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.

Conceptual model of adding antibiotics to dialysate fluid during renal replacement therapy.

Studies have shown significant variability in antibiotic trough concentrations in critically ill patients receiving renal replacement therapy (RRT). The purpose of this study was to assess whether adding beta-lactam antibiotics to dialysate solution can maintain stable antibiotic concentrations during RRT in experimental conditions. A single compartment model reflecting the patient was constructed and connected to the RRT machine. Dialysate fluid was prepared in three different concentrations of meropenem (0 mg/L; 16 mg/L; 64 mg/L). For each dialysate concentration various combinations of dialysate and blood flow rates were tested by taking different samples. Meropenem concentration in all samples was calculated using spectrophotometry method. Constructed experimental model results suggest that decrease in blood meropenem concentration can be up to 35.6%. Moreover, experimental data showed that antibiotic loss during RRT can be minimized and stable plasma antibiotic concentration can be achieved with the use of a 16 mg/L Meropenem dialysate solution. Furthermore, increasing meropenem concentration up to 64 mg/L is associated with an increase antibiotic concentration up to 18.7-78.8%. Administration of antibiotics to dialysate solutions may be an effective method of ensuring a constant concentration of antibiotics in the blood of critically ill patients receiving RRT.

Mild sodium reduction in peritoneal dialysis solution improves hypertension in end stage kidney disease: a case-report study.

INTRODUCTION: Blood Pressure (BP) control is largely unsatisfied in End Stage Kidney Disease (ESKD) principally due to sodium retention. Peritoneal Dialysis (PD) is the most common type of home dialysis, using a peritoneal membrane to remove sodium, though sodium removal remains challenging. METHODS: This is a case-study reporting two consecutive ESKD patients treated by a novel peritoneal PD solution with a mildly reduced sodium content (130 mmol/L) to treat hypertension. RESULTS: In the first case, a 78-year-old woman treated by Continuous Ambulatory PD (CAPD) with standard solution (three 4 h-dwells per day 1.36% glucose 132 mmol/L) showed resistant hypertension confirmed by ambulatory blood pressure monitoring (ABPM), reporting 24 h-BP: 152/81 mmHg, day-BP:151/83 mmHg and night-ABP: 153/75 mmHg, with inversion of the circadian systolic BP rhythm (1.01), despite use of three anti-hypertensives and a diuretic at adequate doses. No sign of hypervolemia was evident. We then switched from standard PD to low-sodium solution in all daily dwells. A six-months low-sodium CAPD enabled us to reduce diurnal (134/75 mmHg) and nocturnal BP (122/67 mmHg), restoring the circadian BP rhythm, with no change in ultrafiltration or residual diuresis. Diet and drug prescription were unmodified too. The second case was a 61-year-old woman in standard CAPD (three 5 h-dwells per day) suffering from hypertension confirmed by ABPM (mean 24 h-ABP: 139/84 mmHg; mean day-ABP:144/88 mmHg and mean night-ABP:124/70 mmHg). She was switched from 132-Na CAPD to 130-Na CAPD, not changing dialysis schedule. No fluid expansion was evident. During low-sodium CAPD, antihypertensive therapy (amlodipine 10 mg and Olmesartan 20 mg) has been reduced until complete suspension. After 6 months, we repeated ABPM showing a substantial reduction in mean 24 h-ABP (117/69 mmHg), mean diurnal ABP (119/75 mmHg) and mean nocturnal ABP (111/70 mmHg). Ultrafiltration and residual diuresis remained unmodified. No side effects were reported in either cases. CONCLUSIONS: This case-report study suggests that mild low-sodium CAPD might reduce BP in hypertensive ESKD patients.

Regional Citrate Anticoagulation for Continuous Kidney Replacement Therapy With Calcium-Containing Solutions: A Cohort Study.

