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Survival Improvement among Patients with End-Stage Renal Disease: Trends over Time for Transplant Recipients and Wait-Listed Patients

Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.

Correspondence to Dr. Bruce Kaplan, University of Michigan Health System, Division of Nephrology, 3914 Taubman Center, Ann Arbor, MI 48109-0364. Phone: 734-763-9041; Fax: 734-936-9621; E-mail: brkaplan{at}umich.edu

	Abstract

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Abstract. Both transplant and dialysis outcomes have improved over recent years. In addition, transplantation has been shown to confer a survival benefit over maintenance dialysis. The study presented here addresses the question of whether the survival benefit of transplantation over maintenance dialysis has changed in the most recent eras. This study was based on data collected by the United States Renal Transplant Scientific Registry and the United States Renal Data System. The study sample consisted of 104,000 patients placed on the renal transplant waiting list between 1988 and 1996, of which 73,707 subsequently received renal transplants. The annualized adjusted mortality rates per 1000 patient-years were calculated by calendar year of placement on the renal transplant waiting list and for kidney transplant recipients. The resulting data were plotted, and linear curve fitting was used to estimate the slope of the change of the adjusted mortality rates by year during the period studied, 1988 to 1996. Overall annual adjusted death rates in the wait-listed patients and transplant recipients per 1000 patient-years decreased for both groups throughout the study period. From 1989 to 1996, the relative risk (RR) for patient death had decreased by 30% for transplant recipients and 23% for wait-listed patients (RR = 0.70 and 0.77; P < 0.0001 each). Slope analysis of the cause-specific mortality rates for cardiovascular disease and infection showed nearly equivalent, linear decreases for both groups. Mortality rates have improved overall and by categories of major cause of death for both renal transplant recipients and patients on the renal transplant waiting list. These favorable trends most likely represent equal advances in transplantation, dialysis, and general medical care.

	Introduction

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Tremendous strides have been made in the general care of patients with end-stage renal disease (ESRD). Improved renal allograft survival has been documented in recent years (1,2,3). In addition, several studies have demonstrated that renal transplantation confers a survival benefit compared with maintenance dialysis (4,5,6,7,8,9,10,11). Improvements also have been seen with patients on dialysis (2, 12, 13). However, it is possible that the trend in improvement over time for dialysis patients may not be of similar magnitude to that of transplant recipients.

The United States Renal Data System (USRDS) reported improving 5-yr survival for transplant recipients during the 1980s (2), but previous studies addressed neither more recent changes in overall mortality rates nor changes in cause-specific mortality rates for renal transplantation and dialysis patients who have been placed on the renal transplant waiting list. Previous studies primarily used graft survival as an end point. This end point usually is a composite of both patients who have lost their graft as a result of renal-specific causes and patients who have died with a functioning graft. Inferences from these data have been made regarding patient survival. However, these studies did not address overall changes in mortality rates or cause-specific mortality rates for transplant recipients and for dialysis patients who have been placed on the renal transplant waiting list. Until now, a direct analysis of this issue has not been performed. It is possible that changes in overall mortality may not mirror the changes in cause-specific mortality. An analysis directed at cause-specific mortality rates would provide insight into specific areas that may need additional attention.

To address these issues, we analyzed data from the USRDS and assessed trends in mortality rates and risk during the past decade for both renal transplant recipients and patients placed on the renal transplant waiting list.

	Materials and Methods

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To evaluate the trends in mortality among patients with ESRD, either on the waiting list for renal transplantation or after renal transplantation, we analyzed patients who were registered in the USRDS database between 1988 and 1996. The data for the analysis were provided by the United States Renal Transplant Scientific Registry and supplemented with ESRD data from the USRDS. Only primary solitary renal transplants were used for the analysis. Transplant recipients were followed from the date of first transplantation until death or the study end date of June 30, 1998. We chose to examine patients who were placed on the renal transplant waiting list as the comparison group for this study. The wait-listed cohort of patients was believed to be the best possible control because wait-listed individuals underwent the same initial screening as those patients who ultimately received a transplant. The wait-listed cohort was followed from the date of first being placed on the waiting list until death or the end of the study; patients were removed from the wait-listed group on the date of transplantation. The primary study end point was patient death. Secondary study end points were cause-specific death secondary to cardiovascular disease, infection, or malignancy. We used Cox proportional hazard models to estimate the role of calendar year on the risk for patient death after placement on the waiting list and after transplantation. The Cox proportional hazard models were adjusted for age, race, gender, cause of ESRD, and year. Year of being placed on the waiting list and of transplantation were categorized as follows: 1988 to 1989 (combined), 1990, 1991, 1992, 1993, 1994, 1995, and 1996. We calculated the annual mortality rates per 1000 patients by year, adjusting for age, race, gender, and cause of ESRD for patients on the renal transplant waiting list and transplant recipients, on the basis of 5 yr of actual or projected follow-up time. The resulting data were plotted as an X-Y scatter plot. Linear curve fitting was used to estimate the slope of the change of the adjusted mortality rates by era. Curve fit was estimated by r². Multiple nonlinear curve estimation procedures (quadratic, cubic, exponential, power, inverse, s, log) were used to explore the hypothesis of non-linear relation between year and adjusted mortality rates.

