Ultrafiltration Failure Research Articles

Effluent Osteopontin levels reflect the peritoneal solute transport rate.

Long-term peritoneal dialysis (PD) is accompanied by low-grade intraperitoneal inflammation and may eventually lead to peritoneal membrane injury with a high solute transport rate and ultrafiltration failure. Osteopontin (OPN) is highly expressed through the stimulation of pro-inflammatory cytokines in many cell types. This study aimed to investigate the potential of OPN as a new indicator of peritoneal deterioration. One hundred nine continuous ambulatory PD patients were analyzed. The levels of OPN and IL-6 in peritoneal effluents or serum were analyzed by ELISA kits. The mean effluent OPN concentration was 2.39 ± 1.87 ng/mL. The OPN levels in drained dialysate were correlated with D/P Cr (p < 0.0001, R = 0.54) and D/D0 glucose (p < 0.0001, R = 0.39). Logistic regression analysis showed that the OPN levels in peritoneal effluents were an independent predictive factor for the increased peritoneal solute transport rate (PSTR) obtained by the peritoneal equilibration test (p < 0.001). The area under the receiver operating characteristic curve of OPN was 0.84 (95% CI: 0.75–0.92) in predicting the increased PSTR with a sensitivity of 86% and a specificity of 67%. The joint utilization of effluent OPN with age, effluent IL-6, and serum albumin further increased the specificity (81%). Thus, OPN may be a useful indicator of peritoneal deterioration in patients with PD.

MO691CORRELATION OF INTRAPERITONEAL PRESSURE AND APEX TIME WITH ULTRAFILTRATION AND BIOCHEMICAL VARIABLES IN PATIENTS IN PERITONEAL DIALYSIS

Abstract Background and Aims Chronic Kidney Disease represents a growing and serious public health problem, which progresses to terminal stage with glomerular filtration rate &amp;lt;15 ml/min/1.73m2. It makes it necessary to implement substitute therapies for renal function with hemodialysis (HD), peritoneal dialysis (PD) or kidney transplantation. It is known that the ultrafiltration (UF) capacity of PD is much lower than that of HD, which explains the higher incidence of overhydration in PD patients, which increases morbidity and mortality in this group of patients, being the second cause of change to HD. Due to this limitation, it is essential to know and fully exploit all the factors that influence the UF in PD. The net UF in DP is the result of 4 forces: 1) the osmotic force, the strongest and only one that is deliberately controlled; 2) intraperitoneal pressure (IPP) modulated by intraperitoneal volume (IPV), UF volume itself, posture, BMI, physical activity, etc.; 3) capillary hydrostatic pressure, modulated by the degree of fluid overload, and 4) capillary oncotic pressure proportional to hypoalbuminemia, in turn related to fluid overload. The IPP with typical values of 10-16 cm H2O, should not exceed 18 cmH2O, this excess leads to the development of mechanical, infectious and functional complications, among them, a decrease in UF. Elevated IPP is a little known cause of UF failure and, due to its easy diagnosis and application, it should be ruled out in cases of overhydration in PD. Another parameter to consider when favoring UF in PD is the residence time of the dialysate solution in the abdominal cavity through the APEX time calculation (functional test derived from the classic peritoneal balance test). In the present study, we intend to define the role of IPP and APEX time as diagnostic and adjunctive evaluation techniques to optimize UF in PD patients. We determined the correlation of IPP and APEX time with ultrafiltration and biochemical variables in PD patients. Method Pilot, observational, cross-sectional, analytical study. Results Thirty patients were included, 10 (33%) patients on PD in the IPD modality and 20 (66.7%) in the CAPD modality. Of which mostly men (53%). The mean residual uresis of the general population was 534.33 ml. The average UF with a 1.5% solution is 238.1, for a 2.5% solution the average UF is 296.2 and for a 4.25% solution the average UF is 535 ml. No statistically significant mean differences were found between both groups. (p ≤ 0.05). The average IPP in the supine position was 13.1 cmH2O, the sitting position was 22.8 cmH2O, and the vertical 25.4 cmH2O, the variability of the PIP in the prone position at 15.8 cmH2O is striking. No statistically significant differences were found between the averages of the analysis groups (p ≤ 0.05). The average calculated APEX time was 42.4 minutes. When performing the correlation of UF with IPP, APEX, Dif. Na, D/P and D/Do, as well as the correlation between APEX time and time in DP. Being able to determine that there is no correlation between the different variables. No statistically significant differences were found. (p ≤ 0.05). Conclusion It is the first study in Mexico that evaluates the usefulness of APEX and IPP time in Adult patients on CAPD and IPD. It was determined that Intraperitoneal Pressure does not influence Ultrafiltration levels. In our study we demonstrated that the APEX time, an index of the optimal ultrafiltration residence time, was not correlated with the UF volumes. Therefore, the adequacy of peritoneal dialysis must not only be based on functional tests, it must be personalized and be based in conjunction with clinical, biochemical, nutritional parameters and functional tests.

Serum CA125 a potential marker of volume status for peritoneal dialysis patients?

