1340: COMPLEMENT ACTIVATION FRAGMENTS ARE INCREASED IN PEDIATRIC SEPSIS-ASSOCIATED ACUTE KIDNEY INJURY

Late-stage anthrax infections are characterized by dysregulated immune responses and hematogenous spread of Bacillus anthracis, leading to extreme bacteremia, sepsis, multiple organ failure, and, ultimately, death. Despite the bacterium being nonhemolytic, some fulminant anthrax patients develop a secondary atypical hemolytic uremic syndrome (aHUS) through unknown mechanisms. We recapitulated the pathology in baboons challenged with cell wall peptidoglycan (PGN), a polymeric, pathogen-associated molecular pattern responsible for the hemostatic dysregulation in anthrax sepsis. Similar to aHUS anthrax patients, PGN induces an initial hematocrit elevation followed by progressive hemolytic anemia and associated renal failure. Etiologically, PGN induces erythrolysis through direct excessive activation of all three complement pathways. Blunting terminal complement activation with a C5 neutralizing peptide prevented the progressive deposition of membrane attack complexes on red blood cells (RBC) and subsequent intravascular hemolysis, heme cytotoxicity, and acute kidney injury. Importantly, C5 neutralization did not prevent immune recognition of PGN and shifted the systemic inflammatory responses, consistent with improved survival in sepsis. Whereas PGN-induced hemostatic dysregulation was unchanged, C5 inhibition augmented fibrinolysis and improved the thromboischemic resolution. Overall, our study identifies PGN-driven complement activation as the pathologic mechanism underlying hemolytic anemia in anthrax and likely other gram-positive infections in which PGN is abundantly represented. Neutralization of terminal complement reactions reduces the hemolytic uremic pathology induced by PGN and could alleviate heme cytotoxicity and its associated kidney failure in gram-positive infections.

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P0531CONTINUOUS HEMODIAFILTRATION WITH PMMA HEMOFILTER MODULATED COMPLEMENT ACTIVATION AND RENAL DYSFUNCTION IN A SWINE MODEL OF SEPSIS-INDUCED ACUTE KIDNEY INJURY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0531 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Alessandra Stasi ◽

ROSSANA FRANZIN ◽

Fabio Sallustio ◽

Chiara Divella ◽

Claudia Curci ◽

...

Keyword(s):

Gene Expression ◽

Acute Kidney Injury ◽

Complement Activation ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Kidney Injury ◽

Swine Model ◽

Complement Factor ◽

Factor B ◽

Renal Biopsies

Abstract Background and Aims Sepsis-induced acute kidney injury (AKI) is a growing health care problem, refractory to conventional treatments. This disease is characterized by an overwhelmed immune response against a primary insult that become responsible for renal dysfunction and poor outcome. Therapeutic strategies based on blood purification have been developed for the treatment of this disease. The use of polymethyl methacrylate (PMMA) membrane hemofilter in continuous hemodiafiltration (CHDF) modality showed better hemodynamic stability and efficient renal support in chronic dialysis maintenance. Here we investigated the efficacy of Hemofeel PMMA membrane (TORAY, Japan) in interfering with Complement activation and renal damage in a swine model of sepsis-induced AKI. Method After 3 hours from LPS infusion, 7 hours of PMMA-CVVH treatment or 7 hours of polysulfone (PSF)-CVVH were performed. Animals were sacrificed after 24h from LPS infusion. Histologic and renal function parameters were analyzed in all pigs. Pentraxin-3 (PTX3) and C5b-9 deposits were assessed on renal biopsies. Systemic Complement activation was evaluated by Wieslab kit. Gene expression profile was obtained from isolated PBMCs by Agilent SurePrint G3 Porcine Gene Expression Microarrays. Genespring and R software were used for the analysis. Results were validated by Real-time PCR. Results Analysis of renal biopsies from septic pigs presented increased interstitial leucocyte infiltrate, extensive collagen deposition and diffuse glomerular thrombi compared to healthy pigs (p<0.05). Confocal analysis showed extensive PTX-3 and C5-b9 deposits at tubulo-interstitial level associated with significant activation of systemic complement classical and alternative pathways (p<0.05). Interestingly, PMMA-CVVH treatment significantly reduced local and systemic complement activation, leucocyte infiltrate and tubule-interstitial fibrosis (p<0.05). On the contrary, no significant improvement was observed by PSF-CVVH treatment. Then, we compared the whole-genome gene expression profiles of swine PBMC. We identified 711 differentially expressed genes comparing PBMC before LPS infusion (LPS T0) and after 24 hours from LPS infusion (LPS T24) and 913 genes comparing gene expression profiles of LPS T24 group with that of septic pigs treated with PMMA-CVVH (PMMA T24 group) (fold change >2 ; false discovery rate <0.05). The most modulated genes were Granzime B, Complement Factor B, Complement Component 4 Binding Protein Alpha, IL-12, SERPINB-1 and TIMP-2 that were closely related to sepsis-induced immunological process. Finally, quantitative PCR confirmed the microarray data indicating that Granzime B and Complement Factor B upregulation in PBMC was significantly hampered by PMMA treatment. Conclusion Our data suggest that LPS induced AKI is characterized by activation of Classical and alternative Complement pathways resulting in significant renal tissue damage. By interfering with complement activation and inflammatory response, PMMA membrane might prevent dysfunctional activation of resident renal cells with prevention of sepsis-induced AKI.

