The selectin antagonist known as recombinant P-selectin glycoprotein ligand IgG (rPSGL-Ig) blocks leukocyte adhesion and protects against transplantation ischemia reperfusion injury (IRI) in animal models. This randomized (1:1) single-center double-blind 47-patient phase 2 study with 6-month follow-up assessed rPSGL-Ig's safety and impact on early graft function at 1 mg/kg systemic dose with pretransplant allograft ex vivo treatment in deceased-donor liver transplant recipients. Safety was assessed in all patients, whereas efficacy was assessed in a prospectively defined per-protocol patient set (PP) by peak serum transaminase (TA) and bilirubin values, and normalization thereof. In PP patients, the incidence of poor early graft function (defined as peak TA >2500 U/L or bilirubin >10 mg/dL), average peak liver enzymes and bilirubin, normalization thereof and duration of primary and total hospitalization trended consistently lower in the rPSGL-Ig group compared to placebo. In patients with donor risk index above study-average, normalization of aspartate aminotransferase was significantly improved in the rPSGL-Ig group (p < 0.03). rPSGL-Ig treatment blunted postreperfusion induction versus placebo of IRI biomarker IP-10 (p < 0.1) and augmented cytoprotective IL-10 (p < 0.05). This is the first clinical trial of an adhesion molecule antagonist to demonstrate a beneficial effect on liver transplantation IRI and supported by therapeutic modulation of two hepatic IRI biomarkers.

Abbreviations:

ACR: acute cellular rejection
AE: adverse event
ALT: alanine amino-transferase
AST: aspartate amino-transferase
DCD: donation after cardiac death
DNF: delayed non-function
IRI: ischemia reperfusion injury
HAHA: human antihuman antibody response
HAT: hepatic artery thrombosis
LFT: liver function test
PK: pharmacokinetics
PEGF: poor early graft function
PNF: primary non-function
SAE: serious adverse event
TA: transaminase
TBR: total serum bilirubin
rPSGL-Ig: recombinant P-selectin glycoprotein ligand IgG fusion protein

Introduction

Ischemia/reperfusion injury (IRI) occurs in organ grafts subjected to prolonged periods of warm/cold ischemia followed by reestablishment of blood flow. IRI remains one of the most understudied yet critical clinical problems, as it often leads to poor early graft function (PEGF) or primary nonfunction (PNF) in transplant recipients. Moreover, it can significantly impact transplantation outcome because it is a major risk factor for both early graft failure and late chronic allograft dysfunction (1–5). The etiology of IRI, an innate immunity-dominated local antigen-independent process, is not well understood but known to involve multiple factors resulting in graft inflammation, hepatocyte death and/or necrosis (6).

Deceased donor liver transplantation is currently achieving success rates of greater than 83% 1-year graft survival (7). Although the number of transplants increased 2.4-fold from 1990 to 2004, the waiting list increased 15-fold with a 5-fold increase in wait-list deaths. With demand greatly exceeding supply of donor livers, and the increased mortality of those awaiting suitable organs, extended criteria donor (ECD) livers have been increasingly utilized (8,9). However, such organs are at higher risk for severe IRI resulting in PNF or PEGF (8,10).

Inhibition of IRI could potentially increase the number of usable ECD organs. In animal studies, blockade of the interaction between the adhesion molecule P-selectin and its endogenous ligand, P-selectin glycoprotein ligand 1 (PSGL-1), with a recombinant soluble form of this ligand (sPSGL) decreased neutrophil infiltration, ameliorated hepatocyte injury and improved survival in nonsteatotic rat models of liver IRI (2). A similar recombinant P-selectin antagonist, known as recombinant P-selectin glycoprotein ligand IgG (rPSGL-Ig), was tested in the obese Zucker rat model of severely steatotic syngeneic liver transplantation. Fatty Zucker livers pretreated with rPSGL-Ig ex vivo after retrieval showed significantly decreased portal resistance, increased bile production and diminished hepatic endothelial neutrophil infiltration, as compared with controls. The survival of lean Zucker recipients of steatotic Zucker isografts increased from 40% to 90% after rPSGL-Ig treatment (11). This effect correlated with significantly improved liver function and decreased hepatocyte injury. Hence, our experimental findings from a clinically relevant rat model of prolonged hepatic cold ischemia followed by transplantation suggest the potential clinical utility of rPSGL-Ig in increasing the donor pool through prevention or amelioration of hepatic IRI in high-risk livers.

We present here the results of a single-center double-blind placebo-controlled phase 2 study, which was designed to assess the safety and potential efficacy of rPSGL-Ig in patients undergoing deceased-donor whole liver transplantation.

Patients and Methods

Study design and population

This study was a single-center, randomized, double-blinded, placebo-controlled study in two parts (A and B), approved by the UCLA Office for the Protection of Research Subjects (IRB #06-11-064-03 and #08-01-074-03) and each patient was consented prior to enrolment. Patients were eligible if recipients of an ABO-compatible primary deceased-donor whole liver allograft, ≥18 years old, and no other prior organ transplant. Recipients of a liver from a donation after cardiac death (DCD), or from donors <6 years of age, were excluded. In both parts patients were randomized 1:1 for infusion of the donor liver with 20 mg rPSGL-Ig or placebo after retrieval via the portal vein and an intravenous (IV) dose of 1 mg/kg of rPSGL-Ig or placebo prior to arterial reperfusion. In part A, enrollment was restricted to 11 patients with MELD < 29 and donor livers with <20% macrosteatotic fat. In part B, the above restrictions were lifted, and another 36 patients were enrolled under an almost identical protocol. This study was not powered for high significance. Sample size was based on feasibility and less on statistical considerations.

Study drug

rPSGL-Ig was the active treatment in this double-blind study. Although not an ideal control for an immunological agent, saline was used as placebo for the IV bolus administration, for regulatory and logistical reasons. University of Wisconsin preservation solution (UW) was used as vehicle/control for donor organ flush. As liver transplantation can involve substantial blood loss during hepatectomy, this led to reduced drug-exposure in several part A patients. Therefore, in part B, patients with intraoperative blood loss of >10 units transfused received another 10 mg/kg IV bolus of study drug immediately after abdominal closure.

IV dosing of study drug (rPSGL-Ig or placebo) was initiated as soon as technically feasible after portal and prior to arterial reperfusion. The flush dose (chilled 200 mL UW solution ± a total of 20 mg of rPSGL-Ig) was always administered to the donor liver during back-table preparation prior to implantation after arrival at UCLA rather than at the donor hospital, because of logistic and regulatory considerations. The ‘target’ time interval between the study drug ex vivo flush and implantation was at least 60 min. Thereafter, while the anastomoses were being performed for liver implantation, the high K⁺ UW solution was flushed out from the liver allograft with approximately 750 mL of physiological solution administered through the portal vein.

