This report was reviewed for medical and scientific accuracy by David A. Laskow, MD, Chief, Kidney/Pancreas Transplant Service, Department of Surgery, University of Medicine & Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey

Introduction

Acute rejection episodes are an unwelcome complication of solid organ transplantation, but several recent clinical studies have helped isolate the specific risks that these complications pose to long-term graft survival. By identifying acute rejection episodes, particularly those occurring 90 days after transplantation, as posing a substantial risk to graft loss, these studies are useful in focusing attention on an area of clinical management where new strategies are needed in order to further improve outcomes.

The critical message of these studies is that risk of graft loss is not confined to the immediate post-transplant period. While initial attention in transplant medicine was focused on minimizing the risk of early graft failure, the greatest current opportunities to further improve outcomes appear to be transitioning to those of late complications. Indeed, Knight and colleagues reported a 5-year graft survival approaching 90% among patients in the lowest risk groups, such as older individuals receiving a relatively young living graft, who did not experience acute or chronic rejection.¹ However, long-term graft survival fell markedly in patients in the highest risk groups, such as young patients receiving an older cadaveric graft whose course was complicated by significant rejection episodes.

An analysis by Sijpkens et al of rejection reactions in 654 patients who underwent cadaveric renal transplants over a 14-year period, has identified late acute rejection as a greater threat than early acute rejection to 10-year survival rates of renal transplants.² At 10 years, transplants had survived in 86% of those with a rejection episode within three months of transplant versus only 45% survival with a rejection episode after three months (P<.01). These results are consistent with other published analyses including a review by Joseph et al^3,4 [discussion to follow]. These data establish late acute rejection episodes as a persistent threat over time and as an appropriate target of strategies designed to improve graft survival.

The reported overall incidence of acute rejection episodes ranges between 10% and 50%, within the first 6 months, and is dependent on several immunologic and non-immunologic risk factors.^5-7 Despite advances in immunosuppression regimens, acute rejection episodes remain one of the most important risk factors of chronic rejection; the most prevalent cause of late renal transplant failure.⁸ As only a proportion of acute rejection episodes result in an adverse outcome, risk stratification is important. The ability to isolate episodes that pose the greatest risk to outcome may lead to new opportunities to improve clinical management.

It is due to the considerable advances in transplant medicine that permit the focus to shift from immediate to long-term graft survival. However, the data confirm that the greatest opportunities to improve long-term outcome is to reduce the risk of late complications such as late acute rejection episodes. Studies such as these should intensify efforts to identify new and innovative strategies.

Early versus Late Acute Rejection Episodes

To investigate whether the timing of the last treated acute rejection episode influenced long-term outcome and compare the risk profiles of early versus late acute rejection, Sijpkens et al chronicled a cohort of 654 patients who underwent cadaveric renal transplants between 1983 and 1997 and whose graft survived at least 6 months.² In this population, 384 (59%) experienced one or more acute rejection episodes over the course of follow-up. Early episodes were experienced by 297 (77%) patients, while late acute rejection episodes occurred in 87 (23%) patients. The median time to the acute rejection episode was 23 days (range, 2 to 88 days) in the early acute rejection group and 244 days (range, 92 to 2,411 days) in the late acute rejection group. Fifty-one patients experienced both early and late acute rejection episodes.

Ten-year graft survival censored for causes of graft loss other than chronic rejection was 94%, 86%, and 45% for patients without, with early, and with late acute rejection episodes, respectively (all P<.01). When patients in the late acute rejection group who also had early acute rejections were compared to those with late acute rejection episodes alone, 10-year graft survival was comparable, indicating no additional risk for patients experiencing both acute and late acute rejection episodes. [Ed. Risk factors for graft loss may include the timing of rejection, the number of rejections and the severity of rejections⁹].

Independent risk factors for early and late acute rejection episodes differed. Early acute rejection episodes were associated with human leukocyte antigen (HLA)-DR mismatches and delayed graft function. HLA-DR mismatches increased the occurrence of early acute rejection episodes (odds ratio 2.28, 95% Confidence Interval (CI), 1.62-3.20) and the risk of early graft failure (Table 1). Delayed graft function increased the risk of acute rejection episodes (odds ratio 2.37, 95% CI, 1.55-3.62). In contrast, late acute rejection episodes correlated with donor organs from older patients (odds ratio 1.28, 95% CI, 1.07-1.53), donor organs from females (odds ratio 1.74, 95% CI, 1.03-2.94), younger recipients (odds ratio 0.75, 95% CI, 0.61-0.93), and major histocompatibility complex (MHC) class I incompatibility (odds ratio 1.33, 95% CI, 1.05-1.68).

