Patients with encapsulating peritoneal sclerosis have increased peritoneal expression of connective tissue growth factor (CCN2), transforming growth factor-β1, and vascular endothelial growth factor.
BACKGROUND
Encapsulating peritoneal sclerosis (EPS) is a devastating complication of peritoneal dialysis (PD). The pathogenesis is not exactly known and no preventive strategy or targeted medical therapy is available. CCN2 has both pro-fibrotic and pro-angiogenic actions and appears an attractive target. Therefore, we studied peritoneal expression of CCN2, as well as TGFβ1 and VEGF, in different stages of peritoneal fibrosis.


METHODS
Sixteen PD patients were investigated and compared to 12 hemodialysis patients and four pre-emptively transplanted patients. Furthermore, expression was investigated in 12 EPS patients in comparison with 13 PD and 12 non-PD patients without EPS. Peritoneal tissue was taken during kidney transplantation procedure or during EPS surgery. In a subset of patients, CCN2 protein levels in peritoneal effluent and plasma were determined. Samples were examined by qPCR, histology, immunohistochemistry, and ELISA.


RESULTS
Peritoneal CCN2 expression was 5-fold higher in PD patients compared to pre-emptively transplanted patients (P < 0.05), but did not differ from hemodialysis patients. Peritoneal expression of TGFβ1 and VEGF were not different between the three groups; neither was peritoneal thickness. Peritoneum of EPS patients exhibited increased expression of CCN2 (35-fold, P < 0.001), TGFβ1 (24-fold, P < 0.05), and VEGF (77-fold, P < 0.001) compared to PD patients without EPS. In EPS patients, CCN2 protein was mainly localized in peritoneal endothelial cells and fibroblasts. CCN2 protein levels were significantly higher in peritoneal effluent of EPS patients compared to levels in dialysate of PD patients (12.0 ± 4.5 vs. 0.91 ± 0.92 ng/ml, P < 0.01), while plasma CCN2 levels were not increased.


CONCLUSIONS
Peritoneal expression of CCN2, TGFβ1, and VEGF are significantly increased in EPS patients. In early stages of peritoneal fibrosis, only CCN2 expression is slightly increased. Peritoneal CCN2 overexpression in EPS patients is a locally driven response. The potential of CCN2 as biomarker and target for CCN2-inhibiting agents to prevent or treat EPS warrants further study.
Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
Alferso C
AC
Abrahams
Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands.
Sayed M
SM
Habib
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
Amélie
A
Dendooven
Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, IL, United States of America.
Bruce L
BL
Riser
Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
Jan Willem
JW
van der Veer
Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
Raechel J
RJ
Toorop
Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands.
Michiel G H
MG
Betjes
Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
Marianne C
MC
Verhaar
Department of Surgery, Box 202, Addenbrooke's Hospital, and Cambridge NIHR Biomedical Research Centre, Cambridge, United Kingdom.
Christopher J E
CJ
Watson
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
Tri Q
TQ
Nguyen
Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
Walther H
WH
Boer
D000328:Adult; D001201:Ascites / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D003430:Cross-Sectional Studies; D005786:Gene Expression Regulation; D006801:Humans; D007676:Kidney Failure, Chronic / Q000628:therapy; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010530:Peritoneal Dialysis / Q000009:adverse effects; D056627:Peritoneal Fibrosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D010537:Peritoneum / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D055513:Connective Tissue Growth Factor