尿肾小管标志物与糖尿病肾病的临床研究进展
摘要
糖尿病肾病(DN)是1型和2型糖尿病主要的微血管并发症,DN是终末期肾病的最常见原因,也是糖尿病发病率和死亡率上升的主要原因。肾小球滤过屏障与糖尿病肾病关系密切,但随着研究的进展,近来发现,肾功能下降的速度与肾小管损伤程度和肾小管间质纤维化程度相关性更明显。过去,微量白蛋白尿被认为是肾小球损伤的早期生物标志物,不过,越来越多的证据质疑其对DN的预测价值,并发现近端小管是DN发展中的重要环节,并且提出"糖尿病性肾小管病"的概念,因此一些肾小管损伤标志物在DN的早期阶段可能比微量白蛋白尿更敏感,本文综述与DN相关肾小管损伤新的重要尿标记物的临床研究进展。
引文
[1] Parving HH,Chaturvedi N,Viberti G,et al. Does microalbuminuria predict diabetic nephropathy[J]. Diabetes Care,2002,25(2):406-407.
[2] Russo LM,Sandoval RM,Campos SB,et al. Impaired tubular uptake explains albuminuria in early diabetic nephropathy[J]. J Am Soc Nephrol,2009,20(3):489-494.
[3] Lee SY,Choi ME. Urinary biomarkers for early diabetic nephropathy:beyond albuminuria[J]. Pediatr Nephrol,2015,30(7):1063-1075.
[4] Dickson LE,Wagner MC,Sandoval RM,et al. The proximal tubule and albuminuria:really[J]. J Am Soc Nephrol,2014,25(3):443-453.
[5] Zeni L,Norden AGW,Cancarini G,et al. A more tubulocentric view of diabetic kidney disease[J]. J Nephrol,2017,30(6):701-717.
[6] Waring WS,Moonie A. Earlier recognition of nephrotoxicity using novel biomarkers of acute kidney injury[J]. Clin Toxicol(Phila),2011,49(8):720-728.
[7] Devarajan P. Biomarkers for the early detection of acute kidney injury[J]. Curr Opin Pediatr,2011,23(2):194-200.
[8] Nielsen SE,Andersen S,Zdunek D,et al. Tubular markers do not predict the decline in glomerular filtration rate in type 1 diabetic patients with overt nephropathy[J]. Kidney Int,2011,79(10):1113-1118.
[9] Assal HS,Tawfeek S,Rasheed EA,et al. Serum cystatin C and tubular urinary enzymes as biomarkers of renal dysfunction in type 2 diabetes mellitus[J]. Clin Med Insights Endocrinol Diabetes,2013,6:7-13.
[10] Kaul A,Behera MR,Rai MK,et al. Neutrophil gelatinase-associated lipocalin:as a predictor of early diabetic nephropathy in type 2 diabetes mellitus[J]. Indian J Nephrol,2018,28(1):53-60.
[11] Bhavsar NA,K9ttgen A,Coresh J,et al. Neutrophil gelatinase-associated lipocalin(NGAL)and kidney injury molecule 1(KIM-1)as predictors of incident CKD stage 3:the Atherosclerosis Risk in Communities(ARIC)Study[J]. Am J Kidney Dis,2012,60(2):233-240.
[12] Tramonti G,Kanwar YS. Review and discussion of tubular biomarkers in the diagnosis and management of diabetic nephropathy[J]. Endocrine,2013,43(3):494-503.
[13] Zhao X,Zhang Y,Li L,et al. Glomerular expression of kidney injury molecule-1 and podocytopenia in diabetic glomerulopathy[J]. Am J Nephrol,2011,34(3):268-280.
[14] El-Ashmawy NE,El-Zamarany EA,Khedr NF,et al. Kidney injury molecule-1(Kim-1):an early biomarker for nephropathy in type II diabetic patients[J]. Int J Diabetes Dev C,2015,35(3):431-438.
[15] Panduru NM,Sandholm N,Forsblom C,et al. Kidney injury molecule-1 and the loss of kidney function in diabetic nephropathy:a likely causal link in patients with type 1 diabetes[J]. Diabetes Care,2015,38(6):1130-1137.
[16] Kanaguchi Y,Suzuki Y,Osaki K,et al. Protective effects of L-type fatty acid-binding protein(L-FABP)in proximal tubular cells against glomerular injury in anti-GBM antibody-mediated glomerulonephritis[J]. Nephrol Dial Transplant,2011,26(11):3465-3473.
