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A M James Shapiro

Publications and source records attributed to A M James Shapiro.

At least 19 recordsLinked to original sources
PubMed2004

Impact of recipient age on outcome of ABO-incompatible living-donor liver transplantation.

BACKGROUND: Transplantation of hepatic grafts from ABO-incompatible donors is controversial because of the risk of hyperacute rejection mediated by preformed anti-ABO antibodies. The aim of the present study was to evaluate the outcome of liver transplants performed with ABO-incompatible living-donor livers and to detect risk factors for development of complications. METHODS: From June 1990 to February 2000, 66 patients, 10 months to 55 years old (median, 2 years old), received 68 ABO-incompatible living-donor liver grafts. The antibody titer and clinical course were followed prospectively during a period ranging from 3 to 11 years. RESULTS: The 5-year patient survival was 59%, 76%, and 80% for ABO-incompatible, ABO-compatible, and ABO-identical grafts, respectively (P<0.01). In patients <1 year old, > or =1 to <8, > or =8 to <16, and and > or =16 years old, 5-year survival was 76%, 68%, 53%, and 22%, respectively. The incidence of intrahepatic biliary complications and hepatic necrosis in ABO-incompatible living-related grafts (18% and 8%, respectively) was significantly (P<0.0001) greater than in ABO-compatible and ABO-identical grafts (both 0.6% and 0%, respectively). Predictive risk factors for increased mortality and morbidity were age greater than 1 year and elevated anti-ABO titers before transplantation. CONCLUSIONS: ABO-incompatible liver transplantation was carried out with relative safety in infants <1 year old but was not satisfactory in children >1 year in long-term follow-up. Patients aged >8 years remain at considerable risk of early fatal outcome because of hepatic necrosis, and new strategies to prevent antibody-mediated rejection are required.

ABO Blood-Group System↗
PubMed2004

Multiple combination therapies involving blockade of ICOS/B7RP-1 costimulation facilitate long-term islet allograft survival.

In recent years a series of novel costimulatory molecules have been identified, including inducible costimulator (ICOS). In a fully major histocompatibility complex (MHC)-mismatched mouse model of islet transplantation, we demonstrate that while monotherapy with CTLA4-Ig, CD40 ligand monoclonal antibody (CD40L mAb) or rapamycin each improves islet allograft survival, graft rejection eventually develops. Immunohistologic analysis of rejected grafts revealed increased ICOS expression, suggesting a role for this costimulatory molecule as an alternate pathway for T-cell activation. The combination of a blocking anti-ICOS mAb with each of the above therapies resulted in significantly improved islet allograft survival, confirming the importance of ICOS signaling in islet allograft rejection. Mechanistic studies conducted in mice treated with anti-ICOS mAb and rapamycin demonstrated a lack of donor-specific immunological tolerance and an absence of regulatory T-cell activity. However, a dramatic effect was seen on acute anti-donor responses whereby anti-ICOS mAb and rapamycin significantly reduced the initial expansion and function of alloreactive T cells. These data demonstrate that blockade of the ICOS/B7RP-1 pathway has potential therapeutic benefit given its role in enhancing islet allograft survival and regulating acute alloresponses in vivo.

Animals↗
PubMed2004

Assessment of the severity of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplantation.

Currently, the major indications for solitary islet transplantation are recurrent severe hypoglycemia and labile glucose control. Quantifying these problems remains subjective. We have developed a scoring system for both hypoglycemia and glycemic lability, established normative data, and used them in patients who have undergone islet transplantation. A composite hypoglycemic score (HYPO score) was devised based on the frequency, severity, and degree of unawareness of the hypoglycemia. In addition, using 4 weeks of glucose records, a lability index (LI) was calculated based on the change in glucose levels over time and compared with a clinical assessment of glycemic lability. A mean amplitude of glycemic excursions (MAGE) was also calculated based on 2 consecutive days of seven readings each day. These scores were determined in 100 randomly selected subjects with type 1 diabetes from our general clinic to serve as a control group and in patients before and after islet transplantation. The mean age of the control diabetic subjects was 38.4 +/- 1.3 years (+/-SE), with a duration of diabetes of 21.5 +/- 1.1 years. The median HYPO score in the control subjects was 143 (25th to 75th interquartile range: 46-423). The LI in the diabetic control subjects was 223 (25th to 75th interquartile range: 130-329 mmol/l(2)/h.week(-1)). The LI correlated much more closely than the MAGE with the clinical assessment of lability. A HYPO score of > or = 1,047 (90th percentile) or an LI > or = 433 mmol/l(2)/h.week(-1) (90th percentile) indicated serious problems with hypoglycemia or glycemic lability, respectively. The islet transplant patients (n = 51) were 42.1 +/- 1.4 years old, with a duration of diabetes of 25.7 +/- 1.4 years. Islet transplant patients had a mean HYPO score of 1,234 +/- 184 pretransplant, which was significantly higher than that of the control subjects (P < 0.001), which became negligible posttransplantation with the elimination of hypoglycemia. The median LI pretransplant was 497 mmol/l(2)/h.week(-1) (25th to 75th interquartile range: 330-692), significantly higher than that of control subjects (P < 0.001), and fell to 40 (25th to 75th interquartile range: 14-83) within a month after the final transplant. In those who had lost graft function, the LI rose again. The HYPO score and LI provide measures of the extent of problems with hypoglycemia and glycemic lability, respectively, complement the clinical assessment of the problems with glucose control before islet transplantation, and will allow comparison of selection of subjects for transplants between centers.

