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Lack of progressive "restrictive" physiology after heart transplantation despite intervening episodes of allograft rejection: comparison of serial rest and exercise hemodynamics one and two years after transplantation.

It has been suggested that the cardiac allograft becomes less compliant either because of repeated episodes of rejection, chronic hypertension, or as a direct consequence of immunosuppression. A corollary to this hypothesis is that this reduction in compliance should be a progressive, rather than a static, change. To test this hypothesis, rest and exercise filling pressures, cardiac outputs, and radionuclide ventriculographic systolic and diastolic indices were measured in 20 patients at 1 and 2 years after heart transplant by means of identical protocols at both study times. Between studies 10 of 20 patients had no rejection, five of 20 had one rejection episode, and five of 20 had more than one rejection episode. There were no significant differences in resting or exercise heart rates, pulmonary wedge pressures, cardiac outputs, left or right ventricular ejection fractions, left ventricular peak filling rates, or time to peak filling between the studies at 1 and 2 years. Only resting right atrial pressure increased between year 1 and year 2 (6 +/- 2 mm Hg vs 8 +/- 4 mm Hg, p = 0.035). These data demonstrate that cardiac allograft function is unchanged between 1 and 2 years after transplantation, despite episodes of intervening rejection and continued immunosuppression. The data further suggest that the previously reported decrease in cardiac allograft compliance does not appear to be caused by a progressive intrinsic abnormality in the allograft, and that other mechanisms for "restrictive" allograft physiology should be sought.

Adolescent↗

Bile duct strictures after adult liver transplantation: a role for biliary reconstructive surgery?

There is no accurate method to determine the functional significance of bile duct strictures after liver transplantation, and although biliary reconstructive surgery (Roux-en-Y hepaticojejunostomy, HJ) is the second-line treatment in patients with persistent allograft dysfunction following failed endoscopic therapy, there is no evidence to support this approach. Liver transplant recipients with allograft dysfunction and demonstrable bile duct strictures who had undergone hepaticojejunostomy were identified from a prospective database. Preoperative and follow-up clinical, biochemical, and radiological data were collected. Perioperative liver biopsies were evaluated prospectively by two histopathologists blinded to clinical information. The biopsies were scored according to presence and severity of biliary features, fibrosis, and coexisting diseases. The effects of preoperative factors on postoperative allograft function were analyzed using SPSS statistical software. After hepatico-jejunostomy, graft function returned to normal in 8/44 patients (18%), improved in 16/44 (36%), but remained abnormal in 20/44 (45%), including 4 patients who subsequently underwent retransplantation. Hepaticojejunostomy was more likely to yield a favorable outcome (improved or normal graft function) when performed within 2 years of transplantation. Prolonged duration of biliary obstruction was associated with development of advanced graft fibrosis at the time of surgery, but neither factor significantly influenced postoperative graft function. In conclusion, biliary reconstruction successfully restores graft function in the majority of patients who present with anastomotic strictures within the first 2 years after liver transplantation. In patients presenting with bile duct strictures late after transplantation, surgery should be reserved for selected patients without histological evidence of graft fibrosis (moderate-severe) or significant nonbiliary pathology.

Anastomosis, Surgical↗

Iron accumulation in lung allografts after transplantation.

Lung transplantation has become a therapeutic option for end-stage pulmonary diseases, but after transplantation, infections and obliterative bronchiolitis (OB) are major causes of long-term morbidity and mortality. OB is a fibroproliferative disease, of poorly understood etiology, characterized by an irreversible decline in allograft function. Because diseases with tissue iron overload are characterized by fibrosis and end-organ failure, we studied the iron concentrations in BAL fluid and lung tissue in 10 lung allograft patients. BAL fluid revealed significantly elevated iron concentrations in allograft patients compared with five normal volunteers (135+/-16.54 micromol/L vs 33.65+/-7.48 micromol/L, respectively). Prussian blue staining of biopsy specimens of lung allograft tissue revealed an accumulation of iron primarily in alveolar macrophages. Immunohistochemical stains for ferritin revealed accumulation of the protein in macrophages, interstitium, vascular walls, and bronchiolar epithelium. Iron studies of the blood (serum ferritin and iron concentrations) revealed no evidence for systemic iron overload. In conclusion, patients with pulmonary allografts appear to have elevated concentrations of iron in lung tissue. This iron overload may place the allografts at increased risk of metal-mediated injury and fibrosis.

