Oral arginine improves blood pressure in renal transplant and hemodialysis patients.

BACKGROUND: Hypertension in kidney transplant (KT) patients may result from attenuated whole-body nitric oxide (NO) content and abnormal NO-mediated vasodilation. Increasing NO bioavailability with L-arginine (ARG) could theoretically restore the NO-mediated vasodilatory response and lower blood pressure. METHODS: In a prospective pilot study, 6 normotensive volunteers and 10 KT patients received oral supplements of ARG (9.0 g/d) for 9 days, then 18.0 g/d for 9 more days. Six hemodialysis (HD) and 4 peritoneal dialysis patients received the same dose for 14 days. Five KT patients received 30 mL/d of canola oil (CanO) in addition to ARG. Systolic (SBP) and diastolic (DBP) blood pressure, creatinine clearance (CCr), and serum creatinine (Cr) were measured at baseline, day 9, and day 18. In a subsequent study, 20 hypertensive KT patients with stable but abnormal renal function were randomized in a crossover study to start ARG-only or ARG+CanO supplements for two 2-month periods with an intervening month of no supplementation. SBP, DBP, CCr, and Cr were measured monthly for 7 months. RESULTS: In the pilot study, ARG reduced the SBP in HD patients from 171.5 +/- 7.5 mmHg (baseline) to 142.8 +/- 8.3 mmHg (p = .028). In the crossover study, SBP was reduced from baseline (155.9 +/- 5.0 mmHg), after the first 2 months (143.2 +/- 3.2 mmHg; p = .03) and subsequent 2 months (143.3 +/- 2.5 mmHg; p = .014) of supplementation. DBP was also reduced after supplementation in both studies. CanO had no effect on blood pressure. Renal function did not change. CONCLUSIONS: Oral preparations of ARG (+/-CanO) were well tolerated for up to 60 consecutive days and had favorable effects on SBP and DBP in hypertensive KT and HD patients.

The economic impact of preservation time in cadaveric liver transplantation.

There has been considerable recent debate concerning the reconfiguration of the cadaveric liver allocation system with the intent to allocate livers to more severely ill patients over greater distances. We sought to assess the economic implications of longer preservation times in cadaveric liver transplantation that may be seen in a restructured allocation system. A total of 683 patients with nonfulminant liver disease, aged 16 years or older, receiving a cadaveric donor liver as their only transplant, were drawn from a prospective cohort of patients who received transplants between January 1991 and July 1994 at the University of California, San Francisco, the Mayo Clinic, Rochester, Minnesota, or the University of Nebraska, Omaha. The primary outcome measure was standardized hospitalization resource utilization from the day of transplantation through discharge. Secondary outcome measures included 2-year patient survival, and 2-year retransplantation rates. Results indicated that each 1-h increase in preservation time was associated with a 1.4% increase in standardized hospital resource utilization (p = 0.014). The effects on 2-year patient survival and retransplantation rates were not measurably affected by an increase in preservation time. We conclude that policies that increase preservation time may be expected to increase the cost of liver transplantation.

Standards for economic and quality of life studies in transplantation.

There are unique requirements in conducting and reporting economic and quality of life investigations in medicine as compared with more traditional studies involving clinical outcomes. In addition, there are several unique characteristics of the discipline of transplantation that also bear attention in economic and quality of life studies. To provide guidelines for future research and reporting of future research, a consensus conference of transplant professionals was convened to discuss these issues. Five different areas were addressed: "Conducting an Economic Analysis," "Reporting an Economic Analysis," "Quality of Life Studies in Transplantation," "Ethical and Conflict of Interest Issues Between Sponsors and Investigators," and "Future Directions for Research." A series of recommendations for each of these areas with reference to relevant literature is presented.

Economic cost of expanded criteria donors in cadaveric renal transplantation: analysis of Medicare payments.