Introduction:Serum cancer antigen 125(SeCA125) has been reported to be increased in patients with heart failure and correlate with both extracellular water (ECW) overload and poor prognosis. Ultrafiltration failure and ECW overload are a major cause of peritoneal dialysis (PD) technique failure. We wished to determine whether SeCA125 could also be a marker of volume status in PD patients.Methods:We contemporaneously measured SeCA125, serum N terminal brain natriuretic peptide (NTproBNP) and ECW by bioimpedance in adult PD patients attending for outpatient assessment of peritoneal membrane function.Results:The median SeCA125 was 19 (12–33) U/mL in 489 PD patients, 61.3% male, median age 61.5 (interquartile range 50–75) years. SeCA125 was positively associated with the ratio of ECW/total body water (TBW) (r = 0.29, p < 0.001), 4-h peritoneal dialysate to serum creatinine ratio (r = 0.23, p < 0.001), NTproBNP) (r = 0.18, p < 0.001), and age (r = 00.17, p = 0.001) and negatively with 24-h PD ultrafiltration volume (r = −0.28, p < 0.001) serum albumin (r = −0.22, p < 0.001), and echocardiographic left ventricular ejection fraction (r = −0.20, p < 0.001), but not with residual renal function or C-reactive protein. Patients with above the median SeCA125, had greater median ECW/TBW 0.403(IQR 0.394–0.410) vs 0.395(0.387–0.404), p < 0.001 and NTproBNP (6870 (IQR 1936–20096) vs 4069 (1345–12291) vs) pg/mL, p = 0.03.Conclusion:Heart failure studies have reported SeCA125 is a marker of ECW overload. Our retrospective analysis suggests that SeCA125 is also associated with ECW volume in PD patients. Further studies are required to determine whether serial measurements of SeCA125 trend with changes in ECW status in PD patients and can be used to aid volume assessments.

Enhanced mPGES-1 Contributes to PD-Related Peritoneal Fibrosis via Activation of the NLRP3 Inflammasome.

Background: Microsomal prostaglandin E synthase-1 (mPGES-1)-derived prostaglandin E2 (PGE2) is a chief mediator of inflammation. However, the role and mechanism of mPGES-1 in peritoneal dialysis (PD)-associated peritoneal fibrosis have not been investigated.Material and Methods: In PD patients, mPGES-1 expression in peritoneum tissues and the levels of PGE2, IL-1β, and IL-18 in the dialysate were examined. In rat peritoneal mesothelial cells (RPMCs), the regulation and function of mPGES-1 and NLRP3 inflammasome were investigated. The expression of extracellular matrix proteins and the components of NLRP3 inflammasome were detected by Western blotting or real-time quantitative PCR.Results: In PD patients with ultrafiltration failure (UFF), mPGES-1 was enhanced in the peritoneum, which was associated with the degree of peritoneal fibrosis. Accordingly, the intraperitoneal PGE2 levels were also positively related to the PD duration, serum C-reactive protein levels, and serum creatinine levels in incident PD patients. In RPMCs, high-glucose treatment significantly induced mPGES-1 expression and PGE2 secretion without affecting the expressions of mPGES-2 and cPGES. Inhibition of mPGES-1 via short hairpin RNA significantly ameliorated the expression of extracellular matrix proteins of RPMCs induced by high glucose. Additionally, high glucose markedly activated NLRP3 inflammasome in RPMCs that was blunted by mPGES-1 inhibition. Furthermore, silencing NLRP3 with siRNA significantly abrogated the expression of extracellular matrix proteins in RPMCs treated with high glucose. Finally, we observed increased IL-1β and IL-18 levels in the dialysate of incident PD patients, showing a positive correlation with PGE2.Conclusion: These data demonstrate that mPGES-1-derived PGE2 plays a critical role in PD-associated peritoneal fibrosis through activation of the NLRP3 inflammasome. Targeting mPGES-1 may offer a novel strategy to treat peritoneal fibrosis during PD.

CT Imaging Characteristics and Influence Factors of Renal Dialysis-Associated Peritoneal Injury.

Peritoneal dialysis (PD), as one of the main renal replacement modalities for end-stage renal disease, gets the advantages of better protection of residual renal function and better quality of survival. However, ultrafiltration failure after peritoneal injury is an important reason for patients to withdraw from PD treatment. Peritonitis is a major complication of peritoneal dialysis, which results in an accelerated process of peritoneal injury due to direct damage from acute inflammation and local release of cytokine TGF-β. In this paper, the application of ultrasound to examine the peritoneum revealed a positive correlation between peritoneal thickness and the development of peritonitis. The results of this study also further confirmed the effect of peritonitis on peritoneal thickening. A multifactorial regression analysis also revealed that peritonitis and its severity were independent risk factors for peritoneal thickening and omental structural abnormalities. This paper reported a correlation between mural peritoneal thickness and peritoneal transit function. In this study, patients with high peritoneal transit and high mean transit were found to be more prone to omental structural abnormalities than patients with low mean and low transit and a higher proportion of patients with mural peritoneal thickening, but this did not reach statistical significance, which may be related to the still small number of cases.

Risk Factors for Early Peritoneal Dialysis Discontinuation: Importance of Heart Failure.

