Gazi B. Zibari

Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients.

Everolimus allows calcineurin‐inhibitor reduction without loss of efficacy and may improve renal‐transplant outcomes. In a 24‐month, open‐label study, 833 de novo renal‐transplant recipients were randomized to everolimus 1.5 or 3.0 mg/day (target troughs 3–8 and 6–12 ng/mL, respectively) with reduced‐exposure CsA, or mycophenolic acid (MPA) 1.44 g/day plus standard‐exposure CsA. Patients received basiliximab ± corticosteroids. The primary endpoint was composite efficacy failure (treated biopsy‐proven acute rejection, graft loss, death or loss to follow‐up) and the main safety endpoint was renal function (estimated glomerular filtration rate [eGFR], by Modification of Diet in Renal Disease [MDRD]) at Month 12 (last‐observation‐carried‐forward analyses). Month 12 efficacy failure rates were noninferior in the everolimus 1.5 mg (25.3%) and 3.0 mg (21.9%) versus MPA (24.2%) groups. Mean eGFR at Month 12 was noninferior in the everolimus groups versus the MPA group (54.6 and 51.3 vs 52.2 mL/min/1.73 m2 in the everolimus 1.5 mg, 3.0 mg and MPA groups, respectively; 95% confidence intervals for everolimus 1.5 mg and 3.0 mg vs MPA: −1.7, 6.4 and −5.0, 3.2, respectively). The overall incidence of adverse events was comparable between groups. The use of everolimus with progressive reduction in CsA exposure, up to 60% at 1 year, resulted in similar efficacy and renal function compared with standard‐exposure CsA plus MPA.

Peritoneoscopic versus surgical placement of peritoneal dialysis catheters: A prospective randomized study on outcome

The most commonly used technique for insertion of peritoneal dialysis (PD) catheters is open surgical approach by minilaparotomy. Percutaneous implantation via the peritoneoscopic technique is expanding. Studies have suggested that PD catheters placed peritoneoscopically have longer survival rate than surgically placed ones. However, these studies were not randomized, where the surgical group had more patients who were obese or had prior abdominal surgery, and therefore, the selection of patients may have biased the results. We conducted a prospective randomized study in which patients underwent PD catheter placement by either the surgical or the peritoneoscopic technique. In the period from October 1992 through October 1995, 148 double-cuff, curled-end, swan-neck PD catheters were placed in 148 patients. The outcome of the 76 patients in whom the PD catheters were placed peritoneoscopically was compared with that of the 72 patients in whom the catheters were placed surgically. Early peritonitis episodes (within 2 weeks of catheter placement) occurred in 9 of 72 patients (12.5%) in the surgical group, versus 2 of 76 patients (2.6%) in the peritoneoscopy group (P = 0.02). This higher rate of infection was most likely related to a higher exit site leak in the surgical group (11.1%) as compared with the peritoneoscopy group (1.3%). Moreover, peritoneoscopically placed catheters were found to have better survival (77.5% at 12 months, 63% at 24 months, and 51.3% at 36 months) than those placed surgically (62.5% at 12 months, 41.5% at 24 months, and 36% at 36 months) with P = 0.02, 0.01, and 0.04, respectively. We conclude that peritoneoscopically placed PD catheters have a longer survival rate than surgically placed ones. Furthermore, the rate of exit site leak and early infection is lower in the peritoneoscopic method.