OBJECTIVE: Regional citrate anticoagulation (RCA) is the preferred anticoagulation method for continuous kidney replacement therapy (CKRT) recommended by KDIGO. Limited availability of calcium-free solutions often imposes challenges to the implementation of RCA for CKRT (RCA-CKRT). The principal purpose of this study was to characterize the outcomes of RCA-CKRT using calcium-containing solutions. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: We evaluated the safety and efficacy of RCA-CKRT with calcium-containing dialysate and replacement fluid used for 128 patients. A total of 571 filters and 1,227 days of CKRT were analyzed. EXPOSURES: Liver disease, sepsis in the absence of liver disease, and sepsis with liver disease. OUTCOMES: Filter life and metabolic complications per 100 CKRT days. ANALYTICAL APPROACH: Linear mixed-effects model and generalized linear mixed-effects models. RESULTS: The majority of patients were male (91; 71.1%), 32 (25%) had liver disease, and 29 (22.7%) had sepsis without liver disease. Median filter life was 50.0 (interquartile range, 22.0-118.0) hours, with a maximum of 322 hours, and was significantly lower (33.5 [interquartile range, 17.5-60.5] h) in patients with liver disease. Calcium-containing replacement solutions were used in 41.6% of all CKRT hours and reduced intravenous calcium requirements by 31.7%. Hypocalcemia (ionized calcium<0.85mmol/L) and hypercalcemia (total calcium>10.6mg/dL) were observed in 6.0 and 6.7 per 100 CKRT days, respectively. Citrate accumulation was observed in 13.3% of all patients and was associated with metabolic acidosis in 3.9%, which was not significantly different in patients with liver disease (9.3%; P = 0.2). LIMITATIONS: Lack of control groups that used calcium-free dialysate and replacement solutions with RCA-CKRT. Possible overestimation of filter life from incomplete data on cause of filter failure. CONCLUSIONS: Our study suggests that RCA-CKRT with calcium-containing solutions is feasible and safe in critically ill patients, including those with sepsis and liver disease.

Experimental evaluation of icodextrin delivery as pressurized aerosol (PIPAC): Antiadhesive and cytotoxic effects.

BACKGROUND: Icodextrin (IDX) is an antiadhesive polymer that can be used as a carrier solution for intraperitoneal (IP) delivery of chemotherapeutic drugs. METHODS: We investigated the suitability of IDX solution as a carrier of Cisplatin and Doxorubicin for delivery as pressurized intraperitoneal aerosol chemotherapy (PIPAC). We examined the sprayability of IDX, the aerosol characteristics, the stability of the molecule after aerosolization, the effects of IDX on the adhesion of MKN45 human gastric cancer cells, the synergistic effect of aerosolized IDX with Cisplatin and Doxorubicin, and the chemical stability of IDX, Cisplatin, and Doxorubicin in combination. RESULTS: Delivery of IDX as PIPAC is feasible with no particular restrictions. The median droplet size of 35.7 µm did not change at increasing concentrations. IDX withstood the shear forces applied by the nebulizer and remained stable after aerosolization (ANOVA, p = 0.97). IDX did not impair the cytotoxic effects of Cisplatin and Doxorubicin (ns). IDX had a significant antiadhesive impact alone (p < 0.03) and in combination with Cisplatin and Doxorubicin (p < 0.02). IDX as a carrier for Cisplatin and Doxorubicin remained stable at 4 °C for three months and did not cause degradation of those two substances. CONCLUSION: The proposed combination takes advantage of the antiadhesive properties of IDX, the cytotoxic effect of Cisplatin and Doxorubicin, and an advanced drug delivery system.

Berberine inhibits intestinal epithelial barrier dysfunction in colon caused by peritoneal dialysis fluid by improving cell migration.

