Can mTOR inhibitors reduce the risk of late kidney allograft failure?

Transplant International

Volumn 21, Issue 1, 2008, Pages 2-10

  Ponticelli, Claudio ^a,b  

^a ISTITUTO AUXOLOGICO ITALIANO   (Italy)

^b NONE   (Italy)

Author keywords

Everolimus; Immunosuppression; mTOR; Rejection; Renal transplantation; Sirolimus

Indexed keywords

ALEMTUZUMAB; ARGININE; BASILIXIMAB; CALCINEURIN INHIBITOR; CORTICOSTEROID; CYCLOSPORIN A; DACLIZUMAB; EVEROLIMUS; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; OMEGA 3 FATTY ACID; PHOSPHATIDYLINOSITOL 3 KINASE; PREDNISONE; RAPAMYCIN; STEROID; TACROLIMUS; THYMOCYTE ANTIBODY;

ANTINEOPLASTIC ACTIVITY; CANCER INCIDENCE; CELL PROLIFERATION; CLINICAL TRIAL; CYTOMEGALOVIRUS INFECTION; DONOR SELECTION; DRUG DOSE INCREASE; DRUG TOLERABILITY; DRUG WITHDRAWAL; GRAFT FAILURE; HOST CELL; HUMAN; HYPERCHOLESTEROLEMIA; HYPERTRIGLYCERIDEMIA; IMMUNOSUPPRESSIVE TREATMENT; INFECTION RISK; KIDNEY ALLOGRAFT; KIDNEY GRAFT REJECTION; LOW DRUG DOSE; MAINTENANCE THERAPY; NEPHROTOXICITY; POSTOPERATIVE PERIOD; PRIORITY JOURNAL; RENAL GRAFT DYSFUNCTION; REVIEW; RISK REDUCTION; SIGNAL TRANSDUCTION; UNSPECIFIED SIDE EFFECT; VASCULAR DISEASE; VIRUS REPLICATION;

ANIMALS; CALCINEURIN; CELL PROLIFERATION; GRAFT REJECTION; HUMANS; IMMUNOSUPPRESSIVE AGENTS; KIDNEY TRANSPLANTATION; PROTEIN KINASES; SIGNAL TRANSDUCTION; SIROLIMUS;

EID: 36649016241     PISSN: 09340874     EISSN: 14322277     Source Type: Journal    
DOI: 10.1111/j.1432-2277.2007.00524.x     Document Type: Review

References (116)

