Effect of Dialysate and Plasma Sodium on Mortality in a Global Historical Hemodialysis Cohort.

SIGNIFICANCE STATEMENT: This large observational cohort study aimed to investigate the relationship between dialysate and plasma sodium concentrations and mortality among maintenance hemodialysis patients. Using a large multinational cohort of 68,196 patients, we found that lower dialysate sodium concentrations (≤138 mmol/L) were independently associated with higher mortality compared with higher dialysate sodium concentrations (>138 mmol/L). The risk of death was lower among patients exposed to higher dialysate sodium concentrations, regardless of plasma sodium levels. These results challenge the prevailing assumption that lower dialysate sodium concentrations improve outcomes in hemodialysis patients. The study confirms that until robust evidence from randomized trials that are underway is available, nephrologists should remain cautious in reconsideration of dialysate sodium prescribing practices to optimize cardiovascular outcomes and reduce mortality in this population. BACKGROUND: Excess mortality in hemodialysis (HD) patients is largely due to cardiovascular disease and is associated with abnormal fluid status and plasma sodium concentrations. Ultrafiltration facilitates the removal of fluid and sodium, whereas diffusive exchange of sodium plays a pivotal role in sodium removal and tonicity adjustment. Lower dialysate sodium may increase sodium removal at the expense of hypotonicity, reduced blood volume refilling, and intradialytic hypotension risk. Higher dialysate sodium preserves blood volume and hemodynamic stability but reduces sodium removal. In this retrospective cohort, we aimed to assess whether prescribing a dialysate sodium ≤138 mmol/L has an effect on survival outcomes compared with dialysate sodium >138 mmol/L after adjusting for plasma sodium concentration. METHODS: The study population included incident HD patients from 875 Fresenius Medical Care Nephrocare clinics in 25 countries between 2010 and 2019. Baseline dialysate sodium (≤138 or >138 mmol/L) and plasma sodium (<135, 135-142, >142 mmol/L) concentrations defined exposure status. We used multivariable Cox regression model stratified by country to model the association between time-varying dialysate and plasma sodium exposure and all-cause mortality, adjusted for demographic and treatment variables, including bioimpedance measures of fluid status. RESULTS: In 2,123,957 patient-months from 68,196 incident HD patients with on average three HD sessions per week dialysate sodium of 138 mmol/L was prescribed in 63.2%, 139 mmol/L in 15.8%, 140 mmol/L in 20.7%, and other concentrations in 0.4% of patients. Most clinical centers (78.6%) used a standardized concentration. During a median follow-up of 40 months, one third of patients ( n =21,644) died. Dialysate sodium ≤138 mmol/L was associated with higher mortality (multivariate hazard ratio for the total population (1.57, 95% confidence interval, 1.25 to 1.98), adjusted for plasma sodium concentrations and other confounding variables. Subgroup analysis did not show any evidence of effect modification by plasma sodium concentrations or other patient-specific variables. CONCLUSIONS: These observational findings stress the need for randomized evidence to reliably define optimal standard dialysate sodium prescribing practices.

2-Deoxy-glucose ameliorates the peritoneal mesothelial and endothelial barrier function perturbation occurring due to Peritoneal Dialysis fluids exposure.

Peritoneal dialysis (PD) and prolonged exposure to PD fluids (PDF) induce peritoneal membrane (PM) fibrosis and hypervascularity, leading to functional PM degeneration. 2-deoxy-glucose (2-DG) has shown potential as PM antifibrotic by inhibiting hyper-glycolysis induced mesothelial-to-mesenchymal transition (MMT). We investigated whether administration of 2-DG with several PDF affects the permeability of mesothelial and endothelial barrier of the PM. The antifibrotic effect of 2-DG was confirmed by the gel contraction assay with embedded mesothelial (MeT-5A) or endothelial (EA.hy926) cells cultured in Dianeal® 2.5 % (CPDF), BicaVera® 2.3 % (BPDF), Balance® 2.3 % (LPDF) with/without 2-DG addition (0.2 mM), and qPCR for αSMA, CDH2 genes. Moreover, 2-DG effect was tested on the permeability of monolayers of mesothelial and endothelial cells by monitoring the transmembrane resistance (RTM), FITC-dextran (10, 70 kDa) diffusion and mRNA expression levels of CLDN-1 to -5, ZO1, SGLT1, and SGLT2 genes. Contractility of MeT-5A cells in CPDF/2-DG was decreased, accompanied by αSMA (0.17 ± 0.03) and CDH2 (2.92 ± 0.29) gene expression fold changes. Changes in αSMA, CDH2 were found in EA.hy926 cells, though αSMA also decreased under LPDF/2-DG incubation (0.42 ± 0.02). Overall, 2-DG mitigated the PDF-induced alterations in mesothelial and endothelial barrier function as shown by RTM, dextran transport and expression levels of the CLDN-1 to -5, ZO1, and SGLT2. Thus, supplementation of PDF with 2-DG not only reduces MMT but also improves functional permeability characteristics of the PM mesothelial and endothelial barrier.