ETHNOPHARMACOLOGICAL RELEVANCE: Berberine is generally extracted from Rhizoma Coptidis (Coptis chinensis Franch), a traditional Chinese medicine, which can be used in the treatment of intestinal diseases, respiratory infections and cardiovascular diseases. Berberine is especially effective for the treatment of gastrointestinal disorders such as diarrhea because of the effect of heat-clearing and detoxifying in traditional Chinese medicine theory. AIM OF THE STUDY: This study aimed to examine the protective effect of berberine (BBR) on the damaged colonic epithelial barrier caused by peritoneal dialysis fluid (PDF). METHODS: The damage to intestinal epithelial barrier was examined by intraperitoneally injecting 4.25% dextrose-containing PDF in mice and establishing a long-term PD model in rats with renal failure. Then, the therapeutic potential of berberine on PD-related colonic injuries was examined. T84 colonic epithelial cells were used to test the effect of PDF and berberine in vitro. The damaging effect of PDF and the protective effect of berberine were evaluated by histology staining, histofluorescence and transmission electron microscopy. The migration of colonic epithelial cell and actin-related protein 2 (Arp2) were tested by wound healing assay and Western blot to determine the possible mechanism in vitro. RESULTS: PD administration induced intestinal epithelial barrier dysfunction in the colon, and berberine alleviated the injury by increasing the tight junction and adhesion junction protein, both in vivo and in vitro. Berberine could also improve the morphology of microvillus. In the wound healing assay, berberine exhibited the ability to promote cell migration, indicating that berberine could probably recover the function of intestinal epithelial cells when the intestinal epithelial barrier was damaged by the PDF. CONCLUSIONS: The present study demonstrates that berberine can ameliorate intestinal epithelial barrier dysfunction in the colon caused by long-term PDF through improving cell migration.

Relationship between measured and prescribed dialysate sodium in haemodialysis: a systematic review and meta-analysis.

BACKGROUND: Dialysate sodium (DNa) prescription policy differs between haemodialysis (HD) units, and the optimal DNa remains uncertain. We sought to summarize the evidence on the agreement between prescribed and delivered DNa, and whether the relationship varied according to prescribed DNa. METHODS: We searched MEDLINE and PubMed from inception to 26 February 2020 for studies reporting measured and prescribed DNa. We analysed results reported in aggregate with random-effects meta-analysis. We analysed results reported by individual sample, using mixed-effects Bland-Altman analysis and linear regression. Pre-specified subgroup analyses included method of sodium measurement, dialysis machine manufacturer and proportioning method. RESULTS: Seven studies, representing 908 dialysate samples from 10 HD facilities (range 16-133 samples), were identified. All but one were single-centre studies. Studies were of low to moderate quality. Overall, there was no statistically significant difference between measured and prescribed DNa {mean difference = 0.73 mmol/L [95% confidence interval (CI) -1.12 to 2.58; P = 0.44]} but variability across studies was substantial (I2 = 99.3%). Among individually reported samples (n = 295), measured DNa was higher than prescribed DNa by 1.96 mmol/L (95% CI 0.23-3.69) and the 95% limits of agreement ranged from -3.97 to 7.88 mmol/L. Regression analysis confirmed a strong relationship between prescribed and measured DNa, with a slope close to 1:1 (ß = 1.16, 95% CI 1.06-1.27; P < 0.0001). CONCLUSIONS: A limited number of studies suggest that, on average, prescribed and measured DNa are similar. However, between- and within-study differences were large. Further consideration of the precision of delivered DNa is required to inform rational prescribing.

