Improving long-term graft survival as a means to reduce retransplantation

  • Leendert C. Paul
Part of the Transplantation and Clinical Immunology book series (TRAC, volume 29)


Long-term follow-up studies of renal transplant patients have shown that chronic rejection is the single most prevalent cause of graft failure after the first post-transplant year [1]. It is not known how many of these patients will undergo retransplantation but data from our own institution suggest that 60-70% of retransplants lost a previous graft due to chronic rejection. There are no large registry data available to directly confirm this impression but of the more than 14000 second cadaver kidney transplants reported to the Collaborative Transplant Study Registry, 57% had a previous graft that had lasted for more than 6 months and 49% had a previous graft that had lasted for more than 1 year. As chronic rejection is the single most important cause of graft failure in this time frame, it would seem that avoidance of chronic rejection will reduce the need for retransplantation. The aim of the current review is to evaluate the risk factors of chronic rejection and to suggest strategies to decrease its prevalence.


Acute Rejection Renal Allograft Mycophenolate Mofetil Renal Transplant Patient Chronic Rejection 
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  1. 1.
    Schweitzer EJ, Matas AJ, Gillingham KJ et al. Causes of renal allograft loss. Progress in the 1980s, challenges for the 1990s. Ann. Surg. 1991; 214: 679–688.PubMedCrossRefGoogle Scholar
  2. 2.
    Paul LC, Häyry P, Foegh M et al. Diagnostic criteria for chronic rejection/accelerated graft atherosclerosis in heart and kidney transplants: joint proposal from the Fourth Alexis Carrel Conference on Chronic Rejection and Accelerated Arteriosclerosis in Transplanted Organs. Transplant. Proc. 1993; 25: 2022–2023.PubMedGoogle Scholar
  3. 3.
    Luo H, Nishioka T, Eigler NL et al. Coronary artery restenosis after balloon angioplasty in humans is associated with circumferential coronary constriction. Arterioscler. Thromb. Vasc. Biol. 1996; 16: 1393–1398.PubMedGoogle Scholar
  4. 4.
    Barrientos A, Portoles J, Herrero JA et al. Glomerular hyperfiltration as a nonimmunologic mechanism of progression of chronic renal rejection. Transplantation 1994; 57: 753–756.PubMedCrossRefGoogle Scholar
  5. 5.
    Cheigh JS, Mouradian J, Soliman M et al. Focal segmental glomerulosclerosis in renal transplants. Am. J. Kidney Dis. 1983; 2: 449–455.PubMedGoogle Scholar
  6. 6.
    Hamburger J, Crosnier J, Dormont JA. Observations in patients with a well tolerated homo-transplanted kidney. Ann. NY Acad. Sci. 1964; 120: 558–577.PubMedCrossRefGoogle Scholar
  7. 7.
    Solez K, Axelsen RA, Benediktsson H et al. International standardization of criteria for the histologie diagnosis of renal allograft rejection: The Banff working classification of kidney transplant pathology. Kidney Int. 1993; 44: 411–422.PubMedCrossRefGoogle Scholar
  8. 8.
    Opelz G. Critical evaluation of the association of acute with chronic graft rejection in kidney and heart transplant recipients. Transplant. Proc. 1997; 29: 73–76.PubMedCrossRefGoogle Scholar
  9. 9.
    Ferguson R. Acute rejection episodes-best predictor of long-term primary cadaveric renal transplant survival. Clin. Transplant. 1994; 8: 328–331.PubMedGoogle Scholar
  10. 10.
    Matas AJ, Gillingham KJ, Payne WD, Najarian JS. The impact of an acute rejection episode on long-term renal allograft survival (t 1/2). Transplantation 1994; 57: 857–859.PubMedCrossRefGoogle Scholar
  11. 11.
    Massy ZA, Guijarro C, Kasiske BL. Clinical predictors of chronic renal allograft rejection. Kidney Int. 1995; 48(Suppl. 52): S85–S88.Google Scholar
  12. 12.
    Massy ZA, Guijarro C, Wiederkehr MR, Ma JZ, Kasiske BL. Chronic renal allograft rejection: immunologic and nonimmunologic risk factors. Kidney Int. 1996; 49: 518–524.PubMedCrossRefGoogle Scholar
  13. 13.
    Almond PS, Matas A, Gillingham KJ et al. Risk factors for chronic rejection in renal allograft recipients. Transplantation 1993; 55: 752–757.PubMedCrossRefGoogle Scholar
  14. 14.
