Top

Drugs

Published in:

01-11-2009 | Review Article

Immunosuppressive Drugs in Kidney Transplantation

Impact on Patient Survival, and Incidence of Cardiovascular Disease, Malignancy and Infection

Author: Dr Roberto Marcén

Published in: Drugs | Issue 16/2009

Abstract

Renal transplant recipients have increased mortality rates when compared with the general population. The new immunosuppressive drugs have improved short-term patient survival up to 95% at 1–2 years, but these data have to be confirmed in long-term follow-up. Furthermore, no particular regimen has proved to be superior over others with regard to patient survival.

Cardiovascular diseases are the most common cause of mortality in renal transplant recipients and while no immunosuppressive drug has been directly associated with cardiovascular events, immunosuppressive drugs have different impacts on traditional risk factors. Corticosteroids and ciclosporin are the agents with the most negative impact on weight gain, blood pressure and lipids. Tacrolimus increases the risk of new-onset diabetes mellitus. Sirolimus and everolimus have the most impact on risk factors for post-transplant hyperlipidaemia. Modifications in immunosuppression could improve the cardiovascular profile but there is little evidence regarding the beneficial effects of these changes on patient outcomes.

Malignancies are also an increasing cause of mortality, overtaking cardiovascular disease in some series. Induction therapy, azathioprine and calcineurin inhibitors (CNIs) are probably the immunosuppressive agents most linked with post-transplant malignancies. Mycophenolate mofetil (MMF) has no negative impact on the incidence of malignancies. Target of rapamycin (mTOR) inhibitors have antioncogenic properties and they are associated with a lower incidence of malignancies. In addition, these agents have been recommended for use to decrease the dose or withdrawal of CNIs in patients with malignancies.

Infections are still an important cause of morbidity and mortality in renal transplant recipients. Some immunosuppressive agents such as MMF increase the incidence of cytomegalovirus infection and the need for prophylactic measures in risk recipients. The use of potent immunosuppressive therapy has resulted in the appearance of BK virus nephropathy, which progresses to graft failure in a high percentage of patients. Although first associated with tacrolimus and MMF immunosuppression, recent data suggest that BK nephropathy appears with any kind of triple therapy.

In conclusion, reducing risk factors for patient death should be a major target to improve outcomes after renal transplantation. Effort should be made to control cardiovascular diseases, malignancies and infections with improved use of immunosuppressive drugs. Preliminary results with belatacept suggest its safety and efficacy, and open new perspectives in the immunosupppression of de novo renal transplant recipients.

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: 1725–30PubMedCrossRef

McDonald SP, Russ GR. Survival of recipients of cadaveric kidney transplants compared with those receiving dialysis treatment in Australia and New Zealand, 1991–2001. Nephrol Dial Transplant 2002; 17: 2212–9PubMedCrossRef

Schweitzer EJ, Matas AJ, Gilligham KJ, et al. Causes of renal allograft loss: progress in the 1980s, challenges for the 1990s. Ann Surg 1991; 214: 679–88PubMedCrossRef

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

Arend SM, Mallat MJK, Westendorp SJW, et al. Patient survival after renal transplantation: more than 25 years follow-up. Nephrol Dial Transplant 1997; 12: 1672–9PubMedCrossRef

Briggs D. Causes of death after renal transplantation. Nephol Dial Transplant 2001; 16: 1545–9CrossRef

Chang SH, Russ GR, Chadban SJ, et al. Trends in kidney transplantation in Australia and New Zealand, 1993–2004. Transplantation 2007; 84: 611–8PubMedCrossRef

Meier-Kriesche HU, Schold JD, Kaplan B. Long-term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant 2004; 4: 1289–95PubMedCrossRef

Diethelm AG, Deierhoi MH, Hudson SL, et al. Progress in renal transplantation: a single center study of 3359 patients over 25 years. Ann Sur 1995; 221: 446–58CrossRef

10.

Prommool S, Jhangri GS, Cockfield SM, et al. Time dependency of factors affecting renal allograft survival. J Am Soc Nephrol 2000; 11: 565–73PubMed

11.

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

12.

Pascual M, Theruvath T, Kawai T, et al. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med 2002; 346: 580–90PubMedCrossRef

13.

Vincenti F, Larsen C, Durrbach A, et al. for the Belatacept Study Group. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005; 353: 770–81

14.

Knoll G, Muirhead N, Trpeski L, et al. Patient survival following renal transplant failure in Canada. Am J Transplant 2005; 5: 1719–24PubMedCrossRef

15.

Kaplan B, Meier-Kriesche HU. Death after graft loss: an important late study end-point in kidney transplantation. Am J Transplant 2002; 2: 970–4PubMedCrossRef

16.

Wing AJ, Brunner FP, Brynger H, et al. Combined report on regular dialysis and transplantation in Europe, VIII, 1977. Proc Eur Dial Transplant Assoc 1978; 15: 2–76PubMed

17.

Kramer P, Broyer M, Brunner FP, et al. Combined report on regular dialysis and transplantation in Europe, XIV, 1983. Proc Eur Dial Transplant Assoc Eur Ren Assoc 1985; 21: 2–65PubMed

18.