[17] Panduru NM,Forsblom C,Saraheimo M,et al. Urinary liver-type fatty acid binding protein is an independent predictor of stroke and mortality in individuals with type 1 diabetes[J]. Diabetologia,2017,60(9):1782-1790.
[18] Araki S,Haneda M,Koya D,et al. Predictive effects of urinary livertype fatty acid-binding protein for deteriorating renal function and incidence of cardiovascular disease in type 2 diabetic patients without advanced nephropathy[J]. Diabetes Care,2013,36(5):1248-1253.
[19] Kim SR,Lee YH,Lee SG,et al. Urinary N-acetyl-β-D-glucosaminidase,an early marker of diabetic kidney disease,might reflect glucose excursion in patients with type 2 diabetes[J]. Medicine(Baltimore),2016,95(27):e4114.
[20] Uwaezuoke SN. The role of novel biomarkers in predicting diabetic nephropathy:a review[J]. Int J Nephrol Renovasc Dis,2017,10:221-231.
[21] Patel DN,Kalia K. Efficacy of urinary N-acetyl-β-D-glucosaminidase to evaluate early renal tubular damage as a consequence of type 2 diabetes mellitus:a cross-sectional study[J]. Int J Diabetes Dev Ctries,2015,35(Supplement3):449-457.
[22] Gluhovschi C,Gluhovschi G,Petrica L,et al. Urinary biomarkers in the assessment of early diabetic nephropathy[J]. J Diabetes Res,2016,2016:4626125.
[23] Kim D,Kim KJ,Huh JH,et al. The ratio of glycated albumin to glycated haemoglobin correlates with insulin secretory function[J]. Clin Endocrinol(Oxf),2012,77(5):679-683.
[24] Suh S,Kim JH. Glycemic variability:How do we measure it and why is it important[J]. Diabetes Metab J,2015,39(4):273-282.
[25] Kim SR,Lee YH,Lee SG,et al. The renal tubular damage marker urinary N-acetyl-β-D-glucosaminidase may be more closely associated with early detection of atherosclerosis than the glomerular damage marker albuminuria in patients with type 2 diabetes[J]. Cardiovasc Diabetol,2017,16(1):16.
[26] Zahra N,Javad MA,Aboalfazl N. Detection of early stage renal disease by elevation of certain low molecular Weight proteins in urine of diabetes patients[J]. Int J Biol Sci Appl,2014,1(1):15-18.
[27] Brott DA,Furlong ST,Adler SH,et al. Characterization of renal biomarkers for use in clinical trials:effect of preanalytical processing and qualification using samples from subjects with diabetes[J]. Drug Des Devel Ther,2015,9:3191-3198.
[28] Ogasawara S,Hosojima M,Kaseda R,et al. Significance of urinary full-length and ectodomain forms of megalin in patients with type 2diabetes[J]. Diabetes Care,2012,35(5):1112-1118.
[29] Petrica L,Vlad A,Gluhovschi G,et al. Glycated peptides are associated with proximal tubule dysfunction in type 2 diabetes mellitus[J]. Int J Clin Exp Med,2015,8(2):2516-2525.
[30] Rao X,Wan M,Qiu C,et al. Role of cystatin C in renal damage and the optimum cut-off point of renal damage among patients with type 2diabetes mellitus[J]. Exp Ther Med,2014,8(3):887-892.
[31] Wu J,Shao X,Lu K,et al. Urinary RBP and NGAL levels are associated with nephropathy in patients with type 2 diabetes[J]. Cell Physiol Biochem,2017,42(2):594-602.
[32] Fiseha T,Tamir Z. Urinary markers of tubular injury in early diabetic nephropathy[J]. Int J Nephrol,2016,2016:4647685.
[33] Saif A,Soliman N. Urinaryα1-microglobulin and albumin excretion in children and adolescents with type 1 diabetes[J]. J Diabetes,2017,9(1):61-64.
[34] Kim SS,Song SH,Kim IJ,et al. Urinary cystatin C and tubular proteinuria predict progression of diabetic nephropathy[J]. Diabetes Care,2013,36(3):656-661.
[35] Satirapoj B,Aramsaowapak K,Tangwonglert T,et al. Novel tubular biomarkers predict renal progression in type 2 diabetes mellitus:a prospective cohort study[J]. J Diabetes Res,2016,2016(4):3102962.
