Blood Purification Modalities Research Articles

Pleiotropic effects of double filtration plasmapheresis.

Double filtration plasmapheresis (DFPP) is a semi-selective blood purification modality derived from the plasma exchange modality. DFPP can be applied to a variety of refractory disorders including metabolic disorders, organ transplants, rheumatic disorders, neurological disorders, and dermatologic disorders. Familial hypercholesterolemia and lipoprotein (a) hyperlipoproteinemia are major chronic metabolic disorders. Lipoprotein apheresis (LA) is applied for those patients to remove low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) (Lp(a)). DFPP is used as one of the modalities in LA. In addition to removing LDL-C and Lp(a), DFPP has pleiotropic effects such as removal of lipid metabolism-related substances, C-reactive protein lowering effect, removal of adhesion molecules, removal of inflammatory cytokines, and anti-oxidative effect. This article summarizes the pleiotropic effects of DFPP based on recent clinical articles.

Preclinical and first-in-human safety studies on a novel magnetism-based haemofiltration method

Extracorporeal haemofiltration devices that selectively remove cytokines could represent an adjunctive treatment in inflammatory diseases. One such device is the “IL-6-Sieve”, wherein magnetic Anti-IL-6 Beads are introduced into an extracorporeal circuit via a Bead Adapter and then removed along with any surface-bound interleukin (IL)-6 by a Filter deployed in a Magnet, before the blood is returned to the patient. We report here on a series of animal studies, and a first-in-human study, on the safety of the IL-6-Sieve. Evaluations focused on the: (a) safety of Filter and Magnet placed in an extracorporeal circuit in sheep; (b) safety of Anti-IL-6 Beads—directly infused intravenously as worst case scenario of misuse; or injected into an extracorporeal circuit using the Bead Adapter, Filter, and Magnet as intended—in sheep; (c) biodistribution of Anti-IL-6 Beads intravenously infused in mice; and (d) safety of Filter and Magnet placed in an extracorporeal circuit in healthy volunteers. No serious adverse events or significant changes in vital signs or routine laboratory parameters occurred in any of the animals or humans. Although safety of the IL-6-Sieve requires further study, these initial evaluations represent a promising start for the translation of this new blood purification modality into clinical use.

Continuous renal replacement therapy and therapeutic plasma exchange in pediatric liver failure.

Patients with acute liver failure (ALF) and acute on chronic liver failure (ACLF) have significant morbidity and mortality. They require extracorporeal blood purification modalities like continuous renal replacement therapy (CRRT) and therapeutic plasma exchange (TPE) as a bridge to recovery or liver transplantation. Limited data are available on the outcomes of patients treated with these therapies. This is a retrospective single-center study of 23 patients from 2015 to 2022 with ALF/ACLF who underwent CRRT and TPE. We aimed to describe the clinical characteristics and outcomes of these patients.Median (IQR) age was 0.93 years (0.57, 9.88), range 16 days to 20 years. Ten (43%) had ALF and 13 (57%) ACLF. Most (n = 19, 82%) started CRRT for hyperammonemia and/or hepatic encephalopathy and all received TPE for refractory coagulopathy. CRRT was started at a median of 2 days from ICU admission, and TPE started on the same day in most. The liver transplant was done in 17 (74%), and 2 recovered native liver function. Four patients, all with ACLF, died prior to ICU discharge without a liver transplant. The median peak ammonia pre-CRRT was 131 µmol/L for the whole cohort. The mean (SD) drop in ammonia after 48h of CRRT was 95.45 (43.72) µmol/L in those who survived and 69.50 (21.70) µmol/L in those who did not (p 0.26). Those who survived had 0 median co-morbidities compared to 2.5 in non-survivors (aOR (95% CI) for mortality risk of 2.5 (1.1-5.7), p 0.028). Conclusion: In this cohort of 23 pediatric patients with ALF or ACLF who received CRRT and TPE, 83% survived with a liver transplant or recovered with their native liver. Survival was worse in those who had ACLF and those with co-morbid conditions. What is Known: • Pediatric acute liver failure is associated with high mortality. • Patients may require extracorporeal liver assist therapies (like CRRT, TPE, MARS, SPAD) to bridge them over to a transplant or recovery of native liver function. What is New: • Standard volume plasma exhange has not been evaluated against high volume plasma exchange for ALF. • The role, dose, and duration of therapeutic plasma exchange in patients with acute on chronic liver failure is not well described.

