Urinary n-acetyl-beta-d-glucosaminidase Excretion: an Indicator of Neuropathy in Type 2 Diabetes

Abstract

Objective:

The established marker for tubular damage, urinary n-acetyl-beta-d-glucosaminidase is significantly increased in type 1 and 2 diabetes patients and is related to albuminuria and other diabetic complications. In this cross sectional study of type 2 diabetes patients with a history of albuminuria, we studied the relationship between excretion of n-acetyl-beta-d-glucosaminidase in urine and diabetic neuropathy.

Methods:

160 type 2 diabetes patients were screened for diabetic peripheral neuropathy and cardiovascular autonomic neuropathy. N-acetyl-beta-d-glucosaminidase excretion was detected in 24 h urine samples.

Results:

Urinary excretion of n-acetyl-beta-d-glucosaminidase correlated significantly with ­glucose control (fasting glucose r=0.18; p=0.04; HbA1c r=0.20; p=0.02) and urine albumin excretion (r=0.22; p=0.01). Binary regression analyses showed that increased urinary n-acetyl-beta-d-glucosaminidase concentration is an independent predictor for presence of clinical symptoms of peripheral neuropathy (OR 1.8 [95%CI 1.2–2.74] and vibration deficiency [OR 1.7; 95% CI 1.2–2.66]. There was also a significant negative association between urinary n-acetyl-beta-d-glucosaminidase and E/I-Ratio (r=−0.21, p<0.02) as well as the 30:15-Ratio (r=−0.24; p<0.01) of heart rate variability. Furthermore, increased n-acetyl-beta-d-glucosaminidase excretion independently predicted cardiovascular autonomic diabetic neuropathy with an OR for decreased E/I-Ratio of 1.7 [95%CI 1.1–2.75]; (p<0.02) and 30:15-Ratio:OR 2.4 [95% CI 1.26–4.45]; (p<0.01).

Conclusion:

Urinary n-acetyl-beta-d-glucosami­nidase excretion is an independent marker for diabetic peripheral and cardiovascular autonomic neuropathy in type 2 diabetic patients.

Key words

type 2 diabetes - peripheral diabetic ­neuropathy - autonomic diabetic ­neuropathy - tubular damage - urinary NAG

^† Prof. Dr. Angelika Bierhaus died on April 15 th , 2012 .

