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ZUSAMMENFASSUNGIm Jahr 2022 wurden die neuen Leitlinien der International Society for Peritoneal Dialysis (ISPD) zur Diagnostik, Prophylaxe und Therapie der Peritonitis publiziert. Die maximal tolerierbare Peritonitisrate pro Zentrum wurde auf 0,4 Episoden/ Jahr herabgesenkt, wobei weniger als 15 % der Peritonitisfälle kulturnegativ sein sollten. Es wird empfohlen, auch die Peritonitisfälle, die vor Beginn der Peritonealdialyse (PD) auftreten, separat zu analysieren. Eine antibiotische Prophylaxe wird vor Katheterimplantation sowie vor Kolonoskopien und invasiven gynäkologischen Prozeduren empfohlen. Besondere hygienische Maßnahmen sind erforderlich, wenn Haustiere vorhanden sind. Anstelle einer Kombinationstherapie kann zur Abdeckung des gramnegativen und grampositiven Keimspektrums auch eine Monotherapie mit einem Cephalosporin der 4. Generation verwendet werden. Bei Wahl eines Aminoglykosids wird eine additive Therapie mit N-Azetylcystein zur Verhinderung der Ototoxizität empfohlen. Sollte 48 h nach Therapiebeginn keine Besserung eintreten, müssen weitere diagnostische Maßnahmen wie etwa die Abnahme neuerlicher Kulturen und Computertomografie des Abdomens durchgeführt werden.

BACKGROUND AND AIMS Due to chronic damage of the peritoneal membrane on long-term treatment, peritoneal dialysis (PD) is a time-limited therapy. Effective PD is achieved by adequate peritoneal ultrafiltration (UF) and small solute clearance while maintaining an appropriate fluid and salt homeostasis. Availability of remote patient monitoring on automated PD (APD) allows clinicians to remotely retrieve data for treatment analysis, proposed to improve clinical outcomes. However, machine-derived data are vastly different from traditionally observed data (e.g. quantity, noise, missing normative values). Recently correlation of daily UF changes on APD with changing peritoneal membrane function in association with clinical risk factors and outcomes has been observed. High intra- and interpatient variability of UF remains not fully explained. We aim at a better understanding of UF variability by submitting APD machine readouts to spectral analysis in association with clinical risk factors of membrane dysfunction. METHOD This was a secondary analysis of the Medical University of Vienna APD cycler treatment data from patients using Homechoice Pro cyclers (Baxter, IL, USA), extracted from the cycler management software (PD link, Baxter). Analysis was conducted using R software (R Core Team 2020). Daily UF was processed using the Lomb-Scargle periodogram (LSP), a method commonly used in astrophysics and neurophysiology to detect rhythms in (unevenly sampled) time series. Peaks of power spectrum, frequencies, and periodicities were compared between patients with and without peritonitis episodes during their PD treatment utilizing a Mann–Whitney U-test and associated with the total number of peritonitis episodes using Kendall rank correlation. A P-value RESULTS LSP analysis was performed on daily UF data from n = 129 APD patients with a mean observation time of 598 days (SD ± 517), male: female 61:39% (n = 79:50), incident: prevalent patients 77:23% (n = 99:30), and diabetic: non-diabetic patients 25:75% (n = 32:97). Observation time extended from the introduction of APD until kidney transplantation (43%, n = 55), transfer to hemodialysis (23%, n = 29), death (27%, n = 35), kidney function recovery (8%, n = 1), or loss to follow-up (7%, n = 9). After inspection of LSPs n = 9 patients were excluded from further analysis as their periodicity matched the time of their clinical endpoint. A total of 45 of the remaining 120 patients (38%) never experienced a peritonitis episode, and a total of 0.3 (SD ± 0.7) peritonitis episodes/patient-year were observed. LSP computation revealed cyclic periodicity in UF in all patients with an overall median peak period length of 329 days (IQR 62–882 days), median peak power of 21 (IQR 7–91), and median peak frequency of 0.42 (IQR 0.36–0.46). Differences between patients with and without peritonitis episodes during PD treatment are displayed in Table 1. Correlation analysis revealed significant association between the number of peritonitis episodes and peak periodicity of UF (tau=0.14, P = 0.04), and peak power (tau = 0.21, P = 0.003). Peak frequency of UF was not significantly correlated. CONCLUSION Patients on APD cycler treatment seem to display cyclic periodicity of UF, being significantly associated with the number of peritonitis episodes and significantly different between patients with and without peritonitis episodes. Smaller-scale periodicity (median 216 days) in patients without peritonitis seems to be disrupted by peritonitis resulting in significantly higher periodicity (median 670 days). The causes and implications of these results remain unclear and need further investigation. However, as peritonitis is a known risk factor for peritoneal membrane dysfunction, prolongation of UF periodicity might reflect disruption of peritoneal membrane function.

