Long-term Peritoneal Dialysis Therapy Research Articles

Peritoneal fibrosis and epigenetic modulation.

Peritoneal dialysis (PD) is an effective treatment for patients with end-stage renal disease. However, peritoneal fibrosis (PF) is a common complication that ultimately leads to ultrafiltration failure and discontinuation of PD after long-term PD therapy. There is currently no effective therapy to prevent or delay this pathologic process. Recent studies have reported epigenetic modifications involved in PF, and accumulating evidence suggests that epigenetic therapies may have the potential to prevent and treat PF clinically. The major epigenetic modifications in PF include DNA methylation, histone modification, and noncoding RNAs. The mechanisms of epigenetic regulation in PF are complex, predominantly involving modification of signaling molecules, transcriptional factors, and genes. This review will describe the mechanisms of epigenetic modulation in PF and discuss the possibility of targeting them to prevent and treat this complication.

Recent analysis of status and outcomes of peritoneal dialysis in the Tokai area of Japan: the second report of the Tokai peritoneal dialysis registry

Early withdrawal within 3years after starting peritoneal dialysis (PD) and PD-related peritonitis have been major obstacles preventing increases in the population of PD patients. To address these problems, we implemented education programs for medical staff. This study analyzed the recent status and outcomes of PD therapy, focusing on findings such as the incidence and prognosis of peritonitis as of 5years after our last study. We investigated background, laboratory data and status of PD therapy, reasons for withdrawal from PD and incidental statements on peritonitis from 2010 to 2012 (R2), and compared findings with those from our last study of 2005-2007 (R1). Early PD therapy withdrawal in R2 clearly improved to 44.7%, compared with 50.9% in R1. Peritonitis incidence improved slightly from once per 42.8months/patient in R1 to once per 47.3months/patient in R2. Notably, PD-related peritonitis as a cause of mortality improved markedly in R2, but outcomes of PD-related peritonitis did not change significantly between R1 and R2. In contrast, social problems increased as a reason for withdrawal from PD therapy. Our efforts at education might have been useful for improving early withdrawal from PD and deaths attributable to PD-related peritonitis. However, since improvements to incidence of PD-related peritonitis were limited by education, further improvement in PD-related peritonitis incidence requires development of new sterilized connecting systems during PD-bag exchanges to decrease PD-related peritonitis opportunities. Construction of medical support systems to address social problems is required to maintain long-term PD therapy.

The Association of Effluent Ca125 with Peritoneal Dialysis Technique Failure.

♦ Cancer antigen 125 (CA125) reflects the mesothelial cell mass lining the peritoneal membrane in individual patients. A decline or absence of mesothelial cells can be observed with duration of peritoneal dialysis (PD) therapy. Technique failure due to peritoneal membrane malfunction becomes of greater importance after 2 years of PD therapy in comparison to the initial period. In this study, we aimed to investigate the association between effluent CA125 and technique survival in incident PD patients with a PD therapy period of at least 2 years. ♦ Within the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD), a Dutch multicenter cohort including 2,000 incident dialysis patients, we identified all PD patients who developed technique failure after 2 years of PD therapy and randomly selected a number of them as cases in a nested case-control study. Controls were PD patients matched on follow-up time without technique failure. Cases and controls were included if they had a dialysate specimen available within 24 ± 6 months of PD therapy for retrospective CA125 determinations. Odds ratios for technique failure related to CA125 were estimated. We used a prospective cohort with incident PD patients from the Academic Medical Center-University of Amsterdam (AMC) for replication of effect estimates. In these patients, absolute risk of technique failure was estimated and related to effluent CA125 levels. ♦ A total of 38 PD patients were selected from the NECOSAD cohort. From the AMC cohort as replication cohort, 91 PD patients were included. Incidence rates of PD technique failure per 100 patient-years were 16.3 in the NECOSAD cohort and 12.9 in the AMC cohort. In both study populations CA125 levels below 12 - 14 kU/L were associated with an increased risk for technique failure. Technique survival rates in the AMC were 87% in patients with levels of CA125 above 12.1 kU/L and 65% for those with CA125 levels below this threshold after a maximum 5-year follow-up. ♦ Patients with high CA125 levels after at least 2 years of PD therapy tend to have better technique survival than patients with low CA125 levels. These results support the importance of effluent CA125 as a risk factor for dropout in long-term PD therapy.

