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Kim M Olthoff

Publications and source records attributed to Kim M Olthoff.

29 records · Page 2Linked to original sources
PubMed2004

Allograft survival following adult-to-adult living donor liver transplantation.

Adult-to-adult living donor liver transplantation (AALDLT) is emerging as a method to treat patients with end-stage liver disease. The aims of this study were to identify donor and recipient characteristics of AALDLT, to determine variables that affect allograft survival, and to examine outcomes compared with those achieved following cadaveric transplantation. Cox proportional hazards models were fit to examine characteristics associated with the survival of AALDLT. Survival of AALDLT was then compared with cadaveric allografts in multivariable Cox models. Older donor age (>44 years), female-to-male donor to recipient relationship, recipient race, and the recipient medical condition before transplant were factors related to allograft failure among 731 AALDLT. Despite favorable donor and recipient characteristics, the rate of allograft failure, specifically the need for retransplantation, was increased among AALDLT (hazard ratio 1.66, 95% C.I. = 1.30-2.11) compared with cadaveric recipients. In conclusion, among AALDLT recipients, selecting younger donors, placing the allografts in recipients who have not had a prior transplant and are not in the ICU, may enhance allograft survival. Analysis of this early experience with AALDLT suggests that allograft failure may be higher than among recipients of a cadaveric liver.

Adult↗
PubMed2004

Severe preservation injury induces Il-6/STAT3 activation with lack of cell cycle progression after partial liver graft transplantation.

Partial liver graft transplantation is a surgical advance developed to overcome severe donor shortage. Survival of these grafts involves recovery from cold ischemia and reperfusion (CIR) injury, immediate regeneration and maintenance of function. Here we examined the outcome of partial liver grafts in comparison to whole grafts following CIR injury. Lewis rats subjected to orthotopic liver transplantation (OLT) with whole grafts preserved in Viaspan were compared to rats receiving 50% and 30% grafts. Outcome was analyzed by survival and regeneration. Transplantation was associated with 100% survival for all grafts, whereas 16 h preservation resulted in 100%, 20% and 0% survival in animals receiving whole, 50% and 30% grafts, respectively. CIR induced increased IL-6 levels in 50% and 30% grafts, and activation of STAT3. Cell cycle progression (cyclin D1) and regeneration (BrdU) was initiated in all livers preserved for 1 or 8 h, but not in partial grafts preserved for 16 h. In conclusion, partial grafts recover from CIR injury through similar molecular pathways to whole grafts. Partial grafts with severe injury fail to achieve cellular proliferation despite the early initiating signals. This failure could be attributed to the impaired ability of the parenchyma to respond to initiating signals for regeneration.

Animals↗
PubMed2003

Dexamethasone inhibits early regenerative response of rat liver after cold preservation and transplantation.

Regeneration is crucial for the recovery of hepatic mass following liver transplantation. Glucocorticoids, immunosuppressive and antiinflammatory agents commonly used in transplantation, are known to inhibit the expression of specific cytokines and growth factors. Some of these proteins, namely tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6), play a critical role in the initiation of liver regeneration. Following cold preservation and reperfusion of the transplanted liver, the normal recovery process is marked by increased expression of TNF-alpha and IL-6, followed by activation of cytokine-responsive transcription factors and progression of the cell cycle resulting in hepatocyte proliferation. We hypothesized that glucocorticoids may influence the repair mechanisms initiated after extended cold preservation and transplantation. Using a rat orthotopic liver transplant model, recipient animals were treated with dexamethasone at the time of transplantation of liver grafts with prolonged cold storage (16 hours). Treatment with dexamethasone suppressed and delayed the expression of TNF-alpha and IL-6 compared with animals receiving no treatment and attenuated downstream nuclear factor kappaB (NF-kappaB), signal transduction and activator of transcription 3 (STAT3), and activation protein 1 (AP-1) activation. This suppression was accompanied by poor cell-cycle progression, delayed cyclin D1 nuclear transposition, and impaired hepatocyte proliferation by BrdU uptake. Histologically, the liver grafts in treated animals demonstrated more injury than controls, which appeared to be necrosis, rather than apoptosis. In conclusion, these data provide evidence that the administration of glucocorticoids at the time of transplantation inhibits the initiation of the regenerative process and may have a deleterious effect on the recovery of liver grafts requiring significant regeneration. This may be particularly relevant for transplantation of partial liver grafts in the living donor setting.

Animals↗
PubMed2003

Overview of pediatric liver transplantation.

Liver transplantation is a successful and useful therapy for children with chronic or end-stage liver disease and those with a variety of extrahepatic metabolic diseases that can be corrected by liver replacement. Major developments in medical management, donor availability and procurement, operative techniques, and post-operative management all contributed to the dramatic improvement in outcome and growth of liver transplantation from its inception in 1963 [1,7,21]. The excellent long-term outcomes that have been achieved are the product of the coordinated efforts of liver transplant surgeons, specialists in pediatric hepatology and other medical areas, nurses, local practitioners, and the patients and their families. Future advances in transplant immunobiology, organ availability and infection control are likely to lead to still greater improvements in short and long-term outcome [34].

