Deceased-donor kidney transplantation: improvement in long-term survival
David Serur, Stuart Saal, John Wang, John Sullivan, Roxana Bologa, Choli Hartono, Darshana Dadhania, Jun Lee, Linda M Gerber, Michael Goldstein, Sandip Kapur, William Stubenbord, Rimma Belenkaya, Marina Marin, Surya Seshan, Quanhong Ni, Daniel Levine, Thomas Parker, Kurt Stenzel, Barry Smith, Robert Riggio, Jhoong Cheigh...
BACKGROUND: Despite marked improvement in short-term renal allograft survival rates (GSR) in recent years, improvement in long-term GSR remained elusive.
METHODS: We analysed the kidney transplant experience at our centre accrued over four decades to evaluate how short-term and long-term GSR had changed and to identify risk factors affecting graft survival. The study included 1476 adult recipients of a deceased-donor kidney transplant who were transplanted between 1963 and 2006 and who had received one of five distinct immunosuppressive protocols.
RESULTS: Five-year actual GSR steadily improved over the years as immunosuppressive therapy evolved (22-86%, P < 0.001) in spite of an increasing trend in the transplantation of higher-risk donor-recipient pairings. For those whose grafts functioned for the first year, subsequent 4-year GSR (5-year conditional GSR) also improved significantly (63-92%, P < 0.001). Acute rejection and delayed graft function (DGF) were the most significant risk factors for actual graft survival, while acute rejection was the only significant risk factor for conditional GSR. Use of kidneys from expanded-criteria donors (ECD) was not a risk factor, compared to the use of standard-criteria donor kidneys for either 5-year actual or conditional GSR. There was an impressive decline in the incidence of acute rejection events (77.4-5.8%, P < 0.001). While the DGF rate had decreased, it still remained high (68.7-38.5%, P < 0.001).
CONCLUSIONS: We found a significant improvement in both short-term and long-term GSR of deceased-donor kidney transplants over the last four decades. These improvements are most likely related to the decreased incidence of acute rejection episodes. Minimizing acute rejection events and preventing DGF could result in further improvement in the GSR. Our experience in the judicious use of ECD kidneys suggests that this source of kidneys could be expanded further.
Neutralization of endotoxin by a phospholipid emulsion in healthy volunteers
Bruce R Gordon, Thomas S Parker, Daniel M Levine, Fred Feuerbach, Stuart D Saal, Betty-Jane Sloan, Cindy Chu, Kurt H Stenzel, Joseph E Parrillo, Albert L Rubin...
J Infect Dis. 2005 May 1;191(9):1515-22. doi: 10.1086/428908. Epub 2005 Mar 24.
ABSTRACT
BACKGROUND: An approach to endotoxin (lipopolysaccharide [LPS]) blockade makes use of the ability of lipoproteins, via surface phospholipids, to bind and neutralize LPS. The aim of the present study was to determine whether the intravenous administration of a protein-free, phospholipid-rich emulsion is an effective method for neutralizing the effects of LPS in healthy persons.
METHODS: This was a double-blind, placebo-controlled study in 20 volunteers. Volunteers received Escherichia coli endotoxin (2 ng/kg) intravenously 2 h into a 6-h infusion of either emulsion (210 mg/kg) or placebo (Intralipid diluted 1 : 64).
RESULTS: The volunteers who received emulsion had a lower mean clinical score (P<.01), temperature (P<.05), pulse rate (P<.05), neutrophil count (P<.05), tumor necrosis factor- alpha level (P<.05), and interleukin-6 level (P<.05) than did the volunteers who received placebo. Response was related to serum phospholipid level. The greatest effects were observed in the volunteers achieving phospholipid levels of approximately 500 mg/dL or higher.
CONCLUSION: Phospholipid emulsion attenuates the clinical and laboratory effects associated with the administration of LPS in humans, suggesting a novel approach to the treatment of endotoxemia.
Safety and pharmacokinetics of an endotoxin-binding phospholipid emulsion
Bruce R Gordon, Thomas S Parker, Daniel M Levine, Stuart D Saal, Lisa Cooper Hudgins, Betty-Jane Sloan, Cindy Chu, Kurt H Stenzel, Albert L Rubin...
Ann Pharmacother. 2003 Jul-Aug;37(7-8):943-50. doi: 10.1345/aph.1C390.
ABSTRACT
BACKGROUND: Lipids and lipoproteins have been shown to bind and neutralize endotoxin and to improve outcomes in animal models of sepsis.
OBJECTIVE: To provide safety and pharmacokinetic data for a protein-free, phospholipid-rich emulsion developed as an agent to neutralize endotoxin, and to study the changes in lipids and lipoproteins following emulsion administration.
METHODS: Thirty healthy male volunteers (aged 18-45 y) were given an emulsion containing 92.5% soy phospholipid, 7.5% soy triglyceride, and 18 mM sodium cholate using a double-blind, placebo-controlled crossover protocol. Emulsion at 3 escalating doses (75, 150, 300 mg/kg) based on phospholipid content was administered by intravenous infusion over 2 hours in the low- and mid-dose groups and 6 hours in the high-dose group.
RESULTS: All subjects completed the protocol without significant toxicities. A slight dose-dependent increase in indirect bilirubin at the 24-hour time point was observed in the emulsion treatment period, with a maximum difference between placebo and emulsion of 0.9 mg/dL. Mean +/- SD peak phospholipid levels were 316 +/- 30, 533 +/- 53, and 709 +/- 86 mg/dL, and phospholipid half-lives were 5.4 +/- 0.6, 5.4 +/- 0.5, and 8.0 +/- 0.8 hours for the low, mid, and high doses, respectively. Increases in total cholesterol, low-density lipoprotein cholesterol and apolipoprotein A-I and B levels were observed. High-density lipoprotein cholesterol decreased immediately following emulsion infusion, but rebounded to above placebo levels by 24 hours.
CONCLUSIONS: A unique phospholipid-rich emulsion was shown to have a favorable safety profile and to expand the blood lipid and lipoprotein pool without the use of human-derived blood products. Lipid levels expected to protect against the physiologic effects of bacterial endotoxin were achieved.
Cholesterol and interleukin-6 concentrations relate to outcomes in burn-injured patients
Holly E Colwell Vanni, Bruce R Gordon, Daniel M Levine, Betty-Jane Sloan, David R Stein, Roger W Yurt, Stuart D Saal, Thomas S Parker...
J Burn Care Rehabil. 2003 May-Jun;24(3):133-41. doi: 10.1097/01.BCR.0000066812.96811.28.
ABSTRACT
The goal of this study was to determine the relationship among lipid concentrations, cytokine concentrations, and clinical outcomes of burn patients. Twenty-eight patients admitted within 24 hours of burn injury, segregated based on burn size, had blood samples drawn 24 and 48 hours after burn injury and then weekly for 3 weeks. Measurements included total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, interleukin (IL)-6, soluble IL-2 receptor, and soluble necrosis factor p55 and p75 receptors. Infection, length of stay (LOS), and survival were monitored. Cholesterol and lipoprotein concentrations decreased by at least 40% in patients with burns >20% total body surface area and inversely correlated with IL-6. Lower cholesterol and higher IL-6 values correlated with higher infection rates and longer LOS. IL-6 was the strongest predictor for LOS. In conclusion, outcomes after burn injury are related to low cholesterol and elevated IL-6 levels.
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