High Osmol Gap Hyponatremia Caused by Icodextrin: A Case Series Report.

Recently, hyperosmolar hyponatremia following excessive off-label use of two exchanges of 2 L icodextrin daily during peritoneal dialysis (PD) was reported. We encountered a cluster of 3 cases of PD patients who developed hyperosmolar hyponatremia during on-label use of icodextrin. This appeared to be due to absorption of icodextrin since after stopping icodextrin, the serum sodium level and osmol gap returned to normal, while a rechallenge again resulted in hyperosmolar hyponatremia. We excluded higher than usual concentrations of specific fractions of dextrins in fresh icodextrin dialysis fluid (lot numbers of used batches were checked by manufacturer). We speculate that in our patients, either an exaggerated degradation of polysaccharide chains by α-amylase activity in dialysate, lymph, and interstitium and/or rapid hydrolysis of the absorbed larger degradation products in the circulation may have contributed to the hyperosmolality observed, with the concentration of oligosaccharides exceeding the capacity of intracellular enzymes (in particular maltase) to metabolize these products to glucose. Both hyponatremia and hyperosmolality are risk factors for poor outcomes in PD patients. Less conventional PD prescriptions such as off-label use of two exchanges of 2 L icodextrin might raise the risk of this threatening side effect. This brief report is intended to create awareness of a rare complication of on-label icodextrin use in a subset of PD patients and/or PD prescriptions.

Associations of neutral pH, low-GDP peritoneal dialysis solutions with patient survival, transfer to haemodialysis and peritonitis.

BACKGROUND: Peritoneal dialysis (PD) solutions containing low levels of glucose degradation products (GDPs) are associated with attenuation of peritoneal membrane injury and vascular complications. However, clinical benefits associated with neutral-pH, low-GDP (N-pH/L-GDP) solutions remain unclear. METHODS: Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the associations between N-pH/L-GDP solutions and all-cause mortality, cause-specific mortality, transfer to haemodialysis (HD) for ≥30 days and PD peritonitis in adult incident PD patients in Australia and New Zealand between 1 January 2005 and 31 December 2020 using adjusted Cox regression analyses. RESULTS: Of 12 814 incident PD patients, 2282 (18%) were on N-pH/L-GDP solutions. The proportion of patients on N-pH/L-GDP solutions each year increased from 11% in 2005 to 33% in 2017. During the study period, 5330 (42%) patients died, 4977 (39%) experienced transfer to HD and 5502 (43%) experienced PD peritonitis. Compared with the use of conventional solutions only, the use of any form of N-pH/L-GDP solution was associated with reduced risks of all-cause mortality {adjusted hazard ratio [aHR] 0.67 [95% confidence interval (CI) 0.61-0.74]}, cardiovascular mortality [aHR 0.65 (95% CI 0.56-0.77)], infection-related mortality [aHR 0.62 (95% CI 0.47-0.83)] and transfer to HD [aHR 0.79 (95% CI 0.72-0.86)] but an increased risk of PD peritonitis [aHR 1.16 (95% CI 1.07-1.26)]. CONCLUSIONS: Patients who received N-pH/L-GDP solutions had decreased risks of all-cause and cause-specific mortality despite an increased risk of PD peritonitis. Studies assessing the causal relationships are warranted to determine the clinical benefits of N-pH/L-GDP solutions.

Randomized trial comparing standard versus thermocontrolled haemodialysis using intradialytic cardiac, brain and renal magnetic resonance imaging.

