclosporine A up-regulates the expression of TGF-β1 and its receptors type I and type II in rat mesangial cells. Nephrol Dial Transplant 2002; 17: 1568–77

    Article  PubMed  CAS  Google Scholar 

  237. Li B, Sehajpal PK, Khanna A, et al. Differential regulation of transforming growth factor β and interleukin 2 genes in human T cells: demonstration by usage of novel competitor DNA constructs in the quantitative polymerase chain reaction. J Exp Med 1991; 174: 1259–62

    Article  PubMed  CAS  Google Scholar 

  238. Yamamoto T, Noble NA, Miller DE, et al. Sustained expression of TGF-βl underlies development of progressive kidney fibrosis. Kidney Int 1994; 45: 916–27

    Article  PubMed  CAS  Google Scholar 

  239. Sharma VK, Bologa RM, Xu G-P, et al. Intragraft TGF-β1 mRNA: a correlate of interstitial fibrosis and chronic allograft nephropathy. Kidney Int 1996; 49: 1297–303

    Article  PubMed  CAS  Google Scholar 

  240. Thomas SE, Andoh TF, Pichler RH, et al. Accelerated apoptosis characterizes cyclosporine-associated interstitial fibrosis. Kidney Int 1998; 53: 897–908

    Article  PubMed  CAS  Google Scholar 

  241. Bakker RC, van Kooten C, van de Lagemaat-Paape ME, et al. Renal tubular epithelial cell death and cyclosporin A. Nephrol Dial Transplant 2002; 17: 1181–8

    Article  PubMed  CAS  Google Scholar 

  242. Halloran PF, Helms LMH, Kung L, et al. The temporal profile of calcineurin inhibition by cyclosporine in vivo. Transplantation 1999; 68: 1356–61

    Article  PubMed  CAS  Google Scholar 

  243. Podder H, Stepkowski SM, Napoli KL, et al. Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations. J Am Soc Nephrol 2001; 12: 1059–71

    PubMed  CAS  Google Scholar 

  244. McAllister VC, Mahalati K, Peltekian KM, et al. A clinical pharmacokinetic study of tacrolimus and sirolimus combination immunosuppression comparing simultaneous to separated administration. Ther Drug Monit 2002; 24: 346–50

    Article  Google Scholar 

  245. Smith KD, Wrenshall LE, Nicosia RF, et al. Delayed graft function and cast nephropathy associated with tacrolimus plus rapamycin use. J Am Soc Nephrol 2003; 14: 1037–45

    Article  PubMed  CAS  Google Scholar 

  246. Jain S, Bicknell GR, Nicholson ML. Tacrolimus has less fibrinogenic potential than cyclosporin A in a model of renal ischaemia-reperfusion injury. Br J Surg 2000; 87: 1563–8

    Article  PubMed  CAS  Google Scholar 

  247. Bicknell GR, Shaw WJA, Pringle JH, et al. Differential effects of cyclosporin and tacrolimus on the expression of fibrosis-associated genes in isolated glomeruli from renal transplants. Br J Surg 2000; 87: 1569–75

    Article  PubMed  CAS  Google Scholar 

  248. Mohamed MAS, Robertson H, Booth TA, et al. TGF-β expression in renal transplant biopsies: a comparative study between cyclosporin-A and tacrolimus. Transplantation 2000; 69: 1002–5

    Article  PubMed  CAS  Google Scholar 

  249. Wang T, Li B-Y, Danielson PD, et al. The immunophilin FKBP12 functions as a common inhibitor of the TGF-β family type 1 receptors. Cell 1996; 86: 435–44

    Article  PubMed  CAS  Google Scholar 

  250. Wang T, Donahoe PK, Zervos AS. Specific interaction of type I receptors of the TGF-β family with the immunophilin FKBP-12. Science 1994; 265: 674–6

    Article  PubMed  CAS  Google Scholar 

  251. Khanna A, Cairns V, Hosenpud JD. Tacrolimus induces increased expression of transforming growth factor-β1 in mammalian lymphoid as well as nonlymphoid cells. Transplantation 1999; 67: 614–9

    Article  PubMed  CAS  Google Scholar 

  252. Nakahama H, Fukunaga M, Kakihara M, et al. Comparative effect of cyclosporine A and FK-506 on endothelin secretion by a cultured renal cell line, LLC-PK1. J Cardiovasc Pharmacol 1991; 17: S172–3

