Methicillin-resistant Staphylococcus aureus infection in liver transplantation: a matched controlled study.

UNLABELLED: The purpose of this study was to evaluate the clinical impact of methicillin-resistant Staphylococcus aureus (MRSA) infections on transplant recipients. METHODS: Liver and kidney recipients with MRSA infections were retrospectively identified and compared to an age, gender, UNOS status, organ transplanted, and transplant date matched (2:1) non-MRSA-infected recipient control group. All MRSA infections were initially treated with vancomycin, and four (33%) liver recipients were converted to linezolid therapy after failing to improve with vancomycin. RESULTS: The overall MRSA infection incidence was 1.4% (24/1770) with MRSA more common in liver (3.75%; 12/320) than kidney transplants (0.8%; 12/1450) (P < .001). The most common sites of MRSA infection were blood (42%), lung (38%), and abdomen (29%). The MRSA group had a greater percentage of prior antibiotic usage (79% vs 40%; P < .0015). The MRSA group experienced more posttransplant complications (52% vs 19%; P < .011)), and exhibited a trend toward greater length of stay in the intensive care unit (7.8 vs 4.6 days; P = .09), but not overall length of stay. Survival was similar in MRSA and non-MRSA groups (75% vs 88%; P = .17). No significant differences in mortality were noted between liver and kidney recipients infected with MRSA (P = .6). CONCLUSION: MRSA infection is associated with a higher incidence of posttransplant complications and antibiotic usage in both liver and kidney recipients compared to patients with MRSA infection.

Pilot study of early corticosteroid elimination after pancreas transplantation.

UNLABELLED: Early corticosteroid withdrawal has recently been shown to be possible in recipients of simultaneous pancreas kidney transplants; however, its feasibility in solitary pancreas recipients has not been documented. In the present study, we provide evidence that early withdrawal can be achieved in pancreas as well as pancreas-kidney recipients. METHODS: Twenty type I diabetics underwent 13 pancreas-kidney transplants and 7 pancreas-only transplants with early withdrawal (methylprednisone 6-day taper). Additional immunosuppression consisted of tacrolimus, mycophenolate mofetil, and thymoglobulin induction (five doses). RESULTS: Transplants included 13 pancreas-kidney, 6 pancreas after kidney transplant, and 1 pancreas after islet transplant. Overall mean follow-up was 7.3 months. One episode of pancreas transplant rejection after pancreas-only transplant was detected on protocol biopsy without biochemical abnormalities. One renal allograft rejection occurred 65 days posttransplant in a pancreas-kidney recipient and was graded as a Banff IA rejection. A single pancreas graft loss occurred due to thrombosis 6 days after pancreas-kidney transplantation. CONCLUSIONS: These results indicate that relatively short thymoglobulin induction (five doses) with tacrolimus and mycophenolate mofetil can allow early withdrawal in both pancreas-kidney and pancreas-only transplant recipients.

Orthotopic liver transplantation from a donor with a history of schistosomiasis.

The shortage of liver donors and the increasing number of patients on the waiting list for liver transplantation have led to a widening of the definition of suitable liver donors. In this case report, we describe transplantation of a liver from a 20-year-old brain-dead donor with a past history of schistosomiasis. Careful evaluation for schistosomiasis-related hepatic complications using hepatic function tests, clinical assessment for manifestations of portal hypertension, as well as abdominal ultrasound, and liver biopsy were performed. At 7 months follow-up, the recipient is doing well with normal liver function. Liver transplantation from a donor with a history of schistosomiasis is acceptable in carefully screened cases.

Successful surgical salvage of partial pancreatic allograft thrombosis.

