糖尿病肾病早期诊断标志物的研究新进展
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摘要
糖尿病肾病(diabetic kidney disease,DKD)是2型糖尿病病人(type 2 diabetes mellitus,T2DM)最常见、最严重的慢性合并症,发病率逐年升高,已成为危害人类的重大疾病。早期经治疗后多可逆转,晚期则发展成终末期肾病。因此,及早诊断和预测DKD对临床治疗显得尤为重要。目前,临床上以微量白蛋白尿(microalbuminuria,MAU)作为诊断2型糖尿病肾损害的早期指标,然而,其预测价值受到质疑。近年来,人们发现蛋白质组学可能成为诊断糖尿病肾病的新工具,触珠蛋白(haptoglobin,HP)这种多功能的急性期时相蛋白可能与DKD的发生及发展密切相关。因此,本文就触珠蛋白与糖尿病肾病发病机制的研究进展进行综述。
Diabetic kidney disease(DKD) as a common and severe chronic complication of type 2 diabetes mellitus(T2DM) has rapidly become an important public health problem. It can be reversed in early stage after treatment,or become end-stage renal disease in advanced stage. Therefore, early diagnosis and prediction of DKD for clinical treatment is particularly important. Although microalbuminuria(MAU) is an early marker for kidney damage in type 2 diabetes mellitus,its predictive value is now questioned. In recent years,it was found that proteomics may become a new tool in the diagnosis of diabetic nephropathy. Haptoglobin(HP) as an acute phase protein with a variety of functions was found may be closely related to the occurrence and development of diabetic nephropathy.Therefore,this article reviewed the progress on research of haptoglobin with the pathogenesis of diabetic nephropathy.
Diabetic kidney disease(DKD) as a common and severe chronic complication of type 2 diabetes mellitus(T2DM) has rapidly become an important public health problem. It can be reversed in early stage after treatment,or become end-stage renal disease in advanced stage. Therefore, early diagnosis and prediction of DKD for clinical treatment is particularly important. Although microalbuminuria(MAU) is an early marker for kidney damage in type 2 diabetes mellitus,its predictive value is now questioned. In recent years,it was found that proteomics may become a new tool in the diagnosis of diabetic nephropathy. Haptoglobin(HP) as an acute phase protein with a variety of functions was found may be closely related to the occurrence and development of diabetic nephropathy.Therefore,this article reviewed the progress on research of haptoglobin with the pathogenesis of diabetic nephropathy.
引文
[1]Gao L,Xin Z,Yuan M X,et al.High prevalence of diabetic retinopathy in diabetic patients concomitant with metabolic syndrome[J].PLo S One,2016,11(1):e0145293.
[2]Yuan M X,Peng Z H,Xin Z,et al.Low prevalence of diabetic retinopathy in a Chinese population[J].Diabetes care,2012,35(8):e61.
[3]Yang J K,Wang Y Y,Liu C,et al.Urine proteome specific for eye damage canpredict kidney damage in patients with type 2 diabetes:a case-control and a5.3-year prospective cohort study[J].Diabetes care,2017,40(2):253-260.
[4]Espinel E,Agraz I,Ibernon M,et al.Renal biopsy in type2 diabetic patients[J].J Clinical Med,2015,4(5):998-1009.
[5]Macisaac R J,Ekinci E I,Jerums G.Markers of and risk factors for the development and progression of diabetic kidney disease[J].Am J Kidney Dis,2014,63(2 Suppl 2):S39-S62.
[6]Coon J J,Zurbig P,Dakna M,et al.CE-MS analysis of the human urinary proteome for biomarker discovery and disease diagnostics[J].Proteomics Clin Appl,2008,2(7-8):964.
[7]Perkins B A,Ficociello L H,Silva K H,et al.Regression of microalbuminuria in type 1 diabetes[J].N Engl J Med,2003,348(23):2285-2293.
[8]Caramori M L,Fioretto P,Mauer M.The need for early predictors of diabetic nephropathy risk:is albumin excretion rate sufficient?[J].Diabetes,2000,49(9):1399-1408.
[9]Perkins B A,Ficociello L H,Roshan B,et al.In patients with type 1 diabetes and new-onset microalbuminuria the development of advanced chronic kidney disease may not require progression to proteinuria[J].Kidney Int,2010,77(1):57-64.
