糖尿病肾病病理特点

1、 糖化终末产物糖化终末产物 肾小球高肾小球高 滤过肥厚滤过肥厚 氧化应激氧化应激 PKC 多元醇通路多元醇通路 活性活性 TGF- Ang- GH/IGF- NO白介素 高血压、高高血压、高 血脂、吸烟血脂、吸烟 遗遗 传传 糖尿病肾病的发病机制 高血糖高血糖 糖尿病肾病糖尿病肾病 Adapted from Breyer JA et al. Am J Kid Dis 1992; 20(6): 535. 时间时间 ( (年年) ) 05 520203030 糖尿病开始糖尿病开始 蛋白尿开始蛋白尿开始终末期肾病终末期肾病 结构改变结构改变 ( (肾小球基底膜增多且系膜扩展肾小球基底膜增多且系膜扩展

2、) ) 高血压高血压 明显肾病明显肾病 (Scr,(Scr,升高升高 GFRGFR降低降低) 初期肾病初期肾病 ( (高滤过高滤过, ,微白蛋白尿微白蛋白尿, ,血压升高血压升高) 临床前的肾病临床前的肾病 美国肾脏基金会肾脏病预后质量倡议(NKFKDOQI)指南标准 光学显微镜检查光学显微镜检查 糖尿病肾病的基本病理变化糖尿病肾病的基本病理变化 呈现两种病理类型呈现两种病理类型 Sl i de 3 N orm al gl om erul us: Hem atoxyl i n and eosi n st ai n of a norm al gl om erul us sect i oned t

3、 hrough the vascul ar pol e. N ot e the w i de-open capi l l ary l um i na and the l arge percent age of the cross-secti onal area of the gl om erul us devot ed t o t he capi l l ary ci rcul at i on. The m esangi al cel l ul ari t y and m at ri x are norm al . Sl i de 1 N orm al gl om erul us: Schem

4、 at i zed draw i ng of a norm al gl om erul us show i ng epi t hel i al cel l s i n green, endot hel i al cel l s i n yel l ow and m esangi al cel l s i n red. N ot e t hat t he gl om erul ar basem ent m em branes (i n bl ack) do not com pl et el y surround capi l l ary l oops, and t hat endot hel i

5、 al cel l s are i n di rect cont act w i t h m esangi al m at ri x (bl ue) at t he m esangi al pol es of capi l l ari es. Burton D RoseBurton D Rose，MD 2000MD 2000 Sl i de 165 Di abet i c nephropat hy: Thi s schem at i zed draw i ng show s t he m arkedl y t hi ckened l am i na densa of t he GBM and

6、i ncreased m esangi al m at ri x m at eri al w hi ch are t he si ne qua non of di abet i c renal di sease. The subsequent sl i des (166-202) dem onst rat e t he spect rum of di abet i c renal di sease (st art i ng w i t h a revi ew of norm al gl om erul ar hi st ol ogy), and i l l ust rat e di st i

7、ngui shi ng poi nt s bet w een ot her t ypes of gl om erul opat hi es w hi ch m ay m i m i c di abet i c nephropat hy. 糖尿病肾病：肾小球基底膜增厚伴系膜基质扩张 Sl i de 167 M oderat e di f f use di abet i c gl om erul oscl erosi s i n an i nsul i n-dependent di abet i c (I DDM ) pat i ent w i t h 16 years durat i on. N

8、 ot e t he w i deni ng of t he gl om erul ar m esangi um , t he rest ri ct i on of t he gl om erul ar capi l l ary ci rcul at i on, t he t hi ckeni ng of t he gl om erul ar basem ent m em brane com pared t o sl i de 1, and t he hyal i nosi s of t he art eri ol ar w al l at t he vascul ar pol e (PAS)

9、. 弥漫性轻度糖尿病肾小球硬化：系膜区基质扩张，GBM增厚，毛细血管腔受 压，血管极小动脉壁增厚 Sl i de 168 M arked di f f use di abet i c gl om erul oscl erosi s. There i s ext rem e expansi on of t he m esangi um w i t h bot h m at ri x and cel l ul ar m at eri al . The capi l l ary l um enal ci rcul at i on i s m arkedl y const ri ct ed (PAS)

10、. W hereas t he pat i ent i n sl i de 2 had norm al renal f unct i on, t hi s pat i ent had overt nephropat hy w i t h prot ei nuri a, hypert ensi on, and a 50% reduct i on i n GFR. 弥漫、严重糖尿病肾小球硬化：系膜区基质及细胞显著增加，毛细血管腔 严重受压；该患者肾小球滤过率下降50%，伴显著蛋白尿、严重高血压 光学显微镜检查光学显微镜检查 糖尿病肾病的病理变化糖尿病肾病的病理变化 S lid e 171 N o

11、d u lar d iab etic g lo m eru lo sclero sis (K im m elstiel-W ilso n lesio n s) in a p atien t w ith o vert d iab etic n ep h ro p ath y an d p ro tein u ria, h yp erten sio n , an d red u ced G FR . N o te th e p alisad in g o f m esan g ial n u clei aro u n d th e p erip h ery o f th e n o d u le