BACKGROUND: Venous thrombosis remains an important cause of pancreatic graft loss. Nevertheless, reports are scarce of treatment alternatives to complete graft removal. We describe a case of surgical salvage of a partial pancreatic graft thrombosis. METHODS: We used descriptive retrospective analysis. RESULTS: A 36-year-old patient with juvenile-onset diabetes mellitus and previous living related renal transplant received a cadaveric pancreas transplant in the right iliac fossa with enteric exocrine drainage and standard vascular anastomosis. Two days after discharge from the hospital, he presented with severe right upper quadrant pain, nausea, vomiting, fever, and leukocytosis. He was taken to the operating room for exploration. The tail of the pancreas, which was kinked under the gallbladder, was necrotic and excised. The remainder of the pancreas looked normal. The patient recovered well from surgery and was discharged home 7 days later. CONCLUSIONS: Partial pancreatectomy is an acceptable surgical alternative for incomplete graft thrombosis.

Interaction of mycophenolate mofetil and HLA matching on renal allograft survival.

INTRODUCTION: The importance of HLA matching for renal transplantation outcomes has been appreciated for several decades. It has been hypothesized that as pharmacologic immunosuppression becomes stronger and more specific, the impact of HLA matching may be vanishing. Mycophenolate Mofetil (MMF) has been demonstrated to both decrease acute rejection and improve three-year graft survival. It is possible that with new immunosuppressive regimens containing MMF the relative effect of HLA matching may be altered. To determine the relative impact of HLA matching in patients on MMF we undertook an analysis of the United States Renal Transplant Data Registry (USRDS). METHODS: All primary, solitary renal transplants registered at the USRDS between January 1995 and June 1997, on initial immunosuppression that included either MMF or AZA were followed until June 1998. Primary study end points were graft and patient survival. Kaplan-Meier analysis was performed to compare AZA vs. MMF treated patients by HLA mismatch. Cox proportional hazard models were used to investigate the interaction between HLA mismatch and AZA versus MMF therapy on the study endpoints. All multivariate analyses were corrected for 13 potential confounding pretransplant variables including intention to treat immunosuppression. RESULTS: A total of 19,675 patients were analyzed (8,459 on MMF and 11,216 on AZA). Overall three year graft survival was higher in the MMF group when compared to the AZA group (87% vs. 84% respectively P<0.001). For both AZA and MMF three-year graft survival improved with fewer HLA donor-recipient mismatches. Comparing zero antigen mismatches to six antigen mismatches, the relative improvement was comparable for both patients on AZA (92.4% vs. 80.6%) and MMF (95.2% vs. 82.9%). By Cox proportional hazard model the relative risk for graft loss decreased significantly in both the AZA and MMF treated patients with increased HLA matching. CONCLUSION: The use of MMF does not obviate the benefits of HLA matching, while HLA matching does not minimize the benefits of MMF on long term graft survival. Our study would suggest that HLA matching and MMF therapy are additive factors in decreasing the risk for renal allograft loss.

Effect of waiting time on renal transplant outcome.

BACKGROUND: Numerous factors are known to impact on patient survival after renal transplantation. Recent studies have confirmed a survival advantage for renal transplant patients over those waiting on dialysis. We aimed to investigate the hypothesis that longer waiting times are more deleterious than shorter waiting times, that is, to detect a "dose effect" for waiting time. METHODS: We analyzed 73,103 primary adult renal transplants registered at the United States Renal Data System Registry from 1988 to 1997 for the primary endpoints of death with functioning graft and death-censored graft failure by Cox proportional hazard models. All models were corrected for donor and recipient demographics and other factors known to affect outcome after kidney transplantation. RESULTS: A longer waiting time on dialysis is a significant risk factor for death-censored graft survival and patient death with functioning graft after renal transplantation (P < 0.001 each). Relative to preemptive transplants, waiting times of 6 to 12 months, 12 to 24 months, 24 to 36, 36 to 48, and over 48 months confer a 21, 28, 41, 53, and 72% increase in mortality risk after transplantation, respectively. Relative to preemptive transplants, waiting times of 0 to 6 months, 6 to 12 months, 12 to 24 months, and over 24 months confer a 17, 37, 55, and 68% increase in risk for death-censored graft loss after transplantation, respectively. CONCLUSIONS: Longer waiting times on dialysis negatively impact on post-transplant graft and patient survival. These data strongly support the hypothesis that patients who reach end-stage renal disease should receive a renal transplant as early as possible in order to enhance their chances of long-term survival.

