Correlation Between Splenectomy and Portal Vein Complications in Living Donor Liver Transplantation.

OBJECTIVES: In adults undergoing living donor liver transplantation (LDLT), the transplanted livers are partial grafts, and the portal venous pressure is higher than that observed with whole liver grafts. In patients undergoing LDLT concomitant with splenomegaly, portal venous flow is often diverted to collateral vessels, leading to a high risk of portal vein thrombosis. In such cases, occlusion of the collateral veins is important; however, complete occlusion of all collaterals without blocking the blood flow through the splenic artery causes portal hypertension and liver failure. We aimed to examine the effect of performing a splenectomy concomitant with LDLT to reduce portal vein complications. METHODS: Between 1991 and 2017, we performed 170 LDLT operations, including 83 in adults. For this cohort study, adult cases were divided into 2 groups. Group I was those who underwent LDLT without splenectomy (n = 60); Group II was those who underwent LDLT with splenectomy for the reduction of portal hypertension (n = 23). We investigated the incident rates of complications, including blood loss, lethal portal vein thrombosis (intrahepatic thrombosis), acute rejection, and so on. We also investigated the survival rates in both groups. RESULTS: The incident rate of lethal portal vein thrombosis in Group II was significantly lower than that observed in Group I (4.4% vs 21.7%, respectively, P = .0363). There were no statistically significant differences observed between the groups with respect to blood loss, survival rates, and other such parameters. CONCLUSION: LDLT concomitant with splenectomy might effectively reduce the occurrence of portal vein complications in adults.

Effect of Middle Hepatic Vein Tributaries Preserving Technique Until Just Before Graft Retrieval on Donors' Surgical Outcomes in Living Donor Liver Transplantation.

BACKGROUND: The technique of preserving the major tributaries of the middle hepatic vein (MHV) (V5 and V8) until just before graft retrieval is beneficial to minimize congestion time of the graft. However, it remains unclear whether this technique exerts a burden on donors in terms of operative time, blood loss, and postoperative hepatic dysfunction. In this study we investigated adverse effects of the MHV tributaries preserving technique until immediately before graft retrieval on donors' surgical outcomes. METHODS: Data from 71 donors who underwent right hepatectomy without MHV for a liver transplantation at our hospital from January 2002 to August 2016 were retrospectively reviewed. Donors were divided into 3 groups as follows: group 1 (n = 12), no MHV tributary reconstruction; group 2 (n = 33), single MHV tributary reconstruction; group 3 (n = 26), 2 or 3 MHV tributaries reconstruction. Donor operation time, blood loss, proportion of the remnant liver, maximum postoperative total bilirubin, aspartate aminotransferase, alanine transaminase, minimum platelets, prothrombin time, albumin level, number of days in hospital from surgery to discharge, and surgical complications were compared. RESULTS: Compared with groups 2 and 3, group 1 exhibited shorter average operational time and less average blood loss, but the difference was not significant. Comparisons of all other factors indicated no significant differences. CONCLUSION: The technique of preserving the major tributaries of the MHV until just immediately before graft retrieval does not appear to impose an apparent burden on donors.

Arterial Complication After Simultaneous Pancreas-Kidney Transplantation From an Abdominal Aortic Aneurysm Donor: A Case Report.

BACKGROUND: With the current disparity between the donor organ availability and recipient needs, various marginal organs with anatomical variations or concomitant diseases have begun to be used. We present a case of simultaneous pancreas-kidney transplantation (SPKTx) from a marginal donor with a giant abdominal aortic aneurysm who was incidentally found to be an organ donor after brain death. CASE PRESENTATION: The donor was a 66-year-old man who died of brain hemorrhage. We performed cannulation of the aorta from the distal part of left common iliac artery because the aneurysm extended from pararenal aorta to the bilateral common iliac artery. Furthermore, we prepared the left common carotid artery as the backup root of cannulation. Fortunately, we could perfuse the organs from the left common iliac artery. Subsequently, we retrieved the heart, liver, pancreas, and kidney grafts and performed SPKTx. The recipient received anatomically and functionally normal organs. At 19 days after transplantation, a rupture of the renal artery occurred on the graft side. We detected the bleeding point and it was managed quickly. CONCLUSIONS: We safely retrieved the organs from a marginal donor and performed the cooperative donation using a creative approach. We dealt with the complications through cautious postoperative management.