Small-Bowel Tumors

BACKGROUND The rarity, delayed presentation, and diagnostic difficulty of small-bowel tumors prompted this study. STUDY DESIGN Charts were reviewed retrospectively for 85 patients with 89 small-bowel tumors (22 primary malignant, 23 primary benign, and 44 metastatic) over a 10-year period (1986-1996) at Louisiana State University Medical Center-Shreveport and two affiliated hospitals in Shreveport. RESULTS Of the primary malignant tumors, 10 carcinoids and 11 duodenal adenocarcinomas were identified. Most primary benign tumors were adenomatous or hyperplastic polyps, diagnosed by esophagogastroduodenoscopy. Metastatic tumors accounted for nearly 50% of all small-bowel tumors. Across all three tumor types, the most common presenting signs and symptoms were abdominal pain and nausea and vomiting. In addition, patients with benign tumors were more commonly presented with gastrointestinal hemorrhage, and those with metastatic tumors were more likely to present with obstruction. The mean interval from the onset of signs and symptoms to operation was 54 days for primary malignant tumors and 330 days for primary benign tumors. Esophagogastroduodenoscopy and computed tomography of the abdomen were occasionally helpful in diagnosis. Among the 22 primary malignant tumors, curative resections were performed in 11 patients (for 9 carcinoids and 2 adenocarcinomas) and palliative resections were performed in 10 patients (for 9 adenocarcinomas and 1 myxoliposarcoma). One patient had carcinomatosis from colon cancer and an incidentally discovered ileal carcinoid; this carcinoid was not included in this group of resections for primary malignant small-bowel tumors. All operations for 39 (of 44) patients with metastatic tumors were palliative. The remaining 5 (of 44) patients had metastatic duodenal cancer (confirmed by esophagogastroduodenoscopy or endoscopic retrograde cholangiopancreatography with biopsy) and did not undergo laparotomy. Surgical complications occurred more commonly with metastatic than with primary malignant tumors. Patients with primary malignant tumors had a 5-year survival rate of 36%. CONCLUSIONS These findings demonstrate that small-bowel tumors are difficult to diagnose because of delayed presentation, nonspecific signs and symptoms, and lack of accurate diagnostic studies. If the overall survival of patients with small-bowel tumors is to be improved, clinicians must have a high index of suspicion and be willing to perform exploratory celiotomy early.

Mouse model of liver ischemia and reperfusion injury : method for studying reactive oxygen and nitrogen metabolites in vivo

The mouse model of liver ischemia and reperfusion injury has proven to be valuable for our understanding of the role that reactive oxygen and nitrogen metabolites play in postischemic tissue injury. This methods paper provides a detailed protocol for inducing partial liver ischemia followed by reperfusion. Liver ischemia is induced in anesthetized mice by cross-clamping the hepatic artery and portal vein for varying lengths of time, resulting in deprivation of blood flow to approximately 70% of the liver. Restoration of blood flow to the ischemic lobes enhances superoxide production concomitant with a rapid and marked decrease in the bioavailability of nitric oxide, resulting in alterations in the redox state of the liver in favor of a more oxidative environment. This hepatocellular oxidative stress induces the activation of oxidant-sensitive transcription factors followed by the upregulation of proinflammatory cytokines and mediators that ultimately lead to liver injury. This model can be induced in any strain or sex of mouse and requires 1-2 months of practice to become proficient in the surgery and animal manipulation. The roles of various reactive metabolites of oxygen and nitrogen may be evaluated using genetically engineered mice as well as selective molecular, cellular, and/or pharmacological agents.

Randomized trial of everolimus-facilitated calcineurin inhibitor minimization over 24 months in renal transplantation.

Background Strategies allowing calcineurin inhibitor minimization while maintaining efficacy may improve renal transplant outcomes. Methods A2309 was a 24-month, phase IIIb, open-label trial of 833 de novo renal transplant recipients randomized to everolimus, targeting trough concentrations of 3–8 or 6–12 ng/mL plus reduced-exposure cyclosporine A (CsA) or to mycophenolic acid (MPA) 1.44 g per day plus standard-exposure CsA. All patients received basiliximab±corticosteroids. The incidence of the primary composite efficacy endpoint and its components (treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up), renal function (serum creatinine and estimated glomerular filtration rate), and adverse events (AEs) were compared at 24 months; as per the protocol, these analyses were not noninferiority. Results Composite efficacy failure rates (95% confidence interval for difference vs. MPA) were 32.9% (−2.2%, 13.0%), 26.9% (−7.9%, 6.8%), and 27.4% at month 24 in the everolimus 3–8 and 6–12 ng/mL and MPA groups, respectively. Mean estimated glomerular filtration rate (Modification of Diet in Renal Disease) at month 24 was 52.2 (−2.1, 5.5 mL/min/1.73 m2), 49.4 (−4.8, 2.7 mL/min/1.73 m2), and 50.5 mL/min/1.73 m2, respectively. AEs were generally mild to moderate in severity and comparable between the groups. AEs leading to discontinuation were reported in 28.5% (P=0.03 vs. MPA), 30.6% (P=0.007 vs. MPA), and 20.5% of patients receiving everolimus 3–8 and 6–12 ng/mL and MPA, respectively. Conclusions Everolimus trough concentrations targeted to 3–8 ng/mL, along with a greater than 60% reduction in CsA exposure, was associated with comparable efficacy and renal function versus MPA plus standard-exposure CsA over the 2-year period. A significantly higher incidence of AEs led to discontinuation in the everolimus groups compared with the MPA group.