Awareness↗
PubMed2004

Short-term storage of the ischemically damaged human pancreas by the two-layer method prior to islet isolation.

A two-layer cold storage method (TLM) allows sufficient oxygen delivery to pancreata during preservation and resuscitates the viability of ischemically damaged pancreata in the canine pancreas transplant model. In this study, we applied a short-term preservation of the TLM to human pancreata after prolonged cold ischemia prior to islet isolation, and investigated the mechanisms of resuscitation of the ischemically damaged human pancreas by the TLM. Human pancreata were procured from cadaveric donors and preserved by the TLM for 3.2 +/- 0.5 h after 11.1 +/- 0.9 h of cold storage in UW (TLM group), or by cold UW alone for 11.0 +/- 0.3 h (UW group). Islet isolations of all pancreata were performed using the Edmonton protocol. Islet recovery and in vitro functional viability of isolated islets were significantly increased in the TLM group compared with the UW group. According to the criteria of the Edmonton protocol, 10/14 cases (71%) in the TLM group were transplanted to patients with type I diabetes mellitus compared with only 5/21 cases (24%) in the UW group. In the metabolic assessment of human pancreata, levels of energetic parameters (ATP, total adenylates, and energy charge) were significantly increased, and malondialdehyde (MDA) levels were significantly decreased after the TLM preservation. There was no observable change in the incidence or degree of mitochondrial injury after the TLM preservation. Additional short-term storage by the TLM resuscitates the ischemically damaged human pancreas by regenerating the energetic status and prevents further damage by oxidative stress, ultimately leading to improvements of islet recovery and in vitro function. Use of the TLM following prolonged storage in UW provides an excellent adjunctive protocol for treating human pancreata for the rigors of the islet isolation process.

Adenosine Triphosphate↗
PubMed2003

Changes in liver enzymes after clinical islet transplantation.

BACKGROUND: Clinical islet transplantation (ITx) shows insulin independence with adequate metabolic control in patients with type 1 diabetes. The aim of this study was to characterize the pattern of elevation in liver enzymes observed after ITx and to investigate any correlation between these elevations and graft characteristics or graft functional outcome. METHODS: Eighty-four consecutive ITx procedures were performed in 42 recipients. Liver function tests (LFT) were assessed during the first 40 days posttransplant. LFT elevated greater than or equal to 2.5 times above the upper limit of normal (ULN) were considered relevant. RESULTS: In 54% of the transplants, the aspartate aminotransferase (AST) increased by more than 2.5 times above ULN. A 5-fold increase in AST was observed in 27% of the procedures. The highest AST levels were observed after the first ITx. AST for all transplants peaked at 7+/-0.5 days at a value of 162+/-23 U/L (P<0.001, compared with the pretransplant values). Changes in alanine aminotransferase were similar to AST. Alkaline phosphatase increased more than 2-fold above ULN in 12% of the procedures. LFT normalized in 90% of the recipients within 4 weeks posttransplant. The remaining 10% normalized within 2 months after ITx. Graft characteristics and graft function were not significantly different when comparing LFT with greater than 5-fold versus less than 2.5-fold increase above ULN. The mean bilirubin remained within the normal range. CONCLUSIONS: After intraportal ITx, a significant increase in LFT levels was noticed in more than 50% of the procedures. These levels normalized spontaneously in 90% of the recipients within 4 weeks. No correlation between the increase in LFT and graft characteristics or graft function was found.

