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

Of recent stratifications designed to isolate treatable risk factors for late failure of allograft transplantation, none may be more helpful than separation of variables by immunologic versus non-immunologic origin. Unlike acute allograft rejection, which is mediated by immunologic factors, late rejection may involve a more complex interplay of immunologic and non-immunologic risks leading to graft dysfunction. The emphasis on immunologic versus non-immunologic factors for graft outcome in the 2 studies reviewed in this Transplantation Express Report create a framework for proactive interventions.

The focus on stratifying variables that affect long-term graft survival are part of an important shift in attention made possible by success in curbing acute rejection. The efforts to differentiate risks by immunologic versus non-immunologic origin, as first observed by Tilney,¹ represent a rational methodology to isolate areas of intervention on which to concentrate attention. This stratification has been revealing. Both studies described herein identify immunologic factors as more consistent determinants of long-term outcome than non-immunologic factors.

In the study undertaken by Humar et al,² an acute rejection episode was essential for increased risk of late graft loss. In isolation, non-immunologic risk factors did not appear to exert much, if any, adverse effect on outcome. In the analysis by Matas et al,³ donor age and recipient race, which have been demonstrated to be independent variables for graft outcome in previous trials, are found only to be significant risk factors for long-term graft dysfunction in cadaver transplant recipients. In contrast, immunologic factors, which generally imposed a greater impact on graft outcome, were significant to the survival of both living donor and cadaver donor transplants.

The message of the second study is consistent with that of the first. In both, immunologic risk factors provide a better prediction of graft survival than non-immunologic risk factors in the acute setting. Both studies indicate that efforts to prevent acute rejection episodes provide the most important opportunity for substantial gains in long-term graft survival.

Successful transplant outcome is a cumulative product of attention to details. The incremental progress in isolating which details deserve the greatest attention at each stage of grafting and recovery deserves credit for the steady improvement in survival documented over the past four decades. The importance of the studies by Matas et al and Humar et al is that they focus attention on immunologic factors in the acute setting to supply direction for improved outcome in the late setting.

Predominant Role of Immunologic Factors in Decreased Long-term Graft Survival

Due to strides in immunosuppressive therapy to prevent early graft loss,⁴ chronic rejection has become the predominant cause of graft failure.⁵ Two hypotheses have evolved that account for the underlying pathogenic process. The first presupposes that immunosuppressive therapies are sufficiently effective that it is now necessary to identify other preventable or treatable risk factors to further improve graft survival.^6,7 The second is that chronic rejection is an immunologic process and a late consequence of inadequate immunosuppression in the acute setting.^8,9 Efforts to address this controversy now powerfully support the latter hypothesis.

Humar and colleagues examined the relative contribution of immunologic and non-immunologic risk factors to late graft loss in 1,587 adult kidney recipients at a single institution.² Recipients were divided into two distinct groups: Group 1 included all those who experienced acute rejection (n = 588) and Group 2 included those who did not experience acute rejection (n = 999). This division was created to assess the relative effects of immunologic and non-immunologic risks. It was presumed that non-immunologic factors would exercise an important influence on outcome in Group 2, whereas immunologic factors, non-immunologic factors, or both could explain late graft loss in Group 1.

Ten-year graft survival in the study population, which excluded recipients who died with function, or of technical failure, primary non-function, or recurrent disease, was 45% in Group 1 versus 91% in Group 2 (P<.001). The very low incidence of chronic rejection in the absence of an acute rejection episode (Group 2) suggests that non-immunologic risks by themselves exert a relatively modest influence on outcome. Chronic rejection was suspected in patients with chronic deterioration of graft function and was confirmed by graft biopsy or nephrectomy. The major difference in graft survival was defined by loss secondary to chronic rejection, an outcome observed in 1.8% of patients in Group 2 but in 23.8% of patients with a previous acute rejection episode (Group 1) (P<.001). Acute rejection was responsible for graft loss in 5.6% of those in Group 1 versus none of those in Group 2. At the last follow-up, still functioning grafts were present in 57.3% of Group 1 versus 94.7% of Group 2 (P<.001).

Using biopsy-confirmed chronic rejection, rather than graft loss, as an endpoint for comparison, those who experienced an acute rejection episode developed chronic rejection sooner and more often than those without a previous rejection (Figure 1). Although cadaver grafts were associated with a higher incidence of biopsy proven chronic rejection than living donor grafts in both groups, the rates remained consistently higher in those with a history of acute rejection. Of those with cadaver grafts (56% of recipients in Group 1 and 43% of recipients in Group 2), evidence of chronic rejection was more common at 10 years in Group 1 than in Group 2 (56.9% vs 6.6%). In the living donor recipients, chronic rejection was observed in 49.8% and 1.7% in Groups 1 and 2, respectively.