BACKGROUND: Ischaemic end-organ damage during haemodialysis (HD) is a significant problem that may be ameliorated by intradialytic cooling. A randomised trial was performed to compare standard HD (SHD; dialysate temperature 37°C) and programmed cooling of the dialysate [thermocontrolled HD (TCHD)] using multiparametric magnetic resonance imaging (MRI) to assess structural, functional and blood flow changes in the heart, brain and kidneys. METHODS: Prevalent HD patients were randomly allocated to receive either SHD or TCHD for 2 weeks before undergoing serial MRI at four time points: pre-, during (30 min and 180 min) and post-dialysis. MRI measures include cardiac index, myocardial strain, longitudinal relaxation time (T1), myocardial perfusion, internal carotid and basilar artery flow, grey matter perfusion and total kidney volume. Participants then crossed to the other modality to repeat the study protocol. RESULTS: Eleven participants completed the study. Separation in blood temperature between TCHD (-0.1 ± 0.3°C) and SHD (+0.3 ± 0.2°C; P = .022) was observed, although there was no difference in tympanic temperature changes between arms. There were significant intradialytic reductions in cardiac index, cardiac contractility (left ventricular strain), left carotid and basilar artery blood flow velocities, total kidney volume, longitudinal relaxation time (T1) of the renal cortex and transverse relaxation rate (T2*) of the renal cortex and medulla, but no differences between arms. Pre-dialysis T1 of the myocardium and left ventricular wall mass index were lower after 2 weeks of TCHD compared with SHD [1266 ms (interquartile range 1250-1291) versus 1311 ± 58 ms, P = .02; 66 ± 22 g/m2 versus 72 ± 23 g/m2, P = .004]. CONCLUSIONS: HD adversely affects cardiac function, reduces carotid and basilar artery blood flow and total kidney volume, but mild dialysate cooling using a biofeedback module did not result in differences in intradialytic MRI measures compared with SHD.

Microdialysis coupled with droplet microfluidics and mass spectrometry for determination of neurotransmitters in vivo with high temporal resolution.

Monitoring the concentration fluctuations of neurotransmitters in vivo is valuable for elucidating the chemical signals that underlie brain functions. Microdialysis sampling is a widely used tool for monitoring neurochemicals in vivo. The volume requirements of most techniques that have been coupled to microdialysis, such as HPLC, result in fraction collection times of minutes, thus limiting the temporal resolution possible. Further the time of analysis can become long for cases where many fractions are collected. Previously we have used direct analysis of dialysate by low-flow electrospray ionization-tandem mass spectrometry (ESI-MS/MS) on a triple quadrupole mass spectrometer to monitor acetylcholine, glutamate, and γ-amino-butyric acid to achieve multiplexed in vivo monitoring with temporal resolution of seconds. Here, we have expanded this approach to adenosine, dopamine, and serotonin. The method achieved limits of detection down to 2 nM, enabling basal concentrations of all these compounds, except serotonin, to be measured in vivo. Comparative analysis with LC-MS/MS showed accurate results for all compounds except for glutamate, possibly due to interference for this compound in vivo. Pairing this analysis with droplet microfluidics yields 11 s temporal resolution and can generate dialysate fractions down to 3 nL at rates up to 3 fractions per s from a microdialysis probe. The system is applied to multiplexed monitoring of neurotransmitter dynamics in response to stimulation by 100 mM K+ and amphetamine. These applications demonstrate the suitability of the droplet ESI-MS/MS method for monitoring short-term dynamics of up to six neurotransmitters simultaneously.

Safety and Feasibility of Regional Citrate Anticoagulation for Continuous Renal Replacement Therapy With Calcium-Containing Solutions: A Randomized Controlled Trial.

BACKGROUND: Calcium-free (Ca-free) solutions are theoretically the most ideal for regional citrate anticoagulation (RCA) in continuous renal replacement therapy (CRRT). However, the majority of medical centers in China had to make a compromise of using commercially available calcium-containing (Ca-containing) solutions instead of Ca-free ones due to their scarcity. This study was designed to probe into the potential of Ca-containing solution as a secure and efficient substitution for Ca-free solutions. METHODS: In this prospective, randomized single-center trial, 99 patients scheduled for CRRT were randomly assigned in a 1:1:1 ratio to one of three treatment groups: continuous veno-venous hemodialysis Ca-free dialysate (CVVHD Ca-free) group, continuous veno-venous hemodiafiltration calcium-free dialysate (CVVHDF Ca-free) group, and continuous veno-venous hemodiafiltration Ca-containing dialysate (CVVHDF Ca-containing) group at cardiac intensive care unit (CICU). The primary endpoint was the incidence of metabolic complications. The secondary endpoints included premature termination of treatment, thrombus of filter, and bubble trap after the process. RESULTS: The incidence of citrate accumulation (18.2% vs. 12.1% vs. 21.2%) and metabolic alkalosis (12.1% vs. 0% vs. 9.1%) did not significantly differ among three groups (p > 0.05 for both). The incidence of premature termination was comparable among the groups (18.2% vs. 9.1% vs. 9.1%, p = 0.582). The thrombus level of the filter and bubble trap was similar in the three groups (p > 0.05 for all). CONCLUSIONS: In RCA-CRRT for CICU population, RCA-CVVHDF with Ca-containing solutions and traditional RCA with Ca-free solutions had a comparable safety and feasibility. TRIAL REGISTRATION: ChiCTR2100048238 in the Chinese Clinical Trial Registry.

