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RELATIONSHIP OF RECIPIENT AGE AND DEVELOPMENT OF CHRONIC ALLOGRAFT FAILURE

Meier-Kriesche, Herwig-Ulf; Ojo, Akinlolu O.; Cibrik, Diane M.; Hanson, Julie A.; Leichtman, Alan B.; Magee, John C.; Port, Friedrich K.; Kaplan, Bruce1

Clinical Transplantation
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SDC

Background. The elderly are the fastest growing segment of the end stage renal disease (ERSD) population. Older renal transplant recipients experience fewer acute rejection episodes than do younger patients. Despite this, death censored graft survival is no better in these older transplant recipients than in younger recipients. We examined the United States Renal Data System (USRDS) database to determine whether recipient age itself has an independent effect on the development of chronic allograft failure (CAF). %

Methods. We analyzed 59,509 patients from the files of the USRDS. To determine whether age was an independent risk factor for CAF, the population was analyzed separately for Caucasians, African-Americans, and other ethnic groups. All renal transplant recipients from 1988 to 1997 were examined. Both univariate and multivariate analysis were performed using chronic allograft failure as the outcome of interest.

Results. Actuarial 8-year censored graft survival was significantly decreased in the older age groups 67% for ages 18–49 vs. 61.8% for ages 50–64 vs. 50.7% for ages 65+ (P <0.001). In the multivariate analysis, recipient age was a strong and independent risk factor for the development of chronic allograft failure in Caucasians (RR 1.29 for ages 50–64, RR 1.67 for ages older than 65). These findings were reinforced by an analysis that was restricted to living donor transplants without acute rejection.

Conclusion. In Caucasians increased recipient age is an independent risk factor for the development of chronic renal allograft failure.

Departments of Medicine The University of Michigan, Ann Arbor, Michigan

Received 6 December 1999.

Accepted 8 February 2000.

1 Address correspondence to: Bruce Kaplan, MD, The University of Michigan Medical Center, Department of Internal Medicine, 3914 Taubman Center, Box 0364, Ann Arbor, MI 48109-0364.

Renal transplantation is a safe and effective option in the treatment of end stage renal disease (ESRD) in the elderly (1–5). Renal transplantation not only improves the quality of life of elderly ESRD patients but also has a positive impact on patient survival (1, 6). The elderly age group (patients older than 65) comprises the fastest growing demographic group of new ESRD patients. For patients 65 years of age and older the incidence of ESRD has increased from about 600 per million per year in 1988 to about 1200 per million per year in 1997 (7). As a result of the aging of the ESRD population, renal transplantation of elderly ESRD patients is becoming an issue of increasing importance.

Chronic allograft nephropathy together with patient death are the major determinants of late graft loss after renal transplantation (8–10). It has been appreciated that elderly renal transplant recipients have a higher intrinsic mortality rate and suffer fewer acute rejection episodes than younger patients (1,5, 11, 12). Therefore, death with a functioning graft is more frequent in this age group and one would assume that graft loss secondary to chronic allograft nephropathy would be less frequent as compared with younger age groups.

In contrast, Tesi (13) has shown that despite less immunological graft loss, graft survival censored for death is not improved in elderly renal transplant recipients. Thus, the possibility exists that older transplant recipients experience a greater intrinsic risk of chronic allograft nephropathy.

Prior attention has mainly been given to donor-dependent aging factors (14). However, it is possible that age-related factors in the recipient may also have a role in the development of chronic allograft nephropathy (15–18). In this respect, several investigations have noted alterations with age in the level of cytokines including transforming growth factor-β (TGF-β) (19–22). In addition, alterations in lipoprotein and homocystine levels might hasten the progression of arteriosclerotic lesions (20, 23–25).

To test the hypothesis that older recipient age confers a higher risk of CAF relative to younger recipient age, we undertook an analysis of all renal transplant recipients registered in the United States Renal Data System (USRDS) database from October 1, 1988 and June 30, 1997.

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METHODS

This study was based on data collected by the U.S. Renal Transplant Scientific Registry and supplemented with end-stage renal disease data in the U.S. Renal Data System. The study sample consisted of patients who underwent solitary primary renal transplantation between October 1, 1988 and June 30, 1997.