The number of patients on peritoneal dialysis (PD) in our hospital has increased during the past 5 years, but the number discontinuing PD has also increased. The purpose of this study was to identify the risk factors for PD discontinuation by analyzing the association between technical survival period (defined as the duration of PD) and various clinical factors. We retrospectively investigated 87 patients who were started on PD at our hospital and attended regularly from April 2015 to March 2020, and we analyzed the association between technical survival period and various clinical factors. We also looked for associations between technical survival period and hospitalizations for heart failure, peritonitis, and exit-site infections among patients undergoing PD. The patients using renin-angiotensin-aldosterone system inhibitors (RASi) (P = 0.0218), those with left ventricular ejection fraction (LVEF) > 50% (P = 0.0194) when they started PD, and those with estimated glomerular filtration rate (eGFR) ≥ 6 (mL/min/1.73 m2) (P = 0.0013) at the initiation of PD showed significantly longer technical survival period, and those who were hospitalized for heart failure had significantly shorter period (P = 0.0008). Treatment of RASi, LVEF > 50% and eGFR ≥ 6 mL/ min/1.73 m2 when the initiation of PD and better volume control to prevent ultrafiltration failure and heart failure may improve technical survival period in patients undergoing PD.

Vascular endothelial growth factor-mediated peritoneal neoangiogenesis in peritoneal dialysis.

Peritoneal dialysis (PD) is an important renal replacement therapy for patients with end-stage renal diseases, which is limited by peritoneal neoangiogenesis leading to ultrafiltration failure (UFF). Vascular endothelial growth factor (VEGF) and its receptors are key angiogenic factors involved in almost every step of peritoneal neoangiogenesis. Impaired mesothelial cells are the major sources of VEGF in the peritoneum. The expression of VEGF will be up-regulated in specific pathological conditions in PD patients, such as with non-biocompatible peritoneal dialysate, uremia and inflammation, and so on. Other working cells (i.e. vascular endothelial cells, macrophages and adipocytes) can also stimulate the secretion of VEGF. Meanwhile, hypoxia and activation of complement system further aggravate peritoneal injury and contribute to neoangiogenesis. There are several signalling pathways participating in VEGF-mediated peritoneal neoangiogenesis including tumour growth factor-β, Wnt/β-catenin, Notch and interleukin-6/signal transducer and activator of transcription 3. Moreover, VEGF is highly expressed in dialysate effluent of long-term PD patients and is associated with peritoneal transport function, which supports its role in the alteration of peritoneal structure and function. In this review, we systematically summarize the angiogenic effect of VEGF and evaluate it as a potential target for the prevention of peritoneal neoangiogenesis and UFF. Preservation of the peritoneal membrane using targeted therapy of VEGF-mediated peritoneal neoangiogenesis may increase the longevity of the PD modality for those who require life-long dialysis.

POS-633 TRENDS IN MORTALITY AMONG PERITONEAL DIALYSIS PATIENTS ACROSS TIME PERIODS: THE IMPACT OF PERITONEAL DIALYSIS-RELATED PERITONITIS

As the global burden of chronic kidney disease continues to increase, so does the need for a cost-effective renal replacement therapy. Peritoneal dialysis (PD) offers several advantages in end-stage renal disease but infectious peritonitis (IP) remains one of the most serious and life threatening complications of PD. The purpose of this study is to assess the prevalence and to evaluate the impact of peritonitis on patient mortality and technique survival with respect to duration of follow-up. We conducted a twenty seven years retrospective study from 1990 till december 2017 in the nephrology department, Fattouma Bourguiba University Hospital (Monastir, Tunisia). The rate of peritonitis, the causative organisms as well as the patient's outcome after its occurrence have been analyzed. We used the Cox regression model to assess whether peritonitis has a negative impact on mortality. The 476 episodes of IP were identified in 206 patients. The mean age of our patients was 45.8.1±16.8 years [11–86] (male to female: sex ratio M/F=2.43). The peritonitis rate (months × patients/peritonitis) was 17.6 (0.68 episode per year). Time to occurrence of peritonitis from the start of peritoneal exchange was 14.53±14 months. Gram-positive cocci (GC+) were involved in 54.7% of microbiologically proven IP cases presented mostly by Staphylococcus aureus. Gram-negative bacilli (GB-) ranked second (37.7%) represented mainly by Pseudomonas. The peritonitis was the main influencing factor on the technique survival causing ultrafiltration failure (p=0.02). The median survival of the DP technique was 68 months (95%, CI [47, 90]). After adjusting for confounders, peritonitis was independently associated with 95% increased risk of all-cause mortality and near 4-fold increased risk of infection-related mortality (hazard ratio, 4.98; 95% confidence interval: 2.47–8.86). Further analyses showed that peritonitis strongly influenced mortality in patients dialysed within the first 2 years. Peritonitis was independently associated with higher risk of all-cause and infection-related mortality in peritoneal dialysis patients, and its impact on technique survival was determinate. Despite the gradual decrease of its rate over periods, peritonitis remains frequent in our center and calls for optimization of means of prevention.

