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ABSTRACT: Hypothermic machine perfusion (HMP) is in its infancy in clinical liver transplantation. Potential benefits include diminished preservation injury (PI) and improved graft function. Molecular data to date has been limited to extrapolation of animal studies. We analyzed liver tissue and serum collected during our Phase 1 trial of liver HMP. Grafts preserved with HMP were compared to static cold stored (SCS) transplant controls. Reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry and transmission electron microscopy (TEM) were performed on liver biopsies. Expression of inflammatory cytokines, adhesion molecules and chemokines, oxidation markers, apoptosis and acute phase proteins and the levels of CD68 positive macrophages in tissue sections were evaluated. RT-PCR of reperfusion biopsy samples in the SCS group showed high expression of inflammatory cytokines, adhesion molecules and chemokines, oxidative markers and acute phase proteins. This upregulation was significantly attenuated in livers that were preserved by HMP. Immunofluorescence showed larger numbers of CD68 positive macrophages in the SCS group when compared to the HMP group. TEM samples also revealed ultrastructural damage in the SCS group that was not seen in the HMP group. HMP significantly reduced proinflammatory cytokine expression, relieving the downstream activation of adhesion molecules and migration of leukocytes, including neutrophils and macrophages when compared to SCS controls.
American Journal of Transplantation 05/2012; 12(9):2477-86. · 6.39 Impact Factor
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J V Guarrera,
S D Henry, B Samstein,
R Odeh-Ramadan,
M Kinkhabwala,
M J Goldstein,
L E Ratner,
J F Renz,
H T Lee,
R S Brown,
J C Emond
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ABSTRACT: Hypothermic machine perfusion (HMP) is widely used to preserve kidneys for transplantation with improved results over cold storage (CS). To date, successful transplantation of livers preserved with HMP has been reported only in animal models. In this, the first prospective liver HMP study, 20 adults received HMP-preserved livers and were compared to a matched group transplanted with CS livers. HMP was performed for 3-7 h using centrifugal perfusion with Vasosol solution at 4-6 degrees C. There were no cases of primary nonfunction in either group. Early allograft dysfunction rates were 5% in the HMP group versus 25% in controls (p = 0.08). At 12 months, there were two deaths in each group, all unrelated to preservation or graft function. There were no vascular complications in HMP livers. Two biliary complications were observed in HMP livers compared with four in the CS group. Serum injury markers were significantly lower in the HMP group. Mean hospital stay was shorter in the HMP group (10.9 +/- 4.7 days vs. 15.3 +/- 4.9 days in the CS group, p = 0.006). HMP of donor livers provided safe and reliable preservation in this pilot case-controlled series. Further multicenter HMP trials are now warranted.
American Journal of Transplantation 12/2009; 10(2):372-81. · 6.39 Impact Factor
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ABSTRACT: It is critical to balance waitlist mortality against posttransplant mortality. Our objective was to devise a scoring system that predicts recipient survival at 3 months following liver transplantation to complement MELD-predicted waitlist mortality. Univariate and multivariate analysis on 21,673 liver transplant recipients identified independent recipient and donor risk factors for posttransplant mortality. A retrospective analysis conducted on 30,321 waitlisted candidates reevaluated the predictive ability of the Model for End-Stage Liver Disease (MELD) score. We identified 13 recipient factors, 4 donor factors and 2 operative factors (warm and cold ischemia) as significant predictors of recipient mortality following liver transplantation at 3 months. The Survival Outcomes Following Liver Transplant (SOFT) Score utilized 18 risk factors (excluding warm ischemia) to successfully predict 3-month recipient survival following liver transplantation. This analysis represents a study of waitlisted candidates and transplant recipients of liver allografts after the MELD score was implemented. Unlike MELD, the SOFT score can accurately predict 3-month survival following liver transplantation. The most significant risk factors were previous transplantation and life support pretransplant. The SOFT score can help clinicians determine in real time which candidates should be transplanted with which allografts. Combined with MELD, SOFT can better quantify survival benefit for individual transplant procedures.
American Journal of Transplantation 10/2008; 8(12):2537-46. · 6.39 Impact Factor
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J V Guarrera,
S H Nasr,
C M Reverte, B Samstein,
T Brown,
V Balachandran,
M J Samuels,
J Kelly,
M A Hardy,
G S Markowitz,
V D D'Agati,
L E Ratner
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ABSTRACT: Our center has recently observed foreign carbohydrate-appearing particles (FP) on transplant postreperfusion biopsy specimens: (PRBx).
To further characterize FPs, we reviewed all renal transplant RBx (30-45 minutes) performed between September 1, 2004 and December 3, 2005. Donor, preservation, and outcome variables were collected among patients with FP.
