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Deleterious effect of waiting time on renal transplant outcome
Deleterious Effect of Waiting Time on Renal Transplant Outcome H.-U. Meier-Kriesche, F.K. Port, A.O. Ojo, A.B. Leichtman, S.M. Rudich, J.A. Arndorfer, J.D. Punch, and B. Kaplan
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RANSPLANTATION has been shown to improve survival when compared to maintenance dialysis for patients with end-stage renal disease (ESRD).1–3 In addition, renal transplantation is a cost-effective modality that offers improved quality of life for patients with ESRD.4 There is some evidence that patients who receive a preemptive renal transplant have a survival advantage when compared to patients who receive a renal transplant after a period of maintenance dialysis therapy.5,6 Other studies7 did not find any effect of length of pretransplant dialysis on patient survival. Neither of these studies detected any correlation of waiting time on dialysis and death-censored graft survival. Studies to date have not yet yielded a conclusive answer to these unresolved issues. Thus, we undertook an analysis of the United States Renal Data System Registry (USRDS) to assess the impact of waiting time on posttransplant patient survival and graft survival with and without censoring at death.
METHODS This study was based on data collected by the US Renal Transplant Scientific Registry and supplemented with end-stage renal disease data in the US Renal Data System. The study sample consisted of patients who underwent solitary primary renal transplantation between October 1, 1988 and June 30, 1997. Patients were followed from transplant date until graft loss or death or until the study end date of June 30, 1998. Waiting time on dialysis was calculated from the start of maintenance dialysis treatment to transplant date. Primary study end points included patient death with functioning graft and death-censored graft failure. As an additional endpoint we evaluated chronic renal allograft failure, defined as graft loss after 6 months posttransplant, censored for patient death or graft loss secondary to acute rejection, graft thrombosis, infection,
From the Departments of Medicine, Epidemiology and Surgery, University of Michigan, Ann Arbor, Michigan. Address reprint requests to Bruce Kaplan, MD, The University of Michigan Medical Center, Department of Internal Medicine, 3914 Taubman Center, Box 0364, Ann Arbor, MI 48109-0364.
Fig 1. Relative risk for deathcensored graft loss by primary disease. Diabetes (DM), hypertension (HTN), and glomerulonephritis (GN).
0041-1345/01/$–see front matter PII S0041-1345(00)02387-3
© 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
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Transplantation Proceedings, 33, 1204–1206 (2001)
DELETERIOUS EFFECT OF WAITING TIME
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Fig 2. Relative risk for death with functioning graft by primary disease. Diabetes (DM), hypertension (HTN), and glomerulonephritis (GN). surgical complications, or recurrent disease. Cox proportional hazard regression was used to estimate the independent effect of waiting time on the primary study endpoints while controlling for relevant risk factors. To account for a potentially dominant era effect, the year of transplantation was included as an explanatory covariate in the Cox proportional hazard analysis. Other potential confounding variables studied were: cyclosporine versus tacrolimus treatment; induction versus no induction treatment; recipient age at transplantation; donor age; donor and recipient race, gender, and CMV IgG antibody status; primary cause of ESRD; donor source (cadaveric vs. living); cold and warm ischemia times; HLA mismatch; presensitization (PRA); and delayed graft function. To evaluate the impact of waiting time separately by cause of endstage renal disease, we built an interaction term between these two factors into the Cox proportional hazard model. In this subanalysis, only patients within the three major primary disease groups (glomerulonephritis (GN), hypertension (HTN), and diabetes mellitus (DM) were analyzed.
RESULTS Death-Censored Graft Survival
Increasing waiting time on dialysis was a significant risk factor for death-censored graft loss after renal transplantation (P ⬍ .001) by Cox proportional hazard analysis. Being on dialysis for up to 6 months prior to transplantation conferred a 17% increased risk for death-censored graft loss as compared to preemptive renal transplantation when adjusted for all factors described in the methods. Dialysis treatment for 6 to 12, 12 to 24, and 24 to 36 months prior to renal transplantation conferred a 37%, 55%, and 68% higher risk for censored graft loss, respectively. Beyond 36 months of dialysis there remained a significantly increased risk of censored graft loss as opposed to preemptive transplantation (P ⬍ .001), however, the relative increase beyond 36 months from 68% to 70% to 74% was small and not statistically significant.