Mast cell involvement in the progression of peritoneal fibrosis in rats with chronic renal failure.

Peritoneal fibrosis is a serious complication in patients with end stage renal disease (ESRD), especially those undergoing long-term peritoneal dialysis therapy. Since the peritoneum is a major site of mast cell accumulation, and since mast cells are known to facilitate the progression of organ fibrosis, they would also contribute to the pathogenesis of peritoneal fibrosis. The aim of this study was to reveal the involvement of mast cells in the progression of peritoneal fibrosis in chronic renal failure. Using a rat model with chronic renal failure (CRF) resulting from 5/6 nephrectomy, we examined the histopathological features of the rat peritoneum and compared them to those of age-matched sham-operated rat peritoneum. By treating the CRF rats with a potent mast cell stabilizer, tranilast, we also examined the involvement of mast cells in the progression of peritoneal fibrosis. The CRF rat peritoneum was characterized by the wide staining of collagen III and an increased number of myofibroblasts, indicating the progression of fibrosis. Compared to sham-operated rat peritoneum, the number of toluidine blue-stained mast cells was significantly higher in the fibrotic peritoneum of CRF rats. The mRNA expression of fibroblast-activating factors and stem cell factor was significantly higher in peritoneal mast cells obtained from CRF rats than in those obtained from sham-operated rats. Treatment with tranilast significantly suppressed the progression of peritoneal fibrosis in CRF rats. This study demonstrated for the first time that the number of mast cells was significantly increased in the fibrotic peritoneum of CRF rats. The proliferation of mast cells and their increased activity in the peritoneum were thought to be responsible for the progression of peritoneal fibrosis.

Late presentation of encapsulating peritoneal sclerosis following renal transplantation and the potential under‐reporting of the incidence and prevalence of encapsulating peritoneal sclerosis

Encapsulating peritoneal sclerosis is an infrequent but potentially devastating complication of peritoneal dialysis. The reported incidence and prevalence of encapsulating peritoneal sclerosis vary markedly between countries. Currently, peritoneal dialysis vintage remains the major risk factor for encapsulating peritoneal sclerosis, and dialysis vintage differs between countries due to the relative competing risks of transplantation, availability of haemodialysis and peritonitis. However, the diagnosis of encapsulating peritoneal sclerosis is often only established when patients have transferred modality to transplantation or haemodialysis. Switching treatment modality may potentially lead to an under-reporting of encapsulating peritoneal sclerosis, as many countries which collect data on dialysis patients in national registries often have separate registries for dialysis and transplant patients, and this may potentially lead to under-reporting of encapsulating peritoneal sclerosis in patients presenting after renal transplantation. Secondly, the question arises as to how long former peritoneal dialysis patients should be followed before a diagnosis of encapsulating peritoneal sclerosis can be confidently excluded. To highlight this point, we present four cases that developed symptomatic encapsulating peritoneal sclerosis more than 5 years, and in once case more than 10 years after the discontinuation of peritoneal dialysis. Delayed or late presentation may not only delay the diagnosis, but also risk surgical interventions by non-specialists. A more robust system is required to record cases of encapsulating peritoneal sclerosis to determine the incidence and prevalence, and so provide accurate information to both patients and clinicians as to the risks of long-term peritoneal dialysis therapy.

Qualitative Profiling of Polyglucose Degradation Products in Peritoneal Dialysis Fluids.

Heat sterilization of peritoneal dialysis (PD) fluids leads to partial degradation of the osmotic agent to form reactive carbonyl structures, which significantly reduce the biocompatibility of PD fluids and impair long-term PD therapy. Hence, it is important to know the exact composition of the degradation products to improve biocompatibility of PD fluids. Our study conducted targeted screening for degradation products in polyglucose (icodextrin)-containing PD fluids (pGDPs) by applying o-phenylenediamine (OPD) to form stable derivatives, which were analyzed by ultrahigh-performance liquid chromatography with hyphenated diode array tandem mass spectrometry (UHPLC-DAD-MS/MS). For the first time, specific degradation products of polyglucose, namely, 4-deoxyglucosone (4-DG) and 3,4-dideoxypentosone (3,4-DDPS), could be identified in PD fluids. Further, a reaction product of 5-hydroxymethylfurfural (5-HMF) and OPD could be characterized to be (5-(1H-benzo[d]imidazol-2-yl)furan-2-yl)methanol. Additionally, 3-deoxyglucosone (3-DG) and 3-deoxygalactosone (3-DGal), both known to be present in glucose-based PD fluids, were also detected in polyglucose-containing fluids. Trapping a hitherto unknown degradation product with OPD yielded 1,4-bis(1H-benzo[d]imidazol-2-yl)-3,4-dihydroxybutan-1-one, which was present in heat- as well as filter-sterilized PD fluids.