Sustained high-efficiency daily diafiltration using a mediator-adsorbing membrane in Burkitt lymphoma with a very high risk of tumor lysis syndrome: a case series with literature review

BackgroundTumor lysis syndrome is an oncological emergency triggered by the rapid release of intracellular materials from lysed malignant cells. Intensive chemotherapy is challenging for patients with severe renal dysfunction and a high risk of tumor lysis syndrome. Sustained high-efficiency daily diafiltration using a mediator-adsorbing membrane (SHEDD-fA) could work not only as a renal replacement therapy, but also as a novel method to control intracellular materials, including cytokines and damage-associated molecular patterns. We aimed to describe two cases of patients with Burkitt’s lymphoma with a very high risk of tumor lysis syndrome who were successfully treated with a combination of chemotherapy and SHEDD-fA.Case presentationThe first case was of a 67-year-old man who was admitted to the intensive care unit for respiratory failure and diagnosed with Burkitt’s lymphoma. Extremely high lactate dehydrogenase levels and anuria, indicating severe acute kidney injury, are considered to be associated with a very high risk of tumor lysis syndrome. SHEDD-fA was initiated prophylactically to prevent exacerbation of tumor lysis syndrome. To ensure the blood concentration of antitumor drugs, SHEDD-fA was stopped temporarily and restarted 6 h after the completion of chemotherapy. No tumor lysis syndrome-related complications were observed. The second case involved a 68-year-old man who was admitted to the intensive care unit due to exacerbation of Burkitt’s lymphoma complicated by severe pneumonia and disseminated intravascular coagulation. The patient exhibited metabolic acidosis, hyperkalemia, hyperuricemia, and anuria. SHEDD-fA was performed immediately. As in the first case, we temporarily discontinued SHEDD-fA before chemotherapy and restarted it 6 h after the completion of chemotherapy. No tumor lysis syndrome-associated complications were observed and renal function recovered. Interleukin-6, interleukin-8, and high-mobility group box-1 protein levels in the blood were lower on the outlet side than on the inlet side.ConclusionsSHEDD-fA allows safe and effective administration of chemotherapy in patients with severe renal dysfunction and a very high risk of tumor lysis syndrome. Our findings indicate that blood purification modality may need to be selected according to tumor lysis syndrome severity.

Double Filtration Plasmapheresis for Desensitization during Haploidentical Stem Cell Transplantation in Patients with Positive Donor-Specific Anti-HLA Antibodies

Background:Donor-specific anti-HLA antibodies (DSA) are a major cause of engraftment failure in patients receiving haploidentical stem cell transplantation (HaploSCT). Effective treatments are needed for these patients, who often have no other donor options and/or are in need to proceed urgently to transplantation. Plasma exchange (PE) is an effective treatment widely used for DSA desensitization. However, a large volume of plasma is required. Double filtration plasmapheresis (DFPP) is a semi-selective blood purification modality derived from the PE modality. DFPP avoids the unnecessary loss of plasma proteins, reduces the need for plasma and increases the efficiency of purification. To define the efficacy of DFPP for DSA-positive patients in HaploSCT, we conducted a nested case-control study. Methods: Patients who underwent HaploSCT in the Bone Marrow Transplantation Center of the First Affiliated Hospital of Zhejiang University School of Medicine from March 2017 to November 2021 were enrolled in the study cohort. Thirty-two patients with positive DSA (MFI≥2000) were treated with desensitization protocol including DFPP. Ninety-six patients (1:3) with negative DSA were randomly matched according to gender, age and transplantation time as the control group. DSA positive patients were given alternate-day DFPP twice before starting one week before the beginning of transplant conditioning. DSA was retested after DFPP treatment. A single dose of rituximab (375 mg/m2) was administrated after completion of DFPP. Results: A total of 32 HaploSCT patients with DSAs were included in the study. The majority of patients in the DSA group were female (75%) and a mean age of 41 (13-63) years . 96 DSA negative patients were selected as controls. The two groups had equivalent subject and donor characteristics, including age, gender, underlying diseases, conditioning regimens and GVHD prophylaxis.20 (62.5%) patients presented anti-HLA class I DSAs (4 of them with > 10000 MFI), 9 (28.1%) presented anti-HLA class II DSA (2 with > 10000 MFI) and 3 (9.3%) presented both anti-HLA class I and II DSA (1 with > 10000 MFI). After DFPP treatment, levels of DSA decreased significantly. The mean MFI values before and after treatment were 7189.56 ±4294.01 vs. 2869.57±3454.55 (P < 0.001), respectively. All patients in DSA group achieved hematopoietic reconstitution within 28 day of transplantation. The mean neutrophils and platelets engraftment time was 13.44±2.42 days and 14.03±3.78 days respectively, which were comparable to control group. In the DSA and control groups, the incidence of grade III-IV aGVHD was 9.37% vs. 10.41% (P < 0.05), the 2-year cumulative recurrence rate was 26.35% vs. 15.62% (P < 0.05) and the overall survival (OS) was 77.20% vs. 81.20% (P < 0.05), respectively. Conclusion: DFPP can significantly reduce the level of DSA in patients before transplantation. Treatment with DFPP and rituximab is effective in promoting engraftment for DSA-positive patients in HaploSCT.