Patient Survival
When adjusting for all factors described in the methods, increasing waiting time on dialysis was also a significant risk factor for patient death with functioning graft after renal transplantation (P ⬍ .001). Maintenance dialysis therapy for up to 6 months prior to transplantation did not confer an increased risk for patient death after transplantation as compared to preemptive renal transplantation. However, more than 6 months of dialysis treatment prior to renal transplantation conferred a significant and progressive increase in the relative risk for patient death after transplantation (P ⬍ .001). Dialysis treatment for 6 to 12, 12 to 24, 24 to 36, 36 to 48, and above 48 months prior to renal transplantation conferred a 21%, 28%, 41%, 53%, and 72% increased adjusted risk for censored graft loss, respectively. As shown in Fig 2, there was also a significant increase in the relative risk for patient death with increasing time of pretransplant dialysis for each of the three major ESRD disease groups.
DISCUSSION
The results of our study demonstrate that waiting time on dialysis is a strong risk factor for decreased patient survival as well as decreased death-censored graft survival following renal transplantation. This effect was independent of all other factors in the model (including recipient age, race, original disease, and donor characteristics) and likely reflects a true negative effect of waiting time on dialysis. This negative effect held equally true for patients with systemic diseases (eg, diabetes mellitus) as well as patients with renal specific disease (eg, glomerulonephritis) and thus is unlikely to be due to a longer exposure to a systemic process. It is interesting to note that not only did waiting time incur a
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greater relative risk for patient death following renal transplantation, but also conferred a similarly strong negative risk factor for death-censored graft survival. In fact, when patients with death-censored graft survival were further subdivided to exclude those patients with surgical problems, infections, acute rejection, and recurrent disease, a similar trend emerged. Thus, this suggested that waiting time on dialysis also confers an increased relative risk for the development of chronic allograft nephropathy. In summary, waiting time emerges as a strong independent risk factor for increased patient mortality and increased graft failure following renal transplantation.
MEIER-KRIESCHE, PORT, OJO ET AL
REFERENCES 1. Port FK, Wolfe RA, Mauger EA, et al: JAMA 270:1339, 1993 2. Edwards EB, Bennett LE, Cecka JM: Transplantation 64: 1274, 1997 3. Wolfe RA, Ashby VB, Milford EL, et al: N Engl J Med 341:1725, 1999 4. Laupacis A, Keown P, Pus N, et al: Kidney Int 50:235, 1996 5. Asderakis A, Augustine T, Dyer P, et al: Nephrol Dial Transplant 13:1799, 1998 6. Cosio FG, Alamir A, Yim S, et al: Kidney Int 53:767, 1998 7. Arend SM, Mallat MJ, Westendorp RJ, et al: Nephrol Dial Transplant 12:1672, 1997
T
RANSPLANTATION has been shown to improve survival when compared to maintenance dialysis for patients with end-stage renal disease (ESRD).1–3 In addition, renal transplantation is a cost-effective modality that offers improved quality of life for patients with ESRD.4 There is some evidence that patients who receive a preemptive renal transplant have a survival advantage when compared to patients who receive a renal transplant after a period of maintenance dialysis therapy.5,6 Other studies7 did not find any effect of length of pretransplant dialysis on patient survival. Neither of these studies detected any correlation of waiting time on dialysis and death-censored graft survival. Studies to date have not yet yielded a conclusive answer to these unresolved issues. Thus, we undertook an analysis of the United States Renal Data System Registry (USRDS) to assess the impact of waiting time on posttransplant patient survival and graft survival with and without censoring at death.
METHODS This study was based on data collected by the US Renal Transplant Scientific Registry and supplemented with end-stage renal disease data in the US Renal Data System. The study sample consisted of patients who underwent solitary primary renal transplantation between October 1, 1988 and June 30, 1997. Patients were followed from transplant date until graft loss or death or until the study end date of June 30, 1998. Waiting time on dialysis was calculated from the start of maintenance dialysis treatment to transplant date. Primary study end points included patient death with functioning graft and death-censored graft failure. As an additional endpoint we evaluated chronic renal allograft failure, defined as graft loss after 6 months posttransplant, censored for patient death or graft loss secondary to acute rejection, graft thrombosis, infection,
From the Departments of Medicine, Epidemiology and Surgery, University of Michigan, Ann Arbor, Michigan. Address reprint requests to Bruce Kaplan, MD, The University of Michigan Medical Center, Department of Internal Medicine, 3914 Taubman Center, Box 0364, Ann Arbor, MI 48109-0364.
Fig 1. Relative risk for deathcensored graft loss by primary disease. Diabetes (DM), hypertension (HTN), and glomerulonephritis (GN).
