The economic benefit of allocation of kidneys based on cross-reactive group matching.

BACKGROUND: Recently the United Network for Organ Sharing (UNOS) began a pilot study to evaluate prospectively the merits of an allocation of cadaveric kidneys based on broader classes of HLA antigens, called cross-reactive groups (CREG). The objectives of the pilot study consider patient outcomes, but not the potential economic impact of a CREG-based allocation. This study predicts the impact of a CREG-based local allocation of cadaveric kidneys on 3-year Medicare payments and graft survival. METHODS: The UNOS renal transplant registry was merged to Medicare claims data for 1991-1997 by the United States Renal Data System. Average accumulated Medicare payments and graft survival up to 3 years posttransplant for first cadaveric renal transplant recipients were stratified by cross-reactive group mismatch categories. The economic impact was defined as the difference in average 3-year costs per transplant between the current and proposed allocation algorithms. Average 3-year costs were computed as a weighted average of costs, where the weights were the actual and predicted distributions of transplants across cross-reactive group categories. RESULTS: Results suggest that an organ allocation based on cross-reactive group matching criteria would result in a 3-year cost savings of $1,231 (2%) per transplant, and an average 3-year graft survival improvement of 0.6%. CONCLUSIONS: Cost savings and graft survival improvements can be expected if CREG criteria were to replace current criteria in the current allocation policy for cadaveric kidneys, although the savings appear to be smaller than may be achievable through expanded HLA matching.

Cadaveric versus living donor kidney transplantation: a Medicare payment analysis.

BACKGROUND: We found previously that the clinical advantages of living donor (LD) renal transplantation lead to financial cost savings compared to either cadaveric donation (CAD) or dialysis. Here, we analyze the sources of the cost savings of LD versus CAD kidney transplantation. METHODS: We used United States Renal Data System data to merge United Network for Organ Sharing registry information with Medicare claims data for 1991-1996. Information was available for 42,868 CAD and 13,754 LD transplants. More than 5 million Medicare payment records were analyzed. We calculated the difference in average payments made by Medicare for CAD and LD for services provided during the first posttransplant year. RESULTS: Average total payments were $39,534 and $24,652 for CAD and LD, respectively (P<0.0001) during the first posttransplant year. The largest source of the difference in payments was in inpatient hospitals, representing $10,653.67 (P<0.0001). For patients who had Medicare as the primary payer, average transplant charges were significantly higher for CAD donation ($79,730 vs. $69,547, P<0.0001); average transplant payments demonstrated no statistical differences ($28,483 vs. $28,447, P = 0.858). Therefore, inferred profitability was significantly higher for LD. CONCLUSIONS: Medicare payments are remarkably lower for LD compared to CAD in every category. The single largest cost saving comes from inpatient hospital services. A portion of the savings from LD could be invested in programs to expand living kidney donation.

The economic implications of HLA matching in cadaveric renal transplantation.

BACKGROUND: The potential economic effects of the allocation of cadaveric kidneys on the basis of tissue-matching criteria is controversial. We analyzed the economic costs associated with the transplantation of cadaveric kidneys with various numbers of HLA mismatches and examined the potential economic benefits of a local, as compared with a national, system designed to minimize HLA mismatches between donor and recipient in first cadaveric renal transplantations. METHODS: All data were supplied by the U.S. Renal Data System. Data on all payments made by Medicare from 1991 through 1997 for the care of recipients of a first cadaveric renal transplant were analyzed according to the number of HLA-A, B, and DR mismatches between donor and recipient and the duration of cold ischemia before transplantation. RESULTS: Average Medicare payments for renal transplant recipients in the three years after transplantation increased from 60,436 dollars per patient for fully HLA-matched kidneys (those with no HLA-A, B, or DR mismatches) to 80,807 dollars for kidneys with six HLA mismatches between donor and recipient, a difference of 34 percent (P<0.001). By three years after transplantation, the average Medicare payments were 64,119 dollars for transplantations of kidneys with less than 12 hours of cold ischemia time and 74,997 dollars for those with more than 36 hours (P<0.001). In simulations, the assignment of cadaveric kidneys to recipients by a method that minimized HLA mismatching within a local geographic area (i.e., within one of the approximately 50 organ-procurement organizations, which cover widely varying geographic areas) produced the largest cost savings (4,290 dollars per patient over a period of three years) and the largest improvements in the graft-survival rate (2.3 percent) when the potential costs of longer cold ischemia time were considered. CONCLUSIONS: Transplantation of better-matched cadaveric kidneys could have substantial economic advantages. In our simulations, HLA-based allocation of kidneys at the local level produced the largest estimated cost savings, when the duration of cold ischemia was taken into account. No additional savings were estimated to result from a national allocation program, because the additional costs of longer cold ischemia time were greater than the advantages of optimizing HLA matching.