12、an d th e fib rillar n atu re o f th e n o d u lar m atrix m aterial. N o te also th e restrictio n o f g lo m eru lar cap illary lu m en al sp ace (P A S ). 结节性肾小球硬化（K-W结节）：伴蛋白尿、高血压及肾小球滤过率下降 糖尿病肾病的糖尿病肾病的其他其他病理变化病理变化 Sl i de 178 A capsul ar drop consi st i ng of hyal i ne PAS posi t i ve m at eri al

13、 deposi t ed on t he pari et al surf ace of Bow m an s m em brane (9 o cl ock). 帽状滴：透明PAS阳性物质沉积于肾小球囊之内侧壁 Sl i de 179 Form at i on of a capsul ar drop by adhesi on of gl om erul ar capi l l ary l oops cont ai ni ng subendot hel i al hyal i ne (t he so-cal l ed “ exudat i ve l esi on” ) t o Bow m an s

14、 capsul e (9 o cl ock and 11 o cl ock). I t i s l i kel y t hat t he gl om erul ar capi l l ary l oops ret ract , deposi t i ng t he hyal i ne m at eri al al ong t he Bow m an s capsul ar w al l . 帽状滴之形成：肾小球毛细血管袢渗出性物质（内皮细胞下透明样物质） 附着与肾小球囊之内侧壁，然后肾小球收缩。小动脉透明样变性（右图） Sl i de 174 Earl y gl om erul ar art

15、eri ol ar hyal i nosi s i n an af f erent art eri ol e. N ot e t he sm oot h, w axy, hom ogenous PAS posi t i ve m at eri al i n t he subendot hel i al space. Thi s I DDM pat i ent had norm al renal f unct i on. 入球小动脉透明样变性早期改变：内皮细胞下非细胞均质成份沉积，肾功能尚 正常 Sl i de 176 Art eri ol ar hyal i nosi s i n bot h

16、af f erent (l ow er l ef t si de) and ef f erent (l ow er ri ght si de) gl om erul ar art eri ol es (PAS). N ot e t he di f f use and nodul ar di abet i c gl om erul oscl erosi s i n t hi s I DDM pat i ent w i t h earl y overt nephropat hy. 入球小动脉与出球小动脉壁透明样变，弥漫性糖尿病结节性肾小球硬化： 型糖尿病引起的临床糖尿病肾病之早期 Sl i de

17、175 Advanced art eri ol ar hyal i nosi s w i t h vi rt ual com pl et e repl acem ent of t he vessel w al l by hyal i ne w axy m at eri al (PAS). 蜡样物质填充于小动脉壁，引起血管腔几乎完全闭塞 Sl i de 200 Thi s and t he subsequent t w o sl i des i l l ust rat e t he at ypi cal l esi ons com m onl y seen i n m i croal bum i

18、 nuri c N I DDM pat i ent s. Som e of t hese pat i ent s, as i l l ust rat ed i n t hi s PAS sl i de, have est abl i shed art eri ol ar hyal i nosi s l esi ons w i t h l i t t l e or no gl om erul ar or t ubul oi nt erst i t i al i nj ury. 2型糖尿病伴微量白蛋白尿：不典型肾脏改变不典型肾脏改变小动脉显著透明样变性，而肾小 球以及肾间质改变不明显 S lid

19、e 1 8 1 Mild e x p a n s io n o f th e in te rs titia l s p a c e a n d tu b u la r b a s e me n t me mb ra n e th ic k e n in g w ith o u t tu b u la r a tro p h y (P A S ). T h is ID D M p a tie n t h a d n o rma l re n a l fu n c tio n . T h is mild d e g re e o f in te rs titia l e x p a n s io

20、n is c o mmo n in d ia b e tic p a tie n ts , e v e n th o s e w h o s e g lo me ru la r a n d v a s c u la r d is e a s e d o n o t p ro g re s s . 间质间隙轻度扩张，伴肾小管基膜增厚，肾小管不萎缩：1型糖尿病患者， 肾功能正常。一些不伴肾小球或肾小管损伤的糖尿病患者也可发生这种小 管间质改变 Sl i de 182 M ore advanced t ubul ar i nt erst i t i al di sease w i t h t ubu

21、l ar at rophy and i nt erst i t i al f i brosi s i ndi cat ed by t he green col or on t he t ri chrom e st ai ni ng. Thi s I DDM pat i ent had m i l d di f f use di abet i c gl om erul oscl erosi s and m i croal bum i nuri a. 肾小管萎缩伴间质纤维化： 1型糖尿病伴轻度弥漫性肾小球硬化及微量白蛋白尿 S lid e 2 0 2 T h is N ID D M p a tie