European Multicentre Trial Group. Cyclosporin in cadaveric renal transplantation: one-year follow-up of a multicentre trial. Lancet 1983; 2: 986–9CrossRef

19.

The Canadian Multicentre Transplant Study Group. A randomized clinical trial of cyclosporine in cadaveric renal transplantation. N Engl J Med 1983; 309: 809–15CrossRef

20.

Najarian JS, Fryd DS, Strand M, et al. A single institution, randomized, prospective trial of cyclosporine versus azathioprine-antilymphocyte globulin for immunosuppression in renal allograft recipients. Ann Surg 1984; 201: 142–57CrossRef

21.

Ponticelli C, Minetti L, Quarto di Palo F, et al. The Milan clinical trial with cyclosporine in cadaveric renal transplantation: a three-year follow-up. Transplantation 1988; 45: 908–13PubMedCrossRef

22.

Ponticelli C, Civati G, Tarantino A et al. Randomized study with cyclosporine in kidney transplantation: 10-year follow-up. J Am Soc Nephrol 1996; 7: 792–7PubMed

23.

Hall BM, Tiller DJ, Hardie I, et al. Comparison of three immunosuppressive regimens in cadaver renal transplantation: long-term cyclosporine, short-term cyclosporine followed by azathioprine and prednisolone, and azathioprine and prednisolone without cyclosporine. N Engl J Med 1988; 318: 1499–507PubMedCrossRef

24.

Hollander AAMJ, van Saase JLCM, Kootte AMM, et al. Beneficial effects of conversion from cyclosporin to azathioprine after kidney transplantation. Lancet 1995; 345: 610–4PubMedCrossRef

25.

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: 1027–34PubMedCrossRef

26.

Gallagher MP, Hall B, Craig J, et al. on behalf of the Australian Multicenter Trial of Cyclosporine Withdrawal Study Group and the ANZ Dialysis and Transplantation Registry. A randomized controlled trial of cyclosporine withdrawal in renal-transplant recipients: 15-year results. Transplantation 2004; 78: 1653–60

27.

Joss N, Rodger RS, McMillan MA, et al. Randomized study comparing cyclosporine with azathioprine one year after renal transplantation: 15-year outcome data. Transplantation 2007; 83: 582–7PubMedCrossRef

28.

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: 43–9PubMedCrossRef

29.

Lindholm A, Albrechtsen D, Tufveson G, et al. A randomized trial of cyclosporine and prednisolone versus cyclosporine, azathioprine, and prednisolone in primary cadaveric renal transplantation. Transplantation 1992; 54: 624–31PubMedCrossRef

30.

Montagnino G, Tarantino A, Bandfi G, et al. A randomized trial comparing triple-drug and double-drug therapy in renal transplantation. Transplantation 1994; 58: 149–54PubMed

31.

Mathew TH, for the Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. A blinded, long-term, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation. Transplantation 1998; 65: 1450–4PubMedCrossRef

32.

US Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil in cadaveric renal transplantation. Am J Kidney Dis 1999; 34: 296–303CrossRef

33.

European Mycophenolate Mofetil Cooperative Study Group. Mycophenolate mofetil in renal transplantation: 3-year results from the placebo-controlled trial. Transplantation 1999; 68: 391–6CrossRef

34.

Halloran P, Mathew T, Tomlanovich S, et al. Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. International Mycophenolate Mofetil Renal Transplant Study Groups. Transplantation 1997; 63: 39–47

35.

Remuzzi G, Cravedi P, Costantini M, et al. Mycophenolate mofetil versus azathioprine for prevention of chronic allograft dysfunction in renal transplantation: the MYSS follow-up randomized, controlled clinical trial. Am J Transplant 2007; 18: 1973–85

36.

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

37.

MacDonald AS, for the Rapamune Global Study Group. A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation 2001; 71: 271–80PubMedCrossRef

38.

Oberbauer R, Kreis H, Johnson RWG, et al. for the Rapamune Maintenance Regimen Study Group. 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

39.

Nashan B, Curtis J, Ponticelli C, et al. on behalf of the 156 Study Group. Everolimus and reduced-exposure cyclosporine in de novo renal-transplant recipients: a threeyear phase II, randomized, multicenter, open label study. Transplantation 2004; 78: 1332–40PubMedCrossRef

40.

Vitko S, Margreiter R, Wimar W, et al. for the RAD B201 Study Group. Three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 2005; 5: 2521–30

41.

Tedesco-Silva H, Vitko S, Pacual J, et al. on behalf of the 2306 and 2307 Study Groups. 12-month safety and efficacy of everolimus with reduced exposure cyclosporine in de novo renal transplant recipients. Transplant Int 2007; 20: 27–36

42.

Lorber MI, Mulgaonkar S, Butt KMH, et al. on behalf of the B251 Study Group. Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: a 3-year randomized, multicenter, phase III study. Transplantation 2005; 80: 244–52

43.

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

44.

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: 775–82PubMedCrossRef

45.

Mayer AD, Dmitrewski J, Squifflet J-P, et al. Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group. Transplantation 1997; 64: 436–43PubMedCrossRef

46.

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

47.

