The cost of kidney transplant over time Background—Kidney transplant improves quality of life and survival compared with dialysis. Despite advances in immunosuppressant regimens and the prevention and treatment of acute rejection, graft survival rates have not improved significantly in the past decade. Although the clinical effectiveness of these regimens has been studied, the impact of changes over time on cost has not. Methods—Costs of kidney transplant were compared between 2 periods demarcated by a programmatic change from cyclosporine (early) to tacrolimus (late) and from nonroutine induction (early) to routine induction (late) therapy in adult patients receiving a first kidney-only transplant in Calgary, Alberta, Canada, in an 8-year period. Results—Complete costs for 3 years after transplant was available for 344 patients, including 161 adult recipients in the early period (April 1, 1998-December 31, 2001) and 183 adult recipients in the late period (January 1, 2002-March 31, 2006). The mean total 3-year cost of transplant for recipients was Can$100 034 in the early period and Can$144 712 in the late period largely attributed to increases in the cost of immunosuppressants (P < .001). Conclusions—Given that the cost of transplant has increased significantly over time, the cost-effectiveness of these and other immunosuppressive regimens should be evaluated carefully. (Progress in Transplantation. 2014;24:257-262) ©2014 NATCO, The Organization for Transplant Professionals doi: http://dx.doi.org/10.7182/pit2014710
K
idney transplant improves quality of life and survival and is associated with lower health care costs than dialysis for patients with end-stage renal disease (ESRD).1-4 Although the outcomes associated with kidney transplant remain better than those of dialysis, during the past decade in Canada, graft survival rates have not increased significantly, despite advances in prevention and treatment of acute rejection.5 Transplant immunosuppressive regimens have changed markedly in the past 10 years, with recent regimens resulting in fewer acute rejection episodes, which may translate into better long-term graft survival.6,7 Tacrolimus, which has a similar mode of action to cyclosporine, may lead to a reduction in steroid use and decreased need for antihypertensive drugs.8 Although clinical outcomes have been studied for these various regimens,6,9,10 the impact on the cost of care, including the cost of immunosuppressive regimens specifically, is uncertain.
Progress in Transplantation, Vol 24, No. 3, September 2014
Lianne Barnieh, PhD, Serdar Yilmaz, MD, PhD, Kevin McLaughlin, MD, PhD, Brenda R. Hemmelgarn, MD, PhD, Scott Klarenbach, MD, MSc, Braden J. Manns, MD, MSc; for the Alberta Kidney Disease Network University of Calgary (LB, SY, KM, BRH, BJM), University of Alberta (SK), Canada Corresponding author: Braden Manns, MD, MSc, Division of Nephrology, Foothills Medical Centre, 1403 29th Street NW, Calgary, Alberta, Canada T2N 2T9 (e-mail: braden.manns @albertahealthservices.ca) To purchase electronic or print reprints, contact: American Association of Critical-Care Nurses 101 Columbia, Aliso Viejo, CA 92656 Phone (800) 899-1712 (ext 532) or (949) 448-7370 (ext 532) Fax (949) 362-2049 E-mail [email protected]
Few studies have systematically analyzed the costs of kidney transplant,2,3,11-16 and in particular the change in costs over time, despite the fact that transplant is a very resource-intensive intervention. Locally, the Southern Alberta Renal Program changed its immunosuppressive regimen from cyclosporine to tacrolimus along with routine induction with daclizumab in January 2002, similar to other regimens found to reduce acute rejection.6 Given this programmatic change in treatment strategy, we assessed whether the cost of kidney transplant had changed in adult patients who received a kidney transplant during the 2 periods, which spanned 8 years. Methods Previously, we compared the cost of deceased donor and living donor transplant in this cohort by using 2 years of follow-up costing data.16 In this article, we expand this analysis by extending the follow-up costing
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Barnieh et al data to 3 years after transplant and comparing the cost of transplant between patients who received a transplant between April 1, 1998 and December 31, 2001 (early period) and patients who received a kidney transplant between January 1, 2002 and March 31, 2006 (late period). This division of the data reflects changes in the protocol of immunosuppressants at this regional transplant center. Setting and Patients The research ethics board at the University of Calgary approved the study. The Southern Alberta Transplant program provides care to all patients seeking a transplant or wishing to donate in the southern part of the province of Alberta through a single location in Calgary, Alberta (catchment population, 1.5 million). The transplant program offers living related, living unrelated, and deceased donor kidney transplant and also offers pancreas transplant for eligible patients with diabetes. During the study period, the Southern Alberta Transplant Program did not transplant kidneys from donors after cardiac death. Maintenance immunosuppression is done with a calcineurin inhibitor, antimetabolite, and prednisone, modified for individual clinical needs. During the period of this study, the antimetabolite of choice was mycophenolic acid; however, on January 1, 2002, the calcineurin inhibitor of choice changed from cyclosporine to tacrolimus. A change from nonroutine induction therapy to routine induction therapy with a monoclonal antibody against CD25 coincided with this. The induction therapy agent switched from basiliximab to daclizumab in 2001, which was given at a dose of 1 mg/kg (rounded up to nearest 25 mg to a max of 100 mg) given on day 0 and day 14. For patients in whom acute rejection developed throughout the study (98% of whom had a biopsy; including 11% who had antibody-mediated rejection), treatment was standardized on the basis of the severity of rejection and tailored to the clinical and histological findings. During this study period, anti-CD20 treatment was not used. Induction with antithymocyte globulin was reserved for patients who were considered to have high immunologic risk or who had delayed graft function develop, and treatment of such patients did not change over time. As in our prior study,16 the electronic clinical database for the Southern Alberta Transplant Program (ALTRA) was used to identify all patients at least 18 years old who were recipients of a first kidney-only transplant between April 1, 1998, and March 31, 2006, in the Southern Alberta Transplant program. Recipients of combined kidney/pancreas transplants were excluded.
