The number of patients with end-stage renal disease (ESRD) is increasing worldwide at a rate of 7% to 8% per year (1). Renal transplantation is the treatment of choice for most patients with ESRD (2) because it improves a patient's quality of life, encourages occupational rehabilitation, and is cost-effective compared with the alternative of dialysis (3). However, because the number of patients awaiting transplants far exceeds the number of kidneys available, maximization of graft survival is of paramount importance.
Advances in immunosuppressive therapy have substantially reduced the severity and rate of acute rejection and improved short- and long-term clinical outcomes for renal transplantation (4). However, despite a high 1-year graft survival rate, long-term graft survival has not improved substantially (5). Chronic rejection remains the main cause of graft loss in long-term studies. The most important predictor of chronic rejection is acute rejection, in particular, episodes that are late, severe, or recurrent (6, 7). Despite advances in immunosuppressive therapy, immunologic injury to the graft remains an important cause of early and late graft failure, with a significant proportion (15%–20%) of renal transplant recipients experiencing acute rejection episodes (AREs) (8). Although these episodes are reversible with heightened doses of steroids and antibody therapy, the implications for increased health care costs and poor long-term outcome underscore the importance of developing therapies to reduce AREs.
As health care funding continues to be scrutinized and constrained, new medicines or therapeutic approaches will have to be evaluated for an acceptable balance between clinical effectiveness and cost, so that the maximum benefit arises from the resources available. Economic evaluations have been performed for several therapeutic interventions in renal transplantation (9, 10). Most of these studies were performed in North America and cannot easily be extrapolated to European settings where patterns of health care use may be substantially different. Data are lacking on the effectiveness of renal transplantation in a general patient population under actual or average treatment condition in Europe.
We have performed a health economic study of kidney transplantation in normal clinical practice in Germany to explore the health and economic consequences of patient characteristics, short-term outcomes, and complications during 2 years posttransplant in a European setting. The major focus of the study was on costs related to adverse events after transplantation. We determined the economic impact of certain key variables such as preoperative risk and post-transplantation complications such as graft failure, acute rejection, delayed graft function, and cytomegalovirus (CMV) infection.
PATIENTS AND METHODS
The study population consisted of 204 patients who underwent a renal transplant in the Department for Visceral and Transplantation Surgery at Medizinische Hochschule Hannover (MHH) between January 1998 and July 2000. All patients were 16 years or older on the date of transplantation. Patients who had participated in clinical trials or who received a combined kidney and pancreas, kidney and liver, or double-kidney transplant were excluded.
We retrospectively reviewed patient files at MHH containing hospitalization records and medical correspondence from external care providers to the transplantation center. An electronic database at the outpatient clinic of the transplantation department provided information on outpatient visits. Estimates of resource use were based on local protocol when detailed records of resource use for certain events were unavailable, for example, for procedures outside MHH.
Data were obtained on the following key clinical events: primary hospitalization for transplantation, immunosuppressive drug use, patient survival, graft survival, acute rejection, delayed graft function, CMV infection, other adverse events and serious complications, treatment of adverse events, treatment of complications, repeat hospitalization, and use of outpatient facilities. The end of follow-up was defined by the last documented date of a patient visit at the outpatient department of MHH at which the blood level of cyclosporine A (CsA) or tacrolimus was measured as proof that the transplanted kidney was still functioning.
The perspective used in the economic analysis was that of the third-party payer with a special focus on hospital costs for the following reasons: (1) Care after transplantation surgery and follow-up were mainly inpatient treatments; outpatient treatment was also provided by the outpatient clinic at the hospital. (2) The cost data supplied by MHH as the most important provider of renal transplantation in Germany were consistent and precise enough for a cost analysis in renal transplantation. Reimbursed amounts were used as a proxy for the costs of outpatient services and drugs.
Direct costs were calculated for three distinct periods after renal transplantation: primary hospitalization after transplantation surgery, the remainder of year 1 after primary hospitalization, and year 2 after transplantation.
Determination of Costs
Costs were determined with a bottom-up approach, in which each unit of resource use was multiplied by the unit cost. Unit costs were derived from different sources and were differentiated between hospital and outpatient setting.
Cost of initial hospitalization.
