Dialysate Levels Research Articles

Intraperitoneally Administered Vancomycin Results in Suboptimal Serum and Peritoneal Effluent Drug Levels in Patients with PD-related Peritonitis

Background Intraperitoneal vancomycin is commonly used to treat peritoneal dialysis (PD)-related peritonitis. Therapeutic drug level monitoring helps optimize the use of vancomycin in CKD patients. We studied whether sufficient serum levels were achieved in patients with PD-related peritonitis treated with the commonly used dose of vancomycin in patients with end stage renal disease. Materials and Methods All consecutive patients with PD-related peritonitis during 19 months were studied. Patients received IP Vancomycin 15 mg/kg Q96H and amikacin 2 mg/kg while awaiting culture reports. Vancomycin concentration in serum and dialysate was determined by a validated liquid chromatography-tandem mass spectrometry assay at 1, 12, 24, and 96 h. The primary outcome was the drug levels in serum and peritoneal fluid, and the secondary outcome was peritonitis treatment failure. Results A total of 45 episodes of PD-related peritonitis were treated, of which 41 fulfilled the inclusion criteria and were included in the PK analysis. Recommended serum vancomycin trough level of >15 mg/L was achieved in only two cases. Twenty-one episodes required catheter removal. Conclusion In patients with PD-related peritonitis, intermittent intraperitoneal administration of 15 mg/kg of vancomycin every 96 h does not achieve the recommended serum and dialysate levels of vancomycin. There is an urgent need for pharmacokinetic studies on commonly used IP antibiotics in the PD population to facilitate correct dose recommendations.

Serum Soluble Suppression of Tumorigenicity-2 Levels Predict Cardiovascular Events in Patients Undergoing Incident Peritoneal Dialysis: A Prospective Cohort Study.

Biomarkers are urgently required to identify peritoneal dialysis (PD) patients at risk of cardiovascular (CV) events. This study aimed to investigate the predictive value of soluble suppression of tumorigenicity-2 (sST2) for CV events in patients undergoing incident PD. In this prospective cohort study, incident PD patients were enrolled. Blood samples to measure sST2 levels were obtained before PD catheter implantation. The patients underwent a standard peritoneal equilibration test (PET) after initiation of PD for 4-6 weeks. The sST2 levels in both serum and dialysate were determined using enzyme-linked immunosorbent assay. CV events were recorded during the follow-up period. A total of 137 patients were enrolled. During the follow-up period of 17.3 months, 49 (35.76%) patients experienced CV events. When patients were dichotomized based on the median values and the calculated cutoff values of sST2, the higher sST2 group had 2.980- and 3.048-fold increased risks of CV events, respectively, when compared with the lower sST2 group. Moreover, the prognostic value of sST2 remained significant as a continuous variable (per 1 standard deviation increase, hazard ratio [HR] = 1.037, 95% confidence interval [CI] 1.010-1.066, p = 0.008). N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were found to indicate a higher risk only when dichotomized based on the calculated cutoff values. Furthermore, serum sST2 and NT-proBNP levels simultaneously above the calculated cutoff values were associated with a higher risk of CV events (HR = 3.398, 95% CI 1.813-6.367, p < 0.001). Baseline serum sST2 level is an independent predictor of the risk of CV events in patients receiving incident PD, and in combination with NT-proBNP level, it can provide a more accurate predictive value.

Osteoprotegerin and Inflammation in Incident Peritoneal Dialysis Patients.

Objectives: Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor family involved in processes in many inflammatory states. OPG concentration is enhanced in the majority of chronic kidney disease (CKD) patients and those undergoing renal replacement therapy. The aim of the study was to assess the relation of OPG and chronic inflammation in peritoneal dialysis (PD) patients and to evaluate whether OPG concentrations in plasma and dialysate were related to plasma and dialysate levels of proinflammatory mediators (interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), interleukin 33 (IL-33) and interleukin 1 receptor-like 1IL-1RL1 (IL-1RL1, sST2)). Methods: The study included 37 patients of the Peritoneal Dialysis Center, Department of Nephrology, Transplantology and Internal Medicine, Szczecin, Poland, 4-6 weeks after the onset of peritoneal dialysis therapy. During a peritoneal equilibration test, plasma (at 2 h) and dialysate (at 4 h) OPG, IL-33, 1IL-1RL1 (sST2), IL-6 and hsCRP concentrations were determined. Results: Plasma concentration of OPG did not correlate with dialysate OPG level (Rs = 0.04, p = 0.8). There was a strong positive correlation between plasma OPG concentrations and plasma IL-1RL1 (sST2) (Rs = 0.41; p = 0.01), plasma IL-6 (Rs = 0.38; p = 0.01) and plasma hsCRP (Rs = 0.35; p = 0.02). Dialysate OPG concentrations were positively associated with dialysate IL-1RL1 (sST2) (Rs = 0.37; p = 0.02) and dialysate IL-6 levels (Rs = 0.44; p = 0.005). Multivariate analysis showed that higher IL-1RL1 (sST2) (ß = +0.38, p = 0.006), higher plasma hsCRP (ß = +0.32, p = 0.02) and older age (ß = +0.35, p = 0.01) were independent determinants of higher plasma OPG concentration and that higher concentrations of dialysate IL-6 (ß = +0.37, p = 0.02) were independent determinants of higher dialysate OPG concentration. Conclusions: Both plasma and dialysate OPG levels are associated with the severity of systemic and local inflammation illustrated by the plasma and dialysate concentrations of IL-1RL1 (sST2), hsCRP and IL-6, suggesting that OPG might have a pivotal role in explaining the milieu of systemic and intraperitoneal inflammation.

