Oral COX-2 inhibitor Celecoxib in Peritoneal Dialysis Patients: effects on peritoneal transport and peritoneal defence.

Peritoneal dialysis (PD) is a well accepted dialysis technique for patients
with end stage renal failure. Currently peritoneal dialysis has been considered
as equal renal replacement modality compared to haemodialysis. Compared to
haemodialysis, peritoneal dialysis is even more advantageous in the protection
of the patients' residual renal function, morbidity-mortality indices, and
quality of life in the first two years of treatment. Despite the benefits of
this treatment modality, chronic instillation of peritoneal dialysis fluid
(PDF) creates an intraperitoneal non-physiological environment that sustains
low-grade inflammation, associated with morphological changes. Peritoneal
fibrosis and new vessel formation are well-described PD side effects and are
thought to be major causes of ultrafiltration (UF) failure and discontinuation
of PD therapy.Cyclooxygenase-2 (COX-2) is the inducible isoform of
cyclooxygenase. In cancer, COX-2 downstream products (mainly prostaglandin E2
(PGE2) and prostaglandin I2 (PGI2)) seem to mediate an angiogenic process
through several mechanisms including vascular endothelial growth factor (VEGF)
production and enhanced endothelial cell survival. COX-2 inhibitors are
commercially available, among them Celecoxib has shown a positive effect on
inhibition of angiogenesis in several in vitro assays and in vivo cancer
models. Celecoxib treatment has beneficial effects on angiogenesis and
inflammation. In vitro experiments have demonstrated that under PD or PD-like
conditions mesothelial and inflammatory cells express COX-2, as do fibroblasts
involved in peritoneal healing after abdominal surgery. A rat peritoneal
exposure model, daily treatment with Celecoxib for 5 weeks completely prevented
ultrafiltration failure which is a dominant factor for treatment failure and
discontinuation of the treatment. It is known that ultrafiltration failure
leading to fluid overload is common in PD-patients. The high prevalence of
fluid overload may partly explain why cardiovascular disease is still the major
cause of mortality (accounting over 40% of all causes of death) in PD-patients.
Since Celecoxib showed in vivo very positive effects on the ultrafiltration
capacity in vivo, this compound may also show positive effects on
cardiovascular diseases as a result of fluid overload might be prevented.
Besides the prevention of ultrafiltration failure, Celecoxib partly reduced
angiogenesis and fibrosis in the rat model for peritoneal dialysis.

Based on the positive effects of Celecoxib on ultrafiltration and peritoneal
injury during PD in rats, we would like to propose a pilot study using
Celecoxib in PD-patients. In this pilot study we will investigate whether the
Cox2 inhibitor Celecoxib can improve peritoneal transport, inflammation and
defence parameters (Ca125, Il-6, TNF, VEGF, hyaluronan, Il-1, Il-8 and MCP-1
levels) during PD.

The study is designed as a pilot study. Eligible patients will be informed
about the study by their physician and will be invited for a screening visit.
At the start of the study the peritoneal function of each patient will be
determined by a peritoneal membrane and effluent test (PET 3.86%). Group 1:
patients will be treated with Celecoxib for a period of three months (2*200
mg/day) after which a second PET is performed. In the following three months,
these patients will not be treated with Celecoxib, after which a third PET will
be performed.
Group 2: patients will not be treated with celecoxib in the first three months.
They will start the celecoxib treatment the second three months. The PET will
be performed similarly to group 1. During the PET visits the docter will
perform physical examination. Patients are asked to bring the last overnight
effluent before coming to the hospital for a PET or a physical visit. The PET
and the overnight effluents are collected for determination of peritoneal
function (ultrafiltration and transport parameters) and peritoneal defence
(Ca125, Il-6, TNF, VEGF, hyaluronan, Il-1, Il-8 and MCP-1). Each subject*s data
will be coded with a unique study number and stored on computer file. Changes
in fluidtypes will be done according to medical insight .

giving Celecoxib

Patients have to use the celebrex pils as extra medication.
Patients need to come t the outpatient clinic for PETs, 3 times (for 4 hrs) in
6 months. The burden is mostly extra time in hospital.