Plasma heparin cofactor II activity is inversely associated with albuminuria and its annual deterioration in patients with diabetes

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Abstract

Aims/Introduction

Thrombin exerts various pathophysiological functions by activating protease‐activated receptors (PARs). Recent data have shown that PARs influence the development of glomerular diseases including diabetic kidney disease (DKD) by regulating inflammation. Heparin cofactor II (HCII) specifically inactivates thrombin; thus, we hypothesized that low plasma HCII activity correlates with DKD development, as represented by albuminuria.

Materials and Methods

Plasma HCII activity and spot urine biomarkers, including albumin and liver‐type fatty acid‐binding protein (L‐FABP), were determined as the urine albumin‐to‐creatinine ratio (uACR) and the urine L‐FABP‐to‐creatinine ratio (uL‐FABPCR) in 310 Japanese patients with diabetes mellitus (176 males and 134 females). The relationships between plasma HCII activities and those DKD urine biomarkers were statistically evaluated. In addition, the relationship between plasma HCII activities and annual uACR changes was statistically evaluated for 201/310 patients (115 males and 86 females).

Results

The mean plasma HCII activity of all participants was 93.8 ± 17.7%. Multivariate‐regression analysis including confounding factors showed that plasma HCII activity independently contributed to the suppression of the uACR and log‐transformed uACR values ( P = 0.036 and P = 0.006, respectively) but not uL‐FABPCR ( P = 0.541). In addition, plasma HCII activity significantly and inversely correlated with annual uACR and log‐transformed uACR increments after adjusting for confounding factors ( P = 0.001 and P = 0.014, respectively).

Conclusions

The plasma HCII activity was inversely and specifically associated with glomerular injury in patients with diabetes. The results suggest that HCII can serve as a novel predictive factor for early‐stage DKD development, as represented by albuminuria.

Abstract

Plasma HCⅡ activity is significantly and inversely associated with urinary albumin excretion but not liver‐type fatty acid‐binding protein in Japanese patients with diabetes.

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Most cited references 34

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Relation between kidney function, proteinuria, and adverse outcomes.

Brenda R. Hemmelgarn, Braden J. Manns, Anita Lloyd … (2010)

The current staging system for chronic kidney disease is based primarily on estimated glomerular filtration rate (eGFR) with lower eGFR associated with higher risk of adverse outcomes. Although proteinuria is also associated with adverse outcomes, it is not used to refine risk estimates of adverse events in this current system. To determine the association between reduced GFR, proteinuria, and adverse clinical outcomes. Community-based cohort study with participants identified from a province-wide laboratory registry that includes eGFR and proteinuria measurements from Alberta, Canada, between 2002 and 2007. There were 920 985 adults who had at least 1 outpatient serum creatinine measurement and who did not require renal replacement treatment at baseline. Proteinuria was assessed by urine dipstick or albumin-creatinine ratio (ACR). All-cause mortality, myocardial infarction, and progression to kidney failure. The majority of individuals (89.1%) had an eGFR of 60 mL/min/1.73 m(2) or greater. Over median follow-up of 35 months (range, 0-59 months), 27 959 participants (3.0%) died. The fully adjusted rate of all-cause mortality was higher in study participants with lower eGFRs or heavier proteinuria. Adjusted mortality rates were more than 2-fold higher among individuals with heavy proteinuria measured by urine dipstick and eGFR of 60 mL/min/1.73 m(2) or greater, as compared with those with eGFR of 45 to 59.9 mL/min/1.73 m(2) and normal protein excretion (rate, 7.2 [95% CI, 6.6-7.8] vs 2.9 [95% CI, 2.7-3.0] per 1000 person-years, respectively; rate ratio, 2.5 [95% CI, 2.3-2.7]). Similar results were observed when proteinuria was measured by ACR (15.9 [95% CI, 14.0-18.1] and 7.0 [95% CI, 6.4-7.6] per 1000 person-years for heavy and absent proteinuria, respectively; rate ratio, 2.3 [95% CI, 2.0-2.6]) and for the outcomes of hospitalization with acute myocardial infarction, end-stage renal disease, and doubling of serum creatinine level. The risks of mortality, myocardial infarction, and progression to kidney failure associated with a given level of eGFR are independently increased in patients with higher levels of proteinuria.

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Association between albuminuria, kidney function, and inflammatory biomarker profile in CKD in CRIC.

Rena R Wing, V. Balakrishnan, Peter A. Kanetsky … (2012)

Increased risk of mortality in patients with CKD has been attributed to inflammation. However, the association between kidney function, albuminuria, and biomarkers of inflammation has not been examined in a large cohort of CKD patients. This study measured the plasma levels of IL-1β, IL-1 receptor antagonist (IL-1RA), IL-6, TNF-α, TGF-β, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and serum albumin in 3939 participants enrolled in the Chronic Renal Insufficiency Cohort study between June 2003 and September 2008. An inflammation score was established based on plasma levels of IL-1β, IL-6, TNF-α, hs-CRP, and fibrinogen. Estimated GFR (eGFR) and serum cystatin C were used as measures of kidney function. Albuminuria was quantitated by urine albumin to creatinine ratio (UACR). Plasma levels of IL-1β, IL-1RA, IL-6, TNF-α, hs-CRP, and fibrinogen were higher among participants with lower levels of eGFR. Inflammation score was higher among those with lower eGFR and higher UACR. In regression analysis adjusted for multiple covariates, eGFR, cystatin C, and UACR were strongly associated with fibrinogen, serum albumin, IL-6, and TNF-α. Each unit increase in eGFR, cystatin C, and UACR was associated with a -1.2% (95% confidence interval, -1.4, -1), 64.9% (56.8, 73.3) and 0.6% (0.4, 0.8) change in IL-6, respectively (P<0.001). Biomarkers of inflammation were inversely associated with measures of kidney function and positively with albuminuria.