Dose response to a single intramuscular injection of recombinant adeno-associated virus-erythropoietin in monkeys.

BACKGROUND: Anemia is a significant problem in many disease states. Erythropoietin (Epo) has been used in the treatment of anemia associated with numerous chronic diseases. This study investigates the dose-response profiles of a single intramuscular (im) injection of a recombinant adeno-associated virus vector (rAAV) containing the Epo gene with the goal of achieving a sustained elevation of hematocrit (Hct). METHODS: Cynomolgus (cm) monkeys were given single injections of different doses of rAAV-cm-Epo. The biological effect of Epo gene expression was monitored by determining the Hct levels and circulating hormone levels by ELISA. Antibody to the rAAV capsid protein was also measured over the 41-week period of the experiment. RESULTS: Epo expression was noted only when 2 x 10(11) or more particles were injected. Epo was noted to be increased as soon as 1 week postinjection and was maximum in 6 to 8 weeks. This level of expression remained constant for nearly 20 weeks. Animals given the highest dose of rAAV developed a higher Hct over the first 8 weeks postinjection than those given an intermediate dose. However, the maximum levels of hemoglobin were the same. There was a weak correlation between amount of rAAV injected and capsid antibody response. CONCLUSIONS: AAV vectors are able to transduce skeletal muscle and are capable of achieving sustained expression and systemic delivery of a therapeutic protein following a single im administration. Dose responses to rAAV-Epo are achievable, although a threshold inoculum of virus is necessary to produce an effect and the therapeutic window is narrow.

Effect of intravascular volume expansion on renal function during prolonged CO2 pneumoperitoneum.

OBJECTIVE: To evaluate whether intravascular volume expansion would improve renal blood flow and function during prolonged CO2 pneumoperitoneum. SUMMARY BACKGROUND DATA: Although laparoscopic living donor nephrectomies have a considerably reduced risk of complications for the donors, significant concerns exist regarding procurement of a kidney in the altered physiologic environment of CO2 pneumoperitoneum. Recent studies have documented adverse effects of CO2 pneumoperitoneum on renal hemodynamics. METHODS: Renal and systemic hemodynamics and renal histology were studied in a porcine CO2 pneumoperitoneum model. After placement of a pulmonary artery catheter, carotid arterial line, Foley catheter, and renal artery ultrasonic flow probe, CO2 pneumoperitoneum (15 mmHg) was maintained for 4 hours. Pigs were randomized into three intravascular fluid protocol groups: euvolemic (3 mLkg/hour isotonic crystalloid), hypervolemic (15 mL/kg/hour isotonic crystalloid), or hypertonic (3 mL/kg/hour isotonic crystalloid plus 1.2 mL/kg/hour 7.5% NaCl). RESULTS: In the euvolemic group, prolonged CO2 pneumoperitoneum caused decreased renal blood flow, oliguria, and impaired creatinine clearance. Both isotonic and hypertonic volume expansions reversed the changes in renal blood flow and urine output, but impaired creatinine clearance persisted. CONCLUSIONS: Intravascular volume expansion alleviates the effects of CO2 pneumoperitoneum on renal hemodynamics in a porcine model. Hypertonic saline (7.5% NaCl) solution may maximize renal blood flow in prolonged pneumoperitoneum, but it does not completely prevent renal dysfunction in this setting. This study suggests that routine intraoperative volume expansion is important during laparoscopic live donor nephrectomy.

Pretransplant systemic inflammation and acute rejection after renal transplantation.