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Association of early hypotension in pediatric sepsis with development of new or persistent acute kidney injury

Pediatric Nephrology ◽

10.1007/s00467-020-04704-2 ◽

2020 ◽

Author(s):

Julie C. Fitzgerald ◽

Michelle E. Ross ◽

Neal J. Thomas ◽

Scott L. Weiss ◽

Fran Balamuth ◽

...

Keyword(s):

Acute Kidney Injury ◽

Kidney Injury ◽

Pediatric Sepsis

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Eculizumab, a novel potential treatment for acute kidney injury associated with preeclampsia/HELLP syndrome

BMJ Case Reports ◽

10.1136/bcr-2018-228709 ◽

2019 ◽

Vol 12 (9) ◽

pp. e228709 ◽

Cited By ~ 11

Author(s):

Hatem Elabd ◽

Mennallah Elkholi ◽

Lewis Steinberg ◽

Anjali Acharya

Keyword(s):

Acute Kidney Injury ◽

Renal Replacement Therapy ◽

Replacement Therapy ◽

Complement Activation ◽

Hellp Syndrome ◽

Kidney Injury ◽

Complement Protein ◽

Igg Antibody ◽

Elevated Liver Enzymes

The kidney is one of the major organs affected in preeclampsia. There is evidence suggesting a role for excessive complement activation in the pathogenesis of preeclampsia. We describe a case of preeclampsia with severe features, including HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) and acute kidney injury (AKI) that developed following caesarian section. The patient required renal replacement therapy. A trial of daily plasma exchange was not effective. The patient received a single dose of eculizumab, a humanised monoclonal IgG antibody that binds to complement protein C5. One week post administration of eculizumab, there was significant improvement in haematologic, hepatic and renal function. Blood pressure had normalised and renal replacement therapy was discontinued. The use of eculizumab may have contributed to recovery of kidney function further supporting the role of complement activation in the pathogenesis of preeclampsia and associated AKI.

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Baicalin Inhibits Renal Cell Apoptosis and Protects Against Acute Kidney Injury in Pediatric Sepsis

Medical Science Monitor ◽

10.12659/msm.899061 ◽

2016 ◽

Vol 22 ◽

pp. 5109-5115 ◽

Cited By ~ 7

Author(s):

Yanping Zhu ◽

Yanxia Fu ◽

Hairong Lin

Keyword(s):

Acute Kidney Injury ◽

Cell Apoptosis ◽

Renal Cell ◽

Kidney Injury ◽

Pediatric Sepsis

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A Precision Medicine Approach to Biomarker Utilization in Pediatric Sepsis-Associated Acute Kidney Injury