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Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis.

Erwin Blessing, Charles Esmon, Hartmut Weiler … (2007)

Data providing direct evidence for a causative link between endothelial dysfunction, microvascular disease and diabetic end-organ damage are scarce. Here we show that activated protein C (APC) formation, which is regulated by endothelial thrombomodulin, is reduced in diabetic mice and causally linked to nephropathy. Thrombomodulin-dependent APC formation mediates cytoprotection in diabetic nephropathy by inhibiting glomerular apoptosis. APC prevents glucose-induced apoptosis in endothelial cells and podocytes, the cellular components of the glomerular filtration barrier. APC modulates the mitochondrial apoptosis pathway via the protease-activated receptor PAR-1 and the endothelial protein C receptor EPCR in glucose-stressed cells. These experiments establish a new pathway, in which hyperglycemia impairs endothelial thrombomodulin-dependent APC formation. Loss of thrombomodulin-dependent APC formation interrupts cross-talk between the vascular compartment and podocytes, causing glomerular apoptosis and diabetic nephropathy. Conversely, maintaining high APC levels during long-term diabetes protects against diabetic nephropathy.

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Author and article information

Contributors

Ken‐ichi Aihara:

ORCID: https://orcid.org/0000-0001-8906-0920

aihara@tokushima-u.ac.jp

Journal

Journal ID (nlm-ta): J Diabetes Investig

Journal ID (iso-abbrev): J Diabetes Investig

Journal ID (doi): 10.1111/(ISSN)2040-1124

Journal ID (publisher-id): JDI

Title: Journal of Diabetes Investigation

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 2040-1116

ISSN (Electronic): 2040-1124

Publication date (Electronic): 23 June 2021

Publication date (Print): December 2021

Volume: 12

Issue: 12 ( doiID: 10.1111/jdi.v12.12 )

Pages: 2172-2182

Affiliations

[ ¹ ] Department of Hematology, Endocrinology and Metabolism Tokushima University Graduate School of Biomedical Sciences Tokushima Japan

[ ² ] Department of Community Medicine and Medical Science Tokushima University Graduate School of Biomedical Sciences Tokushima Japan

[ ³ ] Diabetes Therapeutics and Research Center Institute of Advanced Medical Sciences Tokushima University Tokushima Japan

[ ⁴ ] Department of Pharmacology Tokushima University Graduate School of Biomedical Sciences Tokushima Japan

[ ⁵ ] Department of Bioregulatory Sciences Tokushima University Graduate School of Biomedical Sciences Tokushima Japan

[ ⁶ ] Minami Municipal National Insurance Hospital Minami‐cho Japan

[ ⁷ ] Department of Medical Pharmacology Tokushima University Graduate School of Biomedical Sciences Tokushima Japan

[ ⁸ ] Kondo Naika Hospital Tokushima Japan

[ ⁹ ] Anan Medical Center Anan Japan

[ ¹⁰ ] Fujii Memorial Institute of Medical Sciences Tokushima University Tokushima Japan

Author notes

[*] [* ] * Correspondence

Ken‐ichi Aihara

Tel.: +81‐88‐633‐9267

Fax: +81‐88‐633‐7121

E‐mail address: aihara@ 123456tokushima-u.ac.jp

Author information

Akio Kuroda https://orcid.org/0000-0003-2147-6844

Munehide Matsuhisa https://orcid.org/0000-0003-4624-939X

Ken‐ichi Aihara https://orcid.org/0000-0001-8906-0920

Article

Publisher ID: JDI13602

DOI: 10.1111/jdi.13602

PMC ID: 8668075

PubMed ID: 34043882

SO-VID: 9c546660-09b2-4f2d-a7fc-c2f6c5c6fb7f

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date revision received : 10 May 2021

Date received : 03 March 2021

Date accepted : 20 May 2021

Page count

Figures: 6, Tables: 4, Pages: 11, Words: 7295

Funding

Funded by: Nippon Boehringer Ingelheim Co., Ltd.

Funded by: Ono Pharmaceutical Co., Ltd.

Funded by: Japan Society for the Promotion of Science KAKENHI

Award ID: 19K08680

Funded by: Teijin Pharma Ltd.

Custom metadata

source-schema-version-number 2.0

cover-date December 2021

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.9 mode:remove_FC converted:13.12.2021

Keywords: albuminuria,heparin cofactor ii,protease‐activated receptors

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Keywords: albuminuria, heparin cofactor ii, protease‐activated receptors

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Plasma heparin cofactor II activity is inversely associated with albuminuria and its annual deterioration in patients with diabetes

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Abstract

Aims/Introduction

Materials and Methods

Results

Conclusions

Abstract

Related collections

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Most cited references 34

Relation between kidney function, proteinuria, and adverse outcomes.

Association between albuminuria, kidney function, and inflammatory biomarker profile in CKD in CRIC.

Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis.

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