1、 The complex structure of the mammalian kidney is best understood in the unipapillary form that is common to all small species.肾脏解剖和生理皮质(cortex)髓质(medulla)肾椎体(pyramid)肾乳头(papilla)肾小盏(minor calyces)肾柱(columns)肾大盏(major calyces)肾盂(pelvis)The specific components of the kidney are the nephrons. The mult
2、ipapillary kidney of humans contains roughly one million nephrons. This number is already established during prenatal development; after birth new nephrons cannot be developed, a lost nephron cannot be replaced.短袢长袢a.Renal corpuscle(肾小体)GlomerulusBowmans capsuleb. Renal tubule(肾小管)Proximal convolute
3、d tubule(2)Proximal straight tubule(3)Desending thin limb(4)Ascending thin limb(5)Distal straight tubule(6)Distal convoluted tubule(8)Connecting tubule(9)Collecting duct(10,11,12) Nephronpodocytes，足细胞GBM, 肾小球基底膜endothelia cells, 内皮细胞Mesangium (系膜)The mesangial cells, together with the mesangial matr
4、ix, establish the glomerular mesangium.对肾小球毛细血管袢有支持和保护作用；系膜区是血浆大分子物质的转运通道；系膜细胞有收缩功能并参与免疫反应；可产生多种细胞外基质并分泌多种细胞因子；可在特定条件下分泌肾素。The interstitium of the kidney is sparse. The cellular constituents of the interstitium are fibroblasts(成纤维细胞) and migrating cells of the immune system, including macrophages(巨噬
5、细胞) and dendritic cells(树突状细胞). The space between the cells is filled with extracellular matrix(细胞外基质), i.e. ground substance (proteoglycans蛋白多糖, glycoproteins糖蛋白, fibrils原纤维 ,interstitial fluid组织间液）。排泄功能excretory function内分泌功能endocrine function(2)肾脏生理功能physiological functionThe prime function of th
6、e kidney is to maintain a stable milieu by the selective retention and elimination of water, electrolytes, and the other solutes. Tubular reabsorptionand secretionGlomerular filtrationRenal endocrineThe process of urine formation beginns by production at the level of the glomerular capillary of an u
7、ltrafiltrate of plasma. Glomerular filtration is described in terms of renal clearance. 含氮废物如尿素、肌酐等主要由肾小球滤过排出。马尿酸、苯甲酸、各类胺类及尿酸也有部分经肾小球滤过排出分泌50%重吸收98100%4044%重吸收少量重吸收少量重吸收堆积后可致肾结石尿酸在肾脏内滤过及重吸收过程尿酸经小球滤过后，98%在近端肾小管S1段主动重吸收，50%在S2段分泌，40%-44%在S3段分泌后重吸收。 Integrins, dystroglycans裂隙膜蛋白(分子筛)：Neph1-3, ZO-1,Neph
8、rin, CD2APPodocin, FAT1, P-cadherinGBM(水样胶)裂隙膜(粘附连接)The podocyte plays a crucial role in both the structure and function of the glomerulus. Podocytes counterbalance the hydrostatic pressure within the glomerular capillaries preventing dilation. The podocytes is also necessary in the maintenance of t