Squifflet J-P, Bäckman L, Claesson K, et al. for the European Tacrolimus-MMF Renal Study Group. Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients. Transplantation 2001; 72: 63–9

48.

Krämer BK, del Castillo D, Margreiter R, et al. for the European Tacrolimus Versus Cyclosporin Microemulsion Renal Transplantation Study Group. Efficacy and safety of tacrolimus compared with cyclosporin A in renal transplantation: three-year observational results. Nephrol Dial Transplant 2008; 23: 2386–92

49.

Pascual J, van Hoof JP, Salmela K, et al. Three-year observational follow-up of a multicenter, randomized trial on tacrolimus-based therapy with withdrawal of steroids or mycophenolate mofetil after renal transplant. Transplantation 2006; 82: 55–61PubMedCrossRef

50.

Ciancio G, Burke GW, Gaynor JJ, et al. A randomized long-term trial of tacrolimus/sirolimus versus tacrolimus/mycophenolate mofetil versus cyclosporine (Neoral)/sirolimus in renal transplantation: II. Survival, function, and protocol compliance at 1 year. Transplantation 2004; 77: 252–8

51.

Vitko S, Wlodarczyk Z, Kyllönen L, et al. Tacrolimus combined with two different dosages of sirolimus in kidney transplantation: results of a multicenter study. Am J Transplant 2006; 6: 531–8PubMedCrossRef

52.

Grinyó JM, Campistol JM, Paul J, et al. Pilot randomized study of early tacrolimus withdrawal from a regimen with sirolimus plus tacrolimus in kidney transplantation. Am J Transplant 2004; 4: 1308–14PubMedCrossRef

53.

Ekberg H, Grinyó J, Nashan B, et al. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR study. Am J Transplant 2007; 7: 560–70PubMedCrossRef

54.

Flechner SM, Kurian SM, Solez K, et al. De novo kidney transplantation without use of calcineurin inhibitors preserves renal structure and function at two years. Am J Transplant 2004; 4: 1776–85PubMedCrossRef

55.

Flechner SM, Goldfarb D, Solez K, et al. Kidney transplantation with sirolimus and mycophenolate mofetilbased immunosuppression: 5-year results of a randomized prospective trial compared to calcineurin inhibitor drugs. Transplantation 2007; 83: 883–92PubMedCrossRef

56.

Larson TS, Dean PG, Stegall MD, et al. Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus. Am J Transplant 2006; 6: 514–22PubMedCrossRef

57.

Ekberg H, Tedesco-Silva H, Demirbas A, et al.; ELITE-Symphony Study. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007; 357: 2562–75PubMedCrossRef

58.

Merion RM, White DJG, Thiru S, et al. Cyclosporine: five years’ experience in cadaveric renal transplantation. N Engl J Med 1984; 310: 148–54PubMedCrossRef

59.

Marcen R, Pascual J, Teruel JL, et al. Outcome of cadaveric renal transplant patients treated for 10 years with cyclosporine: is chronic allograft nephropathy the major cause of late graft loss? Transplantation 2001; 72: 57–62PubMedCrossRef

60.

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

61.

Meier-Kriesche H-U, Schold JD, Srinivas TR, et al. Sirolimus in combination with tacrolimus is associated with worse renal allograft survival compared to mycophenolate mofetil combined with tacrolimus. Am J Transplant 2005; 5: 2273–80PubMedCrossRef

62.

Cantarovich M, Durrbach A, Hiesse C, et al. 20-year follow-up results of a randomized controlled trial comparing antilymphocyte globulin induction to no induction in renal transplant patients. Transplantation 2008; 86: 1732–7PubMedCrossRef

63.

Margreiter R, Klempnauer J, Neuhaus P, et al. Alemtuzumab (Campath-1H) and tacrolimus monotherapy after renal transplantation: results of a prospective randomized trial. Am J Transplant 2008; 8: 1480–5PubMedCrossRef

64.

Ciancio G, Burke GW, Gaynor JJ, et al. A randomized trial of thymoglobulin vs alemtuzumab (with lower dose maintenance immunosuppression) vs daclizumab in renal transplantation at 24 months of follow-up. Clin Transplant 2008; 22: 200–10PubMedCrossRef

65.

Tydén G, Gensberg H, Tollemar J, et al. A randomized, double blind, placebo-controlled, study of single-dose rituximab as induction in renal transplantation. Transplantation 2009; 87: 1325–9PubMedCrossRef

66.

Excerpts from the United States Renal Data System 2008 annual data report, Transplantation. Am J Kidney Dis 2009; 53 Suppl. 1: S228-38

67.

Buell JF, Gross TG, Woodle ES. Malignancy after transplantation. Transplantation 2005; 80: S254–64PubMedCrossRef

68.

Lentine KL, Brennan DC, Schnitzler MA. Incidence and predictors of myocardial infarction after kidney transplantation. J Am Soc Nephrol 2005; 16: 496–506PubMedCrossRef

69.

Lentine KL, Schnitzler MA, Abbott KC, et al. De novo congestive heart failure after kidney transplantation: a common condition with poor prognostic implications. Am J Kidney Dis 2005; 46: 720–33PubMedCrossRef

70.

