Top

Pediatric Nephrology

Published in:

04-07-2023 | Albuminuria | Original Article

Plasma leucine-rich α-2-glycoprotein 1 – a novel marker of diabetic kidney disease in children and adolescents with type 1 diabetes mellitus?

Authors: Selda Ayça Altıncık, Didem Yıldırımçakar, Esin Avcı, Bayram Özhan, İlknur Girişgen, Selçuk Yüksel

Published in: Pediatric Nephrology | Issue 12/2023

Abstract

Background

Glomerular endothelial dysfunction and neoangiogenesis play a significant role in the pathogenesis of diabetic kidney disease (DKD). Leucine-rich α-2 glycoprotein 1 (LRG1) is a recently discovered protein that participates in the molecular pathway of inflammation and angiogenesis. We aimed to investigate efficacy of LRG1 to predict estimated glomerular filtration rate (eGFR) decrease in children and adolescents with type 1 diabetes mellitus (T1DM).

Methods

The study comprised 72 participants with diabetes duration for ≥ 2 years. At study initiation, LRG1, urine albumin, eGFR (cystatin C-based, and Schwartz), HbA1c, and lipid values were evaluated and diabetes-related clinical features and anthropometric measurements were collected. These results were compared with final control values after ≥ 1 year. Patients were divided into subgroups according to presence of albuminuria progression, eGFR decrease, and metabolic control parameters.

Results

There was positive correlation between LRG1 level and Schwartz and cystatin C-based eGFR decline (r = 0.360, p = 0.003; r = 0.447, p = 0.001, respectively), and negative correlation between final cystatin C-based eGFR and LRG1 (p = 0.01, r = –0.345). Patients with cystatin C-based eGFR decrease > 10% had significantly higher LRG1 levels (p = 0.03), however, LRG1 was not different between albuminuria progression subgroups. A 0.282 μg/ml increase in LRG1 correlated with a 1% decrease in eGFR in simple linear regression analysis (β = 0.282, %CI 0.11–0.45, p = 0.001) and LRG1 was an independent predictor of GFR decline even in the presence of covariates.

Conclusions

Our study supports the relationship between plasma LRG1 and eGFR decline and suggests LRG1 may be an early marker of DKD progression in children with T1DM.

Graphical abstract

Available only for authorised users

Tuttle KR, Bakris GL, Bilous RW et al (2014) Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care 37:2864–2883. https://doi.org/10.2337/dc14-1296CrossRefPubMedPubMedCentral

Donaghue KC, Marcovecchio LM, Wadwa RP et al (2018) ISPAD clinical practice consensus guidelines 2018: Microvascular and macrovascular complications in children and adolescents. Pediatr Diabetes 19(Suppl 27):262–274. https://doi.org/10.1111/pedi.12742CrossRefPubMedPubMedCentral

Thomas MC, Brownlee M, Susztak K et al (2015) Diabetic kidney disease. Nat Rev Dis Primers 1:15018. https://doi.org/10.1038/nrdp.2015.18CrossRefPubMedPubMedCentral

Navarro-González JF, Mora-Fernández C (2008) The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol 19:433–442. https://doi.org/10.1681/ASN.2007091048CrossRefPubMed

Papadopoulou-Marketou N, Chrousos GP, Kanaka-Gantenbein C (2017) Diabetic nephropathy in type 1 diabetes: a review of early natural history, pathogenesis, and diagnosis. Diabetes Metab Res Rev 33:e2841. https://doi.org/10.1002/dmrr.2841CrossRef

Zent R, Pozzi A (2007) Angiogenesis in diabetic nephropathy. Semin Nephrol 27:161–171. https://doi.org/10.1016/j.semnephrol.2007.01.007CrossRefPubMed

Hong Q, Zhang L, Fu J et al (2019) LRG1 promotes diabetic kidney disease progression by enhancing TGF-β-induced angiogenesis. J Am Soc Nephrol 30:546–562. https://doi.org/10.1681/ASN.2018060599CrossRefPubMedPubMedCentral

Takahashi N, Takahashi Y, Putnam FW (1985) Periodicity of leucine and tandem repetition of a 24-amino acid segment in the primary structure of leucine-rich 2-glycoprotein of human serum. Proc Natl Acad Sci U S A 82:1906–1910. https://doi.org/10.1073/pnas.82.7.1906CrossRefPubMedPubMedCentral

Zou Y, Xu Y, Chen X et al (2022) Research progress on leucine-rich alpha-2 glycoprotein 1: a review. Front Pharmacol 12:809225. https://doi.org/10.3389/fphar.2021.809225CrossRefPubMedPubMedCentral

10.

Wang X, Abraham S, McKenzie JAG et al (2013) LRG1 promotes angiogenesis by modulating endothelial TGF-β signaling. Nature 499:306–311. https://doi.org/10.1038/nature12345CrossRefPubMed

11.

Serada S, Fujimoto M, Ogata A et al (2009) iTRAQ-based proteomic identification of leucine-rich alpha-2 glycoprotein as a novel inflammatory biomarker in autoimmune diseases. Ann Rheum Dis 69:770–774. https://doi.org/10.1136/ard.2009.118919CrossRefPubMed

12.

Ban Z, He J, Tang Z et al (2019) LRG-1 enhances the migration of thyroid carcinoma cells through promotion of the epithelial-mesenchymal transition by activating MAPK/p38 signaling. Oncol Rep 41:3270–3280. https://doi.org/10.3892/or.2019.7123CrossRefPubMedPubMedCentral

13.