    Van Saase JLCM, Van der Woude FJ, Thorogood J et al. The relation between acute vascular and interstitial renal allograft rejection and subsequent chronic rejection. Transplantation 1995; 59: 1280–1285.PubMedGoogle Scholar
  15. 15.
    Yilmaz S, Yilmaz A, H⇛ry P. Chronic renal allograft rejection can be predicted by area under the serum creatinine versus time curve (AUCCr). Kidney Int. 1995; 48: 251–258.PubMedCrossRefGoogle Scholar
  16. 16.
    Cole E, Naimark D, Aprile M et al. An analysis of predictors of long term cadaveric renal allograft survival. Clin. Transplant. 1995; 9: 282–288.PubMedGoogle Scholar
  17. 17.
    Ferguson RM. Aspects of allograft rejection. II: risk factors in renal allograft rejection. Transplant. Rev. 1995; 9: 121–126.CrossRefGoogle Scholar
  18. 18.
    Sanfilippo F, Vaughn WK, Spees EK, Lucas BA. The detrimental effects of delayed graft function in cadaver donor renal transplantation. Transplantation 1984; 38: 643–648.PubMedCrossRefGoogle Scholar
  19. 19.
    Cecka JM, Terasaki PI. The UNOS scientific renal transplant registry. In: Terasaki PI, Cecka JM (eds.), Clinical Transplants 1994. Los Angeles: UCLA Tissue Typing Laboratory, 1995: 1.Google Scholar
  20. 20.
    Ojo AO, Wolfe RA, Held PJ, Port FK, Schmouder RL. Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 1997; 63: 968–974.PubMedCrossRefGoogle Scholar
  21. 21.
    Land W. The potential impact of the reperfusion injury on acute and chronic rejection events following organ transplantation. Transplant. Proc. 1994; 26: 3169–3171.PubMedGoogle Scholar
  22. 22.
    Schneeberger H, Aydemir S, Illner WD, Land W. Nonspecific primary ischemia/reperfusion injury in combination with secondary specific acute rejection-mediated injury of human kidney allografts contributes mainly to development of chronic transplant failure. Transplant. Proc. 1997; 29: 948–949.PubMedCrossRefGoogle Scholar
  23. 23.
    Yilmaz S, Paavonen T, H⇛ry P. Chronic rejection of rat renal allografts. II. The impact of prolonged ischemia time on transplant histology. Transplantation 1992; 53: 823–827.PubMedCrossRefGoogle Scholar
  24. 24.
    Li F, Grauls G, Yin M, Bruggeman CA. Initial endothelial injury and cytomegalovirus infection accelerate the development of allograft arteriosclerosis. Transplant. Proc. 1995; 27: 3552–3554.PubMedGoogle Scholar
  25. 25.
    Yilmaz S, Koskinen PK, Kallio E, Bruggeman CA, H⇛ry PJ, Lemström KB. Cytomegalovirus infection-enhanced chronic kidney allograft rejection is linked with intercellular adhesion molecule-1 expression. Kidney Int. 1996; 50: 526–537.PubMedCrossRefGoogle Scholar
  26. 26.
    Lautenschlager I, Soots A, Krogerus L et al. CMV increases inflammation and accelerates chronic rejection in rat kidney allografts. Transplant. Proc. 1997; 29: 802–803.PubMedCrossRefGoogle Scholar
  27. 27.
    Grattan MT, Moreno-Cabral CE, Starnes VA, Oyer PE, Stinson EB, Shumway NE. Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. JAMA 1989; 261: 3561–3566.PubMedCrossRefGoogle Scholar
  28. 28.
    Herrera GA, Alexander RW, Cooley CF et al. Cytomegalovirus glomerulopathy: a controversial lesion. Kidney Int. 1986; 29: 725–733.PubMedCrossRefGoogle Scholar
  29. 29.
    Nadasdy T, Smith J, Laszik Z, Waner JL, Johnson LD, Silva FG. Absence of association between cytomegalovirus infection and obliterative transplant arteriopathy in renal allograft rejection. Mod. Pathol. 1994; 7: 289–294.PubMedGoogle Scholar
  30. 30.
    Vollmer E, Bosse A, Bogeholz J et al. Apolipoproteins and immunohistological differentiation of cells in the arterial wall of kidneys in transplant arteriopathy. Morphological parallels with atherosclerosis. Pathol. Res. Pract. 1991; 187: 957–962.PubMedGoogle Scholar
  31. 31.
    Fellström B, Dimény E, Larsson E, Claesson K, Tufveson G. Rapidly proliferating arteriopathy in cyclosporin-induced permanently surviving rat cardiac allografts simulating chronic vascular rejection. Clin. Exp. Immunol. 1990; 80: 288–292.PubMedCrossRefGoogle Scholar
  32. 32.
