-
Peritoneal Dialysis International :... Jan 2024Despite several advantages compared to haemodialysis (HD), peritoneal dialysis (PD) remains an underused dialysis technique due to its high technique failure rate...
BACKGROUND
Despite several advantages compared to haemodialysis (HD), peritoneal dialysis (PD) remains an underused dialysis technique due to its high technique failure rate related to membrane fibrosis and peritonitis events. Previous work has suggested a harmful role for the complement system in these processes, highlighting the need for a more comprehensive examination in PD.
METHODS
Plasma levels of C1q, mannose-binding lectin (MBL), Properdin, Factor D, C3d/C3-ratio and soluble membrane attack complex (sC5b-9) were determined in PD patients ( = 55), HD patients ( = 41), non-dialysis chronic kidney disease (CKD) patients ( = 15) and healthy controls ( = 14). Additionally, C1q, MBL, Properdin, Factor D and sC5b-9 levels were assessed in the peritoneal dialysis fluid (PDF). In a subgroup, interleukin-6, matrix metalloproteinase-2 (MMP-2), myeloperoxidase (MPO) and elastase were measured in the PDF.
RESULTS
PD patients had significantly higher systemic levels of sC5b-9 compared to healthy controls, CKD and HD patients ( < 0.001). Plasma levels of C1q and C3d/C3-ratios were significantly associated with systemic sC5b-9 levels ( < 0.001). Locally, sC5b-9 was detected in the PDF of all PD patients, and levels were approximately 33% of those in matched plasma, but they did not correlate. In the PDF, only Properdin levels remained significantly associated with PDF sC5b-9 levels in multivariate analysis ( < 0.001). Additionally, PDF levels of sC5b-9 positively correlated with elastase, MPO and MMP-2 levels in the PDF ( < 0.01).
CONCLUSIONS
Our data reveal both systemic and local complement activation in PD patients. Furthermore, these two processes seem independent considering the involvement of different pathways and the lack of correlation.
Topics: Humans; Peritoneal Dialysis; Matrix Metalloproteinase 2; Properdin; Complement Factor D; Complement C1q; Complement Activation; Dialysis Solutions; Renal Insufficiency, Chronic; Pancreatic Elastase
PubMed: 37794761
DOI: 10.1177/08968608231198984 -
Cureus Aug 2023Sepsis is a life-threatening organ failure caused by a dysregulated response to infection. Fluid resuscitation and vasopressors are used to maintain systolic blood... (Review)
Review
Sepsis is a life-threatening organ failure caused by a dysregulated response to infection. Fluid resuscitation and vasopressors are used to maintain systolic blood pressure and organ perfusion. Fluid resuscitation can be done with liberal or restricted fluids as well as colloids or crystalloid fluids. This review analyses the evidence for the use of liberal or restrictive fluids and colloids or crystalloids for the management of sepsis. A methodical search was conducted across PubMed, Cochrane Library, and ScienceDirect, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines were followed for this study. Randomized controlled trials and retrospective observational studies were included in this study. Liberal and restrictive fluid strategies were found to be comparable in efficacy, but restrictive fluid regimens had the added benefit of a lower incidence of fluid overload. Balanced crystalloids were safer and more effective when compared to normal saline. Albumin replacement was found to be safe and showed efficacy in reducing mortality in patients with sepsis and septic shock.
PubMed: 37779759
DOI: 10.7759/cureus.44317 -
International Journal of Molecular... Sep 2023Zr-based metal-organic framework materials (Zr-MOFs) with increased specific surface area and pore volume were obtained using chemical (two materials, and ) and...
Zr-based metal-organic framework materials (Zr-MOFs) with increased specific surface area and pore volume were obtained using chemical (two materials, and ) and solvothermal () synthesis methods and investigated via FT-IR spectroscopy, TGA, SANS, PXRD, and SEM methods. The difference between and lies in the addition of reactants during synthesis. Nitrogen porosimetry data indicated the presence of pores with average dimensions of ~4 nm; using SANS, the average size of the nanocrystals was suggested to be approximately 30 nm. The patterns obtained through PXRD were characterized by similar features that point to well-crystallized phases specific for the UIO-66 type materials; SEM also revealed that the materials were composed of small and agglomerate crystals. Thermogravimetric analysis revealed that both materials had approximately two linker deficiencies per Zr formula unit. Captopril and ibuprofen loading and release experiments in different buffered solutions were performed using the obtained Zr-based metal-organic frameworks as drug carriers envisaged for controlled drug release. The carriers demonstrated enhanced drug-loading capacity and showed relatively good results in drug delivery. The cumulative percentage of drug release in phosphate-buffered solution at pH 7.4 was higher than that in buffered solution at pH 1.2. The release rate could be controlled by changing the pH of the releasing solution. Different captopril release behaviors were observed when the experiments were performed using a permeable dialysis membrane.
