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Role of ischemia-reperfusion injury in the development of chronic renal allograft damage
Clinical
RENAL
Role of Ischemia-Reperfusion Injury in the Development of Chronic Renal Allograft Damage J.M. Grinyo
I
SCHEMIA-REPERFUSION injury (I-R) has been traditionally considered a deleterious factor on graft outcome in the majority of epidemiologic studies in renal transplantation, in which delayed graft function (DGF) has been used as the marker for I-R-derived graft dysfunction. In many of these studies, DGF, acute rejection, and donor age have been characterized as independent predictors for late graft failure. The association of increased donor age and DGF is followed by an extremely low actuarial graft survival rates at 10 years after transplantation to ⬍40%.1 These poor results have been partially explained by the increased incidence of acute rejection in patients suffering from DGF. However, we have observed that, regardless of acute rejection, DGF amplifies the detrimental effect of advanced donor age on long-term graft outcome.1 On the contrary, some investigators have reported that DGF does not necessarily affect long-term graft outcome,2 although prolonged cold ischemia time, a factor related to I-R injury, has been identified as a risk factor for graft loss at 1 year after transplantation, despite the lack of influence of DGF.3 Because chronic transplant nephropathy is one of the main causes of graft loss at ⬎1 year after transplantation, the identification of risk factors of chronic transplant nephropathy detected in protocol biopsies may also help to characterize the contribution of I-R injury on the development of chronic graft damage. Similar to epidemiologic studies, in protocol biopsy studies, donor age, preexisting lesions, acute rejection, cyclosporine exposure, and cold ischemia time have been identified as independent predictors of chronic transplant nephropathy.4,5
The role of I-R on the development of chronic renal damage has been studied in renal warm and cold ischemia experimental models. Preexisting lesions, cold storage conditions, renal mass, and alloreactivity can mutually interact and influence I-R-derived graft dysfunction. These mutual interactions appear to be crucial with regard to two unavoidable factors in organ transplantation, I-R and alloreactivity. In an experimental design, renal allotransplantation after cold ischemia was associated with high mortality rates, which could not be prevented by the administration of cyclosporine or an anti-ischemic agent (soluble glycoprotein ligand for selectins). The concomitant administration of both agents completely prevented mortality, reduced macrophages and T cell infiltrates early after transplantation, and reduced long-term proteinuria.6 Renal warm ischemia in uninephrectomized rats was followed by acute inflammation with edema and interstitial infiltrate the first week after ischemia,7 and glomerulosclerosis, interstitial fibrosis, tubular atrophy and dilation, and interstitial infiltrate in the long term.7,8 Renal aging has been characterized as a decline in renal function, accelerated apoptosis, and similar histologic lesions. Renal warm ischemia in aging rats exacerbate such lesions.9 In experimental renal transplantation, increased donor age and prolonged cold ischemia times appear to
From the Hospital de Bellvitge, University of Barcelona, Barcelona, Spain. Address reprint requests to Dr Josep M. Grinyo, Servei de Nefrologı´a, Hospital de Bellvitge, Feixa Llarga s/n, L’Hospitalet, 08907 Barcelona, Spain. E-mail: [email protected].
© 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/01/$–see front matter PII S0041-1345(01)02527-1
Transplantation Proceedings, 33, 3741–3742 (2001)
3741
3742
exert an additive deleterious effect.10 In this model, functional deterioration and structural changes progressed in parallel to increasing donor age and prolonged ischemia, indicating that donor age and duration of ischemia may act in a synergistic manner. These experimental data suggest that special logistics are advisable in cadaveric transplantation with older donors to shorten cold ischemia time. Improved cold storage conditions may also help to ameliorate graft function and prevent the development of graft damage. In large animals, adding an anti-ischemic drug to different preservation solutions increased glomerular filtration rate, decreased proteinuria, and reduced early T-cell infiltrates and interstitial fibrosis.11 These data suggest that there is still room to optimize preservation conditions to reduce early and chronic inflammation to improve graft outcome. Experimental models on renal warm ischemia and renal mass reduction have been useful for characterizing the loss of nephrons at ⬎16 weeks after ischemia and the occurrence of tubulointerstitial damage and progressive and severe proteinuria 1 year after ischemia.12 These data may reinforce the double kidney transplant strategy for allografts that would have been discarded for single renal transplantation. Transplant models may also help to dissect the relative contribution of I-R and alloreactivity on the development of chronic lesions.13 Prolonged cold ischemia plays a role in the development of chronic renal graft damage in isografts that can be attenuated by cyclosporine, whereas the effect of this immunosuppressant is much less evident in an allogeneic combination.14 Cold ischemia in the absence of alloresponsiveness mainly induces chronic tubulointerstitial nephritis with mild vascular lesions,15 whereas the association of both factors leads to the development of severe proliferative graft vasculopathy.16 Experimental and clinical data suggest that preventing or attenuating I-R injury may help to improve the results of renal transplantation, especially nowadays with the increasing proportion of marginal donors. Because of the mutual interactions between I-R and the other factors described, complementary strategies seem necessary. Moreover, lessons learned from clinical immunosuppression, in which the association of distinct drugs interfering at different stages the immune response have provided low rates of acute rejection, suggest that similar strategies can be adopted in