Inpatient facility and physician services were assigned on the basis of the specific hospital cost at MHH. Drug prices for immunosuppressants and concomitant medication were obtained from the 2001 German drug compendium (11) and discounted 32% to determine wholesale prices, which were used as a proxy for hospital pharmacy costs. Costs for interventions during the initial hospitalization were derived from the German official inpatient fee schedule (12).
Costs for organ procurement and primary transplantation surgery were not included in our analysis because the focus of the study was the treatment cost related to clinical events after transplantation.
The difference in assessing year 1 and year 2 posttransplantation costs was that year 1 was assumed to have 365 days less the number of days for initial hospitalization. Resource use in the posttransplantation period was assigned to the following six areas: (1) care in the outpatient department of MHH; (2) care at other external outpatient facilities (nonroutine visits and interventions were assigned to year 1 or 2 with the assumption that they followed the distribution of repeat hospitalizations); (3) rehospitalization; (4) immunosuppressive medication; (5) other drugs; and (6) dialysis costs for graft failure. For outpatient care, the frequency of visits was determined from computerized records, and a renal sonogram and standard set of laboratory tests were added for each visit. Rehospitalizations were valued according to the length of stay and the average cost of a hospital day in Germany (13). Details of the immunosuppressive regimen for years 1 and 2 were obtained from the primary hospitalization discharge record and the MHH database on ambulatory care, respectively. For other medications, patient files were reviewed for drugs and dosages at discharge and at 1, 3, 6, 9, and 12 months after primary hospitalization. Prices taken from the German reference drug compendium “Rote Liste” (6) were used for immunosuppressive and concomitant drugs. Graft failure was attributed to the daily costs for ambulatory, center-based dialysis (14).
Analysis of Cost-Drivers
To assess the impact of preoperative demographic and clinical characteristics on costs for renal transplantation, treatment costs for years 1 and 2 were compared between low-risk and high-risk patients. Patients were categorized as low risk if they fulfilled all of the following criteria: age less than 50 years, no coronary heart disease or diabetes, reactive antibody 30% or less, no previous transplantations, and no previous hemolytic uremic syndrome. Patients were considered to be high risk for the following reasons: coronary heart disease or diabetes, reactive antibody greater than 30%, or a previous transplant. Patients with hemolytic uremic syndrome were not included in either risk group because they constitute a specific and small subgroup of patients who require a different treatment protocol. Because costs were not normally distributed, a nonparametric approach was used to determine 95% confidence intervals.
A multiple regression model was used to investigate the relationship between the average cost of care during a time period and the following postoperative events: one or more AREs, delayed graft function, CMV infection, and other serious complications (lymphocele, urine leakage, new-onset diabetes, new-onset dyslipidemia, nephrotoxicity, or bone marrow depression).
Of 204 patients who underwent transplantation, 195 completed 1 year of follow-up, and 149 completed 2 years of follow-up. Forty-six patients completed only 1 year of follow-up, and nine patients completed less than 1 year of follow-up.
Baseline demographic and clinical characteristics are presented in Table 1. Patients had a median age between 45 and 49 years, and approximately two thirds were male. The mean time spent on dialysis was 84.3 months (range 1–351 months). The spectrum of causes of ESRD was similar to that observed in other studies (15); the most frequent cause was glomerulonephritis, which accounted for ESRD in 33.3% of patients. The mean cold ischemia time was 16.9 hr (range 2–39.8 hr). The majority of patients (81.9%) received a cadaveric transplant, 13.7% received a living-related donor transplant, and 4.4% received a transplant from a living, nonrelated donor; the mean human leukocyte antigen mismatch was 2.6. This was the first transplant for 77% of patients.
Baseline immunosuppression for patients consisted of CsA and steroids with mycophenolate mofetil (63.8%) or without mycophenolate mofetil (32.8%). Antibody induction was given to patients with high immunologic risk (64.7%). Patients with previous hemolytic uremic syndrome received a CsA-free immunosuppressive regimen (3.4%).
Patient outcomes during the 2-year period are presented in Table 2. Delayed graft function was reported for 63 of the 204 transplant recipients (30.9%). Forty-nine patients experienced 58 AREs during primary hospitalization, and 33 patients experienced 42 AREs during the remainder of year 1. In year 2, eight patients experienced eight AREs. The overall incidence of AREs was 35.9% in year 1 and 5.4% in year 2.
