Gene transfer using nonviral delivery systems.
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In peritoneal dialysis, loss of peritoneal function is a major factor in treatment failure. The alterations in peritoneal function are related to structural changes in the peritoneal membrane, including peritoneal sclerosis with increased extracellular matrix. Although peritoneal sclerosis is considered reversible to some extent through peritoneal rest, which improves peritoneal function and facilitates morphological changes, there has been no therapeutic intervention and no drug against the development and progression of peritoneal sclerosis. Using recent biotechnological advances in genetic engineering, a strategy based on genetic modification of the peritoneal membrane could be a potential therapeutic maneuver against peritoneal sclerosis and peritoneal membrane failure. Before this gene therapy may be applied clinically, a safe and effective gene delivery system as well as the selection of a gene therapy method must be established. There are presently two kinds of gene transfer vectors: viral and nonviral. Viral vectors are used mainly as a gene delivery system in the field of continuous ambulatory peritoneal dialysis research; however, they have several problems such as immunogenicity and toxicity. On the other hand, nonviral vectors have several advantages over viral vectors. We review here gene transfer using nonviral vector systems in the peritoneum: electroporation, liposomes, and cationized gelatin microspheres. In the field of peritoneal dialysis, gene therapy research using nonviral vectors is presently limited. Improvement in delivery methods together with an intelligent design of targeted genes has brought about large degrees of enhancement in the efficiency, specificity, and temporal control of nonviral vectors. (+info)
Is encapsulating peritoneal sclerosis a threatening issue in continuous ambulatory peritoneal dialysis? The Japanese experience.
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Encapsulating peritoneal sclerosis (EPS) is undoubtedly the most serious complication of continuous ambulatory peritoneal dialysis treatment in Japan, with a mortality rate ranging from about 39% to 49% in reported series. Cases of EPS have been linked to long-term peritoneal dialysis, and limitations on renal transplantation in Japan mean that most Japanese patients have to accept long-term dialysis therapy, which is a critical problem. Treatment alternatives for EPS include total parenteral nutrition, prednisolone administration, and surgical approaches, all of which have varying success rates. Additional therapeutic and new preventive measures have to be established for EPS. (+info)
Preventing peritoneal fibrosis--insights from the laboratory.
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OBJECTIVE: Peritoneal fibrosis is one of the most serious complications of peritoneal dialysis (PD). Peritoneal fibrosis is characterized by activation of the peritoneal resident cells, accumulation and deposition of excess matrix proteins within the interstitium, and neoangiogenesis and vasculopathy of the peritoneal microvasculature. Compelling evidence now exists to show that elevated glucose concentrations present as the osmotic agent in PD solutions are, per se, responsible for those detrimental changes. Until alternative osmotic agents can fully replace glucose in PD solutions, novel therapeutic strategies are essential to preserve the structural and functional properties of the peritoneum. This review highlights recent experimental data that may offer potential strategies for preservation of the peritoneal structure and improvement of clinical outcome. METHOD: Literature review. RESULTS: Compelling evidence now exists to show that the bioincompatible nature of PD solutions--in particular, elevated glucose concentrations and glucose byproducts--play a pivotal role in the initiation of peritoneal fibrosis. Animal and in vitro studies provide some insight into methods that can potentially be employed to alleviate or retard peritoneal fibrosis. Those methods include use of alterative osmotic agents (polyglucose or amino acids), administration of TGFbeta1 antagonists, gene therapy, and pharmacologic interventions. CONCLUSIONS: Knowledge of the pathogenesis of peritoneal fibrosis has allowed independent researchers to design therapeutic strategies that abrogate excess matrix synthesis and deposition in cultured peritoneal cells and in animal models of experimental peritoneal fibrosis alike. Encouraging results have been obtained in those studies, but it remains to be determined whether the studied strategies can alleviate clinical disease. Future studies will enable us to establish specific molecules that can be targeted clinically to restrict the progressive deterioration of the peritoneal membrane as a biologic dialyzing organ. (+info)
The Pan-Thames EPS study: treatment and outcomes of encapsulating peritoneal sclerosis.
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Tamoxifen therapy in kidney-transplant patients presenting with severe encapsulating peritoneal sclerosis after treatment for acute humoral rejection.