GRINYO
the prevention of I-R injury. In this regard, it appears that, in the design of experimental models of I-R, the use of single agents may have been rather simplistic. In experimental models, the interference of the I-R cascade at different steps by using potentially synergistic drugs may help to introduce I-R trials in the clinical setting. In addition, the possible benefits of the interactions between immunosuppressants and anti-ischemic agents should also be reevaluated. In clinical transplantation, the study of early inflammation may contribute to a better understanding of I-R injury and its impact on chronic graft damage. On the other hand, delayed graft function does not appear to be a good marker for I-R, and thus histologic data might be considered as the new endpoint for I-R trials. REFERENCES 1. Moreso M, Sero ´n D, Gil-Vernet S, et al: Nephrol Dial Transplant 14:930, 1999 2. Lehtonen SRK, Isoniemi HM, Salmela KT, et al: Transplantation 64:103, 1997 3. Boom K, Mallat MJK, de Fitjer JW, et al: Kidney Int 58:859, 2000 4. Kuypers DRJ, Champman JR, O’Connell PJ, et al: Transplantation 67:1230, 1999 5. Sero ´n D, Moreso F, Ramo ´n JM, et al: Transplantation 69:1849, 2000 6. Kusaka M, Zandi-Nejad K, Kato S, et al: Transplantation 67:1255, 1999 7. Forbes JM, Hewitson TD, Becker GJ, et al: Kidney Int 57:2375, 2000 8. Torras J, Cruzado JM, Riera M, et al: Kidney Int 56:1798, 1999 9. Lloberas N, Cruzado JM, Torras J, et al: Nephrol Dial Transplant 16:735, 2001 10. Tullius AG, Reutzel-Selke A, Egermann F, et al: J Am Soc Nephrol 11:1317, 2000 11. Goujon JM, Vandewalle A, Baumert H, et al: Kidney Int 58:838, 2000 12. Cruzado JM, Torras J, Riera M, et al: Am J Physiol Renal Physiol 279:F259, 2000 13. Tullius SG, Heemann U, Hancock WW, et al: Ann Surg 220:425, 1994 14. Kouwenhoven E, de Bruin RWF, Heemann UW, et al: Transplantation 68:1004, 1999 15. Herrero-Fresneda I, Torras J, Lloberas N, et al: Transplantation 70:1624, 2000 16. Knight RJ, Dikman S, Liu H, et al: Transplantation 64:1102, 1997
RENAL
Role of Ischemia-Reperfusion Injury in the Development of Chronic Renal Allograft Damage J.M. Grinyo
I
SCHEMIA-REPERFUSION injury (I-R) has been traditionally considered a deleterious factor on graft outcome in the majority of epidemiologic studies in renal transplantation, in which delayed graft function (DGF) has been used as the marker for I-R-derived graft dysfunction. In many of these studies, DGF, acute rejection, and donor age have been characterized as independent predictors for late graft failure. The association of increased donor age and DGF is followed by an extremely low actuarial graft survival rates at 10 years after transplantation to ⬍40%.1 These poor results have been partially explained by the increased incidence of acute rejection in patients suffering from DGF. However, we have observed that, regardless of acute rejection, DGF amplifies the detrimental effect of advanced donor age on long-term graft outcome.1 On the contrary, some investigators have reported that DGF does not necessarily affect long-term graft outcome,2 although prolonged cold ischemia time, a factor related to I-R injury, has been identified as a risk factor for graft loss at 1 year after transplantation, despite the lack of influence of DGF.3 Because chronic transplant nephropathy is one of the main causes of graft loss at ⬎1 year after transplantation, the identification of risk factors of chronic transplant nephropathy detected in protocol biopsies may also help to characterize the contribution of I-R injury on the development of chronic graft damage. Similar to epidemiologic studies, in protocol biopsy studies, donor age, preexisting lesions, acute rejection, cyclosporine exposure, and cold ischemia time have been identified as independent predictors of chronic transplant nephropathy.4,5
The role of I-R on the development of chronic renal damage has been studied in renal warm and cold ischemia experimental models. Preexisting lesions, cold storage conditions, renal mass, and alloreactivity can mutually interact and influence I-R-derived graft dysfunction. These mutual interactions appear to be crucial with regard to two unavoidable factors in organ transplantation, I-R and alloreactivity. In an experimental design, renal allotransplantation after cold ischemia was associated with high mortality rates, which could not be prevented by the administration of cyclosporine or an anti-ischemic agent (soluble glycoprotein ligand for selectins). The concomitant administration of both agents completely prevented mortality, reduced macrophages and T cell infiltrates early after transplantation, and reduced long-term proteinuria.6 Renal warm ischemia in uninephrectomized rats was followed by acute inflammation with edema and interstitial infiltrate the first week after ischemia,7 and glomerulosclerosis, interstitial fibrosis, tubular atrophy and dilation, and interstitial infiltrate in the long term.7,8 Renal aging has been characterized as a decline in renal function, accelerated apoptosis, and similar histologic lesions. Renal warm ischemia in aging rats exacerbate such lesions.9 In experimental renal transplantation, increased donor age and prolonged cold ischemia times appear to
From the Hospital de Bellvitge, University of Barcelona, Barcelona, Spain. Address reprint requests to Dr Josep M. Grinyo, Servei de Nefrologı´a, Hospital de Bellvitge, Feixa Llarga s/n, L’Hospitalet, 08907 Barcelona, Spain. E-mail: [email protected].