Reducing the shortage of donor livers: what would It take to reliably split livers for transplantation into two adult recipients?

This article examines the scientific, technical, and administrative barriers to splitting donor livers for use in two adults. The main scientific barrier is that cadaveric donor livers at their current level of postoperative function are not sufficiently large to support life in two adult recipients. However, glycogenation of livers from young donors may be a method to overcome this problem in the short term. The three technical obstacles to splitting the liver in the midplane are anatomic anomalies that complicate or prevent splitting, the means to detect these anomalies, and the surgical methods to accomplish the split. Anatomic anomalies affecting the biliary drainage and arterial supply of the liver are the most important limiting technical factors. Administrative accommodations in the current methods of organ allocation will be needed if split-liver transplantation in adults is to succeed. A nationwide view of organ allocation requires that the total number of lives saved by the procedure be the priority outcome nationally. If liver transplantation is viewed from this perspective, split-liver transplantation for adults would be a high priority, and incentives should be set to encourage it.

Combined lung and liver transplantation in a girl with cystic fibrosis.

PURPOSE: To describe the anesthetic considerations of a combined lung and liver transplant in a 14-yr-old girl with cystic fibrosis. CLINICAL FEATURES: A 14 yr-old girl with cystic fibrosis presented for combined liver and lung transplantation. Anesthetic management was complex in that the pulmonary, hemodynamic, and hematological changes after cardiopulmonary bypass and lung transplantation made the management of the subsequent liver transplant unique. We used a moderate dose fentanyl and isoflurane anesthetic with invasive monitoring including a pulmonary artery catheter. Upon reperfusion of the new liver our patient exhibited severe pulmonary hypertension that was associated with a decrease in cardiac output and systemic hypotension. Utilizing a pulmonary artery catheter, this episode was treated with an increase of prostaglandin E1 (PGE1) infusion to 0.025 microg x kg(-1) x min(-1) and the initiation of 3 microg x kg(-1) x min(-1) dobutamine. The pulmonary hypertension resolved and the cardiac output and blood pressure returned to baseline levels. CONCLUSION: The anesthetic considerations for a combined lung and liver transplant are complex because of the interactions and alterations in cardiovascular, pulmonary and hemostatic systems. The use of a pulmonary artery catheter was critical to the management of our patient because it allowed us to accurately treat an episode of hypotension occurring during liver transplantation. This episode was secondary to acute pulmonary hypertension which is common after pulmonary transplantation but unusual during liver transplantation. It is also critical that a team approach is used to consider all of the concerns of the multiple services managing these complex patients.

Unusual presentations of nonmycotic hepatic artery pseudoaneurysms after liver transplantation.

The clinical presentation and causes of hepatic artery pseudoaneurysm vary widely in the postoperative liver transplant recipient, although infection is the most common cause. Although uncommon, hepatic artery complications continue to be an important source of morbidity in liver transplant recipients. Thrombosis, stenosis, and pseudoaneurysm formation are the most common posttransplantation arterial complications. Pseudoaneurysms are most commonly mycotic in origin. Prompt recognition of hepatic artery pseudoaneurysms with aggressive intervention (both surgical and angiographic) may decrease the morbidity associated with this rare clinical entity. The records of 263 consecutive patients who underwent orthotopic liver transplantation between 1991 and 1996 were reviewed retrospectively and assessed for hepatic artery complications. Two patients (0.7%) developed hepatic artery pseudoaneurysm, neither associated with infection. Both patients required operative repair and are doing well without vascular complications at a mean follow-up of 22.5 months. The clinical presentation and causes of hepatic artery pseudoaneurysm vary widely in the postoperative liver transplant recipient. Prompt recognition of hepatic artery pseudoaneurysms with aggressive intervention (both surgical and angiographic) may decrease the morbidity associated with this rare clinical entity.