Effects of Subnormothermic Perfusion Before Transplantation for Liver Grafts from Donation After Cardiac Death: A Simplified Dripping Perfusion Method in Pigs.

BACKGROUND: Liver transplantation from donors after cardiac death (DCD) provides a solution to the donor shortage. However, DCD liver grafts are associated with a high incidence of primary graft nonfunction. We investigated the effectiveness of subnormothermic porcine liver perfusion, before transplantation from DCD, on graft viability. METHODS: Landrace pigs (25-30 kg) were randomly allocated to 3 groups (5 per group): heart-beating (HB) graft, transplanted after a 4-hour period of cold storage (CS); DCD graft, retrieved 20 minutes after apnea-induced cardiac arrest (respiratory withdrawal) and transplanted after a 4-hour period of CS; and subnormothermic ex vivo liver perfusion (SELP) graft, retrieved in the same manner as the DCD graft but perfused with a subnormothermic oxygenated Krebs-Henseleit buffer (21-25°C, 10-15 cm H2O) for 30 minutes in a simplified dripping manner, without a machine perfusion system, after the 4-hour period of CS, and subsequently transplanted. RESULTS: Although all animals in the HB group survived for >7 days, all animals in the DCD group died within 12 hours after transplantation. In the SELP group, 2 recipients survived for >7 days and another 2 recipients were killed on day 5. The survival rate was significantly better for SELP than for DCD grafts (P = .0016). The values of tumor necrosis factor α were not significantly different between the SELP and HB groups. Preserved structure of the parenchyma was observed in the SELP group on histologic examination. CONCLUSIONS: A simplified subnormothermic perfusion before liver transplantation is expected to improve graft viability and survival.

A Case of Successful Simultaneous Pancreas-Kidney Transplantation Using the Injured Pancreas Graft.

OBJECTIVE: Graft injuries sometimes occur and may cause complications such as the leakage of pancreatic secretions, which is often lethal. We report our experience of a case of successful simultaneous pancreas-kidney transplantation using injured pancreas graft. PATIENTS AND METHODS: The recipient was a 57-year-old woman with type 1 diabetes mellitus, and the donor was a 30-year-old man with a brain injury. In the donation, the pancreas parenchyma, splenic artery, and gastroduodenal artery were injured iatrogenically. We therefore reconstructed these arteries using vessel grafts and then performed simultaneous pancreas-kidney transplantation. RESULTS: Five days after transplantation, we noted a high titer of amylase in the ascites; therefore, we performed an urgent laparotomy. The origin of the amylase was the injured pancreatic parenchyma, and continued washing and drainage were carried out. We reconstructed the duodenojejunostomy using the Roux-en-Y technique to separate the passage of food from the pancreas graft to prevent injury to other organs due to exposure to pancreatic secretions. Thereafter, we inserted a decompression tube into the anastomosis thorough the blind end of the jejunum. Finally, we inserted 3 drainage tubes for lavage. Following this procedure, the patient recovered gradually and no longer required hemodialysis and insulin therapy. She was discharged from our hospital 56 days after transplantation. CONCLUSION: The restoration of the injured graft was possible by management of pancreatic secretions and use of the donor's vessel grafts. Shortage of donors is a problem throughout the world; thus, it is important to use injured grafts for transplantation if possible.

Splenectomy for Severe Intestinal Bleeding Caused by Portal Hypertensive Enteropathy After Pediatric Living-Donor Liver Transplantation: A Report of Three Cases.

