Clinical Value of Complement Activation Biomarkers in Overt Diabetic Nephropathy

Overview

Journal Kidney Int Rep

Publisher Elsevier

Specialty Nephrology

Date 2019 Jun 14

PMID 31194090

Citations 15

Authors

Karyne Pelletier

Arnaud Bonnefoy

Hugo Chapdelaine

Vincent Pichette

Matthieu Lejars

Francois Madore

Soumeya Brachemi

Stephan Troyanov

Affiliations

Soon will be listed here.

Abstract

Background: Experimental studies support a role of complement activation in diabetic nephropathy (DN), yet few clinical correlates exist. We evaluated urinary levels of sC5b-9 membrane attack complex (MAC) in patients with overt DN, and examined its association with the glomerular filtration rate (GFR) decline, proteinuria, and inflammatory biomarkers. We explored different complement pathways and compared our findings to autoimmune glomerulonephritis.

Methods: We prospectively followed 83 patients with DN and obtained repeated measurements of proteinuria, complement fragments (sC5b-9, C4a, C1q, mannose-binding lectin-associated serine protease [MASP]-1, and factor Bb), monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor (TGF)-β1. We assessed independence and interactions using general linear models and repeated measures analyses and compared levels with subjects with active focal and segmental glomerulosclerosis, ANCA-associated vasculitis, and membranous and IgA nephropathies ( = 63).

Results: The diabetic cohort had an initial GFR of 25 ± 9 ml/min per 1.73 m and a renal function decline of 2.9 ± 3.0 ml/min per 1.73 m per year. All complement biomarkers were strongly intercorrelated and associated with biomarker inflammation and fibrosis, proteinuria, and the rate of renal function decline. There was a significant interaction ( = 0.03) between the level of proteinuria and urinary sC5b-9: in individuals with higher levels of urinary MAC, the relationship between proteinuria and the rate of renal function decline was more pronounced than in those with low urinary MAC. Finally, patients with DN had levels of urinary sC5b-9 comparable to autoimmune glomerulonephritis, when stratified by the level of proteinuria.

Conclusion: Urinary MAC is present in patients with overt DN at levels comparable to autoimmune glomerulonephritis and correlates with the GFR decline, supporting that complement activation and its measurement are clinically relevant in DN.

Citing Articles

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Association between serum complements and kidney function in patients with diabetic kidney disease.

Liu M, Li J, Wang Y, Meng Y, Zheng G, Cai Z Front Endocrinol (Lausanne). 2023; 14:1195966.

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Significance of urine complement proteins in monitoring lupus activity.

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References

Nangaku M, Pippin J, Couser W . Complement membrane attack complex (C5b-9) mediates interstitial disease in experimental nephrotic syndrome. J Am Soc Nephrol. 1999; 10(11):2323-31. DOI: 10.1681/ASN.V10112323. View

Morita Y, Ikeguchi H, Nakamura J, Hotta N, Yuzawa Y, Matsuo S . Complement activation products in the urine from proteinuric patients. J Am Soc Nephrol. 2000; 11(4):700-707. DOI: 10.1681/ASN.V114700. View

Nosadini R, Velussi M, Brocco E, Bruseghin M, Abaterusso C, Saller A . Course of renal function in type 2 diabetic patients with abnormalities of albumin excretion rate. Diabetes. 2000; 49(3):476-84. DOI: 10.2337/diabetes.49.3.476. View

Zhou W, Marsh J, Sacks S . Intrarenal synthesis of complement. Kidney Int. 2001; 59(4):1227-35. DOI: 10.1046/j.1523-1755.2001.0590041227.x. View

Hsu S, Couser W . Chronic progression of tubulointerstitial damage in proteinuric renal disease is mediated by complement activation: a therapeutic role for complement inhibitors?. J Am Soc Nephrol. 2003; 14(7 Suppl 2):S186-91. DOI: 10.1097/01.asn.0000070032.58017.20. View