Clinical and Genotypic Insights Into Higher Prevalence of Palbociclib Associated Neutropenia in Asian Patients.

CDK4/6 inhibitors (CDK4/6i) have shown great efficacy in prolonging progression-free survival and is the current standard of care for hormone positive (HR(+)) metastatic breast cancer (mBC). Despite well tolerability and ease of use, the most common side effect of CDK4/6i is myelosuppression, with neutropenia the most prevalent adverse effect. Studies show that the prevalence and severity of neutropenia are more marked in Asian patients, although details remain obscure. In this study, we retrospectively analyzed 105 Taiwanese patients who received palbociclib for HR(+) HER2(-) mBC at the Taipei Veterans General Hospital. To investigate a possible genetic association for high prevalence of neutropenia, we queried the Taiwan Biobank with publicly available germline databases (ALFA, gnomAD, ExAC, 1000 Genomes project, HapMap), for the allele frequencies of 4 neutropenia-related SNPs (ABCB1_rs1045642, ABCB1_rs1128503, ERCC1_rs3212986, ERCC1_rs11615) and compared between different ethnicities. In addition, one of the patients was a long-term patient with peritoneal dialysis. We quantified the levels of palbociclib in her serum and peritoneal fluid by liquid chromatography-mass spectrometry (LC-MS). Interestingly, in our cohort, early neutropenia nadir (occurred within 56 days of start) was associated with worse treatment outcome, while occurrence of grade 3/4 neutropenia was associated with better outcome. We observed an extremely high incidence of neutropenia (96.2% any grade, 70.4% grade 3/4). In the analyzed germline databases, we discovered a higher SNP frequency of the T allele in ABCB1_rs1128503, a lower frequency of T allele in ABCB1_rs1045642, and a higher SNP frequency of G allele in ERCC1_rs11615. We observed that palbociclib levels in peritoneal dialysate ranged from around 20-50 ppb, and serum levels reached 100-110 ppb during drug administration and decreased to <10 ppb during discontinuation. Our retrospective analysis of real world palbociclib use reveals an association with grade 3/4 neutropenia with better outcome and early neutropenia nadir with worse outcome. Our findings of Asian specific SNPs support a predisposition toward profound and prevalent neutropenia in Asian patients under CDK4/6i. We also report the first pharmacokinetics analysis on a patient with peritoneal dialysis receiving CDK4/6i. In summary, our study provides novel clinical and genotypic insights into CDK4/6i associated neutropenia.

Transfer and biotransformation of the COVID-19 prodrug molnupiravir and its metabolite β-D-N4-hydroxycytidine across the blood-placenta barrier

Molnupiravir is an orally bioavailable prodrug of the nucleoside analogue β-D-N4-hydroxycytidine (NHC) and is used to treat coronavirus disease 2019 (COVID-19). However, the pharmacokinetics and transplacental transfer of molnupiravir in pregnant women are still not well understood. In the present study, we investigated the hypothesis that molnupiravir and NHC cross the blood-placenta barrier into the fetus. A multisite microdialysis coupled with a validated ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC‒MS/MS) system was developed to monitor the dialysate levels of molnupiravir and NHC in maternal rat blood and conceptus (the collective term for the fetus, placenta, and amniotic fluid). Molnupiravir was administered intravenously (100mg/kg, i.v.) on gestational day 16. To investigate the mechanism of transport of molnupiravir across the blood-placenta barrier, we coadministered nitrobenzylthioinosine (NBMPR, 10mg/kg, i.v.) to inhibit equilibrative nucleoside transporter (ENT). We report that molnupiravir is rapidly metabolized to NHC and then rapidly transformed in the fetus, placenta, amniotic fluid, and maternal blood. Our pharmacokinetics analysis revealed that the area under the concentration curve (AUC) for the mother-to-fetus ratio (AUCfetus/AUCblood) of NHC was 0.29±0.11. Further, we demonstrated that the transport of NHC in the placenta may not be subject to modulation by the ENT. Our results show that NHC is the predominant bioactive metabolite of molnupiravir and rapidly crosses the blood-placenta barrier in pregnant rats. The NHC concentration in maternal blood and conceptus was above the average median inhibitory concentration (IC50) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), suggesting a therapeutic effect. These findings support the use of molnupiravir in pregnant patients infected with COVID. This study was supported in part by research grants from the National Science and Technology Council of Taiwan (NSTC 111-2113-M-A49-018 and NSTC 112-2321-B-A49-005).

