Lack of correlation between serum levels of mycophenolate mofetil and kidney transplant outcome in tacrolimus-based immunosupression.
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Biomedical subjects
Publications and source records attributed to F Citterio.
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Steroids are a staple of immunosuppressive therapy in transplantation. Despite the high incidence of side effects associated with steroid therapy, the risk of increased rejection with steroid discontinuation has often outweighed the potential benefits of improved quality of life. With the advent of a number of newer immunosuppressive agents, however, there has been a renewed and heightened focus on the possibility of steroid avoidance or withdrawal protocols that do not place the patient or graft at undue risk. Much of the work in this area is preliminary, and large long-term trials are needed to reach definitive conclusions. Clinical trials need to resolve patient selection criteria for steroid discontinuation, effective and appropriate baseline immunosuppression, and the optimal timing of steroid withdrawal. Appropriate monitoring parameters also need to be developed to reduce the risk of acute rejection, and follow-up of patients who have been withdrawn from steroids will become increasingly important. Nonetheless, the hope is that newer immunosuppressive agents will soon allow for a reduction in steroid use in appropriate patients, with an improvement in patients' long-term quality of life, and fewer healthcare-related costs.
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BACKGROUND: To determine whether the incidence of HHV-8/KSHV infection and the risk of developing KS among organ transplant recipients differ by type of organ transplanted, we calculated the rate of HHV-8/KSHV seroconversion and the risk of developing KS among renal and liver transplant recipients. METHODS: The study population consisted of renal and liver transplant recipients recruited in two transplant centres in Rome, Italy. Both pre-transplant and post-transplant serum samples were available for all participants. The prevalence of HHV-8/KSHV infection before transplantation was calculated. To determine risk factors for infection, we calculated ORs and 95% CI. Seroconversion rates (i.e. attack rates) after transplantation were also calculated. Differences in attack rates were calculated using a binomial test for proportions. RESULTS: Of the 130 participants, 21 (16.1%) were HHV-8/KSHV-positive before transplantation. Women were more likely to be infected than men, whereas no difference was observed by type of organ transplanted. Of the 109 initially negative individuals, 13 (11.9%) developed anti-HHV-8/KSHV antibodies after transplantation. The incidence of HHV-8/KSHV infection tended to be higher among liver transplant recipients. Four renal transplant recipients and none of the liver transplant recipients developed KS after transplantation. The risk of KS was higher among recipients who were already HHV-8/KSHV-positive before transplantation. CONCLUSIONS: HHV-8/KSHV seroconversion rates appear to be higher among liver transplant recipients, compared to renal transplant recipients. However, renal transplant recipients tend to have a higher risk of KS. HHV-8/KSHV reactivation appears to play a greater role on the risk of KS than incident infections.
Nociceptin (NC) and the opioid receptor like-1 receptors are widely distributed in areas of the neuraxis that are part of the descending modulatory pain system. We used the tail-flick assay in mice to assess the interaction between NC and other analgesic compounds acting on different areas of the descending pathway. Given by intracerebroventricular injection, NC induced hyperalgesia at 10 nmol (39% of reduction vs. control group). The same dose of NC reversed analgesia induced by distinct classes of analgesia-producing compounds such as morphine, dynorphin A or baclofen. NC caused a reduction of their antinociceptive effects: 61, 41 and 27%, respectively. Thus, NC at the supraspinal level appears to interact with both opioid and gamma-aminobutyric acid(B) systems producing anti-analgesic effects probably through the descending pathway for pain control.
BACKGROUND: A growing amount of data supports the role of inflammation in the pathophysiology of atherosclerotic diseases but the cellular source of cytokines has not been clearly identified. Cytokines could be produced by inflammatory cells, activated endothelial and smooth muscle cells, and by the tissue exposed to recurrent ischemia. Accordingly, we evaluated whether hypoperfusion induces gene expression of interleukin (IL)-1beta and IL-6 in the skeletal muscle of patients with peripheral arterial disease and critical limb ischemia. METHODS: Skeletal muscle biopsies were obtained, during a femoral-distal bypass, from normoperfused (control) and hypoperfused skeletal muscles in 8 patients. Gene expression was assessed by semiquantitative reverse transcriptase-polymerase chain reaction, using glyceraldehyde-phosphate-deydrogenase mRNA levels as a normalization factor. RESULTS: In the hypoperfused biopsies, the level of IL-1beta gene expression was significantly higher in all but 2 patients (mean upregulation > 8.8 fold, p = 0.043), and the level of IL-6 gene expression was significantly higher in all but 1 patient (mean upregulation > 23.7 fold, p = 0.031). CONCLUSIONS: We report that IL-1beta and IL-6 gene expression is markedly upregulated in hypoperfused skeletal muscle of patients with critical lower limb ischemia. To our knowledge this is the first report of a local activation of the inflammatory cascade at the level of hypoperfused skeletal muscle. This activation, which could worsen symptoms and tissue viability and be involved in the pathophysiology of reperfusion injury, might be considered as a therapeutic target. It remains to be investigated whether our results may also apply to coronary artery disease.