• References

• 1 Grundy SM, Benjamin IJ, Burke GL et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1999; 100: 1134-1146
• 2 Almdal T, Scharling H, Jensen JS et al. The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13 000 men and women with 20 years of follow-up. Arch Intern Med 2004; 164: 1422-1426
• 3 Haffner SM, Lehto S, Ronnemaa T et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339: 229-234
• 4 Gaede P, Lund-Andersen H, Parving HH et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358: 580-591
• 5 Nawroth PP, Rudofsky G, Humpert P. Have we understood diabetes? New tasks for diagnosis and therapy. Exp Clin Endocrinol Diabetes 2010; 118: 1-3
• 6 Kotb NA, Gaber R, Salah W et al. Relations among glycemic control, circulating endothelial cells, nitric oxide, and flow mediated dilation in patients with type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes 2012; 120: 460-465
• 7 Dance N, Price RG, Cattell WR et al. The excretion of N-acetyl-beta-glucosaminidase and beta-galactosidase by patients with renal disease. Clin Chim Acta 1970; 27: 87-92
• 8 Bosomworth MP, Aparicio SR, Hay AW. Urine N-acetyl-beta-D-glucosaminidase – a marker of tubular damage?. Nephrol Dial Transplant 1999; 14: 620-626
• 9 Bazzi C, Petrini C, Rizza V et al. Urinary N-acetyl-beta-glucosaminidase excretion is a marker of tubular cell dysfunction and a predictor of outcome in primary glomerulonephritis. Nephrol Dial Transplant 2002; 17: 1890-1896
• 10 Nauta FL, Boertien WE, Bakker SJ et al. Glomerular and tubular damage markers are elevated in patients with diabetes. Diabetes Care 2011; 34: 975-981
• 11 Gibey R, Dupond JL, Henry JC. Urinary N-acetyl-beta-D-glucosaminidase (NAG) isoenzyme profiles: a tool for evaluating nephrotoxicity of aminoglycosides and cephalosporins. Clin Chim Acta 1984; 137: 1-11
• 12 Kalahasthi RB, Rajmohan H, Rajan B et al. Urinary N-acetyl-beta -D-glucosaminidase and its isoenzymes A & B in workers exposed to cadmium at cadmium plating. J Occup Med Toxicol 2007; 2: 5
• 13 Liangos O, Perianayagam MC, Vaidya VS et al. Urinary N-acetyl-beta-(D)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure. J Am Soc Nephrol 2007; 18: 904-912
• 14 Huang R, Zhou Q, Veeraragoo P et al. Notch2/Hes-1 pathway plays an important role in renal ischemia and reperfusion injury-associated inflammation and apoptosis and the gamma-secretase inhibitor DAPT has a nephroprotective effect. Ren Fail 2011; 33: 207-216
• 15 Araujo FA, Rocha MA, Ferreira MA et al. Implant-induced intraperitoneal inflammatory angiogenesis is attenuated by fluvastatin. Clin Exp Pharmacol Physiol 2011; 38: 262-268
• 16 Fu WJ, Xiong SL, Fang YG et al. Urinary tubular biomarkers in short-term type 2 diabetes mellitus patients: a cross-sectional study. Endocrine 2011;
• 17 Hong CY, Chia KS, Ling SL. Urinary protein excretion in Type 2 diabetes with complications. J Diabetes Complications 2000; 14: 259-265
• 18 Iqbal MP, Sharif HM, Mehboobali N et al. N-acetyl-B-D-glucosaminidase and inflammatory response after cardiopulmonary bypass. J Coll Physicians Surg Pak 2008; 18: 74-77
• 19 Brymora A, Flisinski M, Johnson RJ et al. Low-fructose diet lowers blood pressure and inflammation in patients with chronic kidney disease. Nephrol Dial Transplant 2011;
• 20 Bierhaus A, Nawroth PP. Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications. Diabetologia 2009; 52: 2251-2263
• 21 Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res 2010; 107: 1058-1070
• 22 Mendler M, Schlotterer A, Morcos M et al. Understanding diabetic polyneuropathy and longevity: what can we learn from the nematode Caenorhabditis elegans?. Exp Clin Endocrinol Diabetes 2012; 120: 182-183
• 23 Roose SP, Laghrissi-Thode F, Kennedy JS et al. Comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease. JAMA 1998; 279: 287-291
• 24 von Eynatten M, Liu D, Hock C et al. Urinary adiponectin excretion: a novel marker for vascular damage in type 2 diabetes. Diabetes 2009; 58: 2093-2099
• 25 Humpert PM, Kopf S, Djuric Z et al. Plasma sRAGE is independently associated with urinary albumin excretion in type 2 diabetes. Diabetes Care 2006; 29: 1111-1113
• 26 Levey AS, Stevens LA, Schmid CH et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150: 604-612
• 27 von Eynatten M, Baumann M, Heemann U et al. Urinary L-FABP and anaemia: distinct roles of urinary markers in type 2 diabetes. Eur J Clin Invest 2010; 40: 95-102
• 28 Ziegler D, Siekierka-Kleiser E, Meyer B et al. Validation of a novel screening device (NeuroQuick) for quantitative assessment of small nerve fiber dysfunction as an early feature of diabetic polyneuropathy. Diabetes Care 2005; 28: 1169-1174
• 29 Hilz MJ, Axelrod FB, Hermann K et al. Normative values of vibratory perception in 530 children, juveniles and adults aged 3–79 years. J Neurol Sci 1998; 159: 219-225
• 30 Humpert PM, Kopf S, Djuric Z et al. Levels of three distinct p75 neurotrophin receptor forms found in human plasma are altered in type 2 diabetic patients. Diabetologia 2007; 50: 1517-1522
• 31 Skrha Jr J, Soupal J, Loni Ekali G et al. Skin autofluorescence relates to soluble receptor for advanced glycation end-products and albuminuria in diabetes mellitus. J Diabetes Res 2013; 2013 650694
• 32 Mulder DJ, Water TV, Lutgers HL et al. Skin autofluorescence, a novel marker for glycemic and oxidative stress-derived advanced glycation endproducts: an overview of current clinical studies, evidence, and limitations. Diabetes Technol Ther 2006; 8: 523-535
• 33 Agelink MW, Malessa R, Baumann B et al. Standardized tests of heart rate variability: normal ranges obtained from 309 healthy humans, and effects of age, gender, and heart rate. Clin Auton Res 2001; 11: 99-108
• 34 Price RG. The role of NAG (N-acetyl-beta-D-glucosaminidase) in the diagnosis of kidney disease including the monitoring of nephrotoxicity. Clin Nephrol 1992; 38 (Suppl. 01) S14-S19
• 35 Takao T, Horino T, Kagawa T et al. Possible involvement of intracellular angiotensin II receptor in high-glucose-induced damage in renal proximal tubular cells. J Nephrol 2011; 24: 218-224
• 36 Jin HY, Kang SM, Liu WJ et al. Comparison of peripheral nerve damages according to glucose control timing in experimental diabetes. Exp Clin Endocrinol Diabetes 2012; 120: 451-459
• 37 Samann A, Pofahl S, Lehmann T et al. Diabetic nephropathy but not HbA1c is predictive for frequent complications of Charcot feet – long-term follow-up of 164 consecutive patients with 195 acute Charcot feet. Exp Clin Endocrinol Diabetes 2012; 120: 335-339
• 38 Lukic IK, Humpert PM, Nawroth PP et al. The RAGE pathway: activation and perpetuation in the pathogenesis of diabetic neuropathy. Ann N Y Acad Sci 2008; 1126: 76-80
• 39 Sarafidis PA, Bakris GL. Microalbuminuria and chronic kidney disease as risk factors for cardiovascular disease. Nephrol Dial Transplant 2006; 21: 2366-2374
• 40 Caramori ML, Fioretto P, Mauer M. The need for early predictors of diabetic nephropathy risk: is albumin excretion rate sufficient?. Diabetes 2000; 49: 1399-1408