    Article  PubMed  CAS  Google Scholar 

  253. Baboolal K, Jones GA, Janezic A, et al. Molecular and structural consequences of early renal allograft injury. Kidney Int 2002; 61: 686–96

    Article  PubMed  CAS  Google Scholar 

  254. Murphy GJ, Waller JR, Sandford RS, et al. Randomized clinical trial of the effect of microemulsion cyclosporin and tacrolimus on renal allograft fibrosis. Br J Surg 2003; 90: 680–6

    Article  PubMed  CAS  Google Scholar 

  255. Gjertson DW, Cecka JM, Terasaki PI. The relative effects of FK506 and cyclosporine on short- and long-term kidney graft survival. Transplantation 1995; 60: 1384–8

    Article  PubMed  CAS  Google Scholar 

  256. Vincenti F, Jensik SC, Filo RS, et al. A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years. Transplantation 2002; 73: 775–82

    Article  PubMed  CAS  Google Scholar 

  257. Mayer AD. Chronic rejection and graft half-life: five year follow-up of the European Tacrolimus Multicenter Renal Study: the European Tacrolimus Multicentre Renal Study Group. Transplant Proc 2002; 34: 1491–2

    Article  PubMed  Google Scholar 

  258. Kaplan B, Schold JD, Meier-Kriesche H-U. Long-term graft survival with Neoral and tacrolimus: a paired kidney analysis. J Am Soc Nephrol 2003; 14: 2980–4

    Article  PubMed  CAS  Google Scholar 

  259. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969; 56: 111–28

    PubMed  CAS  Google Scholar 

  260. Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 1985; 37: 1–31

    PubMed  CAS  Google Scholar 

  261. Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet 1999; 354: 407–13

    Article  PubMed  CAS  Google Scholar 

  262. Refsum H, Ueland PM, Nygård O, et al. Homocysteine and cardiovascular disease. Annu Rev Med 1998; 49: 31–62

    Article  PubMed  CAS  Google Scholar 

  263. Boushey CJ, Beresford SA, Omenn GS, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995; 274: 1049–57

    Article  PubMed  CAS  Google Scholar 

  264. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111–3

    Article  PubMed  CAS  Google Scholar 

  265. Verhoef P, Stampfer MJ, Buring JE, et al. Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Am J Epidemiol 1996; 143: 845–59

    Article  PubMed  CAS  Google Scholar 

  266. Jacques PF, Bostom AG, Williams RR, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996; 93: 7–9

    Article  PubMed  CAS  Google Scholar 

  267. de Bree A, Verschuren WM, Blom HJ, et al. The homocysteine distribution: (mis)udging the burden. J Clin Epidemiol 2001; 54: 462–9

    Article  PubMed  Google Scholar 

  268. Ueland PM, Refsum H, Beresford AA, et al. The controversy of homocysteine and cardiovascular risk. Am J Clin Nutr 2000; 72: 324–32

    PubMed  CAS  Google Scholar 

  269. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002; 325: 1202

    Article  PubMed  Google Scholar 

  270. Arnadottir M, Hultberg B, Nilsson-Ehle P, et al. The effect of reduced glomerular filtration rate on plasma total homocysteine concentration. Scan J Clin Lab Invest 1996; 56: 41–6

    Article  CAS  Google Scholar 

  271. Wollesen F, Brattström L, Refsum H, et al. Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney Int 1999; 55: 1028–35

    Article  PubMed  CAS  Google Scholar 

  272. Parsons DS, Reaveley DA, Pavitt DV, et al. Relationship of renal function to homocysteine and lipoprotein(a) levels: the frequency of the combination of both risk factors in chronic renal impairment. Am J Kidney Dis 2002; 40: 916–23

    Article  PubMed  CAS  Google Scholar 

  273. Stam F, van Guldener C, Schalkwijk CG, et al. Impaired renal function is associated with markers of endothelial dysfunction and increased inflammatory activity. Nephrol Dial Transplant 2003; 18: 892–8

    Article  PubMed  Google Scholar 

  274. van Guidener C, Kulik W, Berger R, et al. Homocysteine and methionine metabolism in ESRD: a stable isotope study. Kidney Int 1999; 56: 1064–71

