Acute Care

sphingotest® penKid®


 

UNLOCK TRUE GFR ASSESSMENT

The in vivo measurement of true glomerular filtration rate (GFR) via inulin- related methods is considered the gold standard of assessing kidney function. Nevertheless, determination of true GFR remains complicated, time consuming, expensive and an invasive intervention that is only available for some – until now.

sphingotecs penKid® allows the measurement of actual kidney function with a simple blood draw. Being non- inferior to the gold standard, rising and decreasing penKid® values reveal worsening and improving of kidney function independent from inflammation or any other comorbidity, allowing the inclusion of all critical ill patients.

Reflecting true GFR, penKid® enables the prediction, diagnosis and monitoring of acute kidney injury (AKI) up to two days earlier than serum creatinine (SCr), the gold standard to estimate GFR in today’s daily routine. Knowing about the limitations of serum creatinine such as influence of age, sex or muscle mass the greatest restriction is it’s late response to changing kidney function leading to periods without information. Filling these gaps with adding a marker for true GFR will facilitate close monitoring, improve treatment decisions and reduce mortality in patients with impaired kidney function.
 

 

PROENKEPHALIN

Proenkephalin119-159 (brand name penKid®), is a prohormone fragment of the Proenkephalin A precursor molecule. Proenkephalin A is cleaved into enkephalin peptides, which are biological active and known to stimulate kidney function. Enkephalins are predominantly produced by the heart and kidney with receptors mainly located in the kidney – indicating its role for renal function. Due to the short half-life of enkephalins, the assessment of blood concentrations remained difficult. Sphingotec overcomes this technical hurdle by measuring the stable fragment Proenkephalin119-159 which is produced in equal molar concentrations to enkephalins and fulfills all criteria of a biomarker for laboratory routine.

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IN A NUTSHELL

  •  penKid® plasma concentration represents real-time glomerular filtration rate
  • penKid® predicts future change in serum creatinine up to two days in advance independently from inflammation or any other comorbidities
  •  penKid® enables early prediction, diagnosis and monitoring of acute kidney injury in critical ill patients
  •  penKid® aids medical decision making on treatment with nephrotoxic drugs, renal replacement therapy and hospital discharge
  •  penKid® is applicable in all clinical settings and predicts worsening and improving renal function
  •  sphingotest® penKid® immunoassay measures Proenkephalin119-159 a stable surrogate for the kidney stimulating hormone enkephalin

REFERENCES


[1] Marino et.al. (2015) Diagnostic and short-term prognostic utility of plasma pro-enkephalin (pro-ENK) for acute kidney injury in patients admitted with sepsis
[2] Leijte et. al. (2017) Proenkephalin, the new marker for kidney function on the Intensive Care Unit?
[3] Beunders et. al. (2017) Proenkephalin (PENK) as a Novel Biomarker for Kidney Function
[4] Ng et.al. (2017) Proenkephalin, Renal Dysfunction, and Prognosis in Patients With Acute Heart Failure
[5] Ernst et. al. (2006) Proenkephalin A 119-159, a stable proenkephalin A precursor fragment identified in human circulation
[6] Melander et.al. (2016) Stable Peptide of the Endogenous Opioid Enkephalin Precursor and Breast Cancer Risk
[7] Arbit (2016) Prognostic Usefulness of Proenkephalin in Stable Ambulatory Patients With Heart Failure
[8] Gayat (2018) Back-to-back comparison of penKID with NephroCheck to predict acute kidney injury at admission in intensive care unit a brief report
[9] Kienecker (2018) Proenkephalin and risk of developing chronic kidney disease the Prevention of Renal and Vascular End stage Disease study
[10] Kim (2017) Proenkephalin, Neutrophil Gelatinase-Associated Lipocalin, and estimated glomerular filtration rates in patients with sepsis
[11] Mossanen (2017) Elevated Soluble Urokinase Plasminogen Activator Receptor and Proenkephalin Serum Levels Predict the Development of Acute Kidney Injury after Cardiac Surgery
[12] Ng (2014) Proenkephalin and prognosis after acute myocardial infarction
[13] Shah (2015) Proenkephalin predicts acute kidney injury in cardiac surgery patients
[14] Siong Chan (2018) Proenkephalin in Heart Failure
[15] Schulz (2017) High Level of Fasting Plasma Proenkephalin-A Predicts Deterioration of Kidney Function and Incidence of CKD
[16] Matsue (2016) Clinical correlates and prognostic value of Pro-Enkephalin in acute and chronic heart failure
[17] Holaday JW. et. al. (1983) Cardiovascular effects of endogenous opiate systems
[18] Denning et. al. (2008) Proenkephalin expression and enkephalin release are widely observed in non-neuronal tissues

sphingotest® bio-ADM®


 