These marked differences in outcome argue strongly for control of acute rejection. Even if non-immunologic factors made an important contribution to adverse outcome in those who experienced an acute rejection, they remain within the context of immunologic rejection. For example, if a factor that compromises function, such as limited nephron mass, contributed to late rejection in Group 1, it appeared to do so only in the context of an acute rejection episode. In the group without an acute rejection episode, such non-immunologic factors were not significant. As a result, the data suggest that non-immunologic risk factors, if they play a role at all, would be neutralized by prevention of an acute rejection episode.

Due to a complex interplay likely to exist between immunologic and non-immunologic risk factors for outcome, a study designed to assign a precise value to the risk posed by each may be unreasonable. However, in simple terms, this study demonstrates that chronic rejection in the absence of an acute rejection episode is uncommon. As a result, efforts to prevent acute rejection predict protection against chronic rejection. Overall, the results indicate that within usual care to prevent or minimize non-immunologic factors associated with poor outcome, such as older donor grafts or long duration of graft ischemia, there is now only a modest opportunity to improve outcomes without a reduction in episodes of acute rejection.

Matas and colleagues address similar issues and draw similar conclusions.³ In this study, data from 1,199 adult kidney transplantations were analyzed to evaluate whether immunologic risk, exemplified by rejection, was more important to outcome than non-immunologic factors, such as limited nephron mass or donor age. In this study, non-immunologic risk factors did prove to be predictors of outcome, but only in those who received a cadaver organ. However, rejection with or without delayed graft function was a consistent predictor of adverse outcome regardless of other stratifications.

Multivariate analysis was employed to evaluate the effect on outcome of acute rejection, delayed graft function, recipient race, and donor age and race. Of the 1,199 kidney transplantations performed over an 11-year period, 752 (63%) were from living donors and 447 (37%) from cadavers. Two analyses were performed. One included all transplants. The second was limited to those with survival of at least one year.

Again, the most significant and consistent finding was the role played by immunologic factors in predicting outcome. When death with graft function was censored in patients who received a cadaver graft, acute rejection was associated with a 3.1-fold increased risk of graft loss relative to no acute rejection (P = .0001). When acute rejection was combined with delayed graft function, another marker of immunologic pathology, the risk of graft loss was 6.3-fold greater than the absence of either risk factor (P = .0001). When death with function was not censored, acute rejection and delayed graft function still increased risk of graft loss by 3.2-fold (P = .0001).

In those who received living donor grafts, only immunologic factors were found to be important. In death with function censored, rejection alone increased the risk of graft loss by 9.7-fold (P = .0001) relative to no acute rejection. With delayed graft function, acute rejection increased risk in this population by more than 20-fold (P = .0001). In death with function not censored, the relative risk of graft loss was increased 3.4-fold by rejection alone and 5.4-fold by rejection with delayed graft function (both P = .0001).

In both the cadaver and living donor recipient groups, the importance of immunologic factors was not diminished when risk assessment was limited to those with at least one-year survival. In the cadaver recipient group, the risk of rejection was 8.8-fold greater in patients with acute rejection and delayed graft function than in those without these risk factors (P = .0001). In the living donor group, this combination of risk factors in the group censored for death with function was associated with a relative risk of 26 (P = .0001).

Unlike the living donor group, in whom no other evaluated risk factors were associated with an increased risk of graft loss, recipients of cadaver grafts also had an increased risk of graft loss if they were of black race or if the donor age was ≥50 years. Although these were significant (P values ranged from .02 to .0001), the relative difference in risk was generally lower than for immunologic factors, mostly raising risk by only 2- to 3-fold.

Results of these retrospective analyses do not rule out the importance of non-immunologic factors in living donor recipients. Rather, they suggest that immunologic factors impose a dominant influence on outcome. The consistency of the influence of immunologic factors across every subgroup analyzed in this study reinforces this point. Previous studies have also indicated that such non-immunologic factors as elevated serum creatinine may have independent predictive value,¹⁰ but the importance of acute rejection, delayed graft function, or both has been markedly consistent across a variety of studies and a variety of patient stratifications.^11,12

The results of both this study and that of Humar et al affirm that immunologic risks mediate late rejection, a finding predicted by the infrequency with which chronic rejection is observed without a previous acute rejection episode. Even after recovery, acute rejection episodes appear to be capable of initiating a persistent, if subclinical, pathological process. Such a process is likely to be mediated by local cytokine release that compromises nephron function and survival.