Randomization, blinding and study conduct

Randomization was performed by a biostatistician using a fixed block method and provided as numbered stack of sealed envelopes to UCLA's unblinded investigational pharmacist, who performed study drug preparation (rPSGL-Ig or placebo) based on the assignment in the sealed envelope corresponding to the patient number. The patients, investigators, research nurses and sponsor remained blinded to treatment assignment through the end of the study.

Patient and study data were recorded into predesigned triplicate case report forms (CRFs) and entered into a central database maintained at Clinical Trial Consultants Inc. (CTI), Blue Ash, OH, USA. Safety data were reviewed by an independent Data and Safety Monitoring Board (DSMB), consisting of two transplant surgeons and one biostatistician that had previously served on the DSMB of the YSPSL-0001 renal transplant study (17). A senior clinical research associate from CTI monitored on-site all CRFs 100% against the source documentation for each patient within 2 months after transplantation and each per-protocol study visit.

Immunosuppressive therapy

Immunosuppression was limited to tacrolimus, mycophenolate mofetil and steroids. Sirolimus was allowed when clinically indicated because of suspected tacrolimus neurotoxicity. Use of antibody therapy was also permitted per protocol after biopsy-confirmed rejection. However, none of the four patients who experienced rejection during the study received antibody therapy, rather, the immunosuppression in these patients was adjusted and/or patient was treated with a solumedrol taper.

Endpoints

Safety: Stopping rules for this study are summarized under Table 1. Endpoints for safety were the incidence of PNF, defined as nonrecoverable hepatocellular function necessitating emergency retransplantation or death within 72 h posttransplant (12); delayed nonfunction (DNF), defined as initial marginal graft function necessitating retransplantation within 1 month of transplant; PEGF; hepatic artery thrombosis (HAT); clinical bleeding events (necessitating transfusion of at least two units of packed red blood cells) and drug-related adverse events (AEs) or serious AEs (SAEs). The incidence of biopsy-confirmed rejection events (ACR, Banff grade ≥1) at 6 months was also recorded.

Table 1. Safety: patient/graft survival and SAEs (ITT patient set)

	Placebo (N = 24)	rPSGL-Ig (N = 23)	Overall (N = 47)	p-Value
Patient survival	22 (91.7%)	22 (95.7%)	44 (93.6%)	0.988¹
Graft survival²	22 (91.7%)	21 (91.3%)	43 (91.5%)	0.555¹
SAEs (per patient)
Mean	2.21	2.00	2.11	0.713³
SD	2.19	1.62	1.99

Stopping rules: The stopping rules were as follows: (i) if 2 or greater treatment emergent events of grade 3 NCI toxicity (except for study specific categories as defined in the protocol), then the study would halt for DSMB review and communication to FDA. (ii) In addition to above criterion, two patient deaths prior to 30 days would also halt the study for DSMB review and communication of findings to the FDA. Enrollment would also be halted for DSMB review in case of (iii) more than two cases of PNF; (iv) a treatment emergent HAT event that was not otherwise explained from a technical perspective (i.e., vascular reconstruction, venous compression following closing); (v) two instances of portal vein thrombosis; or (vi) more than four cases of PEGF as defined in the protocol. Any case of PNF counted as well as a PEGF event; hence, one PNF event and three PEGF events would trigger a study halt pending DSMB review. None of these stopping rules were ever triggered, however, the DSMB met per protocol within 1 week after the 6th patient of part A had completed 14 days of follow-up, and again after the 18th patient of part B had completed 14 days of follow up. The DSMB allowed the study to proceed after both meetings. The minutes were submitted to FDA. One patient in part B who died in the operating room from severe reperfusion syndrome was emergency unblinded per protocol and determined to have received placebo.
¹Log-rank (Mantel–Cox) test.
²Within study duration (180 ± 21 days).
³Two-tailed unpaired t-test rPSGL-Ig vs. placebo.

Efficacy: Because of the exploratory nature of this study, it did not have a single primary endpoint. The impact of rPSGL-Ig on IRI was rather evaluated by the following five exploratory endpoints:

1
Categorical classification of transplant IRI based on maximum aspartate aminotransferase (AST) in the first 72 h posttransplant: group 1 <600 U/L; group 2, 600–2500 U/L; group 3, >2500–5000 U/L and group 4 >5000 U/L (13,14).
2
PEGF incidence, with PEGF defined as a peak AST or alanine aminotransferase (ALT) level >2500 U/L during the first three postoperative days (POD) (15) and/or by total serum bilirubin (TBR) >10 mg/dL between POD2 and 7 (16).
3
Early liver function as assessed by average peak serum levels of AST and ALT (POD1–3), and TBR (POD2–7) in treatment versus placebo patients.
4
Treatment groups were also compared for normalization of liver function as assessed by the area under the curve of liver enzyme and TBR from POD1 through 14 (AUC₁₄).
5
Liver biopsy postreperfusion histology as assessed by an UCLA pathologist blinded to study drug treatment. Histologic IRI was defined by a four-point grading scale (13). Presence of IRI was defined as grading scale >0.

Pharmacokinetic (PK) and immunogenicity analysis

Study drug and anti-rPSGL-Ig antibodies in serum were determined as previously described (17) on serum samples drawn at the same timepoints.

Statistical analysis

Because of the exploratory nature of this study, no statistical analysis plan was put in place, rather, safety and efficacy endpoints were scored as stipulated in the study protocol. All statistical tests were two-sided and at the 5% significance level if not specified otherwise. All summaries and analyses were performed using data pooled from parts A and B. Missing data were not estimated or carried forward in any of the analyses. All safety analyses were performed on the Intent-to-Treat (ITT, n = 47) analysis set defined as all randomized patients who received study drug.

Efficacy analysis was performed on a prospectively defined ‘per protocol’ (PP) patient set. Inclusion into the PP set required: (i) the graft was NOT from a living or DCD donor. (ii) Patient AND donor organ were dosed. (iii) Study drug was administered IV to patient PRIOR to arterial reperfusion. (iv). The time elapsed between portal and arterial reperfusion did not significantly exceed 1 h. In part A, all 11 enrolled patients met these conditions. In part B, six patients out of 36 (three rPSGL-Ig-patients and three placebo-patients) did not meet one of these conditions and were therefore excluded from the PP set, which hence included 41 patients.

All statistical analysis was performed using Prizm (GraphPad, San Diego, CA, USA) or SAS (SAS Institute, Cary, NC, USA) software.