[36] Vijay S,Hamide A,Senthilkumar GP,et al. Utility of urinary biomarkers as a diagnostic tool for early diabetic nephropathy in patients with type 2 diabetes mellitus[J]. Diabetes Metab Syndr,2018,12(5):649-652.
[37] Prakoura N,Chatziantoniou C. Matricellular proteins and organ fibrosis[J]. Current Pathobiology Reports,2017,5(2):111-121.
[38] Oka T,Xu J,Kaiser RA,et al. Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling[J]. Circ Res,2007,101(3):313-321.
[39] Shimazaki M,Nakamura K,Kii I,et al. Periostin is essential for cardiac healing after acute myocardial infarction[J]. J Exp Med,2008,205(2):295-303.
[40] Uchida M,Shiraishi H,Ohta S,et al. Periostin,a matricellular protein,plays a role in the induction of chemokines in pulmonary fibrosis[J]. Am J Respir Cell Mol Biol,2012,46(5):677-686.
[41] Bakhtyar N,Wong N,Kapoor A,et al. Clear cell renal cell carcinoma induces fibroblast-mediated production of stromal periostin[J]. Eur J Cancer,2013,49(16):3537-3546.
[42] Hwang JH,Yang SH,Kim YC,et al. Experimental inhibition of periostin attenuates kidney fibrosis[J]. Am J Nephrol,2017,46(6):501-517.
[43] Mael-Ainin M,Abed A,Conway SJ,et al. Inhibition of periostin expression protects against the development of renal inflammation and fibrosis[J]. J Am Soc Nephrol,2014,25(8):1724-1736.
[44] Prakoura N,Chatziantoniou C. Periostin and discoidin domain receptor 1:new biomarkers or targets for therapy of renal disease[J]. Front Med(Lausanne),2017,4:52.
[45] Prakoura N,Chatziantoniou C. Periostin in kidney diseases[J]. Cell Mol Life Sci,2017,74(23):4315-4320.
[46] Satirapoj B,Witoon R,Ruangkanchanasetr P,et al. Urine periostin as a biomarker of renal injury in chronic allograft nephropathy[J].Transplant Proc,2014,46(1):135-140.
[47] Satirapoj B,Tassanasorn S,Charoenpitakchai M,et al. Periostin as a tissue and urinary biomarker of renal injury in type 2 diabetes mellitus[J]. PLo S One,2015,10(4):e0124055.
[48] De S,Kuwahara S,Saito A. The endocytic receptor megalin and its associated proteins in proximal tubule epithelial cells[J]. Membranes(Basel),2014,4(3):333-355.
[49] Amsellem S,Gburek J,Hamard G,et al. Cubilin is essential for albumin reabsorption in the renal proximal tubule[J]. J Am Soc Nephrol,2010,21(11):1859-1867.
[50] De S,Kuwahara S,Hosojima M,et al. Exocytosis-mediated urinary full-length megalin excretion is linked with the pathogenesis of diabetic nephropathy[J]. Diabetes,2017,66(5):1391-1404.
[51] Kuwahara S,Hosojima M,Kaneko R,et al. Megalin-mediated tubuloglomerular alterations in high-fat diet-induced kidney disease[J]. J Am Soc Nephrol,2016,27(7):1996-2008.
[52] Nakamura T,Ushiyama C,Suzuki S,et al. Urinary excretion of podocytes in patients with diabetic nephropathy[J]. Nephrol Dial Transplant,2000,15(9):1379-1383.
[53] Petrica L,Vlad M,Vlad A,et al. Podocyturia parallels proximal tubule dysfunction in type 2 diabetes mellitus patients independently of albuminuria and renal function decline:A cross-sectional study[J]. J Diabetes Complicat,2017,31(9):1444-1450.
[54] Hara M,Yamagata K,Tomino Y,et al. Urinary podocalyxin is an early marker for podocyte injury in patients with diabetes:establishment of a highly sensitive ELISA to detect urinary podocalyxin[J]. Diabetologia,2012,55(11):2913-2919.
[55] Petrica L,Vlad A,Petrica M,et al. Pioglitazone delays proximal tubule dysfunction and improves cerebral vessel endothelial dysfunction in normoalbuminuric people with type 2 diabetes mellitus[J]. Diabetes Res Clin Pract,2011,94(1):22-32.