UNLOCK THE ASSESSMENT OF VASCULAR INTEGRITY

Endothelial dysfunction or loss of vascular integrity is a common root for severe and life threatening disease such as septic shock and congestion in acute heart failure patients. Until now, there was no tool to identify patients with impaired endothelial function, which could aid the evaluation of critical ill patients and thereby aid decision-making.
Now, sphingotecs bio-ADM®, is closing this gap and allows the timely assessment of endothelial dysfunction with a simple blood draw. Rising and decreasing bio-ADM® values reveal worsening and improving of vascular integrity independent from inflammation or any other comorbidity, allowing the inclusion of all critical ill patients. Reflecting the current vascular status, bio-ADM® enables the prediction, diagnosis and monitoring of septic shock up to two days before blood pressure breakdown - and vice versa - the improvement of vascular function leading to better outcomes.
 

 
Furthermore bio-ADM® allows the evaluation of the congestion status of acute heart failure patients in which residual congestion remains poorly assessable. Currently approving diagnosis of complete decongestion with lab results is an obstacle, which concludes to 25% re-hospitalizations within 30 days. The evaluation of bio-ADM® opens an unprecedented opportunity to aid decisions by enabling diagnosis and monitoring of residual congestion.
 

BIOACTIVE ADRENOMEDULLIN

Bioactive Adrenomedullin (bio-ADM®) is a vasoactive peptide hormone, mainly secreted by the endothelial cells and smooth muscles cells, surrounding the blood vessel. bio-ADM® is a protective factor of vascular integrity that stabilizes the endothelial barrier and prevents vascular leakage. Furthermore, bioactive Adrenomedullin is known as a vasodilation factor that acts of vascular smooth muscle cells and regulates blood pressure by regulating blood vessel width.
 


  
Like most peptide hormones, Adrenomedullin is excised from a larger precursor molecule (prohormone). The resulting prohormone fragments are secreted into the bloodstream, but do not possess any biological activity. However, only a certain amount (5-20%) of ADM is converted into biologically active Adrenomedullin. Furthermore, in contrast to prohormone fragments, bio-ADM® plasma levels change dynamically, in correspondence to the changing clinical status of the patient – making it possible to get timely information about the demand for decongestion in acute heart failure and for vasopressors in patients with risk of shock, e.g. in sepsis.
 

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IN A NUTSHELL

  •  sphingotest® bio-ADM® measures the bioactive form of Adrenomedullin, a small soluble peptide mainly released by endothelial cells
  •  bio-ADM® controls vascular integrity – highly relevant for blood pressure control and organ perfusion
  •  bio-ADM® plasma level change dynamically, in correspondence to the changing clinical status of the patient
  •  Measuring bio-ADM® in plasma gives timely information about the demand for decongestive treatment in acute heart failure and for vasopressors in patients with risk of shock, e.g. in septic shock
  •  bio-ADM® is the only marker able to predict and monitor septic shock
  •  bio-ADM® is the only marker able to predict residual congestion in patients with acute heart failure
  •  bio-ADM® aids reducing mortality, re-hospitalization and hospital costs

REFERENCES


[1] Caironi (2017) Circulating Biologically Active Adrenomedullin (bio-ADM) Predicts Hemodynamic Support Requirement and Mortality During Sepsis
[2] Gayat (2018) Determinants of long-term outcome in ICU survivors results from the FROG-ICU study
[3] Geven et.al. (2018) Adreomedullin & Adrenomedullin targeted therapy as treatment strategies relevant for sepsis
[4] Marino (2014) Plasma adrenomedullin is associated with short therm mortality
[5] Self (2016) Plasma bioactive adrenomedullin as a prognostic biomarker in acute heart failure
[6] Simon (2016) Plasma Adrenomedullin in Critically Ill Patients with Sepsis after Major surgery a pilot study
[7] Struck (2013) Epitope specificity of anti-Adrenomedullin antibodies determines efficacy of mortality reduction in a cecal ligation and puncture mouse model
[8] Tolppanen (2017) Adrenomedullin a marker of impaired hemodynamics, organ dysfunction, and poor prognosis in cardiogenic shock
[9] Wagner (2013) Adrenomedullin binding improves catecholamine responsiveness and kidney function in resuscitated murine septic shock
[10] Weber (2017) Sandwich Immunoassay for Bioactive Plasma Adrenomedullin
[11] Yuyun (2016) Prognostic value of human mature adrenomedullin in patients with acute myocardial infarction

ACUTE HEART FAILURE


 
Acute heart failure (AHF) is a relevant public health problem causing the majority of unplanned hospital admissions in patients age 65 years and above. Despite major achievements in the treatment of chronic heart failure (HF) over the last decades, which led to improvement in long-term survival, outcomes of AHF remain poor with a short-term rehospitalisation rate of up to 25 % and 1-year mortality rates reaching up to 30%.