    Article  Google Scholar 

  275. van Guidener C, Donker AJM, Jakobs C, et al. No net renal extraction of homocysteine in fasting humans. Kidney Int 1998; 54: 166–9

    Article  Google Scholar 

  276. Sarnak MJ, Wang S-R, Beck GJ, et al. Homocysteine, cysteine, and B vitamins as predictors of kidney disease progression. Am J Kidney Dis 2002; 40: 932–9

    Article  PubMed  CAS  Google Scholar 

  277. Krmar RT, Ferraris JR, Ramirez JA, et al. Hyperhomocysteinemia in stable pediatric, adolescents, and young adult renal transplant recipients. Transplantation 2001; 71: 1748–51

    Article  PubMed  CAS  Google Scholar 

  278. Födinger M, Buchmayer H, Heinz G, et al. Effect of MTHFR 1298A-C and MTHFR 677C-T genotypes on total homocysteine, folate, and vitamin B12 plasma concentrations in kidney graft recipients. J Am Soc Nephrol 2000; 11: 1918–25

    PubMed  Google Scholar 

  279. Beaulieu AJ, Gohh RY, Han H, et al. Enhanced reduction of fasting total homocysteine levels with supraphysiological versus standard multivitamin dose folic acid supplementation in renal transplant recipients. Arterioscler Thromb Vasc Biol 1999; 19: 2918–21

    Article  PubMed  CAS  Google Scholar 

  280. Fonseca I, Queirós J, Santos MJ, et al. Hyperhomocysteinemia in renal transplantation: preliminary results. Transplant Proc 2000; 32: 2602–4

    Article  PubMed  CAS  Google Scholar 

  281. Stein G, Müller A, Busch M, et al. Homocysteine, its metabolites, and B-group vitamins in renal transplant patients. Kidney Int 2001; 59 Suppl. 78: S262–5

    Article  Google Scholar 

  282. Ducloux D, Motte G, Nguyen NH, et al. Homocysteine, nutritional status and insulin in renal transplant recipients. Nephrol Dial Transplant 2002; 17: 1674–7

    Article  PubMed  CAS  Google Scholar 

  283. Arnadottir M, Hultberg B, Wahlberg J, et al. Serum total homocysteine concentration before and after renal transplantation. Kidney Int 1998; 54: 1380–4

    Article  PubMed  CAS  Google Scholar 

  284. Huh W, Kim B, Kim SJ, et al. Changes of fasting plasma total homocysteine in the early phase of renal transplantation. Transplant Proc 2000; 32: 2811–3

    Article  PubMed  CAS  Google Scholar 

  285. Arnadottir M, Hultberg B, Vladov V, et al. Hyperhomocysteinemia in cyclosporine-treated renal transplant recipients. Transplantation 1996; 61: 509–12

    Article  PubMed  CAS  Google Scholar 

  286. Marcucci R, Fedi S, Brunelli T, et al. High cysteine levels in renal transplant recipients: relationship with hyperhomocysteinemia and 5,10-MTHFR polymorphism. Transplantation 2001; 71: 746–51

    Article  PubMed  CAS  Google Scholar 

  287. Ducloux D, Motte G, Challier B, et al. Serum total homocysteine and cardiovascular disease occurrence in chronic, stable renal transplant recipients: a prospective study. J Am Soc Nephrol 2000; 11: 134–7

    PubMed  CAS  Google Scholar 

  288. Massy ZA, Chadefaux-Vekemans B, Chevalier A, et al. Hyperhomocysteinaemia: a significant risk factor for cardiovascular disease in renal transplant recipients. Nephrol Dial Transplant 1994; 9: 1103–8

    PubMed  CAS  Google Scholar 

  289. Marcucci R, Zanazzi M, Bertoni E, et al. Vitamin supplementation reduces the progression of atherosclerosis in hyperhomocysteinemic renal-transplant recipients. Transplantation 2003; 75: 1551–5

    Article  PubMed  CAS  Google Scholar 

  290. Massy ZA, Mamzer-Bruneel M-F, Chevalier A, et al. Carotid atherosclerosis in renal transplant recipients. Nephrol Dial Transplant 1998; 13: 1792–8

    Article  PubMed  CAS  Google Scholar 

  291. Suwelack B, Gerhardt U, Witta J, et al. Effect of homocysteine on carotid intima-media thickness after renal transplantation. Clin Transplant 2000; 14: 555–60

