病理学课件：Chapter IX The disease of urinary system

1、Chapter IXThe Diseases of Urinary System Kidney - producing urine - important functions Ureter, bladder, urethra - storing or eliminating urineThe Anatomy of the Urinary SystemWhich laboratory? Four basic morphologic components Glomeruli: immunologically mediated Tubules Interstitium Blood vesselsto

2、xic / infectious agentsSome agents affect more than one structure. Main types of urinary diseases Inflammation - glomerulonephritis 肾小球肾炎 - pyelonephritis 肾盂肾炎 Stone urolithiasis - nephrolithiasis 肾结石 - hydronephrosis 肾盂积水 Tumor - renal cell carcinoma - Wilms tumor - urothelial carcinoma ( transitio

3、nal cell carcinoma)Important points Normal structure of glomerulusGlomerular Filtration1. Glomerular filtrating membrane Fenestrated endothelium - 70 100nm Glomerular basement membrane (GBM) - Negatively charged A meshwork of fine fibrils (Col- IV, laminin) Embedded in an amorphous matrix (FN) Rich

4、in heparan sulfate / glycosaminoglycan PAS / PASM staining (+) Visceral epithelium - Podocytes Slit diaphragm 20 30 nm Sieve pore 4 14 nm Cytoskeleton proteins (nephrin, podocin, etc.) A negatively-charged coat GlycocalyxHighly selective albumin proteinuria 2. Mesangial region - axial area of glomer

5、ulus Mesangial cells (MsC) Mesangial matrix 4 MsC / mesangial areaCrescent3. Bowmans capsuleHow to affect renal functions?I Glomerulonephritis GN Primary GN - limited in kidney along Secondary GN - secondary to systemic diseases A group of hypersensitivity diseases two categories Etiology and Pathog

6、enesis Glomerular injury caused by immune complexes I.Deposition of circulating immune complexes in glomeruliII.Antibodies reacting in situ within the glomerulus Intrinsic glomerular antigens (fixed) Molecules planted within the glomeruliI. Circulating immune complex-mediated nephritis Antigens: (1)

7、 exogenous: bacteria (streptococci) , virus (HBV), Treponema pallidum(梅毒螺旋体), parasite, Plasmodium falciparum (恶性疟原虫), foreign serum, drug, toxin (2) endogenous: systemic lupus erythematousus (SLE, 系统性红斑狼疮), macroglobulin (巨球蛋白), thyroglobulin (甲状腺球蛋白), carcinoembryonic antigen (CEA) In most cases,

8、the inciting antigens are unkown. “Innocent bystander” Antigen-antibody complexes are formed in the circulation and then trapped in the glomeruli Immunofluorescence staining(IF): Granular depositsAgIFAbEM: Electron dense depositsAg-Ab complexes formedTrapped in glomeruliActivation of complementsRecr

9、uitment of leukocytesInjuryIF: complements depositionIF: Ig depositionEM: electro-dense depositsLM: inflammatory infiltration Intrinsic cells proliferationII. In situ immune complexes-mediated nephritis intrinsic tissue antigen “planted” antigens from the circulation Caused by1. Anti-Glomerular Base

10、ment Membrane (GBM) disease Antigen: NC1 of 3 of collagen IV (fixed) Self-Ab bind to GBM or LBM Goodpasture syndrome - simultaneous lung and kidney lesions 1% GN Crescentic GN Rapidly progressive GNIF: linear patternEM: No electron dense deposit2. Heymann GN of rat Ag - proximal tubular brush border

11、 (megalin) Resembling human membranous GN IF: Granular pattern EM: Subepithelial electron dense deposit Other causes: DNA, bacteria products, virus protein - “planted antigens”Antibody-mediated glomerular injury Basic pathological changes Extent of glomerular lesionDiffuse almost every glomeruli inv

12、olvedFocal partial (50%) glomeruli involvedGlobal entire capillary loopSegmental partial capillary loopFour essential pathological changes (1) Hypercellularity - intrinsic glomerular cells (EnC, MsC, EpC) inflammatory cellsOutcome: Reduction of GFR Oliguria / anuria 400ml 3.5 g/day proteinuria, hypo