BACKGROUND AND AIMS Infectious complications and peritoneal inflammation occurring in a significant proportion of PD patients lead to progressive peritoneal membrane injury and account for most peritoneal dialysis (PD) technique failures. Reduced peritoneal immune-competence, caused by the continuous exposure to PD fluids, has been described as a therapy-related pathomechanism. We therefore hypothesized a relationship between dialysate interleukin 6 (IL-6) concentrations and peritoneal host defense. We established an ex vivo stimulation assay to test host defense mechanisms in only 9 mL of PD effluent. The aim of this study was to analyse basal inflammation and immune-competence in the PD population at routine conditions to evaluate the assay as surrogate parameter of immune competence and linking it to PD vintage and clinical outcome parameters. METHOD We prospectively analysed 195 serial routine peritoneal equilibration tests (PETs) of 123 stable PD patients treated exclusively with low-GDP, multi-chamber PD fluids during the glucose dwells and compared the data to routine follow-up clinical data. The cohort represents 76% of all eligible PD patients treated between April 2013 and September 2020 at the local Department of Nephrology. The study was approved by the local ethics committee and was conducted in accordance with the Declaration of Helsinki. All participants underwent a standardized 4-h PET with 3.86% glucose PDF as routine follow-up to test peritoneal membrane transport function, with an additional ex vivo cell stimulation protocol. PD effluent samples were obtained at the 1- and 4-h PET timepoints and immediately processed. Effluent samples were collected directly from the drainage bags into standard 9 mL additive-free sample tubes. For ex vivo stimulation, 100 ng/mL toll-like receptor (TLR) 4 agonist LPS and TLR2 agonist Pam3Cys were added to the effluent in the 9 mL collection tubes in duplicates and incubated at 37°C for 24 h. Unstimulated samples kept in parallel were used as controls. IL-6 concentrations were measured with ELISA in the supernatants. RESULTS Patients were stratified into two cohorts (incident and prevalent) at 120 days of continuous PD therapy. The cohorts were statistically indistinguishable except for stratification-specific variables. During a total follow-up period of 2499 patient-months, 55 patients underwent repeated PETs. Ex vivo stimulation of peritoneal cells significantly increased the IL-6 release 20-fold compared to unstimulated controls and resulted in a dwell-time dependent increase, with a significant lower cytokine released at the 1 h PET timepoint. To assess local inflammation, IL-6 concentrations in PD effluent of the 4 h PET were analysed. PD effluent IL-6 concentrations from the entire study cohort or from incident and prevalent patient subcohorts correlated neither with patient characteristics, RRF, disease background (including prior peritonitis) nor with time on PD. Effluent IL-6 concentrations correlated significantly with markers of systemic inflammation, serum CRP and albumin, with PSTR and with peritoneal protein loss. Interestingly, effluent IL-6 concentrations also had predictive value for risk of a subsequent peritonitis episode during follow-up. Effluent IL-6 levels were, in contrast, negatively correlated with ex vivo–stimulated IL-6 release from PD effluent cells, most remarkably in PD patients with history of prior peritonitis. CONCLUSION This longitudinal study provides the first direct evidence in PD patients of a correlation between peritoneal inflammation and impaired peritoneal immune cell function, likely driving infectious complications. Our study results suggest a mechanistic link between peritoneal inflammation and host defense that may foster innovative therapeutic approaches to improve clinical outcomes of chronic PD.

BACKGROUND AND AIMS An adequately functioning catheter is of vital importance for successful long-term treatment and technique survival to peritoneal dialysis (PD) patients. According to the 2021 International Society of Peritoneal Dialysis guidelines on membrane function, catheter drainage problems should be suspected first in patients with low ultrafiltration (UF) capacity. Catheter dysfunction and the consequent decrease in UF are frequent complications in PD patients associated with significant negative clinical outcomes. METHOD We introduce the use of a combination of parameters obtained from daily measurements of the cycler software PD Link (Baxter) for predicting catheter dysfunction in automated peritoneal dialysis (APD) patients. Out of 117 APD patients treated at the Medical University of Vienna from 2015 to 2021, we identified all patients with verified catheter malposition and dysfunction (n = 14, cases) and compared them to controls without clinical evidence of mechanical problems and a recent X-ray confirming position of the PD catheter tip in the recto-vesical/recto-uterine space (n = 19). We retrieved cycler data for 7 days each and tested parameters predictive capability of catheter dysfunction. RESULTS Total number of alarms/week >7 as single predictive parameter of catheter dislocation identified 85.7% (sensitivity) of patients with dislocated catheter and 31.6% (1—specificity) of control patients. A combination of two out of three parameters (number of alarms/week >7, drain time >22 min, UF of last fill CONCLUSION We confirmed our clinical impression that number of alarms, total drain time at the end of cycler session and UF of last fill are good predictors for mechanical drainage problems. In contrast to yearly peritoneal equilibration test measurements, these data provide valuable information for clinical management of PD patients on a daily base and will be easily available in new APD cyclers with devices connected to remote monitoring platforms.