Peritoneal Phosphate Clearance: Determinants and Association With Mortality.

BACKGROUND: Dialytic phosphate removal is a cornerstone of the management of hyperphosphatemia in peritoneal dialysis (PD) patients, but the influencing factors on peritoneal phosphate clearance (PPC) are incompletely understood. Our objective was to explore clinically relevant factors associated with PPC in patients with different PD modality and peritoneal transport status and the association of PPC with mortality. METHODS: This is a cross-sectional and prospective observational study. Four hundred eighty-five PD patients were enrolled and divided into 2 groups according to PPC. All-cause mortality was evaluated after followed-up for at least 3 months. RESULTS: High PPC group showed lower mortality compared with Low PPC group by Kaplan-Meier analysis and log-rank test. Both multivariate linear regression and multivariate logistic regression revealed that high transport status, total effluent dialysate volume per day, continuous ambulatory PD (CAPD), and protein in total effluent dialysate volume appeared to be positively correlated with PPC; body mass index (BMI) and the normalized protein equivalent of total nitrogen appearance (nPNA) were negatively correlated with PPC. Besides PD modality and membrane transport status, total effluent dialysate volume showed a strong relationship with PPC, but the correlation differed among PD modalities. CONCLUSIONS: Higher PPC was associated with lower all-cause mortality risk in PD patients. Higher PPC correlated with CAPD modality, fast transport status, higher effluent dialysate volume and protein content, and with lower BMI and nPNA.

Effect of peritoneal dialysate on bioelectrical impedance analysis variability in pediatric patients receiving peritoneal dialysis.

BACKGROUND: Previous adult studies have yielded conflicting results regarding whether the presence (D +) or absence (D-) of peritoneal dialysate affects the accuracy of bioelectrical impedance analysis (BIA) measurements. The aim of this study was to investigate whether the accuracy of BIA data varies between D + and D- measurements in children. METHODS: This cross-sectional study recruited chronic kidney disease stage 5 patients aged 3 to 18 years who received peritoneal dialysis. Body composition was assessed by multifrequency BIA, and values were compared between D + and D- measurements using the intraclass correlation coefficient (ICC). RESULTS: Fifty paired BIA measurements were collected from 18 patients with a mean age of 13.6 ± 4.1 years and a mean dialysate fill volume of 1,006 ± 239.7 ml/m2. Sixteen out of 17 BIA parameters (94.1%) exhibited excellent correlations between D + and D- measurements (ICC values = 0.954, 0.998). There was a trend of increased fluid status, including extracellular water, edema index, and overhydration, in D + measurements, with mean differences (95% CIs) of 0.5 (0.4, 0.6) L, 0.002 (0.001, 0.002), and 0.1 (0.1, 0.2) L, respectively. Soft lean mass and fat-free mass were higher in D + measurements, with mean differences (95% CIs) of 1.4 (1.2, 1.6), and 1.6 (1.4, 1.8) kg, respectively. In addition, patients older than 10 years had a stronger correlation between D + and D- measurements than younger patients. CONCLUSIONS: A total of 94.1% of BIA parameters exhibited excellent correlations between D + and D- measurements, especially patients older than 10 years. We recommend that BIA measurements be collected from children regardless of the presence of peritoneal dialysate.

Effects of sodium-glucose co-transporter 2 inhibitors on ultrafiltration in patients with peritoneal dialysis: a protocol for a randomized, double-blind, placebo-controlled, crossover trial (EMPOWERED).