The incidence of CMV infection was 29.2% during year 1 (3.9% during primary hospitalization and 27.7% during the remainder of year 1) and 2.0% during year 2. A total of 68 CMV infections occurred during year 1, and 3 infections during year 2, respectively. Six patients had two episodes of infection during year 1, and of these, one patient had another episode during year 2.
Graft failure occurred in 11 patients in year 1 (during primary hospitalization in eight patients and later in the year in three patients). One graft failure occurred in year 2. The cumulative 2-year graft survival rate was 92.0%. Two deaths occurred in year 1.
Costs after Renal Transplantation
The total average cost of care per person during primary hospitalization, excluding transplantation surgery, was €15,380 (range €4,551–€128,076) (Table 3). The average length of stay during primary hospitalization was 22.9 days. Hospital care accounted for the major portion (67%) of costs, with an average of €10,269. Other components of cost were medications including immunosuppressants and other medications (€2,240; 14.6%), laboratory and diagnostic workup (€2,228; 14.5%), dialysis (€629; 4.1%), and repeat surgery (€90; 0.1%).
During the remainder of year 1, the average total cost of care, including care for graft failure, was €18,636. The majority of these costs were ascribed to immunosuppressive medications (€9,723; 52.2%), with rehospitalization (€4,487) accounting for 24.1% of costs. Total transplantation costs in year 1 averaged €34,016 per person.
The total cost of care for year 2 averaged €14,484 per transplant recipient. The cost for immunosuppression (€8,623), although lower than for year 1, represented a larger share (60.0%) of total costs for year 2; the average cost for rehospitalization was also lower (€1,595) and represented 11.0% of total costs. However, the cost for dialysis after graft failure averaged €3,410 (23.5% of total cost for year 2)
Effect of Preoperative Risk Factors on Treatment Costs
Comparative costs for low- and high-risk patients for each time period are presented in Table 4. Although mean costs were somewhat higher for patients with high preoperative risk, the differences were not statistically significant. Average year 1 and year 2 estimated costs for a low-risk patient were €32,737 and €13,215, respectively, compared with €36,224 and €15,685, respectively, for a patient at high risk.
Effect of Postoperative Complications on Treatment Costs
Table 5 displays the multiple linear regression model that was used to analyze the relationship between key clinical events and cost. The coefficients of the model can be interpreted as the average cost associated with the clinical event. An uneventful course of transplantation was associated with an average cost of €30,025 for year 1 and €9,650 for year 2. Costs increased significantly with each clinical event; graft failure resulted in the highest added cost at €36,228, but acute rejection (€9,638), other serious complications (€8,397), delayed graft function (€7,359), and CMV infection (€4,149) also influenced costs significantly. These variables accounted for 71% of the variability in the cost of care.
A second multiple linear regression model was computed to evaluate whether costs for year 2 were influenced by clinical events that occurred in year 1 posttransplantation. Of the five variables, only graft failure and acute rejection impacted future costs significantly. Table 6 shows costs for year 2 for these two influencing variables. Surplus costs for year 2 were €28,082 and €4,360 after experiencing graft failure or an ARE in year 1.
This study provides valid data on patient outcomes, resource use, and cost for patients undergoing renal transplantation in a European setting over a time period of 2 years posttransplantation. Because of the study design, our study captured outcomes and costs derived from a routine clinical setting and therefore provides “real-life” data that reflect the real cost structure. Patients who were enrolled in a clinical trial were excluded to avoid protocol-driven costs. We also show that clinical outcomes such as graft failure, acute rejection, CMV infection, and delayed graft function not only add to the treatment cost of renal transplant recipients but also influence future costs. In this study, treatment costs after renal transplantation averaged €34,016 for the first year and €14,484 for the second year after surgery, excluding cost for organ acquisition, pretransplant care, and cost for surgical procedure in the study. The average cost per year of care for a patient with an uncomplicated course was estimated to be €30,025 for year 1 and €9,650 for year 2. However, as shown by our cost data, 12-month treatment costs were significantly influenced by posttransplantation adverse events, which incurred high additional costs. Graft failure was the major cost driver, adding €36,228 to baseline costs; acute rejection, delayed graft function, and CMV infection also contributed significantly to the cost of care. Graft failure or acute rejection in year 1 also had a significant impact on costs for year 2. Thus, whereas baseline costs for year 2 were €10,880, a failed transplant tripled these costs beyond year 1 because of dialysis maintenance costs.