Watson CJ, Ledwidge MT, Phelan D et al (2011) Proteomic analysis of coronary sinus serum reveals leucine-rich a2-glycoprotein as a novel biomarker of ventricular dysfunction and heart failure. Circ Heart Fail 4:188–197. https://doi.org/10.1161/CIRCHEARTFAILURE.110.952200CrossRefPubMed

14.

Zhang X, Pek SLT, Tavintharan S et al (2019) Leucine-rich α-2-glycoprotein predicts proliferative diabetic retinopathy in type 2 diabetes. J Diabetes Complicat 33:651–656. https://doi.org/10.1016/j.jdiacomp.2019.05.021

15.

Liu J, Pek SLT, Ang K (2017) Plasma leucine-rich a-2-glycoprotein 1 predicts rapid eGFR decline and albuminuria progression in type 2 diabetes mellitus. J Clin Endocrinol Metab 102:3683–3691. https://doi.org/10.1210/jc.2017-00930CrossRefPubMed

16.

Pek SLT, Tavintharan S, Wang X (2015) Elevation of a novel angiogenic factor, leucine-rich- 2-glycoprotein (LRG1), is associated with arterial stiffness, endothelial dysfunction, and peripheral arterial disease in patients with type 2 diabetes. J Clin Endocrinol Metab 100:1586–1593. https://doi.org/10.1210/jc.2014-3855CrossRefPubMed

17.

https://www.kidney.org/professionals/kdoqi/gfr_calculatorped

18.

Rosolowsky ET, Niewczas MA, Ficociello LH et al (2008) Between hyperfiltration and impairment: demystifying early renal functional changes in diabetic nephropathy. Diabetes Res Clin Pract 82(Suppl 1):S46–53. https://doi.org/10.1016/j.diabres.2008.09.018CrossRefPubMed

19.

Bjornstad P, Cherney DZ, Snell-Bergeon JK et al (2015) Rapid GFR decline is associated with renal hyperfiltration and impaired GFR in adults with Type 1 diabetes. Nephrol Dial Transplant 30:1706–1711. https://doi.org/10.1093/ndt/gfv121CrossRefPubMedPubMedCentral

20.

Molitch ME, Steffes M, Sun W et al (2010) Development and progression of renal insufficiency with and without albuminuria in adults with type 1 diabetes in the diabetes control and complications trial and the epidemiology of diabetes interventions and complications study. Diabetes Care 33:1536–1543. https://doi.org/10.2337/dc09-1098CrossRefPubMedPubMedCentral

21.

Bilous R (2008) Microvascular disease: what does the UKPDS tell us about diabetic nephropathy? Diabet Med 25(Suppl 2):25–29. https://doi.org/10.1111/j.1464-5491.2008.02496.xCrossRefPubMed

22.

Nakagawa T, Kosugi T, Haneda M et al (2009) Abnormal angiogenesis in diabetic nephropathy. Diabetes 58:1471–1478. https://doi.org/10.2337/db09-0119CrossRefPubMedPubMedCentral

23.

Fu J, Wei C, Zhang W et al (2018) Gene expression profiles of glomerular endothelial cells support their role in the glomerulopathy of diabetic mice. Kidney Int 94:326–345. https://doi.org/10.1016/j.kint.2018.02.028CrossRefPubMedPubMedCentral

24.

Shirai R, Hirano F, Ohkura N et al (2009) Up-regulation of the expression of leucine-rich (2)-glycoprotein in hepatocytes by the mediators of acute-phase response. Biochem Biophys Res Commun 382:776–779. https://doi.org/10.1016/j.bbrc.2009.03.104CrossRefPubMedPubMedCentral

25.

Wang Y, Xu J, Zhang X et al (2017) TNF-α-induced LRG1 promotes angiogenesis and mesenchymal stem cell migration in the subchondral bone during osteoarthritis. Cell Death Dis 8:e2715. https://doi.org/10.1038/cddis.2017.129CrossRefPubMedPubMedCentral

Title: Plasma leucine-rich α-2-glycoprotein 1 – a novel marker of diabetic kidney disease in children and adolescents with type 1 diabetes mellitus?
Authors: Selda Ayça Altıncık
Didem Yıldırımçakar
Esin Avcı
Bayram Özhan
İlknur Girişgen
Selçuk Yüksel
Publication date: 04-07-2023
Publisher: Springer Berlin Heidelberg
Keywords: Albuminuria
Diabetes
Type 1 Diabetes
Published in: Pediatric Nephrology / Issue 12/2023
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-023-06019-4

At a glance: The STEP trials

Springer Medicine

Plasma leucine-rich α-2-glycoprotein 1 – a novel marker of diabetic kidney disease in children and adolescents with type 1 diabetes mellitus?

Abstract

Background

Methods

Results

Conclusions

Graphical abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Graphical abstract

Please log in to get access to this content

Other articles of this Issue 12/2023

A novel risk score for predicting prolonged length of stay following pediatric kidney transplant

Distress in parents of children with first-onset steroid-sensitive nephrotic syndrome

Chronic, severe abdominal pain in a girl with a renal anomaly: Questions

Congenital anomalies of the kidney and urinary tract: defining risk factors of disease progression and determinants of outcomes

Drugs in treating paediatric acute kidney injury

Insights into human kidney function from the study of Drosophila