    Article  PubMed  CAS  Google Scholar 

  292. Dimény E, Hultberg B, Wahlberg J, et al. Serum total homocysteine concentration does not predict outcome in renal transplant recipients. Clin Transplant 1998; 12: 563–8

    PubMed  Google Scholar 

  293. Hagen W, Födinger M, Heinz G, et al. Effect of MTHFR genotypes and hyperhomocysteinemia on patient and graft survival in kidney transplant recipients. Kidney Int 2001; 59 Suppl. 78: S253–S7

    Article  Google Scholar 

  294. Cole DEC, Ross HJ, Evrovski J, et al. Correlation between total homocysteine and cyclosporine concentrations in cardiac transplant recipients. Clin Chem 1998; 44: 2307–11

    PubMed  CAS  Google Scholar 

  295. Mor E, Helfmann L, Lustig S, et al. Homocysteine levels among transplant recipients: effect of immunosuppressive protocols. Transplant Proc 2001; 33: 2945–6

    Article  PubMed  CAS  Google Scholar 

  296. Ducloux D, Ruedin C, Gibey R, et al. Prevalence, determinants, and clinical significance of hyperhomocyst(e)inemia in renaltransplant recipients. Nephrol Dial Transplant 1998; 13: 2890–3

    Article  PubMed  CAS  Google Scholar 

  297. Ducloux D, Fournier V, Rebibou J-M, et al. Hyperhomocysteinemia in renal transplant recipients with and without cyclosporine. Clin Nephrol 1998; 49: 232–5

    PubMed  CAS  Google Scholar 

  298. Ignatescu MC, Födiger M, Kletzmayr J, et al. Is there a role of cyclosporine A on total homocysteine export from human renal proximal tubular epithelial cells. Kidney Int 2001; 59 Suppl. 78: S258–61

    Article  Google Scholar 

  299. Fernandez-Miranda C, Gómez P, Diaz-Rubio P, et al. Plasma homocysteine levels in renal transplanted patients on cyclosporin or tacrolimus therapy: effect of treatment with folic acid. Clin Transplant 2000; 14: 110–4

    Article  PubMed  CAS  Google Scholar 

  300. Mehra MR, Uber PA, Scott RL, et al. Effect of immunosuppressive regimen on novel markers of atherothrombosis in heart transplantation: homocysteine, C-reactive protein, and mean platelet volume. Transplant Proc 2002; 34: 1866–8

    Article  PubMed  CAS  Google Scholar 

  301. Ignatescu MC, Kletzmayr J, Födiger M, et al. Influence of mycophenolic acid and tacrolimus on homocysteine metabolism. Kidney Int 2002; 61: 1894–8

    Article  PubMed  CAS  Google Scholar 

  302. Quiroga I, Morris-Stiff G, Baboo R, et al. Differential homocysteine levels in renal transplant patients receiving Neoral versus tacrolimus. Transplant Proc 2001; 33: 1209–10

    Article  PubMed  CAS  Google Scholar 

  303. Hamsten A, de Faire U, Walldius G, et al. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; II: 3–9

    Article  Google Scholar 

  304. Thompson SG, Kienast J, Pyke SDM, et al. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris: the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 1995; 332: 635–41

    Article  PubMed  CAS  Google Scholar 

  305. Kannel WB, Wolf PA, Castelli WP, et al. Fibrinogen and risk of cardiovascular disease: the Framingham Study. JAMA 1987; 258: 1183–6

    Article  PubMed  CAS  Google Scholar 

  306. Green D, Ruth KJ, Folsom AR, et al. Hemostatic factors in the Coronary Artery Risk Development in Young Adults (Cardia) study. Arterioscler Thromb 1994; 14: 686–93

    Article  PubMed  CAS  Google Scholar 

  307. Heinrich J, Schulte H, Schonfeld R, et al. Association of variables of coagulation, fibrinolysis and acute-phase with atherosclerosis in coronary and peripheral arteries and those arteries supplying the brain. Thromb Haemost 1995; 73: 374–9

    PubMed  CAS  Google Scholar 

  308. Heinrich J, Balleisen L, Schulte H, et al. Fibrinogen and factor VII in the prediction of coronary risk: results from the PROCAM study in healthy men. Arterioscler Thromb 1994; 14: 54–9