Adult↗

General surgical procedures in renal allograft recipients.

Since elective and emergent nontransplant-related surgical procedures are frequently necessary in renal allograft recipients, it becomes essential to determine the incidence and outcome of these operations in this population. For this reason, a retrospective analysis of 273 consecutive renal transplants performed in 254 patients between January 1978 and November 1985 was accomplished. During this interval, 139 patients underwent 162 nontransplant-related surgical procedures. In the 44 patients who underwent 55 emergent or semiemergent procedures, 8 patients (18 percent) died in the postoperative period. All deaths occurred in patients who underwent major abdominal or thoracic procedures for perforated viscera, gastrointestinal bleeding, or empyema and lung abscess, and all deaths were secondary to sepsis and multiple organ failure. In the survivors of emergent procedures, the mean preoperative and discharge serum creatinine levels were 2.87 mg/dl and 2.82 mg/dl, respectively. In the 95 patients who underwent 107 elective procedures, most of which were performed under general anesthesia, the operative mortality was 4.2 percent. In patients with stable renal allograft function at the time of operation, mean serum creatinine levels preoperatively and at the time of discharge were not significantly different (1.74 mg/dl versus 1.64 mg/dl). In conclusion, emergent operative procedures for intraabdominal or thoracic catastrophes are associated with a high mortality rate in renal allograft recipients. On the other hand, elective surgical procedures can be undertaken with an acceptable mortality rate and no adverse affects on graft function. Of utmost importance in these patients is the close monitoring of the immunosuppressive regimen and the early detection and treatment of potential septic complications.

Adolescent↗

Quantitative evaluation of histological features in "time-zero" liver allograft biopsies as predictors of rejection or graft failure: receiver-operating characteristic analysis application.

Harvest injury in liver transplantation adversely affects both allograft function and subsequent acute rejection. The aim of this study was to use receiver-operating characteristic (ROC) analysis to determine the strength of histological features in time-zero liver allograft biopsies as predictors of subsequent acute rejection episodes or primary allograft failure. The study population consisted of 38 patients who underwent orthotopic liver transplantation between 1989 and 1992. Time-zero biopsies and all subsequent biopsies were retrospectively reviewed. The following time-zero histological features were graded: hepatocyte swelling, centrilobular necrosis, centrilobular hemorrhage, neutrophilic infiltrate, cholestasis, and number of apoptotic cells. Eleven transplants showed primary graft nonfunction; 15 experienced one or more episodes of moderate to severe acute rejection; 4 experienced only mild rejection episodes; and 8 showed no rejection over long follow-up periods. ROC analysis showed that the presence of hepatocyte swelling in the time-zero biopsy is a significant predictor of subsequent moderate to severe rejection. Apoptotic cells, centrilobular hemorrhage, hepatocyte swelling, and centrilobular necrosis were all significant predictors of primary graft failure. No histological feature was predictive of subsequent mild rejection. In conclusion, certain histological features serve as markers for adverse outcomes in the liver transplant population. Patients who show apoptotic cells, centrilobular hemorrhage and necrosis, or hepatocyte swelling in their time-zero biopsy should be monitored carefully for signs of graft failure and rejection.

Adult↗

Combined liver and kidney transplantation in a patient with sickle cell disease.