The kampo medicine Daikenchuto inhibits peritoneal fibrosis in mice.

Long-term peritoneal dialysis therapy causes inflammation and histological changes in the peritoneal membrane. Inflammation generally activates fibroblasts and results in fibroblast-myofibroblast differentiation. Heat-shock protein 47 (HSP 47), a collagen-specific molecular chaperone, is localized in myofibroblasts and is involved in the progression of peritoneal fibrosis. Daikenchuto (DKT), a Kampo medicine, is used to prevent postoperative colon adhesion. It inhibits inflammation and HSP 47 expression in the gastrointestinal tract. We examined the effect of DKT on chlorhexidine gluconate (CG)-induced peritoneal fibrosis in mice injected with 0.1% CG dissolved in 15% ethanol. DKT was dissolved in the drinking water. Histological changes were assessed using Masson trichrome staining. Cells expressing α-smooth muscle actin (α-SMA), HSP 47, phospho-Smad 2/3, F4/80, and monocyte chemotactic protein-1 were examined immunohistochemically. Compared with the control group, the peritoneal tissues of the CG group were markedly thickened, and the number of cells expressing α-SMA, HSP 47, phospho-Smad 2/3, F4/80, and monocyte chemotactic protein-1 was significantly increased. However, these changes were inhibited in the DKT-treated group. These results indicate that DKT can prevent peritoneal fibrosis by inhibiting inflammation and HSP 47 expression.

Anti-C5a complementary peptide ameliorates acute peritoneal injury induced by neutralization of Crry and CD59

In peritoneal dialysis (PD) therapy, physical stresses such as exposure to peritoneal dialysate, catheter trauma, and peritonitis may induce peritoneal injury that can prevent continued long-term PD therapy. Therefore, protection of the peritoneum is an important target to enable long-term PD therapy in patients with end-stage renal disease. We previously showed that neutralization of the membrane complement regulators (CRegs) Crry and CD59 in rat peritoneum provokes development of acute peritoneal injury due to uncontrolled complement activation. C5a is a key effecter molecule of the complement system released during acute inflammation. Control of C5a has been proposed as a strategy to suppress inflammatory reactions and, because peritoneal injury is accompanied by inflammation, we hypothesized that C5a targeted therapy might be an effective way to suppress peritoneal injury. In the present study we used an established acute peritonitis model induced by neutralization of CRegs to investigate the effects on acute peritoneal injury of inhibiting C5a. Intravenous administration of an anti-C5a complementary peptide (AcPepA) up to 4 h after induction of injury significantly and dose-dependently prevented accumulation of inflammatory cells and reduced tissue damage in the model, accompanied by decreased C3b deposition. We show that C5a contributed to the development of peritoneal injury. Our results suggest that C5a is a target for preventing or treating peritoneal injury in patients undergoing prolonged PD therapy or with infectious complications.

Current Status and Practical Use of Effluent Biomarkers in Peritoneal Dialysis Patients

Long-term peritoneal dialysis therapy can lead to alterations in the function and morphology of the peritoneal membrane. Assessment of the peritoneal dialysis membrane usually is done by investigating the transport of small solutes and fluid. Assessment of morphologic alterations and their development would require repetitive peritoneal biopsies that usually are not feasible. Peritoneal tissues are bathed in dialysis solutions during peritoneal dialysis and may secrete or shed substances that can be recovered in peritoneal effluent. These molecular effluent biomarkers may give insight into morphologic changes. In this review, established and emerging candidate biomarkers in peritoneal dialysis are discussed. Additionally, requirements, challenges, and clinical applications of effluent biomarkers in peritoneal dialysis are addressed.