Lentine KL, Rocca Rey LA, Kolli S, et al. Variations in the risk for cerebrovascular events after kidney transplant compared with experience on the waiting list and after graft failure. Clin J Am Soc Nephrol 2008; 3: 1090–101PubMedCrossRef

71.

Ansell D, Udayarej UP, Steenkamp R, et al. Chronic renal failure in kidney transplant recipients; do they receive optimum care? Data from the UK renal registry. Am J Transplant 2007; 7: 1167–76PubMedCrossRef

72.

Marcén R, del Castillo D, Capdevila L, et al. Achieving chronic kidney disease treatment targets in renal transplant recipients: results from a cross-sectional study in Spain. Transplantation 2009; 87: 1340–6PubMedCrossRef

73.

Miller LW. Cardiovascular toxicities of immunosuppressive agents. Am J Transplant 2002; 2: 807–18PubMedCrossRef

74.

Morales JM, Dominguez-Gil B. Cardiovascular risk profile with the new immunosuppressive combinations after renal transplantation. J Hypertens 2005; 23: 1609–16PubMedCrossRef

75.

Chapman J, Marcén R, Arias M, et al. Hypertension after renal transplantation: a comparison of cyclosporine and conventional immnunosuppression. Transplantation 1987; 43: 860–4PubMed

76.

Marcén R, Gallego N, Orofino L, et al. Impairment of tubular secretion of urate in renal transplant patients on cyclosporine. Nephron 1995; 70: 307–13PubMedCrossRef

77.

Krämer BK, Zülke C, Kammerl MC, et al. Cardiovascular risk factors and estimated risk for CAD in a randomized trial comparing calcineurin inhibitors in renal transplantation. Am J Transplant 2003; 3: 982–7PubMedCrossRef

78.

Opelz G, Döhler B, for the Collaborative Transplant Study. Influence of immunosuppressive regimens on graft survival and secondary outcomes after kidney transplantation. Transplantation 2009; 87: 795–802PubMedCrossRef

79.

Pascual J, Bloom D, Torrealba J, et al. Calcineurin inhibitor withdrawal after renal transplantation with alemtuzumab: clinical outcomes and effects on T-regulatory cells. Am J Transplant 2008; 8: 1529–36PubMedCrossRef

80.

Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004; 43 (5 Suppl. 1): S1–S290

81.

EDTA-ERA: European best practice guidelines. Nephrol Dial Transplant 2000; 15 Suppl. 4: 1–67CrossRef

82.

Kasiske BL, Anjum S, Shah R, et al. Hypertension after kidney transplantation. Am J Kidney Dis 2004; 43: 1071–81PubMedCrossRef

83.

Opelz G, Döhler B, for the Collaborative Transplant Study Group. Improved long-term outcomes after renal transplantation associated with blood pressure control. Am J Transplant 2005; 5: 2725–31PubMedCrossRef

84.

Webster AC, Lee VWS, Chapman JR, et al. Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosupression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials. Transplantation 2006; 81: 1234–48PubMedCrossRef

85.

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

86.

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

87.

Marcén R, Morales JM, Arias M, et al. Ischemic heart disease after renal transplantation in patients on cyclosporine in Spain. J Am Soc Nephrol 2006; 17: S286–90PubMedCrossRef

88.

Kasiske B, Cosio FG, Beto J, et al. Clinical practice guidelines for managing dyslipemias in kidney transplant patients: a report from the Managing Dyslipemias in Chronic Kidney Disease Work Group of the National Kidney Foundation Kidney Disease Quality Initiative. Am J Transplant 2004; 7 (4 Suppl.): 13–53CrossRef

89.

Kasiske BL, de Mattos A, Flechner SM, et al. Mammalian target of rapamycin inhibitor dyslipidemia in kidney transplant recipients. Am J Transplant 2008; 8: 1384–92PubMedCrossRef

90.

Weir MR, Fink JC. Risk for posttransplant diabetes mellitus with current immunosuppression medications. Am J Kidney Dis 1999; 34: 1–13PubMedCrossRef

91.

Hold JL, Apelqvist AA, Gu X, et al. Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function. Nature 2006; 443: 345–9CrossRef

92.

Gonwa T, Johnson C, Ahsan N, et al. Randomized trial of tacrolimus+mycophenolate mofetil or azathioprine versus cyclosporine+mycophenolate mofetil after cadaveric kidney transplantation: results at three years. Transplantation 2003; 75: 2048–53PubMedCrossRef

93.

Gourishankar S, Jhangri GS, Tonelli M, et al. Development of diabetes mellitus following kidney transplantation: a Canadian experience. Am J Transplant 2004; 4: 1876–82PubMedCrossRef

94.

Marcén R, Morales JM, del Castillo D, et al. Posttransplant diabetes mellitus in renal allograft recipients: a prospective multicenter study at 2 years. Transplant Proc 2006; 38: 3530–2PubMedCrossRef

95.

Burroughs TE, Swindle J, Takemoto S, et al. Diabetic complications associated with new-onset diabetes mellitus in renal transplant recipients. Transplantation 2007; 83: 1027–34PubMedCrossRef

96.

Kasiske BL, Synder JJ, Gilberston D, et al. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003; 3: 178–85PubMedCrossRef

97.

