1、Human glomerular diseasesObjectivesUnderstand the basic knowledge on the epidemiology,pathology,pathogenesis,clinical manifestations,diagnosis,and treatment for major primary and secondary glomerular diseases.Understand the relationship between basic science findings and clinical features(Bench vers
2、us Bedside).Update the recent findings and clinical trials in the field.Meet the standard of the core curriculum at Shanghai Jiao Tong University School of Medicine.OutlineGlomerulus:structure and functionPathophysiology:Nephrotic syndrome versus nephritic syndromePrimary glomerular diseasesSecondar
3、y glomerular diseasesCase discussion with questions for practiceGlomerular StructureVideo of podocyte EM structure6Podocyte Foot Process3D reconstitution of podocytes from EMPicture of a podocyte from 3D printer using prototyping technology 9Glomerular Filtration BarrierSlit Diaphragm of PodocytesSl
4、it diaphragm580nm40nmGagliardini et al.2010Slit Diaphragm has porespore size 20nm diameterSlit Diaphragm pores are smaller than albuminFoot process of podocytes have negative chargepodocalyxin:Tx-Mb glycoprotein,negatively charged.important for stability of FP to prevent it from collapsingNegative c
5、hargeFaul et al.TRENDS in Cell Biology 2007Highly motileSD is motile and regulated by actinSD is regulated by mechanic forceHydrostatic and oncotic pressuresShear stress from blood circulation in the capillary loop(horizontal).Shear stress from glomerular filtration(vertical)Stretching of podocytes
6、from GBMResistance of GBMHighly motileBloodUrineSD at molecular levelsFiltration barriersize barriercharge barrierMaintenance of the capillary loop shapecounteract intraglomerular pressureSynthesis and maintenance of the GBMMaintenance of the endothelium(VEGF)by crosstalk among cellsPodocyte Functio
7、nHighly differentiated and quiescent cellsPodocyte injury is a major cause of glomerular diseaseMutation of podocyte proteinsStructural changes:EffacementPodocyte loss:Detachment/apoptosisPodocyte ProliferationEffacementreduction of filtration areaimpairment of filtration barrier function:proteinuri
8、aKriz W.et al.1998.Podocyte loss Podocyte Depletion Denuded GBM Protein Leakage Tufts Adhesion GSPodocyte loss causes glomerulosclerosis and podocyte number correlates with the progression of glomerular diseaseGlomerular basement membrane(GBM)1.Composition of GBM:type IV collagen(alpha 3,4,5 chains)
9、laminin,proteoglycans(haparan sulfate),and nidogen2.Mutations of type IV collagen cause hereditary kidney disease(Alport Syndrome).3.Both thicken or thin GBM are associated with glomerular disease(Diabetic nephropathy vs thin basement membranous nephropathy).4.Deposition of immune complex in GBM ca
10、uses glomerular disease(Membranous Nephropathy).Glomerular endothelial cells1.Glomerular endothelial cells have fenestration in their peripheral cytoplasm(60-80nm)and regulate filtration rate.2.Glomerular endothelial cells synthesize matrix for GBM.3.Fenestrations are coated with negative charged gl
11、ycocalyx.4.Glomerular endothelial cells maintain capillary loops5.Glomerular endothelial cell injury causes the rupture of capillary leading to hematuria.6.Glomerular endothelial cells undergo proliferation in the disease condition.Reduction of endothelial fenestration is seen in diabetic nephropath
12、yMesangial cells1.Mesangial cells provide structural support.2.Mesangial cells regulate blood flow of the glomerular capillaries by their contractile activity.2.Mesangial cells phagocytize glomerular basal lamina components and immunoglobulins.4.Mesangial cells are major contributors to the extracel
13、lular matrix.In disease condition,mesangial cells proliferate and synthesize abnormal matrix leading to glomerulosclerosis.Pathogenesis of glomerular diseasesImmune-mediatedInfectionMetabolicImmune-complexAntibodiesROSInflammationInfiltration of immune cellsProliferation of glomerular cellsApoptosis