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Data Collection and Sources Data for recipients and donors was obtained from 3 separate data sources: ALTRA, which collects data for the Southern Alberta Transplant Program; Alberta Health and Wellness, the provincial provider of universally funded health care; and the Alberta Health Services (formerly Calgary Health Region) corporate database, which includes detailed microcosting data for all encounters within the local health region. Direct costs for the recipient were examined for 4 distinct periods: transplant admission, remainder of year 1, year 2, and year 3 after transplant. Recipients’ demographic and clinical data, as well as medication use, laboratory tests, and pretransplant diagnostic imaging were obtained from ALTRA. Other health resource utilization data, including outpatient services (day surgery, ambulatory care, and emergency department visits), diagnostic imaging, hospitalizations, and physician services, were obtained from Alberta Health and Wellness, by using methods described previously.16 Measuring Costs This study took the perspective of the health care payer and included only costs directly related to health care: outpatient services (day surgery, ambulatory care, emergency department visits), posttransplant diagnostic imaging, hospitalizations, physicians services, medications, and laboratory tests. Societal costs, including time and travel costs, as well as costs related to lost productivity, were excluded as information on patients’ activities before or after hospital discharge were not available. In the Canadian health care system, provincial governments are the sole funders of hospitals and physician services for hospitalized patients. The health care costs reported in this study reflect the true costs of care, rather than prices or charges, as closely as can be approximated. All costs were inflated to and reported in 2010 Canadian dollars (Can$1 = US$1), using the Consumer Price Index (Statistics Canada). Censoring Costs As the primary objective of this study was to describe costs over time, patients with a failed graft (n = 17) during the study remained in the analysis. Recipients who moved out of province (n = 6) or who died with a functioning graft (n = 14) were removed from the analysis in subsequent time periods. Although a programmatic change in the management of patients occurred during this study period, some patients were managed with different agents, or a combination of 2 agents. As such, sensitivity analyses considered year 1 costs for those who received, irrespective of period, exclusively cyclosporine (n=105) or exclusively
Progress in Transplantation, Vol 24, No. 3, September 2014
The cost of kidney transplant over time Table 1 Baseline characteristics of recipients, by period Characteristic
1998-2001a 2002-2006a (n = 161) (n = 183)
Age, mean (SD), y
48.3 (12.4) 47.5 (13.8)
Male sex, No. (%) of recipients
99 (61.5)
102 (55.7)
Dialysis, No. (%) of recipients Total Hemodialysis Peritoneal dialysis
144 (89.4) 100 (69.4) 44 (30.6)
159 (86.9) 111 (69.8) 48 (30.2)
Duration of dialysis, No. (%) of recipients Pre-emptive 0-12 months >12 months
17 (10.6) 37 (23.0) 107 (66.5)
24 (13.1) 32 (17.5) 127 (69.4)
Cause of end-stage renal disease, No. (%) of recipients Glomerulonephritis Diabetes mellitus Polycystic kidney disease Hypertensive Reflux Other
64 (39.8) 24 (14.9) 18 (11.2) 13 (8.1) 11 (6.8) 31 (19.3)
Time on transplant list, mean (SD), y
1.3 (1.0)
2.5 (2.0)
Total HLA matches, median (interquartile range)
1 (0-3)
1 (1-3)
Deceased donor transplant, No. (%) of recipients
107 (66.5)
73 (39.9) 35 (19.1) 21 (11.5) 6 (3.3) 9 (4.9) 39 (21.3)
115 (62.8)
a Defined
as calendar years, April 1, 1998, through December 31, 2001; January 1, 2002, through March 31, 2006.
tacrolimus (n = 182) and among those who received induction therapy, those who received exclusively basiliximab (n = 70) versus daclizumab (n = 115). Sensitivity analyses also were done, censoring costs of graft failure and examining costs only for those with a functioning graft 3 years after transplant. Statistical Analysis We used descriptive statistics including the means and 95% confidence intervals (CIs) for normally distributed data and medians with interquartile ranges for skewed variables. Given the nonnormal distribution of costs, we sought methods to enable comparisons of mean costs because those results are more easily interpretable. Nonparametric bootstrap estimates were used to derive 95% CIs and mean cost differences between the early and late period. Bootstrapping does not rely on parametric assumptions about the underlying distribution of data and uses 1000 bias-corrected bootstrap replications that are based on sampling with replacement from the original data. The χ2 test was used to compare differences in proportions. Results Patients Four hundred seventy-five patients received a kidney transplant between April 1, 1998 and March 31, 2006.
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Table 2 Recipient outcomes, by perioda 1998-2001 (n = 161)
2002-2006 (n = 183)
Hospital length of stay for transplant, median (interquartile range), days
8 (6-12)
8 (7-11)
Delayed graft function, No. (%) of recipients
12 (7.5)
15 (8.2)
Any acute rejection event, No. (%) of recipients Year 1 Year 2 Year 3
45 (28.0) 10 (6.4) 3 (2.0)
37 (20.2) 12 (6.7) 5 (2.8)
Any cytomegalovirus infection, No. (%) of recipients Year 1 Year 2 Year 3
21 (13.0) 2 (1.3) 1 (0.7)
30 (16.4) 0 (0) 0 (0)
Total graft failure,b No. (%) of recipients Year 1 Year 2 Year 3
9 (5.6) 5 (3.2) 3 (2.0)
7 (3.8) 5 (2.8) 2 (1.1)
Outcome
a Percent
values are percentage of population alive at the start of the related follow-up period as follows: early–year 1, n = 161; year 2, n = 157; year 3, n = 153; late–year 1, n = 183; year 2, n = 180; year 3, n = 178. b Includes recipients who died with a functioning graft.