[10]Parving H H,Gall M A,Skott P,et al.Prevalence and causes of albuminuria in non-insulin-dependent diabetic patients[J].Kidney Int,1992,41(4):758-762.
[11]Romero P,Salvat M,Fernandez J,et al.Renal and retinal microangiopathy after 15 years of follow-up study in a sample of Type 1 diabetes mellitus patients[J].J Diabetes Complications,2007,21(2):93-100.
[12]Chen Y W,Wang Y Y,Zhao D,et al.High prevalence of lower extremity peripheral artery disease in type 2 diabetes patients with proliferative diabetic retinopathy[J].PLo S One,2015,10(3):e0122022.
[13]American Diabetes Association.Microvascular complications and foot care[J].Diabetes Care,2016,39 Suppl 1:S72-S80.
[14]Dahlquist G,Stattin E L,Rudberg S.Urinary albumin excretion rate and glomerular filtration rate in the prediction of diabetic nephropathy;a long-term follow-up study of childhood onset type-1 diabetic patients[J].Nephrol Dial Transplant,2001,16(7):1382-1386.
[15]Amin R,Turner C,van Aken S,et al.The relationship between microalbuminuria and glomerular filtration rate in young type 1 diabetic subjects:The oxford regional prospective study[J].Kidney Int,2005,68(4):1740-1749.
[16]Costacou T,Ellis D,Fried L,et al.Sequence of progression of albuminuria and decreased GFR in persons with type1 diabetes:a cohort study[J].Am J Kidney Dis,2007,50(5):721-732.
[17]Tabaei B P,Al-Kassab A S,Ilag L L,et al.Does microalbuminuria predict diabetic nephropathy?[J].Diabetes Care,2001,24(9):1560-1566.
[18]He F,Xia X,Wu X F,et al.Diabetic retinopathy in predicting diabetic nephropathy in patients with type 2 diabetes and renal disease:a meta-analysis[J].Diabetologia,2013,56(3):457-466.
[19]Benitez-Aguirre P Z,Sasongko M B,Craig M E,et al.Retinal vascular geometry predicts incident renal dysfunction in young people with type 1 diabetes[J].Diabetes Care,2012,35(3):599-604.
[20]El-Asrar A M,Al-Rubeaan K A,Al-Amro S A,et al.Retinopathy as a predictor of other diabetic complications[J].Int Ophthalmol,2001,24(1):1-11.
[21]Snell-Bergeon J K,Maahs D M,Ogden L G,et al.Evaluation of urinary biomarkers for coronary artery disease,diabetes,and diabetic kidney disease[J].Diabetes Technol Ther,2009,11(1):1-9.
[22]Mischak H,Delles C,Klein J,et al.Urinary proteomics based on capillary electrophoresis-coupled mass spectrometry in kidney disease:discovery and validation of biomarkers,and clinical application[J].Adv Chronic Kidney Dis,2010,17(6):493-506.
[23]Nakhoul F M,Miller-Lotan R,Awaad H,et al.Hypothesis—haptoglobin genotypeand diabetic nephropathy[J].Nat Clin Pract Nephrol,2007,3(6):339-344.
[24]Wicher K B,Fries E.Haptoglobin,a hemoglobin-binding plasma protein,is present in bony fish and mammals but not in frog and chicken[J].Proc Nat Acad Sci USA,2006,103(11):4168-4173.
[25]Hollox E J,Wain L V.Recurrent mutation at the classical haptoglobin structural polymorphism[J].Nat Genet,2016,48(4):347-348.
[26]Amiri A A,Hashemi-Soteh M B,Haghshenas M R,et al.Haptoglobin polymorphism in individuals with type 2 diabetic microangiopathy[J].N Am J Med Sci,2013,5(9):529-535.
[27]Ragab S M,Safan M A,Badr E A,et al.Haptoglobin genotypes polymorphism as a risk factor for subclinical atherosclerosis in beta-thalassemia major children;a single center Egyptian study[J].Hematology,2014,[Epub ahead of print].
[28]Mao L,Dong H,Yang P,et al.MALDI-TOF/TOF-MS reveals elevated serum haptoglobin and amyloid A in Behcet's disease[J].J Proteome Res,2008,7(10):4500-4507.
[29]Asleh R,Ward J,Levy N S,et al.Haptoglobin genotypedependent differences in macrophage lysosomal oxidative injury[J].J Biol Chem,2014,289(23):16313-16325.