BACKGROUND: There are presently no established pre-transplant tests that consistently identify patients who may be at increased risk for acute rejection episodes after renal transplantation. We studied whether pretransplant serum levels of C-reactive protein (CRP), a marker for the presence of systemic inflammation, would predict the occurrence of acute rejection episodes after renal transplantation. METHODS: Pretransplant serum was tested for CRP level in 97 consecutive renal transplant recipients. Time to acute rejection after transplantation was stratified by CRP level and compared using the Kaplan-Meier method. In addition, Cox regression multivariate analysis was performed to assess whether any pretransplant covariates could independently predict the subsequent occurrence of acute rejection episodes. RESULTS: Pretransplant mean CRP levels were higher in patients who subsequently had a rejection episode versus those who had no rejection (22.2+/-2.9 vs. 11.7+/-1.8 microg/ml, respectively, P=0.003). Patients less than the median CRP value had a significantly longer time to rejection compared to those with higher CRP levels (P=0.002). Similarly, patients within the lowest CRP quartile had longer times to rejection when compared with the highest quartile (P=0.006). Cox proportional hazards regression multivariate analysis identified CRP level as the only independent pretransplant risk factor for rejection identified (P=0.044). CONCLUSIONS: Pretransplant systemic inflammation as manifested by elevated serum CRP level independently predicts the risk of acute rejection after renal transplantation and may be useful in stratifying patients at the time of transplantation according to immunological risk. Thus, assessment of pretransplant systemic inflammatory status may be helpful in prospective individualization of immunosuppression therapy after renal transplantation.

Is there a serological difference between men and women with primary biliary cirrhosis?

OBJECTIVE: Primary biliary cirrhosis (PBC) is an autoimmune disease affecting small intrahepatic bile ducts of the liver, causing destruction of the epithelium that results in eventual fibrosis and scarring. We still lack a complete epidemiological description of this disease, although interesting geographic differences in prevalence have been described. One consistent feature has been the relative scarcity of men with PBC. In fact, published ratios of women to men range from 3:1 to as high as 22:1. Thus far, the only clinical difference reported between men and women with PBC is a putative higher risk of hepatocarcinoma in men. Previous serological studies have shown that about 95% of all patients possess antimitochondrial antibodies to members of the highly conserved 2-oxo-acid dehydrogenase family of proteins, namely pyruvate dehydrogenase complex E2 (PDC-E2), branched-chain 2-oxo-acid dehydrogenase complex E2 (BCOADC-E2), and 2-oxo glutarate dehydrogenase complex E2 (OGDC-E2). However, there has been no information as to whether there is a difference in serological response between men and women. Using the serological hallmark of antimitochondrial antibodies (AMAs) and taking advantage of the availability of recombinant mitochondrial autoantigens, investigations were performed to determine if there were any serological differences between men and women with PBC. METHODS: Sera were collected from 88 patients with PBC, of whom 46 were men and 42 were women. Using a combination of immunoblotting and enzyme-linked immunoabsorbent assay (ELISA) against beef heart mitochondria (BHM), recombinant PDC-E2, BCOADC-E2, and OGDC-E2, we determined the relative autoantibody reactivities of our study population. RESULTS: Both men and women with PBC produced high titer antimitochondrial antibodies. The frequency of reactivity was similar in both groups and included, in descending order, PDC-E2, E3BP (Protein X), BCOADC-E2, and finally OGDC-E2. More importantly, antigenic specificity was nearly identical regardless of gender. CONCLUSIONS: AMAs are the serological hallmark of PBC in both men and women, and there is no significant difference in reactivity between the two groups of patients.

Dissection of an iliac artery conduit to liver allograft: treatment with an endovascular stent.

Hepatic artery thrombosis remains one of the most serious complications after orthotopic liver transplantation. Sepsis, biliary leakage and strictures, and retransplantation are often the result of this devastating complication. Because retransplantation or reoperation is sometimes not possible or advisable, other means of reestablishing hepatic artery continuity are desirable. We describe a liver transplant recipient who developed a dissection of an iliac artery conduit after retransplantation that was treated with fibrinolytic therapy followed by successful placement of an endovascular stent.

Renal transplantation at the University of Michigan 1964 to 1999.