POS-655 RISK FACTORS FOR IN-HOSPITAL MORTALITY IN CHRONIC PERITONEAL DIALYSIS PATIENTS ADMITTED WITH COVID-19 AT THE NATIONAL KIDNEY AND TRANSPLANT INSTITUTE OF THE PHILIPPINES

COVID-19 declared a pandemic by the WHO on March 15, 2020 has a global mortality rate of 2.39%, mostly afflicting those with co-morbidities. In end stage renal disease patients, the case fatality rate increases to as high as 40.6% for hemodialysis patients and 50% for peritoneal dialysis patients. This study aimed to determine the outcomes and risk factors for in-hospital mortality of chronic PD patients admitted with COVID-19 from March to September 2020 in the institution with the biggest PD population in the Philippines. This retrospective cohort included all adult chronic PD patients admitted with COVID-19 from March 2020 to September 2020. Inclusion criteria are age > 18 years old, on chronic PD for at least 1 month, positive for COVID-19 by RT-PCR, followed-up until 30 days post discharge. PD patients who expired prior to obtaining COVID-19 RT- PCR results and patients with a dysfunctional PD catheter on admission were excluded from the study. Relationship of PD patients’ baseline demographic and clinical characteristics with outcome was obtained using chi square test or Fischer exact tests for categorical variables and t-test for continuous variables. A p-value of less than 0.05 was statistically significant. Univariate and multivariate logistic regression was used to determine the factors that predict in-hospital mortality amongst the subjects. Of the 1199 active PD patients in our institution, 74(6.2%) chronic peritoneal dialysis (PD) patients were admitted for COVID-19 with mean age of 46.67±17.67, slight predominance of males (51.35%) and mean duration of PD of 20.86±18.69 months. Majority (41.8%) had severe COVID-19 infection. The most common presenting symptoms were difficulty of breathing (51.35%), cough (44.59%) and abdominal pain (41.54%). Anemia (9.3±1.98mg/dL vs. 7.84±1.45mg/dL, p=0.0095), lymphopenia (12.12±5.36x103/uL vs. 9.07±4.94x103/uL, p=0.0497), leukocytosis (8.70±4.00x103/uL vs. 12.45 ± 4.72103/uL, p=0.0026) and ultrafiltration failure in both CAPD and CCPD modalities were significantly associated with mortality.Longer days on CAPD (p=0.0403), lower number of exchanges per day (p=0.0065), and a greater volume of ultrafiltration per day (p=0.009) were significantly associated with survival. This would imply that the volume of ultrafiltration per day was more important for survival, compared to the number of exchanges or cycles performed. (Table 2)PD effluent analysis amongst those who presented with abdominal pain showed that 14(46.67%) had concomitant culture negative peritonitis. Among the 8 subjects who died, 6 (75%) had coexisting PD peritonitis. This may suggest a possibility of COVID-related peritonitis leading to ultrafiltration failure and higher mortality. View Large Image Figure ViewerDownload Hi-res image Download (PPT)Average hospital stay was 17.5 days, temporary shifting to HD was required in 32.43% and in-hospital mortality was 20.27%.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Independent risk factors for in-hospital mortality included severity of COVID-19 infection (p=0.003), abdominal pain (p=0.018), oxygen desaturation (p=0.029), leukocytosis (p=0.013) and anemia (p=0.009). (Table 5) COVID-19 in chronic PD patients resulted in a higher mortality rate compared to the general population. Presence of high risk factors warrant close monitoring and aggressive management. Adequate PD ultrafiltration should be achieved and if not possible, early shift to HD may be helpful.

The peritoneal dialysis orders objective structured clinical examination (OSCE): A formative assessment for nephrology fellows.

Peritoneal dialysis (PD) management is a fundamental nephrology skill, especially with the recent emphasis on home dialysis. We report a prospective multicentre cohort study of a formative objective structured clinical examination (OSCE) assessing competence in managing PD-associated bacterial peritonitis, using the unified model of construct validity. The OSCE was developed by the principal investigators and reviewed by two subject matter experts. The test committee (eight nephrologists and one PD nurse) assessed test item difficulty/relevance and determined passing score. There were 22 test items (7 evidence-based/standard-of-care questions). Passing score was 16/22 (73%). No item had median relevance less than 'important', and all were easy to medium difficulty. Content validity index was 0.91. Preliminary validation (16 board-certified volunteers): mean score was 19 ± 2, with 94% (15/16) passing. Kappa = 0.85 [95% confidence interval (CI) 0.77-0.94]. Cronbach's α = 0.70. Eighty-seven fellows (16 programmes) were tested; 67% passed. Fellows scored significantly less than validators: 17 ± 3 versus 19 ± 2, p < 0.001 [95% CI 1.2-3.6]. Eighty-six per cent of evidence-based/standard-of-care questions were answered correctly by validators versus 54% by fellows; p < 0.001. Ninety-three per cent of fellows recognized that sufficient criteria were present to diagnose peritonitis, but only 17% correctly indicated all three. Seventy-seven per cent recognized peritonitis-associated ultrafiltration failure, but only 17% prescribed 21 days of antibiotic treatment for gram-negative peritonitis. Eighty-five per cent of fellows surveyed agreed/strongly agreed that the OSCE was useful in self-assessing proficiency. Second-year in-training examination and OSCE scores were positively correlated (Pearson's r = 0.57, p < 0.00). The OSCE may be used to formatively assess fellow proficiency in managing PD-associated peritonitis.