[30]Sandim V,Pereira Dde A,Kalume D E,et al.Proteomic analysis reveals differentially secreted proteins in the urine from patients with clear cell renal cell carcinoma[J].Urol Oncol,2016,34(1):5.
[31]Bhensdadia N M,Hunt K J,Lopes-Virella M F,et al.Urine haptoglobin levels predict early renal functional decline in patients with type 2 diabetes[J].Kidney Int,2013,83(6):1136-1143.
[32]Nakhoul F M,Miller-Lotan R,Awaad H,et al.Hypothesis--haptoglobin genotype and diabetic nephropathy[J].Nat Clin Pract Nephrol,2007,3(6):339-344.
[33]Asleh R,Nakhoul F M,Miller-Lotan R,et al.Poor lysosomal membrane integrity in proximal tubule cells of haptoglobin 2-2 genotype mice with diabetes mellitus[J].Free Radic Biol Med,2012,53(4):779-786.
[34]Gburek J,Verroust P J,Willnow T E,et al.Megalin and cubilin are endocytic receptors involved in renal clearance of hemoglobin[J].J Am Soc Nephrol,2002,13(2):423-430.
[35]Fearn A,Sheerin N S.Complement activation in progressive renal disease[J].World J Nephrol,2015,4(1):31-40.
[36]张东亮.基于抗组织纤维化的慢性肾脏病治疗新进展[J].首都医科大学学报,2015,36(3):333-337.
[37]Kelly K J,Liu Y,Zhang J,et al.Renal C3 complement component:feed forward to diabetic kidney disease[J].Am J Nephrol,2015,41(1):48-56.
[38]Bhensdadia N M,Hunt K J,Lopes-Virella M F,et al.Urine haptoglobin levels predict early renal functional decline in patients with type 2 diabetes[J].Kidney Int,2013,83(6):1136-1143.
[39]Liu J J,Liu S,Wong M D,et al.Urinary haptoglobin predicts rapid renal function decline in asians with type 2 diabetes and early kidney disease[J].J Clin Endocrinol Metab,2016,101(10):3794-3802.
[40]Levy A P,Roguin A,Hochberg I,et al.Haptoglobin phenotype and vascularcomplications in patients with diabetes[J].N Engl J Med,2000,343(13):969-970.
[41]Nakhoul F M,Zoabi R,Kanter Y,et al.Haptoglobin phenotype and diabeticnephropathy[J].Diabetologia,2001,44(5):602-604.
[42]Awadallah S,Hamad M.A study of haptoglobin phenotypes in patients withchronic renal failure[J].Ann Clin Biochem,2003,40(Pt 6):680-683.
[43]Bessa S S,Hamdy S M,Ali E M.Haptoglobin gene polymorphism in type 2diabetic patients with and without nephropathy:an egyptian study[J].Eur J Intern Med,2007,18(6):489-495.
[44]Conway B R,Savage D A,Brady H R,et al.Association between haptoglobin genevariants and diabetic nephropathy:haptoglobin polymorphism in nephropathysusceptibility[J].Nephron Exp Nephrol,2007,105(3):e75-e79.
[45]Costacou T,Ferrell R E,Ellis D,et al.Haptoglobin genotype and renal functiondecline in type 1 diabetes[J].Diabetes,2009,58(12):2904-2909.
[46]Koda Y,Soejima M,Yamagishi S,et al.Haptoglobin genotype and diabeticmicroangiopathies in Japanese diabetic patients[J].Diabetologia,2002,45(7):1039-1040.
[2]Yuan M X,Peng Z H,Xin Z,et al.Low prevalence of diabetic retinopathy in a Chinese population[J].Diabetes care,2012,35(8):e61.
[3]Yang J K,Wang Y Y,Liu C,et al.Urine proteome specific for eye damage canpredict kidney damage in patients with type 2 diabetes:a case-control and a5.3-year prospective cohort study[J].Diabetes care,2017,40(2):253-260.
[4]Espinel E,Agraz I,Ibernon M,et al.Renal biopsy in type2 diabetic patients[J].J Clinical Med,2015,4(5):998-1009.
[5]Macisaac R J,Ekinci E I,Jerums G.Markers of and risk factors for the development and progression of diabetic kidney disease[J].Am J Kidney Dis,2014,63(2 Suppl 2):S39-S62.