Of these, 47 received simultaneous kidney/pancreas transplants, 44 were retransplants, 13 had no costs available from the Alberta Health and Wellness, 14 did not have a valid personal health number for linkage with the provincial database, and 13 did not have complete follow-up data available. Of the 344 included patients, 161 (46.8%) received a kidney transplant in the early period (April 1, 1998, through December 31, 2001) and 183 (53.2%) received a kidney in the late period (January 1, 2002, through March 31, 2006). Baseline Characteristics Recipients’ baseline demographic and clinical characteristics are presented in Table 1. Mean age for patients in both time periods was similar, as were the proportion of patients undergoing dialysis, the method of dialysis, and the cause of ESRD. The time spent on the transplant waiting list was longer for recipients in the late period than for recipients in the early period. Recipient Outcomes Recipients’ clinical outcomes during the 2 periods are presented in Table 2. Hospital length of stay for transplant remained unchanged in the 2 periods. Other clinical characteristics appeared similar for both periods. The number of patients with an episode of acute rejection in year 1 was 45 (28.0%) for the early period and 37 (20.2%) for the late period (P = .08). Rates of
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Barnieh et al Table 3 Costs of kidney transplant, by period, from index transplant through 3 years of follow-up Cost, mean (95% CI), 2010 Can$ Recipient
Early period
Late period
Initial admission for transplant
19 890 (18 463-21 316)
25 603 (21 583-29 623)
Remainder year 1
39 653 (35 790-43 515)
72 980 (68 058-77 903)
Year 2
22 610 (19 458-26 793)
24 857 (21 754-27 961)
Year 3
20 081 (16 164-23 998)
22 682 (18 800-26 565)
Total
100 034 144 712 (90 650-109 419) (134 267-155 157)
total graft failure did not differ significantly between the early and late period; the 3-year graft survival (accounting for patients who died with a functioning graft) was 89.4% for the early period and 92.3% for the late period (P = .73). Over an extended follow-up of 7 years, mean graft survival was 6.1 years for the early period and 6.2 years for the late period (P = .57). Costs The unadjusted mean costs for the total 3 years were Can$144 712 for the late period and Can$100 034 for the early period, with a mean difference in costs between the 2 periods of Can$45 011 (95%CI, Can$30 985-Can$59 037, P < .001; Table 3). The difference in total 3-year costs was largely due to a difference in costs during the first year. Figure 1 shows the mean costs for recipients by type of resource use, year after transplant, and period. Outpatient immunosuppressants represented the largest category of resource utilization. During the first year after transplant, immunosuppressant costs were much greater in the late period than in the early period (Can$35 452 vs Can$15 247; mean difference Can$20 306, 95% CI, Can$16 979-Can$26 633; P < .001). This increase in cost was largely driven by more frequent use of induction therapy, specifically the more frequent use of the more expensive induction agent, daclizumab (see sensitivity analysis later). Although costs were higher for anti-infective agents during the first year in the late period, the magnitude of those costs was modest (Can$1635 vs Can$1000), and the mean difference in anti-infective costs during the first year was not statistically significant (mean difference, Can$628; 95% CI, Can$258-Can$1515, P = .17). Relative contributions of each medication as a percentage of overall medication costs for the early and late period for the first year are shown in Figure 2. No significant difference between the early period and the late period was noted for costs of either
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immunosuppressants or anti-infective agents in years 2 and 3. Sensitivity Analyses First-year costs, including the initial admission for transplant and 12 months of follow-up, were significantly different for patients exclusively treated with tacrolimus (Can$94 221, n = 182) versus cyclosporine (Can$56 038, n = 105), with a significant mean difference between tacrolimus and cyclosporine in costs (mean, Can$38 267; 95% CI, Can$30 577-Can$45 958; P < .001). Among those who received induction therapy (as induction therapy was not routine throughout the study period), first-year costs differed for the 2 regimens: mean costs for year 1 were Can$104 537 for those who received daclizumab (n = 115) compared with Can$63 045 for those who received basiliximab (n = 70); the mean difference between daclizumab and basiliximab differed significantly (mean, Can$46 616; 95% CI, Can$31 986-Can$51 246; P < .001). When the overall costs are examined, with costs at graft failure censored (ie, excluding dialysis costs), overall costs were significantly different between the late period (Can$114 470) and the early period (Can$74 313), with a mean difference of Can$40344 (95% CI, Can$31605Can$49 084; P < .001). When examining only costs for those alive with a functioning graft at 3 years after transplant, the difference in overall cost remained significant: total 3-year costs were Can$133 419 in the late period (n = 169) and Can$88 264 in the early period (n = 144), with a mean difference between the early and late periods of Can$45 341 (95% CI, Can$37 376Can$53 307; P < .001). Discussion Our study showed increased overall 3-year costs of transplant corresponding to a change in the immunosuppressive regimen given to recipients. The increase in costs in the late period was largely driven by outpatient medications during the first year, which reflects the protocol that has been in use in our local transplant program and many others.17 Although this same protocol was shown to have superior outcomes in 1 randomized controlled trial6 with limited events and follow-up, it remains to be determined whether this regimen leads to increased graft survival and whether it justifies the increased costs for immunosuppressants. Trial data have demonstrated the superiority of a tacrolimus regimen in clinical outcomes,6,8,18 although the costs have not been previously reported. Although we report the clinical outcomes of the 2 periods, which presumably is in part related to the immunosuppressive regimens used, the objective of our study was to examine cost differences over time. Other increases in costs between the 2 periods were observed in outpatient services; those cost increases may have been due
Progress in Transplantation, Vol 24, No. 3, September 2014
The cost of kidney transplant over time 90 000 80 000 70 000
Cost, 2010 Can$
60 000 50 000 40 000 30 000 20 000 10 000 0 Year 1 early
Year 1 late
Year 2 early
Outpatient anti-infectives Inpatient
Year 2 late
Year 3 early
Outpatient immunosuppressants
Physician
Year 3 late
Outpatient servicesa
Outpatient diagnostic imaging
Outpatient laboratory
Figure 1 Mean recipient costs by type of resource utilization, time from index transplant, and period (2010 Can$). a Outpatient
services include the cost of outpatient transplant clinic visits and services that were not inpatient such as dialysis.