Risk Factors for Encapsulating Peritoneal Sclerosis in Long‐Term Peritoneal Dialysis: A Retrospective Observational Study

Encapsulating peritoneal sclerosis (EPS) is a serious complication that occurs in patients with long-term peritoneal dialysis (PD). Investigation of risk factors that contribute to EPS in patients on long-term PD therapy is needed. In a retrospective, observational study, data were collected for 107 patients treated with PD therapy for more than 5 years. Fifty cases of EPS were compared with 57 cases of non-EPS. To evaluate the impact of PD-associated peritonitis in EPS, univariate and multivariate logistic regression models were applied. Episodes of peritonitis, number of peritonitis episodes and the duration of peritonitis were included as explanatory variables in addition to previously reported risk factors. D/P Cr and serum β2MG levels in the EPS and non-EPS groups were: 0.82 ± 0.10 and 0.67 ± 0.12 (P < 0.01), and 33.8 ± 8.54 and 29.2 ± 8.18 mg/L (P < 0.01), respectively. Episodes of peritonitis, number of peritonitis episodes and the duration of peritonitis was 68% and 42% (P < 0.01), 1.80 ± 2.19 and 0.75 ± 1.07 times (P < 0.01), and 18.1 ± 15.3 and 10.2 ± 4.90 days (P < 0.01), in the EPS and non-EPS groups, respectively. Furthermore, multivariate logistic regression models demonstrated that both D/P Cr and the duration of peritonitis were independently associated with EPS (P < 0.01 and P < 0.05, respectively). In patients on long-term PD therapy, D/P Cr and the duration of peritonitis are independently associated with EPS. Earlier treatment to promote an early recovery from PD-associated peritonitis could be critical in preventing EPS.

Development of Encapsulating Peritoneal Sclerosis Following Bacterial Peritonitis in a Peritoneal Dialysis Patient

Encapsulating peritoneal sclerosis (EPS) isan uncommon and often fatal complication inpatients on peritoneal dialysis (PD) therapy. EPSis a clinical syndrome characterized by symp-toms of impaired intestinal motility, such asanorexia, nausea, vomiting, abdominal fullness,abdominalpain,absentbowelsounds,andconsti-pation.

Gram-Negative Peritonitis in Children Undergoing Long-term Peritoneal Dialysis

The proportion of gram-negative causative organisms in peritoneal dialysis-associated peritonitis is increasing. Little published information for this complication exists in children. The objective of this study is to evaluate the clinical presentation, early and late response to treatment, and identification of factors influencing the outcome of gram-negative peritonitis (GNP) in children. Case series. 104 children (aged 7.9 +/- 5.9 years) with 121 GNP episodes reported to the International Pediatric Peritonitis Registry from October 2001 through December 2004. Patient, clinical, bacteriological, and treatment features. Initial response to empirical treatment was assessed after approximately 72 hours of therapy. Final outcome was judged according to the occurrence of death, technique failure, relapse, need for catheter exchange, and a composite end point defining full functional recovery. 44% of episodes of GNP occurred in children younger than 5 years. Causative organisms included Pseudomonas species, 21%; Klebsiella species, 18%; Escherichia coli, 17%; and Acinetobacter species, 12%. Thirty-two percent of organisms classified as gram-negative were not identified further. Clinical manifestations were severe and uniform for all causative gram-negative agents. A substantial proportion (20%) of organisms were resistant to ceftazidime, with resulting suboptimal response to empirical therapy. By day 3 of initial empiric treatment, 85% of children with GNP had improved clinically (39%, complete resolution; 46%, improvement in symptoms), 10% showed poor response, and 5% had worsening of symptoms. Multivariate analysis identified severe abdominal pain, use of a single-cuff catheter, and intermittent (versus continuous) intraperitoneal ceftazidime administration as independent predictors of worse initial response to treatment. Full functional recovery was achieved in 86% of episodes. Nineteen patients (16%) required catheter removal, 11 (9%) experienced a relapse, 7 (6%) discontinued peritoneal dialysis therapy permanently, and 3 died. Lack of clinical improvement after 72 hours of therapy (odds ratio, 5.39; P < 0.01) and the presence of an exit-site infection (odds ratio, 7.69; P = 0.01) independently increased the risk of an incomplete functional recovery. The study was not designed to assess absolute incidence figures or risk factors for the development of GNP in children. GNP is a significant complication of long-term peritoneal dialysis therapy in children, and a substantial proportion of affected children are at risk of permanent sequelae. Because results of empiric treatment with ceftazidime are suboptimal in the setting of this infection, alternative antimicrobial agents should be reconsidered.