The PP patient set, for efficacy analysis, was further stratified into patients that received high-risk versus low-risk livers. Risk was estimated using the donor risk index (DRI) proposed by Feng et al. (18). Patients with DRI above study average 1.56 (10 placebo and 8 rPSGL-Ig-treated patients) were defined as high risk, whereas those with DRI<1.56 (11 placebo and 12 rPSGL-Ig-treated patients) were defined as low risk (Figure 1).

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

**Distribution of per protocol patient (PP) set into patients with high and low donor risk index (**18) grouped by treatment assignment.

Biomarker analysis

Liver biopsies: Two biopsies were taken from all patients except from one placebo patient who died intraoperatively, and one rPSGL-Ig-treated patient. The prereperfusion biopsy was taken from the allograft while on ice on the back-table, prior to the organ flush. The postreperfusion biopsy was taken immediately prior to abdominal closure at the end of surgery on average ∼2 h after hepatic arterial anastomosis. Biopsy specimens were placed in RNAlater^® solution (Ambion, Austin, TX, USA), refrigerated and shipped within 3 days for analysis at Johns Hopkins University.

RNA isolation and quantitative PCR analysis: Thirteen biomarker transcripts (Figure 6) from liver biopsy RNA were scored essentially as described (19,24). RNA was successfully isolated and transcribed from a total of 45 matched pairs from 22 rPSGL-Ig-treated and 23 placebo patients.

Results

Demographics

Recipient and donor demographics, as well as cold and warm ischemia time and intraoperative blood loss for rPSGL-Ig, placebo, and all patients in the ITT set (N = 47) are presented in Tables 2–4.

Table 2. Recipient demographics (ITT patient set)

Treatment N	Placebo 24	Active 23	Overall 47
Sex
Male	11 (45.8%)	18 (78.3%)	29 (60.4%)
Female	13 (54.2%)	5 (21.7%)	18 (37.5%)
p-value (Fisher's exact test)	0.035
Age (years)
Mean	55.8	57.3	56.5
SD	10.2	9.0	9.6
Min–max	26.7–71.2	37.2–73.9	26.7–73.9
p-value (unpaired t-test)	Not significant
Race/ethnicity
Caucasian	13 (54.2%)	14 (60.9%)	27 (56.3%)
African American	1 (4.2%)	1 (4.3%)	2 (4.2%)
Hispanic/Latino	6 (25.0%)	8 (34.8%)	14 (29.2%)
Asian	4 (16.7%)	0 (0.0%)	4 (8.3%)
Pacific Islander	0 (0.0%)	0 (0.0%)	0 (0.0%)
Primary cause of liver failure
Hepatitis C	9 (37.5%)	11 (47.8%)	20 (41.7%)
Malignant neoplasm	9 (37.5%)	11 (47.8%)	20 (41.7%)
Laennec's cirrhosis	3 (12.5%)	7 (30.4%)	10 (20.8%)
Nonalcoholic steatohepatitis (NASH)	3 (12.5%)	2 (8.7%)	5 (10.4%)
Autoimmune hepatitis	1 (4.2%)	0 (0.0%)	1 (4.2%)
Metabolic disease	2 (8.3%)	1 (4.3%)	3 (6.3%)
Other	7 (29.2%)	2 (8.7%)	9 (18.8%)
MELD
Mean	27.0	25.8	26.4
SD	6.3	5.4	5.9
Min–max	7–40	13–39	7–40
p-value (unpaired t-test)	Not significant

There were no significant differences in recipient demographics between treatment and control groups, except for recipient sex, that was significantly (p < 0.05) skewed toward male in the rPSGL-Ig-treated versus the placebo patients.

Table 3. Donor demographics (ITT patient set)

Treatment N	Placebo 24	Active 23	Overall 47
Sex
Male	12 (50.0%)	15 (65.2%)	27 (56.3%)
Female	12 (50.0%)	8 (34.8%)	20 (41.7%)
p-value (Fisher's exact test)	Not significant
Age (years)
Mean	41.4	38.2	39.9
SD	13.5	14.7	14.1
Min–max	17–63	17–63	17–63
p-value (unpaired t-test)	Not significant
Race/ethnicity
Caucasian	15 (62.5%)	12 (52.2%)	27 (56.3%)
Black or African American	0 (0.0%)	3 (13.0%)	3 (6.3%)
Hispanic/Latino	7 (29.2%)	8 (34.8%)	15 (31.3%)
Asian	1 (4.2%)	0 (0.0%)	1 (2.1%)
Pacific Islander	1 (4.2%)	0 (0.0%)	1 (2.1%)
Donor cause of death
CVA	10 (41.7%)	5 (21.7%)	15 (31.3%)
Trauma	7 (29.2%)	6 (26.1%)	13 (27.1%)
Anoxic injury	4 (16.7%)	11 (47.8%)	15 (31.3%)
Other	1 (4.2%)	1 (4.3%)	2 (4.2%)
Living donor¹	1 (4.2%)	0 (0.0%)	1 (2.1%)
Donor risk index (18)
Mean	1.64	1.52	1.58
SD	0.40	0.29	0.35
Min–max	1.15–2.69	1.08–2.17	1.08–2.69
p-value (unpaired t-test)	Not significant
Donor terminal peak LFTs
AST
Mean (U/L)	184.0	401.3	290.4
SD (U/L)	320.4	559.3	461.5
Min–max	21–1267	27–1827	21–1827
p-value (unpaired t-test)	Not significant
ALT
Mean (U/L)	188.5	211.9	199.9
SD (U/L)	319.9	302.7	308.5
Min–max	15–1258	18–1189	15–1258
p-value (unpaired t-test)	Not significant
Bilirubin
Mean (mg/dL)	1.80	2.92	2.35
SD (mg/dL)	1.48	5.34	3.88
Min–max	0.4–6.0	0.2–26.0	0.2–26.0
p-value (unpaired t-test)	Not significant

¹One of the patients enrolled in this study received a liver from a living donor in the context of a domino liver transplantation. This patient was excluded per protocol from efficacy analysis.