Deployment of a New CRRT/PIRRT Device during the COVID-19 Pandemic Emergency: Organizational Challenges and Implementation Results.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic led to increased demand nationwide for dialysis equipment, including supplies and machines. To meet the demand in our institution, our surge plan included rapid mobilization of a novel continuous renal replacement treatment (CRRT) machine named SAMI. The SAMI is a push-pull filtration enhanced dialysis machine that can conjugate extremely high single-pass solute removal efficiency with very precise fluid balance control. MATERIAL AND METHODS: Machine assembly was conducted on-site by local biomedical engineers with remote assistance by the vendor. One 3-h virtual training session of 3 dialysis nurses was conducted before SAMI deployment. The SAMI was deployed in prolonged intermittent replacement therapy (PIRRT) mode to maximize patients covered per machine per day. Live on-demand vendor support was provided to troubleshoot any issues for the first few cases. After 4 weeks of the SAMI implementation, data on treatments with the SAMI were collected, and a questionnaire was provided to the nurse trainees to assess device usability. RESULTS: On-site installation of the SAMI was accomplished with remote assistance. Delivery of remote training was successfully achieved. 23 PIRRT treatments were conducted in 10 patients. 7/10 of patients had CO-VID-19. The median PIRRT dose was 50 mL/kg/h (IQR [interquartile range] 44 - 62 mL/kg/h), and duration of the treatment was 8 h (IQR 6.3 - 8 h). Solute control was adequate. The user response was favorable to the set of usability questions involving user interface, on-screen instructions, machine setup, troubleshooting, and the ease of moving the machine. CONCLUSION: Assembly of the SAMI and training of nurses remotely are possible when access to vendor employees is restricted during states of emergency. The successful deployment of the SAMI in our institution during the pandemic with only 3-h virtual training supports that operating the SAMI is simple and safe.

Peritoneal dialysis for acute kidney injury: Equations for dosing in pandemics, disasters, and beyond.

BACKGROUND: Peritoneal dialysis (PD) is a viable option for renal replacement therapy in acute kidney injury (AKI), especially in challenging times during disasters and pandemics when resources are limited. While PD techniques are well described, there is uncertainty about how to determine the amount of PD to be prescribed toward a target dose. The aim of this study is to derive practical equations to assist with the prescription of PD for AKI. METHODS: Using established physiological principles behind PD clearance and membrane transport, a primary determinant of dose delivery, equations were mathematically derived to estimate dialysate volume required to achieve a target dose of PD. RESULTS: The main derivative equation is VD = (1.2 × std-Kt/V × TBW)/(tdwell + 4), where VD is the total dialysate volume per day, std-Kt/V is the desired weekly dose, TBW is the total body water, and tdwell is the dwell time. VD can be expressed in terms of dwell volume, vdwell, by VD = (0.3 × std-Kt/V × TBW) - (6 × vdwell). Two further equations were derived which directly describe the mathematical relationship between tdwell and vdwell. A calculator is included as an Online Supplementary Material. CONCLUSIONS: The equations are intended as a practical tool to estimate solute clearances and guide prescription of continuous PD. The estimated dialysate volume required for any dose target can be calculated from cycle duration or dwell volume. However, the exact target dose of PD is uncertain and should be adjusted according to the clinical circumstances and response to treatment. The equations presented in this article facilitate the adjustment of PD prescription toward the targeted solute clearance.

Ensuring Sustainability of Continuous Kidney Replacement Therapy in the Face of Extraordinary Demand: Lessons From the COVID-19 Pandemic.

With the exponential surge in patients with coronavirus disease 2019 (COVID-19) worldwide, the resources needed to provide continuous kidney replacement therapy (CKRT) for patients with acute kidney injury or kidney failure may be threatened. This article summarizes subsisting strategies that can be implemented immediately. Pre-emptive weekly multicenter projections of CKRT demand based on evolving COVID-19 epidemiology and routine workload should be made. Corresponding consumables should be quantified and acquired, with diversification of sources from multiple vendors. Supply procurement should be stepped up accordingly so that a several-week stock is amassed, with administrative oversight to prevent disproportionate hoarding by institutions. Consumption of CKRT resources can be made more efficient by optimizing circuit anticoagulation to preserve filters, extending use of each vascular access, lowering blood flows to reduce citrate consumption, moderating the CKRT intensity to conserve fluids, or running accelerated KRT at higher clearance to treat more patients per machine. If logistically feasible, earlier transition to intermittent hemodialysis with online-generated dialysate, or urgent peritoneal dialysis in selected patients, may help reduce CKRT dependency. These measures, coupled to multicenter collaboration and a corresponding increase in trained medical and nursing staffing levels, may avoid downstream rationing of care and save lives during the peak of the pandemic.

Automated Remote Monitoring for Peritoneal Dialysis and Its Impact on Blood Pressure.