    Article  PubMed  CAS  Google Scholar 

  309. Juhan-Vague I, Roul C, Alessi MC, et al. Increased plasminogen activator inhibitor activity in non insulin dependent diabetic patients: relationship with plasma insulin. Thromb Haemost 1989; 61: 370–3

    PubMed  CAS  Google Scholar 

  310. Juhan-Vague I, Alessi MC, Vague P. Increased plasma plasminogen activator inhibitor 1 levels: a possible link between insulin resistance and atherothrombosis. Diabetologia 1991; 34: 457–62

    Article  PubMed  CAS  Google Scholar 

  311. Segarra A, Chacón P, Martinez-Eyarre C, et al. Circulating levels of plasminogen activator inhibitor type-1, tissue plasminogen activator, and thrombomodulin in hemodialysis patients: biochemical correlations and role as independent predictors of coronary artery stenosis. J Am Soc Nephrol 2001; 12: 1255–63

    PubMed  CAS  Google Scholar 

  312. Labarrere CA, Pitts D, Nelson DR, et al. Vascular tissue plasminogen activator and the development of coronary artery disease in heart-transplant recipients. N Engl J Med 1995; 333: 1111–6

    Article  PubMed  CAS  Google Scholar 

  313. Patrassi GM, Sartori MT, Rigotti P, et al. Reduced fibrinolytic potential one year after kidney transplantation: relationship to long-term steroid treatment. Transplantation 1995; 59: 1416–20

    Article  PubMed  CAS  Google Scholar 

  314. Huser B, Lammle B, Landmann J, et al. Von Willebrand factor and factor VIII in renal transplant recipients under immunosuppression with cyclosporine and steroids: sequential measurements over 4 months in 17 patients. Clin Nephrol 1990; 34: 214–22

    PubMed  CAS  Google Scholar 

  315. Patrassi GM, Dal Bo Zanon R, Boscaro M, et al. Further studies on the hypercoagulable state of patients with Cushing’s syndrome. Thromb Haemost 1985; 54: 518–20

    PubMed  CAS  Google Scholar 

  316. Dal Bo Zanon R, Fornasiero L, Boscaro M, et al. Increased factor VIII associated activities in Cushing’s syndrome: a probable hypercoagulable state. Thromb Haemost 1982; 47: 116–7

    Google Scholar 

  317. Patrassi GM, Sartori MT, Viero ML, et al. The fibrinolytic potential in patients with Cushing’s disease: a clue to their hypercoagulable state. Blood Coagul Fibrinolysis 1992; 3: 789–93

    Article  PubMed  CAS  Google Scholar 

  318. Patrassi GM, Sartori MT, Livi U, et al. Impairment of fibrinolytic potential in long-term steroid treatment after heart transplantation. Transplantation 1997; 64: 1610–4

    Article  PubMed  CAS  Google Scholar 

  319. Sartori MT, Maurizio PG, Sara P, et al. Relation between long-term steroid treatment after heart transplantation, hypofibrinolysis and myocardial microthrombi generation. J Heart Lung Transplant 1999; 18: 693–700

    Article  PubMed  CAS  Google Scholar 

  320. Sartori MT, Patrassi GM, Rigotti P, et al. Improved fibrinolytic capacity after withdrawal of steroid immunosuppression in renal transplant recipients. Transplantation 2000; 69: 2116–21

    Article  PubMed  CAS  Google Scholar 

  321. Sartori MT, Rigotti P, Marchini F, et al. Plasma fibrinolytic capacity in renal transplant recipients: effect of steroid-free immunosuppression therapy. Transplantation 2003; 75: 994–8

    Article  PubMed  CAS  Google Scholar 

  322. Laug WE. Glucocorticoids inhibit plasminogen activator by endothelial cells. Thromb Haemost 1983; 50: 888–92

    PubMed  CAS  Google Scholar 

  323. Huang LQ, Whitworth JA, Chesterman CN. Effects of cyclosporin A and dexamethasone on haemostatic and vasoactive functions of vascular endothelial cells. Blood Coagul Fibrinolysis 1995; 6: 438–45