Sickle cell intrahepatic cholestasis is a potentially fatal end-organ complication of sickle cell anemia. Renal involvement in sickle cell anemia is common, and in some cases, can present as acute renal failure. Although renal transplants have been performed in patients with sickle cell anemia since the late 1960s and a number of liver transplants have been recently performed for these complications, there has not been experience with dual organ transplantation for sickle cell anemia-related complications. We describe the case of a patient with sickle cell anemia who underwent successful combined liver and kidney transplantation after the development of acute sickle cell intrahepatic cholestasis and renal failure requiring continuous venovenous hemodialysis. The patient underwent a successful combined liver and kidney transplant with limited perioperative complications and preserved allograft function. At 22 months posttransplant, the patient expired as a result of an acute pulmonary embolus in the setting of bilateral hip fractures. Autopsy revealed no evidence of liver or kidney allograft rejection and evidence of chronic sickle cell nephropathy in the native kidney. Combined liver and kidney transplantation is a viable therapeutic option in patients with severe end-organ effects of sickle cell anemia.

Acute Kidney Injury↗

Open donor, laparoscopic donor and hand assisted laparoscopic donor nephrectomy: a comparison of outcomes.

PURPOSE: In experienced hands laparoscopic surgery has been shown to be safe for procuring kidneys for transplantation that function identically to open nephrectomy controls. While searching for a safer and easier approach to laparoscopic donor nephrectomy, hand assisted laparoscopic techniques have been added to the surgical armamentarium. We compare allograft function in patients with greater than 1-year followup who underwent open donor (historic series), classic laparoscopic and hand assisted laparoscopic nephrectomy. MATERIALS AND METHODS: The charts of 48 patients who underwent open donor, laparoscopic donor or hand assisted laparoscopic nephrectomy were reviewed. Only patients with greater than 1-year followup and complete charts were included in our study. Of these patients 34 underwent consecutive laparoscopic live donor nephrectomy and 14 underwent open donor nephrectomy. Mean patient age plus or minus standard deviation (SD) was 36.5 +/- 8.4 years for donors and 29 +/- 17 for recipients at transplantation (range 13 months to 69 years). In the laparoscopic group 11 patients underwent the transperitoneal technique, and 23 underwent hand assisted laparoscopic nephrectomy. RESULTS: Total operating time was significantly reduced with the hand assisted laparoscopic technique compared with classic laparoscopy, as was the time from skin incision to kidney removal and warm ischemic time. Average warm ischemic time plus or minus SD was 3.9 +/- 0.3 minutes for laparoscopic nephrectomy and 1.6 +/- 0.2 for hand assisted laparoscopy (p <0.05). Long-term followup of serum creatinine levels revealed no significant differences among the 3 groups. Comparison of those levels for recipients of open nephrectomy versus laparoscopic and hand assisted laparoscopic techniques revealed p values greater than 0.5. No blood transfusions were necessary. Complications included adrenal vein injury in 1 patient, small bowel obstruction in 2, abdominal hernia at the trocar site in 1 and deep venous thrombosis in 1. CONCLUSIONS: Classic laparoscopic donor and hand assisted laparoscopic donor nephrectomies appear to be safe procedures for harvesting kidneys. The recipient graft function is similar in the laparoscopic and open surgery groups.

Adolescent↗

[Replacement of mycophenolate mofetil with azathioprine in patients with renal transplants].

Numerous clinical studies demonstrated that mycophenolate mofetil (MMF) was significantly more effective in prevention of acute rejection episodes than azathioprine. Since the data supporting the long-term benefits of MMF therapy are not available, and considering the high cost of this therapy, we examined the safety of conversion from MMF to azathioprine in renal transplant patients. In 12 renal transplant patients (4 cadaveric and 8 living related donors) on triple immunosuppressive therapy (prednisone/MMF/cyclosporine) conversion from MMF to azathioprine was done after the first six to twelve post-transplant months. The majority of patients were in the low immunological risk of transplantation, and 7 (58.3%) received antithymocite globulin due to the delayed graft function. The mean follow-up period after the conversion to azathioprine was 6.4 months (range 3-12 months). Acute rejection episode was noticed only in one patient 8 months after the conversion following acute graft pyelonephritis. In all other patients graft function remained unchanged. We have concluded that the conversion from MMF to azathioprine in renal transplant patients on triple immunosuppressive therapy is safe and without detrimental effects on short-term allograft function. Long-term follow-up studies on larger number of patients are needed to confirm these observations.