Alanine Transaminase↗
PubMed2003

Percutaneous transhepatic pancreatic islet cell transplantation in type 1 diabetes mellitus: radiologic aspects.

PURPOSE: To report our experience with percutaneous transhepatic pancreatic islet cell transplantation in patients with type 1 diabetes mellitus. MATERIALS AND METHODS: Between March 1999 and May 2002, 34 patients underwent 68 islet cell transplantation procedures. Patients with C-peptide-negative type 1 diabetes were selected on the basis of poor metabolic control (hypoglycemia or lability) despite compliance with optimal medical therapy. Islet cells were isolated from brain-dead donors. Access to the portal vein was gained from a right percutaneous transhepatic approach, and islet cells were infused with intermittent pressure monitoring. Twenty patients underwent two transplantations, seven patients underwent three transplantations, and seven patients underwent one transplantation. Complications during and after the procedure and postprocedural diabetic status were monitored. RESULTS: Successful portal vein cannulation and islet cell infusion were achieved in all cases. Fluoroscopy was used as the primary guidance modality in 58 of 68 (85%) procedures, and ultrasonography was used in 10 of 68 (15%). Total recorded fluoroscopy time varied from 0.6 to 103 minutes, with a median of 6.9 minutes. Potentially serious complications occurred in six of 68 (9%) procedures. Two patients developed portal venous thrombosis, and with subsequent anticoagulation therapy, one of the two developed an expanding hepatic hematoma that required surgery. Clinically important hemorrhage occurred in four patients, three of whom required blood transfusions. Of 26 patients who received completed transplants, all became insulin independent, and 81% (21 of 26) remained insulin free at 1 year. CONCLUSION: The percutaneous transhepatic approach for the implantation of islet cells into the portal vein is a safe procedure, and together with use of current cell separation techniques and an immunosuppressive regimen, offers a marked advance in the treatment of type 1 diabetes mellitus.

Adult↗
PubMed2003

Technical aspects of islet preparation and transplantation.

The introduction of insulin therapy for the management of diabetes mellitus is arguably the greatest milestone in the history of modern medicine. beta-cell replacement therapy is the only treatment that reestablishes and maintains long-term physiological normoglycemia. Until recently, successful clinical outcomes of pancreas transplantation for patients with long-standing diabetes were much superior to that of islet transplantation. Significant advances in islet isolation and purification technology, the development of more specific and less diabetogenic immunosuppressants and the prophylactic administration of antiviral agents have rekindled a worldwide interest in islet transplantation. This chapter will review the rationale of islet transplantation and the development of islet isolation and purification. The challenges facing clinical islet transplantation in the twenty-first century will also be introduced.

Animals↗
PubMed2003

Clinical islet transplant: current and future directions towards tolerance.

The ultimate goal of islet transplantation is to completely correct the diabetic state from an unlimited donor source, without the need for chronic immunosuppressive drug therapy. Although islet transplantation provides an opportunity to develop innovative strategies for tolerance in the clinic, both alloimmune and autoimmune barriers must be controlled, if stable graft function is to be maintained long-term. After islet extraction from the pancreas, the cellular graft may be stored in tissue culture or cryopreserved for banking, providing an opportunity not only to optimally condition the recipient but also to allow in vitro immunologic manipulation of the graft before transplantation, unlike solid organ grafts. As such, islets may be considered a "special case." Remarkable progress has occurred in the last three years, with dramatic improvements in outcomes after clinical islet transplantation. The introduction of a steroid-free, sirolimus-based, anti-rejection protocol and islets prepared from two (or rarely three) donors led to high rates of insulin independence. The "Edmonton Protocol" has been successfully replicated by other centers in an international multicenter trial. A number of key refinements in pancreas transportation, processing, purification on non-ficoll-based media, storage of islets in culture for two days and newer immunological conditioning and induction therapies have led to continued advancement through extensive collaboration between key centers. This review outlines the historical development of islet transplantation over the past 30 years, provides an update on current clinical outcomes, and summarizes a series of unique opportunities for development and early testing of tolerance protocols in patients.

Animals↗
PubMed2003

Improvement of pancreatic islet isolation outcomes using glutamine perfusion during isolation procedure.

