Urine Haptoglobin/Creatinine Ratio Correlates with Tubular Injury Biomarkers and Severity of Albuminuria in Type 2 Diabetes Patients

Abstract

This aim of this study was to investigate the correlation between urine haptoglobin/creatinine ratio(UHCR) and tubular injury biomarkers or severity of albuminuria in type 2 diabetes. Recruited T2DM patients (n=120) were divided into three groups based on urine albumin/creatinine ratio (UACR): normal albuminuria (Normo group, UACR<30 mg/g, n=40), microalbuminuria (Micro group, 30 mg/g ≤UACR<300 mg/g, n=38), and macroalbuminuria (Macro group, UACR ≥300 mg/g, n=42), with matched healthy individuals (NC group, n=30) as controls. ELISA assay was used to detect the levels of urine haptoglobin, NGAL and KIM-1. Automated biochemical analyzer was applied to detect the concentrations of urine creatinine and retinol binding protein (RBP). To eliminate concentration errors, urine NGAL, KIM-1, and RBP were normalized by creatinine and expressed as UHCR, UNCR, UKCR, and URCR, respectively. We found UHCR was significantly increased in T2DM patients as compared with NC group. Among the three diabetic groups, the Macro group had the highest level of UHCR, whereas the Normo group had the lowest level. T2DM patients with higher UHCR levels also had higher levels of UNCR, UKCR, and URCR. Spearman’s correlation analysis indicated that UHCR was positively correlated with UACR, UNCR, UKCR, or URCR levels, and negatively correlated with eGFR. ROC curve analysis showed that UHCR was a sensitive and specific indicator for early diagnosis of DN. Stepwise multiple regression analysis showed that UHCR and UNCR were independent variables for UACR. Our research demonstrated that UHCR correlates with tubular injury biomarkers, including UNCR, UKCR, and URCR, and is independently associated with the severity of albuminuria in T2DM.

Key words

urine haptoglobin - type 2 diabetic nephropathy - tubular injury biomarkers - albuminuria