PubMed: 37762192
DOI: 10.3390/ijms241813887 -
Toxins Sep 2023Reliable models of renal failure in large animals are critical to the successful translation of the next generation of renal replacement therapies (RRT) into humans....
Reliable models of renal failure in large animals are critical to the successful translation of the next generation of renal replacement therapies (RRT) into humans. While models exist for the induction of renal failure, none are optimized for the implantation of devices to the retroperitoneal vasculature. We successfully piloted an embolization-to-implantation protocol enabling the first implant of a silicon nanopore membrane hemodialyzer (SNMHD) in a swine renal failure model. Renal arterial embolization is a non-invasive approach to near-total nephrectomy that preserves retroperitoneal anatomy for device implants. Silicon nanopore membranes (SNM) are efficient blood-compatible membranes that enable novel approaches to RRT. Yucatan minipigs underwent staged bilateral renal arterial embolization to induce renal failure, managed by intermittent hemodialysis. A small-scale arteriovenous SNMHD prototype was implanted into the retroperitoneum. Dialysate catheters were tunneled externally for connection to a dialysate recirculation pump. SNMHD clearance was determined by intermittent sampling of recirculating dialysate. Creatinine and urea clearance through the SNMHD were 76-105 mL/min/m and 140-165 mL/min/m, respectively, without albumin leakage. Normalized creatinine and urea clearance measured in the SNMHD may translate to a fully implantable clinical-scale device. This pilot study establishes a path toward therapeutic testing of the clinical-scale SNMHD and other implantable RRT devices.
Topics: Humans; Swine; Animals; Kidneys, Artificial; Creatinine; Pilot Projects; Silicon; Swine, Miniature; Renal Insufficiency; Dialysis Solutions; Urea
PubMed: 37755973
DOI: 10.3390/toxins15090547 -
Peritoneal Dialysis International :... Jan 2024Long-term peritoneal dialysis is associated with the development of peritoneal membrane alterations, both in morphology and function. Impaired ultrafiltration (UF) is... (Review)
Review
Long-term peritoneal dialysis is associated with the development of peritoneal membrane alterations, both in morphology and function. Impaired ultrafiltration (UF) is the most important functional change, and peritoneal fibrosis is the major morphological alteration. Both are caused by the continuous exposure to dialysis solutions that are different from plasma water with regard to the buffer substance and the extremely high-glucose concentrations. Glucose has been incriminated as the major cause of long-term peritoneal membrane changes, but the precise mechanism has not been identified. We argue that glucose causes the membrane alterations by peritoneal pseudohypoxia and by the formation of advanced glycosylation end products (AGEs). After a summary of UF kinetics including the role of glucose transporters (GLUT), and a discussion on morphologic alterations, relationships between function and morphology and a survey of the pathogenesis of UF failure (UFF), it will be argued that impaired UF is partly caused by a reduction in small pore fluid transport as a consequence of AGE-related vasculopathy and - more importantly - in diminished free water transport due to pseudohypoxia, caused by increased peritoneal cellular expression of GLUT-1. The metabolism of intracellular glucose will be reviewed. This occurs in the glycolysis and in the polyol/sorbitol pathway, the latter is activated in case of a large supply. In both pathways the ratio between the reduced and oxidised form of nicotinamide dinucleotide (NADH/NAD ratio) will increase, especially because normal compensatory mechanisms may be impaired, and activate expression of hypoxia-inducible factor-1 (HIF-1). The latter gene activates various profibrotic factors and GLUT-1. Besides replacement of glucose as an osmotic agent, medical treatment/prevention is currently limited to tamoxifen and possibly Renin/angiotensis/aldosteron (RAA) inhibitors.
Topics: Humans; Peritoneal Dialysis; Glucose; Glycosylation; Peritoneum; Dialysis Solutions; Water; Ultrafiltration
PubMed: 37723976
DOI: 10.1177/08968608231196033 -
Biomedicine & Pharmacotherapy =... Nov 2023Kidney transplantation is the treatment of choice for patients with kidney failure. Compared to dialysis therapy, it provides better quality of life and confers... (Review)
Review
Kidney transplantation is the treatment of choice for patients with kidney failure. Compared to dialysis therapy, it provides better quality of life and confers significant survival advantage at a relatively lower cost. However, the long-term success of this life-saving intervention is severely hampered by an inexorable clinical problem referred to as ischemia-reperfusion injury (IRI), and increases the incidence of post-transplant complications including loss of renal graft function and death of transplant recipients. Burgeoning evidence shows that nitric oxide (NO), a poisonous gas at high concentrations, and with a historic negative public image as an environmental pollutant, has emerged as a potential candidate that holds clinical promise in mitigating IRI and preventing acute and chronic graft rejection when it is added to kidney preservation solutions at low concentrations or when administered to the kidney donor prior to kidney procurement and to the recipient or to the reperfusion circuit at the start and during reperfusion after renal graft preservation. Interestingly, dysregulated or abnormal endogenous production and metabolism of NO is associated with IRI in kidney transplantation. From experimental and clinical perspectives, this review presents endogenous enzymatic production of NO as well as its exogenous sources, and then discusses protective effects of constitutive nitric oxide synthase (NOS)-derived NO against IRI in kidney transplantation via several signaling pathways. The review also highlights a few isolated studies of renal graft protection by NO produced by inducible NOS.