9、he glomerular filtration barrier, and there is evidence that podocytes are necessary in the production of GBM.The main filtration barrier is the GBM, although both the endothelium and epithelial cells contribute. Endothelial cells and the GBM carry fixed negative charges from glycoproteins on their
10、surface; these restrict the filtration of large negatively charged molecules, mainly proteins, and facilitate the passage of positively charged macromolecules. The major components of the GBM include type IV collagen（ IV 型胶原）, heparan sulfate proteoglycans（硫酸肝素蛋白聚糖 ）, and laminin（层粘连蛋白）, 310-373 nmA
11、lport Syndrom: type IV collagen (X 染色体编码a5链基因，a3和a4链的异常）TBMN: type IV collagen (a3或a4基因突变)抗GBM病：免疫对抗IV collagen a3链NCI区的疾病Electrochemical balance: the best equation The ultrafiltrate passing from the glomerular filter has a composition similar to plasma and is modified by various processes within th
12、e tubule to produce the final urine, usually to less than 1% of that filtered. 1.全部由肾小球滤出，肾小管不吸收、不分泌，如菊粉（inulin）。2.全部由肾小球滤出，不被肾小管重吸收、很少被肾小管排泌，比如肌酐（creatinine）。3.全部由肾小球滤出后又被肾小管全部吸收，如葡萄糖（glucose）。4.除肾小球滤出外，大部分通过肾小管周围毛细血管向肾小管分泌后排出，如对氨马尿酸及尿酸（aminohippuric acid and uric acid）主要由肾小管分泌。Vasoactive peptide（血
13、管活性多肽）：作用于肾本身，参与肾的生理功能，主要调节肾的血流动力学和水盐代谢，如RAS, PGE, ET;Nonvasoactive hormone（非血管活性激素）：1a-hydroxylase and EPOMas血管舒张,抗增殖和抗纤溶,抗氧化应激病程course尿检urinalysis肾功能renal function肾组织学histology acute ？chronic ？A on C？(2) Urinalysis1. Proteinuria (300mg/d or PCR200mg/g)蛋白尿 Proteinuria is a major manifestation of re
14、nal disease and a dominant risk factor for deterioration in most renal diseases for which risk factors have defined.2. Albuminuria(300mg/d or PCR250mg/g for man, and 355mg/g for woman) 白蛋白尿3. Microalbuminuria(30mg/d or PCR17-250 for man, and 25-355mg/g for woman) 微量白蛋白尿常用指标常用指标缩写缩写单位单位分级分级正常或轻度升高正常或
15、轻度升高中度升高中度升高*重度升高重度升高*白蛋白排泄率白蛋白排泄率AERmg/24h300蛋白排泄率蛋白排泄率PERmg/24h500白蛋白肌酐比白蛋白肌酐比ACRmg/mmol30mg/g300蛋白肌酐比蛋白肌酐比PCRmg/mmol50mg/g500蛋白试纸蛋白试纸-+*等同于微量蛋白尿；*等同于大量或显性蛋白尿校正终末期肾病HR*心血管死亡风险 校正HR*Van der Velde M, et al. Kidney Int. 2011;79(12):1341-52.Hallan SI, et al. J Am Soc Nephrol 2009;20(5):1069-77. HUNT 2
16、研究65589例成人受试者，随访10.3年*危险比(HR)经年龄、性别、eGFR等因素校正，以中位ACR(8.6mg/g)为参照(HR=1)CKD高危人群队列荟萃分析纳入10项队列研究，共266975例CKD高危患者*ACR，mg/g*CKD高危指为高血压、糖尿病或心血管疾病史。*危险比(HR)校正因素包括：eGFR或ACR、年龄、性别、种族、CVD史、SBP、糖尿病、吸烟和总胆固醇。分别以eGFR 95 ml/min/1.73 m2或ACR 5mg/g(0.6 mg/mmol)作为参照，HR设为1正常微白量蛋白尿大量蛋白尿心血管死亡心血管死亡1-3心血管事件心血管事件4,5心脏缺血性事件心脏