Experimental models in peritoneal dialysis (Review).

Peritoneal dialysis (PD) is one of the most commonly used dialysis methods and plays an important role in maintaining the quality of life of patients with end-stage renal disease. However, long-term PD treatment is associated with adverse effects on the structure and function of peritoneal tissue, which may lead to peritoneal ultrafiltration failure, resulting in dialysis failure and eventually PD withdrawal. In order to prevent the occurrence of these effects, the important issues that need to be tackled are improvement of ultrafiltration, protection of peritoneal function and extension of dialysis time. In basic PD research, a reasonable experimental model is key to the smooth progress of experiments. A good PD model should not only simulate the process of human PD as accurately as possible, but also help researchers to understand the evolution process and pathogenesis of various complications related to PD treatment. To better promote the clinical application of PD technology, the present review will summarize and evaluate the in vivo PD experimental models available, thus providing a reference for relevant PD research.

Peritoneal dialysis in Tunisia: complications, technique and patient's survival (twenty-seven years of experience in a single center).

Introductionperitoneal dialysis (PD) is a renal replacement therapy method that offers various advantages to end-stage renal disease patients. The aim of our study was to analyze patient characteristics, peritonitis and clinical outcome over a 27-year period of PD in our center.Methodsretrospective study of incident patients on PD from January 1990 to December 2017. A total of 304 patients were enrolled in the study group. All patients over 15 years of age entering the dialysis program were included in the study. Patients dropping out from PD within three months were all excluded. Biochemical and demographic variables, peritonitis episodes and patient and technique survival were analyzed.Resultsthe PD prevalence in our center was 4.5% during the study period; the mean age was 46.47 ± 18.6 years; diabetic nephropathy was the main cause of chronic kidney disease: 35.5% (n=108). Cardiovascular disease was the main cause of death: 39.6% (n=34). The peritonitis rate was 0.68 episode per patient-year. Ultrafiltration failure was the most important cause of PD withdrawal: 43% (n=60). Occurrence of peritonitis was the only independent predictor of technique failure: adjusted relative risk [aRR] 5.07, 95% CI 2.69-9.58; p<0.001. The overall non-adjusted patient survival was around 100%, 95% and less than 20% at 1, 4 and 25 years respectively basing on the Kaplan-Meier analysis. The group undergoing renal transplantation had the best survival rate.Conclusionperitonitis remains the most common complication as well as the most provider of technique failure and patient´s transfer to hemodialysis. The technique survival was better in case of absence of peritonitis. However, our series showed the superiority of hemodialysis over PD in terms of overall patient survival.

Blocking core fucosylation of epidermal growth factor (EGF) receptor prevents peritoneal fibrosis progression

Objective Peritoneal fibrosis (PF) ultimately causes ultrafiltration failure and peritoneal dialysis (PD) termination, but there are few effective therapies for it. Core fucosylation, which is catalyzed by α1,6-fucosyltransferase (Fut8) in mammals, may play a crucial role in PF development. This study aims to assess the effects of inhibiting core fucosylation of epidermal growth factor (EGF) receptor on PF rats. Methods PF rats (established by 4.25% glucose dialysate) were treated with either an adenovirus-Fut8 short hairpin RNA (Fut8shRNA) or adenovirus-control. Masson’s staining and net ultrafiltration were performed at week six. Fut8 level and core fucosylation of EGF receptor and collagen I in the peritoneal membrane were assessed, and EGF signaling was detected, including signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa B (NF-κB) and their phosphorylation. Monocyte chemoattractant protein-1 (MCP-1) in peritoneal effluent was examined. Results Fut8 was upregulated in PF rats but decreased after Fut8shRNA treatment. EGF and EGF receptor expression was upregulated in PF rats, while core fucosylation of EGF receptor decreased after Fut8shRNA treatment. Masson’s staining results showed an increase in peritoneal thickness in PF rats but a decrease after Fut8shRNA treatment. Fut8shRNA treatment increased net ultrafiltration, reduced the expression of collagen I and MCP-1 compared to PF rats. Fut8shRNA treatment suppressed phosphorylation of STAT3 and NF-κB in the peritoneal membrane of PF rats. Conclusions Fut8shRNA treatment ameliorated the fibrotic changes in PF rats. A potential mechanism may be that Fut8shRNA treatment inactivated EGF signaling pathway by suppressing the phosphorylation of STAT3 and NF-κB.

SGLT2 Inhibition by Intraperitoneal Dapagliflozin Mitigates Peritoneal Fibrosis and Ultrafiltration Failure in a Mouse Model of Chronic Peritoneal Exposure to High-Glucose Dialysate.