0041-1345/01/$–see front matter PII S0041-1345(00)02387-3
© 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1204
Transplantation Proceedings, 33, 1204–1206 (2001)
DELETERIOUS EFFECT OF WAITING TIME
1205
Fig 2. Relative risk for death with functioning graft by primary disease. Diabetes (DM), hypertension (HTN), and glomerulonephritis (GN). surgical complications, or recurrent disease. Cox proportional hazard regression was used to estimate the independent effect of waiting time on the primary study endpoints while controlling for relevant risk factors. To account for a potentially dominant era effect, the year of transplantation was included as an explanatory covariate in the Cox proportional hazard analysis. Other potential confounding variables studied were: cyclosporine versus tacrolimus treatment; induction versus no induction treatment; recipient age at transplantation; donor age; donor and recipient race, gender, and CMV IgG antibody status; primary cause of ESRD; donor source (cadaveric vs. living); cold and warm ischemia times; HLA mismatch; presensitization (PRA); and delayed graft function. To evaluate the impact of waiting time separately by cause of endstage renal disease, we built an interaction term between these two factors into the Cox proportional hazard model. In this subanalysis, only patients within the three major primary disease groups (glomerulonephritis (GN), hypertension (HTN), and diabetes mellitus (DM) were analyzed.
RESULTS Death-Censored Graft Survival
Increasing waiting time on dialysis was a significant risk factor for death-censored graft loss after renal transplantation (P ⬍ .001) by Cox proportional hazard analysis. Being on dialysis for up to 6 months prior to transplantation conferred a 17% increased risk for death-censored graft loss as compared to preemptive renal transplantation when adjusted for all factors described in the methods. Dialysis treatment for 6 to 12, 12 to 24, and 24 to 36 months prior to renal transplantation conferred a 37%, 55%, and 68% higher risk for censored graft loss, respectively. Beyond 36 months of dialysis there remained a significantly increased risk of censored graft loss as opposed to preemptive transplantation (P ⬍ .001), however, the relative increase beyond 36 months from 68% to 70% to 74% was small and not statistically significant.
Patient Survival
When adjusting for all factors described in the methods, increasing waiting time on dialysis was also a significant risk factor for patient death with functioning graft after renal transplantation (P ⬍ .001). Maintenance dialysis therapy for up to 6 months prior to transplantation did not confer an increased risk for patient death after transplantation as compared to preemptive renal transplantation. However, more than 6 months of dialysis treatment prior to renal transplantation conferred a significant and progressive increase in the relative risk for patient death after transplantation (P ⬍ .001). Dialysis treatment for 6 to 12, 12 to 24, 24 to 36, 36 to 48, and above 48 months prior to renal transplantation conferred a 21%, 28%, 41%, 53%, and 72% increased adjusted risk for censored graft loss, respectively. As shown in Fig 2, there was also a significant increase in the relative risk for patient death with increasing time of pretransplant dialysis for each of the three major ESRD disease groups.
DISCUSSION
The results of our study demonstrate that waiting time on dialysis is a strong risk factor for decreased patient survival as well as decreased death-censored graft survival following renal transplantation. This effect was independent of all other factors in the model (including recipient age, race, original disease, and donor characteristics) and likely reflects a true negative effect of waiting time on dialysis. This negative effect held equally true for patients with systemic diseases (eg, diabetes mellitus) as well as patients with renal specific disease (eg, glomerulonephritis) and thus is unlikely to be due to a longer exposure to a systemic process. It is interesting to note that not only did waiting time incur a
1206
greater relative risk for patient death following renal transplantation, but also conferred a similarly strong negative risk factor for death-censored graft survival. In fact, when patients with death-censored graft survival were further subdivided to exclude those patients with surgical problems, infections, acute rejection, and recurrent disease, a similar trend emerged. Thus, this suggested that waiting time on dialysis also confers an increased relative risk for the development of chronic allograft nephropathy. In summary, waiting time emerges as a strong independent risk factor for increased patient mortality and increased graft failure following renal transplantation.
MEIER-KRIESCHE, PORT, OJO ET AL
REFERENCES 1. Port FK, Wolfe RA, Mauger EA, et al: JAMA 270:1339, 1993 2. Edwards EB, Bennett LE, Cecka JM: Transplantation 64: 1274, 1997 3. Wolfe RA, Ashby VB, Milford EL, et al: N Engl J Med 341:1725, 1999 4. Laupacis A, Keown P, Pus N, et al: Kidney Int 50:235, 1996 5. Asderakis A, Augustine T, Dyer P, et al: Nephrol Dial Transplant 13:1799, 1998 6. Cosio FG, Alamir A, Yim S, et al: Kidney Int 53:767, 1998 7. Arend SM, Mallat MJ, Westendorp RJ, et al: Nephrol Dial Transplant 12:1672, 1997