During procurement, isolation, and transplantation, islets are exposed to high levels of oxidative stress triggering a variety of signaling pathways that can ultimately lead to cell death. Glutamine is an important cellular fuel and an essential precursor for the antioxidant glutathione. The aim of this study was to examine the role of intraductal glutamine administration in facilitating recovery of isolated rat islets from pancreases subjected to a clinically relevant period of warm ischemia. Islets were isolated in Sprague-Dawley (SD) rats (n = 18 per group). Pancreata in groups 1 and 2 were procured immediately while groups 3 and 4 were subjected to 30-min warm ischemia. Groups 2 and 4 were treated intraductally with 5 mM glutamine prior to pancreatectomy. Exposure to 30-min warm ischemia significantly reduced islet yield [groups 1 & 2 (nonischemia): 503 +/- 29 islets/rat vs. groups 3 & 4 (ischemia): 247 +/- 26 islets/rat; p < 0.05]. Intraductal glutamine treatment significantly improved islet yield when pancreata were subjected to 30-min warm ischemia [144 +/- 16 islets/rat without glutamine (group 3) vs. 343 +/- 36 islets/rat with glutamine (group 4), p < 0.05]. Glutamine also significantly improved islet viability (values were 50 +/- 4% in group 4 vs. 27 +/- 3% in group 3, p < 0.05). Similarly, glutathione (reduced) levels were significantly elevated in both glutamine-treated groups; however, this increase was greatest in tissues exposed to ischemia (2.76 +/- 0.04 nmol/mg protein in group 4 vs. 1.66 +/- 0.04 nmol/mg protein in group 3, p < 0.05). Intraductal glutamine administration considerably improves the islet yield, viability, and augments endogenous glutathione levels in pancreata procured after a clinically relevant period of ischemia. Intraductal administration of glutamine at the time of digestive enzyme delivery into the harvested pancreas may represent a simple yet effective tool to improve islet yields in clinical isolations.

Animals↗
PubMed2002

Human islet transplantation from pancreases with prolonged cold ischemia using additional preservation by the two-layer (UW solution/perfluorochemical) cold-storage method.

BACKGROUND: A two-layer (University of Wisconsin solution/perfluorochemical [UW/PFC]) cold-storage method delivers sufficient oxygen to the pancreas during preservation and restores the ischemically damaged pancreas. In this study, we determined whether the additional preservation by the two-layer method could improve islet recovery from human pancreases with prolonged cold storage in UW. METHODS: Human pancreases were procured from cadaveric organ donors and preserved by the two-layer method (UW/PFC) for 2.9+/-0.7 hours (mean+/-SEM) at 4 degrees C after 11.8+/-1.5 hours of cold storage in UW (UW/PFC group, n=7), or by cold UW alone for 11.3+/-0.3 hours (UW group, n=14). The selected pancreases met the criteria of having at least 10 hours of cold storage in UW. All were processed by using a standard protocol of Liberase perfusion with Pefabloc by way of the duct, gentle mechanical dissociation, and Ficoll gradient purification. Transplanted islets were selected with the criteria of the Edmonton protocol (>5,000 islet equivalents [IE]/kg recipient body weight). RESULTS: The islet recovery was significantly increased in the UW/PFC group compared with the UW group (349.2+/-44.1 x 10 and 214.0+/-31.0 x 10 IE, respectively; <0.05). This resulted in islet yields of 4.6+/-1.0 x 10 IE/g of pancreas in the UW/PFC group compared with 2.0+/-0.3 x 10 IE/g of pancreas in the UW group ( <0.05). Five of 7 cases (71%) in the UW/PFC group and 5 of 14 cases (36%) in the UW group were transplanted. The islet grafts in the UW/PFC group improved the ability of glycemic control and decreased exogenous insulin administration in all recipients. CONCLUSIONS: Improvements in methods to preserve and recover ischemically damaged human pancreases before islet isolation and transplant could be extremely beneficial to the field of clinical islet transplantation. This preliminary study shows that additional short preservation by the two-layer (UW/PFC) cold-storage method can significantly improve islet recovery and increase opportunities of islet transplantation from human pancreases after prolonged cold ischemia.

Adenosine↗
PubMed2002

Defining optimal immunosuppression for islet transplantation based on reduced diabetogenicity in canine islet autografts.