Peritoneal dialysis (PD) is limited by glucose-mediated peritoneal membrane (PM) fibrosis, angiogenesis, and ultrafiltration failure. Influencing PM integrity by pharmacologically targeting sodium-dependent glucose transporter (SGLT)-mediated glucose uptake has not been studied. In this study, wildtype C57Bl/6N mice were treated with high-glucose dialysate via an intraperitoneal catheter, with or without addition of selective SGLT2 inhibitor dapagliflozin. PM structural changes, ultrafiltration capacity, and peritoneal equilibration testing (PET) status for glucose, urea, and creatinine were analyzed. Expression of SGLT and facilitative glucose transporters (GLUT) was analyzed by real-time PCR, immunofluorescence, and immunohistochemistry. Peritoneal effluents were analyzed for cellular and cytokine composition. We found that peritoneal SGLT2 was expressed in mesothelial cells and in skeletal muscle. Dapagliflozin significantly reduced effluent transforming growth factor (TGF-β) concentrations, peritoneal thickening, and fibrosis, as well as microvessel density, resulting in improved ultrafiltration, despite the fact that it did not affect development of high-glucose transporter status. In vitro, dapagliflozin reduced monocyte chemoattractant protein-1 release under high-glucose conditions in human and murine peritoneal mesothelial cells. Proinflammatory cytokine release in macrophages was reduced only when cultured in high-glucose conditions with an additional inflammatory stimulus. In summary, dapagliflozin improved structural and functional peritoneal health in the context of high-glucose PD.

Comparison of Longitudinal Membrane Function in Peritoneal Dialysis Patients According to Dialysis Fluid Biocompatibility

IntroductionPreservation of peritoneal function is essential in long-term peritoneal dialysis. Biocompatible dialysis solutions might prevent or postpone the membrane alteration resulting in ultrafiltration failure and consecutive morbidity and mortality.MethodsWe conducted an observational cohort study in which we made a longitudinal comparison between the course of peritoneal solute and fluid transport during treatment with conventional and biocompatible solutions. Therefore, prospectively collected peritoneal transport data from the yearly standard peritoneal permeability analysis were analyzed in 251 incident patients treated between 1994 and censoring in 2016. Fluid transport included small pore and free water transport. Solute transport was assessed by creatinine mass transfer area coefficient and glucose absorption. Linear mixed models including change point analyses were performed. Interaction with peritonitis was examined.ResultsOne hundred thirty-five patients received conventional and 116 biocompatible solutions. Sixty-seven percent (conventional) and 64% (biocompatible) of these underwent minimally three transport measurements. Initially, biocompatible fluids showed higher small solute transport and lower ultrafiltration than conventional fluids up to 3 years. Thereafter, conventional fluids showed an increase in small solute transport (+2.7 ml/min per year; 95% confidence interval [CI]: 0.9 to 4.5) and a decrease of free water transport (−28.0 ml/min per year; 95% CI: −60.4 to 4.4). These were minor or absent in biocompatible treatment. Peritonitis induced a decrease of transcapillary ultrafiltration after 2 years on dialysis with conventional solutions (−291 ml/min per year; 95% CI: −550 to −32) while this was absent in biocompatible treatment.ConclusionDespite a higher initial solute transport with biocompatible solutions, these have less influence on functional long-term peritoneal alterations than conventional solutions.

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.

P1140THE REDUCTION OF THE SIEVING OF SODIUM IS THE FIRST AND EARLY FUNCTIONAL CHANGE OF PERITONEAL MEMBRANE IN A LARGE PATIENT POPULATION ON PERITONEAL DIALYSIS

Abstract Background and Aims The reduction whit time of peritoneal removal of salt and water is an important cause of reduced patient and technique survival in peritoneal (PD) patients. Solute transport increase after the start of PD and continue to increase throughout the course of treatment. Fast peritoneal transport results in ultrafiltration (UF) failure (UFF). UFF is due to the more rapid absorption on glucose, with a loss of the osmotic driving force for UF, and to reduction in osmotic conductance of the peritoneal membrane. The free water transport (FWT), through the aquaporin-1 channels, is about 45% of the total peritoneal UF during a dwell with a hypertonic glucose solution. It has suggested that the reduction of the FWT is due to the peritoneal fibrosis. The peritoneal sieving of sodium (Na) is a decrease (Δ) of the dialysate Na concentration during a peritoneal dwell with a hypertonic solution due to FWT. ΔNa, an indirect measure of the FWT, is maximum after 1 hour of a peritoneal equilibration test (PET) with a 3.86% glucose solution (3.86%-PET). The aim of this study was to evaluate the functional changes of the peritoneal membrane, assessed by the PET-3.86%, in a large patient population on peritoneal dialysis (PD) followed for a long period of time. Method We evaluated the PET-3.86% in a large population of incident PD patients attending 27 Italian dialysis centres. During the 3.86%-PET we calculated the ratio of the concentrations of creatinine in dialysate/plasma (D/PCreat), the ratio between the concentrations of glucose at the end/beginning of the test (D/D0), the UF, uncorrected and corrected for bag overfill, and ΔNa. The 3.86%-PET was repeated each year in each patient. Results We evaluated the results of 758 PET-3.86% in 758 incident PD patients (one test per patient) at the start of the PD therapy and then we evaluated the results of the 3.86%-PET (one test per patient and one test per year of treatment) in 382, 211 and 109 PD patients with at least two, three and four 3.86%-PET, respectively. The mean duration of PD was 5±3 months, 17±3 months, 30±3 months and 41±3 months in PD patients with at least one, two, three and four 3.86%-PET, respectively. ΔNa changed significantly after the second 3.86%-PET (8.8 ± 3.8 to 7.9 ± 4.1 mmol/L, p&amp;lt;0.001), about after 17 months of the start of PD therapy, and its value has continued to decline significantly after 30 months (9.0 ± 3.5 to 8.3 ± 3.6 to 7.6 ± 4.1 mmol/L, p=0.001), in the cohort of PD patients with at least three 3.86%-PET, and after 41 months (9.3 ± 3.2 to 9.0 ± 3.8 to 8.2 ± 4.0 to 7.7 ± 4.0 mmol/L, p=0.02) of PD treatment, in the cohort of PD patients with at least four 3.86%-PET. D/PCreat, D/D0 and UF, uncorrected and corrected for bag overfill, changed significantly only during the fourth 3.86%-PET, about after 41 months of PD treatment. Conclusion The results of this study indicate that the reduction of the ΔNa is the first and an early functional alteration of the peritoneal membrane and may mean that fibrosis of the peritoneal membrane is a process that begins early after the initiation of PD. The ΔNa could be used to evaluate the effect of new solutions and/or new drugs on the functions of the peritoneal membrane since the beginning of the PD therapy.