Calciphylaxis and the arteriolosclerotic ulcer of Martorell (ASUM) represent two entities of cutaneous calcific arteriolopathies. Their differential diagnosis can be challenging, given similarities in their clinical and histological presentation. Calcification patterns have been proposed as a possible discriminative histological criterion, however, a systematic microstructural comparative analysis is lacking.The study aimed at a systematic comparative microstructural analysis of the calcification patterns in calciphylaxis versus ASUM.Skin biopsies of patients with leg ulcers due to calciphylaxis (20) and ASUM (69) diagnosed at three European wound care centres (Vienna, Bern, Zurich) were included. The extent of calcification, arteriolar calcification pattern and presence of extra-arteriolar calcification were assessed.All calciphylaxis and most ASUM patients (77%) presented with arteriolar calcification. Although the mean number of calcified vessels and the proportion of calcified area were significantly higher in calciphylaxis specimens (p = 0.003 and p = 0.0171), there was no significant difference in the pattern of arteriolar calcification (p = 0.177). Interestingly, extra-arteriolar calcification was detected in the majority of both calciphylaxis (93.3%) and ASUM samples (85.2%, p = 0.639). Notably, Alizarin Red S staining was superior to HE for the detection of calcifications of both entities (p = 0.014 and p 0.0001), and to von Kossa staining for ASUM samples (p = 0.0001). However, no differences could be observed between cases with uraemic and non-uraemic calciphylaxis or ulcerations located on the upper and lower leg.Our results indicate that extra-arteriolar calcification is not only present in calciphylaxis, but can also be detected in ASUM suggesting a lack of specificity for this finding. However, more specific calcification stains, such as Alizarin Red S, should be used in suspected cases, as calcifications may be overlooked using conventional HE staining.

New guidelines on evaluation of peritoneal membrane function recommend ruling out catheter dysfunction when evaluating patients with low ultrafiltration capacity. We introduce the use of a combination of parameters obtained from daily measurements of the cycler software for predicting catheter dysfunction in automated peritoneal dialysis patients. Out of 117 patients treated between 2015 and 2021, all patients with verified catheter dysfunction (n=14) were identified and compared to controls (n=19). We retrieved cycler data for seven days each and tested parameters predictive capability of catheter dysfunction. Total number of alarms/week >7 as single predictive parameter of catheter dislocation identified 85.7% (sensitivity) of patients with dislocated catheter and 31.6% (1-specificity) of control patients. A combination of parameters (number of alarms/week >7, drain time >22 min, ultrafiltration of last fill

BackgroundDialysis patients are at high risk for a severe clinical course after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Safety and early immune responses after mRNA-based vaccination have been reported mostly in patients on hemodialysis (HD), whereas reports of peritoneal dialysis (PD) patients remain rare.MethodsIn this retrospective observational study, 39 PD patients had received two doses of the mRNA-1273 Moderna® vaccine. We analyzed SARS-CoV-2 Spike (S) antibody titers 4 weeks after each dose of mRNA-1273 and report local and systemic side effects in PD patients that occurred within one week after each mRNA-1273 dose. Using a quantile regression model we examined factors that might influence SARS-CoV-2 S antibody levels in PD patients.ResultsFour weeks after the first dose of mRNA-1273 vaccine 33 of 39 (84.6%) PD patients seroconverted and presented with 6.62 U/mL (median; IQR 1.57-22.5) anti-SARS-CoV-2 S antibody titers. After the second dose, 38 of 39 (97.4%) PD patients developed anti-SARS-CoV-2 S antibodies and titers increased significantly (median 968 U/mL; IQR 422.5-2500). Pain at the injection site was the most common local adverse event (AE) (71%). Systemic AEs occurring after the first dose were mostly fatigue (33%) and headache (20%). No severe systemic AEs were reported after the first injection. After the second dose the incidence and the severity of the systemic AEs increased. The most common systemic AEs were: fatigue (40.5%), headache (22.5%), joint pain (20%), myalgia (17.5%) and fever (13%). Lower Davies Comorbidity Score (p=0.04) and shorter dialysis vintage (p=0.017) were associated with higher antibody titers after the first dose. Patients with higher antibody titers after the first dose tended to have higher antibody titers after the second dose (p=1.53x10-05).ConclusionsPeritoneal dialysis patients in this cohort had a high seroconversion rate of 97.4%, showed high antibody titers after full vaccination and tolerated the anti-SARS-CoV-2 mRNA-1273 vaccine well without serious adverse events.

BackgroundPeritoneal dialysis (PD) is complicated by a high rate of adverse events that might be attributed to cytotoxicity of currently used PD fluids. However, clinical development of novel PD fluids is virtually non-existent, in part due to difficulties in recruiting sufficiently large populations for adequately powered trials. The aim of this study is to understand the potential impact of introducing composite outcomes on clinical trial feasibility in PD.MethodsA composite outcome “major adverse peritoneal events (MAPE)” was designed to combine clinically relevant complications of PD, such as ( 1 ) technical failure (cause-specific for peritonitis and/or insufficient dialysis), ( 2 ) peritonitis, and ( 3 ) peritoneal membrane deterioration. Incidence rates of individual endpoints were obtained from the literature and expert panel estimations, and population sizes were computed based on Chi-square test for adequately powered confirmatory randomized controlled clinical trials with 2 parallel arms.ResultsIncidence rates for technical failure, peritonitis, and peritoneal membrane deterioration were estimated at 15%, 50%, and 23%, respectively, at 2 years follow-up, with adequate agreement between the literature and expert opinion. Assuming that a given intervention reduces adverse outcomes by 30%, an adequately powered clinical trial needs to recruit up to 1,720 patients when studying individual outcomes. Combining endpoints increases power in simulated trials despite considerable overlap, and the composite outcome MAPE reduces the required population to 202 patients aiming for 80% power.ConclusionIntroduction of the composite outcome MAPE, covering relevant major adverse peritoneal events, may improve the feasibility of clinical trials to adequately test novel PD fluids.