1. 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.
2. Kerr SR, Gillingham KJ, Johnson EM, Matas AJ. Living donors > 55 years: to use or not to use? Transplantation 1999 67 : 999.
3. Meier-Kriesche HU, Cibrik DM, Ojo AO, et al. Interaction between donor and recipient age in determining the risk of chronic renal failure. J Am Geriatr Soc 2002 50 : 195.
4. Morris P, Johnson RJ, Fuggle SV, et al. Analysis of factors that affect outcome of primary cadaveric renal transplantation in the UK. Nephrol Dial Transplant 1999 354 : 1147.
5. Montagnino G, Tarantino A, Cesana B, et al. Prognostic factors of long-term allograft survival in 632 CyA-treated recipients of a primary renal transplant. Transpl Int 1997 10 : 268.
6. Meier-Kriesche HU, Schold JD. The impact of pretransplant dialysis on outcomes in renal transplantation. Semin Dial 2005 18 : 499.
7. Solez K, Colvin RB, Racusen LC, et al. Banff '05 Meeting report: Differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy ('CAN'). Am J Transplant 2007 7 : 518.
8. Le Moine A, Goldman M, Abramowicz D. Multiple pathways to allograft rejection. Transplantation 2002 73 : 1373.
9. Terasaki PI, Cai J. Humoral theory of transplantation: further evidence. Curr Opin Immunol 2005 17 : 541.
10. Cecka JM. The OPTN/UNOS renal transplant registry. Clin Transpl 2005 1.
11. Opelz G. Critical evaluation of the association of acute with chronic graft rejection in kidney and heart transplant recipients. The Collaborative Transplant Study. Transplant Proc 1997 29 : 73.
12. Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 2000 342 : 605.
13. Rush D, Winnipeg Transplant Group. Insights into subclinical rejection. Transplant Proc 2004 2 (Suppl. 71S.
14. Feucht HE. Complement C4d in graft capillaries - the missing link in the recognition of humoral alloreactivity. Am J Transplant 2003 3 : 646.
15. Sijpkens YW, Doxiadis II, Mallat MJ, et al. Early versus late acute rejection episodes in renal transplantation. Transplantation 2003 75 : 204.
16. Butler JA, Roderick P, Mullee M, Mason JC, Peveler RC. Frequency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review. Transplantation 2004 77 : 769.
17. Denhaerynck K, Dobbels F, Cleemput I, et al. Prevalence, consequences and determinants of nonadherence in renal transplant patients: a literature review. Transpl Int 2005 18 : 1121.
18. Helantera I, Koskinen P, Finne P, et al. Persistent cytomegalovirus infection in kidney allografts is associated with inferior graft function and survival. Transpl Int 2006 19 : 893.
19. Sagedal S, Nordal KP, Hartmann A, et al. The impact of cytomegalovirus infection and disease on rejection episodes in renal allograft recipients. Am J Transplant 2002 2 : 850.
20. Tong CY, Bakaran A, Peiris JS, et al. The association of viral infection and chronic allograft nephropathy with graft dysfunction after renal transplantation. Transplantation 2002 27 : 576.
21. Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med 2003 349 : 2326.
22. Bennett WM, DeMattos A, Meyer MM, Andoh T, Barry JM. Chronic cyclosporine nephropathy: the Achilles' heel of immunosuppressive therapy. Kidney Int 1996 50 : 1089.
23. Briggs D. Causes of death after transplantation. Nephrol Dial Transplant 2001 16 : 1545.
24. Ponticelli C, Villa M, Cesana B, Montagnino G, Tarantino A. Risk factors for late kidney allograft failure. Kidney Int 2002 62 : 1848.
25. Vliegen I, Duijvestijn A, Graves G, et al. Cytomegalovirus infection aggravates atherogenesis in apoE knockout mice by both local and systemic immune activation. Microbes Infect 2004 6 : 17.
26. Nerheim PL, Meier JL, Vasef MA, et al. Enhanced cytomegalovirus infection in atherosclerotic human blood vessels. Am J Pathol 2004 164 : 589.
27. Hsue PY, Hunt PW, Sinclair E, et al. Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses. AIDS 2006 20 : 2275.
28. Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998 338 : 1741.
29. Opelz G, Naujokat C, Daniel V, Terness P, Dohler B. Disassociation between risk of graft loss and risk of non-Hodgkin lymphoma with induction agents in renal transplant recipients. Transplantation 2006 81 : 1227.
30. Ekberg H, Grinyo 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.
31. Flechner SM, Feng J, Mastroianni B, et al. The effect of 2-gram versus 1-gram concentration controlled mycophenolate mofetil on renal transplant outcomes using sirolimus-based calcineurin inhibitor drug-free immunosuppression. Transplantation 2005 79 : 926.
32. 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.
33. Srinivas TR, Schold JD, Guerra G, Eagan A, Bucci CM, Meier-Kriesche HU. Mycophenolate mofetil/sirolimus compared to other immunosuppressive regimens in kidney transplantation. Am J Transplant 2007 7 : 586.