BACKGROUND: Volume overload is common and associated with high mortality in patients on peritoneal dialysis (PD). Traditional strategies including diuretics, water/salt restriction, and icodextrin-based solutions cannot always fully correct this condition, necessitating novel alternative strategies. Recent studies confirmed the expression of sodium-glucose cotransporter 2 (SGLT2) in the human peritoneum. Experimental data suggest that SGLT2 inhibitors decrease glucose absorption from the PD solution, thereby increasing the ultrafiltration volume. This trial aims to assess whether SGLT2 inhibitors increase the ultrafiltration volume in patients on PD. METHODS: The EMPOWERED trial (trial registration: jRCTs051230081) is a multicenter, randomized, double-blind, placebo-controlled, crossover trial. Patients with clinically diagnosed chronic heart failure are eligible regardless of the presence of diabetes if they use at least 3 L/day glucose-based PD solutions. Participants will be randomly assigned (1:1) to receive empagliflozin 10 mg once daily and then placebo or vice versa. Each treatment period will last 8 weeks with a 4-week washout period. This study will recruit at least 36 randomized participants. The primary endpoint is the change in the daily ultrafiltration volume from baseline to week 8 in each intervention period. The key secondary endpoints include changes in the biomarkers of drained PD solutions, renal residual function, and anemia-related parameters. CONCLUSIONS: This trial aims to assess the benefit of SGLT2 inhibitors in fluid management with a novel mechanism of action in patients on PD. It will also provide insights into the effects of SGLT2 inhibitors on solute transport across the peritoneal membrane and residual renal function.

Is increased subjective thirst associated with greater interdialytic weight gains, extracellular fluid and dietary sodium intake?

BACKGROUND: Some previous studies have reported an effect of increasing subjective thirst and interdialytic weight gains (IDWG), and that this may be influenced by nonadherence to dietary sodium restrictions, whereas others reported no such association. As such we wished to review the effect of self-reported thirst on IDWGs and dietary sodium intake. METHODS: Dialysis patients were asked to complete visual analogues thirst, distress thermometer (DT) scores and complete a sodium food frequency questionnaire (SFFQ). IDWG and pre and post dialysis volumes were measured with multifrequency bioelectrical impedance. RESULTS: One hundred and eleven patients completed the questionnaires and had bioimpedance measurements: 63% male, mean age 63.8 ± 16.1 years, 33% diabetic with a median thirst score 3 (0-5) and SFFQ 52.0 ± 18, and IDWG 2.1 ± 1.3%. Thirst was associated with DT (r = 0.28, p = 0.004) and negatively with age (r = -0.31, p < 0.001), but not SFFQ, IDWG, extracellular water, or dialysate sodium, or dialysate to plasma gradient. Patients with higher thirst scores were younger (58.0 ± 15.2 vs. 69.4 ± 15.0 years, p < 0.001) with higher DT scores (5 [2-7] vs. 2 [0-5], p < 0.001). On multivariate logistic analysis, only age was associated with self-reported thirst (odds ratio 0.95, 95% confidence limits 0.92-0.98, p < 0.001). CONCLUSION: We found that subjective thirst was greater for younger patients and those who reported higher levels of distress, but no association with IDWGs, dietary sodium intake, or dialysate sodium. However, most of our patients followed the dietary advice, as evidenced by the low SFFQ scores and % IDWGs. Whether thirst increases distress or distress increases subjective thirst remains to be determined.

Differential effects of biocompatible peritoneal dialysis fluids on human mesothelial and endothelial cells in 2D and 3D phenotypes.

INTRODUCTION: Peritoneal dialysis (PD) is a life maintaining treatment in patients with end-stage renal disease. Its chronic application leads to peritoneal mesothelial layer denudation and fibrotic transformation along with vascular activation of inflammatory pathways. The impact of different PD fluids (PDF) on mesothelial and endothelial cell function and repair mechanisms are not comprehensively described. MATERIALS AND METHODS: Mesothelial (MeT-5A) and endothelial cells (EA.hy926) were cultured in 1:1 ratio with cell medium and different PDF (icodextrin-based, amino acid-based, and glucose-based). Cell adhesion, cell migration, and cell proliferation in 2D and spheroid formation and collagen gel contraction assays in 3D cell cultures were performed. RESULTS: Cell proliferation and cell-mediated gel contraction were both significantly decreased in all conditions. 3D spheroid formation was significantly reduced with icodextrin and amino acid PDF, but unchanged with glucose PDF. Adhesion was significantly increased by amino acid PDF in mesothelial cells and decreased by icodextrin and amino acid PDF in endothelial cells. Migration capacity was significantly decreased in mesothelial cells by all three PDF, while endothelial cells remained unaffected. CONCLUSIONS: In 3D phenotypes the effects of PDF are more uniform in both mesothelial and endothelial cells, mitigating spheroid formation and gel contraction. On the contrary, effects on 2D phenotypes are more uniform in the icodextrin and amino acid PDF as opposed to glucose ones and affect mesothelial cells more variably. 2D and 3D comparative assessments of PDF effects on the main peritoneal membrane cell barriers, the mesothelial and endothelial, could provide useful translational information for PD studies.