© 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/01/$–see front matter PII S0041-1345(01)02527-1
Transplantation Proceedings, 33, 3741–3742 (2001)
3741
3742
exert an additive deleterious effect.10 In this model, functional deterioration and structural changes progressed in parallel to increasing donor age and prolonged ischemia, indicating that donor age and duration of ischemia may act in a synergistic manner. These experimental data suggest that special logistics are advisable in cadaveric transplantation with older donors to shorten cold ischemia time. Improved cold storage conditions may also help to ameliorate graft function and prevent the development of graft damage. In large animals, adding an anti-ischemic drug to different preservation solutions increased glomerular filtration rate, decreased proteinuria, and reduced early T-cell infiltrates and interstitial fibrosis.11 These data suggest that there is still room to optimize preservation conditions to reduce early and chronic inflammation to improve graft outcome. Experimental models on renal warm ischemia and renal mass reduction have been useful for characterizing the loss of nephrons at ⬎16 weeks after ischemia and the occurrence of tubulointerstitial damage and progressive and severe proteinuria 1 year after ischemia.12 These data may reinforce the double kidney transplant strategy for allografts that would have been discarded for single renal transplantation. Transplant models may also help to dissect the relative contribution of I-R and alloreactivity on the development of chronic lesions.13 Prolonged cold ischemia plays a role in the development of chronic renal graft damage in isografts that can be attenuated by cyclosporine, whereas the effect of this immunosuppressant is much less evident in an allogeneic combination.14 Cold ischemia in the absence of alloresponsiveness mainly induces chronic tubulointerstitial nephritis with mild vascular lesions,15 whereas the association of both factors leads to the development of severe proliferative graft vasculopathy.16 Experimental and clinical data suggest that preventing or attenuating I-R injury may help to improve the results of renal transplantation, especially nowadays with the increasing proportion of marginal donors. Because of the mutual interactions between I-R and the other factors described, complementary strategies seem necessary. Moreover, lessons learned from clinical immunosuppression, in which the association of distinct drugs interfering at different stages the immune response have provided low rates of acute rejection, suggest that similar strategies can be adopted in
GRINYO
the prevention of I-R injury. In this regard, it appears that, in the design of experimental models of I-R, the use of single agents may have been rather simplistic. In experimental models, the interference of the I-R cascade at different steps by using potentially synergistic drugs may help to introduce I-R trials in the clinical setting. In addition, the possible benefits of the interactions between immunosuppressants and anti-ischemic agents should also be reevaluated. In clinical transplantation, the study of early inflammation may contribute to a better understanding of I-R injury and its impact on chronic graft damage. On the other hand, delayed graft function does not appear to be a good marker for I-R, and thus histologic data might be considered as the new endpoint for I-R trials. REFERENCES 1. Moreso M, Sero ´n D, Gil-Vernet S, et al: Nephrol Dial Transplant 14:930, 1999 2. Lehtonen SRK, Isoniemi HM, Salmela KT, et al: Transplantation 64:103, 1997 3. Boom K, Mallat MJK, de Fitjer JW, et al: Kidney Int 58:859, 2000 4. Kuypers DRJ, Champman JR, O’Connell PJ, et al: Transplantation 67:1230, 1999 5. Sero ´n D, Moreso F, Ramo ´n JM, et al: Transplantation 69:1849, 2000 6. Kusaka M, Zandi-Nejad K, Kato S, et al: Transplantation 67:1255, 1999 7. Forbes JM, Hewitson TD, Becker GJ, et al: Kidney Int 57:2375, 2000 8. Torras J, Cruzado JM, Riera M, et al: Kidney Int 56:1798, 1999 9. Lloberas N, Cruzado JM, Torras J, et al: Nephrol Dial Transplant 16:735, 2001 10. Tullius AG, Reutzel-Selke A, Egermann F, et al: J Am Soc Nephrol 11:1317, 2000 11. Goujon JM, Vandewalle A, Baumert H, et al: Kidney Int 58:838, 2000 12. Cruzado JM, Torras J, Riera M, et al: Am J Physiol Renal Physiol 279:F259, 2000 13. Tullius SG, Heemann U, Hancock WW, et al: Ann Surg 220:425, 1994 14. Kouwenhoven E, de Bruin RWF, Heemann UW, et al: Transplantation 68:1004, 1999 15. Herrero-Fresneda I, Torras J, Lloberas N, et al: Transplantation 70:1624, 2000 16. Knight RJ, Dikman S, Liu H, et al: Transplantation 64:1102, 1997