[56] Lioudaki E,Stylianou KG,Petrakis I,et al. Increased urinary excretion of podocyte markers in normoalbuminuric patients with diabetes[J]. Nephron,2015,131(1):34-42.
[57] Petrica L,Ursoniu S,Gadalean F,et al. Urinary podocyte-associated m RNA levels correlate with proximal tubule dysfunction in early diabetic nephropathy of type 2 diabetes mellitus[J]. Diabetol Metab Syndr,2017,9:31.
[2] Russo LM,Sandoval RM,Campos SB,et al. Impaired tubular uptake explains albuminuria in early diabetic nephropathy[J]. J Am Soc Nephrol,2009,20(3):489-494.
[3] Lee SY,Choi ME. Urinary biomarkers for early diabetic nephropathy:beyond albuminuria[J]. Pediatr Nephrol,2015,30(7):1063-1075.
[4] Dickson LE,Wagner MC,Sandoval RM,et al. The proximal tubule and albuminuria:really[J]. J Am Soc Nephrol,2014,25(3):443-453.
[5] Zeni L,Norden AGW,Cancarini G,et al. A more tubulocentric view of diabetic kidney disease[J]. J Nephrol,2017,30(6):701-717.
[6] Waring WS,Moonie A. Earlier recognition of nephrotoxicity using novel biomarkers of acute kidney injury[J]. Clin Toxicol(Phila),2011,49(8):720-728.
[7] Devarajan P. Biomarkers for the early detection of acute kidney injury[J]. Curr Opin Pediatr,2011,23(2):194-200.
[8] Nielsen SE,Andersen S,Zdunek D,et al. Tubular markers do not predict the decline in glomerular filtration rate in type 1 diabetic patients with overt nephropathy[J]. Kidney Int,2011,79(10):1113-1118.
[9] Assal HS,Tawfeek S,Rasheed EA,et al. Serum cystatin C and tubular urinary enzymes as biomarkers of renal dysfunction in type 2 diabetes mellitus[J]. Clin Med Insights Endocrinol Diabetes,2013,6:7-13.
[10] Kaul A,Behera MR,Rai MK,et al. Neutrophil gelatinase-associated lipocalin:as a predictor of early diabetic nephropathy in type 2 diabetes mellitus[J]. Indian J Nephrol,2018,28(1):53-60.
[11] Bhavsar NA,K9ttgen A,Coresh J,et al. Neutrophil gelatinase-associated lipocalin(NGAL)and kidney injury molecule 1(KIM-1)as predictors of incident CKD stage 3:the Atherosclerosis Risk in Communities(ARIC)Study[J]. Am J Kidney Dis,2012,60(2):233-240.
[12] Tramonti G,Kanwar YS. Review and discussion of tubular biomarkers in the diagnosis and management of diabetic nephropathy[J]. Endocrine,2013,43(3):494-503.
[13] Zhao X,Zhang Y,Li L,et al. Glomerular expression of kidney injury molecule-1 and podocytopenia in diabetic glomerulopathy[J]. Am J Nephrol,2011,34(3):268-280.
[14] El-Ashmawy NE,El-Zamarany EA,Khedr NF,et al. Kidney injury molecule-1(Kim-1):an early biomarker for nephropathy in type II diabetic patients[J]. Int J Diabetes Dev C,2015,35(3):431-438.
[15] Panduru NM,Sandholm N,Forsblom C,et al. Kidney injury molecule-1 and the loss of kidney function in diabetic nephropathy:a likely causal link in patients with type 1 diabetes[J]. Diabetes Care,2015,38(6):1130-1137.
[16] Kanaguchi Y,Suzuki Y,Osaki K,et al. Protective effects of L-type fatty acid-binding protein(L-FABP)in proximal tubular cells against glomerular injury in anti-GBM antibody-mediated glomerulonephritis[J]. Nephrol Dial Transplant,2011,26(11):3465-3473.
[17] Panduru NM,Forsblom C,Saraheimo M,et al. Urinary liver-type fatty acid binding protein is an independent predictor of stroke and mortality in individuals with type 1 diabetes[J]. Diabetologia,2017,60(9):1782-1790.
[18] Araki S,Haneda M,Koya D,et al. Predictive effects of urinary livertype fatty acid-binding protein for deteriorating renal function and incidence of cardiovascular disease in type 2 diabetic patients without advanced nephropathy[J]. Diabetes Care,2013,36(5):1248-1253.