The Michigan Kidney Transplant Program has existed for 35 years. Outcomes have improved dramatically as the one-year survival of cadaver kidney grafts increased from 25% to 85-90%. Patient deaths in the first year are now uncommon. Indications for renal transplantation have been extended to infants, the elderly, diabetics and to patients with other significant health problems who would not have been candidates in the past. Chronic administration of large doses of corticosteroids is no longer necessary and the associated morbidity is largely avoided. Improvements in immunosuppression, especially the introduction of cyclosporine, account for much of this progress. With success has come increasing demand. Unfortunately, the gap between the number of available donor kidneys and the number of patients listed for a cadaver transplant continues to increase rather than diminish. Greater acceptance of volunteer donation, as has occurred in our own program, will help to reduce this shortage. If the past forecasts the future, we can anticipate extraordinary advances during the next 35 years.

Selective targeting of Kupffer cells with liposomal butyrate augments portal venous transfusion-induced immunosuppression.

BACKGROUND: Enhanced Kupffer cell production of the immunosuppressive arachidonic acid metabolite prostaglandin E2 (PGE2) has been shown to be a mechanism of the immunosuppressive effect of portal venous transfusions (PVT). Butyrate, a four-carbon short-chain fatty acid, has received increased attention because of its ability to enhance gene transcription. This study tested the hypothesis that the intrahepatic delivery of butyrate enhances Kupffer cell PGE2 production and thus augments the immunosuppressive effect of PVT. METHODS: Butyrate was incorporated into liposomes and administered intravenously to Lewis rats. Control rats were administered liposomes without butyrate. Twenty-four hours after liposome injection, rats were administered a PVT of 1 ml of Wistar-Furth blood. Kupffer cells were isolated, and PGE2 and tumor necrosis factor-alpha levels were measured in the culture medium after 24 hr. Additionally, Kupffer cells from butyrate-treated and control animals were added to one-way mixed lymphocyte reaction cultures. RESULTS: Intrahepatic delivery of butyrate via liposomes increased Kupffer cell PGE2 (3800+/-1220 vs. 1010+/-119 pg/ml, P<0.05) and decreased tumor necrosis factor-alpha (1670+/-81 vs. 3360+/-415 pg/ml, P<0.01) production as compared with controls. Butyrate also augmented the Kupffer cell-mediated immunosuppression as demonstrated by significant depression of the mixed lymphocyte reaction (690+/-119 vs. 3850+/-148 cpm, P<0.01). CONCLUSION: The results support the hypothesis that intrahepatic delivery of butyrate enhances Kupffer cell PGE2 production, and specific targeting of Kupffer cells with liposomes containing immunomodulating agents such as butyrate may be a useful means of augmenting immunosuppression protocols in organ transplantation.

Improved oxygenation and increased lung donor recovery with high-dose steroid administration after brain death.

BACKGROUND: The number of patients waiting lung transplantation greatly exceeds the supply of donors. This study was conducted to determine the effect of high-dose steroid administration on oxygenation and donor lung recovery after brain death. METHODS: A retrospective analysis was conducted on 118 consecutive organ donors from January 1 through December 31, 1995. Eighty donors received high-dose steroids (methylprednisolone, mean 14.5+/-0.06 mg/kg) after organ procurement organization management began; a second group was composed of 38 patients who received no steroids. PaO2/FiO2 ratios were used to evaluate oxygenation. The number of single and double lungs transplanted served as the endpoint. RESULTS: No differences were noted in hemodynamics, most clinical or demographic variables and initial values of PaO2/FiO2 between groups. However, nonsteroid-treated donors showed an overall decrease in oxygenation (mean decrease in PaO2/FiO2 -34.2+/-14), whereas steroid-treated donors had a significant and progressive increase in oxygenation (mean increase in PaO2/FiO2: 16+/-14) before aortic cross-clamping (p = 0.01). Time before cross-clamping was longer in the steroid-treated patients (p = 0.003). The number of procured lungs was markedly greater in steroid-treated than nonsteroid-treated donors (25/80 patients vs 3/38; p < 0.01). CONCLUSIONS: High-dose methylprednisolone given during donor management results in improved oxygenation at organ recovery. This treatment resulted in a significant increase in the number of lungs transplanted and may have enabled donors to be treated longer.