The Application of Nanoparticles in Diagnosis and Treatment of Kidney Diseases

Nanomedicine is currently showing great promise for new methods of diagnosing and treating many diseases, particularly in kidney disease and transplantation. The unique properties of nanoparticles arise from the diversity of size effects, used to design targeted nanoparticles for specific cells or tissues, taking renal clearance and tubular secretion mechanisms into account. The design of surface particles on nanoparticles offers a wide range of possibilities, among which antibodies play an important role. Nanoparticles find applications in encapsulated drug delivery systems containing immunosuppressants and other drugs, in imaging, gene therapies and many other branches of medicine. They have the potential to revolutionize kidney transplantation by reducing and preventing ischemia–reperfusion injury, more efficiently delivering drugs to the graft site while avoiding systemic effects, accurately localizing and visualising the diseased site and enabling continuous monitoring of graft function. So far, there are known nanoparticles with no toxic effects on human tissue, although further studies are still needed to confirm their safety.

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Drug eluting grafts for hemodialysis access

The Journal of Vascular Access ◽

10.5301/jva.5000671 ◽

2017 ◽

Vol 18 (1_suppl) ◽

pp. S53-S55 ◽

Cited By ~ 2

Author(s):

Marc Glickman

Keyword(s):

Neointimal Hyperplasia ◽

Graft Function ◽

Prosthetic Graft ◽

Great Promise ◽

Graft Material ◽

Eptfe Graft ◽

Gene Therapies ◽

New Methods ◽

Drug Elution ◽

Drug Eluting

The development of new methods for drug elution of graft material, biofiber films and resurfacing of prosthetic graft surfaces offers new opportunities for improvement of graft function in arteriovenous (AV) access. Three areas of research include developing grafts that reduce the development of neointimal hyperplasia, reducing infection and reducing thrombogenicity. The only drug eluting graft presently being used, is the heparin coated expanded polytetrafluoroethylene (ePTFE) graft, which has been shown to decrease the incidence of early thrombosis. New drug eluting grafts include those with paclitaxel and those with antibiotics. The development of a hybrid coated prosthetic graft that can deliver targeted gene therapies holds great promise in the field.

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Attenuation of lung reperfusion injury after transplantation using an inhibitor of nuclear factor-κB

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2000.279.3.l528 ◽

2000 ◽

Vol 279 (3) ◽

pp. L528-L536 ◽

Cited By ~ 76

Author(s):

Scott D. Ross ◽

Irving L. Kron ◽

James J. Gangemi ◽

Kimberly S. Shockey ◽

Mark Stoler ◽

...

Keyword(s):

Lung Function ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Graft Function ◽

Nuclear Factor Κb ◽

Pyrrolidine Dithiocarbamate ◽

Nuclear Factor ◽

Mean Pulmonary Arterial Pressure ◽

Pulmonary Arterial

A central role for nuclear factor-κB (NF-κB) in the induction of lung inflammatory injury is emerging. We hypothesized that NF-κB is a critical early regulator of the inflammatory response in lung ischemia-reperfusion injury, and inhibition of NF-κB activation reduces this injury and improves pulmonary graft function. With use of a porcine transplantation model, left lungs were harvested and stored in cold Euro-Collins preservation solution for 6 h before transplantation. Activation of NF-κB occurred 30 min and 1 h after transplant and declined to near baseline levels after 4 h. Pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of NF-κB, given to the lung graft during organ preservation (40 mmol/l) effectively inhibited NF-κB activation and significantly improved lung function. Compared with control lungs 4 h after transplant, PDTC-treated lungs displayed significantly higher oxygenation, lower Pco2, reduced mean pulmonary arterial pressure, and reduced edema and cellular infiltration. These results demonstrate that NF-κB is rapidly activated and is associated with poor pulmonary graft function in transplant reperfusion injury, and targeting of NF-κB may be a promising therapy to reduce this injury and improve lung function.