Heisel O, Heisel R, Balshaw R, et al. New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and metanalysis. Am J Transplant 2004; 4: 583–95PubMedCrossRef

98.

Vincenti F, Friman S, Scheuermann E, et al.; DIRECT (Diabetes Incidence after Renal Transplantation: Neoral C Monitoring Versus Tacrolimus) Investigators. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus [published errata appeared in Am J Transplant 2008; 8 (1): 1 and 2008; 8 (4): 908]. Am J Transplant 2007; 7: 1506–14PubMedCrossRef

99.

Johnston O, Rose CL, Webster AC, et al. Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J Am Soc Nephrol 2008; 19: 1411–8PubMedCrossRef

100.

Cosio FG, Pesavento TE, Kim S, et al. Patient survival after transplantation: IV. Impact of post-transplant diabetes. Kidney Int 2002; 62: 1440–6

101.

Cole EH, Johnston O, Rose CL, et al. Impact of acute rejection and new-onset diabetes on long-term transplant graft and patient survival. Clin J Am Soc Nephrol 2008; 3: 814–21PubMedCrossRef

102.

Citterio F. Steroid side effects and their impact on transplantation outcome. Transplantation 2001; 72 Suppl.: S75–80PubMed

103.

Ahsan N, Hricik D, Matas A, et al. Prednisone withdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil: a prospective randomized study. Steroid Withdrawal Study Group. Transplantation 1999; 68: 1865–74

104.

Opelz G, Döhler B, Laux G, for the Collaborative Transplant Study. Long-term prospective study of steroid withdrawal in kidney and heart transplant recipients. Am J Transplant 2005; 5 (4 Pt 1): 720–8PubMedCrossRef

105.

Rama I, Cruzado JM, Gil-Vernet S, et al. Steroids can be safely withdrawn from cyclosporine and mycophenolate mofetil-treated renal allograft recipients: long-term results. Transplantation 2005; 80: 164–8PubMedCrossRef

106.

Abramowicz D, Vanrenterghem Y, Squifflet J-P. Efficacy and cardiovascular safety of daclizumab, mycophenolate mofetil, tacrolimus, and early steroids withdrawal in renal transplant recipients: a multicenter, prospective, pilot trial. Clin Transplant 2005; 19: 475–82PubMedCrossRef

107.

Vanrenterghem Y, Lebranchu Y, Hené R, et al. Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection. Transplantation 2000; 70: 1352–9PubMedCrossRef

108.

Vincenti F, Monaco A, Grinyo J, et al. Multicenter randomized prospective trial of steroid withdrawal in renal transplant recipients receiving basiliximab, cyclosporine microemulsion and mycophenolate mofetil. Am J Transplant 2003; 3: 306–11PubMedCrossRef

109.

Borrow R, Loucaidou M, Van Tromp J, et al. Steroid sparing with tacrolimus and mycophenolate mofetil in renal transplantation. Am J Transplant 2004; 4: 1845–51CrossRef

110.

Vitko S, Klinger M, Salmela K, et al. Two corticosteroid-free regimens — tacrolimus monotherapy after basiliximab administration and tacrolimus/mycophenolate mofetil — in comparison with a standard triple regimen in renal transplantation: results of the Atlas study. Transplantation 2005; 80: 1734–41PubMedCrossRef

111.

Rostaing L, Cantarovich D, Mourad G, et al. on behalf of the CARMEN Study Group. Corticosteroid-free immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab induction in renal transplantation. Transplantation 2005; 79: 807–14

112.

Kumar MSA, Heifets M, Moritz MJ, et al. Safety and efficacy of steroid withdrawal two days after kidney transplantation: analysis of results at three years. Transplantation 2006; 81: 832–9PubMedCrossRef

113.

Arnol M, de Mattos AM, Chung JS, et al. Late steroid withdrawal and cardiovascular events in kidney transplant recipients. Transplantation 2008; 86: 1844–8PubMedCrossRef

114.

Rike AH, Mogilishetty G, Alloway RR, et al. Cardiovascular risk, cardiovascular events, and metabolic syndrome in renal transplantation: comparison of early steroid withdrawal and chronic steroids. Clin Transplant 2008; 22: 229–35PubMedCrossRef

115.

Luan FL, Steffick DE, Gadegbeku C, et al. Graft and patient survival in kidney transplant recipients selected for de novo steroid-free maintenance immunosuppression. Am J Transplant 2009; 9: 160–8PubMedCrossRef

116.

Augustine JJ, Hricick DE. Steroid sparing in kidney transplantation: changing paradigms, improving outcomes, and remaining questions. Clin J Am Soc Nephrol 2006; 1: 1080–9PubMedCrossRef

117.

Wong W, Tolkoff-Rubin N, Delmonico FL, et al. Analysis of the cardiovascular risk profile in stable kidney transplant recipients after 50% cyclosporine reduction. Clin Transplant 2004; 18: 341–8PubMedCrossRef

118.

Morales JM, Wrammer L, Kreis H, et al. for the Sirolimus European Renal Transplant Study Group. Sirolimus does not exhibit nephrotoxicity compared to cyclosporine in renal transplant recipients. Am J Transplant 2002; 2: 436–42PubMed

119.