Brain Natriuretic Peptide (BNP) and NT pro-BNP are the current “gold standards” for heart failure diagnosis and commonly used worldwide. BNP is a hormone released by the heart when the ventricles are stretched e.g. by fluid overload. BNP protects the heart from consequences of overload by e.g. increasing natriuresis and diuresis. In heart failure, BNP levels are increased and used to exclude or confirm a diagnosis of heart failure. As 90 % of all acute heart failure cases are accompanied by massive congestion, primary therapy is the treatment with diuretics to reduce symptoms. Subsequent residual congestion at the time of discharge leads to death, or to cost-intensive re–hospitalization. Only two third of the patients respond to diuretic therapy and until now there was no diagnostic tool that aids in monitoring treatment efficacy.

penKid® and bio-ADM® complete diagnostic management tools together with BNP

Proenkephalin (penKid®) as a biomarker of kidney function, closes the gap in kidney control as currently available marker are too late, are influenced by comorbidities such as inflammation or indicating damage and not kidney function. penKid® enables early prediction, diagnosis and monitoring of acute kidney injury (AKI) in order to assess kidney function of critical ill patients - including AHF patients. Treating AHF patients with diuretics is a double-edged sword requiring both, the monitoring of impact on kidney function but also the monitoring of treatment success until complete decongestion.

Bioactive Adrenomedullin (bio-ADM®) is the only available tool that allows the diagnosis of residual congestion in AHF patients. By assessing vascular function it becomes possible to monitor treatment success in patients requiring decongestive treatment e.g. diuretics. This information aids in treatment and discharge decisions – reducing mortality, re-hospitalization and hospital costs.

Currently a promising drug candidate targeting bio-ADM®, the monoclonal and humanized antibody ADRECIZUMAB, is evaluated in a Phase – II double-blinded clinical trial to demonstrate Safety and Tolerability in patients with impaired vascular integrity.

Brain Natriuretic Peptide (BNP), as gold standard for diagnosing Heart Failure in combination with sphingotest® penKid® as kidney function marker and sphingotest® bio-ADM® to diagnose residual congestion, opens unprecedented opportunities for patient management.

SEPSIS


 
Sepsis, as the major cause of death and major cost-driver in intensive care units worldwide is a challenge physician’s face every day. A sepsis begins with a systemic bacterial infection which leads to an overwhelming host response. Systemic inflammation causing poor organ perfusion, which is followed by organ dysfunction. The kidney, with a high rate of blood perfusion, is commonly the first organ failing due to hypo-perfusion which then subsequent leads to multi-organ failure. Extensive vasodilation and vascular leakage are resulting in circulatory breakdown also known as septic shock.

penKid® and bio-ADM® complete diagnostic management tools together with PCT

Procalcitonin (PCT) is the “gold standard” for sepsis management. PCT reflects bacterial infection and systemic response as well as its severity. PCT kinetics in routine are used to adequately monitor antibacterial therapy and have been proven to safely shorten administration times of antibiotics. Managing sepsis with daily monitoring of PCT can substantial cut hospital costs.
The new sepsis definition (sepsis-3) defines sepsis as life-threating organ dysfunction due to dys-regulated host-response. Including organ dysfunction as criteria for sepsis underlines the need of biomarker that early and specific identify patients at risk. For improving outcome and reduce in-hospital costs, monitoring of the actual organ function is needed to guide and improve treatment decisions.

Proenkephalin (penKid®) as a biomarker of kidney function closes the gap in kidney control as currently available marker are too late, are influenced by comorbidities such as inflammation or indicating damage and not kidney function. penKid® enables early prediction, diagnosis and monitoring of acute kidney injury (AKI) in order to assess kidney function of critical ill patients - including sepsis patients. Monitoring penKid® in conjunction with PCT allows the control of both, the good effects of anti-microbial treatments as well as the kidney harming side effects which can be early detected measuring penKid®. Besides loss of organ function, one third of all patients will develop septic shock during they stay.