Table 4. Transplant data and intraoperative assessments (ITT patient set)

Treatment N	Placebo 24	Active 23	Overall 47
Cold ischemia time (hours)
Mean	7.42	7.10	7.26
SD	2.47	2.89	2.66
Min–max	4.22–14.40	2.58–11.92	2.58–14.40
p-value (unpaired t-test)	Not significant
Warm ischemia time (minutes)¹
Mean	73.1	78.3	73.1
SD	14.8	28.9	14.8
Min–max	52–104	55–198²	52–198²
p-value (unpaired t-test)	Not significant
Intraoperative blood loss (units)
Mean	14.8	14.3	14.6
SD	10.6	16.4	13.6
Min–max	2–43	2–75²	2–75²
p-value (unpaired t-test)	Not significant
Patients that received a second IV dose of rPSGL-Ig at the end of surgery³
N	5	6	11
%	20.8%	26.1%	23.4%
p-value (Fisher's exact test)	Not significant

¹Defined as the time elapsed from the moment liver was taken out of ice until arterial anastomosis.
²The 198 min of warm ischemia time (WIT) in one patient were due to major complications during the arterial anastomosis and this patient was excluded per protocol from the efficacy analysis. The second and third longest WIT in this study was 101 min in a placebo patient and 99 min in a rPSGL-Ig patient. In the patient with 198 min WIT, extraordinary blood loss (75 units) also occurred because of the operative complications. The second largest intraoperative blood loss was 35 units in a placebo patient.
³Five placebo patients and three rPSGL-Ig-treated patients did not receive a second dose of IV rPSGL-Ig although their intraoperative blood loss was >10 units. One rPSGL-Ig patient received a second dose of rPSGL-Ig, although patient's intraoperative blood loss was less than 10 units, in violation of the study protocol.

Safety

Deaths: No death occurred in part A but three deaths occurred in part B, two in the placebo arm and one in the rPSGL-Ig-treated arm. One of the deaths in the placebo group was due to PNF while the cause of death of the other placebo patient could not be determined. The one death in the rPSGL-Ig-treated patient group was due to HAT and sepsis. All deaths were determined as unrelated to study drug by the PI and the DSMB.

Graft loss: In addition to three grafts lost due to death, one other rPSGL-Ig-treated patient experienced graft loss within the duration of the study (6 months ± 21days follow-up posttransplant) because of chronic rejection necessitating retransplantation on POD186.

HAT: Two cases of HAT were noted in two rPSGL-Ig-treated patients. One of these eventually died on POD14. This patient was excluded from the PP set, because 2.5 h had elapsed between portal and arterial anastomosis. The other case of HAT was diagnosed over 3 months posttransplant and eventually necessitated retransplantation well outside the study period on POD250. Both cases of HAT were deemed by the PI unrelated to study drug and are fully characterized in Table 5.

Table 5. Arterial and biliary complications

Treatment	Date of transplant	Complication	Date discovered	Cause
rPSGL-Ig	3/28/07	Bile leak	7/14/07	T-tube removal
rPSGL-Ig	8/10/08	Bile leak	8/26/08	T-tube exit site leak
rPSGL-Ig	8/8/08	HAT	8/17/08	Complex reconstruction of donor replaced right hepatic artery, median arcuate ligament syndrome release, splenic artery ligation, anastomosis redone with infra-renal iliac graft. Did well. POD #9: ARDS, hypotensive DX. HAT. Died 8/23/2008
rPSGL-Ig	9/4/08	HAT	1/14/09	10/2/08—HA stenosis on CT 5/12/09—re-OLT. Celiac and splenic arteries found thrombosed at hepatectomy
Placebo	10/22/08	Bile duct anastomotic stricture	11/22/08	Technical; balloon dilated 11/25/08
Placebo	12/17/08	Hyperkalemia after T-tube removal	12/17/08	Non-related

Clinically significant bleeding events: Seven incidences of clinically significant bleeding were noted in four placebo and three rPSGL-Ig-treated patients.

Serious adverse events (SAEs): There were a total of 99 SAEs, with 28 SAEs reported in Part A and 71 SAEs in Part B. All SAEs were expected events, and were defined as ‘unrelated’ or ‘unlikely related’ to study drug. SAE numbers, frequencies and incidences were similar between the treatment and placebo arms (Table 1). There were also no significant differences between rPSGL-Ig and placebo-treated patients in terms of SAEs grouped by System Order Class (MedDRA10, Table 6).

Table 6. Safety: SAEs by system organ class, severity and treatment group

System organ class (MedDRA10)	NCI-grade	Placebo		YSPSL		Total
System organ class (MedDRA10)	NCI-grade	N	%	N	%	N	%
Blood and lymphatic system disorders	All	4	16.7	1	4.3	5	10.6
Blood and lymphatic system disorders	Moderate	4	16.7	1	4.3	5	10.6
Cardiac disorders	All	2	8.3	3	13.0	5	10.6
	Mild	1	4.2	0	0.0	1	2.1
	Moderate	0	0.0	1	4.3	1	2.1
	Life-threatening	1	4.2	2	8.7	3	6.4
Gastrointestinal disorders	All	3	12.5	3	13.0	6	12.8
	Moderate	3	12.5	1	4.3	4	8.5
	Severe	0	0.0	2	8.7	2	4.3
Immune system disorders (excluding rejection)	All	1	4.2	0	0.0	1	2.1
Immune system disorders (excluding rejection)	Severe	1	4.2	0	0.0	1	2.1
Rejection	All	2	8.3	2	8.7	4	8.5
	Moderate	2	8.3	1	4.3	3	6.4
	Life-threatening	0	0.0	1	4.3	1	2.1
Infections and infestations	All	6	25.0	5	21.7	11	23.4
	Moderate	4	16.7	0	0.0	4	8.5
	Severe	2	8.3	3	13.0	5	10.6
	Life-threatening	0	0.0	1	4.3	1	2.1
	Death	0	0.0	1	4.3	1	2.1
Injury, poisoning and procedural complications	All	8	33.3	5	21.7	13	27.7
	Moderate	2	8.3	2	8.7	4	8.5
	Severe	2	8.3	2	8.7	4	8.5
	Life-threatening	3	12.5	1	4.3	4	8.5
	Death	1	4.2	0	0.0	1	2.1
Investigations	All	4	16.7	4	17.4	8	17.0
	Mild	1	4.2	1	4.3	2	4.3
	Moderate	3	12.5	2	8.7	5	10.6
	Severe	0	0.0	1	4.3	1	2.1
Metabolism and nutrition disorders	All	3	12.5	2	8.7	5	10.6
	Mild	2	8.3	1	4.3	3	6.4
	Severe	1	4.2	1	4.3	2	4.3
Psychiatric disorder	All	0	0.0	1	4.3	1	2.1
Psychiatric disorder	Severe	0	0.0	1	4.3	1	2.1
Nervous system disorders	All	2	8.3	0	0.0	2	4.3
Nervous system disorders	Severe	2	8.3	0	0.0	2	4.3
Renal and urinary disorders	All	4	16.7	4	17.4	8	17.0
	Moderate	3	12.5	2	8.7	5	10.6
	Severe	1	4.2	1	4.3	2	4.3
	Life-threatening	0	0.0	1	4.3	1	2.1
Respiratory, thoracic and mediastinal disorders	All	6	25.0	4	17.4	10	21.3
	Moderate	2	8.3	2	8.7	4	8.5
	Severe	4	16.7	2	8.7	6	12.8
Skin and subcutaneous tissue disorders	All	0	0.0	1	4.3	1	2.1
Skin and subcutaneous tissue disorders	Severe	0	0.0	1	4.3	1	2.1
Unknown	All	1	4.3	0	0.0	1	2.1
Unknown	Death	1	4.3	0	0.0	1	2.1

Hepatobiliary and vascular complications are listed separately in Table 5.