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OBJECTIVES: Encapsulating peritoneal sclerosis is a rare but serious complication in patients undergoing peritoneal dialysis. Its mortality rate is approximately 30%, despite treatment with total parenteral nutrition, surgery, tamoxifen, or immunosuppressants. MATERIALS AND METHODS: Of 991 kidney transplants performed at our institution over 9 years, 50 patients were treated for chronic peritoneal dialysis at the time of transplant. RESULTS: Two cases of encapsulating, peritoneal sclerosis occurred in patients receiving pretransplant peritoneal dialysis. Both had received intensive posttransplant treatment for acute humoral rejection. Encapsulating peritoneal sclerosis occurred at 3 months and 4 months after the transplant. Both presented with intestinal pain and gut obstruction. They were given total parenteral nutrition plus tamoxifen (20 mg/d) for 3 months. Outcomes were favorable for 1, though there was no improvement for the second patient, who was then also given sirolimus. He died later from multiorgan failure secondary to digestive-related sepsis, and encapsulating, peritoneal, sclerosis-related symptoms. CONCLUSIONS: When encapsulating, peritoneal sclerosis occurs after kidney transplant, tamoxifen therapy could be implemented. (+info)
Prolonged peritoneal gene expression using a helper-dependent adenovirus.
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BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis. The causes of EPS are not well defined and are likely multifactorial. A suitable animal model would facilitate research into the pathophysiology and treatment of EPS. METHODS: We developed a helper-dependent adenovirus that expresses both green fluorescent protein (GFP) and active transforming growth factor-beta (TGF-beta1; HDAdTGF-beta1). Mice were administered HDAdTGF-beta1 via intraperitoneal injection and the response was compared with mice administered either first-generation adenovirus expressing TGF-beta1 (AdTGF-beta1) or control adenovirus (AdGFP). RESULTS: HDAdTGF-beta1-treated mice continued to express the GFP reporter transgene to day 74, the end of the observation period. Transgene expression lasted less than 28 days in the animals treated with first-generation adenoviruses. Animals treated with first-generation AdTGF-beta1 demonstrated submesothelial thickening and angiogenesis at day 7, with almost complete resolution by day 28. The HDAdTGF-beta1-treated mice demonstrated progressive peritoneal fibrosis with adhesion formation and encapsulation of bowels. Weight gain was significantly reduced in animals treated with HDAdTGF-beta1 compared to both the control-treated animals and the AdTGF-beta1-treated animals. Inflammation was not a major component of the fibroproliferative response. CONCLUSIONS: Peritoneal administration of a first-generation AdTGF-beta1 leads to transient gene expression, resulting in a resolving fibrotic response and histology similar to that seen in simple peritoneal sclerosis. Prolonged TGF-beta1 expression induced by the helper-dependent HDAdTGF-beta1 led to changes in peritoneal morphology resembling EPS. This suggests that TGF-beta1 may be a contributing factor in both simple peritoneal sclerosis and EPS. This model will be useful for elucidation of the mechanism of EPS and evaluation of potential treatment. (+info)
Computed tomographic findings characteristic for encapsulating peritoneal sclerosis: a case-control study.
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BACKGROUND: Computed tomography (CT) is often used to confirm the diagnosis of encapsulating peritoneal sclerosis (EPS) but there is no consensus on specific CT abnormalities. To establish CT findings characteristic for EPS, we compared CT findings between EPS patients and long-term peritoneal dialysis (PD) patients without EPS. METHODS: We included as cases all EPS patients in our center from 1996 to 2008 that underwent a CT scan at the time of diagnosis. Controls were all other long-term PD patients (PD duration > or = 4 years) without EPS that had a CT scan for different reasons. The CT scans were blindly and independently reviewed by 3 radiologists: 2 abdominal radiologists with PD knowledge (Observers 1 and 2) and 1 radiologist without PD experience (Observer 3). RESULTS: We included 15 EPS patients and 16 controls. Observer 1 found 6 CT findings that were significantly more often present in EPS than in controls (p < or = 0.05): peritoneal enhancement, thickening, and calcifications; adhesions of bowel loops; signs of obstruction; and fluid loculation/septation. Observer 2 scored almost identically but Observer 3 scored differently. The sensitivity and specificity of a combination of specific CT findings were, respectively, 100% and 94% for Observers 1 and 2, and 79% and 88% for Observer 3. CONCLUSION: CT scans showed characteristic abnormalities that were significantly more often present in EPS patients compared to long-term PD control patients. CT can be used to confirm the diagnosis of EPS when experienced radiologists apply a combination of specific CT findings. (+info)