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The Implications of Acute Rejection and Reduced Allograft Function on Health Care Expenditures in Contemporary US Kidney Transplantation

Gheorghian, Adrian1; Schnitzler, Mark A.1; Axelrod, David A.2; Kalsekar, Anupama3; L’italien, Gilbert3,4; Lentine, Krista L.1,5

doi: 10.1097/TP.0b013e318255f839
Clinical and Translational Research
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Background The economic ramifications of acute rejection (AR) are not well characterized in a contemporary population of kidney transplant recipients.

Methods Data for Medicare-insured transplant recipients in 2000 to 2007 (n=45,250) were drawn from the United States Renal Data System. AR events were ascertained from the Organ Procurement and Transplantation Network reports covering months 0 to 12 (yr1), 13 to 24 (yr2), and 25 to 36 (yr3) after transplantation. AR was subclassified as antibody (Ab)-treated AR or other management (non-Ab–treated AR). The marginal cost impact of AR events during and before a period of interest was quantified by multivariate linear regression including covariates for recipient, donor, and transplant factors.

Results Among recipients of standard criteria donor allografts, both Ab-treated AR events (yr1, $22,407; yr 2, $18,803; yr3, $13,909) and non-Ab–treated AR events (yr1, $14,122; yr2, $7852; yr3, $8234) were associated with significant increases in the cost of care. Patterns were similar among recipients of living donor and expanded criteria donor transplants. After weighting by population frequency, AR accounted for 2.3% to 3.8% of total costs incurred during 1 year of posttransplantation care. Subanalysis of recipients with yr1 estimated glomerular filtration rate (eGFR) information demonstrated markedly stronger cost variation across eGFR levels. For example, among those with non-Ab–treated AR, adjusted total yr2 costs were $22,747 with eGFR of 60 mL/min/1.73 m2 or higher but $43,881 with eGFR of 30 mL/min/1.73 m2 or lower.

Conclusions AR is a significant contributor to individual posttransplantation costs. However, because of its low frequency, AR accounts for a small proportion of posttransplantation costs in the population. Healthcare costs in patients with AR are markedly higher among those with reduced compared with preserved allograft function.

Supplemental digital content is available in the text.

1 Saint Louis University Center for Outcomes Research, St. Louis, MO.

2 Department of Surgery, Dartmouth-Hitchcock Medical Center, Hanover, NH.

3 Global Health Economics and Outcomes Research, Bristol Myers Squibb, Princeton, NJ.

4 Yale University School of Medicine, New Haven, CT.

This study was supported in part by a grant from Bristol-Myers Squibb.

The sponsor’s support of the research does not cover publication, nor is there any restriction of the authors’ publication rights by the sponsor.

The data reported here have been supplied by the United States Renal Data System. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US government.

The authors declare no other conflicts of interest.

5 Address correspondence to: Krista L. Lentine, M.D., M.S., Saint Louis University Center for Outcomes Research, 3545 Lafayette Ave., Salus Center, 4th Floor, St. Louis, MO 63104.

E-mail: lentinek@slu.edu

M.A.S. participated in designing the study, acquiring and analyzing the data, and writing the article. A.G. and K.L.L. participated in designing the study, analyzing and interpreting the data, and writing the article. D.A.A., A.K., and G.L. participated in designing the study, interpreting the data, and writing the article. All authors agreed to publish the article.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Received 10 August 2011. Revision requested 7 September 2011.

Accepted 15 March 2012.

The economic benefits of kidney transplantation as a renal replacement modality are well established. Compared with dialysis, transplantation is both life extending and cost saving for patients with functional allografts (1). Acute rejection (AR) was historically a major limitation to the success of transplantation. However, the development and widespread use of induction therapy, more potent immunosuppressive agents, and, potentially, the availability of improved techniques to identify donor-specific antibodies (Abs) have contributed to a reduction in the incidence of AR (2). Unfortunately, when AR occurs, clinical management frequently requires costly therapies including transplant allograft biopsy, hospital admission, increased doses of immunosuppressive agents, and, in severe cases, the use of cell-depleting Ab therapies or plasmapheresis (3). Furthermore, many patients never recover full renal function, resulting in shorter allograft survival, particularly among recipients with preexisting allograft dysfunction.