Randomized Control Study on Hemoperfusion Combined with Hemodialysis versus Standard Hemodialysis: Effects on Middle-Molecular-Weight Toxins and Uremic Pruritus

Introduction: Classic hemodialysis schedules present inadequate middle-molecular-weight toxin clearance due to limitations of membrane-based separation processes. Accumulation of uremic retention solutes may result in specific symptoms (e.g., pruritus) and may affect clinical outcome and patient’s quality of life. Hemoperfusion (HP) is a blood purification modality based on adsorption that can overcome such limitations, and thus, it may be interesting to test the efficacy of at least one session per week of HP combined with hemodialysis. This is a randomized, open-label trial, controlled, multicenter clinical study to investigate the effect of long-term HP combined with hemodialysis on middle-molecular-weight toxins and uremic pruritus in maintenance hemodialysis (MHD) patients. Methods: 438 MHD patients from 37 HD centers in China with end-stage kidney disease (63.9% males, mean age 51 years) suffering from chronic intractable pruritus were enrolled in the study. Eligible patients were randomized into four groups: low-flux hemodialysis (LFHD), high-flux hemodialysis (HFHD), HP + LFHD, and HP + HFHD at a 1:1:1:1 ratio. Beta-2 microglobulin (β2M) and parathyroid hormone (PTH) were measured at baseline, 3–6, and 12 months. At the same time points, the pruritus score was evaluated. The primary outcome was the reduction of β2M and PTH, while the secondary outcome was the reduction of the pruritus score. Results: In the two groups HP + LFHD and HP + HFHD, there was a significant decrease of β2M and PTH levels after 12 months compared to the control groups. No significant differences were noted between HP + LFHD and HP + HFHD. Pruritus score reduction was 63% in the HP + LFHD group and 51% in the HP + HFHD group, respectively. Conclusion: The long-term HP + HD can reduce β2M and PTH levels and improve pruritus in MHD patients independently on the use of high- or low-flux dialyzers, showing that the results are linked to the effect of adsorption.

Actual rates of electricity consumption in blood purification modalities

Actual rates of electricity consumption in blood purification modalities

On-line hemodiafiltration therapy for end-stage kidney disease patients: Promises for the future? What's next?

On-line hemodiafiltration (OL-HDF) is currently the most advanced form of blood purification modality leading convective-based therapies in end-stage kidney disease patients. By adding a high convective component to the diffusive clearance achieved with highly permeable dialyzers, OL-HDF reinforces removal of small MWt compounds and enlarges the spectrum of uremic compounds cleared up to middle and large MWt compounds. The biological and clinical benefits of convective-based therapy are currently also being explored in a revisited hybrid modality, combining an increased internal filtration process with a more open membrane. Regular use of ultrapure dialysis fluid required by convective-based therapies improves the bio-incompatibility of the extracorporeal circuit so reducing inflammatory responses. On-line production of substitution fluid, relying on a cold sterilization by ultrafiltration, has several advantages: First, it is a safe and established process; and second, it provides an unlimited amount of substitution fluid at the same cost as regular ultrapure dialysis fluid. As such, OL-HDF is adaptable to all substitution modalities (post, pre, or mixed-HDF), thus allowing the dialytic convective dose to be adjusted to the individual patient needs. The development of OL-HDF opens new pathways such as task automation simplifying care workflow. All these features make OL-HDF the most versatile dialysis modality that can be now integrated in various treatment schedules according to session time and frequency (daily, nocturnal, or alternate day) or location (incenter, satellite, or potentially home-based therapy).