A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients.

BACKGROUND: The aim of this study was to compare the efficacy and safety of Thymoglobulin (a rabbit-derived polyclonal antibody) to Atgam (a horse-derived polyclonal antibody) for induction in adult renal transplant recipients. METHODS: Transplant recipients (n=72) were randomized 2:1 in a double-blinded fashion to receive Thymoglobulin (n=48) at 1.5 mg/kg intravenously or Atgam (n=24) at 15 mg/kg intravenously, intraoperatively, then daily for at least 6 days. Recipients were observed for at least 1 year of follow-up. RESULTS: By 1 year after transplantation, 4% of Thymoglobulin-treated patients experienced acute rejection compared with 25% of Atgam-treated patients (P=0.014). The rate of acute rejection was lower with Thymoglobulin than Atgam (relative risk=0.09; P=0.009). Rejection was less severe with Thymoglobulin than Atgam (P=0.02). No recurrent rejection occurred with Thymoglobulin compared with 33% with Atgam (P=NS). Patient survival was not different, but the composite end point of freedom from death, graft loss, or rejection, the "event-free survival," was superior with Thymoglobulin (94%) compared with Atgam (63%; P=0.0005). Fewer adverse events occurred with Thymoglobulin (P=0.013). Leukopenia was more common with Thymoglobulin than Atgam (56% vs. 4%; P<0.0001) during induction. The mean absolute lymphocyte count remained below baseline with Thymoglobulin throughout the study (P<0.007), but with Atgam, significant lymphocyte reductions occurred only at day 7. The incidence of cytomegalovirus disease was less with Thymoglobulin than Atgam at 6 months (10% vs. 33%; P=0.025). CONCLUSIONS: Brief (7-day) induction with Thymoglobulin resulted in less frequent and less severe rejection, a better event-free survival, less cytomegalovirus disease, fewer serious adverse events, but more frequent early leukopenia than induction with Atgam. These results may in fact be explained by a more profound and durable beneficial lymphopenia.

Improved method for the isolation and purification of human islets of langerhans using Liberase enzyme blend.

To determine the effects of procedural modifications, 23 human islet isolations were analyzed. Isolations were divided into two groups based on the enzyme used. The influence of Liberase, with an improved method of mechanical disassociation of pancreas, was compared to an automated method using Sevac collagenase. Pancreases were processed within 10 h of cross clamping. Following ductal injection of the enzyme, tissue was placed in the digestion chamber for disassociation. Purification was accomplished using a COBE 2991 cell processor and continuous gradients of 1Hypaque EuroFicoll. Isolations in Group I (Sevac) had an average yield of 138,602 +/- 128,364 islet equivalents (IE) (2083 +/- 1679 IE/g) with a purity of 85 +/- 11%. Group II (Liberase) showed an average yield of 389,586 +/- 191,161 IE (5,958 +/- 3,083 IE/g) with a purity of 90 +/- 6.8%. Viability was confirmed by fluorescein diacetate and propidium iodide staining, static incubations, and perifusions. In conclusion, the combination of the enzyme blend, Liberase, and a more gentle system of disassociation has proven to be a more productive method of islet isolation with higher purity than the previously published methods.

Evidence of a role for matrix metalloproteinases in cold preservation injury of the liver in humans and in the rat.

