Spiny mice activate unique transcriptional programs after severe kidney injury regenerating organ function without fibrosis

Background: Midkine has been reported to play a crucial role in inflammatory, hypoxia, and tissue injury processes. We aimed to investigate plasma midkine in septic patients and its association with 28-day mortality and organ function. Methods: Septic patients admitted to the Department of Critical Care Medicine, Zhongda Hospital, a tertiary hospital, from November 2017 to March 2018 were enrolled in the study. The baseline characteristics of the septic patients were recorded at admission. A peripheral blood sample was obtained at admission, and plasma midkine levels were evaluated with an immunoassay. All patients were followed up with for 28 days, with all-cause mortality being recorded. Results: A total of 26 septic patients were enrolled, which included 18 survivors and 8 nonsurvivors at day 28. Plasma midkine levels were significantly elevated in the nonsurvivor group compared with the survivors (ng/L, 763.6 [404.7-1305], 268.5 [147.8-511.4]; P = .0387]. Plasma midkine levels were elevated in septic patients with moderate/severe acute respiratory distress syndrome (ARDS) compared with patients with non/mild ARDS (ng/L, 522.3 [336.6-960.1] vs 243.8 [110.3-478.9]; P = .0135) and in those with acute kidney injury compared with those without (ng/L, 489.8 [259.2-1058] vs 427.9 [129.6-510.3]; P = .0973). Changes in plasma midkine levels were also associated with extravascular lung water index ( P = .063) and pulmonary vascular permeability index ( P = .049). Conclusions: Plasma midkine was associated with 28-day mortality, as well as pulmonary and kidney injury, in septic patients.

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Impact of acute kidney injury on distant organ function: recent findings and potential therapeutic targets

Kidney International ◽

10.1016/j.kint.2015.11.019 ◽

2016 ◽

Vol 89 (3) ◽

pp. 555-564 ◽

Cited By ~ 97

Author(s):

Kent Doi ◽

Hamid Rabb

Keyword(s):

Acute Kidney Injury ◽

Therapeutic Targets ◽

Kidney Injury ◽

Organ Function ◽

Distant Organ

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Plasma Exchange for COVID-19 Thrombo-Inflammatory Disease

Blood ◽

10.1182/blood-2020-138851 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 27-27

Author(s):

Mari Thomas ◽

Nishkantha Arulkumaran ◽

David Brearley ◽

Ferras Alwan ◽

Deepak Singh ◽

...

Keyword(s):

Plasma Exchange ◽

Inflammatory Markers ◽

Ventilatory Support ◽

Kidney Injury ◽

Advisory Board ◽

Organ Function ◽

Period Effects ◽

Critically Ill Adults ◽

Von Willebrand ◽

D Dimer

Introduction Severe COVID-19 disease is associated with a hyperinflammatory, pro-thrombotic state and a high mortality. A thrombotic phenotype rather than a coagulopathy is suggested and we undertook plasma exchange to determine its effects on organ function and thrombo-inflammatory markers. Methods Plasma exchange was carried out in seven critically ill adults with severe COVID-19 respiratory failure (PaO2:FiO2 ratio <200 mmHg) requiring invasive or non-invasive ventilatory support and elevated thrombo-inflammatory markers (LDH>800 IU/L and D dimer>1000 µg/L (or doubling from baseline). Patients received a daily single volume 3 litre plasma exchange for a minimum of five days. No other immunomodulatory medications were initiated during this period. Effects on organ function, thrombo-inflammatory markers and complications were monitored. Seven patients matched for age and baseline biochemistry were a comparator group. Results Coagulation screening revealed no evidence of coagulopathy. However, von Willebrand Factor (VWF) activity, antigen and VWF antigen:ADAMTS13 ratio, Factor VIII and D-dimers were all elevated. Following five days of plasma exchange, plasma levels of all the above, and ferritin levels, were significantly reduced (p<0.05, Figure 1) while lymphocyte count normalized (p<0.05). The PaO2:FiO2 ratio increased from a median(IQR) of 11.6 (10.8- 19.7) kPa to 18.1 (16.0-25.9) kPa (p<0.05). Similar improvements were not observed in controls. Acute kidney injury (AKI) occurred among 5 patients in the control arm but not in patients who underwent plasma exchange. Conclusion Plasma exchange was associated with an improvement in oxygenation, decreased incidence of AKI, normalisation of lymphocytes and reduction in circulating thrombo-inflammatory markers including D-Dimer and VWF Ag:ADAMTS13 ratio. Disclosures Thomas: Ablynx: Honoraria, Other: Advisory Board; Bayer: Honoraria, Speakers Bureau; Sanofi: Honoraria, Other: Advisory Board. Scully:Takeda: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Shire/Takeda: Other: Advisory Board, Research Funding, Speakers Bureau; Novartis: Other: Advisory Board, Speakers Bureau; Takeda: Speakers Bureau; Ablynx/Sanofi: Consultancy, Other: Advisory Board, Speakers Bureau.

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Scarless repair of acute and chronic kidney injury in African Spiny mice (Acomys cahirinus)

10.1101/315069 ◽

2018 ◽

Cited By ~ 4

Author(s):

Daryl M. Okamura ◽

Chris M. Brewer ◽

Paul Wakenight ◽

Nadia Bahrami ◽

Kristina Bernardi ◽

...

Keyword(s):

Wound Repair ◽

Kidney Injury ◽

Organ Injury ◽

Solid Organ ◽

Internal Organs ◽

Terrestrial Mammals ◽

Medical Care Costs ◽

Spiny Mice ◽

Muroid Rodents ◽

And Function

SummarySolid organ fibrosis is a major burden on global health and medical care costs. Muroid rodents of the genus Acomys (African Spiny mice) are terrestrial mammals that evolved remarkable abilities to regenerate severe skin wounds without scar formation. However, whether scar-free wound repair in Acomys extends beyond skin to vital internal organs is not known. Here, we used two aggressive kidney injury models known to produce severe renal fibrosis and show that despite equivalent acute kidney injury, there was rapid restoration of nephron structure and function without fibrosis in Acomys compared to extensive fibrosis leading to renal failure in Mus musculus. These results suggest Acomys species have evolved genomic adaptations for wound healing that activate regenerative repair pathways not only in skin, but also in vital internal organs. Our findings have important implications for discovering a long-sought evolutionary solution to internal organ injury and regeneration.

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