BackgroundResidual renal function (RRF) affects sodium and fluid balance. The aim of this analysis was to examine the impact of RRF on the effect of a sodium-reduced peritoneal dialysis fluid (PDF) on blood pressure (BP).MethodsThis is a post-hoc analysis of a prospective, randomized, controlled double-blind clinical trial with 82 patients on continuous ambulatory PD (CAPD) treated with a low-sodium (125 mmol/L Na) or a standard-sodium (134 mmol/L Na) PDF. Subgroups according to glomerular filtration rate (GFR) at baseline (≤ / > 6 mL/min/1.73 m2) were analyzed for BP and antihypertensive medication.ResultsIn the low-GFR group on low-sodium PDF ( N = 26), systolic BP was reduced from 152 ± 24 mmHg at baseline to 137 ± 21 mmHg at week 12, diastolic BP from 90 ± 16 mmHg to 83 ± 11 mmHg. In the low-GFR group on standard-sodium PDF and in the high-GFR group on both PDF types, only minor changes were observed. For the low-GFR subgroup, the confounder-adjusted mean study group difference in systolic BP at week 12 between low-sodium and standard-sodium PDF was -16.9 (95% confidence interval [CI] -27.2 to -6.6) mmHg, for diastolic BP, it was -7.0 (95% CI -12.6 to -1.4) mmHg. In both GFR subgroups, more patients had a reduced daily dose of antihypertensive medication and fewer patients an increased daily dose in the low-sodium compared with the standard-sodium group at week 12.ConclusionsThe reduction of BP with a sodium-reduced PDF seems to be more effective in patients with no or low RRF than in patients with residual capacity of renal sodium and fluid control.

New‐onset diabetes mellitus (NODM) is observed in both hemodialysis (HD) and peritoneal dialysis (PD) patients. The prevalence of NODM in dialysis patients is slightly higher compared to subjects of the general population. Based on currently published data there is no convincing evidence that the risk of NODM is different between HD and PD patients. Data on the effect of glucose load on risk of NODM in dialysis patients remain controversial. PD modality (automated or continuous ambulatory PD) has no significant influence on NODM incidence. Chronic inflammation is associated with NODM in dialysis patients. Reported differences in NODM between PD and HD patients are possibly also influenced by differences in demographic factors between these patient groups. Mortality in NODM patients is lower than mortality in patients with preexisting DM. This may be partly explained by the younger age and lower number of comorbidities in patients with NODM.

Background and Aims Renal replacement therapy by peritoneal dialysis (PD) is limited in use and duration by progressive impairment of peritoneal membrane integrity and homeostasis. Preservation of peritoneal membrane integrity during chronic PD remains an urgent but long-unmet medical need. PD therapy failure results from peritoneal fibrosis and angiogenesis caused by hypertonic PD fluid (PDF)-induced mesothelial cytotoxicity. The incompletely defined pathophysiological mechanisms involved confound informed selection of therapeutic targets. Addition of cytoprotective agents to PDF have been shown to counteract pathophysiological mechanisms induced by current PDF. Lithium is a well described inhibitor of glycogen synthase kinase 3β and has recently been shown to also have nephroprotective effects in low doses. Here, we aim to characterize icodextrin-based, PDF-induced cellular injury with a combined omics approach and to investigate the effects of LiCl on the PD-induced observed molecular perturbations. Method To investigate mechanisms of acute cellular damage by PDF we chose an in vitro model of primary omental-derived peritoneal mesothelial cells with direct exposure to icodextrin-based PDF, followed by short-term or extended recovery for detection of short-term and long-term changes in transcriptome, proteome, and cell injury. 0, 2.5 or 10 mM LiCl were added to the PDF. In-vitro findings were validated in peritoneal biopsies (n=41) from pediatric PD and CDK5 patients or healthy controls and peritoneal effluents from adult and pediatric PD patients (n=27) or ascites samples (n=4) as control. For in-vivo experiments, healthy and uremic mice (C57/Bl6, female) were chronically exposed to PD-fluid without or with the addition of 5 mM LiCl via an implanted catheter. In-vivo overexpression of CRYAB was induced by i.p. injection of an adenoviral vector. All animal experiments and use of patient samples were approved by the local ethics committees and performed according to animal protection laws or the Declaration of Helsinki, respectively. Results LiCl significantly improved mesothelial cell survival in a dose-dependent manner. Combined transcriptomic and proteomic characterization of icodextrin-based PDF-induced mesothelial cell injury identified αB-crystallin as the mesothelial cell protein most significantly and consistently counter-regulated by LiCl. In-vitro and in-vivo overexpression of αB-crystallin triggered a fibrotic phenotype and PDF-like upregulation of vascular endothelial growth factor (VEGF), CD31-positive cells, and TGFβ-independent activation of TGFβ-regulated targets. In contrast, αB-crystallin knock-down decreased VEGF expression and early mesothelial-to-mesenchymal transition (MMT). LiCl reduced VEGF release and counteracted fibrosis- and angiogenesis-associated processes. αB-crystallin in patient-derived mesothelial cells was specifically upregulated in response to PDF and increased in peritoneal mesothelial cells from pediatric PD patient biopsies, correlating with markers of angiogenesis and fibrosis. Conclusion The cytoprotective effects of LiCl-supplemented PDF may be explained by counter-regulation of PD-induced angiogenesis via the novel target αB-crystallin. Reduction of mesothelial cell damage, peritoneal fibrosis and VEGF suggests therapeutic potential of this intervention. Repurposing LiCl as a cytoprotective PDF additive may offer a translatable therapeutic strategy to combat peritoneal membrane deterioration during PD therapy. Further study of LiCl-supplemented PDF is merited as a realistic approach to improving treatment longevity and patient outcomes during PD treatment.