INTRODUCTION: Peritoneal dialysis (PD) provides a safe, home-based continuous renal replacement therapy for patients. The adherence of the patients to the prescribed dialysis fluids cannot always be monitored by physicians. Remote monitoring automated peritoneal dialysis (RM-APD) can affect patients' compliance with treatment and, thus, clinical outcomes. OBJECTIVE: We aimed to evaluate the clinical outcomes of patients with a remote access program. METHODS: This was an observational study. We analyzed the effect of RM-APD on treatment adherence, dialysis adequacy, and change in blood pressure control, sleep quality, and health-related quality of life during the 6 months of follow-up. RESULTS: A total of 15 patients were enrolled in this study. It was found that there was a significant decrease (99 ± 19 vs. 89 ± 11 mm Hg) in mean arterial blood pressure of patients, and a considerable increase in Kt/V was observed in the sixth month after the RM-APD switch (2.11 ± 0.4 vs. 2.25 ± 0.5). A significant increase was found when comparing the 3-month and 6-month ultrafiltration amounts before RM-APD and the ultrafiltration amount within 6 months after RM-APD (800 mL [500-1,000] and 752 mL [490-986] vs. 824 mL [537-1,183]). The daily antihypertensive pill need (4 [0-7] vs. 2 [0-6]) and alarms received from the device decreased (from 4 [3-8] to 2 [0-3]) at the sixth month of the switch. There was no significant change in sleep quality and health-related quality of life within 6 months. CONCLUSION: This study showed that treatment adherence and ultrafiltration amounts of patients increased with the use of RM-APD, as well as better blood pressure control with fewer antihypertensive drugs.

Intradialytic parenteral nutrition improves nutritional status in a complex cystic fibrosis patient with redo double lung transplant and end-stage renal disease.

This case study reports on the use of intradialytic parenteral nutrition (IDPN) to address severe malnutrition in a 38-year-old woman, redo double lung transplant recipient with a complex medical history including cystic fibrosis and end-stage renal disease (ESRD) on haemodialysis. Gastroparesis and severe postprandial abdominal pain limited oral/enteral nutrition input. The addition of IDPN resulted in a dry weight increase of 13.6% over a 12-month period and an improvement in the patient's malnutrition status from severe (Patient-Generated Subjective Global Assessment (PG SGA) C24) to moderate (PG SGA B7). The patient stated she would recommend IDPN to others in a similar situation. Management of patients with coexisting cystic fibrosis and ESRD with or without haemodialysis requires patient engagement in treatment planning and a multidisciplinary team approach for clinical judgement in the absence of guidelines. As advances in medical care see more patients with these coexisting conditions, IDPN may provide an increasingly useful adjunct therapy.

Individualized dialysate sodium prescriptions using sodium gradients for high-risk hemodialysis patients lowered interdialytic weight gain and achieved target weights.

INTRODUCTION: Large interdialytic weight gain (IDWG) is associated with increased morbidity and mortality in chronic hemodialysis patients. Over 50% of patients at our inner city tertiary academic center dialysis unit had IDWG and target weights (TW) above goal. We conducted an open-label nonrandomized study to explore the effects of an individualized dialysate sodium (DNa) prescription using Na gradients in patients at high risk for large IDWG. Thirty-three patients receiving chronic hemodialysis received individualized DNa prescriptions with a DNa bath of 0 to -2 meq/L below their serum Na level in the intervention group, while patients in the control group were prescribed the standard dialysate Na at 138 mmol/L. Serum Na level, predialysis SBP, symptomatic hypotensive episodes, and %hemodialysis treatments with large IDWG (%TxAIDWG) and above TW(%TxATW) were recorded before and three months after the intervention. We used student t tests to compare continuous variables and Chi-square tests to compare binary variables between the groups at baseline and after the intervention. Age- and sex-adjusted linear regression models were also constructed to assess the differences in each continuous outcome between the groups. Multivariable logistic regression models were conducted by modeling IDWG decrease and above estimated-dry-weight (EDW) decrease as binary dependent variables with adjustment for age, sex, and EDW change. FINDINGS: Patients with individualized DNa concentrations had 3.6 times greater odds of having lower IDWG than those with standard dialysate Na concentration. This significant association remained after adjustment for age, sex, and changes in EDW (OR: 3.63; 95% CI, 1.03-12.9). There was no difference in predialysis BP or symptomatic hypotensive episodes between the two groups. DISCUSSION: Individualized DNa prescriptions appeared to be well tolerated and may be effective for optimal fluid management in high-risk hemodialysis patients.