Bioactive Adrenomedullin (bio-ADM®) is the only available tool to predict the patient’s progression into shock. Diagnosis of patients with shock is simply done by measuring blood pressure. Once the blood pressure decreases, treatment options are rare and today, patients diagnosed with septic shock, have a poor prognosis with mortality rates of up to 80 %. Early intervention by vasopressors can reduce mortality in septic shock patients by 8 % with every hour of earlier treatment. bio-ADM® is able to reduce the time to intervention by simply adding information which is not available till now. It’s dynamic nature allows on top the monitoring of patients at risk. This aids in treatment and discharge decisions – reducing mortality and hospital costs.

Currently a promising drug candidate targeting bio-ADM®, the monoclonal and humanized antibody ADRECIZUMAB, is evaluated in a Phase – II double-blinded clinical trial to demonstrate Safety and Tolerability in patients with impaired vascular integrity.

Procalcitonin (PCT), as gold standard for monitoring of antibiotic treatment success in combination with sphingotest® penKid® as kidney function marker and sphingotest® bio-ADM® to predict septic shock, opens unprecedented opportunities for patient management

IB10 SPHINGOTEST® DPP3

The Assay for Dipeptidyl Peptidase 3, a unique Biomarker for Signaling Pathway
Disruptions Leading to Acute Organ Dysfunction.

IN A NUTSHELL

Dipeptidyl Peptidase 3 (DPP3) is an enzyme at the core of a recently discovered disease mechanism resulting in acute myocardial depression. The degradation of the cardiovascular and renal mediators’ angiotensin II and enkephalin by circulating DPP3 causes signaling pathway disruptions leading to short-term organ dysfunction.1, 2
DPP3 aids in:

  • Stratification of patients at high risk to develop short-term organ dysfunction
  • Guidance for induction or escalation of therapy
  • Monitoring of treatment success

(1)Rising DPP3 blood concentrations, caused by cell death, indicates short-term organ dysfunction.

(2)Decreasing DPP3 blood concentrations indicates successful intervention, whereas increasing or continuously elevated levels identify non-responders.

IB10 sphingotest ® DPP3 is available on whole-blood point of care platform Nexus IB10., delivering results in 20 minutes.

DIPEPTIDYL PEPTIDASE 3

Dipeptidyl Peptidase 3 (DPP3) is a highly conserved, ubiquitously expressed cytosolic peptidase. Due to its substrate specificity, DPP3 plays a role in protein metabolism, blood pressure regulation, pain modulation, and inflammatory processes. The two most prominent DPP3 substrates are the bioactive peptides enkephalin (Enk), which regulates kidney function, and angiotensin II (Ang II), which regulates blood pressure and is activated in cardiovascular diseases, sepsis and septic shock. Many diseases such as acute heart failure, septic shock, myocardial infarction, cardiogenic shock, stroke or burns, are associated with cell death which lead to uncontrolled DPP3 release into the circulation and subsequently to the degradation of its substrates. As a result, Ang II and Enk mediated peptide signaling pathways are disrupted, which leads to organ failure. Thus, high DPP3 plasma levels could be used as indicator for organ dysfunction and as an early predictor of organ failure. Furthermore, high DPP3 blood concentrations have been shown to predict short term mortality. A normalization of DPP3 concentrations within 24 hours immensely improves the patient prognosis and outcome, indicating successful treatment of the patient.

In healthy state, DPP3 is located intracellularly (1a) and is not exposed to its substrate’s angiotensin II (mediator of heart function) and enkephalin (mediator of kidney function). The mediators are active (1b) and maintain normal organ function (1c).

In a diseased state, cell death results in the uncontrolled release of DPP3 (2a). Heart and kidney mediators angiotensin II and enkephalin are then cleaved and inactivated by DPP3 (2b), which subsequently leads to organ dysfunction (2c). DPP3 has not only been identified, as a valuable biomarker but also, as a potent biotarget. 4TEEN4 Pharmaceuticals, is currently developing a DPP3 neutralizing antibody, namely PROCIZUMAB. PROCIZUMAB is under development as a treatment for patients with acute myocardial depression and currently investigated in pre-clinical models.

REFERENCES


[1] Deniau (2019) Circulating dipeptidyl peptidase-3 is a myocardial depressant factor: DPP3 inhibition rapidly and sustainably improves hemodynamics, European Journal of Heart Failure
[2] Takagi (2019) Circulating dipeptidyl-peptidase 3 and alteration in hemodynamics in cardiogenic shock: Results from the OptimaCC Trial, European Journal of Heart Failure
[3] Rehfeld et al. (2018) Novel Methods for the Quantification of Dipeptidyl Peptidase 3 (DPP3) Concentration and Activity in Human Blood Samples

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