We analyzed our study population by age for the incidence of renal allograft failure. Age at transplantation was analyzed both as a continuous variable and as a categorical variable. Because of the strong independent impact of African-American race on the occurrence of chronic renal allograft failure (CAF), we analyzed the data by race groups (Caucasian, African-American, and others).

The primary study endpoint was CAF, defined as graft loss after 6 months posttransplant, censored for patient death or graft loss secondary to acute rejection, graft thrombosis, infection, surgical complications, or recurrent disease. The exclusion of all study events within the first 6 months was undertaken to evaluate the long-term effects on the graft survival.

Secondary study endpoints were graft survival, graft survival censored for patient death with functioning graft, and acute rejection within the first 6 months post transplant. Patients were followed from transplant date until graft loss or death, or until the study end date of June 30, 1998. Kaplan-Meier analysis was used to compare graft survival and graft survival censored for patient death with functioning graft by age group. Breslow tests were used to investigate for statistically significant differences between survival curves.

Cox proportional hazard regression was used to estimate the independent effect of age on chronic allograft failure while controlling for relevant risk factors. To account for a potentially dominant era effect, the year of transplantation was included as an explanatory variate in the Cox proportional hazard analysis. Other independent variables studied in the Cox model were: cyclosporine versus tacrolimus treatment; induction versus no induction treatment; recipient age; donor age; donor and recipient race, gender, and CMV IgG antibody status; primary cause of ESRD; donor source (cadaveric versus living); cold and warm ischemia times; HLA mismatch; presensitization (PRA); acute rejection; and delayed graft function. Delayed graft function was defined as a need for one or more dialysis treatments in the first posttransplant week.

A logistic regression model was used to estimate the independent effect of age on acute rejection. This model was corrected for the same potential confounding factors as the Cox regression above.

A probability of type 1 error α=0.05 was considered to be the threshold of statistical significance. All statistical analysis was performed using SPSS software (version 7.0 for Windows 95, SPSS, Inc., Chicago, IL).

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RESULTS

Table 1 demonstrates the demographics of the Caucasian renal transplant recipients by age group. Of the 42,193 Caucasian study patients, 28,188 patients fell into the age group from 18–49 years, 11,669 patients fell into the group between 50–64 years, and 2,336 were 65 years and older. The older age group had slightly longer cold ischemic time as well as a greater incidence of delayed graft function. In addition, the older age groups had a greater percentage of cadaveric donors as opposed to living donors. Table 2 displays the absolute numbers of several outcomes for each age group. Graft survival (censored for death) was decreased in the older age groups with a marked decrease in those patients older than 65 years of age. Chronic allograft failure accounted for about half the graft loss in each group and was increased in the older age groups. Both patient death and death with a functioning graft (% of patients per year) were increased in the older age groups.

Table 1

Table 1

Table 2

Table 2

Figure 1 depicts the Kaplan-Meier estimates for graft survival by age group. Eight-year graft survivals were significantly decreased in the older age groups. Figure 2 depicts the 8-year Kaplan-Meier estimated graft survival, censored for death with functioning graft, by age group. Excluding death with functioning graft as a cause for graft loss, graft survival was significantly shorter in the older age groups. Figure 3 shows the cumulative risk of CAF over time by age group as calculated at mean of covariates by Cox proportional hazard. With increasing age there is a significantly greater increase of CAF over time.

Figure 1

Figure 1

Figure 2

Figure 2

Figure 3

Figure 3

The results of the Cox-proportional hazard model are shown in Table 3. This analysis reveals that recipient age was an independent risk factor for CAF. Compared to ages 18–49, the age group of 50–64 had a 29% higher relative risk (RR) of CAF (RR=1.29), where ages 65 and above confer a 67% relative risk for the development of CAF (RR=1.67). Of note, donor age had a negative independent impact on the risk of CAF. Hypertension and diabetes also conferred a significant increased risk for the development of CAF (RR=1.28 and 1.58 respectively). As in previous analyses, acute cellular rejection was a strong factor in the risk of subsequent development of CAF. In addition, Mycophenolate Mofetil therapy conferred a decreased risk of CAF compared to Azathioprine (AZA).

Table 3

Table 3

In contrast, the same Cox-proportional hazard model for African-Americans did not show a significant increase in the risk of CAF in the older patients, but rather it demonstrated a 17% increase in the risk for CAF in the youngest age group. The third race group analyzed (not Caucasian and not African-American) showed results similar to the Caucasian group (data not shown).