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Use of peroxiredoxin for preconditioning of heterotopic heart transplantation in a rat

Russian Journal of Transplantology and Artificial Organs ◽

10.15825/1995-1191-2020-2-158-164 ◽

2020 ◽

Vol 22 (2) ◽

pp. 158-164

Author(s):

N. V. Grudinin ◽

V. K. Bogdanov ◽

M. G. Sharapov ◽

N. S. Bunenkov ◽

N. P. Mozheiko ◽

...

Keyword(s):

Heart Transplantation ◽

Reperfusion Injury ◽

Mammalian Cells ◽

Ischemia Reperfusion Injury ◽

Isolated Heart ◽

Ischemia Reperfusion ◽

Signal Transmission ◽

Redox Homeostasis ◽

Heterotopic Heart Transplantation ◽

Wide Range

Peroxiredoxin 6 (Prdx6) is an antioxidant enzyme in the human body that performs a number of important functions in the cell. Prdx6 restores a wide range of peroxide substrates, thus playing a leading role in maintaining redox homeostasis in mammalian cells. In addition to peroxidase activity, Prdx6 has an activity of phospholipase A2, thus taking part in membrane phospholipid metabolism. Due to its peroxidase and phospholipase activity, Prdx6 participates in intracellular and intercellular signal transmission, thereby facilitating the initiation of regenerative processes in the cell, suppression of apoptosis and activation of cell proliferation. Given the functions performed, Prdx6 can effectively deal with oxidative stress caused by various factors, including ischemia-reperfusion injury. On an animal model of rat heterotopic heart transplantation, we showed the cardioprotective potential of exogenous recombinant Prdx6, introduced before transplantation and subsequent reperfusion injury of the heart. It has been demonstrated that exogenous Prdx6 effectively alleviates the severity of ischemia-reperfusion injury of the heart by 2–3 times, providing normalization of its structural and functional state during heterotopic transplantation. The use of recombinant Prdx6 can be an effective approach in preventing/alleviating ischemia-reperfusion injury of the heart, as well as in maintaining an isolated heart during transplantation.

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Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis

10.1101/2020.08.17.253252 ◽

2020 ◽

Author(s):

Caitriona M. McEvoy ◽

Sergi Clotet-Freixas ◽

Tomas Tokar ◽

Chiara Pastrello ◽

Shelby Reid ◽

...

Keyword(s):

Molecular Mechanisms ◽

Ischemia Reperfusion Injury ◽

Ex Vivo ◽

Ischemia Reperfusion ◽

Graft Function ◽

Kidney Injury ◽

Tca Cycle ◽

Proteomics Analysis ◽

Beneficial Effects ◽

Kidney Perfusion

AbstractNormothermic ex-vivo kidney perfusion (NEVKP) results in significantly improved graft function in porcine auto-transplant models of DCD injury compared to static cold storage (SCS); however, the molecular mechanisms underlying these beneficial effects remain unclear. We performed an unbiased proteomics analysis of 28 kidney biopsies obtained at 3 time points from pig kidneys subjected to 30-minutes of warm ischemia, followed by 8 hours of NEVKP or SCS, and auto-transplantation. 70/6593 proteins quantified were differentially expressed between NEVKP and SCS groups (FDR<0.05). Proteins increased in NEVKP mediated key metabolic processes including fatty acid ß-oxidation, the TCA-cycle and oxidative phosphorylation. Comparison of our findings with external datasets of ischemia-reperfusion, and other models of kidney injury confirmed that 47 of our proteins represent a common signature of kidney injury reversed or attenuated by NEVKP. We validated key metabolic proteins (ETFB, CPT2) by immunoblotting. Transcription factor databases identified PPARGC1A, PPARA/G/D and RXRA/B as the upstream regulators of our dataset, and we confirmed their increased expression in NEVKP with RT-PCR. The proteome-level changes observed in NEVKP mediate critical metabolic pathways that may explain the improved graft function observed. These effects may be coordinated by PPAR-family transcription factors, and may represent novel therapeutic targets in ischemia-reperfusion injury.

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The Immunomodulatory Effect of the Gut Microbiota in Kidney Disease

Journal of Immunology Research ◽

10.1155/2021/5516035 ◽

2021 ◽

Vol 2021 ◽

pp. 1-16

Author(s):

Mingxuan Chi ◽

Kuai Ma ◽

Jing Wang ◽

Zhaolun Ding ◽

Yunlong Li ◽

...