Child↗
PubMed2002

Toward further expansion of the organ pool for adult liver recipients: splitting the cadaveric liver into right and left lobes.

BACKGROUND: Current methods of living donor right lobe transplantation can be expanded for use in the cadaveric setting. The aim of this study is to discuss alternative methods for the management of large-for-size cadaveric livers and determine the feasibility of splitting these organs into left and right hemi-livers using similar techniques to those used in the living donor setting. METHODS: The indication for an in situ right-left split procedure was an offer of a large liver for a small recipient with a recipient-donor ratio of greater than 1.5. A total of three livers were split. Mean donor age was 33.3 (range, 22-40) years. Mean weight was 118 (range, 90-150) kg. All donors were without significant medical history and were hemodynamically stable, with normal liver function and short hospital stay. Mean duration of the procurement procedure was 235 (range, 210-270) min. Mean cold ischemia time was 8.5 hr. Mean recipient weight was 58.3 kg, and mean donor to recipient weight ratio was 2.0 (1.6-2.6). United Network for Organ Sharing statuses at the time of transplantation were 1 (n=1), 2A (n=1), and 2B (n=4). RESULTS: Immediate graft function was seen in five recipients. Delayed nonfunction was identified in one recipient of a left lobe, who did not undergo transplantation because of sepsis that resulted in death at 30 days. A second mortality occurred in a left lobe recipient, from a fungal brain abscess at 90 days. Complications related to the split included bile leaks in two patients, one necessitating operative revision. CONCLUSIONS: Splitting of livers from appropriate brain-dead donors into right and left lobes is technically and logistically feasible. The large-for-size organ provides a more substantial amount of liver tissue to each of the adult recipients, which may result in a greater graft to recipient weight ratio than the current standard that is used in the living donor grafting. The importance of this variable will need to be studied, because it may positively impact on the ability of the reduced-size graft to withstand donor-related organ system stress and injury, which is associated with brain death and the inevitable longer period of cold preservation.

Adult↗
PubMed2002

Molecular pathways of regeneration and repair after liver transplantation.

Injury to liver grafts due to cold ischemia, preservation, and reperfusion continues to be an important factor in patient outcome after liver transplantation. The development of therapeutic interventions that can limit ischemic injury, enhance recovery, and improve early graft function can have a major impact on patient morbidity. The mechanisms of hepatic preservation and reperfusion injury, the molecular pathways of graft recovery, and the cells involved remain poorly understood. With significant damage to parenchymal tissue following cold ischemic injury comes the need for replacement or repair of injured cells. In a rat liver transplant model, expression of cytokines and activation of transcription factors associated with the cell cycle resulting in cellular replication correlates with the length of cold ischemia and the degree of damage. The resident liver macrophage, the Kupffer cell, has been implicated as the primary source of inflammatory factors but may also be the source of important growth factors and cytokines that initiate cellular recovery and regeneration. Determining the source of the initiating signal is important, as manipulation of this signal can be used for therapeutic interventions in such fields as transplantation, tumor immunology, and inflammatory disease. These studies demonstrate the critical interrelation between parenchymal cells and cells of the immune system during signaling and recovery from preservation and reperfusion injury in the liver. Further defining the role of these immune cells and their products during the initiation of cellular recovery is essential for developing strategies to improve hepatocellular function after injury.

Animals↗
PubMed2002

The outcome of liver grafts procured from hepatitis C-positive donors.

BACKGROUND: The growing prevalence of hepatitis C virus (HCV) infection in the general population has resulted in an increased frequency of potential organ donors that carry the virus. The survival of grafts from HCV+ donors has not been studied in detail. METHODS: Two study populations were examined retrospectively to assess the survival of liver grafts procured from HCV+ donors. First, we evaluated the survival of all 13 HCV+ and 103 HCV- grafts that were transplanted at our institution to HCV+ recipients from January 1, 1995 to December 31, 1999. In parallel, we analyzed a subset of the United Network for Organ Sharing (UNOS) liver transplant database from the same 5-year time period that was comprised of 14,195 adult patients for whom donor and recipient HCV serologies were known. Kaplan-Meier graft survival for both patient populations was calculated based on donor and recipient HCV serologic status. A Cox proportional hazards analysis was performed on UNOS data to identify variables independently predicting graft survival. RESULTS: For transplants performed at our institution, we found no statistically significant difference in the Kaplan-Meier graft survival of HCV+ and HCV- grafts transplanted to HCV+ recipients (P=0.68). The incidence of biopsy-proven, recurrent HCV posttransplant was similar in recipients receiving either HCV+ or HCV- grafts (4/13 vs. 18/103, chi-square P=0.211). Analysis of UNOS data revealed that the survival of HCV+ grafts in HCV+ recipients was equivalent to the survival of HCV- grafts in HCV+ recipients. Unexpectedly, the survival of grafts in HCV+ recipients in general was significantly inferior to that of grafts in HCV- recipients. Multivariate analysis of all patients found recipient but not donor HCV status to be independently predictive of graft survival. CONCLUSIONS: Analysis of data from a single center and the national UNOS database suggests that transplantation of liver allografts from HCV+ donors to HCV+ recipients results in graft survival comparable to HCV- grafts transplanted to HCV+ recipients. In contrast, recipient HCV positivity is an independent predictor of graft failure compared with patients transplanted for other causes of liver disease.