34. Ponticelli C, Passerini P. Gastrointestinal complications in renal transplant recipients. Transpl Int 2005 18 : 643.
35. Joist H, Brennan DC, Coyne DW. Anemia in the kidney-transplant patient. Adv Chronic Kidney Dis 2006 13 : 4.
36. 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.
37. Bestard O, Cruzado JM, Grinyo JM. Calcineurin-inhibitor-sparing immunosuppressive protocols. Transplant Proc 2005 37 : 3729.
38. Flechner SM, Friend PJ, Brockmann J, et al. Alemtuzumab induction and sirolimus plus mycophenolate mofetil maintenance for CNI and steroid-free kidney transplant immunosuppression. Am J Transplant 2005 5 : 3009.
39. Meier-Kriesche HU, Hricik DE. Are we ready to give up on calcineurin inhibitors? Am J Transplant 2006 6 : 445.
40. Mota A, Arias M, Taskinen EI, et al. Sirolimus-based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant 2004 46 : 953.
41. Russ G, Segoloni G, Oberbauer R, et al. Superior outcomes in renal transplantation after early cyclosporine withdrawal and sirolimus maintenance therapy, regardless of baseline renal function. Transplantation 2005 80 : 1204.
42. 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.
43. Shihab FS, Bennett WM, Yi H, Choi SO, Andoh TF. Sirolimus increases transforming growth factor-beta1 expression and potentiates chronic cyclosporine nephrotoxicity. Kidney Int 2004 65 : 1262.
44. Mulay AV, Cockfield S, Stryker R, Fergusson D, Knoll GA. Conversion from calcineurin inhibitors to sirolimus for chronic renal allograft dysfunction: a systematic review of the evidence. Transplantation 2006 80 : 1153.
45. Nashan B, Curtis J, Ponticelli C, et al. Everolimus and reduced-exposure cyclosporine in de novo renal-transplant recipients: a three-year phase II, randomized, multicenter, open-label study. Transplantation 2004 78 : 1332.
46. Tedesco-Silva Jr. H, Vitko S, Pascual J, et al. 12-month safety and efficacy of everolimus with reduced exposure cyclosporine in de novo renal transplant recipients. Transpl Int 2007 20 : 27.
47. Kasiske BL, Chakkera HA, Louis TA, Ma JZ. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol 2000 11 : 1910.
48. Montagnino G, Tarantino A, Segoloni GP, et al. Long-term results of a randomized study comparing three immunosuppressive schedules with cyclosporine in cadaveric kidney transplantation. J Am Soc Nephrol 2001 12 : 2163.
49. Pascual J, Quereda C, Zamora J, Hernandez D, Spanish Group for Evidence-Based Medicine in Renal Transplantation. Steroid withdrawal in renal transplant patients on triple therapy with a calcineurin inhibitor and mycophenolate mofetil: a meta-analysis of randomized, controlled trials. Transplantation 2004 78 : 1548.
50. Opelz G, Dohler B, Laux G Collaborative Transplant Study. Long-term prospective study of steroid withdrawal in kidney and heart transplant recipients. Am J Transplant 2005 5 : 720.
51. Kumar MS, 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.
52. Vincenti F, Monaco A, Grinyo J, Kinkhabwala M, Roza A. Multicenter randomized prospective trial of steroid withdrawal in renal transplant recipients receiving basiliximab, cyclosporine microemulsion and mycophenolate mofetil. Am J Transplant 2003 3 : 306.
53. Vanrenterghem Y, van Hooff JP, Squifflet JP, et al. Minimization of immunosuppressive therapy after renal transplantation: results of a randomized controlled trial. Am J Transplant 2005 5 : 87.
54. Ciancio G, Burke GW, Gaynor JJ, et al. A randomized trial of three renal transplant induction antibodies: early comparison of tacrolimus, mycophenolate mofetil, and steroid dosing, and newer immune-monitoring. Transplantation 2005 80 : 457.
55. Montagnino G, Sandrini S, Casciani C, et al. A randomized trial of steroid avoidance in renal transplant patients treated with everolimus and cyclosporine. Transplant Proc 2005 37 : 788.
56. Alexander JW, Goodman HR, Cardi M, et al. Simultaneous corticosteroid avoidance and calcineurin inhibitor minimization in renal transplantation. Transpl Int 2006 19 : 295.
57. Jaber JJ, Feustel PJ, Elbahloul O, Conti AD, Gallichio MH, Conti DJ. Early steroid withdrawal therapy in renal transplant recipients: a steroid-free sirolimus and CellCept-based calcineurin inhibitor-minimization protocol. Clin Transplant 2007 21 : 101.
58. Smith MS, Bentz GL, Smith PM, Bivins ER, Yurochko AD. HCMV activates PI(3)K in monocytes and promotes monocyte motility and transendothelial migration in a PI(3)K-dependent manner. J Leukoc Biol 2004 76 : 65.