A probability of type 1 error = 0.05 was considered to be the threshold of statistical significance. All statistical analyses were performed with the use of SPSS software (Version 7.0 for Windows 95; SPSS, Inc., Chicago, IL).

	Results

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Table 1 depicts the characteristics of the transplant recipients and the patients with ESRD who had been placed on the waiting list between 1988 and 1996. The study groups reflect a sample size of exactly 104,000 total patients listed on the renal transplant waiting list during the study period, of which 73,707 patients subsequently received a renal transplant. The demographics are similar for the two groups.

Overall annual death rates in the wait-listed patients and transplant recipients, adjusted for age, race, gender, and cause of ESRD, were calculated per 1000 patient-years and are shown in Figure 1. These rates were calculated on the basis of 5 yr of actual or projected follow-up for each group. The death rates decreased for both transplant recipients and wait-listed patients throughout the study period.

View larger version (51K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Adjusted annual death rates in wait-listed (WL) patients and transplant (Tx) recipients per 1000 patient-years on the basis of 5 yr of actual or projected follow-up.

The relative mortality risk by year is depicted in Figure 2. The mortality risks decreased during the study period for both wait-listed patients and transplant recipients. There was a 30% decrease in the mortality risk for transplant recipients in 1996 compared with those who received a transplant in 1989 (RR = 0.70, P < 0.0001). Similarly, there was a 23% decrease in the mortality risk for patients who were placed on the waiting list in 1996 compared with those who were placed on the waiting list in 1989 (RR = 0.77, P < 0.0001). Throughout this period, death rates on the waiting list were approximately threefold higher than rates for transplant recipients.

View larger version (83K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. Relative mortality risk by year in WL patients and Tx recipients from two Cox proportional hazards models (reference, 1989).

In a closer examination of categories of cause of death, the mortality rates for death secondary to cardiovascular disease decreased linearly for both wait-listed and transplanted patients throughout the study period (Figure 3). The mortality rates were higher for patients who had been placed on the renal transplant waiting list than for transplant recipients, but the decrease was nearly equivalent for the two groups.

View larger version (52K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 3. Mortality secondary to cardiovascular disease. Adjusted annual death rates in WL patients and Tx recipients per 1000 patient-years on the basis of 5 yr of actual or projected follow-up.

In Figure 4, the mortality rates and slopes for death secondary to infection are shown. The rates for death secondary to infection decreased nearly linearly for both wait-listed and transplanted groups. Death rates were three- to fourfold higher in wait-listed patients than in transplant recipients. In contrast, mortality rates for death as a result of malignancy showed no linear trend during the study years (Figure 5). For most years, the death rates as a result of malignancy were higher in the transplant group than in the wait-listed group.

View larger version (50K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 4. Mortality secondary to infectious disease. Adjusted annual death rates in WL patients and Tx recipients per 1000 patient-years on the basis of 5 yr of actual or projected follow-up.

View larger version (49K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 5. Mortality secondary to malignancy. Adjusted annual death rates in WL patients and Tx recipients per 1000 patient-years on the basis of 5 yr of actual or projected follow-up.

Overall deaths in the general population also have been decreasing over time. Based on data from the U.S. Census, Figure 6 displays graphically the mortality rates for cardiovascular deaths in the general population for the same time period as examined in this study (14). The trend in cardiovascular deaths in the general population has decreased steadily over time as it has in patients with ESRD.

View larger version (27K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 6. Mortality secondary to cardiovascular disease in the general population. Five-yr annual adjusted death rates per 1000 patients.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Our study demonstrates that absolute mortality rates have been improving for both renal transplant recipients and patients who have ESRD and who have been placed on the renal transplant waiting list. This improvement in mortality seems to be equivalent for both groups. Both the slope analysis of adjusted mortality rate and the relative risk of mortality have improved in a similar manner for the two groups. It is important to note that whereas overall improvement has been equivalent, transplantation still holds a large survival advantage over maintenance dialysis for patients with ESRD. Analysis for the dialysis group was restricted to wait-listed patients who tend to have substantially lower death rates (4). Therefore, this difference suggests that an intrinsic benefit of transplantation is maintained during the period studied. Our data suggest that both transplantation and dialysis have made advances in clinical care and that these advances have had an equivalent benefit for both groups.

