Long-Term Complications in Peritoneal Dialysis

• Main Authors: Jenq-Wen Huang, 黃政文
• Other Authors: 蔡敦仁
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/35815197495995535509

博士 === 臺灣大學 === 臨床醫學研究所 === 98 === Background Both the prevalence and incidence of end-stage renal disease in Taiwan are the highest in the world. In 2007, the patients receiving dialysis were 52,537 persons in Taiwan. The prevalence was 2,288 per million population and the incidence was 415 patients per million population. According to the statistic data of Bureau of National Health Insurance (BNHI), dialysis therapy cost more than 330 billion NT dollars every year. In average, each dialyzed patient would spend 600 thousand NT dollars every year which is 30 times of the mean of general population. To reduce the medical cost on dialysis, BNHI promotes peritoneal dialysis as a long-term renal replacement modality. However, peritoneal dialysis patients will use high glucose content peritoneal dialysate to achieve ultrafiltration goal whenever they receive this renal replacement modality. Combine with other bio-incompatible factors in the peritoneal dilysate, peritoneum will be damaged by the dialysate and the metabolism of glucose and lipid will be affected by the dialysate in the long run. For these disadvantages of present dialysate, we conducted a serial of studies to investigate the long term complications of peritoneal dialysis. The effects of peritoneal dialysate was divided into two major portions: the first was the clinical effects of high glucose concentration in dialysate on patient survival, technique survival and metabolism in peritoneal dialysis patients. The second was local effects of bio-incompatible peritoneal dialysate on the peritoneum and their possible resolutions. For the long-term effects of peritoneal dialyate, we proposed that glucose content in peritoneal dialysate may result in unfavorable changes on peritoneal character and worsened metabolic profiles. We conducted a retrospective cohort analysis to investigate the impact of initial glucose load on long-term outcomes of peritoneal dialysis patients. In addition, since usage of high glucose concentrations in peritoneal dialyate may result in unfavorable results. We further conducted a study to analyze the factors associated with high glucose load in long-term peritoneal dialysis patients in each year. For the metabolism of glucose and lipid, adiponectin, a cytokine with anti-inflammatory properties that is secreted from adipose tissue, is associated with insulin resistance. It has been demonstrated that adiponectin is a predictor of cardiovascular events in both the general population and patients undergoing hemodialysis, however, its role in peritoneal dialysis patients remains unclear. For the local effect on peritoneum per se, peritoneal fibrosis is a common complication among long-term peritoneal dialysis patients including simple sclerosis and encapsulating peritoneal sclerosis. Encapsulating peritoneal sclerosis is a catastrophic complication of peritoneal dialysis patients. Tamoxifen and steroid are used to treat encapsulating peritoneal sclerosis but there is still limited experience about the therapeutic duration and outcome management. We provide a case series experience of treating encapsulating peritoneal sclerosis patients by using combination therapy of tamoxifen and steroid. Tamoxifen has successfully been used in treating encapsulating peritoneal sclerosis as well as other chronic fibrosis disorder, however, the mechanism of tamoxifen in treating encapsulating peritoneal sclerosis remains unclear. This issue deserve us to do further investigation. Methods In patient survival analysis, a total of 90 patients newly started on peritoneal dialysis were enrolled. All subjects were divided into low, medium, or high glucose load equally in patient number according to the average dialysate glucose concentration prescribed in the first 6 months from peritoneal dialysis initiation. Cox’s regression was used for survival analyses and linear regression was used for analyses of determinants for glucose load. In addition during the following up of these 90 newly-started peritoneal dialysis patients were surveyed for 5 years. We obtained glucose load by calculating annual glucose weight and dialysate volume that were administered. We conducted multiple linear regression analyses with time-dependent covariates to determine factors that influence the annual average dialysate glucose concentration. For analyzing the metabolic effects of adiponectin, serum adiponectin levels, measured using enzyme-linked immunosorbent assay in subjects with normal renal function and patients undergoing hemodialysis or peritoneal dialysis (28 subjects in each group), were analyzed to establish the relationship between adiponectin and lipid levels as well as insulin resistance. In the second study, 104 peritoneal dialysis patients were recruited to analyze the relationships between serum adiponectin level and residual renal and peritoneal function and C-reactive protein level. Independent factors for serum adiponectin level were determined from multiple linear regression. In treating the local effects on peritoneum of long term peritoneal dialysis, encapsulating peritoneal sclerosis patients were enrolled from two medical centers in northern Taiwan between 2005 and 2009. The diagnosis of encapsulating peritoneal sclerosis was made by clinical presentations of ileus and specific image findings. Tamoxifen and steroid were initiated after diagnosis. All medical records and individual laboratory data were reviewed. For investigating molecular mechanism of antifibrotic effects of tamoxifen, a bleach induced peritoneal fibrosis rat model was applied as the in vivo treatment target. Tamoxifen was intraperitoneally injected daily to treat peritoneal fibrosis. The peritoneal fibrosis scores and thickness of