Although late acute rejection episodes were less frequent, results of this analysis are consistent with previous studies that have correlated late acute rejection episodes with long-term graft survival^10,11 and chronic rejection.^12,13 The difference may be related to the reversibility of risks for early acute rejection episodes. Previous studies have suggested that delayed graft function does not severely compromise graft survival,¹⁴ while the HLA-DR effect on organ mismatches, a direct pathway, appears to diminish over time.¹²

In contrast, late acute rejection episodes are more closely associated with the development of chronic allograft nephropathy that may persist despite modern immunosuppressive treatment.¹⁵ At 6 months post-transplantation, those patients with late acute rejection episodes had decreased renal function and more proteinuria than those with early acute rejection episodes. Relative to MHC class II mismatches, the cross-reactive MHC class I mismatches appear to be more prone to stimulating indirect pathways of rejection that may prolong immune stimulation to induce both late acute rejection episodes and chronic rejection.^10,11

The importance of rejection activity over time is indicated by the absence of an increased risk of graft failure among those with early and late acute rejection episodes relative to those with late acute rejection episodes alone. Several studies support speculation that damage caused by persistent interstitial inflammation and tubulitis in patients with late acute rejection episodes leads to interstitial fibrosis and, ultimately, rejection.^16,17

Impact of Late Acute Rejections: Confirmation of Adversity

In an effort to further investigate the relative risk of graft failure by time to rejection, Joseph et al retrospectively reviewed the clinical records of 687 consecutive adult cadaveric renal transplant recipients.³ All patients received cyclosporine-based immunosuppression with a median follow-up of 6.9 years. A total of 349 (50.8%) patients experienced an acute rejection episode, 271 (39.4%) patients developed early acute rejection and 71 (11.4%) patients developed late acute rejection.

The risk of graft failure was significantly higher in those patients who had a rejection episode (relative risk 3.54, 95% CI, 2.59-4.83; P<.001). The risk of graft failure in those patients with a first acute rejection in the first 90 days was significantly lower than that for patients whose first rejection episode occurred after 90 days (Table 2). Compared to patients with no rejection episodes, the relative risk of graft failure in patients experiencing rejection episodes was 3.06 before and 5.27 after 90 days (P<.001).

The difference in long-term graft survival appeared to be significant (P<.05) between patients with no acute rejection, early acute rejection and late acute rejection. Respectively, the 5- and 10-year graft survival rates were 87 and 78%; 63 and 55%; and 45 and 28%. The mean graft survival times were 5.80 years, 5.14 years, and 4.85 years, respectively.

The survival of patients in the 3 groups showed no significant difference. Five-year patient survival was 85% for patients with late acute rejection compared with 81% for patients with early acute rejection and 87% for patients with no acute rejection (P>.05). Similarly, 10-year patient survival rates were 70%, 62% and 72%, respectively (P>.05).

HLA mismatches were found to occur more frequently in those with early acute rejection episodes relative to no acute rejection but not in those with late acute rejection episodes. As in the study by Sijpkens et al,² patients with acute rejection tended to be younger, particularly when compared to those without an acute rejection episode. The mean age in the late, early, and no acute rejection groups were 39.6, 40.8, and 44.0 years, respectively (P<.003).

Acute rejection had a deleterious impact on graft survival, particularly if occurring after 90 days and may be divided into early and late phases. In view of the very poor graft survival associated with late acute rejection, further investigation into the primary etiological factors is warranted. A variety of factors leading to late acute rejection have been proposed. These include race, particularly African-American,¹⁸ suboptimal cyclosporine dosage and levels,^19,20 and cytomegalovirus (CMV) infections, HLA mismatch and high panel reactive antibodies (PRA) levels.^21-23 Based on findings in this study, the investigators advised that late acute rejection should be identified and consideration given to modification of the immunosuppressive regimen in view of the associated poor graft survival rates. Moreover, prevention of late acute rejection offers greater promise of improvement in graft survival than modification of immunosuppression once late acute rejection has occurred. Investigators recommended attention to both adequate doses of immunosuppression and adequate compliance to improve clinical outcome. Additionally, the role of protocol biopsies continues to evolve as a mechanism to facilitate early diagnosis of subclinical acute rejection thereby improving graft histology and function.^24-26

Influence of Acute Rejection on Allograft Survival: Living versus Cadaveric Donors

The increased risk to graft survival from acute rejection episodes is further supported by a study that compared living to cadaveric donor grafts.¹ The study retrospectively evaluated outcomes in 260 patients who had undergone renal transplantation and whose grafts functioned for at least 3 months. Of these, 128 patients received grafts from living related donors and 142 patients received cadaveric grafts.