    Article  PubMed  CAS  Google Scholar 

  324. Pandit HB, Spillert CR. Effect of methylprednisolone on coagulation. J Natl Med Assoc 1999; 91: 453–6

    PubMed  CAS  Google Scholar 

  325. Levi M, Wilmink J, Büller HR, et al. Impaired fibrinolysis in cyclosporine-treated renal transplant patients: analysis of the defect and beneficial effect of fish-oil. Transplantation 1992; 54: 978–83

    Article  PubMed  CAS  Google Scholar 

  326. Malyszko J, Malyszko JS, Pawlak K, et al. The coagulo-lytic system and endothelial function in cyclosporine-treated kidney allograft recipients. Transplantation 1996; 62: 828–30

    Article  PubMed  CAS  Google Scholar 

  327. van den Dorpel MA, Veld AJ, Levi M, et al. Beneficial effects of conversion from cyclosporine to azathioprine on fibrinolysis in renal transplant recipients. Arterioscler Thromb Vasc Biol 1999; 19: 1555–8

    Article  PubMed  Google Scholar 

  328. Vaziri ND, Ismail M, Martin DC, et al. Blood coagulation, fibrinolytic and inhibitory profiles in renal transplant recipients: comparison of cyclosporine and azathioprine. Int J Artif Organs 1992; 15: 365–9

    PubMed  CAS  Google Scholar 

  329. Murphy BG, Yong A, Brown JH, et al. Effect of immunosuppressive drug regime on cardiovascular risk profile following kidney transplantation. Atherosclerosis 1995; 116: 241–5

    Article  PubMed  CAS  Google Scholar 

  330. Schrama YC, van Dam T, Fijnheer R, et al. Cyclosporine is associated with endothelial dysfunction but not with platelet activation in renal transplantation. Neth J Med 2001; 59: 6–15

    Article  PubMed  CAS  Google Scholar 

  331. Morishita E, Nakao S, Asakura H, et al. Hypercoagulability and high lipoprotein(a) levels in patients with aplastic anemia receiving cyclosporine. Blood Coagul Fibrinolysis 1996; 7: 609–14

    Article  PubMed  CAS  Google Scholar 

  332. Vanrenterghem Y, Roels L, Lerut T, et al. Thromboembolic complications and haemostatic changes in cyclosporin-treated cadaveric kidney allograft recipients. Lancet 1985; I: 999–1002

    Article  Google Scholar 

  333. Gruber SA, Pescovitz MD, Simmons RL, et al. Thromboembolic complications in renal allograft recipients: a report from the prospective randomized study of cyclosporine versus azathioprine-antilymphocyte globulin. Transplantation 1987; 44: 775–8

    Article  PubMed  CAS  Google Scholar 

  334. Baker LR, Tucker B, Kovacs IB. Enhanced in vitro hemostasis and reduced thrombolysis in cyclosporine-treated renal transplant recipients. Transplantation 1990; 49: 905–9

    Article  PubMed  CAS  Google Scholar 

  335. Collins P, Wilkie M, Razak K, et al. Cyclosporine and cremaphor modulate von Willebrand factor release from cultured human endothelial cells. Transplantation 1993; 56: 1218–23

    Article  PubMed  CAS  Google Scholar 

  336. Kasiske BL, Chakkera HA, Louis TA, et al. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol 2000; 11: 1910–7

    PubMed  CAS  Google Scholar 

  337. Birkeland SA, Hamilton-Dutoit S. Is posttransplant lymphoproliferative disorder (PTLD) caused by any specific immunosuppressive drug or by the transplantation per se? Transplantation 2003; 76: 984–8

    Article  PubMed  CAS  Google Scholar 

  338. Zanker B, Schneeberger H, Rothenpieler U, et al. Mycophenolate mofetil-based, cyclosporine-free induction and maintenance immunosuppression: first-3-months analysis of efficacy and safety in two cohorts of renal allograft recipients. Transplantation 1998; 66: 44–9

    Article  PubMed  CAS  Google Scholar 

  339. Theodorakis J, Schneeberger H, Illner W-D, et al. Nephrotoxicity-free, mycophenolate-based induction/maintenance immunosuppression in elderly recipients of renal allografts from elderly cadaveric donors. Transplant Proc 2000; 32 Suppl. 1A: 9S–11S

    Article  PubMed  CAS  Google Scholar 

  340. Gregory CR, Huie P, Billingham ME, et al. Rapamycin inhibits arterial intimai thickening caused by both alloimmune and mechanical injury. Transplantation 1993; 55: 1409–18