In this study, renal transplantation costs were derived from a retrospective assessment of comprehensive data on outcomes and resource use. Our estimates may be conservative because all events or resource use may not be documented in patient files. We expect data on hospitalization and diagnostic interventions to be complete, whereas under-reporting would pertain more to recording of medications and dosages, especially if prescribed at external outpatient facilities. Nevertheless, retrospective analysis of patient files for medication is considered more precise than use of average figures derived from overall hospital costs (16). The unit costs in this report are those charged by a single institution, namely, MHH; however, because this facility is the largest provider of renal transplantation services in Germany, use of its cost structure for this study is valid.
A direct comparison of costs from this study with those from other national or international economic reports is difficult because of varying health care practices between countries and between institutions and differences in study design and economic models. Nevertheless, some trends are similar and worth noting. In a Canadian study, each ARE added $3,329 and each graft failure added $15,852 to the initial hospitalization costs of $14,663 (9). Another Canadian study similarly showed that the cost of a failed graft was approximately twofold higher than the cost of a successful transplant in the first year and fourfold higher in the second year (17). A previous German economic evaluation calculated the cost of renal transplantation to €8,764 for an uncomplicated course and €29,859 for a complicated course (18). Complications thus add significantly to the costs of transplantation.
Our 1-year graft survival (94.6%) and acute rejection (35.9%) rates were comparable to those reported in the recent literature (19). The study population at the MMH excluded patients who were enrolled in clinical studies. We found that graft failure was not only the major driver of concurrent costs but also had a substantial influence on costs in the subsequent year. Although many pathologic conditions cause graft failure during the first year after transplantation, the main obstacle to long-term graft survival is acute rejection (6, 7). The major impact of acute rejection, even if successfully reversed, is an insidious graft injury that leads to chronic rejection and graft loss (20). A single ARE can reduce long-term graft survival by 20% to 50% (6). Although graft loss is correlated with severity of acute rejection (21), even a histologically borderline ARE carries a significant risk of graft failure (22). Acute rejection increases hospital length of stay and leads to a higher number of readmissions per patient, thereby increasing transplantation costs (23).
Of the patients in our study, 29.2% developed CMV infection during the first year. From our analysis, each CMV infection resulted in an additional €4,149 in costs per year. CMV not only presents its own medical hazards but also increases the risk of acute rejection and graft failure (24, 25). The economic impact of CMV infection on renal transplantation has been determined to be significant, because it results in extended hospitalization and more than a doubling of costs (25).
Poor long-term renal allograft survival has also been correlated with delayed graft function, which has been implicated as a predisposing factor for acute rejection (26). An economic study of delayed graft function showed that hospital stay increased an average of 7 days in patients with delayed graft function compared with those with immediate graft function, resulting in a significant concomitant increase in costs (27).
With regard to the impact of preoperative risk factors, our study did not find a statistically significant difference in treatment costs after renal transplantation between patients with high or low preoperative risk. However, other reports suggest that transplantation costs would be impacted by the presence of certain risk factors. In one study, prolonged hospitalization was linked to recipient variables such as age more than 55 years, presence of diabetes, cardiac disease, respiratory disease, and reactive antibodies greater than 50% (28).
Preventing acute rejection would thus be a logical approach to improve transplant outcomes and reduce the cost of kidney transplantation. Induction therapy with monoclonal antibodies such as basiliximab provides augmented immunosuppression and lowers the incidence of AREs significantly (15, 19). Economic analyses have demonstrated that despite the initial high cost of immunosuppressant treatment, the overall impact of routine use of basiliximab is to reduce costs through improved clinical outcomes and decreased length of hospitalization (9, 29). Another recent transplant management strategy that results in lowered acute rejection rates and lower costs is C2 monitoring of CsA microemulsion (Neoral, Novartis, Basel, Switzerland) dosage (30).
Pharmacoeconomic methods for comparing the cost effectiveness of competing therapeutic strategies are likely to become critical adjuncts to clinical decision making in the practice of renal transplantation. With heightened financial constraints on health care expenditures, new agents will increasingly require demonstration of cost benefits to justify long-term use. In this study, we presented overall outcomes and costs in actual practice for the first 2 years after renal transplantation and demonstrated the economic impact of some key clinical outcomes, in particular, graft failure and acute rejection. This cost database can serve as the basis for additional economic evaluations of treatment strategies, such as new procedures and drugs after kidney transplantation.
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