22、 n t w ith m ic ro a lb u m in u ria a n d h yp e rte n sio n sh o w s a re a s o f a d va n c e d tu b u lo in te rstitia l in ju ry w ith o u t sig n ific a n t g lo m e ru lo p a th y o r va sc u lo p a th y. T h is a n d th e p re c e d in g tw o slid e s illu stra te th a t m ic ro a lb u m in

23、u ric N ID D M p a tie n ts m a y h a ve re n a l le sio n s w h ic h a re n o t typ ic a l o f th o se se e n in ID D M w h e re th e g lo m e ru la r, a rte rio la r, g lo m e ru lo sc le ro tic , a n d tu b u lo in te rstitia l le sio n s te n d to a d va n c e in p a ra lle l. P a tie n ts w ith

24、 th e p a tte rn s sh o w n in th e la st th re e slid e s te n d n o t to h a ve p ro life ra tive re tin o p a th y a n d , g e n e ra lly, a re m o re o b e se th a n N ID D M p a tie n ts w ith typ ic a l d ia b e tic n e p h ro p a th y. H o w e ve r, p a tie n ts w ith th e se a typ ic a l p a

25、 tte rn s a lso h a ve h ig h e r le ve ls o f h e m o g lo b in A 1 c th a n N ID D M p a tie n ts w ith o u t re n a l in ju ry, su g g e stin g th a t th e se “ a typ ic a l” fo rm s o f in ju ry m a y a lso b e in flu e n c e d b y th e d ia b e tic sta te . 2型糖尿病伴微量白蛋白尿、高血压：不典型肾脏改变不典型肾脏改变肾小球以及肾

26、血管改变 不明显 ，肾间质改变显著 DN 晚期皆进展至肾小球硬化及肾间质纤维化 Sl i de 185 El ect ron phot om i crograph i l l ust rat i ng a norm al gl om erul ar basem ent m em brane w i dt h (bot t om panel ) and di f f use t hi ckeni ng of t he gl om erul ar basem ent m em brane consequent t o di abet es (upper panel ). The basem ent

27、 m em brane w i dt h of t he di abet i c pat i ent show n here i s m ore t han t w i ce norm al t hi ckness. 透射电子显微镜：正常/糖尿病引起的GBM增厚 Sl i de 186 El ect ron phot om i crograph of an I DDM pat i ent w i t h est abl i shed renal l esi ons. Despi t e t he i ncreased GBM w i dt h and m esangi al expansi o

28、n, especi al l y w i t h i ncreased m esangi al m at ri x m at eri al , t hi s pat i ent had norm al renal f unct i on, i ncl udi ng norm al uri nary al bum i n excret i on rat es. 透射电子显微镜：1型糖尿病引起肾病 GBM增厚、系膜区基质增多，肾功能正常、无微量白蛋白尿 Sl i de 187 El ect ron phot om i crograph dem onst rat i ng advanced di a

29、bet i c nephropat hy w i t h m arked t hi ckeni ng of t he GBM , great l y i ncreased m esangi al m at ri x m at eri al , and const ri ct i on of t he capi l l ary l um i na. Thi s I DDM pat i ent had overt di abet i c nephropat hy. 透射电子显微镜：1型糖尿病引起肾病 GBM增厚、系膜区基质增多、毛细血管腔塌陷，肾功能下降、临床蛋白尿 S lid e 1 8 9 I

30、m m u n o flu o re sc e n t m ic ro sc o p y sh o w in g th e lin e a r p a tte rn fo r Ig G sta in in g u su a lly se e n in ID D M d ia b e tic p a tie n ts. N o te th e sta in in g o f th e g lo m e ru la r c a p illa ry b a se m e n t m e m b ra n e , B o w m a n s c a p su le , a n d tu b u la

31、r b a se m e n t m e m b ra n e . In c re a se d lin e a r Ig G a n d a lb u m in sta in in g o f re n a l e xtra c e llu la r b a se m e n t m e m b ra n e s is ve ry c o m m o n ly se e n in d ia b e tic p a tie n ts re g a rd le ss o f w h e th e r o r n o t th e y u ltim a te ly d e ve lo p se r

32、io u s re n a l in ju ry. 1型糖尿病患者、免疫荧光：IgG线样沉积于肾小球毛细血管基底膜、肾小球囊 及肾小管基膜 即使不发展为严重糖尿病肾病的患者也可发生这种改变即使不发展为严重糖尿病肾病的患者也可发生这种改变 Sl i de 188 I m m unof l uorescent m i croscopy l i near i m m unof l uorescent st ai ni ng f or al bum i n al ong t he gl om erul ar capi l l ary basem ent m em brane, Bow m an s capsul e, and t ubul ar basem ent m em brane i n an I DDM pat i ent . 1型糖尿病患者、免疫荧光：白蛋白线样沉积于肾小球毛细血管基底膜、肾小球 囊及肾小管基膜 即使不发展为严重糖尿病肾病的患者也可发生这种改变即使不发展为严重糖尿病肾病的患者也可发生这种改变 型，肾小球基膜增厚：光镜下，活检组织仅有孤立的肾小球基膜增厚和轻度 非特异性增生。