Direct Peritoneal Resuscitation Reduces Lung Injury and Caspase 8 Activity in Brain Death.

Background: Acute brain death (ABD) is associated with inflammation and lung injury. Direct peritoneal resuscitation (DPR) improves blood flow to the vital organs after ABD. DPR reduces lung injury, but the mechanism for this is unknown. Methods: Male Sprague-Dawley rats were randomized to five groups (n = 8/group): (1) Sham (no ABD); (2) Targeted intravenous fluid (TIVF) (ABD plus enough IVF to maintain a MAP of 80 mmHg) at 2 hours post-resuscitation (RES); (3) ABD + TIVF + DPR (TIVF and 30 cc intraperitoneal 2.5% Delflex) at 2 hours post-RES; (4) ABD + TIVF at 4 hours post-RES; and (5) ABD + TIVF + DPR at 4 hours post-RES. Messenger RNA (mRNA) levels were measured using Qiagen qRT PCR. Protein levels were assessed using quantitative ELISAs and the Luminex MagPix system. Results: Use of DPR caused 5.8-fold downregulation of mRNA expression for TNF-α and 2.7-fold decrease for the TNF receptor compared to TIVF alone. Caspase 8 mRNA was also downregulated. Protein levels for TNF-α, TNF receptor, caspase 8, NFκB, and NFκB inhibitor kinase, which promotes dissociation of NFκB inhibitor, were reduced by DPR. Cell death markers M30 and M65 were also decreased with DPR. Conclusions: Use of DPR caused changes in the expression of multiple mRNAs and proteins in the caspase 8 apoptotic pathway. These data represent a mechanism through which DPR exerts its beneficial effects within the lung tissue.

[Risk analysis and validation of the process for producing the substitution fluid for online hemodiafiltration]. / Analyse des risques et validation du procédé de production du liquide de substitution de la technique d'hémodiafiltration en ligne.

INTRODUCTION: Online hemodiafiltration is a technique of dialysis with many advantages, but its use is limited because of the lack of control of microbiological risks. This work conducts a risk analysis of the process for producing substitution liquid for online hemodiafiltration and validates this process from a microbiological point of view. MATERIAL AND METHOD: The risk analysis was carried out following the approach of analysing failure modes, their effects and their criticalities. It identified the "worst case" of the production process being studied. For the validation of this process, we used the limulus amoebocytes lysate assay for bacterial endotoxins and the membrane filtration test for sterility control. RESULTS: We identified 17 failure modes, 13 of which were acceptable. Failure modes that exceeded the acceptability threshold were defined as "worst cases". Sterility monitoring and endotoxin testing, conducted in the "worst case", verified the microbiological quality of the liquid produced to the required standards and subsequently validated the process used. DISCUSSION: This approach has resulted in the identification of as many failure modes as possible. Validating in "worst case" is an extreme challenge to the process and its success provides a sufficient basis to conclude that the technique is safe and, therefore, to validate the process. CONCLUSION: This work has enabled us to validate our production process in extreme cases to promote safer use of the technique.

Parthenolide, an NF-κB inhibitor, alleviates peritoneal fibrosis by suppressing the TGF-ß/Smad pathway.