Can regional anticoagulation with calcium-free dialysate be extended to maintenance hemodialysis?

BACKGROUND: Regional anticoagulation in hemodialysis avoids the use of heparin, which is responsible for both hemorrhagic and non-hemorrhagic complications. Typically, blood is decalcified by injecting citrate into the arterial line of the extracorporeal circuit. Calcium-free dialysate improves anticoagulation efficacy but requires injection of a calcium-containing solution into the venous line and strict monitoring of blood calcium levels. Recent improvements have made regional anticoagulation with calcium-free dialysate safer and easier. OBSERVATIONS: (1) Adjusting the calcium injection rate to ionic dialysance avoids the risk of dyscalcemia, thus making unnecessary the monitoring of blood calcium levels. This adjustment could be carried out automatically by the hemodialysis monitor. (2) As calcium-free dialysate reduces the amount of citrate required, this can be supplied by dialysate obtained from currently available concentrates containing citric acid. This avoids the need for citrate injection and the risk of citrate overload. (3) Calcium-free dialysate no longer needs the dialysate acidification required for avoiding calcium carbonate precipitation in bicarbonate-containing dialysate. CONCLUSIONS: Regional anticoagulation with calcium-free dialysate enables an acid- and heparin-free procedure that is more biocompatible and environmentally friendly than conventional bicarbonate hemodialysis. The availability of specific acid-free concentrates and adapted hemodialysis monitors is required to extend this procedure to maintenance hemodialysis.

Icodextrin-induced acute generalized exanthematous pustulosis in a patient with peritoneal dialysis.

Icodextrin has been widely prescribed for peritoneal dialysis (PD) patients with inadequate ultrafiltration, but icodextrin induced acute generalized exanthematous pustulosis (AGEP) has been not well recognized in clinical practice. We described a young-aged female with IgA nephropathy and end stage kidney disease under continuous automated peritoneal dialysis. She developed skin erythema with exfoliation over the groin 7th day after initiation of icodextrin based PD dialysate. Initially, her scaling skin lesion with pinhead-sized pustules affected the bilateral inguinal folds, and then it extended to general trunk accompanied by pruritus. She was admitted because of deterioration of skin lesion on 14th day of icodextrin exposure. She was afebrile and physical examination was notable for widespread erythematous papules with pruritus extending over her groins and trunk. Pertinent laboratory examination showed leukocytosis of 18 970 cells/µL with neutrophile count of 17 642 cells/µL (92.3%), and c-reactive-protein: 3.39 mg/dL. Skin biopsy revealed multifocal sub corneal abscess with papillary dermal edema, and upper-dermal neutrophilia with perivascular accentuation, consistent with the diagnosis of AGEP. After discontinuation of PD, she underwent temporary high-flux haemodialysis with treatment of steroid and antihistamine. Her dermatologic lesion resolved without any skin sequalae completely within 4 days, and she underwent icodextrin-free peritoneal dialysis at 17th day. This case highlighted the fact that icodextrin-induced AGEP should be early recognized to avoid inappropriate management.

Dermal microdialysis: A method to determine drug levels in the skin of patients with Post kala-azar dermal leishmaniasis (PKDL).

OBJECTIVES: Post-kala-azar-dermal leishmaniasis (PKDL) is an infectious skin disease that occurs as sequela of visceral leishmaniasis (VL) and causes cutaneous lesions on the face and other exposed body parts. While the first-line drug miltefosine is typically used for 28 days to treat VL, 12 weeks of therapy is required for PKDL, highlighting the need to evaluate the extent of drug penetration at the dermal site of infection. In this proof-of-concept study, we demonstrate the use of a minimally invasive sampling technique called microdialysis to measure dermal drug exposure in a PKDL patient, providing a tool for the optimization of treatment regimens. METHODS AND MATERIALS: One PKDL patient receiving treatment with miltefosine (50 mg twice daily for 12 weeks) was recruited to this proof-of-concept study and consented to undergo dermal microdialysis. Briefly, a µDialysis Linear Catheter 66 for skin and muscle, a probe with a semi-permeable membrane, was inserted in the dermis. A perfusate (a drug-free physiological solution) was pumped through the probe at a low flow rate, allowing miltefosine present in the dermis to cross the membrane and be collected in the dialysates over time. Protein-free (dialysates) and total (blood and skin biopsies) drug concentrations were analysed using LC-MS/MS. RESULTS: and conclusions: Using microdialysis, protein-free miltefosine drug concentrations could be detected in the infected dermis over time (Cmax ≈ 450 ng/ml). This clinical proof-of-concept study thus illustrates the potential of dermal microdialysis as a minimally invasive alternative to invasive skin biopsies to quantify drug concentrations directly at the pharmacological site of action in PKDL.