A problem of multi-drug resistant infectious in pediatric lymphoma treatment

The basis of modern high-effective therapeutic programs for pediatric lymphomas is an intensive, risk-adopted therapy, which complicated with myelosuppression. In myelotoxic agranulocytosis condition infectious complications are often and its treatment results depend on duration and level of agranulocytosis, and sensitivity of microorganism to antimicrobial agents. Multi-drug resistant strains of Pseudomonas aeruginosa, Acinetobacter baumannii and etc. are a serious problem in supportive care of postchemotherapy complications, when even multidisciplinary approach with pediatric oncologists/hematologists, microbiologists, clinical pharmacists, surgeons, specialists in extracorporeal blood purification modalities and intensive care are ineffective.

Double filtration plasmapheresis: Review of current clinical applications.

Double filtration plasmapheresis (DFPP) is a semi-selective blood purification modality derived from the plasma exchange (PE) modality. In the DFPP treatment, two types of filters with different pore sizes are used: a plasma separator and a plasma component separator. Blood is separated into plasma and blood cells using a plasma separator. The separated plasma is fractionated into large and small molecular weight components by a plasma component separator. Large molecular weight components, including pathogenic substances, are discarded. Small molecular weight components, including valuable substances such as albumin, are returned to the patient. The advantage of DFPP is that the volume of replacement fluid can be significantly reduced compared to PE. By selecting the optimal pore size model for the plasma component separator, DFPP can be applied to various disorders. The clinical applications of DFPP are reviewed based on recent articles on metabolic disorders, organ transplants, rheumatic disorders, neurological disorders, and dermatologic disorders.

Continuous Veno-Venous Hemodialysis Using the Cardio-Renal Pediatric Dialysis Emergency MachineTM: First Clinical Experiences

We report the first worldwide experience with continuous veno-venous hemodialysis (CVVHD) in children using the last generation Cardio-Renal Pediatric Dialysis Emergency Machine (CARPEDIEM)^TM device. Thirteen children received 1,008 h of CVVHD during 95 sessions, using a 0.15 (n = 7) or a 0.25 m² (n = 6) hemofilter. The median weight was 3 kg (interquartile range [IQR] 2.5–6.2). In 10 patients, CVVHD was conducted using a 5 Fr double-lumen central vascular access, whereas in 3 children, bigger sizes were used (6.5 and 8 Ch). The median prescribed Qb was 17 mL/min (IQR 10–29.5), with a median Qd of 10 mL/min. Circuits were primed with 5% albumin in 12 out of 13 patients, using anticoagulation with heparin in all 13 cases. The median delivered/prescribed time ratio yielded a 100% result (95–100%). The most common cause for “downtime” was clotting that however occurred in only 3% of all treatments. Survivals at continuous renal replacement therapy discontinuation and ICU discharge were 100 and 69% respectively. The CARPEDIEM^TM machine allowed successful delivery of diffusive blood purification modality to very small patients, using small catheters, no blood primes, and excellent concordance between delivered and prescribed treatment duration.

Kidney and bone update : the 5-year history and future of CKD-MBD. Progress of phosphate binders

Hyperphosphatemia is a serious complication which has been linked with an increased risk of cardiovascular mortality in patients with chronic kidney disease. Especially in end stage renal disease (ESRD) patients, the nutritional disturbance due to strict phosphate restriction with protein restriction is certainly associated with patients' survival. Firstly, the aggressive phosphorus removal by blood purification modality is also important for the good control in serum phosphate level. Secondary, the active phosphate binder therapy is actual effective treatment for ESRD patients with hyperphosphatemia. Until recently, none of the available agents fulfilled the criteria of an ideal phosphate binders. However, several phosphate binder such as calcium carbonate, sevelamer hydrochloride, lanthanum carbonate and so on, are available in Japan. This review work is describing about the history and clinical manifestation of these phosphate binders.