Although nephrologists are responsible for the long-term care of dialysis patients, physicians from all disciplines will potentially be involved in the management of patients with kidney failure, including patients on peritoneal dialysis, the major home-based form of kidney-replacement therapy. This review aims to fill knowledge gaps of non-experts in peritoneal dialysis and to highlight key management aspects of in-hospital care of patients on peritoneal dialysis, with a focus on acute scenarios to facilitate prompt decision-making. The clinical pearls provided should enable non-nephrologists to avoid common pitfalls in the initial assessment of peritoneal dialysis-related complications and guide their decision regarding when to refer their patients to a specialist, resulting in improved multidisciplinary patient care.

Peritoneal dialysis (PD) offers specific advantages over hemodialysis, enabling increased autonomy of patients with end-stage renal disease, but PD-related complications need to be detected in a timely manner. Fourier transform infrared (FTIR) spectroscopy could provide rapid and essential insights into the patients&rsquo, risk profiles via molecular fingerprinting of PD effluent, an abundant waste material that is rich in biological information. In this study, we measured FTIR spectroscopic profiles in PD effluent from patients taking part in a randomized controlled trial of alanyl-glutamine addition to the PD-fluid. Principal component analysis of FTIR spectra enabled us to differentiate between effluent samples from patients immediately after completion of instillation of the PD-fluid into the patients&rsquo, cavity and 4 h later as well as between patients receiving PD-fluid supplemented with 8 mM alanyl-glutamine compared with control. Moreover, feasibility of FTIR spectroscopy coupled to supervised classification algorithms to predict patient-, PD-, as well as immune-associated parameters were investigated. PD modality (manual continuous ambulatory PD (CAPD) vs. cycler-assisted automated PD (APD)), residual urine output, ultrafiltration, transport parameters, and cytokine concentrations showed high predictive potential. This study provides proof-of-principle that molecular signatures determined by FTIR spectroscopy of PD effluent, combined with machine learning, are suitable for cost-effective, high-throughput diagnostic purposes in PD.

Background and Aims Infectious complications occur in a significant proportion of patients treated with peritoneal dialysis (PD), limiting its long-term applicability. Reduced peritoneal immune-competence, caused by the continuous exposure to PD-fluids, has been described as a therapy-related pathomechanisms, prompting the need for a tool to assess the functional peritoneal immune status. We established an ex-vivo stimulation assay to test host defence mechanisms in only 9ml of crude PD-effluent. The assay was used in two randomized clinical trials investigating immune-modulatory effects of a novel additive (alanyl-glutamine) to PD-fluid. Here we aimed to evaluate the assay as a method to assess peritoneal immune-competence in the general PD-population and linking it to PD vintage and outcome parameters. Method 462 PD-effluent samples, originating from 148 adult and paediatric PD patients, were stimulated ex-vivo (24h, 37°C) with toll-like receptor (TLR)-agonists lipopolysaccharide (LPS) and Pam3Cys. Unstimulated samples of each effluent were used as controls. Interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) concentrations and the predictive value of the assay for clinical outcome parameters were analyzed using Wilcoxon matched-pairs signed rank test and a mixed model logistic regression analysis. Results Ex-vivo stimulation of peritoneal cells resulted in a dwell-time dependent increase of cytokine release, with a significant lower cytokine released at the 1h PET time point (normalized to unstimulated controls). Ratios between stimulated PDE-samples and unstimulated controls, accounting for a potential increase in basal inflammation, significantly declined with PD therapy duration. Correlation of the cytokine levels with the predefined clinical parameters revealed predictive potential of the assay for the occurrence of infectious complications, as well as of ultrafiltration and technique failure. Conclusion In summary, the current study provides evidence of a correlation of declining local host defence and duration of PD-therapy. These data support the hypothesis of PD-duration dependent progressive impairment of the ability of the peritoneal immune cells to secrete cytokines in response to a pathogenic stimulus and thereby dampening the global peritoneal immuno-competence. The results suggest the utility of this clinically feasible ex-vivo induced cytokine-release assay in crude peritoneal effluent as a surrogate of the functional peritoneal immune competence. Future analyses will have to evaluate the assay as a tool to predict common clinical outcomes and define reference values to facilitate stratification of patient populations, clinical staging and to guide novel therapeutic interventions.