[19] Kim SR,Lee YH,Lee SG,et al. Urinary N-acetyl-β-D-glucosaminidase,an early marker of diabetic kidney disease,might reflect glucose excursion in patients with type 2 diabetes[J]. Medicine(Baltimore),2016,95(27):e4114.
[20] Uwaezuoke SN. The role of novel biomarkers in predicting diabetic nephropathy:a review[J]. Int J Nephrol Renovasc Dis,2017,10:221-231.
[21] Patel DN,Kalia K. Efficacy of urinary N-acetyl-β-D-glucosaminidase to evaluate early renal tubular damage as a consequence of type 2 diabetes mellitus:a cross-sectional study[J]. Int J Diabetes Dev Ctries,2015,35(Supplement3):449-457.
[22] Gluhovschi C,Gluhovschi G,Petrica L,et al. Urinary biomarkers in the assessment of early diabetic nephropathy[J]. J Diabetes Res,2016,2016:4626125.
[23] Kim D,Kim KJ,Huh JH,et al. The ratio of glycated albumin to glycated haemoglobin correlates with insulin secretory function[J]. Clin Endocrinol(Oxf),2012,77(5):679-683.
[24] Suh S,Kim JH. Glycemic variability:How do we measure it and why is it important[J]. Diabetes Metab J,2015,39(4):273-282.
[25] Kim SR,Lee YH,Lee SG,et al. The renal tubular damage marker urinary N-acetyl-β-D-glucosaminidase may be more closely associated with early detection of atherosclerosis than the glomerular damage marker albuminuria in patients with type 2 diabetes[J]. Cardiovasc Diabetol,2017,16(1):16.
[26] Zahra N,Javad MA,Aboalfazl N. Detection of early stage renal disease by elevation of certain low molecular Weight proteins in urine of diabetes patients[J]. Int J Biol Sci Appl,2014,1(1):15-18.
[27] Brott DA,Furlong ST,Adler SH,et al. Characterization of renal biomarkers for use in clinical trials:effect of preanalytical processing and qualification using samples from subjects with diabetes[J]. Drug Des Devel Ther,2015,9:3191-3198.
[28] Ogasawara S,Hosojima M,Kaseda R,et al. Significance of urinary full-length and ectodomain forms of megalin in patients with type 2diabetes[J]. Diabetes Care,2012,35(5):1112-1118.
[29] Petrica L,Vlad A,Gluhovschi G,et al. Glycated peptides are associated with proximal tubule dysfunction in type 2 diabetes mellitus[J]. Int J Clin Exp Med,2015,8(2):2516-2525.
[30] Rao X,Wan M,Qiu C,et al. Role of cystatin C in renal damage and the optimum cut-off point of renal damage among patients with type 2diabetes mellitus[J]. Exp Ther Med,2014,8(3):887-892.
[31] Wu J,Shao X,Lu K,et al. Urinary RBP and NGAL levels are associated with nephropathy in patients with type 2 diabetes[J]. Cell Physiol Biochem,2017,42(2):594-602.
[32] Fiseha T,Tamir Z. Urinary markers of tubular injury in early diabetic nephropathy[J]. Int J Nephrol,2016,2016:4647685.
[33] Saif A,Soliman N. Urinaryα1-microglobulin and albumin excretion in children and adolescents with type 1 diabetes[J]. J Diabetes,2017,9(1):61-64.
[34] Kim SS,Song SH,Kim IJ,et al. Urinary cystatin C and tubular proteinuria predict progression of diabetic nephropathy[J]. Diabetes Care,2013,36(3):656-661.
[35] Satirapoj B,Aramsaowapak K,Tangwonglert T,et al. Novel tubular biomarkers predict renal progression in type 2 diabetes mellitus:a prospective cohort study[J]. J Diabetes Res,2016,2016(4):3102962.
[36] Vijay S,Hamide A,Senthilkumar GP,et al. Utility of urinary biomarkers as a diagnostic tool for early diabetic nephropathy in patients with type 2 diabetes mellitus[J]. Diabetes Metab Syndr,2018,12(5):649-652.
[37] Prakoura N,Chatziantoniou C. Matricellular proteins and organ fibrosis[J]. Current Pathobiology Reports,2017,5(2):111-121.