59. Kudchodkar SB, Yu Y, Maguire TG, Alwine JC. Human cytomegalovirus infection induces rapamycin-insensitive phosphorylation of downstream effectors of mTOR kinase. J Virol 2004 78 : 11030.
60. Kudchodkar SB, Yu Y, Maguire TG, Alwine JC. Human cytomegalovirus infection alters the substrate specificities and rapamycin sensitivities of raptor- and rictor-containing complexes. Proc Natl Acad Sci U S A 2006 103 : 14182.
61. Spencer JV. The cytomegalovirus homolog of interleukin-10 requires phosphatidylinositol 3-kinase activity for inhibition of cytokine synthesis in monocytes. J Virol 2007 81 : 2083.
62. Kotenko SV, Saccani S, Izotova LS, Mirochnitchenko OV, Pestka S. Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10). Proc Natl Acad Sci U S A 2000 97 : 1695.
63. Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac transplant recipients. N Engl J Med 2003 349 : 847.
64. Trotter JE, Wallack A, Steinberg T. Low incidence of cytomegalovirus disease in liver transplant recipients receiving sirolimus primary immunosuppression with 3-day corticosteroid taper. Transpl Infect Dis 2003 5 : 174.
65. Vitko S, Tedesco H, Eris J, et al. Everolimus with optimized cyclosporine dosig in renal transplant recipients: 6-month safety and efficacy results of two randomized studies. Am J Transplant 2004 4 : 626.
66. Webster AC, Lee VW, Chapman JR, Craig JC. Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials. Transplantation 2006 81 : 1234.
67. Reinders ME, Rabelink TJ, Briscoe DM. Angiogenesis and endothelial cell repair in renal disease and allograft rejection. J Am Soc Nephrol 2006 17 : 932.
68. Valujskikh A, Lantz O, Celli S, Matzinger P, Haeger PS. Cross-primed CD8(+) T cell mediate graft rejection via a distinct effector pathway. Nat Immunol 2002 3 : 844.
69. Kerjaschki D. Lymphatic neoangiogenesis in renal transplants: a driving force of chronic rejection? J Nephrol 2006 19 : 403.
70. Ponticelli C. The pleiotropic effects of mTor inhibitors. J Nephrol 2004 17 : 762.
71. Miriuka SG, Rao V, Peterson M, et al. mTOR inhibition induces endothelial progenitor cell death. Am J Transplant 2006 6 : 2069.
72. Lagajj EL, Cramer-Knijnenburg GF, van Kemenade FJ, van Es LE, Bruyin JA, van Krieken JH. Endothelial cell chimerism after renal transplantation and vascular rejection. Lancet 2001 357 : 33.
73. Gregory CR, Huang X, Pratt RE, et al. Treatment with rapamycin and mycophenolic acid reduces arterial intimal thickening produced by mechanical injury and allows endothelial replacement. Transplantation 1995 59 : 655.
74. Schmid C, Heemann U, Azuma H, Tilney NL. Rapamycin inhibits transplant vasculopathy in long-surviving rat heart allografts. Transplantation 1995 60 : 729.
75. Ikonen TS, Gummert JF, Serkova N, et al. Efficacies of sirolimus (rapamycine) and cyclosporine in allograft vascular disease in non-human primates: through levels of sirolimus correlate with inhibition of progression of arterial intimal thickening. Transpl Int 2000 13 (Suppl. 1 S314.
76. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of sirolimus-eluted stent with a standard stent for coronary revascularization. N Engl J Med 2000 346 : 1773.
77. Tsuchiya Y, Lansky AJ, Costa RA, et al. Effect of everolimus-eluting stents in different vessel sizes (from the pooled FUTURE I and II trials). Am J Cardiol 2006 98 : 464.
78. Serruys PW, Kutryk MJB, Ong ATL. Drug therapy: coronary-artery stents. N Engl J Med 2006 354 : 483.
79. Pinney SP, Mancini D. Cardiac allograft vasculopathy: advances in understanding its pathophysiology, prevention, and treatment. Curr Opin Cardiol 2004 19 : 170.
80. Penn I. Post-transplant malignancy: the role of immunosuppression. Drug Saf 2000 23 : 101.
81. Sheil AG. Organ transplantation and malignancy: inevitable linkage. Transplant Proc 2002 34 : 2436.
82. Sawyers CL. Will mTOR inhibitor make it as cancer drug? Cancer Cell 2003 4 : 343.
83. Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL. The PTEN/MMAC1 tumor suppressor phosphate functions as a negative regulator of the phosphoinositide-3-kinase/Akt pathway. Proc Natl Acad Sci USA 1998 95 : 15587.
84. Brennan P, Mehl AM, Jones M, Rowe M. Phosphatidylinositol 3-kinase is essential for the proliferation of lymphoblastoid cells. Oncogene 2002 21 : 1263.
85. Mirza AM, Kohn AD, Roth RA, McMahon M. Oncogenic transformation of cells by a conditionally active form of the protein kinase Akt/PKB. Cell Growth Diff 2000 11 : 279.
86. Neshat MS, Mellinghoff IK, Tran C, et al. Enhanced sensitivity of PTEN deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA 2001 98 : 10314.
87. Panwalkar A, Verstovsek S, Giles FJ. Mammalian target of rapamycin inhibition as therapy for hematologic malignancies. Cancer 2004 100 : 657.