BACKGROUND: The use of expanded criteria donors (ECDs) in cadaveric renal transplantation is increasing in the US. We assess the economic impact of the use of ECDs to the Medicare end stage renal disease program. METHODS: The United Nations for Organ Sharing renal transplant registry was merged to Medicare claims data for 42,868 cadaveric renal transplants performed between 1991-1996 using USRDS identifiers. Only recipients for whom Medicare was the primary payer were considered, leaving 34,534 transplants. An ECD was defined as (1) age < or =5 or > or =55 years, (2) nonheart-beating donors, donor history of (3) hypertension or (4) diabetes. High-risk recipients (HRR) were age >60 years, or a retransplant. Medicare payments from the pretransplant dialysis period were projected forward to provide a financial "breakeven point" with transplantation. RESULTS: There were 25,600 non-HRR transplants, with 5,718 (22%) using ECDs, and 8,934 HRR transplants, of which 2,200 (25%) used ECDs. The 5-year present value of payments for non-ECD/non-HRR donor/recipient pairings was $121,698 vs. $143,329 for ECD/non-HRR pairings (P<0.0001) and, similarly was $134,185 for non-ECD/HRR pairings vs. $165,716 for ECD/HRR pairings (P<0.0001). The break even point with hemodialysis ranged from 4.4 years for non-ECD/ non-HRR pairings to 13 years for the ECD/HRR combinations but was sensitive to small changes in graft survival. Transplantation was always less expensive than hemodialysis in the long run. CONCLUSIONS: The impact of ECDs on Medicare payments is most pronounced in high-risk recipients. Cadaveric renal transplantation is a cost-saving treatment strategy for the Medicare ESRD program regardless of recipient risk status or the use of ECDs.

The cost-effectiveness of transplantation with expanded donor kidneys.

Transplantation with EDKs is a cost-effective therapy for ESRD as compared to hemodialysis across a variety of clinical and financial scenarios. In many cases the costs of pursuing transplantation with these donors will exceed hospital reimbursement for the procedure, providing a financial disincentive to pursuing a clearly cost-effective therapy.

The influence of clinical variables on hospital costs after orthotopic liver transplantation.

BACKGROUND: The burgeoning influence of managed care in transplantation, coupled with a shrinking health-care dollar, has placed most transplant programs under intense pressure to cut costs. We undertook a retrospective cost-identification analysis to determine what clinical variables influenced financial outcomes after orthotopic cadaver liver transplants (OLTx). METHODS: Fifty patients receiving 53 transplants between April 1995 and November 1996 were reviewed. Clinical data were obtained from our institution's transplant database, and total costs (not charges) for the transplant admission and the 6 months after transplant were obtained with use of an activity-based cost accounting system (HBOC Trendstar, Atlanta, Ga). RESULTS: The average total cost of second transplants (n = 5) was $97,262 greater than for first transplants (n = 48, P < .05). Patients transplanted initially as United Network for Organ Sharing (UNOS) status 2 (n = 20) incurred average costs that were $51,762 higher than for patients transplanted as UNOS status 3 (n = 28, P = .008). Patients with a major bacterial or fungal infection (n = 28) incurred average costs $46,282 higher than recipients who were infection free (n = 22, P = .02). Multivariate analysis demonstrated that only length of stay, retransplantation, and postoperative dialysis were significantly and independently correlated with costs (r2 = .605). When the model was repeated with preoperative variables alone, only UNOS status was significantly correlated with 6-month total costs (P = .006, r2 = .16). CONCLUSIONS: Length of stay is the most important determinant of costs after OLTx. Rational strategies to design cost-effective protocols after OLTx will require further studies to truly define the cost of various morbidities and outcomes after OLTx.

Use of low-dose OKT3 as induction therapy in liver transplantation.

BACKGROUND: A pilot study was performed to prospectively evaluate the safety and efficacy of "low-dose" OKT3 induction after liver transplantation. METHODS: Sixteen patients received a 5- to 10-day course of OKT3 (2.5 mg i.v. daily) along with azathioprine, prednisone, and the delayed introduction of cyclosporine (Neoral). RESULTS: Patient and graft survival rates at 1 year were 88% and 82%. Five patients (31%) had biopsy-proven rejection; all five were treated successfully with steroids. There were 15 infections in 12 patients, including 5 cytomegalovirus infections. Adverse events attributed to OKT3 consisted of low-grade fever (five patients), transient hypoxemia (three patients), and transient hypotension (two patients). Pharmacy acquisition costs for OKT3 averaged $2,139 less as compared to a group of historical controls receiving full-dose therapy. CONCLUSIONS: Low-dose OKT3 induction appears to be a safe and useful method of postoperative immunosuppression after liver transplantation. Its ultimate clinical, immunologic, and economic efficacy awaits determination by randomized trial.

Economic costs of expanded criteria donors in renal transplantation.