to increased use of dialysis and increased use of day medicine facilities for infusions. The changes in protocol observed in this study are consistent with what is occurring at other centers.17 The resulting changes in cost are due to the change in protocol, from cyclosporine to tacrolimus, and the use of daclizumab as part of a standard induction protocol. Part of the increase in costs for daclizumab may be attributed to its delivery, as it involves 4 to 5 weekly doses, all but 2 of which are given as an outpatient; this was apparent in the increased costs for daclizumab compared with basiliximab.
100 % of overall medication costs
90 80 70 60 50 40 30 20 10 0 Year 1 early period Other Cyclosporine
Year 1 late period Anti-infectives Basiliximab
Daclixumab Tacrolimus
Figure 2 Relative contributions of medications as a percentage of overall medication costs in early and late period, year 1 (2010 Can$).
Progress in Transplantation, Vol 24, No. 3, September 2014
Limitations The costing data used in this study from the early period date from almost 15 years ago. However, transplant medications in the latter period at our center have not changed significantly since 2001. Although the generalizability of costs from one center to another may be limited, given the standardization of regimens, we think that any differences are likely to hold across similar health care systems. We considered the cost of brand-name immunosuppressant agents (ie, cyclosporine and mycophenolate mofetil), rather than
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Barnieh et al the generic price, because the generic medications were available only after this study was completed. However, if we had considered lower costs for cyclosporine, this would have further increased the magnitude of difference in costs between the early and late period. Finally, although the increase in costs was mostly due to daclizumab, which is no longer in use, the emergence of other high-cost drugs in transplant continues, and the results of this analysis continue to be relevant. Summary This study is the first that we know of to look at the differences in the cost of kidney transplant during the past 15 years. Although some of the medications are no longer in use, we did notice a significant increase in costs, without significant improvements in clinical outcomes, for patients treated in the later observation period. Unlike many areas in medicine, where care patterns change slowly, patterns of transplant practice tend to change quickly. Our study suggests that these changes have had significant economic implications for programs—the cost-effectiveness of current treatment strategies should be examined while future trials of new immunosuppressive regimens should consider the impact on both relevant outcomes and costs. Financial Disclosures Lianne Barnieh is supported by a Health Research Fellowship from Alberta Innovates-Health Solutions (AI-HS). Scott Klarenbach is supported by Population Health Investigator Awards from AI-HS, while Braden Manns is supported by a Health Scholar award from AI-HS. Brenda Hemmelgarn is also supported by the Roy and Vi Baay Chair in Kidney Research.
References 1. Landreneau K, Lee K, Landreneau MD. Quality of life in patients undergoing hemodialysis and renal transplantation: a
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meta-analytic review. Nephrol Nurs J. 2010;37(1):37-44. 2. Laupacis A, Keown P, Pus N, et al. A study of the quality of life and cost-utility of renal transplantation. Kidney Int. 1996; 50(1):235-242. 3. de Wit G, Ramsteijn PG, de Charro FT. Economic evaluation of end stage renal disease treatment. Health Policy. 1998;44(3): 215-232. 4. Matas AJ, Gillingham KJ, Humar A, et al. 2202 kidney transplant recipients with 10 years of graft function: what happens next? Am J Transplant. 2008;8(11):2410-2419. 5. Canadian Institute for Health Information. Canadian Organ Replacement Register Annual Report: Treatment of End-Stage Organ Failure in Canada, 2001 to 2010. Ottawa, ON:CIHI; 2011. 6. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357(25):2562-2575. 7. Meier-Kreische HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant. 2004;4(3):378-383. 8. Knoll GA, Bell RC. Tacrolimus versus cyclosporine for immunosuppression in renal transplantation: meta-analysis of randomised trials. BMJ. 1999;318(7191):1104-1107. 9. Goldfarb-Rumyantzev AS, Smith L, Shihab FS, et al. Role of maintenance immunosuppressive regimen in kidney transplant outcome. Clin J Am Soc Nephrol. 2006;1(3):563-574. 10. Guerra G, Ciancio G, Gaynor JJ, et al. Randomized trial of immunosuppressive regiments in renal transplantation. J Am Soc Nephrol. 2011;22(9):1758-1768. 11. Eggers PW, Kucken LE. Cost issues in transplantation. Surg Clin North Am. 1994;74(5):1259-1267. 12. Pace KT, Dyer SJ, Phan V, et al. Laparoscopic v open donor nephrectomy: a cost-utility analysis of the initial experience at a tertiary-care center. J Endourol. 2002;16(7):495-508. 13. Levy AR, Sobolev B, James D, et al. The costs of change: direct medical costs of solid organ transplantation in British Columbia, Canada, 1995-2003. Value Health. 2009;12(2):282-292. 14. Howard K, Salkeld G, White S, et al. The cost-effectiveness of increasing kidney transplantation and home-based dialysis. Nephrology. 2009;14(1):123-132. 15. Erek E, Sever MS, Akoglu E, et al. Cost of renal replacement therapy in Turkey. Nephrology. 2004;9(1):33-38. 16. Barnieh L, Manns BJ, Klarenbach S, McLaughlin K, Yilmaz S, Hemmelgarn BR. A description of the costs of living and standard criteria deceased donor kidney transplantation. Am J Transplant. 2011;11(3):478-488. 17. Knoll G. Trends in kidney transplantation over the past decade. Drugs. 2008;68(suppl 1):3-10. 18. Bowman LJ, Brennan DC. The role of tacrolimus in renal transplantation. Expert Opin Pharmacother. 2008;9(4):635-643.