Acute rejection: Four incidences of biopsy-confirmed ACR were noted in two rPSGL-Ig patients and in two placebo patients (one incidence per patient). One of these in a rPSGL-Ig patient progressed to chronic rejection and necessitated retransplantation on POD186.

Efficacy

Binary endpoints: Presence of IRI was scored by the blinded pathologist in 39 out of the total of 41 postreperfusion biopsies (82.3%) in the PP patient set. In fact, mild to severe IRI was also scored in three of the prereperfusion biopsies in the PP set. Only two placebo patients scored into peak AST category 3, whereas none scored into category 4. PEGF was experienced by five patients, four of which had received placebo. After stratification by low and high DRI (cf. ‘Patients and Methods’), four out of 10 high-risk patients treated with placebo experienced DGF versus zero out of 8 high-risk patients treated with rPSGL-Ig (p = 0.0915, cf. Table 7).

Table 7. Binary and categorical efficacy endpoints by treatment group

	N	Presence of IRI	Peak AST category				PEGF	DRI >1.56
	PP patient set							DRI >1.56
	N	Presence of IRI	1	2	3	4	PEGF	N	PEGF
rPSGL-Ig	20	16 (80.0%)	6 (30.0%)	14 (70.0%)	0 (0.0%)	0 (0.0%)	1 (5.0%)	8	0 (0.0%)
Placebo	21	18 (85.7%)	9 (42.9%)	10 (47.6%)	2 (9.5%)	0 (0.0%)	5 (23.8%)	10	4 (40.0%)
p-Value		ns¹	ns²				ns¹		0.0915¹

DRI, donor risk index (18).
¹Fisher's exact test (90% confidence interval).
²Mantel-Haenzel chi-square test.

Early liver allograft function: Serum liver enzyme and total bilirubin (TBR) levels were determined in all patients at least once a day during hospitalization at UCLA. For all evaluable patients, and for the high DRI stratum, the peak values and their normalization (area under the curve days 0–14, AUC₁₄) were determined and averages tabulated in Table 8. For the minority of patients who were discharged from hospital prior to POD13, the postdischarge contribution to AUC₁₄ was computed by linear interpolation of LFTs between the day of discharge and the POD14 study visit.

Table 8. Liver function endpoints by treatment group in PP and high DRI patients

Group	Patient set	N		Peak U/L	AUC₁₄ (U/L) × days	Peak U/L	AUC₁₄ (U/L) × days	Peak mg/dL	AUC₁₄ (mg/dL) × days
Group	Patient set	N		ALT		AST		TBR
Placebo	PP	21	AVG	516.2	2166.5	1005.9	1897.4	4.09	44.9
			SEM	105.5	391.0	190.4	383.0	1.08	11.9
	High DRI	10	AVG	676.1	2820.6	1286.0	2650.4	5.68	63.3
			SEM	203.2	702.6	358.1	703.7	2.14	23.4
YSPSL	PP	20	AVG	455.6	1917.7	885.9	1494.4	3.72	34.7
			SEM	81.7	283.0	125.3	192.6	0.93	6.3
	High DRI	8	AVG	515.6	2319.4	950.5	1529.2	2.51	24.9
			SEM	125.6	527.7	156.7	248.1	0.51	4.6
Overall	PP	41	AVG	486.6	2045.2	947.3	1700.8	3.91	39.9
			SEM	66.5	241.0	114.1	217.2	0.71	6.8
	High DRI	18	AVG	604.8	2597.8	1136.9	2152.1	4.27	46.2
			SEM	124.1	447.0	209.4	418.5	1.24	13.7

None of the above differences in endpoints was statistically significant (p < 0.1, unpaired two-tailed t-test) for rPSGL-Ig versus placebo patients.

Average postoperative peak AST, peak ALT and peak TBR were consistently lower in the treatment arm versus placebo. AST, ALT and TBR also appeared to normalize more rapidly in the treated patients versus the placebo patients. These differences were more pronounced when computed for the high-risk stratum only (Figure 2). The more rapid AST normalization in the high-risk strata of the rPSGL-Ig-treated versus placebo patients was statistically significant (p = 0.024). Because the LFTs of patients discharged early (prior to POD13) were already low when compared to patients with longer primary hospitalizations, the LFT interpolation between discharge and POD14 study visit did not impact considerably on the treatment group averages.

Biomarkers of hepatic ischemia reperfusion injury

The mRNA levels encoding a number of previously suggested hepatic IRI biomarkers were measured by Q-PCR in 45 matched pre- and postreperfusion biopsy pairs and compared to transcripts encoding three housekeeping genes. Relative transcript levels in the postreperfusion biopsies were then compared to the prereperfusion levels. In part A, biomarker transcript levels were also compared to those in a commercial normal liver RNA control. Average transcript levels and postreperfusion induction are tabulated in Table 9. All biomarkers except HMGB-1, TLR4 and, unexpectedly HO-1, were induced postreperfusion, significantly so for Bcl-1, Bcl-2, E-selectin, IL-10, IFN-γ, IP-10, MCP-1 and TNFα. As shown in Figure 3, in placebo patients, IP-10, a marker previously implicated in hepatic IRI in animal models, was induced 20-fold on average upon allograft reperfusion, whereas in rPSGL-Ig-treated patients this induction was blunted (3.3-fold induction only, p < 0.1). Vice versa, postreperfusion induction of the ‘protective’ biomarker IL-10 was significantly augmented (p = 0.043) in the rPSGL-Ig-treated (3.8-fold) versus placebo patients (2.2-fold). Although the average differences were borderline statistically significant, we noted large variations in biomarker responses between individual patients, which warrant caution in interpretation of linear statistics. IL-6 induction also tended to be blunted in rPSGL-Ig-treated patients (data not shown). Postreperfusion levels of transcripts encoding HO-1 and antiapoptotic Bcl-1 and Bcl-2 were not impacted by rPSGL-Ig in our patients.