The logistic regression model for the risk of acute rejection in all patients during the first 6 months after transplantation is displayed in Table 4. In older age groups, a decreased risk for the occurrence of acute rejection was noted. Delayed graft function and the absence of induction therapy also conferred an independent risk for acute rejection during the first 6 months posttransplant.

Table 4

Table 4

To further confirm the independent effect of recipient age on the development of CAF, we analyzed a subgroup of 11,009 Caucasian patients who had received a living donated kidney and had not suffered an acute rejection episode within the first 6 months posttransplant (data not shown). In this more homogenous subgroup analysis, older age remained a strong independent risk for the development of CAF. Compared to ages 18–49, the age group of 50–64 had a 47% higher relative risk (RR) of CAF (RR=1.47, P =0.03), although patients ages 65 and older confer a 66% relative risk for the development of CAF (RR=1.66, P <0.001).

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DISCUSSION

Our study indicates that older recipient age is an important independent risk factor for the development of chronic allograft failure. This effect was independent of donor age, cold ischemic time, delayed graft function, and acute rejection which are historically the most important determinants of long-term allograft survival. Additional factors that conferred an increased risk of chronic allograft failure were acute rejection, delayed graft function, African-American donor race, diabetes mellitus and hypertension as cause for ESRD, and cadaveric donor source. These factors have been demonstrated previously to be strongly related to shortened censored graft survival and support our results.

To further validate the results of our analysis we analyzed a subgroup of patients who had received a living donor transplant and had not suffered any rejection episodes in the first 6 months after transplantation. Even in this relatively homogeneous group of patients, the relative risk for the development of chronic allograft failure was increased significantly in the oldest age group (age 65 and older).

We did not confirm the same trend among African-American renal transplant recipients. In fact, the youngest age group had significantly more CAF as compared with the older African-American patients. African-American race in itself is a strong independent risk factor for CAF and together with acute rejection constitutes the most important determinant for CAF. In our analysis we found that African-American renal transplant recipients have a 70% higher risk of CAF as opposed to Caucasians. This strong inherent risk may override the age effect in African-Americans. It is also possible that factors not captured in the database such as noncompliance, recurrent or stronger rejection, or altered pharmacokinetic handling of drugs, might be responsible for the increased risk for CAF in younger African-Americans.

We believe our definition of chronic allograft failure (graft failure not secondary to death, recurrent disease, acute rejection, technical problems, thrombosis, or other attributable cause occurring more than 6 months after transplantation) is the best approximation of chronic allograft nephropathy that can be obtained from a database of this size. It is likely that the overwhelming majority of graft losses defined as chronic allograft failure in our study were secondary to chronic allograft nephropathy.

The pathogenesis of the increased risk of chronic allograft failure in older transplant recipients is not readily available from this database. Baseline immunosuppression was no different in older transplant recipients than in younger recipients and it is highly unlikely that pharmacokinetic differences in immunosuppressive medications could explain this relationship. It is possible that older transplant recipients might have altered serum cholesterol concentrations or different blood pressure control; however, given the aggressive antihypertensive therapy and antilipidemic therapy that is practiced in most transplant centers it is unlikely that this could account for the entire risk noted.

Much attention has been paid to the aging process in the donor and subsequent negative effects on longevity of the renal allograft (14, 17, 26, 27). It is possible that aging also induces changes in serum and blood elements, which may play a role in hastening the lesions typical of CAN. Support for this hypothesis are investigations that have demonstrated up-regulation of HLA-DR with age (21), altered IL-6 production in older individuals (22), as well as increased concentration of TGF- β in stimulated lymphocytes (19). Nonimmunological factors that may also hasten the progression of arteriosclerotic lesions in elderly individuals include increased homocysteine concentrations, increased apolipoprotein E and I levels, and altered insulin-like growth factor levels (20, 23–25).

In summary, our study demonstrates that recipient age is an important risk factor for the development of chronic allograft failure among Caucasian renal transplant recipients. This effect is independent of all known donor factors as well as other baseline recipient factors. The pathogenesis of this increased risk cannot be elucidated by our study, but it likely includes age-related changes in both immunological and nonimmunological mediators in the aging milieu of the recipient.

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