Shedding Light on a Hidden Killer – Why Sepsis Is So Deadly

Worldwide, more people die of sepsis than of cancer.¹ Sepsis is defined as a dysregulated host response to an infection that ultimately leads to organ dysfunction. The condition is associated with various complications such as shock, a dangerous drop in blood pressure that may be of cardiac or a vascular etiology. In sepsis, one of the first and most affected organs is the kidney, often resulting in acute kidney injury (AKI).

The underlying pathomechanisms behind the clinical symptoms are often unclear and hard to detect in clinical routine. Thus, there is a high demand to identify a patient’s progression to sepsis and its more severe forms earlier, and to gain deeper insights about the pathological processes leading to this life-threatening condition (Figure 1).


Figure 1. The burden of sepsis and in vitro diagnostics. Credit: SphingoTec


This article will highlight the latest medical findings in the identification of the major pathways in sepsis and the real-time assessment of organ function using novel biomarkers.

How to improve patient outcomes and clinical decisions

Better diagnostics results in better therapy, thus medical advancements start at the beginning of the patient journey. The identification of new diagnostic molecules that are timely and informative can help clinicians understand the etiology of a patient’s clinical symptoms and support treatment decisions.

Three major pathways in sepsis have been identified which ultimately lead to mortality and offer potential as diagnostic targets:

1.      Endothelial dysfunction

In sepsis patients, vascular leakage and vasodilation may result in a dangerous blood pressure drop, resulting in septic shock.  Both symptoms are linked to the hormone bioactive adrenomedullin (bio-ADM). To re-seal the compromised endothelial barrier the body produces bio-ADM. But this hormone also has vasodilatory functions and expands the blood vessel, leading to a drop in blood pressure and hypoperfusion.

Organ hypoperfusion is monitored using lactate, a parameter that identifies reduced blood oxygenation of tissues and is used as a reference in the diagnosis of septic shock. However, lactate is rather unspecific and insensitive since it is influenced by many other physiological and pathological processes.

By measuring the levels of bio-ADM in the blood on top of lactate, it becomes possible to identify patients at risk of shock and guide hemodynamic therapy. Since bio-ADM is an active hormone, an increase or decrease in the blood levels also allows therapy success to be monitored.

2.      Cardiac depression

The cytosolic enzyme dipeptidyl peptidase 3 (DPP3) is normally found within cells, where it has a positive role of recycling cellular proteins. When uncontrolled cell death occurs, such as in sepsis, DPP3 is released into the blood stream where it cleaves angiotensin II, reducing the vascular tone and causing cardiac depression. Recent studies have demonstrated that circulating DPP3 is linked to severe organ dysfunction, worsening organ failure, need for hemodynamic treatments and short-term mortality. Early awareness of the severity of the situation enables more informed treatment decisions.^2,3

3.      Acute kidney injury

One in two patients with septic shock develops AKI and are at increased risk of both severe morbidity and higher mortality.⁴ Serum creatinine is the current diagnostic standard for AKI and is used to calculate the estimated glomerular filtration rate (eGFR), a surrogate parameter quantifying kidney function. Despite the widespread use of serum creatinine measurement, it has significant limitations as a tool for assessing the eGFR as it is delayed in information and influenced by certain medications, comorbidities and other nonrenal factors including age, gender and protein intake.

Accumulating evidence shows that by indirectly measuring the levels of the kidney-stimulating hormone enkephalin, the impaired renal function can be detected earlier.⁵ Proenkephalin (penKid) is a precursor hormone resulting from enkephalin production and has been shown to provide better representation of the true GFR in sepsis patients.⁶ Moreover, measuring the penKid levels can predict AKI, worsening of kidney function and organ failure independently from inflammation and other co-morbidities.

Sepsis management now and in the future

Clinicians today face a disease where the underlying mechanisms leading to organ dysfunction and mortality are unknown. Important information usually comes too late and is unspecific.

Appropriate therapies and organ support interventions are a cornerstone for successful treatment of patients with sepsis and each hour delay in therapeutic intervention represents a linear increase in the risk of mortality. In the evolution of the disease, novel biomarkers can help clinicians improve patient management by timely diagnosing and monitoring the function of the endothelium and of the kidney, and by assessing the risk of cardiac depression.⁷ The real-time assessment of organ function can support clinical decision in implementing personalized strategies, and in the timely initiation of organ support.

References:

1.       About Sepsis. The UK Sepsis Trust website. https://sepsistrust.org/about/about-sepsis/references-and-sources/. Accessed August 9, 2021.

2.       Mebazaa A, Geven C, Hollinger A, et al. Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study. Crit Care. 2018;22(1):354. doi: 10.1186/s13054-018-2243-2

3.       Blet A, Deniau B, Santos K, et al. Monitoring circulating dipeptidyl peptidase 3 (DPP3) predicts improvement of organ failure and survival in sepsis: a prospective observational multinational study. Crit Care. 2021 doi: 10.1186/s13054-021-03471-2

4.       Rosenqvist M, Bronton K, Hartmann O, Bergmann A, Struck J, Melander O. Proenkephalin a 119–159 (PenKid) – a novel biomarker for acute kidney injury in sepsis: an observational study. BMC Emerg Med. 2019;19(1):75. doi: 10.1186/s12873-019-0283-9

5.       Caironi P, Latini R, Struck J, et al. Circulating proenkephalin, acute kidney injury, and its improvement in patients with severe sepsis or shock. Clin Chem. 2018;64(9):1361-1369. doi: 10.1373/clinchem.2018.288068

6.       Beunders R, van Groenendael R, Leijte GP, Kox M, Pickkers P. Proenkephalin compared to conventional methods to assess kidney function in critically ill sepsis patients. Shock. 2020;54(3):308-314. doi: 10.1097/SHK.0000000000001510

7.       Van Lier D, Kox M, Pickkers P. Promotion of vascular integrity in sepsis through modulation of bioactive adrenomedullin and dipeptidyl peptidase 3. J Intern Med. 2021;289(6):792-806. doi: 10.1111/joim.13220