P1149PERITONEAL MEMBRANE CHARACTERISTICS OVER TIME: A LONGITUDINAL STUDY

Abstract Background and Aims Modified PET (use of 3.86% glucose dialysate instead of 2.27%) and temporal drainage at one hour allows a more complete study of peritoneal membrane transport, as it provides information about sodium sieving, free water transport (FWT) and ultrafiltration failure (UFF). Longitudinal data using this PET are sporadic. Aims of our study were a) longitudinal follow-up of the membrane function using modified PET b) evaluation of UFF and association with clinical and membrane characteristics. Method We analyzed all modified PET tests performed in our unit during the last 9 years. Patients who underwent the first test during the first year of treatment and then once a year were included. We estimated classic peritoneal transport parameters like D/P creatinine, D/D0 glucose and ultrafiltration (UF) at 4 hours. Moreover we calculated sodium seiving expressed as Dip/DPNa= (Dialysate sodium time 0/plasma sodium)-(Dialysate sodium time 1 hour/plasma sodium)], sodium removal (in one hour) and FWT. We collected clinical and lab data of the patients too. Results A total of 219 PETs were performed in 85 PD patients, (median age 64 years (range 18-45). The baseline membrane characteristics of the patients were: DP creatinine=0.74±0.11, D/D0glucose=0.28±0.08, DipDPNa=0.05±0.04, sodium removal=29,804 ±26,894 (mmol/L), FWT=214.9±194.7 ml and UF =655.1±265.5 ml. On multivariate regression analysis D/P creatinine, FWT and sodium removal were significant independent covariates accounting for 50% of the variability of ultrafiltration . The patients were followed-up for a median of 36 months (range 2.4-143).For the repeated measurements, the analysis showed that the observed values of D/Pcre,D/D0, Dip/DPNa, FWT and UF remained rather stable across the different time measurements. During the study, 23 out of 85 pts developed peritoneal UF failure (UFF). Analysis was performed using univariate random effects logistic time-series models and only D/D0 (OR=0.84, P=0.001), D/P Cre (OR=1.15, p&amp;lt;0.001), urine volume (OR=1.26, p=0.027) and sodium removal (OR=0.99, p=0.003) were significantly associated with relative risk of UFF development. Conclusion Surprisingly, our patients present a stable membrane function over time. Possible explanations could be the low peritonitis rate and strict use of hypertonic glucose dialysates. Ultrafiltration failure was correlated with higher D/P creatinine and lower D/D0 glucose values, higher baseline urine volume and lower sodium sieving.

P1186PRELIMINARY RESULTS OF THE FIRST PHASE II CLINICAL TRIAL ON THE USE OF AN INNOVATIVE GLUCOSE-SPARING PD SOLUTION (FIRST)