Frontiers in Pediatrics ◽

10.3389/fped.2021.632248 ◽

2021 ◽

Vol 9 ◽

Author(s):

James D. Odum ◽

Hector R. Wong ◽

Natalja L. Stanski

Keyword(s):

Acute Kidney Injury ◽

Inflammatory Response ◽

Precision Medicine ◽

Biomarker Discovery ◽

Kidney Injury ◽

Critically Ill Children ◽

Diagnostic Strategies ◽

Increased Risk ◽

Pediatric Sepsis ◽

The Individual

Sepsis is a leading cause of morbidity and mortality in critically ill children, and acute kidney injury (AKI) is a frequent complication that confers an increased risk for poor outcomes. Despite the documented consequences of sepsis-associated AKI (SA-AKI), no effective disease-modifying therapies have been identified to date. As such, the only treatment options for these patients remain prevention and supportive care, both of which rely on the ability to promptly and accurately identify at risk and affected individuals. To achieve these goals, a variety of biomarkers have been investigated to help augment our currently limited predictive and diagnostic strategies for SA-AKI, however, these have had variable success in pediatric sepsis. In this mini-review, we will briefly outline the current use of biomarkers for SA-AKI, and propose a new framework for biomarker discovery and utilization that considers the individual patient's sepsis inflammatory response. Now recognized to be a key driver in the complex pathophysiology of SA-AKI, understanding the dysregulated host immune response to sepsis is a growing area of research that can and should be leveraged to improve the prediction and diagnosis of SA-AKI, while also potentially identifying novel therapeutic targets. Reframing SA-AKI in this manner – as a direct consequence of the individual patient's sepsis inflammatory response – will facilitate a precision medicine approach to its management, something that is required to move the care of this consequential disorder forward.

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The role of complement activation in rhabdomyolysis-induced acute kidney injury

PLoS ONE ◽

10.1371/journal.pone.0192361 ◽

2018 ◽

Vol 13 (2) ◽

pp. e0192361

Author(s):

XuDong Huang ◽

Wei Zhao ◽

LiXia Zhang ◽

XinJun Yang ◽

LiHui Wang ◽

...

Keyword(s):

Acute Kidney Injury ◽

Complement Activation ◽

Kidney Injury

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Plasma exchange for thrombotic microangiopathy secondary to dermatomyositis associated with acute kidney injury and complement activation: a case report with literature review

Renal Replacement Therapy ◽

10.1186/s41100-019-0244-5 ◽

2019 ◽

Vol 5 (1) ◽

Author(s):

Norifumi Hayashi ◽

Keiichirou Okada ◽

Yuko Tsuruyama ◽

Yu Kagaya ◽

Sho Kumano ◽

...

Keyword(s):

Acute Kidney Injury ◽

Intensive Care ◽

Case Report ◽

Plasma Exchange ◽

Complement Activation ◽

Thrombotic Microangiopathy ◽

Kidney Injury ◽

Ivig Therapy ◽

Case Presentation ◽

Life Threatening

Abstract Background Thrombotic microangiopathy (TMA) in patients with connective tissue disease is rare but life-threatening. In particular, the survival rate of patients with dermatomyositis (DM) that develop TMA is low. The effectiveness of plasma exchange (PEX) therapy is unclear for the treatment of TMA secondary to DM. Case presentation We describe a case of a 28-year-old woman who developed severe DM complicated by aspiration pneumonia from dysphagia and acute kidney injury. The patient was unresponsive to corticosteroids and intravenous immunoglobulin (IVIG) therapy and developed TMA. In this case, immunofluorescence of skin biopsy revealed that complement activation was involved in the pathogenesis of DM. After 6 PEX therapies, thrombocytopenia improved. She was successfully treated by intensive care and PEX therapy. Conclusions PEX therapy was effective to treat TMA secondary to DM associated with complement activation.