Oberbauer R, Segoloni G, Campistol JM, et al. for the Rapamune Maintenance Regimen Study Group. Early cyclosporine withdrawal from a sirolimus-based regimen results in better renal allograft survival and renal function at 48 months after transplantation. Transplant Int 2005; 18: 22–8

120.

Artz M, 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: 937–45PubMedCrossRef

121.

Cantarovich D, Renou M, Megnigbeto A, et al. Switching from cyclosporine to tacrolimus in patients with chronic transplant dysfunction or cyclosporine-induced adverse events. Transplantation 2005; 79: 72–8PubMedCrossRef

122.

Marcén R, Chahin J, Alercón A, et al. Conversion from cyclosporine microemulsion to tacrolimus in stable kidney transplant patients with hypercholesterolemia is related to an improvement in cardiovascular risk profile: a prospective study. Transplant Proc 2006; 38: 2427–30PubMedCrossRef

123.

Margreiter R, Prohanka E, Sparacino V, et al. on behalf of the European Switch to Tacrolimus Study Group. Open prospective multicenter study of conversion to tacrolimus therapy in renal transplant patients experiencing ciclosporin-related side-effects. Transplant Int 2005; 18: 816–23

124.

Luan FL, Zhang H, Schaubel DE, et al. Comparative risk of impaired glucose metabolism associated with cyclosporine versus tacrolimus in the late posttransplant period. Am J Transplant 2008; 8: 1871–7PubMedCrossRef

125.

Baid-Agrawal S, Delmonico FL, Tolkoff-Rubin N, et al. Cardiovascular risk profile after conversion from cyclosporine A to tacrolimus in stable renal transplant recipients. Transplantation 2004; 77: 1199–202PubMedCrossRef

126.

Kiberd B, Panek R. Cardiovascular outcomes in the outpatient kidney transplant clinic: the Framingham risk score revisited. Clin J Am Soc Nephrol 2008; 3: 822–8PubMedCrossRef

127.

Shihab FS, Waid TH, Conti DJ, et al. on behalf of the CRAF Study Group. Conversion from cyclosporine to tacrolimus in patients at risk for chronic allograft failure: 60-months results of the CRAF study. Transplantation 2008; 85: 1261–9

128.

Bouchta NB, Ghisdal L, Abramowicz D, et al. Conversion from tacrolimus to cyclosporin is associated with a significant improvement of glucose metabolism in patients with new onset diabetes mellitus after renal transplantation. Tansplant Proc 2005; 37: 1857–60CrossRef

129.

Murray JE, Gleason R, Bartholomay A. Third report of the human kidney transplant registry. Transplantation 1965; 35: 294–302CrossRef

130.

Danpanich E, Kasiske BL. Risk factors for cancer in renal transplant recipients. Transplantation 1999; 68: 1859–64PubMedCrossRef

131.

Kahan BD, Yakupoglu YK, Knight RJ, et al. Low incidence of malignancy among sirolimus/cyclosporine-treated renal transplant recipients. Transplantation 2005; 80: 749–58PubMedCrossRef

132.

Kessler M, Jay N, Molle R, et al. Excess risk of cancer in renal transplant patients. Tranplant Int 2006; 19: 909–14

133.

Wimmer CD, Rentxch M, Crispin A, et al. The janus face of immunosuppression — de novo malignancy after renal transplantation: the experience of the Transplantation Center Munich. Kidney Int 2007; 71: 1271–8PubMedCrossRef

134.

Végso G, Tóth M, Hídvegí M, et al. Malignancies after renal transplantation during 33 years at a single center. Path Oncol Res 2007; 13: 63–9CrossRef

135.

Adami J, Gäbel H, Lindelöf B, et al. Cancer risk following organ transplantation: a nationwide cohort study in Sweden. Br J Cancer 2003; 89: 1221–7PubMedCrossRef

136.

Kasiske BL, Snyder JJ, Gilbertson DTG, et al. Cancer after kidney transplantation in the United States. Am J Transplant 2004; 4: 905–13PubMedCrossRef

137.

Vajdic CM, McDonald SP, McCredie MRE, et al. Cancer incidence before and after kidney transplantation. JAMA 2006; 296: 2823–31PubMedCrossRef

138.

Webster AC, Craig JC, Simpson JM, et al. Identifying high risk groups and quantifying absolute risk of cancer after kidney transplantation: a cohort study of 15183 recipients. Am J Transplant 2007; 7: 2140–15PubMedCrossRef

139.

Bustami RT, Ojo AO, Wolfe RA, et al. Immunosuppression and the risk of post-transplant malignancy among cadaveric first kidney transplant recipients. Am J Transplant 2004; 4: 83–7CrossRef

140.

Cowlrick I, Delvental H, Kaipainem K, et al. Three-year follow-up of malignancies in tacrolimus-treated renal recipients: an analysis of European multicentre studies. Clin Transplant 2008; 22: 372–7PubMedCrossRef

141.

Pedotti P, Cardillo M, Rossini G, et al. Incidence of cancer after kidney transplant: results from the North Italy transplant program. Transplantation 2003; 76: 1448–51PubMedCrossRef

142.