    Article  PubMed  CAS  Google Scholar 

  341. Cao W, Mohacsi P, Shorthouse R, et al. Effects of rapamycin on growth factor-stimulated vascular smooth muscle cell DNA synthesis. Transplantation 1995; 59: 390–5

    PubMed  CAS  Google Scholar 

  342. Ikonen TS, Gummert JF, Hayase M, et al. Sirolimus (rapamycin) halts and reverses progression of allograft vascular disease in non-human primates. Transplantation 2000; 70: 969–75

    Article  PubMed  CAS  Google Scholar 

  343. Mancini D, Pinney S, Burkhoff D, et al. Use of rapamycin slows progression of cardiac transplantation vasculopathy. Circulation 2003; 108: 48–53

    Article  PubMed  CAS  Google Scholar 

  344. Morice M-C, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346: 1773–80

    Article  PubMed  CAS  Google Scholar 

  345. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003; 349: 1315–23

    Article  PubMed  CAS  Google Scholar 

  346. Schofer J, Schlüter M, Gershlick AH, et al. Sirolimus-eluting stents for treatment of patients with long atherosclerotic lesions in small coronary arteries: double-blind, randomised controlled trial (E-SIRIUS). Lancet 2003; 362: 1093–9

    Article  PubMed  CAS  Google Scholar 

  347. Morelon E, Stern M, Kreis H. Interstitial pneumonitis associated with sirolimus therapy in renal-transplant recipients. N Engl J Med 2000; 343: 225–6

    Article  PubMed  CAS  Google Scholar 

  348. Morelon E, Stern M, Israël-Biet D, et al. Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients. Transplantation 2001; 72: 787–90

    Article  PubMed  CAS  Google Scholar 

  349. Luan FL, Ding R, Sharma VK, et al. Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney Int 2003; 63: 917–26

    Article  PubMed  CAS  Google Scholar 

  350. Luan FL, Hojo M, Maluccio M, et al. Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy. Transplantation 2002; 73: 1565–72

    Article  PubMed  CAS  Google Scholar 

  351. Law BK, Chytil A, Dumont N, et al. Rapamycin potentiates transforming growth factor β-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells. Mol Cell Biol 2002; 22: 8184–98

    Article  PubMed  CAS  Google Scholar 

  352. Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 2002; 8: 128–35

    Article  PubMed  CAS  Google Scholar 

  353. Muthukkumar S, Ramesh TM, Bondada S. Rapamycin, a potent immunosuppressive drug, causes programmed cell death in B lymphoma cells. Transplantation 1995; 60: 264–70

    Article  PubMed  CAS  Google Scholar 

  354. Nepomuceno RR, Balatoni CE, Natkunam Y, et al. Rapamycin inhibits the interleukin 10 signal transduction pathway and the growth of Epstein Barr virus B-cell lymphomas. Cancer Res 2003; 63: 4472–80

    PubMed  CAS  Google Scholar 

  355. Johnson C, Ahsan N, Gonwa T, et al. Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporin (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Transplantation 2000; 69: 834–41

    Article  PubMed  CAS  Google Scholar 

  356. van Gelder T, ter Meulen CG, Hené R, et al. Oral ulcers in kidney transplant recipients treated with sirolimus and mycophenolate mofetil. Transplantation 2003; 75: 788–91

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

All authors have participated in several multicentre trials evaluating tacrolimus-based immunosuppression and have performed studies unravelling the cardiovascular effects of calcineurin inhibitors, which were funded by the producing company of tacrolimus. However, no sources of funding have been provided for this review and there are no conflicts of interest directly relevant to the content of this review.

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  1. Department of Nephrology, University Hospital Maastricht, Maastricht, The Netherlands

    Johannes M. M. Boots, Maarten H. L. Christiaans & Johannes P. van Hooff

  2. Department of Nephrology, Rijnmond-Zuid Medical Centre, PO Box 9119, Rotterdam, 3007 AC, The Netherlands

    Johannes M. M. Boots

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Boots, J.M.M., Christiaans, M.H.L. & van Hooff, J.P. Effect of Immunosuppressive Agents on Long-Term Survival of Renal Transplant Recipients. Drugs 64, 2047–2073 (2004). https://doi.org/10.2165/00003495-200464180-00004

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