Progress in Transplantation, Vol 24, No. 3, September 2014
K
idney transplant improves quality of life and survival and is associated with lower health care costs than dialysis for patients with end-stage renal disease (ESRD).1-4 Although the outcomes associated with kidney transplant remain better than those of dialysis, during the past decade in Canada, graft survival rates have not increased significantly, despite advances in prevention and treatment of acute rejection.5 Transplant immunosuppressive regimens have changed markedly in the past 10 years, with recent regimens resulting in fewer acute rejection episodes, which may translate into better long-term graft survival.6,7 Tacrolimus, which has a similar mode of action to cyclosporine, may lead to a reduction in steroid use and decreased need for antihypertensive drugs.8 Although clinical outcomes have been studied for these various regimens,6,9,10 the impact on the cost of care, including the cost of immunosuppressive regimens specifically, is uncertain.
Progress in Transplantation, Vol 24, No. 3, September 2014
Lianne Barnieh, PhD, Serdar Yilmaz, MD, PhD, Kevin McLaughlin, MD, PhD, Brenda R. Hemmelgarn, MD, PhD, Scott Klarenbach, MD, MSc, Braden J. Manns, MD, MSc; for the Alberta Kidney Disease Network University of Calgary (LB, SY, KM, BRH, BJM), University of Alberta (SK), Canada Corresponding author: Braden Manns, MD, MSc, Division of Nephrology, Foothills Medical Centre, 1403 29th Street NW, Calgary, Alberta, Canada T2N 2T9 (e-mail: braden.manns @albertahealthservices.ca) To purchase electronic or print reprints, contact: American Association of Critical-Care Nurses 101 Columbia, Aliso Viejo, CA 92656 Phone (800) 899-1712 (ext 532) or (949) 448-7370 (ext 532) Fax (949) 362-2049 E-mail [email protected]
Few studies have systematically analyzed the costs of kidney transplant,2,3,11-16 and in particular the change in costs over time, despite the fact that transplant is a very resource-intensive intervention. Locally, the Southern Alberta Renal Program changed its immunosuppressive regimen from cyclosporine to tacrolimus along with routine induction with daclizumab in January 2002, similar to other regimens found to reduce acute rejection.6 Given this programmatic change in treatment strategy, we assessed whether the cost of kidney transplant had changed in adult patients who received a kidney transplant during the 2 periods, which spanned 8 years. Methods Previously, we compared the cost of deceased donor and living donor transplant in this cohort by using 2 years of follow-up costing data.16 In this article, we expand this analysis by extending the follow-up costing
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Barnieh et al data to 3 years after transplant and comparing the cost of transplant between patients who received a transplant between April 1, 1998 and December 31, 2001 (early period) and patients who received a kidney transplant between January 1, 2002 and March 31, 2006 (late period). This division of the data reflects changes in the protocol of immunosuppressants at this regional transplant center. Setting and Patients The research ethics board at the University of Calgary approved the study. The Southern Alberta Transplant program provides care to all patients seeking a transplant or wishing to donate in the southern part of the province of Alberta through a single location in Calgary, Alberta (catchment population, 1.5 million). The transplant program offers living related, living unrelated, and deceased donor kidney transplant and also offers pancreas transplant for eligible patients with diabetes. During the study period, the Southern Alberta Transplant Program did not transplant kidneys from donors after cardiac death. Maintenance immunosuppression is done with a calcineurin inhibitor, antimetabolite, and prednisone, modified for individual clinical needs. During the period of this study, the antimetabolite of choice was mycophenolic acid; however, on January 1, 2002, the calcineurin inhibitor of choice changed from cyclosporine to tacrolimus. A change from nonroutine induction therapy to routine induction therapy with a monoclonal antibody against CD25 coincided with this. The induction therapy agent switched from basiliximab to daclizumab in 2001, which was given at a dose of 1 mg/kg (rounded up to nearest 25 mg to a max of 100 mg) given on day 0 and day 14. For patients in whom acute rejection developed throughout the study (98% of whom had a biopsy; including 11% who had antibody-mediated rejection), treatment was standardized on the basis of the severity of rejection and tailored to the clinical and histological findings. During this study period, anti-CD20 treatment was not used. Induction with antithymocyte globulin was reserved for patients who were considered to have high immunologic risk or who had delayed graft function develop, and treatment of such patients did not change over time. As in our prior study,16 the electronic clinical database for the Southern Alberta Transplant Program (ALTRA) was used to identify all patients at least 18 years old who were recipients of a first kidney-only transplant between April 1, 1998, and March 31, 2006, in the Southern Alberta Transplant program. Recipients of combined kidney/pancreas transplants were excluded.