the submesothelial zone over the liver surface were measured as indicators for the severity of PF. Besides, human peritoneal mesothelial cells were used as an in vitro model to test the antifibrotic effect of tamoxifen. Gene expressions of transforming growth factors beta, connective tissue growth factor and collagen were investigated using quantitative polymerase chain reactions. Results In analysis of effects of glucose load, the mean follow-up period was 40.1 ± 11.8 months. Patients with higher glucose load showed a significantly worse cumulative technique survival (log rank p=0.002). In Cox’s regression analysis, patients with lower glucose load had significantly better technique survival (p=0.035). In linear regression analysis, preexisting diabetes mellitus (p<0.001), lower serum albumin (p=0.012), and lower weekly renal Kt/V (p=0.019) were significantly correlated with higher glucose load. In analyzing the dterminants of glucose load in each year, there were 47 men and 43 women and the mean age was 53.4 ± 13.9 years. The technique survival rates were 91.0%, 84.1%, and 77.6% for beginning of the second, third, and fourth year of peritoneal dialysis therapy, respectively. The presence of diabetes mellitus, high body mass index (BMI), and low weekly renal Kt/V were significantly correlated with high average glucose concentration of the dialysate during the first, second, and third years. For patients undergoing peritoneal dialysis for more than 3 years, residual renal function deteriorated, and only diabetes significantly affected higher glucose concentration of the dialysate in the fourth year. For analyzing the impacts of adiponecctin on peritoneal dialysis patients, No significant difference was demonstrated comparing the serum adiponectin levels of peritoneal dialysis and hemodialysis patients, however, both were significantly higher than that of the control subjects (p<0.01). Negative associations were demonstrated between adiponectin, and triglyceride (p<0.01) and insulin levels (p<0.05), and homeostatic model assessment of insulin resistance (HOMAIR) (p<0.01) for the former two groups, however, a positive association was demonstrated for high density lipoprotein (p<0.05). Neither hemodialysis nor peritoneal dialysis removed adiponectin significantly, with levels for the latter group negatively associated with residual renal function (p<0.01) and C-reactive protein (p < 0.001). Peritoneal dialysis patients using glucose-lowering agents had lower adiponectin levels, however, lipid-lowering agents and renin-angiotensin blockades did not appear to affect them. The independent determinants for serum adiponectin level in peritoneal dialysis patients were triglyceride, hemodialysis, CRP, and BMI, after adjustment for age, sex, peritoneal dialysis duration and diabetes. Adiponectin levels were not associated with left-ventricular mass or ejection fraction, however. In treating encapsulating peritoneal sclerosis, there was a total of 10 encapsulating peritoneal sclerosis patients (M/F: 3/7) with a mean age of 47.8 ± 9.6 years and a mean peritoneal dialysis duration of 8.7 ± 3.8 years. Refractory peritonitis was the preceding event in nine patients. Tamoxifen 10 mg twice daily and steroid equivalent to 0.5-1.0 mg/Kg/day were administered. Eight patients showed improvement of enteral feeding within 1 week of treatment but two of them died in the following period (nine days and seven months respectively). One patient achieved a partial improvement of clinical symptoms after two weeks of therapy and one patient was refractory to this regimen. Complications of this regimen such as gastrointestinal bleeding, perforation, and myocardial infarction mostly resulted from the steroid therapy. The study of molecular mechanism of antifibrotic effects of tamoxifen showed that tamoxifen could reduce the peritoneal fibrosis severity and submesothelial zone in bleach induced rat peritoneal fibrosis model. In HPMC, tamoxifen showed paradoxical effects between collagen I and TGF-β. Tamoxifen also inhibited TGF-β induced collagen and CTGF. Conclusion Form our serial studies, for the long term survival, higher glucose load during initial period of peritoneal dialysis was associated with higher prevalent diabetes, lower serum albumin, and lower residual renal function, and effectively predicted worse survival of peritoneal dialysis therapy. Patients with diabetes, high body mass index, and low residual renal function were more likely to require high glucose load for peritoneal dialysis therapy, especially during the first 3 years. After 3 years of peritoneal dialysis, diabetes was the only significant factor that determined a need for higher glucose load. In order to decrease the glucose load in chronic peritoneal dialysis patients, alternative osmotic agents such as icodextrin or amino acids should be considered in the daily peritoneal dialysis regimens. For the adiponectin, as for the hemodialysis patients, the peritoneal dialysis subjects had high adiponectin levels, not removed effectively using either of the studied dialysis modalities. In addition to a significant relationship with the components of insulin resistance, adiponectin was associated with CRP in these patients. These results indicate that adiponectin level in peritoneal dialysis patients may be a good indicator of cardiovascular disease risk. For treating encapsulating peritoneal sclerosis, the combination of tamoxifen and steroid is effective in ameliorating encapsulating peritoneal sclerosis symptoms in 80% of the patients. Chronicity of encapsulating peritoneal sclerosis might predict a treatment failure. Steroid could be tapered off if symptoms improve. And the possible antifibrotic effect of tamoxifen is through inhibiting CTGF to block collagen synthesis, although it enhances TGF-β which increases fibrosis. These results provide a possible molecular mechanism for tamoxifen.