ZusammenfassungDurch langzeitige intraperitoneale Anwendung von Glukoselösungen treten bei PD-Patienten (PD: Peritonealdialyse) morphologische und funktionelle Schäden an der Peritonealmembran auf. Es gibt keine eindeutige Evidenz, dass PD-Lösungen mit alternativen osmotischen Substanzen (Icodextrin, Aminosäuren) langfristig einen günstigen Einfluss auf peritonealeSchäden bei chronischen PD-Patienten haben. Dennoch ist die klinische Bedeutung von icodextrinhaltigen PD-Lösungen zur Optimierung des Salz- und Wasserhaushaltes uneingeschränkt. In rezenten Metaanalysen haben Low-GDP-Lösungen (GDP: Glukosedegradationsprodukte) harte Endpunkte wie Peritonitis und technisches Versagen nicht signifikant beeinflusst. Dennoch weisen einzelne kleinere Studien und Kohortenstudien darauf hin, dass diese Lösungen morphologische Schäden der Peritonealmembran reduzieren. Alanyl-Glutamin als Zusatz zur PD-Lösung hat in ersten klinischen Studien zu membranprotektiven, immunmodulatorischen und antiinflammatorischen Effekten geführt. Klinische Studien mit längerer Beobachtungszeit müssen zeigen, ob dies auch mit einer verbesserten Peritonitisrate, einem verbesserten technischen Überleben und/oder Überleben von PD-Patienten assoziiert ist.

Background A positive pregnancy test in acute or chronically ill patients has implications for the use of potentially mutagenic or teratogenic products in urgent medical therapies such as the use of chemotherapies or therapies with immunosuppressants, for anesthesia, and for time-sensitive indications like urgent surgery or organ Transplantation. Despite a lack of evidence, it is currently believed that human chorionic gonadotropin serum concentrations are always elevated in female dialysis patients even without pregnancy. It is also believed that human chorionic gonadotropin cannot be used to confirm or exclude pregnancy. Methods Human chorionic gonadotropin was examined in female dialysis patients (18–50 years of age), and was classified as positive above 5 mlU/ml. In addition, fertility status was determined. For an enhanced index test, the cut-off of 5 mIU/ml was used for potentially fertile patients and 14 mIU/ml for infertile patients to calculate diagnostic test accuracy. The ideal cut-off for human chorionic gonadotropin was estimated using Liu’s method with bootstrapped 95% confidence intervals. Predictors of human chorionic gonadotropin increase were analyzed using multivariable linear regression. Results Among 71 women, two (2.8%) were pregnant, 46 (64.8%) potentially fertile, and 23 (32.4%) infertile. We observed human chorionic gonadotropin concentrations > 5 mIU/ml in 10 patients, which had a sensitivity of 100% (95% confidence interval: 100 to 100), a specificity of 86% (95% confidence interval: 77 to 94), a positive predictive value of 17% (95% confidence interval: 8 to 25) and a negative predictive value of 100% (95% confidence interval: 100 to 100) for the diagnosis of pregnancy. Using a cut-off > 14 mIU/ml for infertile patients or the exclusion of infertile patients increased specificity to 93% or 98%, respectively. The ideal cut-off was 25 mIU/ml (95% confidence interval: 17 to 33). Pregnancy and potential fertility, but not age, were independent predictors of human chorionic gonadotropin. Conclusion Human chorionic gonadotropin is elevated > 5mIU/ml in 14.5% of non-pregnant dialysis patients of child-bearing age. In potentially fertile women, this cut-off can be used to exclude pregnancy. In case of an unknown fertility status, the ideal human chorionic gonadotropin cut-off was 25 mIU/ml.

Life-saving renal replacement therapy by peritoneal dialysis (PD) is limited in use and duration by progressive impairment of peritoneal membrane integrity and homeostasis. Preservation of peritoneal membrane integrity during chronic PD remains an urgent but long unmet medical need. PD therapy failure results from peritoneal fibrosis and angiogenesis caused by hypertonic PD fluid (PDF)-induced mesothelial cytotoxicity. However, the pathophysiological mechanisms involved are incompletely understood, limiting identification of therapeutic targets. We report that addition of lithium chloride (LiCl) to PDF is a translatable intervention to counteract PDF-induced mesothelial cell death, peritoneal membrane fibrosis, and angiogenesis. LiCl improved mesothelial cell survival in a dose-dependent manner. Combined transcriptomic and proteomic characterization of icodextrin-based PDF-induced mesothelial cell injury identified αB-crystallin as the mesothelial cell protein most consistently counter-regulated by LiCl. In vitro and in vivo overexpression of αB-crystallin triggered a fibrotic phenotype and PDF-like up-regulation of vascular endothelial growth factor (VEGF), CD31-positive cells, and TGF-β-independent activation of TGF-β-regulated targets. In contrast, αB-crystallin knockdown decreased VEGF expression and early mesothelial-to-mesenchymal transition. LiCl reduced VEGF release and counteracted fibrosis- and angiogenesis-associated processes. αB-crystallin in patient-derived mesothelial cells was specifically up-regulated in response to PDF and increased in peritoneal mesothelial cells from biopsies from pediatric patients undergoing PD, correlating with markers of angiogenesis and fibrosis. LiCl-supplemented PDF promoted morphological preservation of mesothelial cells and the submesothelial zone in a mouse model of chronic PD. Thus, repurposing LiCl as a cytoprotective PDF additive may offer a translatable therapeutic strategy to combat peritoneal membrane deterioration during PD therapy.