    R⇄s↭en-Sokolowski A, Tilly-Kiesi M, Ustinov J et al. Hyperlipidemia accelerates allograft arteriosclerosis (chronic rejection) in the rat. Arterioscler. Thromb. 1994; 14: 2032–2042.Google Scholar
  33. 33.
    Dimény E, Fellström B, Larsson E, Tufveson G, Lithell H. Chronic vascular rejection and hyperlipoproteinemia in renal transplant patients. Clin. Transplant. 1993; 7: 482–487.Google Scholar
  34. 34.
    Dimény E, Tufveson G, Lithell H, Larsson E, Siegbahn A, Fellström B. The influence of pretransplant lipoprotein abnormalities on the early results of renal transplantation. Eur. J. Clin. Invest. 1993; 23: 572–579.PubMedCrossRefGoogle Scholar
  35. 35.
    Isoniemi H, Taskinen E, H⇛ry P. Histological chronic allograft damage index accurately predicts chronic renal allograft rejection. Transplantation 1994; 58: 1195–1198.PubMedCrossRefGoogle Scholar
  36. 36.
    Brazy PC, Pirsch JD, Beizer FO. Factors affecting renal allograft function in long-term recipients. Am. J. Kidney Dis. 1992; 19: 558–566.PubMedGoogle Scholar
  37. 37.
    Markell MS, Sumrani N, Dibenedetto A, Friedman EA. Effect of early hyperlipidemia on graft and patient survival in cyclosporine-treated renal transplant patients. Am. J. Kidney Dis. 1993; 22: 233–239.PubMedGoogle Scholar
  38. 38.
    Knight RJ, Kerman RH, Welsh M et al. Chronic rejection in primary renal allograft recipients under cyclosporine prednisone immunosuppressive therapy. Transplantation 1991; 51: 355–359.PubMedCrossRefGoogle Scholar
  39. 39.
    Kobashigawa JA, Katznelson S, Laks H et al. Effect of pravastatin on outcomes after cardiac transplantation. N. Engl. J. Med. 1995; 333: 621–627.PubMedCrossRefGoogle Scholar
  40. 40.
    Katznelson S, Wilkinson AH, Kobashigawa JA et al. The effect of pravastatin on acute rejection after kidney transplantation-a pilot study. Transplantation 1996; 61: 1469–1474.PubMedCrossRefGoogle Scholar
  41. 41.
    Modena FM, Hostetter TH, Salahudeen AK, Najarian JS, Matas AJ, Rosenberg ME. Progression of kidney disease in chronic renal transplant rejection. Transplantation 1991; 52: 239–244.PubMedCrossRefGoogle Scholar
  42. 42.
    Cheigh JS, Haschemeyer RH, Wang JCL et al. Hypertension in kidney transplant recipients. Effect on long-term renal allograft survival. Am. J. Hypertens. 1989; 2: 341–348.PubMedGoogle Scholar
  43. 43.
    Cosio FG, Falkenhain ME, Pesavento TE et al. Relationships between arterial hypertension and renal allograft survival in African-American patients. Am. J. Kidney Dis. 1997; 29: 419–427.PubMedGoogle Scholar
  44. 44.
    Barenbrock M, Colmorgen U, Firschka E et al. A multicenter, randomized, double-blind, placebo-controlled, two-year trial to study the effect of nitrendipine on chronic renal transplant function. Clin. Nephrol. 1995; 43: 388–391.PubMedGoogle Scholar
  45. 45.
    Terasaki PI, Cecka JM, Gjertson DW, Cho Y, Takemoto S, Cohn M. A ten year prediction for kidney transplant survival. In: Terasaki PI, Cecka JM (eds.), Clinical Transplants 1992. Los Angeles: UCLA Tissue Typing Laboratory, 1992: 501.Google Scholar
  46. 46.
    Myers BD, Ross J, Newton L, Leutscher J, Perlroth M. Cyclosporine-associated chronic nephropathy. N. Engl. J. Med. 1984; 311: 699–705.PubMedCrossRefGoogle Scholar
  47. 47.
    Burke JF, Pirsch JD, Ramos EL et al. Long-term efficacy and safety of cyclosporine in renaltransplant patients. N. Engl. J. Med. 1994; 331: 358–363.PubMedCrossRefGoogle Scholar
  48. 48.