17、缺血性事件6冠心病冠心病7心肌梗死后存活心肌梗死后存活8-10脑卒中脑卒中11发生发生2型糖尿病型糖尿病12 1. Hillege. Circulation. 2002;106:1777-82. 2. Romundstad. Am J Kidney Dis. 2003;42:466-73. 3. Klausen. Circulation. 2004;110:32-5. 4. Gerstein. JAMA. 2001;286:421-6. 5. Wachtell. Ann Int Med. 2003;139:901-6. 6. Borch-Johnsen. Arterioscl Thromb V
18、asc Biol. 1999;19:1992-7. 7. Tuttle. Am J Kidney Dis.1999;34:918-25. 8. Wright. Ann Intern Med. 2002;137:563-70. 9. Anavekar. New Engl J Med. 2004;351:1285-95. 10. Berton. Diabetologia. 2004;47:1511-8. 11. Yuyun. J Intern Med. 2004;255:247-56. 12. Brantsma, Diabetes Care. 2005;28:2525-30.a. Physiolo
19、gy: The greater part of normal urine protein is Tamm-Horsfall protein, with some albumin and globulin. Lowgrade proteinuria may be orthostatic-only present after standing. b. Glomerularc. Tubulard. Overflow肾小球性肾小管性溢出性功能、体位性蛋白尿3个个/HP 10万万/h 50万万/12hRenal hemeturesisNaked eye(肉眼)Microscopic(镜下)* * 肾性血
20、尿: 肾小球疾病; 感染性疾病; 畸形; 肿瘤; 缺血性; 创伤* 肾后性: 机械性; 炎症性; 肿瘤; 妇科疾病* 继发性: 如血液系统* 伪性血尿泌尿系全身性邻近器官 运动性NAGRBPLySKIM-1As a marker of tubular injury管型尿- 5000个/12hEpithelial cell cast: 急性肾炎; 慢性肾炎晚期; ATN; 间质性肾炎; 中毒; 肾移植Granular cast: 急性肾炎后期; 慢性肾炎; 药物中毒Waxy cast: 肾小管病变重, 预后差. 慢性肾炎晚期; 慢性肾衰竭; 肾淀粉样变性Erythrocyte castHyali
21、ne cast肾小球滤过率glomerula filtration rate, (GFR)单位时间(min)内经肾小球滤出的血浆液体量(ml)UltrasoundCTMRI, MRUAngiographyIVPRadionuclide examinationIndications:1. Nephrotic syndrom2. Acute renal failure3. Non-Nephrotic proteinuria4. Mild proteinuria associated with hematuria5. Unexplained chronic failure6. Renal trans
22、plant dysfunctionNormal glomerulusa 脏层上皮细胞 b GBM c 内皮细胞 d 系膜 e 副系膜Pre-existing renal impairment (Scr1.5mg/dl);Diabetes（糖尿病）Age75 yearsFluid depletion（脱水）Myeloma（骨髓瘤）Concurrent nephrotoxic drugsUricosuria（高尿酸）Ionic contrast（离子型造影剂）1. Nephrotic Syndrom（肾病综合征）2. Nephritic Syndrom（肾炎综合征）3. Asymptomatic
23、Urine abnormalities （无症状性尿检异常）4. Acute renal failure and Rapidly progressive renal failure Syndrom（急性肾衰竭和急进性肾衰竭综合征）5. Chronic kidney disease(CKD)(慢性肾脏病)第第1期期 renal function normal GFR 90 ml/min第第2期期 function mild decrease 60-89第第3期期 function moderate decrease 30-59第第4期期 function severe decrease 15-2
24、9第第5期期 renal failure 15CKD:肾脏损伤或GFR60 ml/min 持续3月Pathologic and immune pathogenetic(病理和免疫病因)Antihypertensive therapy（抗高血压）reduce Proteinuria （减少蛋白尿）Erythropoiesis-stimulating agents(Epo, Darbepoetin), actived VitD3 and HMG-CoA reductase inhibitorsDietary therapy（饮食治疗）Renal replacement therapy(HD,PD