Background Renal loss of potassium (K+) and magnesium (Mg2+) in salt losing tubulopathies (SLT) leads to significantly reduced Quality of Life (QoL) and higher risks of cardiac arrhythmia. The normalization of K+ is currently the most widely accepted treatment target, however in even excellently designed RCTs the increase of K+ was only mild and rarely normalized. These findings question the role of K+ as the ideal marker of potassium homeostasis in SLT. Aim of this hypothesis-generating study was to define surrogate endpoints for future treatment trials in SLT in terms of their usefulness to determine QoL and important clinical outcomes. Methods Within this prospective cross-sectional study including 11 patients with SLTs we assessed the biochemical, clinical and cardiological parameters and their relationship with QoL (RAND SF-36). The primary hypothesis was that QoL would be more dependent of higher aldosterone concentration, assessed by the transtubular-potassium-gradient (TTKG). Correlations were evaluated using Pearson’s correlation coefficient. Results Included patients were mainly female (82%, mean age 34 ± 12 years). Serum K+ and Mg2+ was 3.3 ± 0.6 mmol/l and 0.7 ± 0.1 mmol/l (mean ± SD). TTKG was 9.5/3.4–20.2 (median/range). While dimensions of mental health mostly correlated with serum Mg2+ (r = 0.68, p = 0.04) and K+ (r = 0.55, p = 0.08), better physical health was associated with lower aldosterone levels (r = -0.61, p = 0.06). TTKG was neither associated with aldosterone levels nor with QoL parameters. No relevant abnormalities were observed in neither 24 h-ECG nor echocardiography. Conclusions Hyperaldosteronism, K+ and Mg2+ were the most important parameters of QoL. TTKG was no suitable marker for hyperaldosteronism or QoL. Future confirmatory studies in SLT should assess QoL as well as aldosterone, K+ and Mg2+.

Background: Peritoneal dialysis (PD) solutions with reduced sodium content may have advantages for hypertensive patients; however, they have lower osmolarity and solvent drag, so the achieved Kt/V-urea may be lower. Furthermore, the increased transperitoneal membrane sodium gradient can influence sodium balance with consequences for blood pressure (BP) control.Study Design: Prospective, randomized, double-blind clinical trial to prove the noninferiority of total weekly Kt/V-urea with low-sodium versus standard-sodium PD solution, with the lower confidence limit above the clinically accepted difference of 0.5. Setting & Participants: Hypertensive patients (1 antihypertensive drug, including diuretics, or office systolic BP 130 mm Hg) on continuous ambulatory PD therapy from 17 sites.Intervention: 108 patients were randomly assigned (1:1) to 6-month treatments with either low-sodium (125 mmol/L of sodium; 1.5%, 2.3%, or 4.25% glucose; osmolarity, 338-491 mOsm/L) or standard-sodium (134 mmol/L of sodium; 1.5%, 2.3%, or 4.25% glucose; osmolarity, 356-509 mOsm/L) PD solution.Outcomes: Primary end point: weekly total KtNurea; secondary outcomes: BP control, safety, and tolerability. Measurements: Total KtNurea was determined from 24-hour dialysate and urine collection; BP, by office measurement.Results: Total Kt/Vurea after 12 weeks was 2.53 +/- 0.89 in the low -sodium group (n = 40) and 2.97 +/- 1.58 in the control group (n = 42). The noninferiority of total KtNurea could not be confirmed. There was no difference for peritoneal KtNurea (1.70 +/- 0.38 with low sodium, 1.77 +/- 0.44 with standard sodium), but there was a difference in renal KtNurea (0.83 +/- 0.80 with low sodium, 1.20 +/- 1.54 with standard sodium). Mean daily sodium removal with dialysate at week 12 was 1.188 g higher in the low-sodium group (P Limitations: Broader variability of study population than anticipated, particularly regarding residual kidney function.Conclusions: The noninferiority of the low -sodium PD solution for total Kt/Vurea could not be proved; however, it showed beneficial clinical effects on sodium removal and BP. Am J Kidney Dis. 67(5):753-761. 2016 Fresenius Medical Care. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.orgIlicenses/by-nc-nd14.01).

Bioimpedance spectroscopy (BIS) is routinely used in peritoneal dialysis patients and might aid fluid status assessment in patients with liver cirrhosis, but the effect of ascites volume removal on BIS-readings is unknown. Here we determined changes in BIS-derived parameters and clinical signs of fluid overload from before to after abdominal paracentesis. Per our pre-specified sample size calculation, we studied 31 cirrhotic patients, analyzing demographics, labs and clinical parameters along with BIS results. Mean volume of the abdominal paracentesis was 7.8 ± 2.6 L. From pre-to post-paracentesis, extracellular volume (ECV) decreased (20.2 ± 5.2 L to 19.0 ± 4.8 L), total body volume decreased (39.8 ± 9.8 L to 37.8 ± 8.5 L) and adipose tissue mass decreased (38.4 ± 16.0 kg to 29.9 ± 12.9 kg; all p 0.002). Correlation of BIS-derived parameters from pre to post-paracentesis ranged from R² = 0.26 for body cell mass to R² = 0.99 for ECV. Edema did not correlate with BIS-derived fluid overload (FO ≥ 15% ECV), which occurred in 16 patients (51.6%). In conclusion, BIS-derived information on fluid status did not coincide with clinical judgement. The changes in adipose tissue mass support the BIS-model assumption that fluid in the peritoneal cavity is not detectable, suggesting that ascites (or peritoneal dialysis fluid) mass should be subtracted from adipose tissue if BIS is used in patients with a full peritoneal cavity.

