Abstract
Background
Renal involvement was thought to occur more than 10 years after onset of diabetes, but recent studies provide evidence that it starts even in the pre-diabetes stage. However, there is no sensitive marker to detect these changes at such early stages. Novel urinary biomarkers have showed promising results in detection of early nephropathy in pre-diabetics.
Methods
A total of 91 subjects (diabetes 61 and pre-diabetes 30) were enrolled into the study. Urinary biomarkers such as urine Neutrophil Gelatinase-Associated Lipocalin (NGAL), urine Cystatin C and urine albumin–creatinine ratio (UACR) were estimated. Subjects were further divided in four groups on the basis of UACR: pre-diabetes with normoalbuminuria (21); pre-diabetes with microalbuminuria (9); diabetes with normoalbuminuria (37); and diabetes with microalbuminuria (24). The relationship of UACR, NGAL, and Cystatin C was estimated.
Results
Urine levels of NGAL and Cystatin C were significantly higher in microalbuminuria group compared to normoalbuminuria. UACR was positively correlated to urine NGAL–creatinine ratio (UNCR) and urine Cystatin C–creatinine ratio (UCCR) in both diabetes and pre-diabetes. On logistic regression odds ratio of UNCR to predict microalbuminuria in diabetes and pre-diabetes was 1.070 (p = 0.000) and 1.138 (p = 0.010), respectively. Area under curve was determined by ROC analysis, and UNCR was found to be better than UCCR for estimating microalbuminuria.
Conclusion
Tubular damage may play major role in development of nephropathy in pre-diabetes. Newer markers like urine NGAL and Cystatin C are raised early in diabetes and pre-diabetes nephropathy.
Similar content being viewed by others
References
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014;37:s81–90.
Thomas MC, Burns WC, Cooper ME. Tubular changes in early diabetic nephropathy. Adv Chronic Kidney Dis. 2005;12:177–86.
Comper WD, Hilliard LM, Nikolic-Paterson DJ, Russo LM. Disease dependent mechanism of albuminuria. Am J Physiol Renal Physiol. 2008;295:F1589–600.
Krolewski AS, Niewczas MA, Skupien J, et al. Early progressive renal decline precedes the onset of microalbuminuria and its progression to macroalbuminuria. Diabetes Care. 2014;37:226–34.
Molitch ME, Steffes M, Sun W, Epidemiology of Diabetes Interventions and Complications Study Group, et al. 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. 2010;33:1536–43.
Kramer HJ, Nguyen QD, Curhan G, Hsu CY. Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA. 2003;289:3273–7.
National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis. 2012;60:850–86.
Barratt J, Topham P. Urine proteomics: the present and future of measuring urinary protein components in disease. CMAJ. 2007;177:361–8.
Jeon YK, Kim MR, Huh JE, Mok JY, et al. Cystatin C as an early biomarker of nephropathy in patients with type 2 diabetes. J Korean Med Sci. 2011;26:258–63.
Nielsen SE, Schjoedt KJ, Astrup AS, Tarnow L, et al. Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Injury Molecule 1 (KIM1) in patients with diabetic nephropathy: a cross-sectional study and the effects of lisinopril. Diabet Med. 2010;27(10):1144–50.
Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis. 2002;40:221–6.
Filler G, Bokenkamp A, Hofmann W, Le Bricon T, et al. Cystatin C as a marker of GFR -history, indications, and future research. Clin Biochem. 2005;38:1–8.
Yang J, Mori K, Li JY, Barasch J. Iron, lipocalin, and kidney epithelia. Am J Physiol Renal Physiol. 2003;285:F9–18.
Mishra J, Ma Q, Prada A, Mitsnefes M, et al. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol. 2003;14:2534–43.
Mishra J, Mori K, Ma Q, Kelly C, Barasch J, Devarajan P. Neutrophil gelatinase associated lipocalin: a novel early urinary biomarker for cisplatin nephrotoxicity. Am J Nephrol. 2004;24:307–15.
Mishra J, Dent C, Tarabishi R, Mitsnefes MM, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet. 2005;365:1231–8.
Kim SS, Song SH, Kim IJ, Jeon YK, et al. Urinary Cystatin C and Tubular proteinuria predict progression of diabetic nephropathy. Diabetes Care. 2013;36:656–61.