BACKGROUND: The incidence of portal vein thrombosis after pediatric living-donor liver transplantation (LDLT) is reported to be higher than that after deceased-donor or adult liver transplantation. Portal vein thrombosis can cause portal hypertension and related complications, including portal hypertensive gastropathy or portal hypertensive enteropathy (PHE). PHE, in particular, can lead to severe intestinal bleeding, which is extremely difficult to treat. However, the pathogenesis of and appropriate treatment for PHE are not clearly defined, especially after pediatric LDLT. METHODS: Herein, we report three cases of refractory intestinal bleeding caused by PHE after pediatric LDLT, which were treated with splenectomy. RESULTS: The time between LDLT and splenectomy was 43, 92, and 161 months, respectively. All 3 patients were discharged from the hospital without any peri-operative complications and were doing well, with no adverse effects at 174, 81, and 12 months after splenectomy, respectively. Although shunt surgeries, including the use of a meso-Rex shunt, are reported to be a useful option when the portal vein is completely occluded, adhesiotomy around the liver graft would be required, which could damage the hepatopetal collateral vessels that maintain portal vein flow to the graft. Therefore, shunt surgeries, which can lead to re-transplantation, are considered to be highly risky as a first-line treatment option, particularly considering the limited accessibility to deceased donor organs in our country. CONCLUSIONS: Our data demonstrate that simple splenectomy, although considered a palliative treatment, can be a safe and effective method to control severe intestinal bleeding caused by PHE after pediatric LDLT.

Poor Long-Term Outcomes of Adult Liver Transplantation Involving Elderly Living Donors.

BACKGROUND: Donor hepatectomy requires particular care to ensure the safety of the donor and the success of the liver transplantation. The aim of this study was to evaluate the effect of donor age on the postoperative outcomes of liver transplant donors and the long-term graft survival rates. METHODS: We retrospectively reviewed 56 consecutive adult patients who underwent living donor liver transplantation at our institution between April 2001 and August 2010. Donors and recipients were divided into 2 groups, based on the age of the donor: the elderly donor group (donor age ≥50 years) and the younger donor group (donor age <50 years). Perioperative variables, postoperative complication rates, and long-term graft survival rates were compared between the 2 groups. RESULTS: The average ages in the elderly donor group and younger donor group were 58 years and 32 years, respectively. Baseline data excluding the age of the donor did not differ between the groups, nor did the overall complication rates of the donors. Hospital stays were longer in the elderly donor group than in the younger donor group (25 vs 18 days, P < .05). The 1-, 3-, and 5-year graft survival rates were 80%, 60%, and 50% in the elderly donor group, and 89%, 87%, and 82% in the younger donor group, respectively (P = .0002). CONCLUSIONS: Donor hepatectomy can be performed safely in elderly patients. However, compared with younger donors, their hospital stays were longer and the graft survival rates were shorter.

The Significance of Screening for HLA Antibodies in the Long-Term Follow-up of Pediatric Liver Transplant Recipients.

BACKGROUND: Post-transplant donor-specific anti-HLA antibodies (DSA) reportedly have detrimental effects on the outcomes of organ transplantation. However, the prevalence of post-transplant DSA in the long term after pediatric liver transplantation remains unclear, and the significance of post-transplant DSA is unknown. The aim of this cross-sectional study was to determine the prevalence of and characteristics of patients with post-transplant DSA. MATERIALS AND METHODS: Of the 84 pediatric liver transplant recipients who were followed up in the outpatient department of our institution, 34 patients with available HLA typing data were included after they or their parent(s) provided informed consent for DSA evaluations. Luminex single-antigen bead assays were performed, and a mean fluorescence intensity of ≥1000 was used as the cut-off for a positive reaction. RESULTS: No class I DSA were detected, whereas class II DSA were detected in 11 patients (32%). There were no differences in age at transplantation, immunosuppressive drugs, or follow-up period between the DSA-positive and DSA-negative patients. The rate of positive pre-transplant complement-dependent cytotoxicity crossmatch was higher with class II DSA than without, although the difference was not statistically significant. CONCLUSIONS: The utility of screening for class I DSA was insignificant in the long-term follow-up of pediatric liver transplant recipients. The prevalence of class II DSA was relatively high; therefore, screening for class II DSA might be justified, although a follow-up survey of the association between post-transplant class II DSA and the long-term clinical course needs to be conducted.