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Data Collection and Sources Data for recipients and donors was obtained from 3 separate data sources: ALTRA, which collects data for the Southern Alberta Transplant Program; Alberta Health and Wellness, the provincial provider of universally funded health care; and the Alberta Health Services (formerly Calgary Health Region) corporate database, which includes detailed microcosting data for all encounters within the local health region. Direct costs for the recipient were examined for 4 distinct periods: transplant admission, remainder of year 1, year 2, and year 3 after transplant. Recipients’ demographic and clinical data, as well as medication use, laboratory tests, and pretransplant diagnostic imaging were obtained from ALTRA. Other health resource utilization data, including outpatient services (day surgery, ambulatory care, and emergency department visits), diagnostic imaging, hospitalizations, and physician services, were obtained from Alberta Health and Wellness, by using methods described previously.16 Measuring Costs This study took the perspective of the health care payer and included only costs directly related to health care: outpatient services (day surgery, ambulatory care, emergency department visits), posttransplant diagnostic imaging, hospitalizations, physicians services, medications, and laboratory tests. Societal costs, including time and travel costs, as well as costs related to lost productivity, were excluded as information on patients’ activities before or after hospital discharge were not available. In the Canadian health care system, provincial governments are the sole funders of hospitals and physician services for hospitalized patients. The health care costs reported in this study reflect the true costs of care, rather than prices or charges, as closely as can be approximated. All costs were inflated to and reported in 2010 Canadian dollars (Can$1 = US$1), using the Consumer Price Index (Statistics Canada). Censoring Costs As the primary objective of this study was to describe costs over time, patients with a failed graft (n = 17) during the study remained in the analysis. Recipients who moved out of province (n = 6) or who died with a functioning graft (n = 14) were removed from the analysis in subsequent time periods. Although a programmatic change in the management of patients occurred during this study period, some patients were managed with different agents, or a combination of 2 agents. As such, sensitivity analyses considered year 1 costs for those who received, irrespective of period, exclusively cyclosporine (n=105) or exclusively
Progress in Transplantation, Vol 24, No. 3, September 2014
The cost of kidney transplant over time Table 1 Baseline characteristics of recipients, by period Characteristic
1998-2001a 2002-2006a (n = 161) (n = 183)
Age, mean (SD), y
48.3 (12.4) 47.5 (13.8)
Male sex, No. (%) of recipients
99 (61.5)
102 (55.7)
Dialysis, No. (%) of recipients Total Hemodialysis Peritoneal dialysis
144 (89.4) 100 (69.4) 44 (30.6)
159 (86.9) 111 (69.8) 48 (30.2)
Duration of dialysis, No. (%) of recipients Pre-emptive 0-12 months >12 months
17 (10.6) 37 (23.0) 107 (66.5)
24 (13.1) 32 (17.5) 127 (69.4)
Cause of end-stage renal disease, No. (%) of recipients Glomerulonephritis Diabetes mellitus Polycystic kidney disease Hypertensive Reflux Other
64 (39.8) 24 (14.9) 18 (11.2) 13 (8.1) 11 (6.8) 31 (19.3)
Time on transplant list, mean (SD), y
1.3 (1.0)
2.5 (2.0)
Total HLA matches, median (interquartile range)
1 (0-3)
1 (1-3)
Deceased donor transplant, No. (%) of recipients
107 (66.5)
73 (39.9) 35 (19.1) 21 (11.5) 6 (3.3) 9 (4.9) 39 (21.3)
115 (62.8)
a Defined
as calendar years, April 1, 1998, through December 31, 2001; January 1, 2002, through March 31, 2006.
tacrolimus (n = 182) and among those who received induction therapy, those who received exclusively basiliximab (n = 70) versus daclizumab (n = 115). Sensitivity analyses also were done, censoring costs of graft failure and examining costs only for those with a functioning graft 3 years after transplant. Statistical Analysis We used descriptive statistics including the means and 95% confidence intervals (CIs) for normally distributed data and medians with interquartile ranges for skewed variables. Given the nonnormal distribution of costs, we sought methods to enable comparisons of mean costs because those results are more easily interpretable. Nonparametric bootstrap estimates were used to derive 95% CIs and mean cost differences between the early and late period. Bootstrapping does not rely on parametric assumptions about the underlying distribution of data and uses 1000 bias-corrected bootstrap replications that are based on sampling with replacement from the original data. The χ2 test was used to compare differences in proportions. Results Patients Four hundred seventy-five patients received a kidney transplant between April 1, 1998 and March 31, 2006.
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Table 2 Recipient outcomes, by perioda 1998-2001 (n = 161)
2002-2006 (n = 183)
Hospital length of stay for transplant, median (interquartile range), days
8 (6-12)
8 (7-11)
Delayed graft function, No. (%) of recipients
12 (7.5)
15 (8.2)
Any acute rejection event, No. (%) of recipients Year 1 Year 2 Year 3
45 (28.0) 10 (6.4) 3 (2.0)
37 (20.2) 12 (6.7) 5 (2.8)
Any cytomegalovirus infection, No. (%) of recipients Year 1 Year 2 Year 3
21 (13.0) 2 (1.3) 1 (0.7)
30 (16.4) 0 (0) 0 (0)
Total graft failure,b No. (%) of recipients Year 1 Year 2 Year 3
9 (5.6) 5 (3.2) 3 (2.0)
7 (3.8) 5 (2.8) 2 (1.1)
Outcome
a Percent
values are percentage of population alive at the start of the related follow-up period as follows: early–year 1, n = 161; year 2, n = 157; year 3, n = 153; late–year 1, n = 183; year 2, n = 180; year 3, n = 178. b Includes recipients who died with a functioning graft.