Currently, there is a paucity of data on the economic impact of AR in kidney transplant patients. Prior analyses have not considered the impact of AR timing and treatment strategies on the economic impact of AR events. To advance understanding of the economic implications of AR in contemporary practice, we examined national registry data for a recent cohort of Medicare-insured kidney transplant recipients in the United States. Specifically, we developed estimates of the cost of Ab-treated AR and non-Ab–treated AR based on individual recipient Medicare expenditures. These costs were further characterized by the time of the AR in relationship to transplantation and the degree of allograft dysfunction. Finally, we developed a population-based estimate of the proportion of total costs of care attributable to the management of AR, which integrates both the marginal cost impacts and frequency of AR events.

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RESULTS

Associations of Donor and Recipient Factors With Medicare Expenditures

There were 48,179 Medicare-insured transplant recipients in the study period, of whom 45,250 recipients met the inclusion criteria for the first-year economic analysis. Median follow-up period was 2.8 years. The distributions of clinical traits among the Medicare-insured transplant recipients who met the eligibility criteria for the first-year cost sample are shown in Table 1. Recipient factors associated with increased Medicare expenditures during the first year after transplantation included older recipient age, longer time on dialysis before transplantation, diabetes, and African American race (Table 2A). Donor and transplant factors that increase costs include increased donor age, African American donor race, cytomegalovirus positivity, and history of delayed graft function. As expected, graft failure was associated with a large increase in first-year costs (>$50,000).

TABLE 1

TABLE 1

TABLE 2

TABLE 2

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Economic Implications of AR: Marginal Costs of Events

In multivariate models that adjusted for donor and recipient factors, both Ab-treated AR and non-Ab–treated AR were associated with increases in posttransplantation healthcare costs. Among standard criteria donor (SCD) kidney recipients, Ab-treated AR resulted in incremental marginal costs of $22,407 in the first year, $18,603 in the second year, and $13,909 in the third year after transplantation (Table 2). The increased marginal costs associated with non-Ab–treated AR in the periods of evaluation were lower at $14,122 in the first year, $7852 in the second year, and $8234 in the third year after SCD transplantation. Patterns were similar among living donor (LD) and expanded criteria donor (ECD) transplant recipients, except that parameters were not statistically significant for the year 2 cost impact of Ab-treated AR among ECD recipients, year 3 impact of Ab-treated AR among LD recipients, or most AR events among the smaller sample of ECD recipients. AR diagnosed in the year preceding the year of analysis resulted in smaller, but still significant, increases in marginal costs, specifically prior non-Ab–treated AR among SCD and LD recipients for year 2 and year 3 period costs, as well as Ab-treated AR among ECD recipients for year 2 costs and among SCD recipients for year 3 costs. This suggests that AR has a lasting economic impact even among patients who sustain or recover allograft function.

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Proportion of Total Costs Attributable to AR

Using frequency data from the entire sample, we estimated the proportion of the total costs of posttransplantation care that were attributable to AR (Table 3). AR accounted for 2.3% to 3.8% of total period costs among SCD and LD recipients, and a similar proportion of year 1 and year 2 period costs among ECD recipients. The third-year cost contribution for AR among ECD recipients was not computed given the absence of significant marginal cost parameters.

TABLE 3

TABLE 3

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Variation in the Economic Impact of AR According to Allograft Function Level