14、 of glomerular cellsAbnormal matrix synthesisGeneticsMutation of structural proteinsPodocyte injuryGBM thickeningMesangial expansionCrescentsInjury of glomeruli results in a multiplicity of signs and symptoms of disease1.Proteinuria caused by altered glomerular filtration unit(GBM,podocytes,and endo
15、thelial cells)2.Hematuria caused by rupture of capillary walls3.Azotemia caused by impaired filtration of nitrogenous wastes4.Oliguria or anuria caused by reduced urine production5.Edema caused by salt and water retention 6.Hypertension caused by fluid retention and disturbed hormonal regulation.7.S
16、pecific glomerular diseases produce characteristic syndromes.8.Different glomerular diseases can produce the same syndrome.Proteinuria is defined as urinary protein excretion of greater than 150 mg per day.Definition of ProteinuriaMeasurement of Proteinuria1.Dipstick:Trace to 3+:affected by urine co
17、ncentration2.24 hour urine quantification of protein:Difficult to have complete urine collection over 24 hours3.Determination of urine protein/creatinine ratio:Easy collection and correlates well with 24 hour urine protein data.Mechanism of Proteinuria1.Most common cause:alteration of glomerular fil
18、tration unit2.Protein overload:light chain in multiple myeloma3.Tubular dysfunction:reduced reabsorptionNEPHROTIC SYNDROMEThe nephrotic syndrome is characterized by a urine protein-creatinine ratio above 3.5 mg/mg or 3.5gm/day,hypoalbuminemia,hyperlipidemia,lipiduria,edema,and hypercoagulability.Thi
19、s syndrome may manifest as a primary kidney disease or occur secondary to a systemic disease.The nephrotic syndrome is usually caused by injury of the glomerular filtration barrier.The nephritic syndrome,also known as glomerulonephritis(GN),is characterized by hematuria,proteinuria,oliguria,hyperten
20、sion,and kidney insufficiency,caused mostly by immune-mediated glomerular inflammation.NEPHRITIC SYNDROMEHematuriaNormal individuals excrete up to 2 M RBCs into the urine daily-1-3 RBC/HPF.Microscopic hematuria is defined as more than 2 RBCs/HPF on spun urine,without change of urine color.Gross hema
21、turia:change of urine color due to the presence of RBCs.Dipsticks detect lysis of 3-5 RBCs/HPF,which is less sensitive than microscopic examination.Normal appearing red blood cellsDysmorphic red blood cellsRed blood cell castPossible Causes of HematuriaKidneyUreterBladderProstateUrethra1.Glomerulone
22、phritis:primary or secondary2.Pyelonephritis 3.Kidney stone4.Infarction,papillary necrosis,sickle cell dis5.Malignancy.6.malignant HTN7.Trauma.8.Bleeding disorder9.Hydronephrosis.10.Renal vein thrombosis1.Cystitis;2.Tumor;3.Trauma;4.Varicosities1.BPH,2.Prostatitis,3.Tumor,4.Infarction1.Stone,2.Stric
23、ture,3.Tumor,4.TraumaDifferential Diagnosis of HematuriaHematuria with pyuria:UTI,AIN.UTI:Dysuria,fever,CVA tenderness.AIN:medications,urine eosinophiliaHematuria with proteinuria:GNHematuria with proteinuria,or RBC casts or dysmorphic RBCs suggests GN,need serology studies,if increased serum Cr:ren
24、al biopsy within 48hrs.Hematuria with flank pain:renal stone.Asymptomatic hematuria and all patients with gross hematuria:GU referral to rule out cancerQuestionsWhat is the major function of podocyte?What is the name of the key molecule in the slit diaphragm?What is the foot process effacementWhat i
25、s the unique feature of glomerular endothelial cellsWhat is the consequence of mesangial cell activation in glomerular disease?What is the difference between Nephrotic and Nephritic syndromes?What is the difference between Nephrotic and Nephritic syndromeNephrotic syndrome:Massive proteinuria3.5 g/dayHypoalbuminuriaHyperlipidemiaEdemaHypercoagulabilityAssociated with cell lossNephritic syndromeHematuriaHypertensionOliguriaRenal failureSystemic syndromeAssociated with cell proliferationNephrotic and nephritic syndromes could occur together