Relationship Between Bile Duct Reconstruction and Complications in Living Donor Liver Transplantation.

OBJECTIVES: In living donor liver transplantation (LDLT), the recipient bile duct is thin and short. Bile duct complications often occur in LDLT, with persistent long-term adverse effects. Recently, we began to perform microsurgical reconstruction of the bile duct. The purpose of this study was to investigate the relationship between bile duct reconstruction methods and complications in LDLT. METHODS: From 1991 to 2014, we performed 161 LDLTs (pediatric:adult = 90:71; left lobe:right lobe = 95:66). In this study, we retrospectively investigated the initial bile duct complications in LDLT and performed univariate and multivariate analyses to identify the independent risk factors for complications. RESULTS: The most frequent complication was biliary stricture (9.9%), followed by biliary leakage (6.8%). On univariate and multiple logistic regression analysis, the independent risk factors for biliary stricture were bile leakage (P = .0103) and recurrent cholangitis (P = .0077). However, there were no risk factors for biliary leakage on univariate analysis in our study. The reconstruction methods (hepaticojejunostomy or duct-to-duct anastomosis) and reconstruction technique (with or without microsurgery) were not risk factors for biliary stricture and leakage. CONCLUSION: In this study, the most frequent complication of LDLT was biliary stricture. The independent risk factors for biliary stricture were biliary leakage and recurrent cholangitis. Duct-to-duct anastomosis and microsurgical reconstruction of the bile duct were not risk factors for biliary stricture and leakage.

Successful Case of Somatostatin Analog Stopping Gastrointestinal Bleeding, One of the Most Frequent Complications After Simultaneous Pancreas-kidney Transplantation: A Case Report.

OBJECT: Pancreas transplantation has the highest surgical complication rate of all routinely performed organ transplantation procedures. The complications are not only caused by the pancreas itself but also occur due to issues with the transplant recipient. We report the case of a patient who experienced massive gastrointestinal bleeding after simultaneous pancreas-kidney transplantation (SPK), which was stopped successfully using somatostatin analog. PATIENTS AND METHODS: The patient was a 45-year-old woman with diabetes mellitus type 1 who underwent SPK with enteric drainage. She had melena 5 days after SPK. RESULTS: At first, we suspected that the melena was caused by the transplanted duodenum because of rejection and ischemic changes. The patient experienced severe bleeding 9 days after SPK. We quickly performed open surgery and inserted an endoscope from the recipient's ileum to investigate the transplanted duodenum. However, no bleeding source was found, including in the transplanted duodenum and the recipient's ileum end. We determined that the bleeding source was the recipient's ascending colon. We attempted to perform endovascular treatment but could not detect the source of the bleeding; therefore, we used somatostatin analog to let the blood vessels shrink and reduce pancreatic output. Thereafter, the function of the transplanted pancreas and kidney gradually recovered, and the recipient was discharged 154 days after SPK. CONCLUSION: Gastrointestinal bleeding is a lethal complication and has several different causes, such as mucosal rejection, ischemic changes, and exocrine output of the pancreas graft. Somatostatin analog is one of the most acceptable treatments for patients who have gastrointestinal bleeding after SPK.

Insulin resistance as a risk factor for new-onset diabetes after kidney transplantation.

INTRODUCTION: New-onset diabetes after transplantation (NODAT) is a serious and common complication after kidney transplantation. Insulin resistance, together with ß-cell dysfunction, plays an essential role in the development of diabetes. Homeostasis model assessment of insulin resistance (HOMA-IR), which is calculated as [fasting plasma glucose (mmol/L) × fasting insulin (mU/L)]/22.5, is widely used as an index of insulin resistance. However, the correlation between pretransplant HOMA-IR and the development of NODAT has not been fully established. METHODS: We performed a retrospective study of 44 nondiabetic patients who underwent living donor kidney transplantation in our hospital from July 2006 to October 2009. We compared the HOMA-IR and demographic variables of patients who developed NODAT with those who did not. RESULTS: Five patients (11.4%) developed NODAT within 3 years after transplantation. There were no differences in demographic variables between patients who developed NODAT and those who did not. Logistic regression analysis revealed that HOMA-IR was a predictive factor of NODAT (odds ratio, 2.88; 95% CI, 1.11-9.59; P < .05). CONCLUSIONS: Our results indicate that high HOMA-IR might be an important predictive factor for NODAT. These findings underline the importance of routine pretransplant measurements of fasting plasma glucose and serum insulin for evaluating HOMA-IR.