Associations of AR within the first-year after transplantation and estimated glomerular filtration rate (eGFR) at the first transplant anniversary with subsequent costs in year 2 after transplantation were computed among the subsample of transplant recipients who met inclusion criteria for the year 2 cost sample and also had available information for computation of eGFR at the first transplant anniversary (n=32,520). After adjustment for eGFR and the other baseline recipient, donor, and transplant factors considered in this study but without adjustment for death or graft failure in year 2, Ab-treated AR and non-Ab–treated AR within the first year were associated with significant marginal increases in second-year costs of $5755 and $5019, respectively (Table 4A). Compared with patients with first-anniversary eGFR of 60 mL/min/1.73 m2 or higher, second-year costs were similar for those with eGFR of 45 to 59 mL/min/1.73 m2. However, lower eGFR levels were associated with significant marginal second-year cost increases of $2854 for eGFR of 30 to 44 mL/min/1.73 m2 and a marked increase of $16,349 for eGFR of lower than 30 mL/min/1.73 m2. Predicted second-year total costs according to first-year AR status and eGFR level from this model are shown in Figure 1. Among patients with first-year eGFR of 60 mL/min/1.73 m2 or higher, multivariate-adjusted total second-year costs in those with Ab-treated AR, non-Ab–treated AR, and no AR were $22,667, $22,747, and $19,934, respectively. By contrast, in those with first-year eGFR of 30 mL/min/1.73 m2 or lower, adjusted total second-year costs in those with Ab-treated AR, non-Ab–treated AR, and no AR were $45,068, $43,881, and $34,938, respectively. After additional adjustment for death and graft failure in year 2, the marginal impact of both AR and eGFR on second-year costs showed similar patterns but with lower magnitudes (Table 4A). Patterns were also similar for third-year costs (Table 4B, Fig. 1).

TABLE 4

TABLE 4

FIGURE 1

FIGURE 1

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DISCUSSION

Despite improvements in transplantation practice, AR continues to impact graft and patient survival, increasing the cost of transplantation among recipients of SCD, LD and ECD transplants. In this study of a contemporary cohort of US kidney transplant recipients, we found that both Ab-treated AR and non-Ab–treated AR are associated with increases in the cost of care. However, the cost impact of AR is markedly higher among affected patients with compromised allograft function. We also found that, although AR events are costly complications for affected individuals, given the low contemporary incidence of AR, the costs attributable to AR represent a relatively small proportion of posttransplantation costs when considered at the population level.

The cost of AR treatment itself, including admission, diagnostic testing, and Ab therapy, and the potential need for additional medical interventions are likely mediators of the increased costs of care associated with AR events. Although average costs are high for an episode of AR, the contribution of AR to total annual costs of care are relatively low. This reflects the low incidence of AR, particularly late after transplantation in an era of induction therapy. Furthermore, joint assessment of the cost impacts of first-year AR and eGFR level on subsequent costs revealed that substantial reductions in allograft function (defined by eGFR) result in significantly greater increases in the cost of medical care for transplant recipients.

Despite the high initial cost of renal transplantation, the subsequent cost savings associated with avoidance of dialysis and related complications contribute to a highly beneficial cost-effectiveness ratio (1). Although differing in magnitude, the cost-effectiveness of kidney transplantation is generalizable across all donor types including ECD transplants. The economic impact of transplantation reflects the integrated effects of donor and recipient characteristics, medical management, and reimbursement practice. Prior analyses have demonstrated a profound increase in the cost of transplantation using organs with high-risk characteristics (older donors, donors after cardiac death, and kidneys with prolonged ischemia times) (4–6). These characteristics increase the risk of delayed graft function, resulting in longer hospital stays, increased need for posttransplantation dialysis, and subsequent readmissions. Although many of these factors are immutable, it is possible that mechanical devices including pulsatile perfusion of donor allografts may help to decrease the cost of care (7).

As demonstrated in this analysis, the development of AR is also associated with dramatic increases in the cost of posttransplantation care for an individual patient. However, currently available immunosuppressive agents are also expensive, requiring careful analysis to determine both the clinical and economic implications of their use. For example, recent data suggest that use of thymoglobulin can decrease the incidence of AR and rehospitalization, offsetting increased expenditures for pharmaceuticals (8). Alternative agents, including alemtuzumab, seem to offer both clinical and economic benefits through the reduction of early AR and lower pharmacy expenditures (9, 10). In the later period of transplantation, it is clear that strategies that increase medication adherence, thus reducing the development of AR, are crucial to controlling posttransplantation costs (11).