Previous studies have determined that proteases are important in cold preservation injury to the liver. The purpose of this study was to determine the role of matrix metalloproteinases (MMPs) in cold preservation injury. Effluents were collected from rat livers after various periods of preservation either in Eurocollins solution or in University of Wisconsin (UW) solution. Effluents were also collected from 17 human donor livers stored in UW solution. To determine whether sinusoidal endothelial cells released MMPs when placed in the cold, these cells were isolated from rat livers and cultured at 4 degrees C. Gelatin zymography, quantitative assay of gelatinolytic activity, immunoprecipitation, and Western blotting were used to identify metalloproteinases and to measure their activity. Human and rat liver effluents contained gelatin-digesting bands on zymography. Their appearance was inhibited by specific metalloproteinase inhibitors and also by lactobionate, the major ingredient of UW solution. The most prominent bands in humans and the rat appeared at approximately 72 kd and 92 kd, suggesting that they were the MMPs 72-kd gelatinase and 92-kd gelatinase. Supernatants of isolated rat sinusoidal endothelial cells stored in the cold contained similar bands. In the rat, the proteinases were present in both latent and active forms, but, in humans, predominately the latent form was seen. In humans, there were four prominent bands in the gelatin zymography. By immunoprecipitation, two of the bands were identified as the 92-kd gelatinase and a dimer or polymer of 92-kd gelatinase. Using Western blotting with a monoclonal antibody, a third band was identified as 72-kd gelatinase. In quantitative terms, gelatinolytic activity increased with time of cold storage in humans and in the rat. In the rat, gelatinolytic activity was greater when Eurocollins was the preservative than when UW solution was used. Taken together, these results indicate an important role for MMPs in the injury produced by cold preservation of the liver.

Liver transplantation after jejunoileal bypass for morbid obesity.

BACKGROUND: Jejunoileal (JI) bypass was developed as a therapy for morbid obesity in the late 1960s but has since been abandoned because of a high rate of complications, including cirrhosis. The need for liver transplantation after JI bypass has been infrequent, with only four previous patients reported in the literature; however, because the time to develop symptomatic end-stage liver disease after JI bypass may be quite long (25 years or more), the incidence of patients who will require liver transplantation may only now be increasing. STUDY DESIGN: We reviewed our experience with JI bypass and liver transplantation in 380 consecutive adult patients since 1985. RESULTS: Four patients underwent liver transplantation for cirrhosis after JI bypass, all within the last 48 months. The mean duration of time from JI bypass to transplantation was 22.3 years. All patients had complications, in addition to their liver disease, which were related to the JI bypass, which included nephrolithiasis, cholelithiasis, vitamin deficiencies, renal insufficiency, and d-lactic acidosis. One patient had the JI bypass taken down before transplantation, which precipitated acute liver and renal failure, necessitating urgent transplantation. One patient, who had the JI bypass taken down at the time of transplant, has developed recurrent morbid obesity, while the other three patients have not. The one patient who has not had the JI bypass taken down has not developed evidence of recurrent liver disease and is followed with monthly liver function tests and yearly biopsies. CONCLUSIONS: The incidence of patients who require liver transplantation after JI bypass may be on the increase. Take down of the JI bypass may precipitate acute liver failure in the cirrhotic patient. JI bypass should be accomplished either at the time of transplantation or if signs of liver dysfunction occur after transplantation. Liver transplant recipients can be at risk for recurrent obesity after takedown of the JI bypass. Transplantation for those patients with decompensated cirrhosis after JI bypass has demonstrated excellent early results.

A pharmacoeconomic comparison of antithymocyte globulin and muromonab CD3 induction therapy in renal transplant recipients.

Antithymocyte globulin (ATG) and muromonab CD3 (OKT3) are currently the only antilymphocyte preparations that are commercially available for induction immunosuppressive therapy for renal allograft transplantation in the US. ATG, in the usually prescribed doses, is more expensive than muromonab CD3, but muromonab CD3 is associated with more severe adverse effects that may affect clinical outcome and overall cost. We performed a retrospective study of all adult recipients of a first cadaveric renal allograft, who underwent transplantation between January 1991 and December 1994 who received either ATG (n = 92) or muromonab CD3 (n = 91) for induction therapy at our transplant centre. The average age of recipients was older (50 vs 44 yrs; p = 0.001) and extended donors were more commonly used in the ATG group (41 vs 13%; p = 0.0001) compared with the muromonab CD3 group. Nevertheless, at 1 year post-transplant, the incidence of rejection was lower (34 vs 47%) and graft survival was better (93 vs 85%; p = 0.03) in the ATG group. Patients who received ATG were discharged earlier (9.4 vs 13.3 days; p = 0.0001) and had similar serum creatinine levels on the day of discharge (2.4 +/- 1.5 vs 2.1 +/- 1.1 mg/dl; p = 0.25). Overall, the 1-year hospitalisation costs of transplantation and readmissions were similar [$US39,937 +/- 17,014 vs $US42,850 +/- 20,923 (currency year 1994); p = 0.22]. This is the first comparison of ATG and muromonab CD3 in renal transplant recipients to consider clinical as well as economic outcomes. For renal transplant patients in whom induction therapy is used at our centre, the initial expense of ATG can be justified by improved graft survival, fewer rejection episodes, and shorter hospital stays, which are associated with similar overall transplantation costs.