Evaluation of Enhanced Peritoneum Permeability in Methylglyoxal-treated Rats as a Diagnostic Method for Peritoneal Damage

As peritoneal damage in long-term peritoneal dialysis therapy is a major problem correlated to patient prognosis, diagnosis of peritoneal damage is important. To develop a diagnostic method for peritoneal damage, we focused on hyperpermeability across the peritoneum in a pathogenic peritoneal damage condition. In this study, disposition characteristics of an intraperitoneally injected marker substance in peritoneal damaged rats were analyzed. Peritoneal damaged rats were prepared by intraperitoneal injection of a glucose degradation product, methylglyoxal (MGO), for five or ten consecutive days. Phenolsulfonphthalein (PSP), as a marker substance, was intraperitoneally or intravenously injected into MGO-treated rats. Subsequently, the PSP disposition characteristics were pharmacokinetically analyzed. In both cases of 5 and 10 days treatment of MGO, absorption of PSP after intraperitoneal injection was significantly enhanced. Plasma concentration and urinary excretion of PSP in MGO-treated rats were also higher than those in saline-treated rats in the early phase. On the contrary, there was no significant difference in terms of the pharmacokinetic parameters of intravenously injected PSP in saline- or MGO-treated rats. These results indicated that intraperitoneally injected MGO primarily acts on the peritoneal membrane; therefore, the peritoneal permeability of the marker substance was enhanced. We demonstrated that pharmacokinetic analysis of peritoneum permeability might be a potent diagnostic method for peritoneal damage in experimental animals and patients receiving peritoneal dialysis.

The Plasma Leak–to–Response Hypothesis: A Working Hypothesis on the Pathogenesis of Encapsulating Peritoneal Sclerosis after Long-Term Peritoneal Dialysis Treatment

Encapsulating peritoneal sclerosis (EPS) is one of the most serious complications of long-term peritoneal dialysis (PD). Long-term PD therapy has been suggested as a risk factor for EPS development among patients in Japan and Australia. Although the primary mechanism of EPS development has not been clarified, histologic changes of the peritoneum associated with prolonged PD are postulated to be causally related. The present article proposes a working hypothesis--the plasma leak-to-response hypothesis--that vascular alterations in the peritoneum of long-term PD patients play a crucial role in the initiation and development of EPS.

Beyond the membrane—The role of new PD solutions in enhancing global biocompatibility

Since the introduction of continuous ambulatory peritoneal dialysis (CAPD) during the late 1970s as a form of home-based, self-care renal replacement therapy, peritoneal dialysis (PD) has become an appealing alternative for the treatment of patients with end-stage renal disease (ESRD). A significant amount of research over the last 25 years has resulted in continuous improvements in the quality of PD treatment. Survival of patients on PD is now at least as good as with hemodialysis, especially during the first years of treatment, and results are gradually improving. Considerable progress has been made in understanding the nature of the interactions between the dialysis solution and the peritoneal membrane, how these interactions may result in structural alterations to the membrane, and how peritoneal solute and fluid transport are influenced by these alterations. During recent years, as PD technique survival has improved and peritonitis rates declined, PD researchers have focused more attention on ways to improve the biocompatibility of dialysis solutions with the goal of extending the life of the peritoneum as a dialyzing membrane, which may improve and extend the life of the PD patient. The reason for this research focus is the observation that the characteristic structural and functional alterations to the peritoneal membrane during long-term PD treatment may be the consequence of the continuous exposure to solutions with high concentrations of glucose, glucose degradation products (GDPs), and lactate, low pH, and high osmolality. It is now clear that these alterations to the peritoneal membrane may have a profound effect on the well-being of the patient on long-term PD therapy. According to the Consensus Conference on Biocompatibility held in 1994 [1], biocompatibility is “the ability of a material, device or system to perform without a clinically significant host response in a specific application.” When applied to PD, biocompatibility refers to the ability