Cognitive dysfunction and impaired neuroplasticity following repeated exposure to the synthetic cannabinoid JWH-018 in male mice.

Psychotic disorders have been reported in long-term users of synthetic cannabinoids. This study aims at investigating the long-lasting effects of repeated JWH-018 exposure. Male CD-1 mice were injected with vehicle, JWH-018 (6mg·kg-1 ), the CB1 -antagonist NESS-0327 (1mg·kg-1 ) or co-administration of NESS-0327 and JWH-018, every day for 7days. After 15 or 16 days washout, we investigated the effects of JWH-018 on motor function, memory, social dominance and prepulse inhibition (PPI). We also evaluated glutamate levels in dialysates from dorsal striatum, striatal dopamine content and striatal/hippocampal neuroplasticity focusing on the NMDA receptor complex and the neurotrophin BDNF. These measurements were accompanied by in vitro electrophysiological evaluations in hippocampal preparations. Finally, we investigated the density of CB1 receptors and levels of the endocannabinoid anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and their main synthetic and degrading enzymes in the striatum and hippocampus. The repeated treatment with JWH-018 induced psychomotor agitation while reducing social dominance, recognition memory and PPI in mice. JWH-018 disrupted hippocampal LTP and decreased BDNF expression, reduced the synaptic levels of NMDA receptor subunits and decreased the expression of PSD95. Repeated exposure to JWH-018, reduced hippocampal CB1 receptor density and induced a long-term alteration in AEA and 2-AG levels and their degrading enzymes, FAAH and MAGL, in the striatum. Our findings suggest that repeated administration of a high dose of JWH-018 leads to the manifestation of psychotic-like symptoms accompanied by alterations in neuroplasticity and change in the endocannabinoid system.

Pharmacokinetic Properties of Dapagliflozin in Hemodialysis and Peritoneal Dialysis Patients.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors attenuate incident cardiovascular outcomes, irrespective of baseline GFR, in conservatively managed CKD. As this condition inexorably progresses to demanding KRT, drug withdrawal is supported by the current lack of evidence of safety of SGLT2 inhibitors in dialysis. This study was a prospective, single-center, open-label trial ( ClinicalTrials.gov identifier: NCT05343078 ) aimed at assessing the pharmacokinetic properties and safety of dapagliflozin in patients with kidney failure on regular dialysis regimens compared with those with type 2 diabetes and age- and sex-matched controls with normal kidney function. Peripheral blood samples were collected from both groups every 30 minutes for 4 hours and again after 48 hours after ingestion of dapagliflozin 10 mg, which occurred immediately before dialysis session initiation in the kidney failure group. This protocol occurred in drug-naïve patients and again after six daily doses of dapagliflozin to assess whether the drug had accumulated. The plasma and dialysate levels of dapagliflozin at each time point were determined by liquid chromatography and used to calculate pharmacokinetics parameters (peak concentration [C max ] and area under the plasma concentration-versus-time curve) for each participant. Dapagliflozin C max was 117 and 97.6 ng/ml in the kidney failure and control groups, respectively, whereas the corresponding accumulation ratios were 26.7% and 9.5%. No serious adverse events were reported for either group. Dapagliflozin recovered from dialysate corresponded to 0.10% of the administered dose. In patients with kidney failure on dialysis, dapagliflozin was well tolerated, was slightly dialyzable, and had nonaccumulating pharmacokinetic properties. Pharmacokinetics and Dialyzability of Dapagliflozin in Dialysis Patients (DARE-ESKD 1), NCT05343078.

Time-averaged concentration estimation of uraemic toxins with different removal kinetics: a novel approach based on intradialytic spent dialysate measurements.