Depurative capacity of molecular adsorbent recycling system (MARS): A focus on bilirubin removal

The molecular adsorbent recycling system (MARS) is now widely used in the treatment of patients with hepatic failure (HF). A great deal of interest has been directed toward its effect on clinical outcome, whereas its depurative capacity also needs attention. Bilirubin, a tightly albumin-bound toxin accumulating in patients with HF, is regarded as a surrogate to evaluate the depurative capacity of albumin-bound toxins by blood purification modalities. The removal of bilirubin by MARS is difficult to predict, because both the clearance of bilirubin and the reduction ratio of bilirubin after a single session differ between patients and sessions. A reduction of depurative capacity over the course of a treatment is observed. Furthermore, the later sessions are likely less efficient than previous ones. It cannot be taken for granted that the reduction of depurative capacity is due to the saturation and reduced efficiency of the adsorbent columns used in MARS. The answer lies in the property of bilirubin/albumin binding. The removal of bilirubin by MARS is a diffusion process, dependent on the free bilirubin concentration. Bilirubin binds to albumin in 3 ways with different affinity. High-affinity binding bilirubin is difficult to dissociate from albumin and is accompanied by a smaller free fraction, which means it is also difficult for MARS to remove. The factors affecting the free fraction of bilirubin will impact on bilirubin removal by MARS. Among them, the molar ratio of bilirubin to albumin is the most important one. Other factors include the interaction of other agents with bilirubin/albumin binding, the albumin concentration, plasma ion strength, and pH.

On‐line Hemodiafiltration Does Not Induce Inflammatory Response in End‐stage Renal Disease Patients: Results From a Multicenter Cross‐over Study

On-line hemodiafiltration (HDF) represents the supreme blood purification modality for end-stage renal disease (ESRD) patients. Large-volume infusion of on-line prepared substitution fluid may, however, expose patients to inflammatory contaminants. As a result, on-line HDF might aggravate chronic inflammation, which correlates with malnutrition, cardiovascular disease, and mortality among ESRD patients. In a multicenter cross-over study, 27 ESRD patients were randomly assigned to treatment with on-line HDF and low-flux hemodialysis (HD). After 6 months, patients were crossed to the other treatment modality, and treatment continued for another 6 months. Both on-line HDF and low-flux HD were conducted with polysulfone membranes and ultrapure dialysis fluid. Samples were drawn at the end of each treatment period. Inflammatory parameters were elevated in the study population when compared to healthy controls. Induction of interleukin-1 receptor antagonist (IL-1Ra) and tumor necrosis factor alpha (TNF-alpha) was comparable for on-line HDF and low-flux HD, and there was no intradialytic increase in cytokine production. As a result, interleukin-6 (IL-6) plasma levels did not differ significantly between the two treatment modalities. Similarly, no difference between on-line HDF and low-flux HD was observed for C-reactive protein (CRP) and albumin. Markers of endothelial cell activation (soluble intercellular and vascular cell adhesion molecules sICAM-1 and sVCAM-1) as well as the cardiovascular risk marker cardiac troponin T (cTnT) remained elevated compared to healthy subjects, but showed no difference between the two treatment modalities. On-line HDF, as the most effective renal replacement therapy, does not provoke inflammatory response and is both safe and highly biocompatible.

Treatment of multiple organ failure through sepsis by surgery and blood purification.