Table 9. Normalized biomarker transcript levels and their postreperfusion induction

Liver reference¹			Bcl2 0.39	HMOX1² 31.26	HMGB1 3.59	IFNβ 0.00	IFNγ 0.00	IL6 0.02	IL10 0.79	IP 10 0.05	TLR4² 2.42	TNFα² 0.04	BC11³	MCP1³	SELE³
Pre	% hkpg	AVG	0.88	15.03	1.76	1.80	0.06	2.62	1.41	0.68	3.00	0.12	28.72	14.36	0.67
Pre		SEM	0.20	3.07	0.29	0.87	0.02	2.33	0.33	0.24	0.35	0.04	5.64	3.88	0.25
Post	% hkpg	AVG	6.79	19.59	2.07	4.68	0.48	10.20	4.89	2.41	2.59	0.33	47.59	150.36	5.71
Post		SEM	2.37	3.99	0.61	2.07	0.19	6.32	1.53	0.72	0.44	0.07	11.71	47.77	1.67
Ind.	FC	AVG	16.99	1.34	1.80	65.52	44.31	72.81	5.33	22.42	0.87	4.61	2.08	31.01	132.95
		SEM	5.99	0.20	0.38	53.37	21.86	32.95	1.10	12.24	0.10	1.01	0.38	16.06	69.23
		p-value⁴	0.014	0.201	0.513	0.178	0.023	0.069	0.021	0.024	0.189	0.032	0.033	0.005	0.003

Pre = preperfusion biopsy; post = postperfusion biopsy; % hkpg =% of average of three house-keeping genes in same sample; FC = fold change; AVG = arithmetic mean; SEM = standard error of the mean; SELE = E-selectin.
Biomarker transcript levels were normalized to transcripts encoding glyceraldehyde 3-phosphate dehydrogenase, β-actin and phosphoglycerate kinase-1 in the same sample.
¹Normal liver mRNA from Ambion.
²Part A only (11 paired samples).
³Part B only (34 paired samples).
⁴Two-tailed paired t-test.

Hospital resource utilization

We measured the length of time spent postoperatively in the intensive care unit (ICU), as well as primary and total hospitalization in all evaluable patients and compared these between treatment arms (Figure 4). Although not reaching statistical significance due to the low number of patients enrolled, the rPSGL-Ig-treated patients experienced less primary and total hospitalization, with the latter reduced by 14 days on average.

rPSGL-Ig pharmacokinetics (PK)

rPSGL-Ig concentrations appeared to peak at 12 h. Thereafter, drug levels declined steadily through POD30. By POD90 rPSGL-Ig-levels had declined approximately 10-fold and on POD180 only very low rPSGL-Ig-levels if any were detected. In part A, drug exposure was noted >2-fold reduced in patients that had experienced significant intraoperative blood loss. Therefore, in part B, a second IV bolus of study drug was administered to patients after an intraoperative blood loss of >10 units. Average c_max, AUC and serum half-life in the rPSGL-Ig-treated patients are tabulated in Table 8.

rPSGL-Ig-immunogenicity

All anti-rPSGL-Ig antibodies samples were determined to be nonreactive. Thus, at least within the duration of the study, rPSGL-Ig did not elicit human antihuman antibody responses.

Discussion

rPSGL-Ig is a recombinant inhibitor of the initial tethering of leukocytes to activated platelets and endothelium, which is mediated by selectins binding to PSGL-1. In small animal models of solid organ transplantation, perioperative treatment with rPSGL-Ig was safe, and ameliorated IRI (11,20,21).

Here, we report the results of a phase 2a study to establish the safety of rPSGL-Ig in de novo deceased-donor orthotopic whole liver transplant recipients. Efficacy assessments explored trends of potential impact of rPSGL-Ig on early liver allograft function. Overall, the administration of rPSGL-Ig in all patients was uneventful and no specific safety concerns were raised from using this drug in the perioperative period, in agreement with previous clinical data (17,22,23). The distribution of the SAEs was similar between the rPSGL-Ig-treated and placebo arm, no SAE deemed related to study drug and all of them were expected in this patient population.

Although this study was not designed and powered for efficacy, our results suggest trends toward improvement of early liver function posttransplantation effected by rPSGL-Ig as compared with placebo, in terms of peak liver enzyme and bilirubin levels and normalization thereof. Although these effects were not statistically significant on their own, the average AST, ALT and bilirubin peak values and normalizations (AUC day 0–14) were all lower in the treatment arm versus the placebo arm. When evaluable patients were stratified into receiving a high or low donor risk graft using a published index, rPSGL-Ig's potential benefit appeared to be restricted to the high DRI patients, bordering at statistical significance for AST normalization. Although we analyzed both AST and ALT it is not surprising that there is a more rapid normalization of AST due to its shorter half-live. Furthermore, although ALT may be more ‘liver specific’, AST has been shown to be a very sensitive maker of early graft dysfunction (14). In the high-risk stratum, rPSGL-Ig also further reduced the PEGF incidence, which was significant at the 90% confidence interval. Other stratifications, by MELD score, by histological IRI, or by macro and/or microsteatotic fat content did not augment the observed treatment effect and also did not reveal significant correlations to short-term outcome.

rPSGL-Ig did not appear to impact hepatic IRI evidenced by histopathology. However, this method of determining IRI is limited by sampling bias and the fact that a subset of patient had evidence for IRI already in the preperfusion biopsy. In fact, experimental animal data on IR liver damage, assessed by histological Suzuki's criteria, do not always correlate with liver function as reflected by serum ALT/AST levels (Kupiec-Weglinski, unpublished data).

Biomarkers of IRI are sought for as more objective surrogate endpoints and predictors of outcome. In our recent renal biomarker study (24) within our double-blinded randomized placebo-controlled renal transplant clinical trial (17), targeting the selectin cascade with rPSGL-Ig attenuated the postreperfusion renal increase of MCP-1 and TGFβ (p < 0.05) transcripts. In hepatic IRI animal models, IP-10, IL-10 and HO-1, along with antiapoptotic genes, were suggested to correlate or inversely correlate with local inflammation and hepatocyte death (20,25,26). Here, we compared biomarker transcript levels in pre- and postreperfusion liver biopsies. We found that proinflammatory and antiapoptotic transcripts were induced upon reperfusion. rPSGL-Ig treatment appeared to reduce induction of IP-10 and IL-6, and augment induction of the cytoprotective biomarker IL-10. Although due to the large variations in individual patient's biomarker responses these data need to be interpreted with caution and substantiated in larger sample sizes, our present findings in humans support the concept that IP-10 expression can serve as marker for hepatic IRI, which is most likely mediated through the TLR4 signaling pathway (26,27). The augmented IL-10 expression in the rPSGL-Ig treatment group is also consistent with our previous animal model data (26,28). However, unlike in most animal studies, we failed to validate HO-1 as a biomarker of hepatic IRI. HO-1 promoter studies based on (GT)m microsatellite polymorphisms suggest that stronger HO-1 expression protects from organ IRI, and conversely, polymorphisms correlating with lower HO-1 response worsen the pathology (29). Hence, more analyses are needed to precisely attribute a cytoprotective action to HO-1 in transplant patients. Immunohistochemical determination of active P-selectin on the biopsies was also considered, but not implemented because of technical obstacles.