Keyword(s):

Kidney Disease ◽

Gut Microbiota ◽

Intestinal Microbiota ◽

Ischemia Reperfusion Injury ◽

Therapeutic Potential ◽

Kidney Diseases ◽

Ischemia Reperfusion ◽

Intestinal Flora ◽

Inflammatory Factors ◽

Renal Diseases

The human gut microbiota is a complex cluster composed of 100 trillion microorganisms, which holds a symbiotic relationship with the host under normal circumstances. Intestinal flora can facilitate the treatment of human metabolic dysfunctions and interact with the intestinal tract, which could influence intestinal tolerance, immunity, and sensitivity to inflammation. In recent years, significant interests have evolved on the association of intestinal microbiota and kidney diseases within the academic circle. Abnormal changes in intestinal microbiota, known as dysbiosis, can affect the integrity of the intestinal barrier, resulting in the bacterial translocation, production, and accumulation of dysbiotic gut-derived metabolites, such as urea, indoxyl sulfate (IS), and p-cresyl sulfate (PCS). These processes lead to the abnormal activation of immune cells; overproduction of antibodies, immune complexes, and inflammatory factors; and inflammatory cell infiltration that can directly or indirectly cause damage to the renal parenchyma. The aim of this review is to summarize the role of intestinal flora in the development and progression of several renal diseases, such as lupus nephritis, chronic kidney disease, diabetic nephropathy, and renal ischemia-reperfusion injury. Further research on these mechanisms should provide insights into the therapeutic potential of regulating intestinal flora and intervening related molecular targets for the abovementioned nephropathy.

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Restoring Mitochondrial Function While Avoiding Redox Stress: The Key to Preventing Ischemia/Reperfusion Injury in Machine Perfused Liver Grafts?

International Journal of Molecular Sciences ◽

10.3390/ijms21093132 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3132 ◽

Cited By ~ 3

Author(s):

Julia Hofmann ◽

Giorgi Otarashvili ◽

Andras Meszaros ◽

Susanne Ebner ◽

Annemarie Weissenbacher ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ex Vivo ◽

Ischemia Reperfusion ◽

Graft Function ◽

Ros Production ◽

Machine Perfusion ◽

Redox Stress ◽

Molecular Events ◽

Regulate Cell Death

Mitochondria sense changes resulting from the ischemia and subsequent reperfusion of an organ and mitochondrial reactive oxygen species (ROS) production initiates a series of events, which over time result in the development of full-fledged ischemia-reperfusion injury (IRI), severely affecting graft function and survival after transplantation. ROS activate the innate immune system, regulate cell death, impair mitochondrial and cellular performance and hence organ function. Arresting the development of IRI before the onset of ROS production is currently not feasible and clinicians are faced with limiting the consequences. Ex vivo machine perfusion has opened the possibility to ameliorate or antagonize the development of IRI and may be particularly beneficial for extended criteria donor organs. The molecular events occurring during machine perfusion remain incompletely understood. Accumulation of succinate and depletion of adenosine triphosphate (ATP) have been considered key mechanisms in the initiation; however, a plethora of molecular events contribute to the final tissue damage. Here we discuss how understanding mitochondrial dysfunction linked to IRI may help to develop novel strategies for the prevention of ROS-initiated damage in the evolving era of machine perfusion.

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Inhibition of TLR2 promotes graft function in a murine model of renal transplant ischemia‐reperfusion injury

The FASEB Journal ◽

10.1096/fj.11-195396 ◽

2011 ◽

Vol 26 (2) ◽

pp. 799-807 ◽

Cited By ~ 48

Author(s):

Conrad A. Farrar ◽

Brian Keogh ◽

William McCormack ◽

Aisling O'Shaughnessy ◽

Andrew Parker ◽

...