For the treatment of multiple organ failure (MOF) through sepsis, we have commonly applied various blood purification modalities during the perioperative period. From January 1996 to December 2000, 33 patients with MOF through sepsis were admitted and operated on in the First Department of Surgery, Akita University School of Medicine, and 21 of these 33 patients were treated using various blood purification modalities during the perioperative period: endotoxin-adsorbing therapy using polymyxin B (PMX) in 17 patients, continuous hemofiltration (CHF)/continuous hemodiafiltration (CHDF) in 15 patients, and plasma exchange (PE) and CHDF in 3 patients. Of the outcome of these 33 patients with MOF through sepsis, 17 survived and 16 died (48% mortality). Of the 21 patients with MOF through sepsis treated by surgery and blood purification, 12 survived and 9 died (43% mortality). We evaluated APACHE II and the number of failed organs before operation. Amongst the group with 12 survivors and 9 deaths, Acute Physiology and Chronic Health Evaluation II (APACHE II) was 15 +/- 5, 23 +/- 2 and the number of failed organs was 2.7 +/- 0.7, 3.9 +/- 0.8, respectively. An increased APACHE II score and number of failed organs were significantly associated with mortality. As to the treatment of MOF through sepsis due to acute peritonitis, patients with APACHE II scores ranging from 15 to 20, and those with 2-3 failed organs seem to be the candidates for the application of blood purification during the perioperative period.

Monocyte Apoptosis in Uremia Is Normalized with Continuous Blood Purification Modalities

Uremia is associated with a state of immune dysfunction. Dysregulation of homeostasis may be directly related to abnormal apoptosis regulation in uremia, which is crucial for the maintenance of the biological system. We demonstrated that plasma from three groups of uremic subjects, i.e. hemodialysis (HD) patients, peritoneal dialysis (PD) patients and patients with predialysis chronic renal failure (CRF), has different apoptotic potential on U937 monocytes. The plasma of HD and CRF subjects when incubated with U937 cells induced higher levels of apoptosis compared with that of PD and control subjects (HD 26.08 ± 11.39, CRF 24.87 ± 9.07, PD 12.13 ± 4.51, controls 11.69 ± 4.02). Furthermore, the phagocytic ability of U937 cells incubated with the various plasma demonstrated an impaired response in the HD and CRF subjects (HD 27.56 ± 6.67, CRF 30.24 ± 9.08, PD 36.55 ± 9.80, controls 40.04 ± 6.98). These results suggest that continuous blood purification, such as in PD, may have advantages over intermittent therapies in removing uremic apoptotic molecules and potentially maintaining biological function and homeostasis.

Elimination study of silver in a hemodialyzed burn patient treated with silver sulfadiazine cream

Silver sulfadiazine (SSD) cream is a potent agent for the treatment of bums. In a patient with end-stage renal disease, we observed a marked elevation in serum silver concentration in the course of 2 weeks of SSD cream therapy (200 g/d). Serum concentration of silver reached a maximum of 291 ng/mL in association with a rapid deterioration of mental status. SSD therapy was discontinued, and hemodialysis, hemofiltration , or plasma exchange was continually performed. Four months later, the patient died. At autopsy, profoundly elevated levels of silver were found in brain tissues of this patient (617.3, 823.7 ng/g wet tissue weight in the cerebrum and cerebellum, respectively). To determine the most efficient therapy to remove silver from serum, we compared hemodialysis (HD), hemofiltration (HF), and plasma exchange (PE). Both plasma exchange and hemofiltration were effective in decreasing serum silver, and their effects were additive. By contrast, HD was ineffective in reducing serum silver. This case illustrates that, on SSD cream therapy, burn patients with disturbed renal function are at risk of accumulating silver in serum and tissue to the level that may cause neuralgic decompensation. Removal of serum silver can best be effected by PE, particularly when combined with HF. In contrast, HD per se does not appear efficacious. None of these blood purification modalities improves deterioration of neurological status potentially attributable to silver deposition in brain tissues.

A Mathematical Model for Flow, Pressure, and Ultrafiltration Rate in Extracorporeal Filtration of Blood

A mathematical model of extracorporeal hydraulics (pressures and flows) has been developed for common extracorporeal blood purification modalities. The model includes a description of the blood pathway which accounts for Hagan-Poi-seuille flow and for pathway contractions and expansions. The hemofïlter description accounts for membrane-limited and boundary layer limited ultrafiltration. In vitro experiments using human blood in ultrafiltration circuits have been conducted to test the validity of this model. Pressures and flows of blood and ultrafiltrate were measured as a function of ultrafiltrate pressure. Computer simulations developed from the model were run based on the experimental starting conditions. The results of these simulations were compared with those obtained by experiment. The agreement among results was good. This model can be used to evaluate the effect of design parameter changes on circuit pressures and flows for systems such as hemodialysis, hemofiltration, or continuous arteriovenous hemofiltration.