Dapagliflozin in peritoneal dialysis patients: a pilot study evaluating peritoneal membrane function.

BACKGROUND: Patients taking SGLT-2 inhibitors may experience delayed peritoneal fibrosis, better ultrafiltration of water and toxins, and higher survival rates. We aimed to evaluate the possible effects of Dapagliflozin in changing the peritoneal solute transfer rate, reducing peritoneal glucose absorption, and, hence, increasing ultrafiltration. METHODOLOGY: A pilot pre-post interventional study was used to evaluate 20 patients on continuous ambulatory peritoneal dialysis (CAPD) enrolled in a one-month self-controlled study [Trial#: NCT04923295]. Inclusion criteria included being over 18, and having a Peritoneal Dialysis (PD) vintage of at least six months. All participants were classified as having high or average high transport status based on their Peritoneal Equilibrium Test with a D0/D4 > 0.39. and using at least two exchanges with 2.35% dextrose over the previous three months before enrollment. RESULTS: Following the treatment, 13 patients had an increase in median D4/D0 from 0.26 [0.17-0.38] to 0.31 [0.23-0.40], while seven patients had a decline from 0.28 [0.17-0.38] to 0.23 [0.14-0.33]. Additionally, nine patients had a decrease in median D/P from 0.88 [0.67-0.92] to 0.81 [0.54-0.85], while 11 patients had an increase from 0.70 [0.6-0.83] to 0.76 [0.63-0.91]. CONCLUSION: According to the findings of this study, Dapagliflozin usage in peritoneal dialysis patients did not result in a reduction in glucose absorption across the peritoneal membrane. Additionally, Dapagliflozin was also associated with a small increase in sodium dip, a decrease in peritoneal VEGF, and a decrease in systemic IL-6 levels all of which were not statistically significant. Further large-scale studies are required to corroborate these conclusions.

The effect of ascending- descending ultrafiltration and sodium profiles on blood pressure in hemodialysis patients: a randomized cross-over study.

BACKGROUND: Considering no previous research into the utilization of ascending/descending ultrafiltration and linear sodium profiles in improving blood pressure among hemodialysis patients, the present study aimed to explore the effect of the A/D-UF along with linear sodium profiles on HD patients with hypotension. METHODS: Applying a crossover design, this clinical trial was fulfilled between December 2022 and June 2023 on 20 patients undergoing HD, randomized into two groups, each one receiving two intervention protocols, viz., (a) an intervention protocol in which the liquid sodium in the dialysis solution was linear and the UF profiling was A/D, and (b) a routine protocol or HD, wherein both liquid sodium and UF in the dialysis solution remained constant. The HD patients' BP was then checked and recorded at six intervals, namely, before HD, one, two, three, and four hours after it, and following its completion, within each session. The data were further statistically analyzed using the IBM SPSS Statistics 20 and the related tests. RESULTS: In total, 20 patients, including 12 men (60%) and 8 women (40%), with the mean age of 58.00 ± 14.54 on HD for an average of 54 months, were recruited in this study. No statistically significant difference was observed in the mean systolic and diastolic BP levels in the group receiving the A/D-UF profile all through the desired hours (p > 0.05), indicating that the patients did not face many changes in these two numbers during HD. Our cross-over clinical trial demonstrated a statistically significant reduction in symptomatic IDH episodes from 55 to 15% with the application of the A/D-UF profile (p < 0.05). CONCLUSION: The study demonstrated that the A/D-UF profile could contribute to the stability of blood pressure levels among HD patients, with no significant fluctuations observed during treatment sessions. TRIAL REGISTRATION: This study was registered in the Iranian Registry of Clinical Trials (no. IRCT20180429039463N5) on 07/01/2023.

Comparison of the pre-dilution and post-dilution methods for online hemodiafiltration.

