Persistent Transforming Growth Factor-Beta 1 Expression May Predict Peritoneal Fibrosis in CAPD Patients with Frequent Peritonitis Occurrence

Abstract

The efficiency of continuous ambulatory peritoneal dialysis depends on the permeability of the peritoneal membrane. Peritoneal fibrosis (PF) causes loss of the dialytic function. Several studies have indicated that PF is closely related to the proliferation of peritoneal fibroblasts and the deposition of extracellular matrix. Transforming growth factor-beta 1 (TGF-β1) plays a major role in stimulating extracellular matrix deposition. Frequent peritonitis occurrence may cause persistent TGF-β1 mRNA expression. In an attempt to search for a factor related to PF, we designed a longitudinal study to measure TGF-β1 levels in dialysate and TGF-β1 mRNA expression in peritoneal mononuclear cells from peritoneal dialysate before onset, once a week during peritonitis, and after peritonitis in high and low peritonitis occurrence (HPO and LPO) patients. Fifteen patients with a LPO rate and 5 patients with a HPO rate were followed up longitudinally. Meanwhile, TGF-β1 levels and TGF-β1 mRNA expression were augmented in peritoneal dialysate effluents before, during, and after the episodes of peritonitis. The peritoneal permeability was evaluated by the peritoneal equilibration test. The results revealed that in the LPO group, TGF-β1 and TGF-β1 mRNA were detectable at early stages of peritonitis, but the levels decreased rapidly and were undetectable 2 weeks after peritonitis. On the other hand, in the HPO group, TGF-β1 and TGF-β1 mRNA persisted for a long time. We could detect TGF-β1 and TGF-β1 mRNA in dialysate effluents and peritoneal mononuclear cells even 2, 3, and 4 weeks after episodes of peritonitis. When compared with that of first or second episode of peritonitis, the peritoneal function evaluated with the peritoneal equilibration test was found to obviously deteriorate during the third episode of peritonitis. These findings were confirmed by an in situ hybridization technique to evaluate the relationship between TGF-β1 mRNA expression and PF from biopsied peritoneal specimens. These findings suggest that the high TGF-β1 levels in the dialysate are related to an increased expression of TGF-β1 in the peritoneum. Thus, the persistent TGF-β1 expression in the peritoneum may serve as a useful parameter in predicting PF in continuous ambulatory peritoneal dialysis patients with frequent peritonitis occurrence.

Effects of Mycophenolate Mofetil and Rapamycin on Peritoneal Fibrosis in an Experimental Model of Peritoneal Dialysis

“…Margetts et al reported that active TGF-β1 induced a prolonged submesothelial fibrosis that might be in connection with elevated expression of α-smooth muscle actinpositive myofibroblasts in the interstitium (41,42). Increased dialysate concentrations of TGF-β1 were reported to correlate with poorer outcomes in PD patients, while they were thought to stimulate myofibroblastic response in mesothelial cells, which triggers peritoneal fibrosis (17,43). VEGF is also closely related to TGF-β1 activity during PD.…”

“…Evidence from clinical studies indicates TGF-β1 presence in the peritoneum, which is up-regulated during episodes of peritonitis. Elevated levels of TGF-β1 in dialysate concentrations have been shown to be associated with poorer outcomes in PD patients (8,9,17).…”

TGF-β1 Gene Polymorphisms and Peritoneal Equilibration Test Results in CAPD Patients

“…[6,7,12,13,[23][24][25] It is not clear yet which alleles cause higher amounts of the TGF-β1 protein.…”

“…[5] TGF-β1-induced fibroblast proliferation, stimulation of collagen synthesis, and enhanced matrix accumulation contribute to the development of fibrogenesis. [6,7] TGF-βl gen polymorphisms in the signal sequence genetically may be responsible for increased TGFβl production. Seven polymorphisms in the TGF-βl gene have been reported in a great number of studies.…”

“…[8] At present, the basis for increased TGF-βl production in humans is unknown; however, recent evidence suggests that genetic factors may have a significant role to play in the increased TGFβl production. [7] The rate of increase in TGF-βl production in response to different stimuli such as high glucose or inflammatory cytokines may be different in each patient. TGF-β1 gen polymorphisms may be responsible for this difference.…”