• References

• 1 Ceranowicz P, Warzecha Z, Dembinski A. Peptidyl hormones of endocrine cells origin in the gut--their discovery and physiological relevance. J Physiol Pharmacol 2015; 66: 11-27
• 2 Woodmansey C, McGovern AP, McCullough KA. et al. Incidence, demographics, and clinical characteristics of diabetes of the exocrine pancreas (Type 3c): A retrospective cohort study. Diabetes care 2017; 40: 1486-1493
• 3 Cho NH, Shaw JE, Karuranga S. et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 2018; 138: 271-281
• 4 Lozano R, Naghavi M, Foreman K. et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the global burden of disease study 2010. Lancet 2012; 380: 2095-2128
• 5 Gregg EW, Li Y, Wang J. et al. Changes in diabetes-related complications in the united states, 1990–2010. New Engl J Med 2014; 370: 1514-1523
• 6 Afkarian M, Zelnick LR, Hall YN. et al. Clinical manifestations of kidney disease among us adults with diabetes, 1988-2014. JAMA 2016; 316: 602-610
• 7 Pugliese G. Updating the natural history of diabetic nephropathy. Acta Diabetol 2014; 51: 905-915
• 8 Penno G, Solini A, Orsi E. et al. Non-albuminuric renal impairment is a strong predictor of mortality in individuals with type 2 diabetes: The renal insufficiency and cardiovascular events (RIACE) Italian multicentre study. Diabetologia 2018; 61: 2277-2289
• 9 Andersen CB, Torvund-Jensen M, Nielsen MJ. et al. Structure of the haptoglobin-haemoglobin complex. Nature 2012; 489: 456-459
• 10 Arredouani MS, Kasran A, Vanoirbeek JA. et al. Haptoglobin dampens endotoxin-induced inflammatory effects both in vitro and in vivo. Immunology 2005; 114: 263-271
• 11 Bhensdadia NM, Hunt KJ, Lopes-Virella MF. et al. Urine haptoglobin levels predict early renal functional decline in patients with type 2 diabetes. Kidney Int 2013; 83: 1136-1143
• 12 Liao WL, Chang CT, Chen CC. et al. Urinary proteomics for the early diagnosis of diabetic nephropathy in Taiwanese patients. J Clin Med 2018; 7 pii: E483
• 13 Zager RA, Vijayan A, Johnson AC. Proximal tubule haptoglobin gene activation is an integral component of the acute kidney injury “stress response”. Am J Physiol-Renal 2012; 303: F139-F148
• 14 Tervaert TW, Mooyaart AL, Amann K. et al. Pathologic classification of diabetic nephropathy. JASN 2010; 21: 556-563
• 15 Dalla Vestra M, Saller A, Bortoloso E. et al. Structural involvement in type 1 and type 2 diabetic nephropathy. Diabetes Metab 2000; 26 (Suppl 4) 8-14
• 16 Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabetic Med 1998; 15: 539-553
• 17 KDOQI. KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis 2007; 49: S12-S154
• 18 Levey AS, Bosch JP, Lewis JB. et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of diet in renal disease study group. Ann Intern Med 1999; 130: 461-470
• 19 Sporek M, Dumnicka P, Gala-Bladzinska A. et al. Angiopoietin-2 is an early indicator of acute pancreatic-renal syndrome in patients with acute pancreatitis. Mediat Inflamm 2016; 5780903
• 20 Kusnierz-Cabala B, Gala-Bladzinska A, Mazur-Laskowska M. et al. Serum uromodulin levels in prediction of acute kidney injury in the early phase of acute pancreatitis. Molecules 2017; 22: 988
• 21 Zylka A, Dumnicka P, Kusnierz-Cabala B. et al. Markers of glomerular and tubular damage in the early stage of kidney disease in type 2 diabetic patients. Mediat Inflamm 2018; 2018: 7659243
• 22 Liu JJ, Liu S, Wong MD. et al. Urinary haptoglobin predicts rapid renal function decline in asians with type 2 diabetes and early kidney disease. J Clin Endocrinol Metab 2016; 101: 3794-3802
• 23 Zeni L, Norden AGW, Cancarini G. et al. A more tubulocentric view of diabetic kidney disease. J Nephrol 2017; 30: 701-717
• 24 Yang JK, Wang YY, Liu C. et al. Urine proteome specific for eye damage can predict kidney damage in patients with type 2 diabetes: A case-control and a 5.3-year prospective cohort study. Diabetes care 2017; 40: 253-260
• 25 Sporek M, Gala-Błądzińska A, Dumnicka P. et al. Urine NGAL is useful in the clinical evaluation of renal function in the early course of acute pancreatitis. Folia Med Cracov 2016; 1: 13-25
• 26 Mishra J, Qing MA, Prada A. et al. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 2003; 14: 2534-2543
• 27 Mishra J, Dent C, Tarabishi R. et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005; 365: 1231-1238
• 28 Zylka A, Gala-Bladzinska A, Dumnicka P. et al. Is urinary ngal determination useful for monitoring kidney function and assessment of cardiovascular disease? A 12-month observation of patients with type 2 diabetes. Dis Markers 2016; 8489543
• 29 Han WK, Bailly V, Abichandani R. et al. Kidney injury molecule-1 (kim-1): A novel biomarker for human renal proximal tubule injury. Kidney Int 2002; 62: 237-244
• 30 De Carvalho JA, Tatsch E, Hausen BS. et al. Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin as indicators of tubular damage in normoalbuminuric patients with type 2 diabetes. Clin Biochem 2016; 49: 232-236
• 31 Norden AG, Lapsley M, Unwin RJ. Urine retinol-binding protein 4: A functional biomarker of the proximal renal tubule. Adv Clin Chem 2014; 63: 85-122