[38] Oka T,Xu J,Kaiser RA,et al. Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling[J]. Circ Res,2007,101(3):313-321.
[39] Shimazaki M,Nakamura K,Kii I,et al. Periostin is essential for cardiac healing after acute myocardial infarction[J]. J Exp Med,2008,205(2):295-303.
[40] Uchida M,Shiraishi H,Ohta S,et al. Periostin,a matricellular protein,plays a role in the induction of chemokines in pulmonary fibrosis[J]. Am J Respir Cell Mol Biol,2012,46(5):677-686.
[41] Bakhtyar N,Wong N,Kapoor A,et al. Clear cell renal cell carcinoma induces fibroblast-mediated production of stromal periostin[J]. Eur J Cancer,2013,49(16):3537-3546.
[42] Hwang JH,Yang SH,Kim YC,et al. Experimental inhibition of periostin attenuates kidney fibrosis[J]. Am J Nephrol,2017,46(6):501-517.
[43] Mael-Ainin M,Abed A,Conway SJ,et al. Inhibition of periostin expression protects against the development of renal inflammation and fibrosis[J]. J Am Soc Nephrol,2014,25(8):1724-1736.
[44] Prakoura N,Chatziantoniou C. Periostin and discoidin domain receptor 1:new biomarkers or targets for therapy of renal disease[J]. Front Med(Lausanne),2017,4:52.
[45] Prakoura N,Chatziantoniou C. Periostin in kidney diseases[J]. Cell Mol Life Sci,2017,74(23):4315-4320.
[46] Satirapoj B,Witoon R,Ruangkanchanasetr P,et al. Urine periostin as a biomarker of renal injury in chronic allograft nephropathy[J].Transplant Proc,2014,46(1):135-140.
[47] Satirapoj B,Tassanasorn S,Charoenpitakchai M,et al. Periostin as a tissue and urinary biomarker of renal injury in type 2 diabetes mellitus[J]. PLo S One,2015,10(4):e0124055.
[48] De S,Kuwahara S,Saito A. The endocytic receptor megalin and its associated proteins in proximal tubule epithelial cells[J]. Membranes(Basel),2014,4(3):333-355.
[49] Amsellem S,Gburek J,Hamard G,et al. Cubilin is essential for albumin reabsorption in the renal proximal tubule[J]. J Am Soc Nephrol,2010,21(11):1859-1867.
[50] De S,Kuwahara S,Hosojima M,et al. Exocytosis-mediated urinary full-length megalin excretion is linked with the pathogenesis of diabetic nephropathy[J]. Diabetes,2017,66(5):1391-1404.
[51] Kuwahara S,Hosojima M,Kaneko R,et al. Megalin-mediated tubuloglomerular alterations in high-fat diet-induced kidney disease[J]. J Am Soc Nephrol,2016,27(7):1996-2008.
[52] Nakamura T,Ushiyama C,Suzuki S,et al. Urinary excretion of podocytes in patients with diabetic nephropathy[J]. Nephrol Dial Transplant,2000,15(9):1379-1383.
[53] Petrica L,Vlad M,Vlad A,et al. Podocyturia parallels proximal tubule dysfunction in type 2 diabetes mellitus patients independently of albuminuria and renal function decline:A cross-sectional study[J]. J Diabetes Complicat,2017,31(9):1444-1450.
[54] Hara M,Yamagata K,Tomino Y,et al. Urinary podocalyxin is an early marker for podocyte injury in patients with diabetes:establishment of a highly sensitive ELISA to detect urinary podocalyxin[J]. Diabetologia,2012,55(11):2913-2919.
[55] Petrica L,Vlad A,Petrica M,et al. Pioglitazone delays proximal tubule dysfunction and improves cerebral vessel endothelial dysfunction in normoalbuminuric people with type 2 diabetes mellitus[J]. Diabetes Res Clin Pract,2011,94(1):22-32.
[56] Lioudaki E,Stylianou KG,Petrakis I,et al. Increased urinary excretion of podocyte markers in normoalbuminuric patients with diabetes[J]. Nephron,2015,131(1):34-42.
[57] Petrica L,Ursoniu S,Gadalean F,et al. Urinary podocyte-associated m RNA levels correlate with proximal tubule dysfunction in early diabetic nephropathy of type 2 diabetes mellitus[J]. Diabetol Metab Syndr,2017,9:31.
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