Topics: Humans; Kidney Transplantation; Nitric Oxide; Quality of Life; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Kidney; Reperfusion Injury; Nitric Oxide Synthase Type III
PubMed: 37722191
DOI: 10.1016/j.biopha.2023.115530 -
BMC Nephrology Sep 2023Few drug dosing recommendations for patients receiving home hemodialysis (HHD) have been published which has hindered the adoption of HHD. HHD regimens vary widely and...
BACKGROUND
Few drug dosing recommendations for patients receiving home hemodialysis (HHD) have been published which has hindered the adoption of HHD. HHD regimens vary widely and differ considerably from conventional, thrice weekly, in-center hemodialysis in terms of treatment frequency, duration and blood and dialysate flow rates. Consequently, vancomycin and daptomycin clearances in HHD are also likely to be different, consequently HHD dosing regimens must be developed to ensure efficacy and minimize toxicity when these antibiotics are used. Many HHD regimens are used clinically, this study modeled ten common HHD regimens and determined optimal vancomycin and daptomycin dosing for each HHD regimen.
METHODS
Monte Carlo simulations using pharmacokinetic data derived from the literature and demographic data from a large HHD program treating patients with end stage kidney disease were incorporated into a one-compartment pharmacokinetic model. Virtual vancomycin and daptomycin doses were administered post-HHD and drug exposures were determined in 5,000 virtual patients receiving ten different HHD regimens. Serum concentration monitoring with subsequent dose changes was incorporated into the vancomycin models. Pharmacodynamic target attainment rates were determined for each studied dose. The lowest possible doses that met predefined targets in virtual patients were chosen as optimal doses.
RESULTS
HHD frequency, total dialysate volumes and HHD durations influenced drug exposure and led to different dosing regimens to meet targets. Antibiotic dosing regimens were identified that could meet targets for 3- and 7-h HHD regimens occurring every other day or 4-5 days/week. HHD regimens with 3-day interdialytic periods required higher doses prior to the 3-day period. The addition of vancomycin serum concentration monitoring allowed for calculation of necessary dosing changes which increased the number of virtual subjects meeting pharmacodynamic targets.
CONCLUSIONS
Doses of vancomycin and daptomycin that will meet desired pharmacodynamic targets in HHD are dependent on patient and HHD-specific factors. Doses used in conventional thrice weekly hemodialysis are unlikely to meet treatment goals. The antibiotic regimens paired with the HHD parameters studied in this analysis are likely to meet goals but require clinical validation.
Topics: Humans; Vancomycin; Daptomycin; Hemodialysis, Home; Monte Carlo Method; Anti-Bacterial Agents; Dialysis Solutions
PubMed: 37710245
DOI: 10.1186/s12882-023-03314-y -
Journal of Translational Medicine Sep 2023Peritoneal dialysis (PD) remains limited due to dialysis failure caused by peritoneal fibrosis. Tamoxifen (TAM), an inhibitor of estrogen receptor 1 (ESR1), has been...
BACKGROUND
Peritoneal dialysis (PD) remains limited due to dialysis failure caused by peritoneal fibrosis. Tamoxifen (TAM), an inhibitor of estrogen receptor 1 (ESR1), has been reported to treat fibrosis, but the underlying mechanism remains unknown. In this study, we sought to explore whether tamoxifen played an anti-fibrotic role by affecting transcription factor ESR1.
METHODS
ESR1 expression was detected in the human peritoneum. Mice were daily intraperitoneally injected with 4.25% glucose PD dialysate containing 40 mM methylglyoxal for 2 weeks to establish PD-induced peritoneal fibrosis. Tamoxifen was administrated by daily gavage, at the dose of 10 mg/kg. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay were performed to validate ESR1 bound H19 promoter. Gain-of-function and loss-of-function experiments were performed to investigate the biological roles of H19 on the mesothelial-mesenchymal transition (MMT) of human peritoneal mesothelial cells (HPMCs). Intraperitoneal injection of nanomaterial-wrapped 2'-O-Me-modified small interfering RNA was applied to suppress H19 in the mouse peritoneum. RNA immunoprecipitation and RNA pull-down assays demonstrated binding between H19 and p300. Exfoliated peritoneal cells were obtained from peritoneal dialysis effluent to analyze the correlations between ESR1 (or H19) and peritoneal solute transfer rate (PSTR).