Of these, 47 received simultaneous kidney/pancreas transplants, 44 were retransplants, 13 had no costs available from the Alberta Health and Wellness, 14 did not have a valid personal health number for linkage with the provincial database, and 13 did not have complete follow-up data available. Of the 344 included patients, 161 (46.8%) received a kidney transplant in the early period (April 1, 1998, through December 31, 2001) and 183 (53.2%) received a kidney in the late period (January 1, 2002, through March 31, 2006). Baseline Characteristics Recipients’ baseline demographic and clinical characteristics are presented in Table 1. Mean age for patients in both time periods was similar, as were the proportion of patients undergoing dialysis, the method of dialysis, and the cause of ESRD. The time spent on the transplant waiting list was longer for recipients in the late period than for recipients in the early period. Recipient Outcomes Recipients’ clinical outcomes during the 2 periods are presented in Table 2. Hospital length of stay for transplant remained unchanged in the 2 periods. Other clinical characteristics appeared similar for both periods. The number of patients with an episode of acute rejection in year 1 was 45 (28.0%) for the early period and 37 (20.2%) for the late period (P = .08). Rates of
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Barnieh et al Table 3 Costs of kidney transplant, by period, from index transplant through 3 years of follow-up Cost, mean (95% CI), 2010 Can$ Recipient
Early period
Late period
Initial admission for transplant
19 890 (18 463-21 316)
25 603 (21 583-29 623)
Remainder year 1
39 653 (35 790-43 515)
72 980 (68 058-77 903)
Year 2
22 610 (19 458-26 793)
24 857 (21 754-27 961)
Year 3
20 081 (16 164-23 998)
22 682 (18 800-26 565)
Total
100 034 144 712 (90 650-109 419) (134 267-155 157)
total graft failure did not differ significantly between the early and late period; the 3-year graft survival (accounting for patients who died with a functioning graft) was 89.4% for the early period and 92.3% for the late period (P = .73). Over an extended follow-up of 7 years, mean graft survival was 6.1 years for the early period and 6.2 years for the late period (P = .57). Costs The unadjusted mean costs for the total 3 years were Can$144 712 for the late period and Can$100 034 for the early period, with a mean difference in costs between the 2 periods of Can$45 011 (95%CI, Can$30 985-Can$59 037, P < .001; Table 3). The difference in total 3-year costs was largely due to a difference in costs during the first year. Figure 1 shows the mean costs for recipients by type of resource use, year after transplant, and period. Outpatient immunosuppressants represented the largest category of resource utilization. During the first year after transplant, immunosuppressant costs were much greater in the late period than in the early period (Can$35 452 vs Can$15 247; mean difference Can$20 306, 95% CI, Can$16 979-Can$26 633; P < .001). This increase in cost was largely driven by more frequent use of induction therapy, specifically the more frequent use of the more expensive induction agent, daclizumab (see sensitivity analysis later). Although costs were higher for anti-infective agents during the first year in the late period, the magnitude of those costs was modest (Can$1635 vs Can$1000), and the mean difference in anti-infective costs during the first year was not statistically significant (mean difference, Can$628; 95% CI, Can$258-Can$1515, P = .17). Relative contributions of each medication as a percentage of overall medication costs for the early and late period for the first year are shown in Figure 2. No significant difference between the early period and the late period was noted for costs of either
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immunosuppressants or anti-infective agents in years 2 and 3. Sensitivity Analyses First-year costs, including the initial admission for transplant and 12 months of follow-up, were significantly different for patients exclusively treated with tacrolimus (Can$94 221, n = 182) versus cyclosporine (Can$56 038, n = 105), with a significant mean difference between tacrolimus and cyclosporine in costs (mean, Can$38 267; 95% CI, Can$30 577-Can$45 958; P < .001). Among those who received induction therapy (as induction therapy was not routine throughout the study period), first-year costs differed for the 2 regimens: mean costs for year 1 were Can$104 537 for those who received daclizumab (n = 115) compared with Can$63 045 for those who received basiliximab (n = 70); the mean difference between daclizumab and basiliximab differed significantly (mean, Can$46 616; 95% CI, Can$31 986-Can$51 246; P < .001). When the overall costs are examined, with costs at graft failure censored (ie, excluding dialysis costs), overall costs were significantly different between the late period (Can$114 470) and the early period (Can$74 313), with a mean difference of Can$40344 (95% CI, Can$31605Can$49 084; P < .001). When examining only costs for those alive with a functioning graft at 3 years after transplant, the difference in overall cost remained significant: total 3-year costs were Can$133 419 in the late period (n = 169) and Can$88 264 in the early period (n = 144), with a mean difference between the early and late periods of Can$45 341 (95% CI, Can$37 376Can$53 307; P < .001). Discussion Our study showed increased overall 3-year costs of transplant corresponding to a change in the immunosuppressive regimen given to recipients. The increase in costs in the late period was largely driven by outpatient medications during the first year, which reflects the protocol that has been in use in our local transplant program and many others.17 Although this same protocol was shown to have superior outcomes in 1 randomized controlled trial6 with limited events and follow-up, it remains to be determined whether this regimen leads to increased graft survival and whether it justifies the increased costs for immunosuppressants. Trial data have demonstrated the superiority of a tacrolimus regimen in clinical outcomes,6,8,18 although the costs have not been previously reported. Although we report the clinical outcomes of the 2 periods, which presumably is in part related to the immunosuppressive regimens used, the objective of our study was to examine cost differences over time. Other increases in costs between the 2 periods were observed in outpatient services; those cost increases may have been due
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The cost of kidney transplant over time 90 000 80 000 70 000
Cost, 2010 Can$
60 000 50 000 40 000 30 000 20 000 10 000 0 Year 1 early
Year 1 late
Year 2 early
Outpatient anti-infectives Inpatient
Year 2 late
Year 3 early
Outpatient immunosuppressants
Physician
Year 3 late
Outpatient servicesa
Outpatient diagnostic imaging
Outpatient laboratory
Figure 1 Mean recipient costs by type of resource utilization, time from index transplant, and period (2010 Can$). a Outpatient
services include the cost of outpatient transplant clinic visits and services that were not inpatient such as dialysis.
to increased use of dialysis and increased use of day medicine facilities for infusions. The changes in protocol observed in this study are consistent with what is occurring at other centers.17 The resulting changes in cost are due to the change in protocol, from cyclosporine to tacrolimus, and the use of daclizumab as part of a standard induction protocol. Part of the increase in costs for daclizumab may be attributed to its delivery, as it involves 4 to 5 weekly doses, all but 2 of which are given as an outpatient; this was apparent in the increased costs for daclizumab compared with basiliximab.