[6]Coon J J,Zurbig P,Dakna M,et al.CE-MS analysis of the human urinary proteome for biomarker discovery and disease diagnostics[J].Proteomics Clin Appl,2008,2(7-8):964.
[7]Perkins B A,Ficociello L H,Silva K H,et al.Regression of microalbuminuria in type 1 diabetes[J].N Engl J Med,2003,348(23):2285-2293.
[8]Caramori M L,Fioretto P,Mauer M.The need for early predictors of diabetic nephropathy risk:is albumin excretion rate sufficient?[J].Diabetes,2000,49(9):1399-1408.
[9]Perkins B A,Ficociello L H,Roshan B,et al.In patients with type 1 diabetes and new-onset microalbuminuria the development of advanced chronic kidney disease may not require progression to proteinuria[J].Kidney Int,2010,77(1):57-64.
[10]Parving H H,Gall M A,Skott P,et al.Prevalence and causes of albuminuria in non-insulin-dependent diabetic patients[J].Kidney Int,1992,41(4):758-762.
[11]Romero P,Salvat M,Fernandez J,et al.Renal and retinal microangiopathy after 15 years of follow-up study in a sample of Type 1 diabetes mellitus patients[J].J Diabetes Complications,2007,21(2):93-100.
[12]Chen Y W,Wang Y Y,Zhao D,et al.High prevalence of lower extremity peripheral artery disease in type 2 diabetes patients with proliferative diabetic retinopathy[J].PLo S One,2015,10(3):e0122022.
[13]American Diabetes Association.Microvascular complications and foot care[J].Diabetes Care,2016,39 Suppl 1:S72-S80.
[14]Dahlquist G,Stattin E L,Rudberg S.Urinary albumin excretion rate and glomerular filtration rate in the prediction of diabetic nephropathy;a long-term follow-up study of childhood onset type-1 diabetic patients[J].Nephrol Dial Transplant,2001,16(7):1382-1386.
[15]Amin R,Turner C,van Aken S,et al.The relationship between microalbuminuria and glomerular filtration rate in young type 1 diabetic subjects:The oxford regional prospective study[J].Kidney Int,2005,68(4):1740-1749.
[16]Costacou T,Ellis D,Fried L,et al.Sequence of progression of albuminuria and decreased GFR in persons with type1 diabetes:a cohort study[J].Am J Kidney Dis,2007,50(5):721-732.
[17]Tabaei B P,Al-Kassab A S,Ilag L L,et al.Does microalbuminuria predict diabetic nephropathy?[J].Diabetes Care,2001,24(9):1560-1566.
[18]He F,Xia X,Wu X F,et al.Diabetic retinopathy in predicting diabetic nephropathy in patients with type 2 diabetes and renal disease:a meta-analysis[J].Diabetologia,2013,56(3):457-466.
[19]Benitez-Aguirre P Z,Sasongko M B,Craig M E,et al.Retinal vascular geometry predicts incident renal dysfunction in young people with type 1 diabetes[J].Diabetes Care,2012,35(3):599-604.
[20]El-Asrar A M,Al-Rubeaan K A,Al-Amro S A,et al.Retinopathy as a predictor of other diabetic complications[J].Int Ophthalmol,2001,24(1):1-11.
[21]Snell-Bergeon J K,Maahs D M,Ogden L G,et al.Evaluation of urinary biomarkers for coronary artery disease,diabetes,and diabetic kidney disease[J].Diabetes Technol Ther,2009,11(1):1-9.
[22]Mischak H,Delles C,Klein J,et al.Urinary proteomics based on capillary electrophoresis-coupled mass spectrometry in kidney disease:discovery and validation of biomarkers,and clinical application[J].Adv Chronic Kidney Dis,2010,17(6):493-506.
[23]Nakhoul F M,Miller-Lotan R,Awaad H,et al.Hypothesis—haptoglobin genotypeand diabetic nephropathy[J].Nat Clin Pract Nephrol,2007,3(6):339-344.
[24]Wicher K B,Fries E.Haptoglobin,a hemoglobin-binding plasma protein,is present in bony fish and mammals but not in frog and chicken[J].Proc Nat Acad Sci USA,2006,103(11):4168-4173.
[25]Hollox E J,Wain L V.Recurrent mutation at the classical haptoglobin structural polymorphism[J].Nat Genet,2016,48(4):347-348.