Background In patients with refractory heart failure (HF) peritoneal dialysis (PD) is associated with improved functional status and decrease in hospitalization. However, previous studies did not focus on right ventricular dysfunction as an important pathophysiologic component of cardiorenal syndrome. Methods In a prospective cohort study PD was started in 40 patients with refractory right HF (with/without left HF). Refractoriness to conservative therapy was defined as persistent right heart congestion/ascites with intensified diuretic treatment and/or ≥2 hospitalizations within 6 months because of cardiac decompensation despite optimal medical treatment, and/or acute renal failure during intensified conservative treatment of cardiac decompensations. Results Patient survival was 55.0% at 1 year, 35.0% at 2 years and 27.5% at 3 years. The number of hospitalization days declined after initiation of PD for both cardiac [13 (IQR 1–53) days before vs. 1 (IQR 0–12) days after start of PD, p

Peritoneal dialysis (PD) is a modality of renal replacement therapy in which the high volumes of available PD effluent (PDE) represents a rich source of biomarkers for monitoring disease and therapy. Although this information could help guide the management of PD patients, little is known about the potential of PDE to define pathomechanism-associated molecular signatures in PD. We therefore subjected PDE to a high-performance multiplex proteomic analysis after depletion of highly-abundant plasma proteins and enrichment of low-abundance proteins. A combination of label-free and isobaric labeling strategies was applied to PDE samples from PD patients (n = 20) treated in an open-label, randomized, two-period, cross-over clinical trial with standard PD fluid or with a novel PD fluid supplemented with alanyl-glutamine (AlaGln). With this workflow we identified 2506 unique proteins in the PDE proteome, greatly increasing coverage beyond the 171 previously-reported proteins. The proteins identified range from high abundance plasma proteins to low abundance cellular proteins, and are linked to larger numbers of biological processes and pathways, some of which are novel for PDE. Interestingly, proteins linked to membrane remodeling and fibrosis are overrepresented in PDE compared with plasma, whereas the proteins underrepresented in PDE suggest decreases in host defense, immune-competence and response to stress. Treatment with AlaGln-supplemented PD fluid is associated with reduced activity of membrane injury-associated mechanisms and with restoration of biological processes involved in stress responses and host defense. Our study represents the first application of the PDE proteome in a randomized controlled prospective clinical trial of PD. This novel proteomic workflow allowed detection of low abundance biomarkers to define pathomechanism-associated molecular signatures in PD and their alterations by a novel therapeutic intervention.

The ability of cells to respond and survive stressful conditions is determined, in part, by the attachment of O-linked N-acetylglucosamine (O-GlcNAc) to proteins (O-GlcNAcylation), a post-translational modification dependent on glucose and glutamine. This study investigates the role of dynamic O-GlcNAcylation of mesothelial cell proteins in cell survival during exposure to glucose-based peritoneal dialysis fluid (PDF). Immortalized human mesothelial cells and primary mesothelial cells, cultured from human omentum or clinical effluent of PD patients, were assessed for O-GlcNAcylation under normal conditions or after exposure to PDF. The dynamic status of O-GlcNAcylation and effects on cellular survival were investigated by chemical modulation with 6-diazo-5-oxo-L-norleucine (DON) to decrease or O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino N-phenyl carbamate (PUGNAc) to increase O-GlcNAc levels. Viability was decreased by reducing O-GlcNAc levels by DON, which also led to suppressed expression of the cytoprotective heat shock protein 72. In contrast, increasing O-GlcNAc levels by PUGNAc or alanyl-glutamine led to significantly improved cell survival paralleled by higher heat shock protein 72 levels during PDF treatment. Addition of alanyl-glutamine increased O-GlcNAcylation and partly counteracted its inhibition by DON, also leading to improved cell survival. Immunofluorescent analysis of clinical samples showed that the O-GlcNAc signal primarily originates from mesothelial cells. In conclusion, this study identified O-GlcNAcylation in mesothelial cells as a potentially important molecular mechanism after exposure to PDF. Modulating O-GlcNAc levels by clinically feasible interventions might evolve as a novel therapeutic target for the preservation of peritoneal membrane integrity in PD.

During the past years new developments in peritoneal dialysis (PD) technique have resulted in continuous improvement of patient outcome. The importance of salt and fluid balance, residual renal function and peritoneal glucose load are of increasing interest, whereas small solute clearances have lost importance. In patients with high peritoneal transport rates automated PD (APD) is indicated. However, APD can also be chosen as initial PD treatment since recent studies show comparable or even better survival as compared to continuous ambulatory PD patients. Alternative PD solutions improve peritoneal ultrafiltration (icodextrin), reduce peritoneal glucose load (amino acid solution, icodextrin) and protect the peritoneal membrane (solutions with low concentration of glucose degradation products). Infection risk can be reduced when using antibiotic creams, but resistances should be considered. Ongoing studies will clarify if non-antibiotic agents, e.g. medihoney, are effective in preventing PD-associated infections. Due to these improvements PD and hemodialysis have become equivalent treatments.