Adult↗

[Simultaneous orthotopic liver and heterotopic pancreas-duodenum transplantation in a diabetic patient with end-stage liver disease].

OBJECTIVE: To study the effect of combined transplantation of the liver and the pancreas in diabetic patients with end-stage liver disease, and explore the optimal surgical procedure. METHODS: Simultaneous orthotopic liver and heterotopic pancreas-duodenum transplantations were performed in a patient diagnosed as having chronic hepatitis B, hepatocirrhosis, hepatic cellular cancer, and insulin-dependent diabetes. Immunosuppression therapy utilized prednisone, tacrolimus (FK506), mycophenolate mofetil (MMF), and simulect. The function of the liver graft, serum amylase and lipase, blood glucose, and C-peptide were monitored after transplantation. RESULTS: Insulin was withdrawn at the 6th day after operation, good liver allograft functional recovery was achieved, without such complications as pancreatitis, thrombosis, and localized infections. CONCLUSION: End-stage liver disease with concomitant insulin-dependent diabetes is the indication for combined liver-pancreas transplantations, for which simultaneous orthotopic liver and heterotopic pancreas-duodenum transplantations may constitute the optimal surgical approaches as the primary choice.

Diabetes Mellitus, Type 1↗

Nitric oxide formation in acutely rejecting cardiac allografts correlates with GTP cyclohydrolase I activity.

Inducible nitric oxide synthase (iNOS) is a prominent component of the complex array of mediators in acute graft rejection. While NO production is determined by iNOS expression, BH4 (tetrahydrobiopterin), a cofactor of iNOS synthesized by GTP cyclohydrolase I, has been considered critical in sustaining NO production. In the present study, we examined time-dependent changes in iNOS and GTP cyclohydrolase I in rat cardiac allografts. The increase in iNOS protein and mRNA in allografts was similar at POD4 (post-operative day 4) and POD6. However, the peak increase in intragraft NO level at POD4 was not sustained at POD6. This disparity could not be explained by any decrease in iNOS enzyme activity measured ex vivo with optimal amounts of substrate and cofactors. Lower iNOS activity could be explained by changes in total biopterin levels in allografts at POD4 that was decreased to baseline at POD6. Changes in biopterin production correlated with lower GTP cyclohydrolase I protein levels but not by any change in GTP cyclohydrolase I mRNA. Functionally, allografts displayed bradycardia and distended diastolic and systolic dimensions at POD6 but not at POD4. Likewise, histological rejection scores were increased at POD4 but with a secondary increased stage at POD6. It is hypothesized that the dissimilar amounts of NO at early and later stages of rejection is due to uncoupling of iNOS arising from disproportionate synthesis of BH4. These findings provide insight into a potential pathway regulating NO bioactivity in graft rejection. Such knowledge may potentially assist in the design of newer strategies to prevent acute graft rejection.

Animals↗

Transforming growth factor beta-induced connective tissue growth factor and chronic allograft rejection.

Late loss of allograft function is primarily attributed to chronic rejection (CR). There are no effective treatments for CR and the underlying cause of the disease is unknown. This study compared events that occurred within cardiac allografts placed in mice that received either anti-CD4 therapy and develop CR or anti-CD40L therapy and do not develop CR. Both TGFbeta and connective tissue growth factor (CTGF), which is induced by TGFbeta, were expressed in grafts with CR but were not expressed in grafts without CR. TGFbeta transfection of allografts in anti-CD40L-treated recipients resulted in CTGF expression and CR. However, TGFbeta transfection of syngeneic grafts did not result in CTGF expression or CR. These data indicate that TGFbeta alone is insufficient to induce CR and that CTGF is required. Further, antigenic stimulation is required for TGFbeta induction of CTGF. Thus, CTGF may serve as a therapeutic target for CR.