Nauta FL, Boertien WE, Bakker SJL, Goor HV, et al. Glomerular markers are elevated in patients with diabetes. Diabetes Care. 2011;34:975–81.
Wu J, Ding Y, Zhu C, Shao X, et al. Urinary TNF-α and NGAL are correlated with the progression of nephropathy in patients with type 2 diabetes. Exp Ther Med. 2013;6:1482–8.
Fu WJ, Li BL, Wang SB, Chen ML, et al. Changes of the tubular markers in type 2 diabetes mellitus with glomerular hyperfiltration. Diabetes Res Clin Pract. 2012;95(1):105–9.
Holman RR, Paul SK, Bethel MA, Matthews DR, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.
Remuzzi G, Macia M, Ruggenenti P. Prevention and treatment of diabetic renal disease in type 2 diabetes: the BENEDICT study. J Am Soc Nephrol. 2006;17(S2):S90–7.
Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253–9.
Borgman JM, Skorecki K. Chronic kidney disease. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL,editors. Harrison’s principles of internal medicine. 18th ed. New York: McGraw-Hill; 2012. p. 2308–2321.
Levey AS, Bosch JP, Lewis JB, Green T, 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;130:461–70.
Tapp RJ, Shaw JE, Zimmet PZ, Balkau B, et al. Albuminuria is evident in the early stages of diabetes onset: results from the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Am J Kidney Dis. 2004;44(5):792–8.
Tarsio JF, Reger LA, Furcht LT. Molecular mechanisms in basement membrane complications of diabetes. Alterations in heparin, laminin, and type IV collagen association. Diabetes. 1988;37(5):532–9.
Duncan ER, Walker SJ, Ezzat VA, Wheatcroft SB, et al. Accelerated endothelial dysfunction in mild prediabetic insulin resistance: the early role of reactive oxygen species. Am J Physiol Endocrinol Metab. 2007;293:E1311–9.
Makris K, Nikolaki E, Nanopoulos K, Pirqakis KM, et al. Measurement of Cystatin C in human urine by particle enhanced turbidimetric immunoassay on automated biochemistry analyzer. Clin Biochem. 2013;46(12):1128–30.
Conti M, Moutereau S, Zater M, Lallali K, et al. Urinary Cystatin C as a specific marker of tubular dysfunction. Clin Chem Lab Med. 2006;44(3):288–91.
Woo KS, Choi JL, Kim BR, Kim JE, et al. Urinary neutrophil gelatinase-associated lipocalin levels in comparison with glomerular filtration rate for evaluation of renal function in patients with diabetic chronic kidney disease. Diabetes Metab J. 2012;36:307–13.
Lacquaniti A, Donato V, Pintaudi B, Vieste GD, et al. ‘‘Normoalbuminuric’’ diabetic nephropathy: tubular damage and NGAL. Acta Diabetol. 2013;50:935–42.
Assal HS, Tawfeek S, Rasheed EA, Lebedy DE, et al. Serum cystatin C and tubular urinary enzymes as biomarkers of renal dysfunction in type 2 diabetes mellitus. Clin Med Insights Endocrinol Diab. 2013;6:7–13.
Fu WJ, Xiong SL, Fang YG, Wen S, et al. Urinary tubular biomarkers in short-term type 2 diabetes mellitus patients: a cross-sectional study. Endocrine. 2012;41(1):82–8.
Mori K, Lee HT, Rapoport D, Drexler IR, et al. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest. 2005;115(3):610–21.
Kaseda R, Iino N, Hosojima M, Takeda T, et al. Megalin-mediated endocytosis of cystatin C in proximal tubule cells. Biochem Biophys Res Commun. 2007;357(4):1130–4.
Vaidya VS, Waikar SS, Ferguson MA, et al. Urinary biomarkers for sensitive and specific detection of acute kidney injury in humans. Clin Transl Sci. 2008;1(3):200–8.
Russo LM, Sandoval RM, Campos SB, et al. Impaired tubular uptake explains albuminuria in early diabetic nephropathy. J Am Soc Nephrol. 2006;17:2937–44.
Conflict of interest
The authors have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Garg, V., Kumar, M., Mahapatra, H.S. et al. Novel urinary biomarkers in pre-diabetic nephropathy. Clin Exp Nephrol 19, 895–900 (2015). https://doi.org/10.1007/s10157-015-1085-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10157-015-1085-3