Although the statistical significance of our data is limited by the sample size, we believe this is the first clinical trial to demonstrate a beneficial effect of an adhesion molecule antagonist on IRI in liver transplantation. Other clinical strategies reported to ameliorate IRI in liver transplantation include donor treatment with steroids (30), caspase inhibition (31), ATG induction therapy (32), donor organ flush with calcineurin inhibitor (33) and nitric oxide (NO) inhalation (34). All these studies report somewhat improved posttransplant liver function resulting from experimental treatments, with ATG allowing for more compromised liver grafts to be transplanted with less clinical evidence of IRI and improved function. However, except for the NO trial, these studies involved immunosuppressive agents or post hoc analysis. Importantly, rPSGL-Ig is the first systemically administered non-immunosuppressive agent shown in a prospective randomized double-blinded clinical trial to reduce liver IRI, with improved early liver function correlating to beneficial modulation of hepatic IRI biomarkers. Our data provide an adequate safety profile and indicate a beneficial impact of rPSGL-Ig on hepatic IRI and early liver allograft function in recipients of deceased donor liver transplants. Further studies with appropriate dose ranging are required to establish rPSGL-Ig as a safe and effective treatment modality for transplantation IRI in deceased-donor transplantation. Such a modality, in addition of providing short and potentially long-term benefit to patients, might also increase the pool of usable donor livers, because currently about 20% of available donor livers are not being utilized because they are deemed high risk for hepatic IRI and subsequent poor graft function and survival.

Acknowledgments

This study was funded by Y's Therapeutics, Inc. and by the Dumont-UCLA Research Foundation. GSL was supported in part by a grant from the National Institutes of Health (5K08HD057555-03). The authors thank Charles Lassman for expert review of liver histological specimens.

Disclosure

The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. SH is a salaried employee of Y's Therapeutics, Inc. ECS was also a salaried employee of Y's Therapeutics, Inc. (until April 2007). No other conflicts of interest.