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Urine complement activation fragments are increased in patients with kidney injury after cardiac surgery

AJP Renal Physiology ◽

10.1152/ajprenal.00130.2019 ◽

2019 ◽

Vol 317 (3) ◽

pp. F650-F657 ◽

Cited By ~ 1

Author(s):

Jennifer Laskowski ◽

Heather Thiessen Philbrook ◽

Chirag R. Parikh ◽

Joshua M. Thurman

Keyword(s):

Acute Kidney Injury ◽

Cardiac Surgery ◽

Complement Activation ◽

Alternative Pathway ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Urine Biomarkers ◽

Pathway Activation ◽

Alternative Pathway Of Complement ◽

Subsequent Rise

Experiments in mouse models have shown that the complement cascade is activated within the kidney after ischemia-reperfusion and that complement activation contributes to tubular injury in this setting. Less is known, however, about complement activation in human kidneys after ischemia or whether complement activation in the tubulointerstitium can be detected by measurement of complement fragments in the urine. We hypothesized that urine biomarkers of complement activation would rapidly increase in patients who develop ischemic acute kidney injury, signaling complement activation within the kidney. We confirmed that the alternative pathway of complement is activated in the kidneys of mice after ischemia-reperfusion, and we found that levels of factor B fragments (generated during alternative pathway activation) rapidly increase in the urine. We next performed a case-control study in which we measured complement fragments in human urine samples from patients undergoing cardiac surgery using ELISAs. The level of Ba increased after cardiac surgery and was significantly higher in patients who developed acute kidney injury. The increase in Ba also correlated with magnitude of the subsequent rise in serum creatinine and with the need for hemodialysis during the hospitalization. These findings demonstrate that the alternative pathway of complement is activated in patients who develop acute kidney injury after cardiac surgery and that increases in the level of urine Ba may be a predictive and functional biomarker of severe kidney injury.

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Validity of Urine Syndecan-1 as A Predictor of Acute Kidney Injury In Pediatric Sepsis Patients

Indonesian Journal of Anesthesiology and Reanimation ◽

10.20473/ijar.v3i22021.62-70 ◽

2021 ◽

Vol 3 (2) ◽

pp. 62

Author(s):

Bambang Pujo Semedi ◽

Arie Utariani ◽

Nugroho Setia Budi ◽

Ninik Asmaningsih ◽

Lucky Andriyanto

Keyword(s):

Acute Kidney Injury ◽

Serum Concentration ◽

Kidney Injury ◽

Preventive Therapy ◽

Prediction Ability ◽

Resuscitation Room ◽

Urine Examination ◽

Patient Will ◽

Standard Parameter ◽

Pediatric Sepsis

Introduction: AKI (Acute Kidney Injury) complications in sepsis patients generally occur 24 hours after admission to ICU. Creatine Serum Concentration is a standard parameter to diagnose AKI. Unfortunately, the changes in creatine serum concentration will only be seen several days after the decrease of renal function to 50%. The low detection ability has been linked with time loss before preventive therapy is commenced. Furthermore, this instigates the need for biomarkers to ensure early detection. Objective: This study aimed to identify cut-off points of urine syndecan-1 and to measure the prediction ability of urine syndecan-1 towards the AKI occurrence in pediatric sepsis patients. Materials and methods: This study was a prospective cohort study performed at a single center in Dr. Soetomo General Hospital, Surabaya. The inclusion criterion was all children admitted to the resuscitation room from October until December 2019. Furthermore, urine sampling is carried out at 0, 6, 12, and 24 hours for a syndecan-1 urine examination, and every procedure performed on the patient will be recorded. This action was continued up to the third day and aimed to evaluate some factors related to AKI at 48-72 hours of admission. Result and Discussion: Out of 41 pediatric sepsis patients, 30 patients fulfilled the inclusion criteria and 57% had AKI. The value of urine syndecan-1 at hour-0 and hour-6 was significantly featured a cut-off point. Conclusion: The value of urine syndecan-1 at hour-0 and hour-6 are valid parameters to predict the occurrence of AKI grades 1, 2, and 3 in pediatric septic patients at 48-72 hours after their hospital admission. The best cut-off value of urine syndecan-1 at the 0th hour was 0.67 ng/ml.

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