With respect to the assumptions of our models and interpretation, because the model parameters reflect AR in prior and current periods, the approach assumes that the cost impact of an AR event is realized by the end of the next period. If cost impacts of AR extend beyond the next period, the total estimated cost impact may not be completely captured, resulting in conservative estimates of the economic implications of AR. This approach has been used to estimate the cost impact of other complications in transplantation such as posttransplantation diabetes mellitus and cytomegalovirus infection (12, 13). Alternatives to our ordinary least squares (OLS) models, such as regressions estimating the determinants of the natural log of Medicare payments, may be more efficient but also may produce biased estimates and are difficult to interpret. Because we have access to cost data for very large samples, we used the unbiased estimator. Our past work has demonstrated nearly identical results with OLS cost regression and regressions on the natural log of Medicare payments (13), and OLS has become our standard in analyses of the economic impact of complications in transplantation (7,14).

Limitations of our study include the lack of histologic definitions of the AR events within the Organ Procurement and Transplantation Network (OPTN) registry. The OPTN does not track which AR episodes represent cellular or humoral rejection. However, because both humoral and cellular rejections are known to contribute to late allograft loss, the effects demonstrated here are likely to be true for population-based analyses. Furthermore, the need for Ab treatment is an excellent marker of the severity of rejection, as was demonstrated by relative impacts on both economic and clinical outcomes (15). Second, our sample was limited to patients insured by Medicare, and findings may not be generalizable to patients with private health insurance. Because Medicare benefits expire at 3 years after transplantation except in the case of those older than 65 years or with disability, our economic analyses focused on AR events within the first 3 years after transplantation. However, the limitations of the sample restriction are mitigated by the size and diversity of the study sample. Finally, as a sample of transplant recipients in 2000 to 2007, the patients are expected to have been managed primarily with calcineurin inhibitor– or mammalian target of rapamycin–based immunosuppression. The implications of other maintenance immunosuppression regimens for the cost and outcome from AR may be different than those that are reported in this analysis.

In conclusion, AR remains an important source of expense after renal transplantation. Strategies to reduce the incidence of AR have the potential to extend graft life and reduce overall costs. Although clinical consequences of AR may increase with later AR events after transplantation (15), the marginal cost impacts seem lower for later events. The net economic impact of AR depends strongly upon the degree of preservation of allograft function.

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MATERIALS AND METHODS

Data Sources

Study data were drawn from the records of the United States Renal Data System, which integrate OPTN records with Medicare billing claims (16). This study was conducted in accordance with the Health Insurance Portability and Accountability Act of 1996, and all standards regarding the security and privacy of an individual’s health information were maintained.

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Study Samples

The primary study sample comprised recipients of first single-organ kidney transplants in the United States in 2000 to 2007 with Medicare as the primary payer at the time of transplantation. This sample was used to estimate the incidence of AR across the spectrum of donor organ types (SCD, LD, and ECD). We defined ECD transplants according to the United Network for Organ Sharing (UNOS)/OPTN criteria as allografts from deceased donors 60 years or older, or those from donors aged 50 to 59 years with at least two of the following: history of hypertension, terminal serum creatinine level greater than 1.5 mg/dL, or cerebrovascular cause of death (17). These data were used to determine the proportion of costs attributable to AR across the entire Medicare-insured sample. A subsample of patients who survived with graft function to the first transplant anniversary and had available information for the computation of eGFR at 12 months was also used to examine the combined impact of AR and eGFR on subsequent costs in years 2 and 3 after transplantation. Finally, analytic samples for the economic analyses comprised patients with Medicare at the start of a given period who sustained coverage to the period end or died or experienced graft failure within the period.

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Outcome Variable Definitions

The primary economic measure was actual payments for all health care services made by Medicare. Payments were evaluated at 1-year intervals during the first, second, or third years after transplantation. The cost analysis was limited to 3 years because Medicare transplantation benefits expire at 3 years except in the cases of people 65 years or older or with certain disabilities. Patient costs were included in analysis of an interval if: (1) the recorded Medicare eligibility extended continuously from the beginning to the end of the period or (2) Medicare eligibility ended in an interval because of death or graft loss. Monetary figures were adjusted to the prices in the year 2007 medical care component of the Consumer Price Index (18).