Kt/Vurea is the most used marker to estimate dialysis adequacy; however, it does not reflect the removal of many other uraemic toxins, and a new approach is needed. We have assessed the feasibility of estimating intradialytic serum time-averaged concentration (TAC) of various uraemic toxins from their spent dialysate concentrations that can be estimated non-invasively online with optical methods. Serum and spent dialysate levels and total removed solute (TRS) of urea, uric acid (UA), indoxyl sulphate (IS) and β2-microglobulin (β2M) were evaluated with laboratory methods during 312 haemodialysis sessions in 78 patients with four different dialysis treatment settings. TAC was calculated from serum concentrations and evaluated from TRS and logarithmic mean concentrations of spent dialysate (MlnD). Mean (± standard deviation) intradialytic serum TAC values of urea, UA, β2M and IS were 10.4±3.8mmol/L, 191.6±48.1µmol/L, 13.3±4.3mg/L and 82.9±43.3µmol/L, respectively. These serum TAC values were similar and highly correlated with those estimated from TRS [10.5±3.6mmol/L (R 2=0.92), 191.5±42.8µmol/L (R 2=0.79), 13.0±3.2mg/L (R 2=0.59) and 82.7±40.0µmol/L (R 2=0.85)] and from MlnD [10.7±3.7mmol/L (R 2=0.92), 191.6±43.8µmol/L (R 2=0.80), 12.9±3.2mg/L (R 2=0.63) and 82.2±38.6µmol/L (R 2=0.84)], respectively. Intradialytic serum TAC of different uraemic toxins can be estimated non-invasively from their concentration in spent dialysate. This sets the stage for TAC estimation from online optical monitoring of spent dialysate concentrations of diverse solutes and for further optimization of estimation models for each uraemic toxin.

Stroke Literature Synopsis (Preclinical).

Stroke Literature Synopsis (Preclinical).

Investigating the Early Events after Skin-Barrier Disruption Using Microdialysis—A Human Ex Vivo Skin Model

Skin-barrier restoration following abrasive trauma is facilitated by mediator release from skin-resident cells, a process that has been investigated primarily in mice or simplified human systems with previous studies focusing on a limited number of biomarkers. Here, we demonstrate how early events caused by skin-barrier disruption can be studied in a human ex vivo skin model. Ten relevant biomarkers were recovered from the interstitial fluid by skin microdialysis with subsequent sample analysis using a multiplex platform. As a control, the biomarker profiles obtained from microdialysis sampling were compared to profiles of skin biopsy homogenates. We found that nine (GM-CSF, CXCL1/GROα, CXCL8/IL-8 CXCL10/IP-10, IL-1α, IL-6, MIF, TNF-α, and VEGF) of the 10 biomarkers were significantly upregulated in response to abrasive trauma. Only dialysate levels of CCL27/CTACK were unaffected by skin abrasion. Biomarker levels in the homogenates corresponded to dialysate levels for CCL27/CTACK, CXCL1/GROα, CXCL8/IL-8, and IL-6. However, IL-1α showed an inverse trend in response to trauma, and biopsy levels of MIF were unchanged. GM-CSF, CXCL10/IP-10, TNF-α, and VEGF were not detected in the biopsy homogenates. Our results suggest that the human ex vivo skin model is a reliable approach to study early events after disruption of the skin barrier.

MO690HIGHER EXPRESSION OF TOLL LIKE RECEPTOR AND CELL ADHESION MOLECULES ARE ASSOCIATED WITH RECURRENT/RELAPSE PERITONITIS AND MORTALITY IN PATIENT ON CAPD