Transforming growth factor (TGF)-ß/Smad signalling plays a central role in the pathogenesis of peritoneal fibrosis related to peritoneal dialysis (PD). Parthenolide (PTL), a naturally occurring phytochemical, is isolated from the shoots of feverfew (Tanacetum parthenium) and displays analgesia, anti-inflammation and anticancer activities. In this study, we examined the therapeutic potential of PTL on PD-related peritoneal fibrosis induced by daily intraperitoneal injection of 4.25% dextrose-containing PD fluid (PDF) in vivo and TGF-ß1-induced epithelial-mesenchymal transition (EMT) in vitro. PTL was administered daily before PDF injection or after 14 days of PDF injection. Both PTL treatments showed a protective effect on peritoneal fibrosis and prevented peritoneal dysfunction. Similarly, PTL suppressed the expression of fibrotic markers (fibronectin and collagen I) and restored the expression of the epithelial marker (E-cadherin) in TGF-ß1-treated HMrSV5 cells. Furthermore, PTL inhibited TGF-ß1-induced Smad2 and Smad3 phosphorylation and nuclear translocation but did not influence Smad1/5/9 phosphorylation or activate other downstream signalling pathways of TGF-ß1, including AKT, extracellular signal-regulated kinase (ERK) or p38. In conclusion, PTL treatment may represent an effective and novel therapy for PD-associated peritoneal fibrosis by suppressing the TGF-ß/Smad pathway.

Flexitrate regional citrate anticoagulation in continuous venovenous hemodiafiltration: a retrospective analysis.

BACKGROUND: Flexitrate, an innovative regional citrate anticoagulation (RCA) protocol, was compared to traditional RCA (tRCA) and Heparin anticoagulation protocols in intensive care patients treated with continuous renal replacement therapy (CRRT). METHODS: A single-center, retrospective, cohort study, was done in a 26-bed intensive care unit in a large community hospital. Eighty dialysis sessions (Flexitrate = 2852 h, tRCA = 3580 h and Heparin = 2026 h), performed in 53 patients, were evaluated for filter life, RCA control, and metabolic control. RESULTS: In the Flexitrate cohort, 3.8% of filters clotted, compared to 16.9% with tRCA and 28.3% with Heparin (p < 0.001 for Flexitrate compared to either tRCA or Heparin). Filter survival was significantly improved with Flexitrate compared to tRCA (HR 0.24, p = 0.018) or Heparin (HR 0.14, p = 0.004). Anticoagulation control was superior with Flexitrate with Patient Ionized Calcium out of target a median of 16% of the time, compared to 27% for tRCA (p < 0.001). Filter Ionized Calcium was out of target a median of 6.8% of the time, compared to 23% for tRCA (p = 0.03). Flexitrate produced significantly less alkalosis, hypernatremia, and hypocalcemia than tRCA, and overall metabolic control was comparable to Heparin anticoagulation. The only adverse metabolic outcome with Flexitrate was increased hypomagnesemia. CONCLUSIONS: The Flexitrate protocol extended filter life, delivered more consistent anticoagulation, and provided superior metabolic control compared to a tRCA protocol. Filter life was superior to Heparin anticoagulation, with similar metabolic control. A randomized control trial comparing these protocols is recommended.

Modified regional citrate anticoagulation is optimal for hemodialysis in patients at high risk of bleeding: a prospective randomized study of three anticoagulation strategies.