[26]Amiri A A,Hashemi-Soteh M B,Haghshenas M R,et al.Haptoglobin polymorphism in individuals with type 2 diabetic microangiopathy[J].N Am J Med Sci,2013,5(9):529-535.
[27]Ragab S M,Safan M A,Badr E A,et al.Haptoglobin genotypes polymorphism as a risk factor for subclinical atherosclerosis in beta-thalassemia major children;a single center Egyptian study[J].Hematology,2014,[Epub ahead of print].
[28]Mao L,Dong H,Yang P,et al.MALDI-TOF/TOF-MS reveals elevated serum haptoglobin and amyloid A in Behcet's disease[J].J Proteome Res,2008,7(10):4500-4507.
[29]Asleh R,Ward J,Levy N S,et al.Haptoglobin genotypedependent differences in macrophage lysosomal oxidative injury[J].J Biol Chem,2014,289(23):16313-16325.
[30]Sandim V,Pereira Dde A,Kalume D E,et al.Proteomic analysis reveals differentially secreted proteins in the urine from patients with clear cell renal cell carcinoma[J].Urol Oncol,2016,34(1):5.
[31]Bhensdadia N M,Hunt K J,Lopes-Virella M F,et al.Urine haptoglobin levels predict early renal functional decline in patients with type 2 diabetes[J].Kidney Int,2013,83(6):1136-1143.
[32]Nakhoul F M,Miller-Lotan R,Awaad H,et al.Hypothesis--haptoglobin genotype and diabetic nephropathy[J].Nat Clin Pract Nephrol,2007,3(6):339-344.
[33]Asleh R,Nakhoul F M,Miller-Lotan R,et al.Poor lysosomal membrane integrity in proximal tubule cells of haptoglobin 2-2 genotype mice with diabetes mellitus[J].Free Radic Biol Med,2012,53(4):779-786.
[34]Gburek J,Verroust P J,Willnow T E,et al.Megalin and cubilin are endocytic receptors involved in renal clearance of hemoglobin[J].J Am Soc Nephrol,2002,13(2):423-430.
[35]Fearn A,Sheerin N S.Complement activation in progressive renal disease[J].World J Nephrol,2015,4(1):31-40.
[36]张东亮.基于抗组织纤维化的慢性肾脏病治疗新进展[J].首都医科大学学报,2015,36(3):333-337.
[37]Kelly K J,Liu Y,Zhang J,et al.Renal C3 complement component:feed forward to diabetic kidney disease[J].Am J Nephrol,2015,41(1):48-56.
[38]Bhensdadia N M,Hunt K J,Lopes-Virella M F,et al.Urine haptoglobin levels predict early renal functional decline in patients with type 2 diabetes[J].Kidney Int,2013,83(6):1136-1143.
[39]Liu J J,Liu S,Wong M D,et al.Urinary haptoglobin predicts rapid renal function decline in asians with type 2 diabetes and early kidney disease[J].J Clin Endocrinol Metab,2016,101(10):3794-3802.
[40]Levy A P,Roguin A,Hochberg I,et al.Haptoglobin phenotype and vascularcomplications in patients with diabetes[J].N Engl J Med,2000,343(13):969-970.
[41]Nakhoul F M,Zoabi R,Kanter Y,et al.Haptoglobin phenotype and diabeticnephropathy[J].Diabetologia,2001,44(5):602-604.
[42]Awadallah S,Hamad M.A study of haptoglobin phenotypes in patients withchronic renal failure[J].Ann Clin Biochem,2003,40(Pt 6):680-683.
[43]Bessa S S,Hamdy S M,Ali E M.Haptoglobin gene polymorphism in type 2diabetic patients with and without nephropathy:an egyptian study[J].Eur J Intern Med,2007,18(6):489-495.
[44]Conway B R,Savage D A,Brady H R,et al.Association between haptoglobin genevariants and diabetic nephropathy:haptoglobin polymorphism in nephropathysusceptibility[J].Nephron Exp Nephrol,2007,105(3):e75-e79.
[45]Costacou T,Ferrell R E,Ellis D,et al.Haptoglobin genotype and renal functiondecline in type 1 diabetes[J].Diabetes,2009,58(12):2904-2909.
[46]Koda Y,Soejima M,Yamagishi S,et al.Haptoglobin genotype and diabeticmicroangiopathies in Japanese diabetic patients[J].Diabetologia,2002,45(7):1039-1040.