Post transplant lymphocele: a single centre experience

Abstract:  The occurrence of post renal transplant lymphocele is variable and the best approach to treatment is not well defined. The purpose of this study was to find out the incidence of post transplant lymphocele at our centre, identify demographic or surgical factors that may have influenced lymphocele formation, and distinguish the best approach to treatment. The charts of 138 consecutive renal transplant recipients from 1996 to 2001 were retrospectively reviewed. The demographic characteristics, comorbid illnesses, occurrence of lymphocele and its treatment modality were recorded. A total of 36 (26%) patients developed lymphoceles. There was a significant relationship between an increased body mass index (BMI) and lymphocele occurrence (P > 0.01). The recurrence rate with drainage alone was 33%, which decreased to 25% with sclerotherapy. In comparison, both laparoscopic and open surgical marsupialization had a much lower but similar recurrence rate of 12%. The laparoscopic method had less morbidity, a shortened hospital stay, and less infection than open surgery.

Improvement in 3-Month Patient-Reported Gastrointestinal Symptoms After Conversion From Mycophenolate Mofetil to Enteric-Coated Mycophenolate Sodium in Renal Transplant Patients

Background. The benefit of conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) in terms of gastrointestinal symptom burden has been evaluated previously using patient-reported outcomes. However, data are lacking concerning the sustained effect of conversion over time, and the potential impact of concomitant calcineurin inhibitor. Methods. In this 3-month, prospective, multicenter, longitudinal, open-label trial, MMF-treated renal transplant patients with gastrointestinal symptoms receiving cyclosporine or tacrolimus were converted to equimolar doses of EC-MPS. Change in gastrointestinal symptom burden was evaluated using a validated Gastrointestinal Symptom Rating Scale (GSRS). Results. A significant improvement in GSRS score was observed from baseline (2.61, 95% CI 2.54–2.68) to month 1 (1.87, 95% CI 1.81–1.93) after conversion to EC-MPS and was sustained to month 3 (1.81, 95% CI 1.74–188; both P<0.0001 versus baseline). The mean change in overall GSRS score from baseline to month 1 was −0.74 overall (cyclosporine: −0.73 and tacrolimus: −0.74; all P<0.0001 versus baseline), with a slight further improvement (−0.79) at month 3 (cyclosporine: −0.82 and tacrolimus: −0.78; all P<0.0001 versus baseline). A significant improvement in GSRS subscale scores was also observed in the total population regardless of calcineurin inhibitor at month 1, sustained to month 3 (all P<0.0001 versus baseline). The improvement in GSRS score postconversion was similar in African-American and non-African-American patients, and in diabetic and nondiabetic patients. Conclusions. This exploratory study in 728 patients demonstrates that following conversion from MMF to EC-MPS, regardless of concomitant calcineurin inhibitor, GSRS is improved and sustained over 3 months.

