Zinc alpha 2 glycoprotein as an early biomarker of diabetic nephropathy in patients with type 2 diabetes mellitus

Original Article | Artigo Original Zinc alpha 2 glycoprotein as an early biomarker of diabetic nephropathy in patients with type 2 diabetes mellitus Zinco-alfa2-glicoproteina (ZAG) como biomarcador precoce de nefropatia diabética em pacientes com diabetes mellitus tipo 2 Authors Abstract Resumo Mohamed Elsheikh1 Introduction: Although microalbuminuria remains the gold standard for early detection of diabetic nephropathy (DN), it is not a sufficiently accurate predictor of DN risk. Thus, new biomarkers that would help to predict DN risk earlier and possibly prevent the occurrence of end-stage kidney disease are being investigated. Objective: To investigate the role of zinc-alpha-2-glycoprotein (ZAG) as an early marker of DN in type 2 diabetic (T2DM) patients. Methods: 88 persons were included and classified into 4 groups: Control group (group I), composed of normal healthy volunteers, and three patient groups with type 2 diabetes mellitus divided into: normo-albuminuria group (group II), subdivided into normal eGFR subgroup and increased eGFR subgroup > 120 mL/min/1.73m2), microalbuminuria group (group III), and macroalbuminuria group (group IV). All subjects were submitted to urine analysis, blood glucose levels, HbA1c, liver function tests, serum creatinine, uric acid, lipid profile and calculation of eGFR, urinary albumin creatinine ratio (UACR), and measurement of urinary and serum ZAG. Results: The levels of serum and urine ZAG were higher in patients with T2DM compared to control subjects and a statistically significant difference among studied groups regarding serum and urinary ZAG was found. Urine ZAG levels were positively correlated with UACR. Both ZAG levels were negatively correlated with eGFR. Urine ZAG levels in the eGFR ˃ 120 mL/ min/1.73m2 subgroup were higher than that in the normal eGFR subgroup. Conclusion: These findings suggest that urine and serum ZAG might be useful as early biomarkers for detection of DN in T2DM patients, detectable earlier than microalbuminuria. Keywords: Diabetic Nephropathies; Biomarkers. Introdução: Embora a microalbuminúria continue sendo o padrão ouro para a detecção precoce da nefropatia diabética (ND), ela não é um preditor suficientemente preciso do risco de ND. Assim, novos biomarcadores para prever mais precocemente o risco de ND e possivelmente evitar a ocorrência de doença renal terminal estão sendo investigados. Objetivo: Investigar a zinco-alfa2-glicoproteína (ZAG) como marcador precoce de ND em pacientes com debates mellitus tipo 2 (DM2). Métodos: Os 88 indivíduos incluídos foram divididos em quatro grupos: grupo controle (Grupo I), composto por voluntários saudáveis normais; e três grupos de pacientes com DM2 assim divididos: grupo normoalbuminúria (Grupo II), subdivididos em TFG normal e TFG > 120 mL/min/1,73 m2), grupo microalbuminúria (Grupo III) e grupo macroalbuminúria (Grupo IV). Todos foram submetidos a urinálise e exames para determinar glicemia, HbA1c, função hepática, creatinina sérica, ácido úrico, perfil lipídico, cálculo da TFG, relação albumina/ creatinina (RAC) e dosagem urinária e sérica de ZAG. Resultados: Os níveis séricos e urinários de ZAG foram mais elevados nos pacientes com DM2 em comparação aos controles. Foi identificada diferença estatisticamente significativa entre os grupos estudados em relação aos níveis séricos e urinários de ZAG. Os níveis urinários de ZAG foram positivamente correlacionados com a RAC. Ambos os níveis de ZAG foram negativamente correlacionados com TFG. Os níveis urinários de ZAG no subgrupo com TFG ˃ 120 mL/min/1,73m2 foram maiores do que no subgrupo com TFG normal. Conclusão: Constatamos que a ZAG sérica e urinária pode ser um útil biomarcador precoce para detecção de ND em pacientes com DM2, sendo detectável mais precocemente que microalbuminúria. Palavras-chave: Nefropatias Diabéticas; Biomarcadores. Khaled A Elhefnawy1 George Emad1 Mabrouk Ismail1 Maher Borai2 Faculty of Medicine, Internal Medicine Department, Zagazig University, Egypt. 2 Faculty of Medicine, Clinical Pathology Department, Zagazig University, Egypt. 1 Submitted on: 10/01/2018. Approved on: 01/11/2019. Correspondence to: Khaled A Elhefnawy. E-mail: DOI: 10.1590/2175-8239-JBN-2018-0200 509 Zinc alpha 2 glycoprotein in diabetic nephropathy Introduction Diabetic nephropathy is associated with mortality and morbidity in patients with diabetes mellitus.1 The most common method of detecting the early signs of diabetic nephropathy is the measurement of microalbuminuria.2 However, pathological abnormalities have been reported to occur before the onset of microalbuminuria.3 In chronic cases of diabetic nephropathy, renal function correlates better with the degree of tubulointerstitial injury rather than with glomerular lesions, suggesting that researchers should look for tubular biomarkers in order to identify patients with diabetic nephropathy.4 There has been an increasing interest in identifying other biomarkers that might give a sensitive and rapid means of detecting the progression of diabetic nephropathy. In this aspect, biomarkers that reflect tubular damage have been suggested by many investigators.5,6 Zinc-alpha-2-glycoprotein (ZAG) is a protein of interest because of its ability to play many important functions in the human body, including fertilization and lipid mobilization. Its structural organization and folding characteristics are similar to the MHC class I antigen-presenting molecule; hence, ZAG may have a role in the immune response. The function of ZAG under physiologic and cancerous conditions remains mysterious; however, it is considered a tumor biomarker for various carcinomas. There are several unrelated functions attributed to ZAG, such as RNase activity, regulation of melanin production, hindering of tumor proliferation, and transport of nephritic by-products7. ZAG is present in a variety of epithelia and is secreted into many body fluids.8 It was found that urine ZAG increased specifically in patients with diabetes and it may be used as a biomarker for specific and accurate analysis of diabetic nephropathy.9 Immunohistochemical analyses have shown that ZAG is expressed mainly in the tubules of the human kidney.10 We hypothesized that the urine and serum concentrations of ZAG might increase earlier than microalbuminuria in diabetic nephropathy. This study aimed to determine the role of ZAG in the early diagnosis of diabetic nephropathy by estimating the 510 Braz. J. Nephrol. (J. Bras. Nefrol.) 2019;41(4):509-517 concentrations of urine and serum ZAG in patients with type 2 diabetes mellitus (T2DM), according to their levels of albuminuria. Subjects and methods Study design: This was a case-control study carried out in the Internal Medicine and Clinical Pathology departments, Faculty of Medicine, Zagazig University, from December 2017 to August 2018. Participants and groups: A total of 88 persons were included after their written informed consent and classified (...truncated)