Picomolar Sensitivity Analysis of Multiple Bradykinin-Related Peptides in the Blood Plasma of Patients With Hereditary Angioedema in Remission: A Pilot Study

Marceau, François; Rivard, Georges‐Étienne; Hébert, Jacques; Gauthier, Julie; Bachelard, Hélène; Gangnus, Tanja; Burckhardt, Bjoern B.

doi:10.3389/falgy.2022.837463

Cited by 4 publications

(3 citation statements)

References 33 publications

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“…The biomarkers of kinin-mediated disorders include the consumption of kininogen(s) and the detection of circulating kinin metabolites such as fragments BK 1-5 and BK 2-9 , and the detection of plasma kallikrein activity, for instance, using the synthetic substrate based on the C-terminal BK sequence HD-Pro-Phe-Arg-pNA. These assays are technically challenging, but one or more of them have been applied to hereditary angioedema (HAE), either during attacks or in remission [15,16] to other edematous conditions such as ascites, secondary to liver cirrhosis [17] and chronic urticaria [18,19], and to animal models of sepsis and sickle cell disease [20,21].…”

Section: Kallikrein-kinin Systems: the Formation And Clearance Of Kininsmentioning

confidence: 99%

Drugs of the Kallikrein–Kinin System: An Overview

Marceau

2023

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The kallikrein–kinin system consists of the two kininogen substrates present in the blood plasma, and two serine proteases: the plasma and tissue kallikreins. The action of the latter on kininogens produces small peptides, the kinins, short-lived, but endowed by powerful pharmacologic actions on blood vessels and other tissues. Many recent and exciting therapeutic developments in the field are briefly summarized. Notably, various novel strategies are being clinically developed to inhibit the formation of bradykinin or block its receptors in the management of hereditary angioedema. The interventions include orally bioavailable drugs, biotechnological proteins, and gene therapy. These approaches are currently explored in a variety of other inflammatory and thrombotic disorders. Harnessing controlled kinin formation is also of potential therapeutic interest, as shown by the clinical development of recombinant tissue kallikrein for ischemic stroke and renal disease. The biomarkers of kinin-mediated disorders, frequently implicating edemas, include the consumption of kininogen(s), plasma kallikrein activity, and the detection of circulating kinin metabolites such as fragments BK1–5 and BK2–9. Novel opportunities to clinically apply the underexploited drugs of the kallikrein–kinin system are briefly reviewed. This personal perspective is offered by an observer of and a participant in drug characterization throughout the last four decades.

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Section: Kallikrein-kinin Systems: the Formation And Clearance Of Kininsmentioning

confidence: 99%

Drugs of the Kallikrein–Kinin System: An Overview

Marceau

2023

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“…With advancing scientific methodology, kinins may evolve into promising biomarkers in the future. First attempts were made by applying the here presented approach also to plasma levels in hereditary angioedema patients [ 41 ]. In hereditary angioedema with C1 esterase inhibitor deficiency in remission, a significant increase in BK 2-9 , BK 1-5 and the sum of eleven kinins was found when compared to a healthy collective.…”

Section: Discussionmentioning

confidence: 99%

Mass spectrometric study of variation in kinin peptide profiles in nasal fluids and plasma of adult healthy individuals

2022

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Background The kallikrein-kinin system is assumed to have a multifunctional role in health and disease, but its in vivo role in humans currently remains unclear owing to the divergence of plasma kinin level data published ranging from the low picomolar to high nanomolar range, even in healthy volunteers. Moreover, existing data are often restricted on reporting levels of single kinins, thus neglecting the distinct effects of active kinins on bradykinin (BK) receptors considering diverse metabolic pathways. A well-characterized and comprehensively evaluated healthy cohort is imperative for a better understanding of the biological variability of kinin profiles to enable reliable differentiation concerning disease-specific kinin profiles. Methods To study biological levels and variability of kinin profiles comprehensively, 28 healthy adult volunteers were enrolled. Nasal lavage fluid and plasma were sampled in customized protease inhibitor prespiked tubes using standardized protocols, proven to limit inter-day and interindividual variability significantly. Nine kinins were quantitatively assessed using validated LC–MS/MS platforms: kallidin (KD), Hyp4-KD, KD1-9, BK, Hyp3-BK, BK1-8, BK1-7, BK1-5, and BK2-9. Kinin concentrations in nasal epithelial lining fluid were estimated by correlation using urea. Results Circulating plasma kinin levels were confirmed in the very low picomolar range with levels below 4.2 pM for BK and even lower levels for the other kinins. Endogenous kinin levels in nasal epithelial lining fluids were substantially higher, including median levels of 80.0 pM for KD and 139.1 pM for BK. Hydroxylated BK levels were higher than mean BK concentrations (Hyp3-BK/BK = 1.6), but hydroxylated KD levels were substantially lower than KD (Hyp4-KD/KD = 0.37). No gender-specific differences on endogenous kinin levels were found. Conclusions This well-characterized healthy cohort enables investigation of the potential of kinins as biomarkers and would provide a valid control group to study alterations of kinin profiles in diseases, such as angioedema, sepsis, stroke, Alzheimer’s disease, and COVID-19.

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“…In addition, a newly developed LC-MS/MS methodology for the measurement of plasma peptides in the kallikrein-kinin system [51] might be helpful as well. This method has been successfully used to detect increased concentrations of the bradykinin metabolites bradykinin 1-5 and bradykinin 2-9 in patients with HAE [52] representing uncertain cases of drug-induced-angioedema mediated by bradykinin. Nevertheless, it is not yet established in everyday clinical practice and further research and a structured guideline is necessary.…”

Section: Drug-induced-angioedema Mediated By Bradykininmentioning

confidence: 99%

Bradykinin-Mediated Angioedema Induced by Commonly Used Cardiovascular Drugs

Hahn,

Greve,

Bas

et al. 2023

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ACE inhibitors, sartans, and sacubitril are among the most important drugs for the prevention of cardiovascular mortality and morbidity. At the same time, they are known to cause non-allergic bradykinin-mediated angioedema, a potentially fatal swelling of the mucosa and/or submucosa and deeper skin without signs of urticaria or pruritus, occurring mainly in the head and neck region. In contrast with hereditary angioedema, which is also mediated by bradykinin, angioedema triggered by these drugs is by far the most common subtype of non-allergic angioedema. The molecular mechanisms underlying this type of angioedema, which are discussed here, are not yet sufficiently understood. There are a number of approved drugs for the prevention and treatment of acute attacks of hereditary angioedema. These include inhibitors of bradykinin synthesis that act as kallkrein inhibitors, such as the parenterally applied plasma pool, and recombinant C1 esterase inhibitor, ecallantide, lanadelumab, and the orally available berotralstat, as well as the bradykinin receptor type 2 antagonist icatibant. In contrast, no diagnostic tools, guidelines, or treatments have yet been approved for the diagnosis and treatment of acute non-allergic drug-induced angioedema, although it is more common and can take life-threatening courses. Approved specific drugs and a structured diagnostic workflow are needed for this emergency diagnosis.

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Picomolar Sensitivity Analysis of Multiple Bradykinin-Related Peptides in the Blood Plasma of Patients With Hereditary Angioedema in Remission: A Pilot Study

Cited by 4 publications

References 33 publications

Drugs of the Kallikrein–Kinin System: An Overview

Drugs of the Kallikrein–Kinin System: An Overview

Mass spectrometric study of variation in kinin peptide profiles in nasal fluids and plasma of adult healthy individuals

Bradykinin-Mediated Angioedema Induced by Commonly Used Cardiovascular Drugs

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