The use of contaminated donor organs in transplantation

Introduction. Organ transplantation has become an accepted means of treating end‐stage organ disease in recent years with acceptable patient and graft survival. Transplant recipients have an increased risk of infectious complications due to multiple factors including decreased host resistance from chronic end‐stage organ failure as well as from the immunosuppression required to prevent graft rejection. 
Hypothesis. Therefore, the use of contaminated allografts could result in life‐threatening infections in organ recipients. 
Method. In this study, transplant patients receiving organs from donors with positive blood or urine cultures, from 1993 to 1997, were retrospectively reviewed. 
Results. There was a total of 599 organ donors in our state. Forty‐six (7.5%) had positive blood cultures and 25 (4.5%) had positive urine cultures. A total of 179 patients received organs from these contaminated donors, 36 of which were transplanted at our center. In this group, there were 16 kidney, 9 liver, and 11 heart transplants. Both donors and recipients received prophylactic broad‐spectrum antibiotics, which were adjusted based on culture and sensitivity results. The most common organisms isolated from the blood were staphylococci followed by streptococci and Gram‐negative organisms. Three of the 9 liver transplant patients in the series died with a mortality of 33%. Two of the 3 patients who died had sepsis but the responsible organisms were different from those recovered from the donor. The rest (66%) did well and have acceptable liver function. None of the 16 renal transplant recipients developed an infection and all survived. One patient developed acute irreversible rejection requiring transplant nephrectomy. There was one death in the heart transplant group resulting in a mortality of 9%. This death was not attributed to infectious processes. Three of 11 heart transplant patients grew organisms in the post‐operative period that were similar to those found in the corresponding donors. However, no patient suffered significant morbidity or mortality from these infections and all recovered. The recipients of contaminated organs had levels of organ function similar to those of randomly chosen recipients of non‐contaminated organs, and both groups had similar lengths of hospital stay. 
Conclusion. Only 3 of 36 organ recipients had infections caused by organisms found in the contaminated donor organs for a rate of 8%. Contaminated donor organs seem to fare as well as non‐contaminated donor organs and there was no increase in morbidity or mortality. Contamination of organs should not be an absolute contraindication to the use of these organs in transplantation.

ICAM-1 upregulation in distant tissues after hepatic ischemia/reperfusion: A clue to the mechanism of multiple organ failure

BACKGROUND/PURPOSE Endothelial cell adhesion molecules (ECAMs) are felt to play an important role in ischemia/reperfusion (I/R) injury by causing adhesion of leukocytes to endothelial cells. It is possible that ECAMs play a role in multiple organ system failure. ICAM-1 is one of the adhesion molecules that has been shown to be upregulated in response to cytokines. This upregulation leads to leukocyte endothelial cell interaction (adhesion) and to neutrophil infiltration of the affected tissue. The purpose of our study was to measure ICAM-1 expression in the liver and other organs after hepatic ischemia/reperfusion (I/R). METHODS A laparotomy was performed on 14 Sprague-Dawley rats; 45 minutes of occlusive ischemia to the left lateral lobe was followed by 5 hours of reperfusion. The rat was injected with I125-labeled ICAM-1 MAb and I131-labeled nonbinding MAb (to control for nonspecific accumulation of ICAM-1 MAb). Entire organs were harvested and accumulated activity was measured in each organ. ICAM-1 levels were expressed as percent injected dose per gram of tissue. Control animals underwent sham laparotomy. RESULTS ICAM-1 was upregulated in the ischemic lobe of the liver, nonischemic lobe of the liver, heart, kidney, intestine, and pancreas. Up-regulation in the lung was not significant. Both the lung and liver had high constitutive levels of ICAM-1. CONCLUSIONS These data show that (1) significant hepatic upregulation of ICAM-1 after hepatic ischemia/reperfusion and (2) significant ICAM-1 upregulation in other tissues (heart, kidney, and intestine) after hepatic ischemia/reperfusion. The ICAM-1 upregulation in distant organs is likely mediated by cytokines such as tumor necrosis factor (TNF). These data show that leukocyte endothelial cell interactions in distant organs may be mediated by hepatic ischemia/reperfusion. This is a possible explanation for how failure of one organ can lead to failure of others in multiple organ system failure.

Endoscopic diagnosis and management of biliary complications following orthotopic liver transplantation

Nonoperative management of biliary complications (BC) with endoscopic retrograde cholangiopancreatography (ERCP) is a natural sequel to the emergence of choledochocholedochostomy as the preferred biliary reconstruction for orthotopic liver transplantation (OLT). Overall, therapeutic ERCPs efficacy for posttransplant BC is difficult to assess because most published data are retrospective, anecdotal, or in abstract form, and there are no prospective, randomized studies. Thus, endoscopic management of posttransplant BC must be individualized. While T-tube-related late bile leaks and ductal calculi are amenable to endoscopic therapy, its efficacy for strictures is more difficult to define. Refined surgical technique has prevented many unifocal anastomotic lesions, while multifocal strictures (for which endoscopic therapeutic experience is minimal) are increasingly prevalent. Whether endoscopic sphincterotomy is appropriate for posttransplant sphincter of Oddi dysfunction is controversial, because the disorder may be transient and the risk significant. Multicenter, prospective studies are needed to determine more accurately the optimal role of endoscopic therapy after OLT.