100 % of overall medication costs
90 80 70 60 50 40 30 20 10 0 Year 1 early period Other Cyclosporine
Year 1 late period Anti-infectives Basiliximab
Daclixumab Tacrolimus
Figure 2 Relative contributions of medications as a percentage of overall medication costs in early and late period, year 1 (2010 Can$).
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Limitations The costing data used in this study from the early period date from almost 15 years ago. However, transplant medications in the latter period at our center have not changed significantly since 2001. Although the generalizability of costs from one center to another may be limited, given the standardization of regimens, we think that any differences are likely to hold across similar health care systems. We considered the cost of brand-name immunosuppressant agents (ie, cyclosporine and mycophenolate mofetil), rather than
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Barnieh et al the generic price, because the generic medications were available only after this study was completed. However, if we had considered lower costs for cyclosporine, this would have further increased the magnitude of difference in costs between the early and late period. Finally, although the increase in costs was mostly due to daclizumab, which is no longer in use, the emergence of other high-cost drugs in transplant continues, and the results of this analysis continue to be relevant. Summary This study is the first that we know of to look at the differences in the cost of kidney transplant during the past 15 years. Although some of the medications are no longer in use, we did notice a significant increase in costs, without significant improvements in clinical outcomes, for patients treated in the later observation period. Unlike many areas in medicine, where care patterns change slowly, patterns of transplant practice tend to change quickly. Our study suggests that these changes have had significant economic implications for programs—the cost-effectiveness of current treatment strategies should be examined while future trials of new immunosuppressive regimens should consider the impact on both relevant outcomes and costs. Financial Disclosures Lianne Barnieh is supported by a Health Research Fellowship from Alberta Innovates-Health Solutions (AI-HS). Scott Klarenbach is supported by Population Health Investigator Awards from AI-HS, while Braden Manns is supported by a Health Scholar award from AI-HS. Brenda Hemmelgarn is also supported by the Roy and Vi Baay Chair in Kidney Research.
References 1. Landreneau K, Lee K, Landreneau MD. Quality of life in patients undergoing hemodialysis and renal transplantation: a
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meta-analytic review. Nephrol Nurs J. 2010;37(1):37-44. 2. Laupacis A, Keown P, Pus N, et al. A study of the quality of life and cost-utility of renal transplantation. Kidney Int. 1996; 50(1):235-242. 3. de Wit G, Ramsteijn PG, de Charro FT. Economic evaluation of end stage renal disease treatment. Health Policy. 1998;44(3): 215-232. 4. Matas AJ, Gillingham KJ, Humar A, et al. 2202 kidney transplant recipients with 10 years of graft function: what happens next? Am J Transplant. 2008;8(11):2410-2419. 5. Canadian Institute for Health Information. Canadian Organ Replacement Register Annual Report: Treatment of End-Stage Organ Failure in Canada, 2001 to 2010. Ottawa, ON:CIHI; 2011. 6. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357(25):2562-2575. 7. Meier-Kreische HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant. 2004;4(3):378-383. 8. Knoll GA, Bell RC. Tacrolimus versus cyclosporine for immunosuppression in renal transplantation: meta-analysis of randomised trials. BMJ. 1999;318(7191):1104-1107. 9. Goldfarb-Rumyantzev AS, Smith L, Shihab FS, et al. Role of maintenance immunosuppressive regimen in kidney transplant outcome. Clin J Am Soc Nephrol. 2006;1(3):563-574. 10. Guerra G, Ciancio G, Gaynor JJ, et al. Randomized trial of immunosuppressive regiments in renal transplantation. J Am Soc Nephrol. 2011;22(9):1758-1768. 11. Eggers PW, Kucken LE. Cost issues in transplantation. Surg Clin North Am. 1994;74(5):1259-1267. 12. Pace KT, Dyer SJ, Phan V, et al. Laparoscopic v open donor nephrectomy: a cost-utility analysis of the initial experience at a tertiary-care center. J Endourol. 2002;16(7):495-508. 13. Levy AR, Sobolev B, James D, et al. The costs of change: direct medical costs of solid organ transplantation in British Columbia, Canada, 1995-2003. Value Health. 2009;12(2):282-292. 14. Howard K, Salkeld G, White S, et al. The cost-effectiveness of increasing kidney transplantation and home-based dialysis. Nephrology. 2009;14(1):123-132. 15. Erek E, Sever MS, Akoglu E, et al. Cost of renal replacement therapy in Turkey. Nephrology. 2004;9(1):33-38. 16. Barnieh L, Manns BJ, Klarenbach S, McLaughlin K, Yilmaz S, Hemmelgarn BR. A description of the costs of living and standard criteria deceased donor kidney transplantation. Am J Transplant. 2011;11(3):478-488. 17. Knoll G. Trends in kidney transplantation over the past decade. Drugs. 2008;68(suppl 1):3-10. 18. Bowman LJ, Brennan DC. The role of tacrolimus in renal transplantation. Expert Opin Pharmacother. 2008;9(4):635-643.
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