Stratta P, Morellini V, Musetti C, et al. Malignancy after kidney transplantation: results of 400 patients from a single center. Clin Transplant 2008; 22: 424–7PubMedCrossRef

143.

Kauffman HM, Cherikh WS, McBride MA, et al. Post-transplant de novo malignancies in renal transplant recipients: the past and present. Transplant Int 2006; 19: 607–20CrossRef

144.

Cherikh WS, Kauffman HM, McBride MA, et al. Association of the type of induction immunosuppression with posttransplant lymphoproliferative disorder, graft survival, and patient survival after primary transplantation. Transplantation 2003; 76: 1289–93PubMedCrossRef

145.

Opelz G, Döhler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2003; 4: 222–30CrossRef

146.

Guba M, Graeb C, Jauch K-W, et al. Pro- and anti-cancer effects of immunosuppressive agents used in organ transplantation. Transplantation 2004; 77: 1777–82PubMedCrossRef

147.

McGeown MG, Douglas JF, Middleton D. One thousand renal transplants at Belfast City Hospital: post-graft neoplasia 1968–1999, comparing azathioprine only with cyclosporine-based regimens in a single center. In: Cecka JM, Terasaki PI, editors. Clinical transplant, 2000. Los Angeles (CA): UCLA Immunogenetics Center, 2000: 193–202

148.

Marcén R, Pascual J, Tato AM, et al. Influence of immunosuppression on the prevalence of cancer after kidney transplantation. Transplant Proc 2003; 35: 1714–6PubMedCrossRef

149.

Dantal J, Hourmant M, Cantarovich D, et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet 1998; 351: 623–8PubMedCrossRef

150.

Robson R, Cecka JM, Opelz G, et al. Prospective registry-based observational cohort study of the long-term risk of malignancies in renal transplant patients treated with mycophenolate mofetil. Am J Transplant 2005; 5: 2954–60PubMedCrossRef

151.

Campistol JM, Eris J, Oberbauer R, et al. Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol 2006; 17: 581–9PubMedCrossRef

152.

Haller M, Oberbauer R. Calcineurin inhibitor minimization, withdrawal and avoidance protocols after kidney transplantation. Transplant Int 2009; 22: 69–77CrossRef

153.

Schena FP, Pascoe MD, Alberu J, et al. on behalf of the Sirolimus CONVERT Trial Study Group. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation 2009; 87: 233–42

154.

Kauffman HM, Cherikh W, Cheng Y, et al. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation 2005; 80: 883–9PubMedCrossRef

155.

Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med 2005; 352: 1317–23PubMedCrossRef

156.

Campistol JM, Schena FP. Kaposi’s sarcoma in renal transplant recipients: the impact of proliferation signal inhibitors. Nephrol Dial Transplant 2007; 22 Suppl. 1: I17–22PubMedCrossRef

157.

Campistol JM, Albanell J, Arns W, et al. Use of proliferation signal inhibitors in the management of post-transplant malignancies: clinical guidance. Nephrol Dial Transplant 2007; 22 Suppl. 1: i36–41PubMedCrossRef

158.

Rubin RH, Wolfson JS, Cosimi AB, et al. Infection in the renal transplant recipient. Am J Med 1981; 70: 405–11PubMedCrossRef

159.

Fisman JS, Rubin RH. Infection in organ-transplant recipients. New Engl J Med 1998; 338: 1741–51CrossRef

160.

Alangaden GJ, Thyagarajan R, Gruber SA, et al. Infectious complications after kidney transplantation: current epidemiology and associated risk factors. Clin Transplant 2006; 20: 401–9PubMedCrossRef

161.

Snyder JJ, Israni AK, Peng Y, et al. Rates of first infection following kidney transplant in the United States. Kidney Int 2009; 75: 317–26PubMedCrossRef

162.

Dharnidharka VR, Caillard S, Agodoa LY, et al. Infection frequency and profile in different age groups of kidney transplant recipients. Transplantation 2006; 81: 1662–7PubMedCrossRef

163.

Dharnidharka VR, Agodoa LY, Abbott KC. Risk factors for hospitalization for bacterial or viral infection in renal transplant recipients: an analysis of USRDS data. Am J Transplant 2007; 7: 653–61PubMedCrossRef

164.

Rostaing L, Guilbeau-Frugier C, Kamar N. Rituximab for humoral rejection after renal transplantation: an update. Transplantation 2009; 87: 1261PubMedCrossRef

165.

Sagedal S, Hartmann A, Nordal KP, et al. Impact of early cytomegalovirus infection and disease on long-term recipient and kidney graft survival. Kidney Int 2004; 66: 329–37PubMedCrossRef

166.

Rowshani AT, Bemelman FJ, van Leeuwen EM, et al. Clinical and immunological aspects of cytomegalovirus infection in solid organ transplant recipients. Transplantation 2005; 79: 381–6PubMedCrossRef

167.

Weikert BC, Blumberg EA. Viral infection after renal transplantation: surveillance and management. Clin J Am Soc Nephrol 2008; 3: S76–86PubMedCrossRef

168.