88. Shi Y, Gera J, Hu L, Hsu JH, Bookstein Li W, Lichtenstein A. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 2002 62 : 5027.
89. Majewski M, Korecka M, Joergensen J, et al. Immunosuppressive TOR kinase inhibitor everolimus (RAD) suppresses growth of cells derived from posttransplant lymphoproliferative disorder at allograft-protecting doses. Transplantation 2003 75 : 1710.
90. 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.
91. Sin SH, Roy D, Wang MR, et al. Rapamycin is efficacious against primary effusion lymphoma (PEL) cell lines in vivo by inhibiting autocrine signaling. Blood 2007 109 : 2165.
92. Guba M, Graeb C, Jauch KW, Geissler EK. Pro- and anti-cancer effects of immunosuppressive agent used in organ transplantation. Transplantation 2004 77 : 1777.
93. Guba V, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nature Med 2002 8 : 128.
94. Luan FL, Ding R, Sharma VK, et al. Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney Int 2003 63 : 917.
95. Abraham RT. mTOR a positive regulator of tumor cell responses to hypoxia. Curr Top Microbiol Immunol 2004 279 : 299.
96. Dancey JE. Therapeutic targets: MTOR and related pathways. Cancer Biol Ther 2006 5 : 1065.
97. Kahan BD, Knight R, Schoenberg L, et al. Ten years of sirolimus therapy for human renal transplantation. The University of Texas at Houston experience. Transplant Proc 2003 35 : S25.
98. Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant 2004 18 : 446.
99. Kauffman HM, Cherikh WS, Cheng Y, Hanto DW, Kahan BD. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation 2005 80 : 883.
100. Fernandez A, Marcen R, Pascual J, et al. Conversion from calcineurin inhibitors to everolimus in kidney transplant recipients with malignant neoplasia. Transplant Proc 2006 38 : 2453.
101. Campistol JM, Gutierrez-Dalmau A, Torregrosa JV. Conversion to sirolimus: a successful treatment for posttransplantation Kaposi's sarcoma. Transplantation 2004 77 : 760.
102. Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N Engl J Med 2005 352 : 1317.
103. Mohsin N, Budruddin M, Pakkyara A, et al. Complete regression of visceral Kaposi's sarcoma after conversion to sirolimus. Exp Clin Transplant 2005 3 : 366.
104. Lebbe C, Euvrard S, Barrou B, et al. Sirolimus conversion for patients with posttransplant Kaposi's sarcoma. Am J Transplant 2006 6 : 2164.
105. Chueh SC, Kahan BD. Dyslipidemia in renal transplant recipients treated with a sirolimus and cyclosporine-based immunosuppressive regimen: incidence, risk factors, progression, and prognosis. Transplantation 2003 76 : 375.
106. Kovarik JM. Everolimus: a proliferation signal inhibitor targeting primary causes of allograft dysfunction. Drugs Today 2004 40 : 101.
107. Parameswara VK, Sule AJ, Esser V. Have we overlooked the importance of serine/threonine protein phosphatases in pancreatic beta-cells? Role played by protein phosphatase 2A in insulin secretion. JOP 2005 8 : 303.
108. Teutonico A, Schena PF, Di Paolo S. Glucose metabolism in renal transplant recipients: effect of calcineurin inhibitor withdrawal and conversion to sirolimus. J Am Soc Nephrol 2005 16 : 3128.
109. Shah OJ, Wang Z, Hunter T. Inappropriate activation of the TSC/Rheb/mTOR/S6 K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 2004 14 : 1650.
110. Kreis H, Cisterne JM, Land W. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute rejection in renal allograft recipients. Transplantation 2000 69 : 1252.
111. Sennesael JJ, Bosmans JL, Bogers JP, Verbeelen D, Verpooten GA. Conversion from cyclosporine to sirolimus in stable renal transplant recipients. Transplantation 2005 80 : 1578.
112. Saurina A, Campistol JM, Piera C, et al. Conversion from calcineurin inhibitors to sirolimus in chronic allograft dysfunction: changes in glomerular haemodynamics and proteinuria. Nephrol Dial Transplant 2006 2 : 488.
113. Coombes JD, Mreich E, Liddle C, Rangan GK. Rapamycin worsens renal function and intratubular cast formation in protein overload nephropathy. Kidney Int 2005 68 : 2599.
114. Straathof-Galema L, Wetzels JF, Dijkman HB, Steenbergen EJ, Hilbrands LB. Sirolimus-associated heavy proteinuria in a renal transplant recipient: evidence for a tubular mechanism. Am J Transplant 2006 2 : 429.
115. Valente JF, Hricick D, Weigel K, et al. Comparison of sirolimus versus mycophenolate mofetil on surgical complications and wound healing in adult kidney transplantation. Am J Transplant 2003 3 : 1128.
116. Langer RM, Kahan BD. Incidence, therapy, and consequences of lymphocele after sirolimus-cyclosporine-prednisone immunosuppression in renal transplant recipients. Transplantation 2002 27 : 804.