Abstract Background and Aims CAPD is an established modality of treatment for patients with end stage renal disease (ESRD). Peritonitis is a leading cause of technique failure and death in patients on CAPD. Studies on expressions of host genetic factors like TLRs, CAMs, Pro and Anti-inflammatory cytokines and their link to peritonitis and other co-morbidity and functional status are lacking throughout the world. Hence the present study was done to determine the expressions of TLR2 and TLR4, CAMs and inflammatory cytokines in patients on CAPD. Method A total of 110 ESRD patients categorized into 3 groups: 1- CAPD patients (n=45), group 2- CAPD with peritonitis patients (n=35), and group 3- CAPD patients with recurrent/relapsing peritonitis. (n=30) from department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Raebareli Road, Lucknow were included in the study. Blood sample was collected for analysis of cytokines and Cell adhesion molecules level and RNA extraction. Dialysate (only from patients undergoing PD with or without peritonitis)- whole drained bag; 50-100 ml for microscopy and culture for bacterial and fungal pathogens using automated BACTEC culture system in patients with peritonitis and supernatant was collected for cytokine ELISA. Statistical analysis: One-way ANOVA (Two tailed) and non-parametric student t-test used for statistical analysis of differences between the group. Results mRNA expression of TLR 2 and TLR 4 expression was higher in peritonitis and recurrent/relapsing peritonitis group as compared to CAPD patient without peritonitis group. mRNA expression of TNF-alpha, IL-1B and IFN-gamma was higher in peritonitis group of patients compared to all other group of patients. mRNA expression of IL-10 and IL-4 was also highest in Peritonitis group. Level of IL-1β and TNF-alpha was observed to be elevated in peritonitis and recurrent/relapse peritonitis patients compared to CAPD in sera and dialysate. IL-12 level in Sera was also elevated in peritonitis patients but its level in dialysate was highest in CAPD without peritonitis as compared to peritonitis and recurrent/relapse. IL-10 and IL-4 was observed to be elevated in peritonitis group followed by CAPD with recurrent/relapse peritonitis in sera whereas in dialysate level of IL-4 was higher in both peritonitis group and Recurrent groups of patients but IL-10 level was highest in peritonitis group but less in recurrent/relapse. mRNA Expression levels of adhesion molecule ICAM-1 and LFA-1 were observed to be higher in Peritonitis and Recurrent groups as compared to the CAPD without peritonitis; whereas, in sera the level of ICAM-1 was higher in peritonitis patients. However, in dialysate its level was observed to be almost similar. Level of LFA-1 was observed to be higher in peritonitis group in dialysate but in sera its level was higher in Recurrent group with peritonitis. Conclusion It is likely that CAMs are also involved in the pathogenesis of CAPD peritonitis, its morbidity and mortality. TLRs activation by bacterial molecules leads to the induction of chemokines and cytokines through the activation of NF-ķB pathway and may be responsible for atherosclerosis, morbidity, and mortality in ESRD patients. Elevated level of ICAM-1, IL-1beta, TNF-a and IFN-G may be responsible for chronic inflammation in PD patients.

Hyaluronan reduces colitis-induced intraperitoneal inflammation during peritoneal dialysis.

Peritoneal dialysis induces the inflammatory response within the peritoneal cavity, which contributes to the progressive damage of the peritoneum. Due to close contact of the peritoneal cavity and the intestines, there is the possibility that the visceral disorders can affect the intraperitoneal inflammation during peritoneal dialysis. Study of the effect of acute colitis on the intraperitoneal inflammation in conditions of peritoneal dialysis and evaluation of the protective effect of hyaluronan in that scenario. In rats with the dextran sulphate-induced colitis, 6-h peritoneal dialysis was performed with dianeal 2.5% +/- hyaluronan 10 mg/dL. In the control group, rats without colitis were studied. Peritoneal permeability and dialysate inflammation were studied at the end of the dialysate exchange. In rats with colitis, intraperitoneal inflammatory reaction was increased as compared with the control group and reflected by the following studied parameters: dialysate cell count (+26%, p < 0.01), number of neutrophils (+75%, p < 0.01), generation of free radicals in the leukocytes (+70%, p < 0.05), dialysate level of elastase (+102%, p < 0.01), tumor necrosis factor α (+48%, p < 0.01) and monocyte chemoattractant protein-1 (+42%, p < 0.01). Drained dialysate volume was lower (-21%, p < 0.01) and peritoneal permeability increased in rats with colitis (+55%, p < 0.01). In animals with the hyaluronan supplemented dialysis fluids, the intensity of the intraperitoneal inflammation was reduced. Visceral inflammation during colitis induces the inflammatory reaction within the peritoneal cavity that may accelerate damage to the peritoneum. Supplementation of the dialysis fluid with hyaluronan reduces the intensity of that effect.

Associations between dialysate interleukin-6 and Tie-2 and peritoneal solute transport rate and outcomes for patients undergoing peritoneal dialysis: A prospective cohort study.

