2型糖尿病肾损害的病理分型及其临床意义
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摘要
研究背景
糖尿病肾脏损害是糖尿病严重的并发症,它是发达国家终末期肾病的首位病因,在我国终末期肾病中的所占比例也在迅速上升。糖尿病肾损伤的发病机制不完全清楚,糖尿病肾脏疾病的病理分型/分级标准存在广泛争议,尚无获得广泛认可、能准确评估预后的标准。2型糖尿病相关的肾病在临床、病理以及预后特征方面都存在显著的异质性。国内外许多学者因此提出了不典型糖尿病肾病的概念,这些患者病程短、糖尿病视网膜病变少、代谢紊乱严重,病理特点不同于1型糖尿病患者经典的肾小球病变,而肾小管、间质、血管病变相对突出,肾功能下降速度更慢。然而,这方面的研究尤其是病理分型与预后相关性的随访队列研究还很缺乏,因此有必要对我国2型糖尿病肾脏病变进行临床、病理研究。
目的
进一步探讨2型糖尿病病理分型及其与临床指标的相关性；研究该分型对患者肾功能下降速度及相关结局事件的预测价值；寻找对于2型糖尿病肾病预后有较高预测价值的临床及病理指标。
方法：
入组标准：2001年1月至2011年12月期间于北京协和医院住院接受肾活检,临床和病理资料保存完整、符合1997年WHO诊断标准的2型糖尿病患者；排除肾脏病理以非糖尿病肾病(NDRD)为主的患者。符合上述条件患者共119例,对随访期大于等于6个月的患者(共92例)进行分析。
病理资料：根据光镜下所见将患者分为典型糖尿病肾小球病(DG,共51例)和不典型糖尿病相关肾病(ADRG,共41例)两组,根据光镜、电镜、免疫组化结果,分别定量/半定量方式评价肾小球、血管、小管间质病变及足细胞密度。
临床资料：收集活检前后2周内患者的临床资料,分析两组患者是否存在显著性差异。
随访资料：通过病案检索及电话对上述患者队列进行随访,比较病理分型对患者预后(死亡、需要规律维持性透析、肌酐倍增、接受眼科手术、心脑血管并发症)的预测价值,应用回归分析探索与肾脏结局事件的独立相关的临床及病理指标。
结果
1.DG组患者年龄较高,血红蛋白、血ALB显著较低,糖尿病病程较长、空腹血糖较高、DR程度较重,收缩压较高,血尿、蛋白尿、肾功能损害情况较ADRD重;ADRD组BMI及TG、均显著较高。
2.DG组系膜体积分数[Vv(mes/glom)]、基底膜厚度(GBMW)显著较高,而足细胞相对密度[Nv(epi/glom)]则显著较低；DG组肾小管萎缩积分、肾间质病变积分、肾血管病变积分均显著高于ADRD组。
3.随访期间DG组肌酐增加速率显著大于ADRD组；DG组发生肾脏结局事件共29例,死亡12例,发生糖尿病眼底事件31人次、心血管事件4人次；ADRD无终点事件发生,随访期间发生糖尿病眼底事件2人次、心血管事件4人次。DG组中位生存时间为23(6,40)个月,中位肾脏无事件生存期为32(19,45)个月,两组生存率比较存在显著性差异。
4.Cox回归分析提示,校正CKD分期后,病理类型为DG、GBM厚、血管及小管间质病变严重等病理表现是肾脏结局事件的危险因素。但只有系膜体积分数是独立于CKD分期、尿蛋白及年龄的肾脏预后的预测因素。
结论
1.根据病理是否符合典型TIDM肾病的特点,可将T2DM相关的肾病患者分为DG和ADRD。
2. ADRD组病理表现和肾损害情况明显轻于DG,而在代谢指标、糖尿病眼底病变等临床状况方面与DG组差异显著,提示二者是有着不同病理生理机制的肾损害类型
3.两种病理类型患者随访期内肾生存率差异显著,多因素Cox回归分析提示系膜体积分数是肾脏结局事件的独立影响因素。
Background
Nephropathy is a severe complication of diabetes mellitus. Being the major cause of ESRD in developed countries, it also presents as a rising cause of kidney failure in China. The underline mechanism of kidney injury in diabetes remains unclear. At the same time, the pathological classification/grading criteria of diabetic nephropathy are still under debate, due to the lack of widely recognized, highly predictive systems. Type2diabetes mellitus kidney disease has revealed a highly heterogeneous nature in clinical, pathological and prognostic dimensions, which lead to the concept of "atypical diabetes related renal disease". It is characterized by short diatetes histories, fewer retinopathies, heavier metabolic disturbance, slower renal function loss, and specific pathological features manifested by disproportionally severe tubulal,thterstitial and vascular lesions and distinguished from classical glomerulopathy represented by type1diabetes mellitus patients. Whoever, cohort study in this field is largely insufficient especially on relationship between pathological classification and prognosis. Therefore, it is necessary to perform clinical and pathological researches on T2DM kidney disease in China.