A total of 135 PRBx were performed (45 deceased donors [DD] and 90 live donors [LD]). Fifteen PRBx demonstrated FP. All 15 cases were DD kidneys that underwent machine perfusion (MP) on the Waters RM3 (Waters Medical Systems, Rochester, Minn, United States) with Belzer MP solution (Trans Med, Elk River, Minn, United States). Donor age was 39.8 +/- 15.7 years. Terminal creatinine level was 1.45 +/- 0.8 mg/dL. Two of 15 were flushed in situ with HTK solution (no starch). Cold ischemia time was 28.8 +/- 9.1 hours with 14.3 +/- 5.1 hours of MP. In 13 of 15 patients, perfusion parameters were excellent (flow > 100 mL; resistance < .35). CHARACTERISTICS OF FP: Particles were 10-30 mu and globular in shape. FP were not visible on hematoxylin and eosin stain, but stained strongly periodic acid-Schiff-(PAS) positive and were refractile under polarized light. FP were seen segmentally within glomerular capillaries in all cases and in peritubular capillaries in 3. In 11 of the 15 cases with FP, focal glomerular fibrin thrombi or intracapillary neutrophil margination was seen. Ten of 15 patients with FP had a biopsy within the first week with no identifiable FP.
Recipient age was 45.3 +/- 11.6 years. Eight patients (53.3%) had delayed graft function. Biopsy-proven rejection occurred in 3 patients (20%). Three-month creatinine level was 1.59 +/- 0.35 mg/dL. One graft was lost to early thrombosis in a patient with a hypercoagulable state and 1 patient died of sepsis at 2 months. All remaining 13 patients are alive with excellent graft function at a median follow-up of 6.7 months (range, 3-17 months).
Microscopic intrarenal particles may be seen on DD kidney PRBx after MP. These FPs likely originate from surgical gloves. FPs are too small to be captured by standard filters but clear spontaneously and do not have deleterious effects on renal function or outcomes.
Transplantation Proceedings 12/2006; 38(10):3384-7. · 1.00 Impact Factor
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ABSTRACT: The application of xenotransplantation faces daunting immunological hurdles, some of which might be overcome with the induction of tolerance. Porcine organs transplanted into primates are subject to several types of rejection responses. Hyperacute rejection mediated by naturally occurring xenoreactive antibodies and complement can be overcome without tolerance. Acute vascular rejection and cellular rejection, however, may present important opportunities for immunological tolerance, and humoral rejection might be approached by various mechanisms including (i) clonal deletion, (ii) anergy, (iii) immune deviation, (iv) induction of immunoregulatory or suppressor cells, or (v) veto cells. B-cell tolerance, useful for preventing humoral rejection, might be approached through clonal anergy. It remains to be determined, however, whether tolerance induction is required for xenotransplantation and by which means the various mechanisms of tolerance can be applied in the setting of xenotransplantation. Regardless, the study of tolerance will surely expand understanding of the physiology and pathophysiology of the immune system.
Philosophical Transactions of The Royal Society B Biological Sciences 06/2001; 356(1409):749-58. · 6.40 Impact Factor
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ABSTRACT: Liver transplantation from living related donors was unthinkable until recently, when the safety of modern hepatic surgery became widely appreciated. The first step was the successful demonstration that parts of livers could be transplanted. This technique, termed reduced-size liver transplantation, evolved into reliable procedures to allow parents to donate small parts of their livers to small children. More recently, right hepatectomy, in which up to 70% of the liver is resected for donation, has been performed in adults. As the demand for liver transplantation continues to increase, the development of ethically sound, medically and surgically optimal programs for routine use of living donors has become essential. This chapter provides a broad overview of the evolution and current state of liver transplantation with living donors.
Annual Review of Medicine 02/2001; 52:147-60. · 9.94 Impact Factor
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ABSTRACT: The major problem in the field of renal transplantation is currently the shortage of available kidneys. However, the use of animals as a source of kidneys, i.e., xenotransplantation, is increasingly being viewed as a potential solution to this problem. One preeminent hurdle to xenotransplantation is the immune response of the recipient against the graft; other hurdles include the physiologic limitations of the transplant, infection, and ethical considerations. This review summarizes what is currently known regarding the obstacles to xenotransplantation and some potential solutions to those problems.
Journal of the American Society of Nephrology 02/2001; 12(1):182-93. · 9.66 Impact Factor
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ABSTRACT: TNF alpha and IL-1 beta have previously been shown to increase the IGFBP-1 concentration in plasma and liver under in vivo conditions. The present study demonstrates that another inflammatory cytokine, IL-6, also elevates a 30- to 32-kDa IGF binding protein in the plasma of mice. Moreover, IL-6 produced dose- and time-dependent increases in IGFBP-1 production by HepG2 cells. The maximal IL-6-induced increase in IGFBP-1 was comparable to that observed with dexamethasone, and this increase was attenuated by diltiazem or dantrolene, both of which are known to reduce the cytosolic Ca2+ concentration. Finally, incubation of HepG2 cells with TNF alpha or IL-1 beta also increased IGFBP-1 in a dose-dependent manner. These results demonstrate that IGFBP-1 production is mediated directly by proinflammatory cytokines and suggest that this mechanism may be important for the upregulation of IGFBP-1 seen in catabolic conditions associated with overexpression of these cytokines.
Biochemical and Biophysical Research Communications 12/1996; 228(2):611-5. · 2.48 Impact Factor