Objectives:We designed this prospective observational study to clarify the associations between dialysate IL-6, a marker of ongoing peritoneal inflammation, Tie2, an important factor in angiogenesis in the peritoneum, and a high peritoneal solute transport rate (PSTR) in patients undergoing peritoneal dialysis (PD) and to investigate their outcome predictive roles.Methods:A total of 60 stable continuous ambulatory peritoneal dialysis (CAPD) patients from a single center in China were analyzed in this prospective study. We measured dialysate levels of IL-6 and Tie-2 using ELISAs. Our primary study endpoint was all-cause mortality with 10 years’ follow-up.Results:For the evaluation of PSTR, we used the Dialysis/Plasma creatinine (D/Pcr) ratio. We subdivided the patients into two groups for statistical evaluation: low and low average D/Pcr (<0.64; L/A), and high and high average D/Pcr (≥0.65; H/A) transporters. The mean levels of dialysates IL-6 (21.71 ± 8.88 pg/mL) and Tie-2 (1.23 ± 0.43 ng/mL) were significantly higher in the H/A (high and high average, group than those in the L/A group (13.94 ± 5.43 pg/mL, p<0.001 and 0.95 ± 0.43 ng/mL, p=0.019; respectively). Moreover, IL-6 and Tie-2 were positively correlated with D/Pcr (r=0.366, p=0.004 and r=0.402, p=0.001; respectively). Both dialysates IL-6 and Tie-2 were independent determinants of a high peritoneal solute transport rate. After follow-up for 42.65±18.08 months, 30 patients (50.0%) had died. An increased D/Pcr increased the risk of all-cause mortality in patients with CAPD (p=0.018), but the dialysates IL-6 and Tie2 were not independent predictors of all-cause mortality (p>0.05).Conclusion:Our results suggest that patients undergoing CAPD have a high peritoneal solute transport status with local peritoneal inflammation and angiogenesis. Increased D/Pcr is a relative risk factor for mortality and technique failure in patients undergoing CAPD.

CA-125 and CCL2 may indicate inflammation in peritoneal dialysis patients.

Introduction:Progressive structural changes in the peritoneal membrane occur over the course of treatment in peritoneal dialysis (PD), resulting in an increase in cytokines such as CCL2 and structural changes in peritoneal membrane triggering an increase in CA-125 in dialysate, which reflects a probable local inflammatory process, with possible loss of mesothelial cells. Thus, the current study aimed to evaluate the association between plasma and CCL2 and CA-125 dialysate levels in patients undergoing PD.Methods:Cross-sectional study was conducted with 41 patients undergoing PD. The assessments of CA-125 and CCL2 levels were performed using a capture ELISA. Correlations were estimated using Spearman's correlation and the investigation of the association between the explanatory variables (CCL2) and response variable (CA-125) was done for crude ratio of arithmetic means and adjusted utilizing generalized linear models.Results:A moderate positive correlation was observed between the levels of CA-125 and CCL2 in the dialysate (rho = 0.696). A statistically significant association was found between the levels in the CCL2 and CA-125 dialysate (RoM=1.31; CI = 1.20-1.43), which remained after adjustment for age (RoM = 1.31; CI=1.19-1.44) and for time in months of PD (RoM=1.34, CI=1.22-1.48).Conclusion:The association of CA-125 levels with CCL2 in the dialysate may indicate that the local inflammatory process leads to temporary or definitive changes in peritoneal membrane. A better understanding of this pathogenesis could contribute to the discovery of new inflammatory biomarkers.

Striatal and nigral muscarinic type 1 and type 4 receptors modulate levodopa-induced dyskinesia and striato-nigral pathway activation in 6-hydroxydopamine hemilesioned rats

Acetylcholine muscarinic receptors (mAChRs) contribute to both the facilitation and inhibition of levodopa-induced dyskinesia operated by striatal cholinergic interneurons, although the receptor subtypes involved remain elusive. Cholinergic afferents from the midbrain also innervate the substantia nigra reticulata, although the role of nigral mAChRs in levodopa-induced dyskinesia is unknown. Here, we investigate whether striatal and nigral M1 and/or M4 mAChRs modulate dyskinesia and the underlying striato-nigral GABAergic pathway activation in 6-hydroxydopamine hemilesioned rats. Reverse microdialysis allowed to deliver the mAChR antagonists telenzepine (M1 subtype preferring), PD-102807 and tropicamide (M4 subtype preferring), as well as the selective M4 mAChR positive allosteric modulator VU0152100 in striatum or substantia nigra, while levodopa was administered systemically. Dyskinetic movements were monitored along with nigral GABA (and glutamate) and striatal glutamate dialysate levels, taken as neurochemical correlates of striato-nigral pathway and cortico-basal ganglia-thalamo-cortical loop activation. We observed that intrastriatal telenzepine, PD-102807 and tropicamide alleviated dyskinesia and inhibited nigral GABA and striatal glutamate release. This was partially replicated by intrastriatal VU0152100. The M2 subtype preferring antagonist AFDX-116, used to elevate striatal acetylcholine levels, blocked the behavioral and neurochemical effects of PD-102807. Intranigral VU0152100 prevented levodopa-induced dyskinesia and its neurochemical correlates whereas PD-102807 was ineffective. These results suggest that striatal, likely postsynaptic, M1 mAChRs facilitate dyskinesia and striato-nigral pathway activation in vivo. Conversely, striatal M4 mAChRs can both facilitate and inhibit dyskinesia, possibly depending on their localization. Potentiation of striatal and nigral M4 mAChR transmission leads to powerful multilevel inhibition of striato-nigral pathway and attenuation of dyskinesia.

