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Sepsis, a medical emergency

The global burden of sepsis world-wide counts for 49 million cases a year1, with a high mortality rate of 11 million2 deaths. In Germany alone, over 320,000 patients2 are affected by sepsis showing clearly that sepsis is not only a disease for poor or middle-income countries. Recent research has identified new molecules that are informative and help clinicians understand the etiology of the patient’s clinical symptoms, paving the way for a tailored medicine in the field of sepsis.

Bioactive adrenomedullin and endothelial function

One major cause of shock in sepsis is the loss of the endothelial function. The endothelium is the interior wall of the blood vessels that acts as a barrier separating the blood from its surroundings. The hormone controlling this barrier function is bioactive Adrenomedullin (bio-ADM). In sepsis patients, the blood vessels become leaky and more bio-ADM is produced to re-seal the compromised barrier. But this hormone also expands the blood vessel, leading to a drop in blood pressure. 

This blood pressure drop leads to organ hypoperfusion, which routinely is monitored using lactate, a parameter that identifies reduced blood oxygenation of tissue and is used for the diagnosis of septic shock. However, lactate is rather unspecific to sepsis and insensitive since it is influenced by many other physiological and pathological processes. By measuring the levels of bio-ADM in the blood, it is possible to early identify patients at risk of shock and guide vasoprotective therapy. Since bio-ADM is an active hormone, an increase or decrease in the blood levels also allows to monitor the therapy success.

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DPP3 and cardiac depression

Another cause of shock has cardiac etiology and recent research has identified a new disease mechanism leading to cardiac depression. The release of the cardiac depressant factor Dipeptidyl Peptidase 3 (DPP3) into the blood stream causes the inactivation of the heart-stimulating hormone Angiotensin II, a process leading to cardiac depression and consequently hemodynamic instability.

The cytosolic enzyme DPP3 is normally found intracellular where it has a positive role of recycling cellular proteins. But when  uncontrolled cell death occurs, DPP3 is released into the blood stream where it encounters its substrate angiotensin II. Recent studies have demonstrated that circulating DPP3 is a major cause for severe organ dysfunction in patients with worsening hemodynamics. The enzyme has a short half-life, this is why the DPP3 blood levels are changing dynamically according to the patient status and monitoring the blood levels of circulating DPP3 can quickly identify those patients at high risk of developing short-term organ dysfunction.

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Proenkephalin and true glomerular filtration rate

Sepsis is a condition in which mortality is linked to organ dysfunction, and acute kidney injury occurs in 40-50% of septic patients.3 One in two patients with septic shock develop AKI and are at increased risk of both severe morbidity and higher mortality. Serum creatinine (SCr) is the current diagnostic standard and is used to calculate the estimated glomerular filtration rate (eGFR), a surrogate parameter quantifying kidney function.

This assessment though requires serial measurements and creatinine metabolism is affected by inflammation, fluid overload and the use of nephrotoxic agents.4,5,6 Accumulating evidence shows that by indirectly measuring the levels of the kidney-stimulating hormone enkephalin, the impaired renal function can be earlier detected. Proenkephalin (penKid) is a precursor hormone resulting out of enkephalin production and has been shown to provide the best representation of the true glomerular filtration rate (true GFR) in normal subjects and critical care patients.7 Moreover, measuring the penKid levels can predict AKI, and worsening and improving of kidney function independently from inflammation and other comorbidities.4

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Biomarkers impact on health and disease

Appropriate therapies and organ support interventions are cornerstone for the success in the treatment of patients with sepsis and each hour delay in the therapeutic intervention represents a linear increase in the risk of mortality8.

Later in the evolution of the disease, the novel biomarkers for acute care settings can help clinicians improve the patient management by timely diagnosing and monitoring the function of the endothelium (bio-ADM) and of the kidney (penKid), and by assessing the risk of cardiac depression due to the release of the DPP3 enzyme. The real-time assessment of these important organs can support clinical decision in implementing personalized vaso- and nephroprotective strategies, and in the timely initiation of organ support.

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IB10 sphingotest® bio-ADM® and penKid® are rapid point-of-care (POC) immunoassays available on our Nexus IB10 platform.

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Reference Literature

1. Rudd et al (2020), Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study, The Lancet, DOI:https://doi.org/10.1016/S0140-6736(19)32989-7
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2. C Fleischmann-Struzek et al (2018), Challenges in assessing the burden of sepsis and understanding the inequalities of sepsis outcomes between National Health Systems: secular trends in sepsis and infection incidence and mortality in Germany, Intensive Care Med, DOI: 10.1007/s00134-018-5377-4
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3. Gomez et al (2016), Sepsis-induced acute kidney injury, Curr Opin Crit Care, DOI: 10.1097/MCC.0000000000000356
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4. Caironi P, et al. (2018): Circulating Proenkephalin, acute kidney injury, and its improvement in patients with severe Sepsis or shock. Clin Chem. doi: 10.1373/clinchem.2018.288068
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5. Moledina DG, et al. (2018): Phenotyping of acute kidney injury: beyond serum Creatinine. Semin Nephrol. doi: 10.1016/j.semnephrol.2017.09.002.
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6. Ronco C. (2016): Acute kidney injury: from clinical to molecular diagnosis. Critical Care. Doi: 10.1186/s13054-016-1373-7.
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7. Beunders, R. et al., Proenkephalin compared to conventional methods to assess kidney function in critically ill sepsis patients, Shock,, doi:10.1097/SHK.0000000000001510
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8. Ferrer et al (2014), Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program, Crit Care Med, DOI: 10.1097/CCM.0000000000000330
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