Depression and its association with peritonitis in long-term peritoneal dialysis patients

Background:Depression is the most common psychological disorder among patients with end-stage renal disease and has been associated with mortality in patients maintained on hemodialysis therapy. Peritonitis is the leading cause of technique failure among long-term peritoneal dialysis (PD) patients. This prospective study is designed to examine the relationship between depression and peritonitis. Methods:All patients on long-term PD therapy in our unit between January 1, 1997, and January 31, 2002, completed a Beck Depression Inventory (BDI) assessment at 6-month intervals. BDI scores were analyzed 2 ways. First, patients were placed into either group I (BDI score < 10) or group II (BDI score ≥ 11) and were reclassified based on subsequent scores. Second, multivariable analysis was performed looking at initial BDI score as a risk factor for peritonitis, adjusting for age older than 65 years, diabetes, coronary artery disease, and race. Results:One hundred sixty-two patients were enrolled, and 281 individual BDI assessments were completed. There was a significantly greater incidence of diabetes and coronary artery disease in group II. Rates for overall and gram-positive peritonitis were significantly greater in group II patients compared with group I patients. Using Cox regression, only BDI score of 11 or greater was associated with the development of peritonitis (hazard ratio, 2.7; 95% confidence interval, 1.2 to 6.0). Conclusion:There is an association between BDI score of 11 or greater and the development of peritonitis. Whether treatment of depression can impact on the rate of peritonitis remains to be examined.

Patterns of infection in patients maintained on long-term peritoneal dialysis therapy with multiple episodes of peritonitis

The causes of peritonitis in patients with end-stage renal disease maintained on long-term peritoneal dialysis (PD) are unclear. One possible explanation for peritonitis, particularly in patients with multiple episodes of infection, is the release of planktonic bacteria from biofilm on the walls of catheters. Bacteria form biofilm on the walls of catheters within 48 hours of their placement. If this explanation were correct, one would expect there to be reappearance of organisms causing infection in patients with multiple episodes of peritonitis. The charts of all patients starting long-term PD at New Haven CAPD from January 1, 1990, through July 31, 2000, were reviewed. Patients were included in the study if they had experienced more than one episode of culture-positive peritonitis and complete data were available concerning cultured organisms and antibiotic sensitivity patterns. Episodes of infection, organisms, and sensitivities and catheter changes were reviewed. Of 630 patients, 198 were identified as meeting these criteria. There were 114 men; 104 patients were white. Of 198 patients, 157 (80%) had at least one repeat infection with the same organism. In 124 (79%) patients, more than 50% of the peritonitis episodes were caused by the same organism. Of 90 patients who had more than four episodes of infection in their history, 59 (65%) had at least half or more of their episodes caused by the same organism. Sequential analyses for independence revealed that for Staphylococcus epidermidis and for Staphylococcus aureus, there was a significantly increased likelihood for these organisms to follow themselves as causative organisms of peritonitis. When the data were analyzed using the Spearman correlation test, the results indicated that the likelihood of repeat infections occurring was significantly greater than by chance alone. Of 67 patients with catheter changes and subsequent peritonitis, only 10 (15%) developed repeat infections with the same organism after the catheter change. Eight of these were due to yeast. These data support the hypothesis that bacterial biofilm on the walls of peritoneal catheters may be associated with peritonitis in patients maintained on long-term PD and may contribute to at least some of these episodes of infection. © 2002 by the National Kidney Foundation, Inc.

Clinical study on effect of TCM treatment in decreasing frequency of peritoneal dialysis

Traditional Chinese herbal medicine was used in combination with peritoneal dialysis (PD) in order to improve the renal function and reduce the frequency of PD. The results indicated that, after 3 months of PD+TCM, the serum BUN, creatinine and mean arterial pressure of therapeutic group lowered and the hemoglobin elevated as compared with those after 1 month of PD (P < 0.01), the difference of above-mentioned criteria between PD+TCM group and less frequent PD (LEPD) group was significant too, while there was no obvious difference in comparison of the PD+TCM group with regular PD group (P > 0.05). The effective rate and the edema cure rate of TCM+PD group were superior to the LFPD group, but had no evident difference as compared with the regular PD group. The results revealed that PD combined with TCM treatment might reduce the frequency of PD for the uremia patient deserved long-term PD therapy.