Peter J. Margetts

Quality of life in multiple sclerosis patients with urinary disorders: discriminative validation of the English version of Qualiveen.

The Qualiveen questionnaire is a urinary disorder (UD)-specific health related quality of life (HRQL) instrument. Recent data suggests Qualiveen has excellent validity in French-speaking multiple sclerosis (MS) patients. Aim: To assess discriminative measurement properties of the English version of Qualiveen. Methods>: Fifty-five Canadian MS out-patients completed a set of questionnaires, including Qualiveen, MSQOL-54, a MS-specific HRQL questionnaire, urinary function assessments and the Expanded Disability Status Scale (EDSS) twice at an interval of two to four weeks. Results: Qualiveen proved internally consistent (Cronbach’s alpha coefficients 0.73 to 0.90 for the four Qualiveen domains) and test–retest reliable (intraclass correlation coefficients 0.88 to 0.94). Consistent with a priori predictions, we found a strong association between overall Qualiveen score and the degree of incontinence (0.63), a moderate correlation with the type of urinary symptoms (0.49), a weak association with manner of voiding (0.28) and weak or absent correlations with MSQOL-54 domains, EDSS bladder/bowel and global EDSS. Predictions proved generally accurate (weighted κ = 0.65). Conclusion: The internal consistency, test–retest reliability and cross-sectional construct validity of the English version of Qualiveen are excellent, and similar to the original French version. Further studies should explore Qualiveen’s longitudinal validity and responsiveness.

Cutaneous presentation of post-renal transplant lymphoproliferative disorder: a series of four cases

We report detailed histological and molecular characteristics of four post transplant lymphoproliferative disorders (PTLD) presenting in the skin of renal transplant patients, and their clinical outcome.

Twist: a new player in the epithelial–mesenchymal transition of the peritoneal mesothelial cells

BACKGROUND The peritoneal membrane is a vital structure for peritoneal dialysis (PD) patients. It has been increasingly recognized that the transition of the peritoneal lining mesothelial cells into a more fibroblastic phenotype is a key step in peritoneal membrane injury. METHODS Relevant literature was reviewed and summarized. RESULTS Epithelial-to-mesenchymal transition (EMT) is a basic cellular process that occurs in a variety of physiologic and pathologic processes. The hallmark of this process is a loss of epithelial markers, and E-cadherin is a prototypical epithelial transmembrane protein. E-cadherin expression is suppressed at many levels and the gene is regulated by a family of transcription factors. Twist is one of the lesser studied E-cadherin regulatory factors, which belongs to a larger family of basic helix-loop-helix DNA-binding proteins. In this issue of Nephrology Dialysis Transplantation, Cuixiang Li reports on in vitro experiments where the expression of Twist led to a decreased expression of E-cadherin and the evidence of EMT. In an in vivo model of dialysate exposure, Li demonstrates that Twist expression is increased in the injured peritoneal tissues. CONCLUSIONS These important observations are the first to link Twist to mesothelial cell EMT and peritoneal membrane injury. Like most novel observations, this paper leaves many questions unanswered. Twist is only one of several transcription factors involved in EMT and how these factors interact will require further investigations. Furthermore, the question of whether Twist interacts at multiple levels in the EMT process, or simply gives an initial push to the process, is left unanswered. Finally, to bring these early significant findings to the bedside as potential therapies for PD patients will require further innovation.

Matrix metalloproteinase 9 is associated with peritoneal membrane solute transport and induces angiogenesis through β-catenin signaling

Background. For patients using peritoneal dialysis (PD), the peritoneal membrane can develop fibrosis and angiogenesis, leading to ultrafiltration failure, chronic hypervolemia and increased risk of technique failure and mortality. Matrix metalloproteinases (MMPs), and specifically the gelatinases (MMP2 and MMP9), may be involved in peritoneal membrane injury. Methods. From stable PD patients, mesothelial cells were assayed for MMP gene expression. MMP9 was overexpressed in mouse peritoneum by adenovirus, and MMP9−/− mice were subjected to transforming growth factor &bgr; (TGF-&bgr;)–induced peritoneal fibrosis. Results. MMP9 mRNA expression correlated with peritoneal membrane solute transport properties. Overexpression of MMP9 in the mouse peritoneum induced submesothelial thickening and angiogenesis. MMP9 induced mesothelial cell transition to a myofibroblast phenotype measured by increased alpha smooth muscle actin and decreased E-cadherin expression. Angiogenesis was markedly reduced in MMP9−/− mice treated with an adenovirus expressing active TGF-&bgr; compared with wild-type mice. TGF-&bgr;-mediated E-cadherin cleavage was MMP9 dependent, and E-cadherin cleavage led to &bgr;-catenin-mediated signaling. A &bgr;-catenin inhibitor blocked the angiogenic response induced by AdMMP9. Conclusions. Our data suggest that MMP9 is involved in peritoneal membrane injury possibly through cleavage of E-cadherin and induction of &bgr;-catenin signaling. MMP9 is a potential biomarker for peritoneal membrane injury and is a therapeutic target to protect the peritoneal membrane in PD patients.

Peritoneal Dialysis Catheter Increases Leukocyte Recruitment in the Mouse Parietal Peritoneum Microcirculation and Causes Fibrosis

♦ Background: The objective of this study was to examine the effects of a conventional dialysis solution and peritoneal catheter on leukocyte-endothelial cell interactions in the microcirculation of the parietal peritoneum in a subacute peritoneal dialysis (PD) mouse model. ♦ Methods: An intraperitoneal (IP) catheter with a subcutaneous injection port was implanted into mice and, after a 2-week healing period, the animals were injected daily for 6 weeks with a 2.5% dextrose solution. Intravital microscopy (IVM) of the parietal peritoneum microcirculation was performed 4 hours after the last injection of the dialysis solution. Leukocyte-endothelial cell interactions were quantified and compared with catheterized controls without dialysis treatment and naïve mice. ♦ Results: The number of rolling and extravascular leukocytes along with peritoneal fibrosis and neovascularization were significantly increased in the catheterized animals compared with naïve mice but did not significantly differ between the 2 groups of catheterized animals with sham injections or dialysis solution treatment. ♦ Conclusion: The peritoneal catheter implant increased leukocyte rolling and extravasation, peritoneal fibrosis and vascularization in the parietal peritoneum independently from the dialysis solution treatment.

Experimental systems to study the origin of the myofibroblast in peritoneal fibrosis

Peritoneal fibrosis is one of the major complications occurring in long-term peritoneal dialysis patients as a result of injury. Peritoneal fibrosis is characterized by submesothelial thickening and fibrosis which is associated with a decline in peritoneal membrane function. The myofibroblast has been identified as the key player involved in the development and progression of peritoneal fibrosis. Activation of the myofibroblast is correlated with expansion of the extracellular matrix and changes in peritoneal membrane integrity. Over the years, epithelial to mesenchymal transition (EMT) has been accepted as the predominant source of the myofibroblast. Peritoneal mesothelial cells have been described to undergo EMT in response to injury. Several animal and in vitro studies support the role of EMT in peritoneal fibrosis; however, emerging evidence from genetic fate-mapping studies has demonstrated that myofibroblasts may be arising from resident fibroblasts and pericytes/perivascular fibroblasts. In this review, we will discuss hypotheses currently surrounding the origin of the myofibroblast and highlight the experimental systems predominantly being used to investigate this.