Animals↗

Hyperosmolar nonketotic syndrome and steroid diabetes. Occurrence after renal transplantation.

So-called steroid (glucocorticoids) diabetes developed in 11 (5.5%) of 202 patients receiving 216 renal allografts between December 1963 and June 1974. In three of the 11 patients, hyperosmolar nonketotic syndrome was present at diagnosis; all of the three recovered. Eight of the 11 patients survived with functioning allografts, and only one of the eight requires insulin. Hyperglycemia has been detected in most transplant patients tested in the immediate postoperative period. Factors (including stress from surgery and treatment with drugs such as furosemide) predispose to this condition.

Adolescent↗

Role of CXCR3 and CCR5 in allograft rejection.

UNLABELLED: Chemokines are known to participate in allograft rejection by mediating leukocyte trafficking. Despite redundancy in chemokine family, several chemokine-chemokine receptor interactions have proven critical in alloimmune responses. We sought to determine the effect of combined blockade of CXCR3 and CCR5, two critical chemokine receptors, in acute rejection. METHODS: Heterotopic heart transplantation was performed using BALB/c to B6/129 mice deficient in CCR5. Following transplantation these mice were treated with goat anti-CXCR3 serum every other day. In the control group, BALB/c hearts were transplanted in wild type B6/129 recipients and treated with goat serum alone. No immunosuppression was given to either group. Recipient mice were then assessed daily for allograft function by abdominal palpation, and graft survival was confirmed by laparotomy. RESULTS: The donor hearts in the control group were rejected at 6 +/- 1 days posttransplantation. Combined blockade of CXCR3 and CCR5 prolonged allograft survival versus control; all allografts survived to 24 days. In addition, there was a decrease in graft infiltrating CD4 and CD8 lymphocytes in the experimental group at 24 days. CONCLUSION: Combined CXCR3 and CCR5 blockade is effective in prolonging allograft survival in a fully MHC mismatched murine model. Combined chemokine blockade holds promise in control of acute rejection in organ transplantation.

Animals↗

Prevention of acute lung allograft rejection in rat by CTLA4Ig.

CTLA4 immunoglobulin (CTLA4Ig), which binds with a high affinity to B7-1 and B7-2, interrupts T-cell activation by inhibiting costimulatory signal. CTLA4Ig has been used in hopes of achieving antigen-specific tolerance induction in several solid organ transplants. In lung allograft rejection, however, its use has been controversial in terms of its effect on prevention of rejection. In the present study, the effect of murine CTLA4Ig on rat-lung allograft rejection was investigated. Rat left-lung transplantation was performed in an RT1 incompatible donor (Brown Norway; BN)-recipient (F344) combination. All allografts (n = 12) without any treatment were rejected within 7 days after transplantation. A single injection of murine form CTLA41g at a dose of 100 microg intraperitoneally (ip) or intravenously (iv) on day 1 post-transplantation achieved long-term graft survival (>90days) in 2/5 (40%) and 3/8 (38%), respectively. Moreover, 6/7 (86%) allografts in rats that received iv injection of 500 microg CTLA4Ig survived more than 90days. Allograft survival in the CTLA4Ig 500 microg iv recipient group was significantly longer than that in the no-treatment control or control immunoglobulin group (p <0.01). Four out of seven recipients bearing functional allografts for more than 90 days with the CTLA4Ig treatment accepted donor-specific skin grafts, whereas all third-party skin grafts (n=3) were rejected. Prevention of rat-lung allograft rejection could be achieved by intravenous administration of CTLA4Ig, resulting in long-term allograft survival with acceptance of donor-specific skin grafts.

Abatacept↗

Nonhuman primate models in type 1 diabetes research.