Objectives
Further explore relationship between pathological classification and clinical features in T2DM kidney disease; explore the predictive value of the classification for renal outcome events and renal function decreasing speed; search for efficient predictive pathological and clinical factors for renal prognosis in T2DM kidney disease.
Methods
Case selection:We enrolled a cohort of119T2DM patients who were diagnosed by1997WHO criteria and underwent renal biopsy in PUMCH hospital between2001and2011, with intact clinical and pathological data and no evidence for NDKD. Patients with follow-up time shorter than6months are ruled out for final analysis.
Pathological data:Patients are divided into typical diabetic glomerulopathy (DG, n=51) and atypical diabetes-related renal disease (ADRD,n=41) according to findings under LM, and evaluated for glomerular, vascular, tubular and interstitial lesion and podocyte density quantitative/semi-quantitatively, according to LM, EM and immunohistochemistry findings.
Clinical data:Clinical data within2weeks from biopsy date are collected and compared.
Prognostics:Through follow-up research by medical documents and telephone inquiry, prognosis related events (death, need for regular renal replacement therapy, double of SCr, diabetic ophthalmic event, CVD, etc.) are collected for regression analysis.
Results
1. Patients in DG group are characterized by older age, lower Hb and ALB, longer diabetes history, more severe DR, higher PBG and SBP, as well as more severe hematuria, proteinuria and kidney function damage; ADRD patients show significantly higher BMI, TG,
2. Mesangial functional volume, GBM width are significantly higher and relative podocyte density is significantly lower in DG group; and scores for tubular atrophy, interstitial lesion and vascular lesion are also significantly higher in DG group.
3. During follow-up, SCr increasing speed is significantly faster than ADRD group. In DG group,29renal outcome events,12death events,31DR renal events and4CVD events are observed, and median survival time and median non-events renal survival time are23(6,40) and32(19,45) months. No renal outcome events are observed in ADRD group and2DR renal events and4CVD events are observed. Survival rates are significantly different between two groups.
4. Cox regression model indicates that the classified as DG, thicker GBM width and heavier vascular, tubular and interstial lesion are risk factors for renal outcome events adjusted for CKD stage. Only high mesangial fractional volume is the renal outcome risk factor independent from CKD stage, proteinuria and age.
Conclusions
1. T2DM kidney disease can be divided into DG and ADRD, according to features typical of T1DM kidney disease.
2. ADRD is largely distinguished from DG by significantly milder pathological manifestation and renal lesions, worse metabolic disturbance, fewer DR, indicating a essentially different pathophysiological mechanism.
3. Renal survival rates are significant different between two groups, and mesangial fractional volume is the renal outcome predictive factors independent of CKD stage, proteinuria and age.
糖尿病肾脏损害是糖尿病严重的并发症,它是发达国家终末期肾病的首位病因,在我国终末期肾病中的所占比例也在迅速上升。糖尿病肾损伤的发病机制不完全清楚,糖尿病肾脏疾病的病理分型/分级标准存在广泛争议,尚无获得广泛认可、能准确评估预后的标准。2型糖尿病相关的肾病在临床、病理以及预后特征方面都存在显著的异质性。国内外许多学者因此提出了不典型糖尿病肾病的概念,这些患者病程短、糖尿病视网膜病变少、代谢紊乱严重,病理特点不同于1型糖尿病患者经典的肾小球病变,而肾小管、间质、血管病变相对突出,肾功能下降速度更慢。然而,这方面的研究尤其是病理分型与预后相关性的随访队列研究还很缺乏,因此有必要对我国2型糖尿病肾脏病变进行临床、病理研究。
目的
进一步探讨2型糖尿病病理分型及其与临床指标的相关性；研究该分型对患者肾功能下降速度及相关结局事件的预测价值；寻找对于2型糖尿病肾病预后有较高预测价值的临床及病理指标。
方法：
入组标准：2001年1月至2011年12月期间于北京协和医院住院接受肾活检,临床和病理资料保存完整、符合1997年WHO诊断标准的2型糖尿病患者；排除肾脏病理以非糖尿病肾病(NDRD)为主的患者。符合上述条件患者共119例,对随访期大于等于6个月的患者(共92例)进行分析。
病理资料：根据光镜下所见将患者分为典型糖尿病肾小球病(DG,共51例)和不典型糖尿病相关肾病(ADRG,共41例)两组,根据光镜、电镜、免疫组化结果,分别定量/半定量方式评价肾小球、血管、小管间质病变及足细胞密度。
临床资料：收集活检前后2周内患者的临床资料,分析两组患者是否存在显著性差异。