RESULTS
ESR1 was increased significantly in the peritoneum after long-term exposure to PD dialysate. Tamoxifen treatment ameliorated high glucose-induced MMT of HPMCs, improved ultrafiltration rate, and decreased PSTR of mouse peritoneum. Tamoxifen reduced the H19 level by decreasing the ESR1 transcription of H19. Depletion of H19 reversed the pro-fibrotic effect of high glucose while ectopic expression of H19 exacerbated fibrotic pathological changes. Intraperitoneal injection of nanomaterial-wrapped 2'-O-Me-modified siRNAs targeting H19 mitigated PD-related fibrosis in mice. RNA immunoprecipitation (RIP) and RNA pull-down results delineated that H19 activated VEGFA expression by binding p300 to the VEGFA promoter and inducing histone acetylation of the VEGFA promoter. ESR1 and H19 were promising targets to predict peritoneal function.
CONCLUSIONS
High glucose-induced MMT of peritoneal mesothelial cells in peritoneal dialysis via activating ESR1. In peritoneal mesothelial cells, ESR1 transcribed the H19 and H19 binds to transcription cofactor p300 to activate the VEGFA. Targeting ESR1/H19/VEGFA pathway provided new hope for patients undergoing peritoneal dialysis.
Topics: Animals; Humans; Mice; Dialysis Solutions; Fibrosis; Glucose; Peritoneum; RNA; Vascular Endothelial Growth Factor A; Tamoxifen
PubMed: 37697303
DOI: 10.1186/s12967-023-04470-3 -
Internal Medicine (Tokyo, Japan) Apr 2024A hypercalcemic crisis due to primary hyperparathyroidism is a life-threatening condition. We herein report a 71-years-old man with hypercalcemic crisis due to primary...
A hypercalcemic crisis due to primary hyperparathyroidism is a life-threatening condition. We herein report a 71-years-old man with hypercalcemic crisis due to primary hyperparathyroidism with parathyroid adenoma. Generally, hemodialysis or continuous hemodiafiltration using calcium-free or low-calcium dialysate is performed early for hypercalcemic crisis. In this case, continuous hemodialysis with a common calcium concentration dialysate improved the hypercalcemic crisis, and parathyroidectomy was performed. The patient recovered sufficiently. Prediction of hypercalcemia crisis, appropriate introduction and methods of blood purification therapy, and timing decisions for parathyroidectomy are required for therapeutic management of hypercalcemic crisis with parathyroid adenoma.
Topics: Male; Humans; Aged; Calcium; Hypercalcemia; Parathyroid Neoplasms; Hyperparathyroidism, Primary; Dialysis Solutions; Calcium, Dietary; Renal Dialysis
PubMed: 37690849
DOI: 10.2169/internalmedicine.1764-23 -
PloS One 2023Diffuse midline gliomas (DMG) are the most aggressive brain tumors of childhood and young adults, with documented 2-year survival rates <10%. Treatment failure is due in... (Clinical Trial)
Clinical Trial
Diffuse midline gliomas (DMG) are the most aggressive brain tumors of childhood and young adults, with documented 2-year survival rates <10%. Treatment failure is due in part to the function of the BBB. Intratumoral microdialysis sampling is an effective tool to determine brain entry of varied agents and could help to provide a better understanding of the relationship of drug permeability to DMG treatment responsivity. This is a non-randomized, single-center, phase 1 clinical trial. Up to seven young adult (18-39 years) patients with recurrent high-grade or diffuse midline glioma will be enrolled with the goal of 5 patients completing the trial over an anticipated 24 months. All patients will take abemaciclib pre-operatively for 4.5 days at twice daily dosing. Patients will undergo resection or biopsy, placement of a microdialysis catheter, and 48 hours of dialysate sampling coupled with timed plasma collections. If intratumoral tumor or brain dialysate sampling concentrations are >10nmol/L, or tumor tissue studies demonstrate CDK inhibition, then restart of abemaciclib therapy along with temozolomide will be administered for maintenance therapy and discontinued with evidence of radiologic or clinical disease progression. The poor survival associated with diffuse midline gliomas underscore the need for improved means to evaluate efficacy of drug delivery to tumor and peritumoral tissue. The findings of this novel study, will provide real-time measurements of BBB function which have the potential to influence future prognostic and diagnostic decisions in such a lethal disease with limited treatment options. Trial registration: Clinicaltrials.gov, NCT05413304. Registered June 10, 2022, Abemaciclib Neuropharmacokinetics of Diffuse Midline Glioma Using Intratumoral Microdialysis.
Topics: Young Adult; Humans; Feasibility Studies; Microdialysis; Clinical Protocols; Dialysis Solutions; Glioma
PubMed: 37682953
DOI: 10.1371/journal.pone.0291068