References

1 Carter YM, Davis RD. Primary graft dysfunction in lung transplantation. Semin Respir Crit Care Med 2006; 27: 501–507.
10.1055/s-2006-954608
PubMed Web of Science® Google Scholar
2 Dulkanchainun TS, Goss JA, Imagawa DK et al. Reduction of hepatic ischemia/reperfusion injury by a soluble P-selectin glycoprotein ligand-1. Ann Surg 1998; 227: 832–840.
10.1097/00000658-199806000-00006
CAS PubMed Web of Science® Google Scholar
3 Goes N, Urmson J, Ramassar V, Halloran PF. Ischemic acute tubular necrosis induces an extensive local cytokine response. Evidence for induction of interferon-gamma, transforming growth factor-beta 1, granulocyte-macrophage colony-stimulating factor, interleukin-2, and interleukin-10. Transplantation 1995; 59: 565–572.
10.1097/00007890-199502270-00022
CAS PubMed Web of Science® Google Scholar
4 Kusaka M, Nadeau KC, Takada M, Nagano H, Shaw GD, Tilney NL. Influence of initial antigen-independent events on acute allograft rejection: Inhibition by a soluble P-selectin ligand and low-dose cyclosporine in combination. Transplant Proc 1998; 30: 1027–1028.
10.1016/S0041-1345(98)00136-5
CAS PubMed Web of Science® Google Scholar
5 Takada M, Nadeau KC, Shaw GD, Marquette KA, Tilney NL. The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand. J Clin Invest 1997; 99: 2682–2690.
10.1172/JCI119457
CAS PubMed Web of Science® Google Scholar
6 Kupiec-Weglinski JW, Busuttil RW. Ischemia and reperfusion injury in liver transplantation. Transplant Proc 2005; 37: 1653–1656.
10.1016/j.transproceed.2005.03.134
CAS PubMed Web of Science® Google Scholar
7 HHS/HRSA/HSB/DOT. OPTN/SRTR Annual Report: Transplant Data 1998–2007. 2008.
Google Scholar
8 Busuttil RW, Tanaka K. The utility of marginal donors in liver transplantation. Liver Transpl 2003; 9: 651–663.
10.1053/jlts.2003.50105
PubMed Web of Science® Google Scholar
9 Tector AJ, Mangus RS, Chestovich P et al. Use of extended criteria livers decreases wait time for liver transplantation without adversely impacting posttransplant survival. Ann Surg 2006; 244: 439–450.
10.1097/01.sla.0000234896.18207.fa
PubMed Web of Science® Google Scholar
10 Mirza DF, Gunson BK, Da Silva RF, Mayer AD, Buckels JA, McMaster P. Policies in Europe on “marginal quality” donor livers. Lancet 1994; 344: 1480–1483.
10.1016/S0140-6736(94)90294-1
CAS PubMed Web of Science® Google Scholar
11 Amersi F, Farmer DG, Shaw GD et al. P-selectin glycoprotein ligand-1 (rPSGL-Ig)-mediated blockade of CD62 selectin molecules protects rat steatotic liver grafts from ischemia/reperfusion injury. Am J Transplant 2002; 2: 600–608.
10.1034/j.1600-6143.2002.20704.x
CAS PubMed Web of Science® Google Scholar
12 Shaked A, Nunes FA, Olthoff KM, Lucey MR. Assessment of liver function: Pre- and peritransplant evaluation. Clin Chem 1997; 43(8 Pt 2): 1539–1545.
CAS PubMed Web of Science® Google Scholar
13 Khan AW, Fuller BJ, Shah SR, Davidson BR, Rolles K. A prospective randomized trial of N-acetyl cysteine administration during cold preservation of the donor liver for transplantation. Ann Hepatol 2005; 4: 121–126.
10.1016/S1665-2681(19)32075-7
CAS PubMed Google Scholar
14 Rosen HR, Martin P, Goss J et al. Significance of early aminotransferase elevation after liver transplantation. Transplantation 1998; 65: 68–72.
10.1097/00007890-199801150-00013
CAS PubMed Web of Science® Google Scholar
15 Basile J, Busuttil A, Sheiner PA et al. Correlation between von Willebrand factor levels and early graft function in clinical liver transplantation. Clin Transplant 1999; 13(1 Pt 1): 25–31.
10.1034/j.1399-0012.1999.t01-2-130104.x
CAS PubMed Web of Science® Google Scholar
16 Deschenes M, Belle SH, Krom RA, Zetterman RK, Lake JR. Early allograft dysfunction after liver transplantation: A definition and predictors of outcome. National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Transplantation 1998; 66: 302–310.
10.1097/00007890-199808150-00005
CAS PubMed Web of Science® Google Scholar
17 Gaber AO, Mulgaonkar S, Kahan BD et al. rPSGL-Ig (rPSGL-Ig) for improvement of early renal allograft function: a double-blind, placebo-controlled, multi-center phase IIa study. Clin Transplant 2010, in press.
Google Scholar
18 Feng S, Goodrich NP, Bragg-Gresham JL et al. Characteristics associated with liver graft failure: The concept of a donor risk index. Am J Transplant 2006; 6: 783–790.
10.1111/j.1600-6143.2006.01242.x
CAS PubMed Web of Science® Google Scholar
19 Ascon M, Ascon DB, Liu M et al. Renal ischemia-reperfusion leads to long term infiltration of activated and effector-memory T lymphocytes. Kidney Int 2009; 75: 526–535.
10.1038/ki.2008.602
CAS PubMed Web of Science® Google Scholar
20 Farmer DG, Shen XD, Amersi F et al. CD62 blockade with P-Selectin glycoprotein ligand-immunoglobulin fusion protein reduces ischemia-reperfusion injury after rat intestinal transplantation. Transplantation 2005; 79: 44–51.
10.1097/01.TP.0000146965.64706.E8
CAS PubMed Web of Science® Google Scholar
21 Gasser M, Waaga-Gasser AM, Grimm MW et al. Selectin blockade plus therapy with low-dose sirolimus and cyclosporin a prevent brain death-induced renal allograft dysfunction. Am J Transplant 2005; 5(4 Pt 1): 662–670.
10.1111/j.1600-6143.2005.00763.x
CAS PubMed Web of Science® Google Scholar
22 Mertens P, Maes A, Nuyts J et al. Recombinant P-selectin glycoprotein ligand-immunoglobulin, a P-selectin antagonist, as an adjunct to thrombolysis in acute myocardial infarction. The P-Selectin Antagonist Limiting Myonecrosis (PSALM) trial. Am Heart J 2006; 152: 125.e1–125.e8.
10.1016/j.ahj.2006.04.020
CAS PubMed Web of Science® Google Scholar
23 Tanguay JF, Krucoff M, Gibbons R. Efficacy of a novel P-selectin antagonist, rPSGL-Ig for reperfusion therapy in acute myocardial infarction: The RAPSODY Trial. J Am Coll Cardiol 2003: [Abstract 404A.
10.1016/S0735-1097(03)81179-8
Google Scholar
24 Cheadle C, Watkins T, Ehrlich E et al. Effects of anti-adhesive therapy on kidney biomarkers of ischemia reperfusion injury in human deceased donor kidney allografts. Clin Transplants, in press.
Google Scholar
25 Liu Z, Xu W, Zhang X, Cui D, Liu B. Expression of the CXC chemokine receptor 3 and its ligands in ischemia-reperfusion injury of liver in rats. Transplant Proc 2008; 40: 1300–1302.
10.1016/j.transproceed.2007.11.076
CAS PubMed Web of Science® Google Scholar
26 Zhai Y, Shen XD, Gao F et al. CXCL10 regulates liver innate immune response against ischemia and reperfusion injury. Hepatology 2008; 47: 207–214.
10.1002/hep.21986
CAS PubMed Web of Science® Google Scholar
27 Shen XD, Ke B, Zhai Y et al. Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model. Liver Transpl 2007; 13: 1435–1443.
10.1002/lt.21251
CAS PubMed Web of Science® Google Scholar
28 Ke B, Shen XD, Tsuchihashi S et al. Viral interleukin-10 gene transfer prevents liver ischemia-reperfusion injury: Toll-like receptor-4 and heme oxygenase-1 signaling in innate and adaptive immunity. Hum Gene Ther 2007; 18: 355–366.
10.1089/hum.2007.181
CAS PubMed Web of Science® Google Scholar
29 Buis CI, Van Der Steege G, Visser DS et al. Heme oxygenase-1 genotype of the donor is associated with graft survival after liver transplantation. Am J Transplant 2008; 8: 377–385.
10.1111/j.1600-6143.2007.02048.x
CAS PubMed Web of Science® Google Scholar
30 Kotsch K, Ulrich F, Reutzel-Selke A et al. Methylprednisolone therapy in deceased donors reduces inflammation in the donor liver and improves outcome after liver transplantation: A prospective randomized controlled trial. Ann Surg 2008; 248: 1042–1050.
10.1097/SLA.0b013e318190e70c
PubMed Web of Science® Google Scholar
31 Baskin-Bey ES, Washburn K, Feng S et al. Clinical trial of the pan-caspase inhibitor, IDN-6556, in human liver preservation injury. Am J Transplant 2007; 7: 218–225.
10.1111/j.1600-6143.2006.01595.x
CAS PubMed Web of Science® Google Scholar
32 Bogetti D, Sankary HN, Jarzembowski TM et al. Thymoglobulin induction protects liver allografts from ischemia/reperfusion injury. Clin Transplant 2005; 19: 507–511.
10.1111/j.1399-0012.2005.00375.x
CAS PubMed Web of Science® Google Scholar
33 St Peter SD, Post DJ, Rodriguez-Davalos MI, Douglas DD, Moss AA, Mulligan DC. Tacrolimus as a liver flush solution to ameliorate the effects of ischemia/reperfusion injury following liver transplantation. Liver Transplant 2003; 9: 144–149.
10.1053/jlts.2003.50018
PubMed Web of Science® Google Scholar
34 Lang JD Jr., Teng X, Chumley P et al. Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation. J Clin Invest 2007; 117: 2583–2591.
10.1172/JCI31892
CAS PubMed Web of Science® Google Scholar

Citing Literature

Volume11, Issue4

April 2011

Pages 786-797

AST and ASTS members - please log in via your Society website for full journal access.

AST Members >>
ASTS Members >>

rPSGL-Ig for Improvement of Early Liver Allograft Function: A Double-Blind, Placebo-Controlled, Single-Center Phase II Study†