Effects of elevated tacrolimus trough levels in association with infectious enteritis on graft function in renal transplant recipients.

BACKGROUND: The bioavailability of oral tacrolimus is influenced by enterocyte metabolism, which involves CYP3A and P-glycoprotein. Viral infection-induced intestinal inflammation damages the enterocytes and causes unfavorable elevations in blood tacrolimus levels in transplant recipients, which may lead to nephrotoxicity. METHODS: From May 2000 to May 2011, 56 renal transplant recipients receiving tacrolimus at our hospital suffered from infectious enteritis with diarrhea. We investigated the tacrolimus trough levels before and after the onset of enteritis and evaluated the influence of elevated tacrolimus trough levels on the rate of changes in serum creatinine levels. RESULTS: Elevated tacrolimus trough levels were observed in 52 recipients (93%) after the onset of diarrhea, and the mean value was 2.3 times higher than that before the onset of enteritis (P = .0175). Tacrolimus trough levels returned to their previous levels 2 weeks after the onset of enteritis, even in recipients with >2-fold increase, following dose adjustments. Serum creatinine levels did not significantly differ between recipients with >2-fold increase in tacrolimus trough levels and those with <2-fold increase in trough levels during a 6-month period after the onset of enteritis. CONCLUSIONS: Elevations in the tacrolimus trough levels due to infectious enteritis with diarrhea can improve in ∼2 weeks by adjusting the tacrolimus dosage. Such temporary elevations in the tacrolimus trough levels may not produce serious nephrotoxicity even in recipients with remarkably elevated trough levels.

Medication compliance in renal transplant patients during the Great East Japan Earthquake.

INTRODUCTION: Oral immunosuppressant suspension induces renal graft dysfunction in renal transplant patients. After the Great East Japan Earthquake, not only were drugs lost in the tsunami, but visiting hospitals became difficult owing to information and transportation network disruption. We investigated medication compliance in renal transplant patients and actions taken immediately after the earthquake. MATERIALS AND METHODS: We included 315 patients who were visiting our outpatient department as of March 11, 2011, from June to August 2011. Information was collected from questionnaires, medical records, and outpatient diaries. RESULTS: The questionnaire collection rate was 93%, with valid replies from 296 patients. One hundred eighty-five patients (62%) had stockpiled oral medications before the earthquake; of these, 131 (44%) always carried medications with them. Forty-five patients (16%) had difficulties with continuing oral immunosuppressants after the earthquake (supply delay, 29 patients; drugs lost in tsunami, 9; others, 10). Of these 48, oral medication was suspended in 18 for 3 days at maximum. As to outpatient prescriptions, out-of-hospital prescriptions were sent by fax to 17 patients, prescription drugs were sent from our hospital by mail or home delivery services to 11, and prescriptions were given to 13 who visited other hospitals. Because of the difficulty in requesting prescriptions from disaster base hospitals, drugs prescribed at our hospital were delivered to 3 severely damaged institutions for patients living in surrounding areas. After the earthquake, our usual self-management guidance proved effective. CONCLUSION: Further examination of the infrastructure for communicating with patients and supplying drugs is needed.

Body fat percentage as a marker of new-onset diabetes mellitus after kidney transplantation.