Cardiovascular death accounts for more than 50% of all deaths of patients with ESRD (15). Both transplant recipients and wait-listed patients showed evidence of a decrease in mortality during the years studied. Again, the intrinsic benefit of transplantation has been maintained. Because the incidence of cardiovascular death is higher among wait-listed patients, the absolute number of patients who have benefited over the years is higher in this group. In terms of assessing the relative improvement, the slope of each line indicates that the improvements are virtually equal for both groups. The improvement in cardiovascular mortality in these groups is mirrored by the improvement in death rates as a result of cardiovascular disease observed in the general population. This indicates that a substantial part of the improvement in cardiovascular death for both transplant recipients and wait-listed patients is reflective of the general improvements in the diagnosis and treatment of cardiovascular disease and not solely the result of isolated improvements in transplantation or dialysis.

Death rates from infection also have improved to a similar degree for transplant recipients and wait-listed patients. Interestingly, wait-listed patients throughout the years studied had a substantially higher mortality secondary to infection than transplant recipients, despite the immunosuppressive therapy necessitated by transplantation.

No clear trends over time emerge for deaths as a result of malignancy. The appearance of a decrease in malignant deaths, specifically among transplant recipients, in the most proximate years may reflect a favorable drift; however, this was not statistically significant. This could be due to the nature of malignant deaths and the need for longer follow-up to detect a statistically significant trend in the data (16). Interestingly, transplantation at any given time point does not show a statistically significant increase in death from malignancy over wait-listed patients.

Because of the nature of the multivariate analyses, we are confident that the above findings are not reflective of changes in the age, race, gender, or cause of ESRD demographics over time.

It is possible that cause-specific death rates may be reported low for transplant recipients because the cause of death is more frequently underreported in this group than in the dialysis groups (2). This should not affect the results of the trends because a review of multiple previous Annual Data Reports of the USRDS suggests that the fraction with unknown or missing cause of death has not changed during the years of the recent study.

In summary, overall mortality rates have improved for both renal transplant recipients and patients on the renal transplant waiting list. Little evidence supports that newer immunosuppressive agents have increased mortality secondary to infection. In addition, cardiovascular mortality has improved for both of these groups as well as for the general population. These favorable trends in all likelihood represent similar advances in transplantation, dialysis, and general medical care.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D: Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med342 : 605-612,2000[Abstract/Free Full Text]
2. United States Renal Data System: USRDS 1999 Annual Data Report, Bethesda, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases,1999
3. Cecka JM: The UNOS Scientific Renal Transplant Registry—Ten years of kidney transplants. In: Clinical Transplants, edited by Terasaki PI, Cecka JM, Los Angeles, UCLA Tissue Typing Laboratory,1998 , pp 1-14
4. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, Held PJ, Port FK: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med341 : 1725-1730,1999[Abstract/Free Full Text]
5. Schnuelle P, Lorenz D, Trede M, Van Der Woude FJ: Impact of renal cadaveric transplantation on survival in end-stage renal failure: Evidence for reduced mortality risk compared with hemodialysis during long-term follow-up. J Am Soc Nephrol 9:2135 -2141, 1998[Abstract]
6. Ojo AO, Port FK, Wolfe RA, Mauger EA, Williams L, Berling DP: Comparative mortality risks of chronic dialysis and cadaveric transplantation in black end-stage renal disease patients. Am J Kidney Dis 24: 59-64,1994[Medline]
7. Port FK, Wolfe RA, Mauger EA, Berling DP, Jiang K: Comparison of survival probabilities for dialysis patients vs cadaveric renal transplant recipients. JAMA 270:1339 -1343, 1993[Abstract]
8. Port FK, Weller JM, Swartz RD: Survival with end-stage renal disease. N Engl J Med 309:1520 , 1993
9. Krakauer H, Grauman JS, McMullan MR, Creede CC: The recent US experience in the treatment of end-stage renal disease by dialysis and transplantation. N Engl J Med308 : 1558-1563,1983[Abstract]
10. Higgins MR, Grace M, Dossetor JB: Survival of patients treated for end-stage renal disease by dialysis and transplantation. Can Med Assoc J 177:880 -883, 1977
11. Lowrie EG, Lazarus JM, Mocelin AJ, Bailey GL, Hampers CL, Wilson RE, Merrill JP: Survival of patients undergoing chronic hemodialysis and renal transplantation. N Engl J Med288 : 863-867,1973
12. Wolfe RA, Held PJ, Hulbert-Shearon TE, Agodoa LYC, Port FK: A critical examination of trends in outcomes over the past decade. Am J Kidney Dis 32[Suppl 4]:S9 -S15, 1998[Medline]
13. Port FK, Orzol SM, Held PJ, Wolfe RA: Trends in treatment and survival for hemodialysis patients in the United States. Am J Kidney Dis 32[Suppl 4]:S34 -S38, 1998[Medline]
14. National Vital Statistics Reports, Vol.47 , No. 3, Bethesda, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System,1998
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