Graft Survival↗
PubMed2002

Use of EBV PCR for the diagnosis and monitoring of post-transplant lymphoproliferative disorder in adult solid organ transplant patients.

Epstein-Barr virus (EBV) is known to be involved in the majority of patients who develop post-transplant lymphoproliferative disorder after solid organ transplant. We conducted a retrospective study to determine the utility of qualitative and quantitative Epstein-Barr virus polymerase chain reaction (PCR) for the diagnosis and monitoring of post-transplant lymphoproliferative disorder in adult solid organ transplant patients. Peripheral blood leukocytes obtained from 35 adult solid organ transplant patients consecutively referred for evaluation of possible post-transplant lymphoproliferative disorder, were tested by EBV PCR at the time of initial evaluation and at time points thereafter. Eighteen of 35 (51%) patients were ultimately diagnosed with post-transplant lymphoproliferative disorder by tissue biopsy. Fifteen of 18 (83%) patients were found to have EBER-1 positive tumors by in situ hybridization. EBV PCR was positive in 7 of 15 patients, suggesting a sensitivity of 39%. Seventeen patients without post-transplant lymphoproliferative disorder and three with EBER-1 negative post-transplant lymphoproliferative disorder all had negative EBV PCR tests, suggesting a specificity of 100%. We observed that declines in EBV DNA load were associated with response to therapeutic interventions, such as reduction in immunosuppression, rituximab therapy and chemotherapy. We conclude that peripheral blood EBV PCR may have a role in the diagnosis and monitoring of post-transplant lymphoproliferative disorder in adult solid organ transplant patients.

Adult↗
PubMed2002

Interleukin-6 from intrahepatic cells of bone marrow origin is required for normal murine liver regeneration.

Interleukin-6 (IL-6) is required for normal liver regeneration, but the specific cellular source of this growth factor is unknown. We investigated whether this signal originates from the resident macrophage, the Kupffer cell. Using a murine model of bone marrow transplantation, we replaced recipient bone marrow-derived cells, including Kupffer cells, with cells of donor genetic phenotype. Recipients deficient in IL-6 (IL-6(-/-)) were lethally irradiated, then rescued with 10(7) donor bone marrow cells capable of expressing IL-6 (IL-6(+/+)). Conversely, IL-6(+/+) recipients received IL-6(-/-) marrow. Successful engraftment was measured by the presence of the Y chromosome SRY locus in the livers of female recipients receiving male marrow, in situ IL-6 expression by Kupffer cells, and up-regulation of IL-6 in splenocytes after activation with lipopolysaccharide (LPS). Kupffer cell isolation in IL-6(-/-) females receiving IL-6(+/+) male marrow clearly showed the presence of the SRY locus and IL-6 disrupted allele, whereas males receiving female marrow demonstrated no SRY or IL-6 signals, confirming the extent of replacement. Replacement of these cells in IL-6(-/-) mice with IL-6(+/+) bone marrow successfully restored the regenerative response after partial hepatectomy (PHx) as indicated by signal transduction and activator of transcription 3 (STAT3) activation and hepatocyte DNA replication. Alternatively, complete replacement of Kupffer cells in IL-6(+/+) mice by transplantation with IL-6(-/-) cells significantly inhibited liver regeneration and was partially restored by administration of IL-6. This investigation demonstrates a paracrine mechanism by which cells of bone marrow origin, most likely Kupffer cells, regulate the regenerative capacity of the hepatocyte through IL-6 expression.

Animals↗
PubMed2002

Living donor liver transplantation: summary of a conference at The National Institutes of Health.

Living donor liver transplantation for adults was developed only recently in an attempt to increase the pool of donor organs; to reduce morbidity and mortality; and to improve the long-term survival of patients in need of liver transplant. Within a few brief years, this procedure has gained widespread support by both the public and transplant community. The procedure will soon be performed by nearly 80% of all liver transplant programs in the United States. Unfortunately, the long-term risks of the procedure to the recipient and especially the donor remain undefined. In response to the rapid growth and enthusiasm for this procedure, the National Institutes of Health sponsored a workshop, the goals of which were to review the scientific, medical, and nonmedical issues associated with living donor liver transplantation, and to define questions for future basic and clinical investigations which could improve the success and applicability of this procedure.

Adult↗