BACKGROUND: New-onset diabetes after transplantation (NODAT) is a serious metabolic complication that can follow kidney transplantation. Several risk factors, including obesity, have been related to NODAT development. Obesity is defined as an excessive accumulation of body fat, and body fat percentage (BF%) has been commonly measured by different techniques, including bioelectrical impedance analysis. However, the correlation between an increase in BF% and the development of NODAT during outpatient follow-up has not yet been explored. We aimed to elucidate the association between BF% changes and the development of NODAT. METHODS: We performed a retrospective study involving 45 patients without diabetes who underwent kidney transplantation in our hospital between March 2008 and December 2010. We compared the BF% and demographic variables of patients who did and did not develop NODAT during follow-up. RESULTS: Four patients (8.9%) developed NODAT during a mean follow-up period of 30.3 months. The post-transplantation increase in BF% was much higher in NODAT+ patients than the NODAT- patients. Univariate analysis indicated that the rate of increase in BF% was a risk factor for NODAT (hazard ratio [HR], 1.08 [1.02-1.18]; P < .005). CONCLUSIONS: A large increase in BF% may be a risk factor for NODAT. These findings underline the importance of routine BF% measurements in medical practice.

The relationship between recurrences and immunosuppression on living donor liver transplantation for hepatocellular carcinoma.

OBJECTIVES: Living donor liver transplantation (LDLT) offers timely transplantation for patients with hepatocellular carcinoma (HCC). If ABO-incompatible LDLT is feasible, the needs for pretransplantation treatments may be eliminated. It is known that negative impacts of immunosuppression are limited among LDLT for HCC, however, we believe that excessive immunosuppression is one of the risk factors for recurrence. We compared the impacts of immunosuppression for LDLT with hepatectomy outcomes for HCC. METHODS: From 1991 to 2010, we performed 144 LDLTs including 14 patients with HCC. Seven met the Milan criteria. Immunosuppressive therapies were based on tacrolimus plus methylprednisolone plus CD25 antibody. For ABO-incompatible cases, we also used mycophenolate mofetil and rituximab. Five cases underwent strong imunosuppressive therapy (steroid pulse or rituximab) within 180 days. In addition, we performed hepatectomy for 180 HCC cases from 1997 to 2010. RESULTS: Overall survival rates of the LDLT cohort and hepatectomy groups were similar, but disease-free 5-year survival rates (DFS) of the LDLT cohort were significantly better than those of the hepatectomy group (total = 54.4% versus 27.4%, within the Milan criteria cases, 71.4% versus 33.8%). Thus, the negative impact of immunosuppression on recurrence was less than the benefit of a whole liver resection. Among strongly immunosuppressed cases, 5-years DFS rates were significantly worse than among other immunosuppressed cases (20.0% versus 76.2%). Upon univariate analysis, the factors associated with HCC recurrence were alpha-fetoprotein levels and steroid doses within 180 days, but multivariate analysis did not show a predictor for recurrence. CONCLUSION: Patients who are strongly immunosuppressed may have several negative impacts for recurrences. More careful indications must be selected for ABO-incompatible cases.

Outcomes of renal transplantation after end-stage renal disease due to diabetic nephropathy: a single-center experience.

BACKGROUND: Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) worldwide. However, data on renal transplantation outcomes in diabetic nephropathy among Japanese remain inadequate. This retrospective study was conducted to summarize our renal transplantation experience in diabetic ESRD patients. METHODS: We retrospectively studied 462 patients who underwent kidney transplantation between 1989 and 2011, including 23 with diabetic ESRD (DM group) and 439 with nondiabetic ESRD (NDM group). We compared demographic and clinical variables between these 2 groups. RESULTS: Mean age was higher in the DM group (48.0 vs 38.2 years; P < .001), and there was no significant difference in gender or donor source. The 1-, 3-, and 5-year graft survival rates in the DM and NDM groups were 100% vs 98.3% (ns), 82.4% vs 94.9% (P < .05), and 66.7% vs 90.3% (P < .01), respectively. The 1-, 3-, and 5-year patient survival rates were 95.0% vs 96.5% (ns), 88.2% vs 95.2% (ns), and 84.6% vs 92.9% (ns), respectively. One patient (4.3%) in the DM group and 6 (1.4%) in the NDM group died from cardiovascular disease during the follow-up period (ns). The incidence of rejection did not differ between the DM and NDM groups. There were no significant differences in the total infection rate or the urinary tract infection rate. CONCLUSIONS: Renal transplantation in diabetic ESRD patients yields good results in terms of patient survival and complications, suggesting that renal transplantation can be performed in these patients and should become a more established treatment option.