Keyword(s):

Renal Transplant ◽

Reperfusion Injury ◽

Murine Model ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Graft Function

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Three-Year Outcomes of a Randomized, Double-Blind, Placebo-Controlled Study Assessing Safety and Efficacy of C1 Esterase Inhibitor for Prevention of Delayed Graft Function in Deceased Donor Kidney Transplant Recipients

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.04840419 ◽

2019 ◽

Vol 15 (1) ◽

pp. 109-116 ◽

Cited By ~ 6

Author(s):

Edmund Huang ◽

Ashley Vo ◽

Jua Choi ◽

Noriko Ammerman ◽

Kathlyn Lim ◽

...

Keyword(s):

Confidence Interval ◽

Graft Failure ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Controlled Trial ◽

Graft Function ◽

Deceased Donor ◽

Delayed Graft Function ◽

C1 Esterase Inhibitor ◽

Esterase Inhibitor

Background and objectivesDelayed graft function is related to ischemia-reperfusion injury and may be complement dependent. We previously reported from a randomized, placebo-controlled trial that treatment with C1 esterase inhibitor was associated with a shorter duration of delayed graft function and higher eGFR at 1 year. Here, we report longer-term outcomes from this trial.Design, setting, participants, & measurementsThis is a post hoc analysis of a phase 1/2, randomized, controlled trial enrolling 70 recipients of deceased donor kidney transplants at risk for delayed graft function (NCT02134314). Subjects were randomized to receive C1 esterase inhibitor 50 U/kg (n=35) or placebo (n=35) intraoperatively and at 24 hours. The cumulative incidence functions method was used to compare graft failure and death over 3.5 years. eGFR slopes were compared using a linear mixed effects model.ResultsThree deaths occurred among C1 esterase inhibitor–treated patients compared with none receiving placebo. Seven graft failures developed in the placebo group compared with one among C1 esterase inhibitor–treated recipients; the cumulative incidence of graft failure was lower over 3.5 years among C1 esterase inhibitor–treated recipients compared with placebo (P=0.03). Although no difference in eGFR slopes was observed between groups (P for group-time interaction =0.12), eGFR declined in placebo-treated recipients (−4 ml/min per 1.73 m2 per year; 95% confidence interval, −8 to −0.1) but was stable in C1 esterase inhibitor–treated patients (eGFR slope: 0.5 ml/min per 1.73 m2 per year; 95% confidence interval, −4 to 5). At 3.5 years, eGFR was 56 ml/min per 1.73 m2 (95% confidence interval, 42 to 70) in the C1 esterase inhibitor group versus 35 ml/min per 1.73 m2 (95% confidence interval, 21 to 48) in the placebo group, with an estimated mean eGFR difference of 21 ml/min per 1.73 m2 (95% confidence interval, 2 to 41 ml/min per 1.73 m2).ConclusionsTreatment of patients at risk for ischemia-reperfusion injury and delayed graft function with C1 esterase inhibitor was associated with a lower incidence of graft failure.

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Prognostic value of endogenous and exogenous metabolites in liver transplantation

Biomarkers in Medicine ◽

10.2217/bmm-2020-0073 ◽

2020 ◽

Vol 14 (12) ◽

pp. 1165-1181

Author(s):

Xiao-fu Xiong ◽

Ding-ding Chen ◽

Huai-jun Zhu ◽

Wei-hong Ge

Keyword(s):

Liver Transplantation ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Immunosuppressive Agents ◽

Graft Function ◽

Individual Variability ◽

Pathological Examination ◽

Biochemical Tests ◽

Monitoring Method ◽

End Stage

Liver transplantation has been widely accepted as an effective intervention for end-stage liver diseases and early hepatocellular carcinomas. However, a variety of postoperative complications and adverse reactions have baffled medical staff and patients. Currently, transplantation monitoring relies primarily on nonspecific biochemical tests, whereas diagnosis of multiple complications depends on invasive pathological examination. Therefore, a noninvasive monitoring method with high selectivity and specificity is desperately needed. This review summarized the potential of endogenous small-molecule metabolites as biomarkers for assessing graft function, ischemia-reperfusion injury and liver rejection. Exogenous metabolites, mainly those immunosuppressive agents with high intra- and inter-individual variability, were also discussed for transplantation monitoring.

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