The recent success of "steroid-free" immunosuppressive protocols and improvements in islet preparation techniques have proven that pancreatic islet transplantation (PIT) is a valid therapeutic approach for patients with type 1 diabetes. However, there are major obstacles to overcome before PIT can become a routine therapeutic procedure, such as the need for chronic immunosuppression, the loss of functional islet mass after transplantation requiring multiple islet infusion to achieve euglycemia without exogenous administration of insulin, and the shortage of human tissue for transplantation. With reference to the first obstacle, stable islet allograft function without immunosuppressive therapy has been achieved after tolerance was induced in diabetic primates. With reference to the second obstacle, different strategies, including gene transfer of antiapoptotic genes, have been used to protect isolated islets before and after transplantation. With reference to the third obstacle, pigs are an attractive islet source because they breed rapidly, there is a long history of porcine insulin use in humans, and there is the potential for genetic engineering. To accomplish islet transplantation, experimental opportunities must be balanced by complementary characteristics of basic mouse and rat models and preclinical large animal models. Well-designed preclinical studies in primates can provide the quality of information required to translate islet transplant research safely into clinical transplantation.

Animals↗

Extracorporeal membrane oxygenation for perioperative support in pediatric heart transplantation.

Extracorporeal membrane oxygenation has demonstrated effectiveness for cardiopulmonary support in a variety of clinical situations. This article reviews the cases in which extracorporeal membrane oxygenation was used as an adjunct to pediatric cardiac transplantation. Twenty children, aged 7 days to 17 years, with cardiac failure refractory to conventional therapy received extracorporeal membrane oxygenation for 6 to 192 hours. In 4 cases it was used as a bridge to transplantation; in 10 cases it facilitated resuscitation of the cardiac allograft in the immediate postoperative period; and in 6 cases it complemented therapy for severe rejection in the late postoperative period. Twelve patients survived extracorporeal membrane oxygenation, 7 of whom lived more than 8 months. One long-term survivor was in the bridge-to-transplant group, 4 in the immediate postoperative group, and 2 in the rejection group. All survivors have normal cardiac allograft function. These data suggest that extracorporeal membrane oxygenation can be used to support profound cardiac failure in the pediatric heart transplant patient as a bridge to transplantation, in the resuscitation of the cardiac allograft, or to supplement a rejecting allograft.

Adolescent↗

Long-term outcome of cadaveric pediatric en bloc transplantation--a 15-year experience.

Pediatric en bloc transplantation of infant organs into adult recipients is a recognized technique to expand the number of kidneys available for transplantation. We reviewed our experience with this technique over a 15-year period to determine the long-term outcomes. Twelve patients underwent pediatric en bloc transplantation from donors aged <4 years. All transplants functioned immediately with no graft thrombosis. Two patients died 12 and 10 years posttransplant with functioning grafts. The remaining 10 recipients experienced excellent graft function with a mean follow-up time of 73.8 months (range, 10 to 169 months) with no evidence of hyperfiltration injury. We conclude that pediatric en bloc transplantations achieve excellent long-term allograft function in selected recipients.

Adult↗

Elevation of cytotoxic lymphocyte gene expression is predictive of islet allograft rejection in nonhuman primates.

Hyperglycemia and increased insulin requirements are indicators of ongoing islet allograft rejection, but there are no methods to predict or confirm rejection. Elevation of cytotoxic lymphocyte (CL) gene expression in peripheral blood (PB) has been correlated with renal allograft rejection in humans, but no published study has assessed the utility of monitoring these markers as predictors of rejection before the onset of clinical symptoms. We have established quantitative real-time PCR methods to determine the levels of mRNA transcripts for the CL genes granzyme B (GB), perforin, and fas ligand in blood samples from rhesus and cynomolgus monkeys. Four rhesus monkeys with long-term islet allograft function were studied. Antirejection (anti-CD154) therapy was discontinued, and weekly PB samples were obtained to determine whether the levels of mRNA transcripts for CL genes correlated with and/or were predictive of islet allograft rejection, defined as a loss of C-peptide production. For all monkeys, elevation of CL gene expression preceded rejection by 83--197 days, with GB as the best predictor. Elevated mRNA levels were sustained for 2--2.5 months in three of four animals and 1 month in the other, thus suggesting that the testing of these parameters may have practical applications in clinical islet cell transplantation.

Animals↗