Control of cytomegalovirus-associated morbidity in renal transplant patients using intensive monitoring and either preemptive or deferred therapy.

The objective of this randomized, prospective study was to compare preemptive to deferred treatment of cytomegalovirus (CMV) infection in high-risk renal transplant recipients. Conducted at a university-affiliated transplant center, the study included 36 renal allograft recipients with donor or recipient CMV-seropositivity who received anti-thymocyte induction therapy. Ganciclovir was administered intravenously for 21 days upon detection of CMV viremia (preemptive, N = 15) or detection of CMV viremia associated with a CMV syndrome (deferred, N = 21). Shell vial culture, conventional culture, and polymerase chain reaction (PCR) were performed upon buffy-coat specimens weekly for 12 to 16 wk. CMV and non-CMV-associated charges were calculated. The comparative sensitivities of PCR, shell vial culture, and conventional culture were 91%, 44%, and 47%, respectively. A delay in specimen processing of > 24 h severely compromised the sensitivity of culture techniques but not that of PCR. Preemptive therapy tended to decrease symptomatic CMV episodes (0.4 versus 0.6 episodes per patient randomized; P = 0.22). One patient in each group had organ involvement, and no patient died. Allograft function and survival were similar. Ganciclovir use was increased in the preemptive group (1.2 versus 0.6 courses per patient randomized; P = 0.02). CMV-associated charges were $10,368 (preemptive) versus $5,752 (deferred); P = 0.13. PCR is superior to conventional monitoring to detect CMV viremia. Culture cannot be considered the "gold standard" for detection of CMV viremia, especially when transport of specimens over distances results in processing delays. Preemptive therapy may reduce symptomatic CMV infections in renal transplant recipients. It was associated with higher CMV-related charges but equivalent overall charges versus deferred treatment with intensive monitoring. Either strategy can achieve control of CMV infection after renal transplantation.

Prophylactic oral ganciclovir compared with deferred therapy for control of cytomegalovirus in renal transplant recipients.

BACKGROUND: Treatment with prophylactic oral acyclovir, intravenous ganciclovir, or immunoglobulins to prevent cytomegalovirus (CMV) infection and disease in renal transplantation is associated with variable efficacy and significant expense. We studied control of CMV in renal transplant recipients using either prophylactic oral ganciclovir or deferred therapy with intensive monitoring with polymerase chain reaction (PCR) analysis. METHODS: Forty-two recipients were followed for 6 months after transplantation. Ganciclovir (1000 mg p.o. t.i.d.; n=19) or acyclovir (200 mg p.o. b.i.d.; n=23) was begun at transplantation and continued for 12 weeks. PCR for CMV was performed on buffy-coat specimens every week for 15 weeks and at months 5 and 6. RESULTS: No patients in the ganciclovir group, compared with 14 of 23 patients (61%) in the deferred-therapy group (P<0.0001), developed CMV disease during the first 12 weeks. In the ganciclovir group, 4 of 19 patients (21%) subsequently experienced 5 episodes, whereas 14 patients in the deferred-therapy group experienced 18 episodes (P=0.013 for subjects and P=0.026 for episodes). The time to disease was also delayed in the ganciclovir group compared with the deferred-therapy group (133+/-17 days vs. 51+/-7 days; P<0.0001). Oral ganciclovir also prevented CMV viremia during prophylaxis (2/19 patients [11%] vs. 23/23 patients [100%]). Time to CMV viremia was delayed in the ganciclovir group; however, 13/19 patients (68%) ultimately showed PCR evidence for CMV viremia (P=0.005). CONCLUSIONS: An initial 12-week course of oral ganciclovir prevents CMV disease and infection in renal transplant recipients during prophylaxis, and the benefits persist after discontinuation.