BACKGROUND: Recommended regular saline flushing presents clinical ineffectiveness for hemodialysis (HD) patients at high risk of bleeding with heparin contraindication. Regional citrate anticoagulation (RCA) has previously been used with a Ca2+ containing dialysate with prefiltered citrate in one arm (RCA-one). However, anticoagulation is not always achievable and up to 40% results in serious clotting in the venous expansion chamber. In this study, we have transferred one-quarter of the TSC from the prefiltered to the post filter based on RCA-one, which we have called RCA-two. The objective of this study was to compare the efficacy and safety of RCA-two with either saline flushing or RCA-one in HD patients with a high bleeding risk. METHOD: In this investigator-initiated, multicenter, controlled, prospective, randomized clinical trial, 52 HD patients (77 sessions) were randomized to the RCA-2 and RCA-one group in part one of the trial, and 45 patients (64 sessions) were randomized to the RCA-2 and saline group in part two of the trial. Serious clotting events, adverse events and blood analyses were recorded. RESULTS: Serious clotting events in the RCA-two group were significantly lower compared with the RCA-one and saline group (7.89% vs. 30.77%, P = 0.011; 3.03% vs. 54.84%, P < 0.001, respectively). The median circuit survival time was 240 min (IQR 240 to 240) in the RCA-two group, was significantly longer than 230 min (IQR 155 to 240, P < 0.001) in the RCA-one group and 210 min (IQR 135 to 240, P = 0.003) in the saline group. The majority of the AEs were hypotension, hypoglycemia and chest tightness, most of which were mild in intensity. Eight patients (20.51%) in the RCA-one group, 4 patients (12.90%) in the saline group and 10 patients (26.31%) in the RCA-two group, P > 0.05. CONCLUSIONS: Our data demonstrated that the modified anticoagulation protocol was more effective and feasible during hemodialysis therapy for patients at high risk of bleeding. TRIAL REGISTRATION: GDREC, GDREC2017250H. Registered February 2, 2018; retrospectively registered.

Factors Affecting Intermittent Infusion Hemodiafiltration.

BACKGROUND: Intermittent infusion hemodiafiltration -(I-HDF) has been performed for a number of years since this mode of dialysis became available with dialyzers used in Japan. It has been effective in some cases and ineffective in others. In this study, we analyzed and clarified these differences. SUMMARY: We conducted a retrospective study to determine the factors affecting the effectiveness of I-HDF treatment in some patients and ineffectiveness in others and classified the complex causes associated with volume load that were identified. Key Messages: Bolus dialysate infusion in I-HDF affects the volume load (preload), and repeated bolus dialysate infusion influences both preload and afterload in patients with valvular heart disease. In this study, I-HDF was effective when brain natriuretic peptide levels, cardiothoracic ratio, and ultrafiltration rate were well controlled and cardiac load was low. I-HDF was shown to be effective in patients who are prone to developing hypotension at the end of a dialysis session. There were several factors, including different types of load, involved in inefficiency of I-HDF.

Relationship between Dose of Bolus Dialysate Infusion and Blood Pressure in Intermittent Infusion Hemodiafiltration.

BACKGROUND: Intermittent infusion hemodiafiltration is a recently developed convective method of renal replacement therapy using cyclic back-filtration infusion. Quick and regular infusion prevents intradialytic hypotension. However, the optimal dose of bolus dialysate infusion required to stabilize blood pressure has not been reported. Here, we investigated the relationship between the dose of bolus dialysate infusion and blood pressure. SUMMARY: A total of 77 patients on maintenance hemodialysis were enrolled in this study. Dialysate was infused rapidly by backward filtration at a rate of 150 mL/min at 30-min intervals using an automated dialysis machine. The effects with two bolus infusion volumes (100 and 200 mL) were compared, each for an observation period of 2 weeks. Systolic blood pressure (SBP) was measured at the start and at the end of each dialysis session, and the highest SBP and lowest SBP measurements were also recorded. Patients were divided according to dry weight into a <52 kg group and a ≥52 kg group, and various parameters were compared between the 100 and 200 mL bolus infusion volumes in each group. Among patients in the <52 kg group, SBP did not vary at any of the time points. However, for patients in the ≥52 kg group, SBP at the end of treatment was significantly lower in the 100-mL group than in the 200-mL group (141 ± 20 vs. 144 ± 21 mm Hg, p = 0.041), and the minimum SBP was also lower in the 100-mL group than in the 200-mL group (127 ± 17 vs. 131 ± 18 mm Hg, p = 0.010). Key Messages: Among patients with a dry weight of ≥52 kg, blood pressure was more stable when a bolus fluid volume of 200 mL was used, compared with a volume of 100 mL. However, for patients with a dry weight of <52 kg, the significance of the difference in bolus fluid volumes disappeared. Thus, the replacement fluid volume might be better determined based on the patient's dry weight. TRIAL REGISTRATION: UMIN 000028145, Registered July 10, 2017.