    Hollander AAMJ, Van Saase JLCM, Kootte AMM et al. Beneficial effects of conversion from cyclosporin to azathioprine after kidney transplantation. Lancet 1995; 345: 610–614.PubMedCrossRefGoogle Scholar
  49. 49.
    Isoniemi H, Nurminen M, Tikkanen MJ et al. Risk factors predicting chronic rejection of renal allografts. Transplantation 1994; 57: 68–72.PubMedCrossRefGoogle Scholar
  50. 50.
    Larsen CP, Elwood ET, Alexander DZ et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 1996; 381: 434–438.PubMedCrossRefGoogle Scholar
  51. 51.
    Azuma H, Chandraker A, Nadeau K et al. Blockade of T-cell costimulation prevents development of experimental chronic renal allograft rejection. Proc. Natl. Acad. Sci. USA 1996; 93: 12439–12444.PubMedCrossRefGoogle Scholar
  52. 52.
    Geerling RA, Bruin RWF de, Scheringa M et al. Suppression of acute rejection prevents graft atherosclerosis after allogeneic aorta transplantation in the rat. Transplantation 1994; 58: 1258–1263.PubMedCrossRefGoogle Scholar
  53. 53.
    Gregory CR, Huang X, Pratt RE et al. Treatment with rapamycin and mycophenolic acid reduces arterial intimai thickening produced by mechanical injury and allows endothelial replacement. Transplantation 1995; 59: 655–661.PubMedCrossRefGoogle Scholar
  54. 54.
    Schmid C, Heemann U, Azuma H, Tilney NL. Rapamycin inhibits transplant vasculopathy in long-surviving rat heart allografts. Transplantation 1995; 60: 729–733.PubMedCrossRefGoogle Scholar
  55. 55.
    R⇄s↭en-Sokolowski A, Yilmaz S, Tufveson G, H⇛ry P. Partial inhibition of allograft arteriosclerosis (chronic rejection) by 15-deoxyspergualin. Transplantation 1994; 57: 1772–1777.Google Scholar
  56. 56.
    MacDonald AS, Sabr K, MacAuley MA, McAllister VC, Bitter-Suermann H, Lee L. Effects of leflunomide and cyclosporine on aortic allograft chronic rejection in the rat. Transplant. Proc. 1994; 26: 3244–3245.PubMedGoogle Scholar
  57. 57.
    Morris RE, Huang X, Gregory CR et al. Studies in experimental models of chronic rejection: use of rapamycin (sirolimus) and isoxazole derivatives (leflunomide and its analogue) for the suppression of graft vascular disease and obliterative bronchiolitis. Transplant. Proc. 1995; 27: 2068–2069.PubMedGoogle Scholar
  58. 58.
    Swan SK, Crary GS, Guijarro C, O’Donnell MP, Keane WF, Kasiske BL. Immunosuppressive effects of leflunomide in experimental chronic vascular rejection. Transplantation 1995; 60: 887–890.PubMedCrossRefGoogle Scholar
  59. 59.
    R⇄s↭en-Sokolowski A, Aho P, Myll→niemi M, Kallio E, H⇛ry P. Inhibition of early chronic rejection in rat aortic allografts by mycophenolate mofetil (RS61443). Transplant. Proc. 1995; 27: 435.Google Scholar
  60. 60.
    Azuma H, Binder J, Heemann U, Tullius SG, Tilney NL. Effect of RS61443 on chronic rejection of rat kidney allografts. Transplant. Proc. 1995; 27: 436–437.PubMedGoogle Scholar
  61. 61.
    Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS, for the FK506 kidney transplant study group. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. Transplantation 1997; 63: 977–983.PubMedCrossRefGoogle Scholar
  62. 62.
    Gjertson DW, Cecka JM, Terasaki PI. The relative effects of FK506 and cyclosporine on short-and long-term kidney graft survival. Transplantation 1995; 60: 1384–1388.PubMedCrossRefGoogle Scholar
  63. 63.
    Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995; 60: 225–232.PubMedCrossRefGoogle Scholar
  64. 64.
    The European Mycophenolate Mofetil Cooperative Study Group. Placebo controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. Lancet 1995; 345: 1321–1326.Google Scholar
  65. 65.
    Keown P, H⇛ry P, Mathew T et al. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 1996; 61: 1029–1037.CrossRefGoogle Scholar
  66. 66.
    Halloran P, Mathew T, Tomlanovich S, Groth C, Hooftman L, Barker C. Mycophenolate mofetil in renal allograft recipients-a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. Transplantation 1997; 63: 39–47.PubMedCrossRefGoogle Scholar
  67. 67.