At 5 years, the living related group exhibited an 86% graft survival compared with 71% for the cadaveric group (P = .02). Additionally, the living related grafts showed a 92% freedom from graft loss to chronic rejection, compared with 74% for cadaveric grafts (P = .002). Among patients who were free from acute rejection, there was no significant difference in risk of graft loss at 5 years between the living related and cadaveric groups (90% vs 88%, P = .76).

Among grafts that suffered an acute rejection within the first 3 months after transplantation, the difference in overall survival between living donor grafts and cadaveric approached statistical significance (P<.07). The cumulative difference at 5 years was statistically significant (cadaveric graft survival 40%; living related graft survival 73%, P<.014, z-test). Additionally, there was a 5-year chronic rejection-free survival of 81% from living related grafts compared with 41% for the cadaveric group (P = .007, z-test).

Overall graft survival among cadaveric graft recipients was poorer than among recipients of living related donors, regardless of whether the donor was older or younger than 50 years. Investigators noted that of all factors studied, early renal function was the most sensitive predictor of long-term graft loss (P<.0001) (Table 3) as has been documented in several studies.^27,28 Among graft recipients with a serum creatinine <2 mg/dL 3 months after transplantation, there were no graft losses to chronic rejection within the first 5 years after transplantation versus diminished long-term graft survival in both groups when creatinine was >2 mg/dL.

While early acute rejection episodes were associated with a substantial reduction in 5-year graft survival rates, living allografts had a far better survival than cadaveric grafts due to a slower progression from acute to chronic rejection. Neither the severity of acute rejection nor the need for antibody therapy to reverse an acute rejection episode affected risk of graft loss, suggesting that recovery function is more important than any single episode in threatening graft survival.

Conclusion

More aggressive efforts to prevent acute rejection episodes may be warranted to reduce the risk of chronic rejection and improve long-term graft survival. Factors with the potential to reduce risk of acute rejection include maintaining long-term immunosuppression, more aggressive immunosuppression strategies, immunosuppression with a low risk of complications, and recognizing the risk for rejection when contemplating changes to immunosuppression therapy. The role of protocol biopsies continues to be assessed as a diagnostic intervention in detecting subclinical acute rejection. Prospective trials to test strategies with the potential to reduce acute rejection episodes and improve survival are clearly warranted.