Abstract Background and Aims High amounts of glucose as the main osmotic agent for peritoneal dialysis (PD) could be harmful, as it may significantly increase cardiovascular morbidity and mortality. Glucose has long-term detrimental effects on the peritoneum, which ultimately may result in ultrafiltration failure, worsening fluid overload and cardiovascular disease. The absorption of glucose from the dialysate accentuates the disturbances of the carbohydrate metabolism, which is already impaired in the uremic state, leading to insulin resistance. XyloCore (Iperboreal Pharma, Pescara, Italy), is a low glucose containing PD solution (PDS) proposed as an alternative to glucose PDS only regimen. It has been formulated replacing most of the glucose with two crystalloid agents, D-xylitol and L-carnitine. PDS containing osmolar agents like xylitol and L-Carnitine added to glucose, used for the nocturnal exchange, may lead to a significant reduction of glucose level in PDS during the night dwell, while preserving or even improving the depurative efficacy of the standard PDS containing 2.5% glucose. The reduction of glucose level could be further enhanced if the PDS with xylitol and carnitine will be used for the diurnal exchanges and a PDS with icodextrin will substitute the standard PDS containing glucose 2.5% for the nocturnal dwell. The aims of the study are to evaluate the effects of (I) the XyloCore PDS IPX15 [containing glucose (0.5%), xylitol (1.5%) and L-carnitine (0.02%) as osmotic agents, as compared to the standard 2.5% glucose PDS] for the nocturnal exchange, and (II) the XyloCore PDS IPX07 [containing glucose (0.5%), xylitol (0.7%) and L-carnitine (0.02%), as compared to the standard 1.5% glucose PDS] for the diurnal (short dwell) exchanges. Method Prospective, randomized, controlled clinical trial in stable ESRD patients treated by CAPD (study protocol registered as NCT 04001036). Key inclusion criteria are: ESRD treated for at least three months with CAPD, stable clinical condition within the four weeks before the screening, hemoglobin ≥ 9g/dL, absence of acute peritonitis and/or peritoneal catheter infection in the three months before. Key exclusion criteria are: androgen therapy, active infections, congestive heart failure stage III and IV NYHA; major cardiovascular events in the last 3 months, clinically relevant cardiac arrhythmia; clinically relevant abnormal hepatic tests; treatment with L-carnitine in the previous three months, pregnancy, life expectancy of less than one year, allergy to L-carnitine or xylitol. The sample size is 40 patients. Treatment duration is 4 weeks plus a 4 weeks safety follow up with no treatment. Primary end-point is the daily peritoneal ultrafiltration volume. Secondary end-points are the peritoneal equilibration test (D/P creatinine, D/P glucose), weekly total Kt/V urea, weekly total creatinine clearance, Adverse Events. Results Two centers participate in the study. One center has so far recruited 10 patients, 6 in the IPX15 group and 4 in the IXP07 group. The six patients in the IXP15 group were 4 males and 2 males, aged 69.5 ±5.1 years. The four patients in the IXP07 were all male, mean age 56 ± 12 years. One patient already completed the study period. Results for Kt/V, creatinine clearance, D/P creatinine, D/P glucose, ultrafiltration volume, at time (T) 0 are 1.17, 85.6, 0.75, 0.18, 400 ml, respectively; at T28 (days) are 3.1, 80, 0.82, 0.23, 400 ml respectively, and at T56 are 3.5, 80, 0.77, 023, 450 ml, respectively. D/P glucose results indicate that this patient is a high transporter and D/P creatinine that the patient was an average/ high transporter. There were no adverse events reported and tolerability has been excellent so far. Conclusion In the first 10 ESRD patients included in the study, XyloCore PDS used for 4 weeks has been well tolerated without significant adverse events. The study is in progress.

P1225PREVALENCE AND PROGNOSTIC SIGNIFICANCE OF DIABETES IN PERITONEAL DIALYSIS: TECHNIQUE AND PATIENT SURVIVAL

Abstract Background and Aims Diabetes in recent years is climbing up as the number one cause of chronic kidney disease (CKD). Clinical statistics suggest that Diabetics on peritoneal dialysis (PD) tend to have a poorer prognosis than others. Thus, the aim of this study is to determine the clinical outcomes and to evaluate the survival rates as well as the predictors of mortality among this group. Method It‘s a retrospective study carried out in the nephrology Department of Fattouma Bourguiba Hospital (Monastir, Tunisia) from 1990 to 2017 including 304 PD patients. We compared two groups: diabetic and non diabetic patients in term of survival and factors in correlation. Results A total of 110 diabetic versus 194 non diabetic patients were reported. The mean age of diabetic group was 55.14 ± 15 years with a sex ratio 2.33 (men/women). In addition to diabetes, comorbid diseases included hypertension (47.3%) and cardiopathy (32.7%). The mean Charlson score of diabetic group was 5.22±1.5 versus 2.72±1.23 in the other group. A total of 62.7% (n=69) of the patients performed PD with the help of another person mostly a member of the family. The PD modality often used was CAPD (71%). Only six patients made a compulsory choice to begin PD due to vascular access while sixty diabetics chose PD to maintain autonomy (54.5%). During the follow-up period, transfers to hemodialysis (40.9%) and death (53.6%) were the most common cause of withdrawal from PD. In total, 45 patients were transferred to hemodialysis because of infectious complications (31%), Ultrafiltration failure (31%), catheter dysfunction (27%), and psychological intolerance (11%). The death was unrelated to PD in 83% of cases mostly due to considerable burden of cardiovascular events (23 patients). The median survival of the diabetic patients was 15.8 years versus 20.8 years in non diabetic ones with significant difference between the 2 groups (p=0.0001). Diabetes was associated with worse prognosis (OR:147, p=0.0001). The median survival adjusted to the diabetes group was 180 months. Kaplan–Meier analysis showed that diabetes was associated with a significant increase in mortality (p=0.006). Global median survival of the technique was estimated to 68 months (95%, IC [47 ,90]), and it was correlated to the presence or the absence of diabetes. In fact, the technique survival among diabetic patients was estimated to 80% after 12 years and 25% after 20 years whereas, in the other group it approaches 90% and 35% respectively. Conclusion This study confirms the pejorative impact of diabetes in the technique and patient survival in DP. So, it stresses the importance of organizing appropriate care upstream to prevent the development of cardiovascular morbidities and infectious complications in DP.