Hansen T, Thiel S, Knudsen S, Gravholt C, Christiansen J, Mogensen C . Elevated levels of mannan-binding lectin in patients with type 1 diabetes. J Clin Endocrinol Metab. 2003; 88(10):4857-61. DOI: 10.1210/jc.2003-030742. View

Qin X, Goldfine A, Krumrei N, Grubissich L, Acosta J, Chorev M . Glycation inactivation of the complement regulatory protein CD59: a possible role in the pathogenesis of the vascular complications of human diabetes. Diabetes. 2004; 53(10):2653-61. DOI: 10.2337/diabetes.53.10.2653. View

Gross J, de Azevedo M, Silveiro S, Canani L, Caramori M, Zelmanovitz T . Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care. 2004; 28(1):164-76. DOI: 10.2337/diacare.28.1.164. View

Saraheimo M, Forsblom C, Hansen T, Teppo A, Fagerudd J, Pettersson-Fernholm K . Increased levels of mannan-binding lectin in type 1 diabetic patients with incipient and overt nephropathy. Diabetologia. 2004; 48(1):198-202. DOI: 10.1007/s00125-004-1594-1. View

10.

Hovind P, Hansen T, Tarnow L, Thiel S, Steffensen R, Flyvbjerg A . Mannose-binding lectin as a predictor of microalbuminuria in type 1 diabetes: an inception cohort study. Diabetes. 2005; 54(5):1523-7. DOI: 10.2337/diabetes.54.5.1523. View

11.

Hansen T, Gall M, Tarnow L, Thiel S, Stehouwer C, Schalkwijk C . Mannose-binding lectin and mortality in type 2 diabetes. Arch Intern Med. 2006; 166(18):2007-13. DOI: 10.1001/archinte.166.18.2007. View

12.

Ogrodowski J, Hebert L, Sedmak D, Cosio F, Tamerius J, Kolb W . Measurement of SC5b-9 in urine in patients with the nephrotic syndrome. Kidney Int. 1991; 40(6):1141-7. DOI: 10.1038/ki.1991.326. View

13.

Flyvbjerg A . Diabetic angiopathy, the complement system and the tumor necrosis factor superfamily. Nat Rev Endocrinol. 2010; 6(2):94-101. DOI: 10.1038/nrendo.2009.266. View

14.

Tervaert T, Mooyaart A, Amann K, Cohen A, Cook H, Drachenberg C . Pathologic classification of diabetic nephropathy. J Am Soc Nephrol. 2010; 21(4):556-63. DOI: 10.1681/ASN.2010010010. View

15.

Camilla R, Brachemi S, Pichette V, Cartier P, Laforest-Renald A, MacRae T . Urinary monocyte chemotactic protein 1: marker of renal function decline in diabetic and nondiabetic proteinuric renal disease. J Nephrol. 2010; 24(1):60-7. DOI: 10.5301/jn.2010.1458. View

16.

Wang H, Vinnikov I, Shahzad K, Bock F, Ranjan S, Wolter J . The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via complement inhibition. Thromb Haemost. 2012; 108(6):1141-53. DOI: 10.1160/TH12-07-0460. View

17.

Wada J, Makino H . Inflammation and the pathogenesis of diabetic nephropathy. Clin Sci (Lond). 2012; 124(3):139-52. DOI: 10.1042/CS20120198. View

18.

Verhave J, Bouchard J, Goupil R, Pichette V, Brachemi S, Madore F . Clinical value of inflammatory urinary biomarkers in overt diabetic nephropathy: a prospective study. Diabetes Res Clin Pract. 2013; 101(3):333-40. DOI: 10.1016/j.diabres.2013.07.006. View

19.

Noris M, Remuzzi G . Overview of complement activation and regulation. Semin Nephrol. 2013; 33(6):479-92. PMC: 3820029. DOI: 10.1016/j.semnephrol.2013.08.001. View

20.

Levin A, Stevens P . Summary of KDIGO 2012 CKD Guideline: behind the scenes, need for guidance, and a framework for moving forward. Kidney Int. 2013; 85(1):49-61. DOI: 10.1038/ki.2013.444. View