BACKGROUND: The recent results of clinical islet transplantation have improved substantially with the introduction of a more potent but less diabetogenic immunosuppressant protocol. The successful development of this protocol was based in part on the outcomes of studies reported herein, addressing the diabetogenic potential of a series of immunosuppressant agents used alone or in combination in a canine islet autograft model. Although it is recognized that failure to achieve long-term insulin independence in human islet allotransplantation has been multifactorial, with low engraftment mass, acute or chronic rejection, autoimmune recurrence, loss of islet-acinar integrity, heterotopic site, denervation, and insulin resistance all being implicated to varying degrees, avoidance of diabetogenic immunosuppression has been pivotal to the enhanced outcomes of clinical islet transplantation. We here explore the effects of clinically relevant doses of cyclosporine or tacrolimus when given alone or in combination with glucocorticoids on long-term canine islet autograft function. METHOD: Dogs (n=8) underwent total pancreatectomy, islet isolation, and intrasplenic autotransplantation and were normoglycemic with stable long-term graft function 3 months to 8 years posttransplant. The frequently sampled intravenous glucose tolerance test (FSIGT) was performed predrug (baseline), at 1 month of therapy (on drug), and again 1 month after withdrawal of therapy (postdrug). RESULTS: Monotherapy treatments with low- or high-dose prednisone, Neoral, or tacrolimus had minimal impact on islet autograft function. The combination of Neoral and prednisone led to a marked impairment in glucose decay (25% decline from 1.77+/-0.2 to 1.24+/-0.2, P<0.05), without significant change in insulin responsiveness or glucose effectiveness. However, insulin sensitivity was markedly impaired while on therapy (7.10+/-1.2 to 3.10+/-0.5, P<0.01). Importantly, glucose decay and insulin sensitivity failed to return to baseline after withdrawal of therapy. The combination of tacrolimus and glucocorticoids led to permanent and irreversible diabetes in all recipients (n=6, P<0.001). Similar treatment of healthy control dogs led to a 44% decrease in glucose decay (P<0.01). CONCLUSIONS: Immunosuppression must be specifically tailored for islet transplantation and be glucocorticoid free if insulin independence is to be sustained clinically.

Animals↗
PubMed2002

Effect of core pancreas temperature during cadaveric procurement on human islet isolation and functional viability.

BACKGROUND: Success of human pancreatic islet isolation depends largely on the techniques used during pancreas procurement and the quality of the gland. Warm ischemia of the pancreas of any duration during organ procurement may be detrimental to subsequent islet yield and functional viability of the islets. The aim of this study was to correlate pancreas procurement technique with the core temperature within the pancreas during in situ procurement to the recovery and in vitro function of isolated human islets. METHODS: Alternative pancreata were recovered from human cadaveric organ donors with needle-point myocardial temperature probes placed within the body of the pancreas. After vascular flushing with University of Wisconsin organ preservation solution, the first group of human pancreata were removed after standard liver and kidney procurement followed by in situ dissection of the pancreas. The second group of pancreata were removed using a similar protocol, except that the lesser sac was opened (and the spleen was mobilized to the midline) rapidly at the time of aortic cross-clamp. An additional 3-4 L of ice slush solution was placed behind and in front of the pancreas and replenished throughout the procurement process for the liver and kidneys. Immediately after recovery, in both groups, the pancreas was placed in cold University of Wisconsin solution and transported to the islet isolation laboratory for processing. Islets were isolated using a standard protocol of Liberase perfusion via the duct, gentle mechanical dissociation, and Ficoll purification. RESULTS: The absence of in situ ice-chilling of the entire pancreas during liver and kidney procurement caused the core pancreas temperature to rise to a peak of 18.2 degrees C; but when the pancreas was surrounded and replenished with iced saline slush, the core pancreas temperature was maintained at approximately 4 degrees C. The lower pancreas temperature correlated with a significantly higher recovery of islets in the group of pancreata surrounded with iced saline (223+/-35x10(3) IE vs. 103+/-26x10(3) IE; mean +/- SEM). Functional ability of the islets was also significantly improved in glucose static incubation, with a stimulation index of 4.4+/-0.3 in the iced-saline pancreas group versus 3.0+/-0.4 in the standard procurement group (P<0.05, paired t test). CONCLUSIONS: Procurement technique and the maintenance of a low temperature of the pancreas are critical to subsequent islet recovery and function. Maintaining a low pancreas temperature during procurement through the addition and replenishment of iced saline slush surrounding the anterior and posterior aspects of the pancreas greatly improves islet yield and functional viability of the isolated islets and is essential for success in clinical islet transplantation.

Adult↗