Online hemodiafiltration (OL-HDF) is a treatment modality using diffusion and ultrafiltration. There are two types of dilution methods in OL-HDF: pre-dilution, which is commonly provided in Japan, and post-dilution, which is commonly provided in Europe. The optimal OL-HDF method for individual patients is not well studied. In this study, we compared the clinical symptoms, laboratory data, spent dialysate, and adverse events of pre- and post-dilution OL-HDF. We conducted a prospective study of 20 patients who underwent OL-HDF between January 1, 2019 and October 30, 2019. Their clinical symptoms and dialysis efficacy were evaluated. All patients underwent OL-HDF every 3 months in the following sequence: first pre-dilution, post-dilution, and second pre-dilution. We evaluated 18 patients for the clinical study and 6 for the spent dialysate study. No significant differences in spent dialysates regarding small and large solutes, blood pressure, recovery time, and clinical symptoms were observed between the pre- and post-dilution methods. However, the serum α1-microglobulin level in post-dilution OL-HDF was lower than that in pre-dilution OL-HDF (first pre-dilution: 124.8 ± 14.3 mg/L; post-dilution: 116.6 ± 13.9 mg/L; second pre-dilution: 125.8 ± 13.0 mg/L; first pre-dilution vs. post-dilution, post-dilution vs. second pre-dilution, and first pre-dilution vs. second pre-dilution: p = 0.001, p < 0.001, and p = 1.000, respectively). The most common adverse event was an increase in transmembrane pressure in the post-dilution period. Compared to pre-dilution, the post-dilution method decreased the α1-microglobulin level; however, there were no significant differences in clinical symptoms or laboratory data.

On the total albumin losses during haemocatharsis.

Excessive albumin losses during HC (haemocatharsis) are considered a potential cause of hypoalbuminemia-a key risk factor for mortality. This review on total albumin losses considers albumin "leaking" into the dialysate and losses due to protein/membrane interactions (i.e. adsorption, "secondary membrane formation" and denaturation). The former are fairly easy to determine, usually varying at the level of ~ 2 g to ~ 7 g albumin loss per session. Such values, commonly accepted as representative of the total albumin losses, are often quoted as limits/standards of permissible albumin loss per session. On albumin mass lost due to adsorption/deposition, which is the result of complicated interactions and rather difficult to determine, scant in vivo data exist and there is great uncertainty and confusion regarding their magnitude; this is possibly responsible for neglecting their contribution to the total losses at present. Yet, many relevant in vitro studies suggest that losses of albumin due to protein/membrane interactions are likely comparable to (or even greater than) those due to leaking, particularly in the currently favoured high-convection HDF (haemodiafiltration) treatment. Therefore, it is emphasised that top research priority should be given to resolve these issues, primarily by developing appropriate/facile in vivo test-methods and related analytical techniques.

Comparison of citrate dialysate in pre- and post-dilution online hemodiafiltration: effect on clot formation and adequacy of dialysis in hemodialysis patients.

BACKGROUND: Citrate dialysate (CD) has been successfully used in conventional hemodialysis and continuous renal replacement therapy; however, no study has compared pre- and post-dilution online hemodiafiltration (oL-HDF). Therefore, we aimed to investigate the efficacy of citrate anticoagulation for oL-HDF and the metabolic changes and quality of life of patients on hemodialysis treated using both modes. METHOD: Eight dialysis patients were treated with CD containing 0.8 mmol of citric acid for 4 weeks in each phase. Visual clotting scores were investigated as the primary endpoints. Adequacy of dialysis, laboratory parameters, and quality of life were measured as secondary objectives. RESULTS: The mean clotting scores in the pre-dilution mode were significantly lower than those in the post-dilution mode and in all phases except the heparin-free phase (p < 0.001 in the baseline phase, p = 0.001 in phase 1, and p = 0.023 in phase 2). The values of Kt/V in both modalities were comparable except during the baseline phase, in which the values of pre-dilution were significantly greater than post-dilution (2.36 ± 0.52/week vs. 1.87 ± 0.33/week;95% CI -0.81 to -0.19, p = 0.002). The patient's quality of life regarding their physical activity level was significantly higher in the post-dilution mode than in the pre-dilution mode at baseline and in phase 1 (p = 0.014 and 0.004 at baseline and in phase 1, respectively). Metabolic changes did not differ between the two modes. CONCLUSION: Citrate dialysate decreased or prevented anticoagulation in both pre- and post-dilution modes of oL-HDF without significant side effects and had comparable adequacy of dialysis.