Effect of synthetic protease inhibitor gabexate mesilate on attenuation of coagulant activity and cytokine release in a rat model of islet transplantation.

BACKGROUND: The instant blood-mediated inflammatory reaction (IBMIR), in which the activation of coagulation cascade plays a key role, is one of the serious obstacles to successful islet engraftment. Gabexate mesilate (GM) is well known to elicit anticoagulant and antiinflammatory effects. The aim of this study was to evaluate the effect of GM on syngeneic IBMIR. METHODS: Syngeneic rat islet grafts (2.5 IEQ/g) were transplanted intraportally into 2 groups (control group and GM group; n = 10-11) of streptozotocin-induced diabetic rats. The GM group was injected intravenously with GM for 30 minutes before islet infusion to 1 hour after. The control group was injected with equivalent amount of saline solution. Plasma samples were collected before and 0.5, 1, 3, 6, and 24 hours after transplantation, and several proinflammatory mediators, including interleukin-6 and high-mobility group Box 1 were measured. Curative rate, intravenous glucose tolerance test, and insulin amount in the recipients' livers were also evaluated. RESULTS: Little difference was observed in any proinflammatory mediators. Whereas none of the animals in the control group became normoglycemic, 2 of 6 rats transplanted with the same number of islets in the GM group became normoglycemic during the study period. The glucose tolerance response was significantly ameliorated in the GM group compared with the control group (P < 0.001). The insulin amount in the liver of the recipients was considerably higher in the GM group (5.6 ± 4.1 vs 12.6 ± 5.3 ng/IEQ; P < .05). CONCLUSIONS: These data suggest that GM improves islet engraftment not through suppressing the proinflammatory cytokines but as an anticoagulant. We therefore think that GM could be a useful anticoagulant to control IBMIR induced in clinical islet transplantation, although antiinflammatory reagents are considered to be needed for the ideal regimen.

Expression of receptors for anaphylatoxins C3a and C5a on rat islet preparations.

BACKGROUND: Complement activation has been implicated in the development of the instant blood-mediated inflammatory reaction (IBMIR). In particular, anaphylatoxins C3a and C5a elicit a broad range of proinflammatory effects, including chemotaxis of inflammatory cells and cytokine release. We have previously shown that 2 types of receptors for C5a are expressed on isolated islets. In the present study, we investigated this component in detail. METHODS: C3aR, C5aR, and C5L2, together with CD11b and CD31, on freshly isolated islets (fresh group) and islets cultured with (cytokine group) or without (culture group) TNF-α, IL-1ß, and IFN-γ for ∼12 hours were analyzed by flow cytometry. In addition, these 3 kinds of receptors were analyzed on nonendocrine cells. RESULTS: C5aR and C5L2 were expressed on the isolated islets (C5aR: 7.91 ± 2.83%; C5L2: 2.45 ± 1.34%) and the expression of both C5a receptors was markedly attenuated by culture for 12 hours (C5aR: P < .005; C5L2: P < .05). Compared with the culture group, the expression was significantly up-regulated in the cytokine group (C5aR: P < .05; C5L2: P = .05). C5aR-positive cells expressed CD11b but not CD31. In contrast to islets, nonendocrine cells expressed C5L2 predominantly. C3aR was scarcely expressed on isolated islets or nonendocrine cells. CONCLUSIONS: These data suggest that C5aR and C5L2 are expressed on CD11b-positive leukocytes in islet preparations. Depletion of C5a receptors by culturing appropriately could be an attractive therapeutic strategy in clinical islet transplantation.

Rituximab therapy and reduction of immunosuppression to rescue graft function after renal posttransplantation lymphoproliferative disorder found by macrohematuria in a pancreas and kidney transplant recipient: a case report.