These data do not resolve the controversy in a unilateral fashion. Although the preponderance of data now indicate that chronic rejection is the product of inadequately controlled immunologic factors stimulated by acute rejection episodes, graft survival is clearly influenced by a vast array of risk factors. Improved immunosuppression during the acute recovery period appears to be critically important to reducing the risk of chronic rejection, but efforts to provide comprehensive risk management through both non-immunologic and immunologic risk factors is still likely to provide the greatest opportunity for optimal graft survival.

Impact of Immunosuppression on Rejection

Immunosuppressive therapy after kidney transplantation continues to evolve. There are a variety of pharmacologic combinations from which to choose, based on immunologic risk and side effect profiles. Along with improving clinical care, combinations of newer immunosuppressive agents have produced one-year patient survival approaching 100% and graft survival exceeding 90%.¹³ The efficacy and side effect profiles of selected immunosuppressive regimens are illustrated in Figure 2.

Occasionally, patients develop side effects that may necessitate conversion from one immunosuppressive agent to another. For example, patients receiving cyclosporine and at risk for chronic renal allograft failure (defined as serum creatinine ≥2 mg/dL for males and ≥1.7 mg/dL for females, or >30% increase in post-transplant serum creatinine nadir), experienced a decline in serum creatinine when converted to tacrolimus (+0.3 mg/dL from baseline with cyclosporine, -0.1 mg/dL from baseline with tacrolimus; P = .003).¹⁴ Moreover, therapeutic intervention with tacrolimus resulted in improved renal function, lipid profiles, and fewer cardiovascular events. Similarly, tacrolimus-treated patients exhibiting tremor or gastrointestinal intolerance may show symptom improvement with conversion to cyclosporine.¹⁵

Conclusion

Now that acute rejection has become a rare cause of graft loss, efforts to improve allograft survival have been redirected to preventing chronic rejection. The data generated from studies by Humar and Matas help to address the controversy of whether the opportunities for preventing chronic rejection lie with such non-immunologic variables as better selection of donor grafts or with further advances in controlling immunologic response to abort pathologic processes. The consistency with which immunologic risks predict outcome encourage efforts to direct greater clinical attention to prevention of acute rejection episodes in order to improve late outcome.

References

1. Tilney NL. Thoughts on the immunobiology of chronic allograft rejection. Transplant Proc. 1995;27:2123-2125.
2. 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.
3. Matas AJ, Gillingham KJ, Humar A, Dunn DL, Sutherland DER, Najarian JS. Immunologic and nonimmunologic factors: different risks for cadaver and living donor transplantation. Transplantation. 2000;69:54-58.
4. 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.
5. Massy ZA, Guijarro C, Wiederkehr MR, Ma JZ, Kasiske BL. Chronic renal allograft rejection: immunologic and non-immunologic risk factors. Kidney Int. 1996;49:518-524.
6. Brenner BM, Cohen RA, Milford EL. In renal transplantation, one size may not fit all. J Am Soc Nephrol. 1992;3:162-169.
7. Terasaki PI, Koyama H, Cecka HM, Gjertson DW. The hyperfiltration hypothesis in human renal transplantation. Transplantation. 1994;57:1450-1454.
8. Almond PS, Matas A, Gillingham K, et al. Risk factors for chronic rejection in renal allograft recipients. Transplantation. 1993;55:752-756.
9. Matas AJ. Risk factors for chronic rejection: a clinical perspective. Transpl Immunol. 1998;6:1-11.
10. Humar A, Johnson EM, Payne WD, et al. Effect of initial slow graft function on renal allograft rejection and survival. Clin Transplant. 1997;11:623-627.
11. Troppmann C, Gillingham KJ, Benedetti E, et al. Delayed graft function, acute rejection, and outcome after cadaver renal transplantation: a multivariate analysis. Transplantation. 1995;59:962-968.
12. 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.
13. Chan L, Gaston R, Hariharan S. Evolution of immunosuppression and continued importance of acute rejection in renal transplantation. Am J Kidney Dis. 2001;38(suppl 6):S2-S9.
14. Waid T for the CRAF Study Group. Prograf as secondary intervention vs continuation of cyclosporine in patients at risk for chronic renal allograft failure (CRAF) results in improved renal function, decreased CV risk, and no increased risk for diabetes. Presented at the American Transplant Congress 2003: The Fourth Joint American Transplant Meeting, May 30-June 4, 2003, Washington, DC. Abstract 1111.
15. Abouljoud MS, Kumar MS, Brayman KL, Emre S, Bynon JS the OLN-452 Study Group. Neoral rescue therapy in transplant patients with intolerance to tacrolimus. Clin Transplant. 2002;16:168-172.

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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