Sagedal SS, Hartmann A. Cytomegalovirus infection in renal transplant recipients is associated with impaired survival irrespective of expected mortality risk. Clin Transplant 2007; 21: 309–13PubMedCrossRef

169.

Hartmann A, Sagedal S, Hjetmesaeth J. The natural course of cytomegalovirus infection and disease in renal transplant recipients. Transplantation 2006; 82: S15–7PubMedCrossRef

170.

Opelz G, Döhler B, Ruhenstroth A. Cytomegalovirus prophylaxis and graft outcome in solid organ transplantation: a collaborative transplant study group. Am J Transplant 2004; 4: 928–36PubMedCrossRef

171.

Kalil AC, Levitsky J, Leyden E, et al. Meta-analysis: the efficacy of strategies to prevent organ disease by CMV in solid organ transplant recipients. Ann Intern Med 2005; 143: 870–80PubMed

172.

Kliem V, Fricke L, Wollbrink T, et al. Improvement in long term renal graft allograft survival due to CMV prophylaxis with oral ganciclovir: results of a randomized clinical trial. Am J Transplant 2008; 8: 975–83PubMedCrossRef

173.

Brennan DC, Agha I, Bohl DL, et al. Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. Am J Transplant 2005; 5: 582–94PubMedCrossRef

174.

Basse G, Mengelle C, Kamar N, et al. Prospective evaluation of BK virus DNAemia in renal transplant patients and their transplant outcome. Traplant Proc 2007; 39: 84–7CrossRef

175.

Hirsch HH, Knowles W, Dickenmann M, et al. Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med 2002; 347: 488–96PubMedCrossRef

176.

Hariharan S. BK virus nephritis after renal transplantation. Kidney Int 2006; 69: 655–62PubMedCrossRef

177.

Dall A, Hariharan S. BK virus nephritis after renal transplantation. Clin J Am Soc Nephrol 2008; 3 Suppl. 2: S68–75PubMedCrossRef

178.

Bohl DL, Brennan DC. BK virus nephropathy and kidney transplantation. Clin J Am Soc Nephrol 2007; 2 Suppl. 1: S36–46PubMedCrossRef

179.

Drachenberg CB, Papadimitriou JC. Polyomavirus-associated nephropathy: update and diagnosis. Transplant Infect Dis 2006; 8: 68–75CrossRef

180.

Ramos E, Drachenberg CB, Papadimitriou JC, et al. Clinical course of polyoma virus nephropathy in 67 renal transplant patients. J Am Soc Nephrol 2002; 13: 1245–51

181.

Vasudev B, Hariharan S, Hussian SA, et al. BK virus nephritis: risk factors, timing and outcomes in renal transplant recipients. Kidney Int 2005; 68: 1834–9PubMedCrossRef

182.

Beimler J, Sommerer C, Zeier M. The influence of immunosuppression on the development of BK virus nephropathy: does it matter? Nephrol Dial Transplant 2007; 22 Suppl. 8: viii66–71PubMedCrossRef

183.

Saad ER, Bresnahan BA, Cohen EP, et al. Successful treatment of BK viremia using reduction in immunosuppression without antiviral therapy. Transplantation 2008; 85: 850–4PubMedCrossRef

184.

Weis AS, Gralla J, Chan L, et al. Aggressive immunosuppression minimization reduces graft loss following diagnosis of BK virus-associated nephropathy: a comparison of two reduction strategies. Clin J Am Soc Nephrol 2008; 3: 1812–9CrossRef

185.

Trofe J, Hirsch HH, Ramos E. Polyomavirus-associated nephropathy: update of clinical management in kidney transplant patients. Transplant Infect Dis 2006; 8: 76–85CrossRef

186.

Smith JM, Rudser K, Gillen D, et al. Risk of lymphoma after renal transplantation varies with time: an analysis of the United States renal data system. Transplantation 2006; 81: 175–80PubMedCrossRef

187.

Holmes MV, Caplin B, Smith C, et al. Prospective monitoring of Epstein-Barr virus DNA in adult renal transplant recipients during the early posttrasplant period: role of mycophenolate mofetil. Transplantation 2009; 87: 852–6PubMedCrossRef

188.

Jain AB, Marcos A, Pokharna R, et al. Rituximab (chimeric anti CD20 antibody) for posttransplant lymphoproliferative disorder after solid organ transplantation in adults: long-term experience from a single center. Transplantation 2005; 80: 1692–8PubMedCrossRef

Title: Immunosuppressive Drugs in Kidney Transplantation
Impact on Patient Survival, and Incidence of Cardiovascular Disease, Malignancy and Infection
Author: Dr Roberto Marcén
Publication date: 01-11-2009
Publisher: Springer International Publishing
Published in: Drugs / Issue 16/2009
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI: https://doi.org/10.2165/11319260-000000000-00000

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Immunosuppressive Drugs in Kidney Transplantation

Impact on Patient Survival, and Incidence of Cardiovascular Disease, Malignancy and Infection

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 16/2009

Enzyme Replacement Therapy for Fabry Disease

Predictors of Treatment Response in Chronic Hepatitis B

Medical Therapy of Acromegaly

Lanthanum Carbonate

Pemetrexed

Gefitinib