Roles of peritoneal clearance and residual kidney removal in control of uric acid in patients on peritoneal dialysis

BackgroundThere have been few systematic studies regarding clearance of uric acid (UA) in patients undergoing peritoneal dialysis (PD). This study investigated peritoneal UA removal and its influencing factors in patients undergoing PD.MethodsThis cross-sectional study enrolled patients who underwent peritoneal equilibration test and assessment of Kt/V from April 1, 2018 to August 31, 2019. Demographic data and clinical and laboratory parameters were collected, including UA levels in dialysate, blood, and urine.ResultsIn total, 180 prevalent patients undergoing PD (52.8% men) were included. Compared with the normal serum UA (SUA) group, the hyperuricemia group showed significantly lower peritoneal UA clearance (39.1 ± 6.2 vs. 42.0 ± 8.0 L/week/1.73m2; P = 0.008). Furthermore, higher transporters (high or high-average) exhibited greater peritoneal UA clearance, compared with lower transporters (low or low-average) (42.0 ± 7.0 vs. 36.4 ± 5.6 L/week/1.73 m2; P < 0.001). Among widely used solute removal indicators, peritoneal creatinine clearance showed the best performance for prediction of higher peritoneal UA clearance in receiver operating characteristic curve analysis [area under curve (AUC) 0.96; 95% confidence interval [CI], 0.93–0.99]. Peritoneal UA clearance was independently associated with continuous SUA [standardized coefficient (β), − 0.32; 95% CI, − 6.42 to − 0.75] and hyperuricemia [odds ratio (OR), 0.86; 95% CI, 0.76–0.98] status, only in patients with lower (≤2.74 mL/min/1.73 m2) measured glomerular filtration rate (mGFR). In those patients with lower mGFR, lower albumin level (β − 0.24; 95%CI − 7.26 to − 0.99), lower body mass index (β − 0.29; 95%CI − 0.98 to − 0.24), higher transporter status (β 0.24; 95%CI 0.72–5.88) and greater dialysis dose (β 0.24; 95%CI 0.26–3.12) were independently associated with continuous peritoneal UA clearance. Furthermore, each 1 kg/m2 decrease in body mass index (OR 0.79; 95% CI 0.63–0.99), each 1 g/dL decrease in albumin level (OR 0.08; 95%CI 0.01–0.47), and each 0.1% increase in average glucose concentration in dialysate (OR 1.56; 95%CI 1.11–2.19) were associated with greater peritoneal UA clearance (> 39.8 L/week/1.73m2).ConclusionsFor patients undergoing PD who exhibited worse residual kidney function, peritoneal clearance dominated in SUA balance. Increasing dialysis dose or average glucose concentration may aid in controlling hyperuricemia in lower transporters.

A new microdialysis probe for continuous lactate measurement during fetal monitoring: Proof of concept in an animal model.

IntroductionCardiotocography (CTG) is currently the most commonly used method for intrapartum fetal monitoring during labor. However, a high false‐positive rate of fetal acidosis indicated by CTG leads to an increase in obstetric interventions. We developed a microdialysis probe that is integrated into a fetal scalp electrode allowing continuous measurement of lactate subcutaneously, thus giving instant information about the oxygenation status of the fetus. Our aim was to establish proof of concept in an animal model using a microdialysis probe to monitor lactate subcutaneously.Material and methodsWe performed an in vivo study in adult male wild‐type Wistar rats. We modified electrodes used for CTG monitoring in human fetuses to incorporate a microdialysis membrane. Optimum flow rates for microdialysis were determined in vitro. For the in vivo experiment, a microdialysis probe was inserted into the skin on the back of the animal. De‐oxygenation and acidosis were induced by lowering the inspiratory oxygen pressure. Oxygenation and heart rate were monitored. A jugular vein cannula was inserted to draw blood samples for analysis of lactate, pH, pco 2, and saturation. Lactate levels in dialysate were compared with plasma lactate levels.ResultsBaseline blood lactate levels were around 1 mmol/L. Upon de‐oxygenation, oxygen saturation fell to below 40% for 1 h and blood lactate levels increased 2.5‐fold. Correlation of dialysate lactate levels with plasma lactate levels was 0.89 resulting in an R 2 of .78 in the corresponding linear regression.ConclusionsIn this animal model, lactate levels in subcutaneous fluid collected by microdialysis closely reflected blood lactate levels upon transient de‐oxygenation, indicating that our device is suitable for subcutaneous measurement of lactate. Microdialysis probe technology allows the measurement of multiple compounds in the dialysate, such as glucose, albumin, or inflammatory mediators, so this technique may offer the unique possibility to shed light on fetal physiology during the intrapartum period.