BACKGROUND: Living related kidney transplantation is considered a gold standard of renal transplantation in order to overcome end-stage renal disease within the same family members. Living donation, albeit decreasing cadaveric donor shortage, exposes donors to the risk of surgical complications. METHODS: In order to assess the postoperative complication rate in donors and recipients, we reviewed retrospectively 90 consecutive living related kidney transplants in a multicentric study. All nephrectomies were performed extraperitoneally through a left flank incision. RESULTS: Major perioperative complications (first 3 weeks after surgery) occurred in 12 subjects: these included bleeding (2.2%), symptomatic pneumothorax (1.1%), iliac thrombophlebitis (3.3%), iliac artery dissection (1.1%), laparotomic dehiscence (2.2%), perirenal hematoma (1.1%), renal artery stenosis (1.1%), urinary fistula (1.1%). Minor perioperative complications took place in 8 cases. One recipient died. Donor postoperative major complications occurred in 2 subjects. CONCLUSIONS: On the basis of these results we conclude that living related kidney transplantation is an important treatment of end stage renal disease, due to the associated low major complication rate and the high feasibility of this methodology.
Patients with advanced peripheral vascular disease have an increased cardiac morbidity and mortality. The aim of this study was to assess the predictive value of rest and stress echocardiography for perioperative and late cardiac events in 110 patients undergoing limb revascularization. All patients underwent preoperative clinical and echocardiographic evaluation at rest and by dipyridamole stress testing to assess cardiac risk. Patients with > or =3 clinical Eagle markers, low left ventricular ejection fraction at rest, or positive dipyridamole stress test results were considered at high cardiac risk. To record adverse cardiac events, all patients were monitored during and after surgery, and followed for at least 1 year after hospital discharge. Cardiac complications occurred in 10 patients (9.7%) perioperatively (2 fatal myocardial infarctions), and in 13 (13%) at 1-year follow-up (7 fatal myocardial infarctions). Echocardiographic evaluation was the best predictor of early (p <0.00003) and late (p <0.0003) cardiac complications. No patient with a negative dipyridamole stress test result and good left ventricular ejection fraction had cardiac complications, either postoperatively or during follow-up. Clinical evaluation does not appear sufficiently sensitive for predicting perioperative cardiac events, but was valuable in predicting late cardiac complications (p <0.0002). Our data show that echocardiographic evaluation of resting dysfunction and of the ischemic response to dipyridamole is a good predictor of perioperative cardiac risk, and is superior to generally available clinical data. Echocardiographic evaluation is useful in defining a low-risk group of patients who can safely undergo limb revascularization, whichever surgical procedure is proposed.
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Vascular surgery can be safely performed in approximately 60% of patients with advanced peripheral vascular disease, because of the high frequency of concomitant coronary artery disease and consequent increased risk of perioperative cardiac complications. The aim of this study was to validate the hypothesis that endovascular revascularization could be safely applied to high-cardiac-risk patients with a lower incidence of perioperative cardiac complications. One hundred and fourteen patients with peripheral vascular disease referred for revascularization underwent preoperatively a clinical and echocardiographic evaluation, at rest and under dipyridamole stress test, to assess the cardiac risk. Patients with high clinical score (according to Goldman and Detsky), or low left ventricular ejection fraction at rest, or positive dipyridamole stress test, were considered at high cardiac risk. To record adverse cardiac events, all patients were monitored during surgery, postoperatively, and followed up for 18 months after hospital discharge. Forty-eight patients (42%) were found to be at high cardiac risk. In this high-cardiac-risk group, endovascular surgery was performed in 37/48 patients (77%) (group A), while the remaining 11/48 patients (23%) were bypassed with open surgery (group B). Postoperative cardiac complications occurred in 16% of patients in group A and in 45% of patients in group B with two deaths (p < 0.05). At follow-up, 51% of patients in group A and 44% of patients in group B had suffered late cardiac events (p=ns), with 10 deaths in group A and three deaths in group B (p=ns). Limb salvage rate was similar in the two groups (95% group A, 100% group B; p=ns). These data show that high-cardiac-risk patients with limb-threatening ischemia have significantly less perioperative cardiac complications when treated by endovascular procedures instead of bypass surgery. Follow-up data on cardiac events confirm the severity of concomitant coronary artery disease in patients with peripheral vascular disease.
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The targets of preformed natural antibodies need to be identified whenever the use of pig organs is considered for human transplantation. In this study we used extracorporeal perfusion of pig organs with human blood, immunocytological techniques and immuno-electron microscopy to identify the targets and the nature of human preformed natural antibodies against pig antigens. The antibodies were found to be mainly of the IgG and IgM type and directed not only against endothelial cells, but also against mesenchymal and epithelial structures. To reproduce an in vivo situation, a Bio-pump was used to xenoperfuse pig kidneys and livers with human fresh oxygenated blood at 37 degrees C, drawn from polycythaemic patients. Biopsies showed a deposition of human IgG and IgM on tubuli and glomeruli of pig kidneys and on endothelial cells of pig livers. Preperfusion of pig liver with human blood for 45 minutes before perfusion of kidneys significantly reduced the deposition of the natural antibodies.