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Predictor Variable Definitions

The primary predictor of interest was AR as defined by OPTN reporting. The OPTN surveys centers for information on clinical events among individual transplant recipients at 6 months, 1 year, and then annually. Data on AR are identified according to the period covered by a specific reporting form, but dates of AR within the period are not collected. We defined AR based on center reporting on the OPTN survey that an AR event occurred. Immunosuppression records were used to subclassify AR as Ab-treated or non-Ab-treated as a measure of AR severity. Ab-treated AR was defined by administration of polyclonal Abs, such as antithymocyte globulin or antilymphocyte globulin, or monoclonal Abs, such as OKT3, alemtuzumab, or rituximab, for the indicated purpose of treating AR. Patients with any Ab-treated AR event in a period were classified as having Ab-treated AR in that period, as the first level of classification. Patients with other indications of AR in a period who did not meet the criteria for Ab-treated AR were classified as having non-Ab–treated AR in the given period.

Renal function at 1 year after transplantation was defined by eGFR as computed with the abbreviated Modification of Diet in Renal Disease equation as: eGFR (mL/min/1.73 m2)=186×(serum creatinine [mg/dL])−1.154× age−0.203×(1.212, if African American)×(0.742, if female) (19). Serum creatinine values were drawn from the OPTN 1-year recipient follow-up reporting form. The abbreviated Modification of Diet in Renal Disease equation has superior performance for prediction of measured GFR among renal transplant patients when compared with the Nankivell and Cockcroft-Gault formulas (20). Renal function was categorized by levels of function as: > 60, 45−59, 30−44, and <30 mL/min/1.73 m2.

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Statistical Analysis

Data management and analysis were performed with SAS for Windows software, version 9.2 (SAS Institute Inc., Cary, NC). Continuous data were summarized as means (SDs), and categorical data were summarized as proportions. Cost period analyses considered the proportion of patients who met eligibility criteria for inclusion in a given cost period (as defined previously) who experienced AR events within the cost period of interest.

The marginal cost impacts of AR events during and before the cost periods of interest (first, second, and third years after transplantation) were computed by OLS regression equations as: E(Y)=β1X12X2+…βkXk, where E(Y) indicates Medicare payments within a period of interest, Xk indicates the value of a given predictor variable, and βk indicates the marginal costs associated with a 1-unit change in a given variable after adjustment for other observed factors in the model. Thus, for binary variables such as AR, the βk parameters quantify the marginal costs associated with AR compared with no AR in a given or prior period, respectively. Estimates were adjusted for the recipient, donor, and transplant factors in the UNOS survival models (see Appendix, SDC,http://links.lww.com/TP/A670). In addition to the UNOS covariates, the primary cost period models were also adjusted for the impact of death and graft failure within the period of interest. The cost (in dollars) contribution of AR to population costs within a given period was computed with a weighted average, as: Σ(proportion of period sample with AR event)×(marginal cost impact of that AR event). The proportion of total period costs attributable to AR was computed as: Σ[(proportion of period sample with AR event)×(marginal cost impact of that AR event)]/(total period costs).

The combined impact of AR within the first year and eGFR at the first transplant anniversary on second- and third-year period costs was examined among subsamples of patients who met criteria for the second- and third-year cost samples, respectively, and also had available information for the computation of eGFR at the first anniversary. These models were explored with and without adjustment for death and graft failure within the period of interest. Predicted second- and third-year costs according to AR status and eGFR level at the first anniversary were computed from these multivariable regression models, with values of adjustment covariates set to sample averages.

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References

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14. Schnitzler MA, Johnston K, Axelrod D, et al.. Associations of renal function at 1-year after kidney transplantation with subsequent return to dialysis, mortality, and healthcare costs. Transplantation 2011; 91: 1347.
15. Gheorghian A, Schnitzler MA, Axelrod DA, et al.. The implications of acute rejection and reduced allograft function on health care expenditures in contemporary US kidney transplantation. Transplantation 2012; 94: 241. In press.
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19. Levey AS, Greene T, Kusek JW, et al.. A simplified equation to prediction glomerular filtration rate from serum creatinine. J Am Soc Nephrol 2000; 11: 155A.
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Keywords:

Acute rejection; Glomerular filtration rate; Health care costs; Kidney transplantation; Medicare

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