    Sporn MB, Roberts AB. Peptide growth factors are multifunctional. Nature 1988; 332: 217–219.PubMedCrossRefGoogle Scholar
  68. 68.
    Nadeau KC, Azuma H, Tilney NL. Sequential cytokine dynamics in chronic rejection of rat renal allografts: Roles for cytokines RANTES and MCP-1. Proc. Natl. Acad. Sci. USA 1995; 92: 8729–8733.PubMedCrossRefGoogle Scholar
  69. 69.
    Akyürek LM, Paul LC, Funa K, Larsson E, Fellström BC. Smooth muscle cell migration into intima and adventitia during development of transplant vasculopathy. Transplantation 1996; 62: 1526–1529.PubMedCrossRefGoogle Scholar
  70. 70.
    Stein-Oakley AN, Tzanidis A, Fuller PJ, Jablonski P, Thomson NM. Expression and distribution of epidermal growth factor in acute and chronic renal allograft rejection. Kidney Int. 1994; 46: 1207–1215.PubMedCrossRefGoogle Scholar
  71. 71.
    H⇛ry P, Isoniemi H, Yilmaz S et al. Chronic allograft rejection. Immunol. Rev. 1993; 134: 33–81.CrossRefGoogle Scholar
  72. 72.
    Aziz S, Tada Y, Gordon D, McDonald TO, Fareed J, Verrier ED. A reduction in accelerated graft coronary disease and an improvement in cardiac allograft survival using low molecular weight heparin in combination with cyclosporine. J. Heart Lung Transplant. 1993; 12: 634–643.PubMedGoogle Scholar
  73. 73.
    H⇛ry P, R⇄s↭en A, Ustinov J, Mennander A, Paavonen T. Somatostatin analog Lanreotide inhibits myocyte replication and several growth factors in allograft arteriosclerosis. FASEB J. 1993; 7: 1055–1060.Google Scholar
  74. 74.
    H⇛ry P, Myll→niemi M, Aavik E et al. Stable D-peptide analogue of insulin-like growth factor-1 inhibits smooth muscle proliferation after carotid ballooning injury in the rat. FASEB J. 1995; 9: 1336–1344.Google Scholar
  75. 75.
    Benediktsson H, Chea R, Davidoff A, Paul LC. Antihypertensive drug treatment in chronic renal allograft rejection in the rat. Effect on structure and function. Transplantation 1996; 62: 1634–1642.PubMedCrossRefGoogle Scholar
  76. 76.
    Furukawa Y, Matsumori A, Hirozane T, Sasayama S. Angiotensin II receptor antagonist TCV-116 reduces graft coronary artery disease and preserves graft status in a murine model-a comparative study with captopril. Circulation 1996; 93: 333–339.PubMedGoogle Scholar
  77. 77.
    Barnas U, Schmidt A, Haas M, Oberbauer R, Mayer G. The effects of prolonged angiotensin-converting enzyme inhibition on excretory kidney function and proteinuria in renal allograft recipients with chronic progressive transplant failure. Nephrol. Dial Transplant. 1996; 11: 1822–1824.PubMedGoogle Scholar
  78. 78.
    Hunsicker LG, Bennett LE. Design of trials of methods to reduce late renal allograft loss: the price of success. Kidney Int. 1995; 48(Suppl. 52): S120–S123.Google Scholar
  79. 79.
    Kasiske BL, Massy ZA, Guijarro C, Ma JZ. Chronic renal allograft rejection and clinical trial design. Kidney Int. 1995; 48(Suppl. 52): S116–S119.Google Scholar
  80. 80.
    Myll→niemi M, R⇄s↭en-Sokolowski A, Vuoristo P, Kallio E, Land W, H⇛ry P. Lack of effect of recombinant human Superoxide dismutase on cold ischemia-induced arteriosclerosis in syngeneic rat aortic transplants. Transplantation 1996; 61: 1018–1022.CrossRefGoogle Scholar
  81. 81.
    Kobashigawa JA, Kasiske BL. Hyperlipidemia in solid organ transplantation. Transplantation 1997; 63: 331–338.PubMedCrossRefGoogle Scholar
  82. 82.
    Arnadottir M, Berg A-L. Treatment of hyperlipidemia in renal transplant recipients. Transplantation 1997; 63: 339–345.PubMedCrossRefGoogle Scholar
  83. 83.
    Bittar AE, Keitel E, Garcia CD et al. Patient non-compliance as a cause of late kidney graft failure. Transplant. Proc. 1992; 24: 2720–2721.PubMedGoogle Scholar

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  • Leendert C. Paul

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