INTRODUCTION: Posttransplantation lymphoproliferative disorder (PTLD) remains an uncommon complication of solid organ transplantation, with a high mortality rate reported after conventional therapies. Epstein-Barr virus (EBV) may cause PTLD, but most EBV infections after transplantation are clinically silent reactivations, so the detection of PTLD is often delayed. Recently we experienced the rare case of intrarenal graft PTLD found by macrohematuria in a simultaneous pancreas and kidney transplant recipient. The grafts were saved by treatments with rituximab, cyclophosphamide, hydroxydaunorubicin, and prednisone-based chemotherapy (R-CHOP) after reduction of immunosuppression (IR). METHODS: This 37-year-old man with insulin-dependent diabetes underwent simultaneous pancreas and kidney transplantation (SPK) with enteric drainage. Six months after transplantation, he displayed macrohematuria, which we investigated by blood tests, computer tomography (CT) scan, positron emission tomography (PET)-CT, and magnetic resonance imaging, recognizing a tumor in the transplanted renal graft. An open biopsy showed a CD20-positive PTLD. We started treatments with IR, rituximab (375 mg/m(2), weekly for 2 cycles) and R-CHOP therapy: rituximab (375 mg/m(2)) plus CHOP every 3 weeks for 6 cycles. RESULTS: IR and R-CHOP therapy achieved a complete remission (CR). CR has continued for 14 months at the time of writing. The maximum level of EBV DNA was 259 copies/µg DNA, but 2 months after these therapies, the level had decreased to normal. The patient had no impairment of pancreas and kidney graft functions. CONCLUSIONS: The outcome of intragraft PTLD in the kidney of an SPK recipient suggested that the negative impact of IR on graft function may be compensated by the immunosuppressive effects of rituximab, allowing reduced immunosuppression during chemotherapy.

C5a-inhibitory peptide combined with gabexate mesilate prevents the instant blood-mediated inflammatory reaction in a rat model of islet transplantation.

BACKGROUND: The instant blood-mediated inflammatory reaction (IBMIR), in which the activation of both the coagulation and the complement cascades plays a key role, is one of the main obstacles to successful islet transplantation. At present, however, no useful protocol is clinically available. Therefore the aim of this study was to examine whether complementary peptides against an active region of C5a were safe to suppress IBMIR, owing to their extremely low molecular mass, when combined with a clinically available anticoagulant. METHODS: Complement receptors on pancreatic tissues and isolated islets were analyzed by immunohistochemical staining and flow cytometry. Two-and-a-half islet equivalents per gram of syngeneic rat islet grafts were transplanted intraportally into 4 groups of 10-13 animals each after streptozotocin induction of diabetes: control, gabexate (Gab), C5a-inhibitory peptide (C5aINH), and C5aINH plus Gab. Recipients injected with equivalent amounts of saline solution served as control subjects. Plasma samples were collected at 0, 0.5, 1, 3, 6, and 24 h after transplantation for analysis. We also evaluated the curative rate, intravenous glucose tolerance test, and insulin amounts in the liver of the recipients. RESULTS: C3a receptor (C3aR) was scarcely expressed on the isolated islets with relatively strong expression of C5a receptor (C5aR): C3aR: 0.44 +/- 0.38%; C5aR: 7.91 +/- 2.83%). However, C5aR was not expressed on pancreatic tissues before the isolation procedures. Thrombin-antithrombin complex was significantly suppressed in the 3 treated groups (P = .0015). The curative rate was also significantly improved (0% vs 33% vs 67% vs 100%, respectively; P = .03). Glucose tolerance was significantly improved among the 3 treated groups (P < .0005). Insulin amounts in the liver were considerably higher among treated versus control hosts. Notably, the treatment did not affect the increased body weight of the recipient. CONCLUSIONS: This study suggested that C5a-inhibitory peptide combined with gabexate mesilate may be a useful approach to control the IBMIR induced in clinical islet transplantation and one that is free of side effects.