References

1. Knight RJ, Burrows L, Bodian C. The influence of acute rejection on long-term renal allograft survival: a comparison of living and cadaveric donor transplantation. Transplantation. 2001;72:69-76.
2. Sijpkens YWJ, Doxiadis IIN, Mallat MJK, et al. Early versus late acute rejection episodes in renal transplantation. Transplantation. 2003;75:204-208.
3. Joseph JT, Kingsmore DB, Junor BJR, et al. The impact of late acute rejection after cadaveric kidney transplantation. Clin Transplant. 2001;15:221-227.
4. Humar A, Kerr S, Gillingham KJ, et al. Features of acute rejection that increase risk for chronic rejection. Transplantation. 1999;68:1200-1203.
5. Reisaeter AV, Leivestad T, Vartdal F, et al. A strong impact of matching for a limited number of HLA-DR antigens on graft survival and rejection episodes: a single-center study of first cadaveric kidneys to non-sensitized recipients. Transplantation. 1998;66:523-528.
6. Mathew TW: A blinded, long-term randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: results at three years. Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation. 1998;65:1450-1454.
7. Pollard SG, Lear PA, Ready AR, et al. Comparison of microemulsion and conventional formulations of cyclosporine A in preventing acute rejection in de novo kidney transplantation patients. The U.K. Neoral Renal Study Group. Transplantation. 1999;68:1325-1331.
8. Paul LC. Chronic allograft nephropathy: an update. Kidney Int. 1999;56:783-793.
9. Matas AJ, Gillingham KJ, Payne WD, Najarian JS. The impact of an acute rejection episode on long-term renal allograft survival (t1/2). Transplantation. 1994;57:857-859.
10. Sijpkens YW, Doxiadis IIN, de Fijter JW, et al. Sharing cross-reactive groups of MHC class I improves long-term graft survival. Kidney Int. 1999;56:1920-1927.
11. Zantvoort FA. D'Amaro J, Persijn GG, et al. The impact of HLA-A matching on long-term survival of renal allografts. Transplantation. 1996;61:841-844.
12. Sayegh MH. Why do we reject a graft? Role of indirect allorecognition in graft rejection. Kidney Int. 1999;56:1967-1979.
13. Rogers NJ, Lechler RI. Allorecognition. Am J Transplantation. 2001;1:97-102.
14. Massy ZA, Guijarro C, Wiederkehr MR, et al. Chronic renal allograft rejection: immunologic and non-immunologic risk factors. Kidney Int. 1996;49: 518-524.
15. Solez K, Vincenti F, Filo RS. Histopathologic findings from 2-year protocol biopsies from a U.S. multicenter kidney transplant trial comparing tacrolimus versus cyclosporine: a report of the FK506 Kidney Transplant Study group. Transplantation. 1998;66:1736-1740.
16. Bonsib SM, Abul-Ezz SR, Ahmad I, et al. Acute rejection-associated tubular basement membrane defects and chronic allograft nephropathy. Kidney Int. 2000;58:2206-2214.
17. Chen Y, Baltzan M, George D, et al. Fate of recurrent acute interstitial cellular rejection in an HLA identical kidney transplant recipient: impact of donor microchimerism. Clin Nephrol. 1997;48:300-306.
18. Vasquez EM, Benedetti E, Pollak R. Late AR is more prevalent among African-American renal allograft recipients and is frequently associated with allograft loss. Transplant Proc. 1998;30:1173-1175.
19. Sumethkul V, Jirasiritham S, Chiewsilip P. Late onset AR of renal allografts, an indicator of suboptimum cyclosporin dosage. Transplant Proc. 1996;28:1461-1462.
20. Tejani A, Sullivan EK. Higher maintenance cyclosporine dose decreases the risk of graft failure in North American children: a report of the North American Paediatric Renal Transplant Co-operative Study. J Am Soc Nephrol. 1996;7:550-555.
21. Reinke P, Fietze E, Ode-Hakim S, et al. Late-acute renal allograft rejection and symptomless cytomegalovirus infection. Lancet. 1994;344:1737-1738.
22. Humar A, Hassoun A, Kandaswamy R, Payne WD, Sutherland DER, Matas AJ. Immunologic factors: the major risk for decreased long-term renal allograft survival. Transplantation. 1999;68:1842-1846.
23. McKenna RM, Lee KR, Gough JC, et al. Matching for private or public HLA epitopes reduces AR episodes and improves two-year renal allograft function. Transplantation. 1998;66:38-43.
24. Yamamoto H, Tanabe K, Ishida H, et al. Serial protocol biopsies to identify silent tubulointerstitial infiltrates that may contribute to chronic allograft nephropathy in stable renal allografts. Presented at the American Transplant Congress 2003: The Fourth Joint American Transplant Meeting, May 30-June 4, 2003, Washington, DC. Abstract 281.
25. Gwinner W, Mengel M, Radermacher J, et al. Protocol biopsies in renal transplant recipients: results and impact on therapy. Presented at the American Transplant Congress 2003: The Fourth Joint American Transplant Meeting, May 30-June 4, 2003, Washington, DC. Abstract 1135.
26. Kumar MSA, Xiao SG, Fyfe B, et al. Incidence of subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN) in primary kidney transplant recipients. Presented at the American Transplant Congress 2003: The Fourth Joint American Transplant Meeting, May 30-June 4, 2003, Washington, DC. Abstract 282.
27. Hariharan S, McBride MA, Cherikh WS, Tolleris CB, Bresnahan BA, Johnson CP. Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int. 2002;62:311-318.
28. Siddiqi N, Johnson CP, McBride MA, Maghirag J, Bresnahan BA, Hariharan S. Correlation between risk factors for renal dysfunction (serum creatinine >1.5 mg/dL or 2.0 mg/dL) at 1 year post-transplant and long-term graft failure: an analysis of UNOS data. Am J Transplant. 2002;2(suppl 3):468. Abstract 1312.

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Disclosure
David A. Laskow, MD
Grant/Research Support-Prime Investigator for Protocol 02-0-158 - A Phase III Study; Speakers Bureau-Fujisawa Healthcare, Inc., Roche

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from Fujisawa Healthcare, Inc.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Transplantation Express Report™ does not include discussion of treatment and indications outside of current approved labeling. This Transplantation Express Report™ was made possible through an educational grant from Fujisawa Healthcare, Inc.

© 2003 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education