随访资料：通过病案检索及电话对上述患者队列进行随访,比较病理分型对患者预后(死亡、需要规律维持性透析、肌酐倍增、接受眼科手术、心脑血管并发症)的预测价值,应用回归分析探索与肾脏结局事件的独立相关的临床及病理指标。
结果
1.DG组患者年龄较高,血红蛋白、血ALB显著较低,糖尿病病程较长、空腹血糖较高、DR程度较重,收缩压较高,血尿、蛋白尿、肾功能损害情况较ADRD重;ADRD组BMI及TG、均显著较高。
2.DG组系膜体积分数[Vv(mes/glom)]、基底膜厚度(GBMW)显著较高,而足细胞相对密度[Nv(epi/glom)]则显著较低；DG组肾小管萎缩积分、肾间质病变积分、肾血管病变积分均显著高于ADRD组。
3.随访期间DG组肌酐增加速率显著大于ADRD组；DG组发生肾脏结局事件共29例,死亡12例,发生糖尿病眼底事件31人次、心血管事件4人次；ADRD无终点事件发生,随访期间发生糖尿病眼底事件2人次、心血管事件4人次。DG组中位生存时间为23(6,40)个月,中位肾脏无事件生存期为32(19,45)个月,两组生存率比较存在显著性差异。
4.Cox回归分析提示,校正CKD分期后,病理类型为DG、GBM厚、血管及小管间质病变严重等病理表现是肾脏结局事件的危险因素。但只有系膜体积分数是独立于CKD分期、尿蛋白及年龄的肾脏预后的预测因素。
结论
1.根据病理是否符合典型TIDM肾病的特点,可将T2DM相关的肾病患者分为DG和ADRD。
2. ADRD组病理表现和肾损害情况明显轻于DG,而在代谢指标、糖尿病眼底病变等临床状况方面与DG组差异显著,提示二者是有着不同病理生理机制的肾损害类型
3.两种病理类型患者随访期内肾生存率差异显著,多因素Cox回归分析提示系膜体积分数是肾脏结局事件的独立影响因素。
Background
Nephropathy is a severe complication of diabetes mellitus. Being the major cause of ESRD in developed countries, it also presents as a rising cause of kidney failure in China. The underline mechanism of kidney injury in diabetes remains unclear. At the same time, the pathological classification/grading criteria of diabetic nephropathy are still under debate, due to the lack of widely recognized, highly predictive systems. Type2diabetes mellitus kidney disease has revealed a highly heterogeneous nature in clinical, pathological and prognostic dimensions, which lead to the concept of "atypical diabetes related renal disease". It is characterized by short diatetes histories, fewer retinopathies, heavier metabolic disturbance, slower renal function loss, and specific pathological features manifested by disproportionally severe tubulal,thterstitial and vascular lesions and distinguished from classical glomerulopathy represented by type1diabetes mellitus patients. Whoever, cohort study in this field is largely insufficient especially on relationship between pathological classification and prognosis. Therefore, it is necessary to perform clinical and pathological researches on T2DM kidney disease in China.
Objectives
Further explore relationship between pathological classification and clinical features in T2DM kidney disease; explore the predictive value of the classification for renal outcome events and renal function decreasing speed; search for efficient predictive pathological and clinical factors for renal prognosis in T2DM kidney disease.
Methods
Case selection:We enrolled a cohort of119T2DM patients who were diagnosed by1997WHO criteria and underwent renal biopsy in PUMCH hospital between2001and2011, with intact clinical and pathological data and no evidence for NDKD. Patients with follow-up time shorter than6months are ruled out for final analysis.
Pathological data:Patients are divided into typical diabetic glomerulopathy (DG, n=51) and atypical diabetes-related renal disease (ADRD,n=41) according to findings under LM, and evaluated for glomerular, vascular, tubular and interstitial lesion and podocyte density quantitative/semi-quantitatively, according to LM, EM and immunohistochemistry findings.
Clinical data:Clinical data within2weeks from biopsy date are collected and compared.
Prognostics:Through follow-up research by medical documents and telephone inquiry, prognosis related events (death, need for regular renal replacement therapy, double of SCr, diabetic ophthalmic event, CVD, etc.) are collected for regression analysis.
Results
1. Patients in DG group are characterized by older age, lower Hb and ALB, longer diabetes history, more severe DR, higher PBG and SBP, as well as more severe hematuria, proteinuria and kidney function damage; ADRD patients show significantly higher BMI, TG,
2. Mesangial functional volume, GBM width are significantly higher and relative podocyte density is significantly lower in DG group; and scores for tubular atrophy, interstitial lesion and vascular lesion are also significantly higher in DG group.
