Decreased plasma kallikrein activity is associated with reduced kidney function in individuals with type 1 diabetes

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Abstract

Aims/hypothesis

Plasma kallikrein is the central mediator of the plasma kallikrein–kinin system, which is involved both in vascular control and thrombin formation cascades. The plasma kallikrein–kinin system has also been considered protective in pathological conditions, but the impact of plasma kallikreins on diabetic nephropathy remains unknown. The objective of this cross-sectional study was to explore the association of plasma kallikrein with diabetic nephropathy.

Methods

We measured plasma kallikrein activity in 295 individuals with type 1 diabetes at various stages of diabetic nephropathy, and we tested the genetic association between the plasma kallikrein–kinin system and kidney function in 4400 individuals with type 1 diabetes.

Results

Plasma kallikrein activity was associated with diabetes duration ( p < 0.001) and eGFR ( p < 0.001), and plasma kallikrein activity was lower with more advanced diabetic nephropathy, being lowest in individuals on dialysis. The minor alleles of the KNG1 rs5030062 and rs710446 variants, which have previously been associated with increased plasma pre-kallikrein and/or factor XI (FXI) protein levels, were associated with higher eGFR (rs5030062 β = 0.03, p = 0.01; rs710446 β = 0.03, p = 0.005) in the FinnDiane cohort of 4400 individuals with type 1 diabetes.

Conclusions/interpretation

Plasma kallikrein activity and genetic variants known to increase the plasma kallikrein level are associated with higher eGFR in individuals with type 1 diabetes, suggesting that plasma kallikrein might have a protective effect in diabetic nephropathy.

Electronic supplementary material

The online version of this article (10.1007/s00125-020-05144-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Most cited references 14

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Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989–2013: a multicentre prospective registration study

Christopher C. Patterson, Valma Harjutsalo, Joachim Rosenbauer … (2018)

Against a background of a near-universally increasing incidence of childhood type 1 diabetes, recent reports from some countries suggest a slowing in this increase. Occasional reports also describe cyclical variations in incidence, with periodicities of between 4 and 6 years.

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Contact system revisited: an interface between inflammation, coagulation, and innate immunity.

A T Long, E Kenne, R Jung … (2016)

The contact system is a plasma protease cascade initiated by factor XII (FXII) that activates the proinflammatory kallikrein-kinin system and the procoagulant intrinsic coagulation pathway. Anionic surfaces induce FXII zymogen activation to form proteolytically active FXIIa. Bacterial surfaces also have the ability to activate contact system proteins, indicating an important role for host defense using the cooperation of the inflammatory and coagulation pathways. Recent research has shown that inorganic polyphosphate found in platelets activates FXII in vivo and can induce coagulation in pathological thrombus formation. Experimental studies have shown that interference with FXII provides thromboprotection without a therapy-associated increase in bleeding, renewing interest in the FXIIa-driven intrinsic pathway of coagulation as a therapeutic target. This review summarizes how the contact system acts as the cross-road of inflammation, coagulation, and innate immunity.

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The kallikrein-kinin system in health and in diseases of the kidney.

Oliver Smithies, Masao Kakoki (2009)

Since kallikrein was discovered as a vasodilatory substance in human urine, the kallikrein-kinin system (KKS) has been considered to play a physiological role in controlling blood pressure. Gene targeting experiments in mice in which the KKS has been inactivated to varying degrees have, however, questioned this role, because basal blood pressures are not altered. Rather, these experiments have shown that the KKS has a different and important role in preventing changes associated with normal senescence in mice, and in reducing the nephropathy and accelerated senescence-associated phenotypes induced in mice by diabetes. Other experiments have shown that the KKS suppresses mitochondrial respiration, partly by nitric oxide and prostaglandins, and that this suppression may be a key to understanding how the KKS influences senescence-related diseases. Here we review the logical progression and experimental data leading to these conclusions, and discuss their relevance to human conditions.

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Author and article information

Contributors

Per-Henrik Groop:

ORCID: https://orcid.org/0000-0003-4055-6954

per-henrik.groop@helsinki.fi

Journal

Journal ID (nlm-ta): Diabetologia

Journal ID (iso-abbrev): Diabetologia

Title: Diabetologia

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0012-186X

ISSN (Electronic): 1432-0428

Publication date (Electronic): 8 April 2020

Publication date PMC-release: 8 April 2020

Publication date (Print): 2020

Volume: 63

Issue: 7

Pages: 1349-1354

Affiliations

[1 ]Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland

[2 ]GRID grid.7737.4, ISNI 0000 0004 0410 2071, Abdominal Center Nephrology, , University of Helsinki and Helsinki University Hospital, ; Helsinki, Finland

[3 ]GRID grid.7737.4, ISNI 0000 0004 0410 2071, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, , University of Helsinki, ; Helsinki, Finland

[4 ]GRID grid.1002.3, ISNI 0000 0004 1936 7857, Department of Diabetes, Central Clinical School, , Monash University, ; Melbourne, VIC Australia

Author information

Per-Henrik Groop https://orcid.org/0000-0003-4055-6954

Article

Publisher ID: 5144

DOI: 10.1007/s00125-020-05144-1

PMC ID: 7286847

PubMed ID: 32270254

SO-VID: 696a670a-354e-44d9-8d9a-72dda1d5b052

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 9 December 2019

Date accepted : 5 March 2020

Funding

Funded by: University of Helsinki including Helsinki University Central Hospital

Open Access :

Open access funding provided by University of Helsinki including Helsinki University Central Hospital.

Custom metadata

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: diabetic nephropathy,kidney function,plasma kallikrein,plasma kallikrein–kinin system,type 1 diabetes

Data availability:

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: diabetic nephropathy, kidney function, plasma kallikrein, plasma kallikrein–kinin system, type 1 diabetes

Decreased plasma kallikrein activity is associated with reduced kidney function in individuals with type 1 diabetes

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Abstract

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Electronic supplementary material

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Journal of the ASEAN Federation of Endocrine Societies

Most cited references 14

Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989–2013: a multicentre prospective registration study

Contact system revisited: an interface between inflammation, coagulation, and innate immunity.

The kallikrein-kinin system in health and in diseases of the kidney.

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