CRF Release in the Nucleus Accumbens Promotes Arousal in Anticipation of Cocaine Availability: Implications for Stress‐Induced Drug‐Seeking

Dopamine signaling within the nucleus accumbens core (NAcC) is critical to the generation of motivated behaviors in both appetitive and aversive contexts. Within the accumbens, various neuropeptides influence motivational states through the modulation of dopamine release dynamics. Here, microdialysis studies show that the stress peptide corticotropin releasing factor (CRF) is released in the NAcC when rats are exposed to environmental contexts that predict either an aversive outcome (i.e. social defeat) or drug‐reward opportunity (i.e. cocaine availability), and moreover, intra‐NAcC infusion of exogenous CRF elicits a robust increase in extracellular dopamine. The present studies further interrogate accumbens‐specific CRF actions as a candidate mechanism for maladaptive arousal evoked by drug‐predictive stimuli – a hallmark feature of cocaine dependence. In order to assess the role of NAcC‐CRF on instrumental responding directed towards cocaine procurement, male Long‐Evans rats were trained to self‐administer cocaine under a heterogeneous chained schedule of reinforcement (FIFR) in order to dissociate anticipatory (‘drug‐seeking’) from consummatory (‘drug‐taking’) behavior. Completion of a fixed‐interval (10 min) was followed by a period (10 min) of continuously reinforced responding (0.32mg/kg cocaine; FR1) on another lever. Microdialysis conducted during this procedure revealed that extracellular dopamine levels within the NAcC gradually ‘ramp up’ across the fixed‐interval in parallel with lever pressing activity, as drug availability approaches. Similarly, dialysate levels of CRF were specifically and progressively elevated during the fixed‐interval component preceding drug‐access, but were unaffected by drug‐taking. Infusion of CRF into the NAc produced a rapid elevated tonic dopamine levels that was accompanied by enhanced responding during the fixed‐interval component of the procedure, but notably did not affect subsequent cocaine intake. Conversely, pharmacological blockade of CRF‐R2, dampened extracellular dopamine levels in the NAc and suppressed lever pressing behavior during the fixed‐interval. Taken together, these data suggest that in response to appetitive or aversive stimuli, CRF may be a critical mediator of motivated processes that are classically associated with dopamine transmission. To this end, stress‐evoked CRF release in the NAc may represent a candidate mechanism by which stress triggers aberrant cocaine‐seeking.Support or Funding InformationNIDA R01‐DA031734 to KAM

Выбор уровня натрия в диализирующем растворе в достижении целей оптимального диализа: одноцентровое пилотное исследование

Выбор уровня натрия в диализирующем растворе в достижении целей оптимального диализа: одноцентровое пилотное исследование

Lorcaserin bidirectionally regulates dopaminergic function site-dependently and disrupts dopamine brain area correlations in rats

Lorcaserin, which is a selective agonist of serotonin2C receptors (5-HT2CRs), is a new FDA-approved anti-obesity drug that has also shown therapeutic promise in other brain disorders, such as addiction and epilepsy. The modulation of dopaminergic function might be critical in the therapeutic effect of lorcaserin, but its exact effect is unknown. Here, we studied the effect of the peripheral administration of lorcaserin on the ventral tegmental area (VTA), the substantia nigra pars compacta (SNc) dopaminergic neural activity, dopamine (DA) dialysis levels in the nucleus accumbens and striatum and on DA tissue levels in 29 different rat brain regions. Lorcaserin (5–640 μg/kg, i.v.) moderately inhibited only a subpopulation of VTA DA neurons, but had no effect on the SNc neurons. Lorcaserin (0.3, 3 mg/kg, i.p.) did not change VTA and SNc DA population neural activity but slightly decreased the firing rate and burst firing of the spontaneously active VTA neurons, without altering DA extracellular dialysate levels in both the nucleus accumbens and the striatum. Quantitative analysis of DA and metabolites tissue contents of the 29 areas studied revealed that lorcaserin (0.3 or 3 mg/kg, i.p.) only affected a few brain regions, i.e., increased DA in the central amygdala, ventral hypothalamus and nucleus accumbens core and decreased it in the ventromedial striatum. On the other hand, lorcaserin dramatically changed the direction and reduced the number of correlations of DA tissue content among several brain areas. These effects on DA terminal networks might be significant in the therapeutic mechanism of lorcaserin.This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’.