3. During follow-up, SCr increasing speed is significantly faster than ADRD group. In DG group,29renal outcome events,12death events,31DR renal events and4CVD events are observed, and median survival time and median non-events renal survival time are23(6,40) and32(19,45) months. No renal outcome events are observed in ADRD group and2DR renal events and4CVD events are observed. Survival rates are significantly different between two groups.
4. Cox regression model indicates that the classified as DG, thicker GBM width and heavier vascular, tubular and interstial lesion are risk factors for renal outcome events adjusted for CKD stage. Only high mesangial fractional volume is the renal outcome risk factor independent from CKD stage, proteinuria and age.
Conclusions
1. T2DM kidney disease can be divided into DG and ADRD, according to features typical of T1DM kidney disease.
2. ADRD is largely distinguished from DG by significantly milder pathological manifestation and renal lesions, worse metabolic disturbance, fewer DR, indicating a essentially different pathophysiological mechanism.
3. Renal survival rates are significant different between two groups, and mesangial fractional volume is the renal outcome predictive factors independent of CKD stage, proteinuria and age.
引文
1. Foundation NK. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease [J]. AmJ Kidney Dis.2007;49(2 Suppl 2):S12-154..
2. Fioretto P, Mauer M, Brocco E, et al. Patterns of renal injury in NIDDM patients with microalbuminuria. Diabetologia.1996;39(12):1569-76..
3. Gambara V, Mecca G, Remuzzi G, Bertani T. Heterogeneous nature of renal lesions in type II diabetes. Journal of the American Society of Nephrology:JASN.1993;3(8):1458-66..
4. Tervaert TWC, Mooyaart AL, Amann K, et al. Pathologic classification of diabetic nephropathy. Journal of the American Society of Nephrology:JASN.2010;21(4):556-63..
5. Nosadini R, Velussi M, Brocco E, et al. Course of renal function in type 2 diabetic patients with abnormalities of albumin excretion rate. Diabetes.2000;49(3):476-84..
6. Fioretto P, Caramori ML, Mauer M. The kidney in diabetes:dynamic pathways of injury and repair. The Camillo Golgi Lecture 2007. Diabetologia.2008;51(8):1347-55..
7.徐鹏杰,李航,徐亚兰,文煜冰,李学旺.糖尿病并发慢性肾脏病临床病理特点分析.中华肾脏病杂志.2010；26(10)：731-5.
8. Okada T, Nagao T, Matsumoto H, et al. Histological predictors for renal prognosis in diabetic nephropathy in type 2 diabetes patients with overt proteinuria. Nephrology (Carlton, Vic).2011..
9. Mauer SM, Steffes MW, Ellis EN, et al. Structural-functional relationships in diabetic nephropathy. The Journal of clinical investigation.1984;74(4):1143-55..
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[30]MacIsaac RJ, Tsalamandris C, Panagiotopoulos S, et al. Normoalbuminuric renal insufficiency in type 2 diabetes. Diabetes Care 2004;27:195-200
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[32]OsterbyR, Gall MA, SchmitzA, et al. Glomerular structure and function in proteinuric type 2 (non insulin dependent) diabetic patients. Diabetologia 1993;36:1064-1070
[33]Dalla Vestra M, Masiero A, Roiter AM et al. Is podocyte injury relevant in diabetic nephropathy? Studies in patients with type 2 diabetes. Diabetes 2003;52:1031-1035
[34]White KE, Bilous RW Structural alterations to the podocyte are related to proteinuria in type 2 diabetic patients. Nephrol Dial Transplant 2004;19:1437-1440
[35]Lewis EJ, Hunsicker LG, Clarke WR, et al. Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. NEngl JMed 2001;345(12):851-860.
[36]Brenner BM, Cooper ME, de Zeeuw D, et al. RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345(12):861-869.
[37]Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993;329(20):1456-1462.
[38]Ahmed AK, Kamath NS, El Kossi M et al. The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced chronic kidney disease. Nephrol Dial Transplant 2010;25(12):3977-82.
[39]Onuigbo MA. Reno-prevention vs. reno-protection:a critical re-appraisal of the evidence-base from the large RAAS blockade trials after ONTARGET-a call for more circumspection. QJM 2009; 102:155-167
[40]Fioretto P, Steffes MW, Rich SS et al. Is diabetic nephropathy inherited? Studies of glomerular structure in type 1 diabetic sibling pairs. Diabetes 1999;48:865-869
[41]Krolewski M, Eggers PW, Warram JH Magnitude of end-stage renal disease in IDDM:a 35 year follow-up study. Kidney Int 1996;50:2041-2046