BACKGROUND: The organ shortage has increased interest in the use of "expanded criteria" donors (ECDs). Although much has been written concerning the clinical outcomes associated with the use of such donors, little has been published concerning the financial results associated with their use. METHODS: A retrospective cost identification study of recipients of kidneys from expanded criteria cadaveric donors was used. RESULTS: Of a total of 78 cadaveric renal transplants in fiscal year 1995, there were 38 kidneys (49%) transplanted from ECDs. Graft survival at 1 year was not statistically different between patients who received kidneys from ECDs and those who received non-ECD kidneys (84% vs. 85%, respectively). Length of stay (P < 0.05), serum creatinine at 1 year after transplantation (P < 0.01), and the percentage of patients requiring hemodialysis (P < 0.05) were all higher among patients who received kidneys from ECDs. Cold ischemic time was significantly longer in patients who received kidneys from ECDs (31.4+/-12 hr vs. 24.0+/-9 hr; P < 0.05). The total average and median costs were $12,190 and $10,911 higher in recipients of kidneys from ECDs as compared with non-ECD controls (P < 0.01). Stepwise linear regression demonstrated that length of stay was the major clinical determinant of total costs; only the use of antilymphocyte induction was otherwise significantly associated. When kidneys from ECDs were transplanted into "high-risk" recipients (age > 60 or retransplant patient), the average total costs were $15,311 more than when kidneys from ECDs were transplanted into non-high-risk patients (n=16 and 21, respectively; P < 0.05) and $20,680 more than when a non-ECD, non-high-risk pairing was undertaken (n=26; P < 0.05). CONCLUSIONS: Kidney transplantation with organs from ECDs is significantly more expensive than with organs from non-ECDs, even in the face of similar graft survival rates. Further study is needed to determine the cost-effectiveness of renal transplantation utilizing kidneys from ECDs vis-a-vis hemodialysis.

Infectious complications after OKT3 induction in liver transplantation.

The present study examines the incidence, risk factors, bacteriology, and mortality of infectious episodes and the role of antimicrobial prophylactic regimens after OKT3 induction in liver transplantation. Infections occurring in the first 6 months were evaluated according to the Centers for Disease Control criteria in 102 transplant recipients. Patients were administered OKT3 for 5 to 10 days, beginning intraoperatively, azathioprine, low-dose prednisone, and delayed introduction of cyclosporine. There were 140 major and 30 minor infections for an incidence of 1.7 infections per patient. Twenty-seven patients (26%) had no infectious episodes during the 6 months of follow-up. Bacterial and fungal infections peaked during the first month posttransplantation, whereas viral infections peaked during the second month. Infection-related mortality was 10%. One-year survival rate of patients who suffered a major infection was less than those who were infection free, but the difference was not statistically significant (79% vs. 89%; P = .61). There was a significantly higher incidence of enterococcal infections under cefotetan prophylaxis than under ampicillin-sulbactam (.375 vs. 11 infections per patient; P = .0017). There were 14 episodes of cytomegalovirus disease (14%) but no cytomegalovirus-related mortality or graft loss, and all cases responded to ganciclovir treatment. Bivariate and multivariate analyses identified only retransplantation as a risk factor for infection. In conclusion, OKT3 induction after liver transplantation is associated with a manageable incidence of bacterial, viral, or fungal infections. This is caused by, at least in part, improved anti-infective prophylaxis.

Clinical and economic outcomes of expanded criteria donors in renal transplantation.

Although graft and patient survival rates were similar between recipients of kidneys from ECDs and non-ECDs, transplantation with organs from ECDs was significantly more expensive. Multivariate analysis using stepwise linear regression demonstrated length of stay to be a strong proxy for total hospital costs. Inherent tensions between the overall good clinical outcomes associated with the use of ECDs in terms of graft survival and the markedly increased costs seen with these organs are evident.

Tumor necrosis factor-alpha decreases hepatocyte bile salt uptake and mediates endotoxin-induced cholestasis.

Tumor necrosis factor-alpha (TNF alpha), a cytokine that is produced in a variety of inflammatory diseases associated with cholestasis, is believed to be the primary mediator of the systemic effects of endotoxin. Thus, we have investigated the role of TNF alpha in the pathogenesis of endotoxin-induced cholestasis in intact animals, and in the uptake of taurocholate by cultured hepatocytes. Male Sprague-Dawley rats received either intravenous (IV) endotoxin (7.5 mg/kg) or monoclonal anti-TNF alpha antibody followed by endotoxin. Basal bile flow and bile salt excretion were measured for a 2-hour period, after which all animals received an IV bolus of taurocholate (10 mumol/100 g body weight). Endotoxin decreased basal bile flow by 41% and bile salt stimulated bile flow by 38% (n = 12; P < .01). Basal bile salt excretion was decreased 86% after endotoxin administration. Passive immunization with anti-TNF alpha antibody blocked this endotoxin-associated cholestasis. In addition, rat hepatocytes were isolated and cultured in the presence of either endotoxin (10 micrograms/mL) or TNF alpha (100 ng/mL) for 24 hours. These primary hepatocyte cultures exhibited a dose- and time-dependent, noncompetitive, inhibition of taurocholate uptake. We postulate that TNF alpha is an important mediator of the cholestasis of sepsis.