25、and Transplantation) （肾脏替代治疗：血透，腹透，肾移植）conbined treatment of traditional Chinese medicine and western medicine（中西）不同药物作用在不同靶点，可以起协同作用各种药物剂量减半，减少不良反应和毒性合用可增加药物浓度There are ample data suggesting the importance of RRF(residual renal function，残余肾功能) in dialysis patients. PD has been shown, among other fa
26、ctors, to be better than HD in the preservation of RRF.Peritoneal dialysis is a more optimal treatment than hemodialysis for ESRD patients ？对血压和血脂监测和控制应始自CKD诊断之时；而对贫血、营养及钙磷代谢、甲旁腺功能的监测应始自CKD第三期并于四期后加强监测的强度。并且在CKD第四期应由肾脏科专科医师进行诊断和治疗并作替代治疗的准备。应根据病人的CKD分期对每一个人制订定期监测的项目和治疗的计划。 Molecular cellular Biology;
27、Molecular marker and analysis of candidated genesMechanism of progress in CKD (RAS,KKS,ETA,ETB; Agalsidase- ) Pathogenesis to reveal by multichannelHereditary diseaseEarly discern and prevent of CKDBasic research of RRT多渠道揭示肾脏疾病的发病机制慢性肾脏疾病进展机制的研究CKD早期识别及防治在各种肾小球疾病的发展过程中，在多种损伤因子的作用下，肾脏内炎症，单核或巨噬细胞浸润，各
28、种趋化和黏附分子释放，细胞损伤，凋亡和增生，特别是足细胞的损伤，凋亡和转分化，引起大量蛋白尿，最后导致纤维化和肾小球硬化，是肾小球疾病发展，恶化，肾功能丧失的共同途径溶质转运分子基础研究；AVP作用的细胞生物学效应；水通道研究；蛋白尿形成机制。RAAS；醛固酮阻滞剂；视黄醛衍生物；半乳糖苷酶A（1）多渠道揭示肾脏疾病的发病机制早期诊断，无创伤性检查及诊断，判断预后，指导治疗二个切入点：1.转化医学 Translation medicine 2. 蛋白组学技术和生物信息学(proteomics and bioinformatics technique) 技术相结合，分离病人血，尿中特殊成分作为B
29、MAKI: over 20Gansevoort RT, et al. J Am Soc Nephrol 2009;20(3):465-8.约40的CKD2期患者合并高血压,随着GFR下降,高血压发病率进一步增高, CKD4期的患者高血压发病率超过75%。 American Journal of Kidney Diseases.2004;43(5suppl1):S1-290.肾损伤肾损伤高血压高血压蛋白尿蛋白尿其他其他 GFR高血压高血压蛋白尿蛋白尿其他其他肾肾衰衰血管紧张素II在肾脏疾病事件链中起到重要作用大量蛋白尿微量蛋白尿肾性蛋白尿内皮功能障碍终末期肾病（ERSD）死亡危险因素糖尿病高血压
30、等Ang II高血压肾小球内压 压力依赖性途径细胞因子细胞外基质(ECM)直接损伤肾脏非压力依赖性途径慢性肾脏疾病进展机制的研究 血液动力学效应血液动力学效应改善肾小球内三高改善肾小球内三高非血液动力学效应非血液动力学效应降低系统降低系统高血压高血压扩张出球小动脉扩张出球小动脉强于入球小动脉强于入球小动脉改善肾小球滤过改善肾小球滤过膜选择通透性膜选择通透性减少肾小球内细减少肾小球内细胞外基质蓄积胞外基质蓄积减少尿蛋白，延缓肾小减少尿蛋白，延缓肾小球硬化球硬化尿蛋白尿蛋白出球小动脉扩张出球小动脉扩张Conceptual Model for CKD2002 KDOQI GuidelinesConc
31、eptual Model for CKD (revised)Levey AS. Am J Kidney Dis 2009肾病防治策略进展KDIGO 2012指南正常风险增加损伤GFR肾衰竭死亡并发症CKD风险因素筛查诊断&治疗治疗伴随疾病，减慢进程评估进程，治疗并发症，准备替换透析&移植减少CKD风险因素，CKD筛查易感因素启动因素进展因素进展因素终末期因素The specific components of the kidney are the nephrons;The renal physiological function is excretory function and endocr
32、ine function;The filtration barrier consits of Podocyte, GBM and endothelial cell;The renal function include glomerular filtration and tubular reabsorption and secretion;We evaluate the renal disease by course, urinalysis, renal function and Biopsy;We usually diagnose the renal disease with “Syndrom”;The treatment involves many decks;Prospect of renal disease: CKD is treatable and also.