13、albuminemia, hyperlipidemia, lipiduria, edema (MCD, MN)Chronic renal failureAzotemia uremia progressing for months to yearsAsymptomatic urinary abnormalitiesSubtle or mild Clinicopathologic correlations The classification of GN Histological classification Primary glomerulonephritis (GN) Diffuse prol

14、iferative GN Crescentic GN Membranous GN Lipoid nephrosis (minimal change disease) Focal segmental glomerulosclerosis Membranoproliferative GN IgA nephropathy Chronic GNSecondary GN Systemic lupus erythematosus (SLE) Diabetes mellitus Amyloidosis Goodpasture syndrome Polyarteritis nodosa Wegener gra

15、nulomatosis Henoch-Schonlein purpura Bacterial endocarditisHereditary disordersNephrotic syndromeDerangement in capillary wallsIncreased permeability of GBMHeavy proteinuria (3.5g per day)Decreased serum albuminhypoalbuminemiaDecreased plasma collid osmotic pressureRetention of salt andwater by the

16、kidneyedemaSynthesis of lipoproteins by liverAbnormal transport of circulating lipid particlesImpairment of lipoproteins breakdownHyperlipidemialipiduriaPlasma protein escape into ultrafiltrate Nephrotic edemaPitting edema （凹陷性水肿）Minimal-change disease (MCD, 微小病变病微小病变病) Foot process disease （足突病）Lip

17、oid nephrosis （脂性肾病） Clinical features 1. Most in young children 2. Nephrotic syndrome ( highly-selective albumin proteinuria ) The most common cause of nephrotic syndrome in Children 3. Respond to corticosteroid therapy ( 90% ) Pathogenesis Disorder of T cell function Secretion of cytokine (IL-8, T

18、NF) Abnormal expression of cytoskeleton proteins Podocyte injury Increased permeability of GBM Morphology Gross: Enlarged pale kidneys “大白肾” Gray yellow strands or spots 黄色条纹SwollenLM: Nearly normal glomeruli Cytoplasmic lipids in tubular epithelial cells IF: Generally negative EM：Diffuse effacement

19、 of the foot processesMicrovillous transformationReversible after corticosteroid therapy，concomitant with remission of the proteinuria Consequence Good prognosis ( 90% ) A few cases dependent on steroid or resistant 5% chronic renal failure after 25 yearsMembranous GN（MGN, 膜性肾炎膜性肾炎/病）病） A spectrum o

20、f changes in the GBM Subepithelial immune complex deposits GBM thickening Ab reacting in situ to intrisic or planted Ag A form of chronic immune complex nephritisTwo categories Secondary ( known agents, 15% ) Drug, Underlying malignant tumors, Infections, SLE and other autoimmune disorders, globulin

21、 Primary ( unknown agents, 85%) resemble Heymann GN of rat related to HLA susceptibility A direct action of C5b-C9 on podocytes “Finding the manipulator behind the scene(s)”抓出幕后黑手Reverse the injuryIgG亚型染色有助区别Clinical features 1. More common in adults 2. Nephrotic syndrome (nonselective proteinuria)

22、3. Insidious onset , slow progression 4. Not usually respond to corticosteroid therapy Morphology Gross: Enlarged pale kidneysLM: Uniform, Diffuse thickening of capillary wallIF: IgG + , C3 +, granular pattern along the GBM EM: Subepithelial deposition EM: ( I -IV stages)Spikesspike Consequence Indo

23、lent In 10 years, 10% dead & renal sufficiency Improvement and recovery ( about 10% - 30% ) Focal segmental glomerulosclerosis(FSGS, 局灶节段性肾小球硬化）局灶节段性肾小球硬化） Focal Segmental +sclerosisPrimary - Idiopathic, unknown cause Book P310: Pathogenesis “FSGS and MCD are part of a continuum and that MCD may tra

24、nsform into FSGS. ” An out-of-date concept Two separate entitiesSecondary - drugs (interferon-, lithium), viruses (HIV), immunologic diseases, physical agents (obesity), and hereditary diseases Pathogenesis Glomerular capillary pressure, glomerular hypertrophy, hyperlipidemia/obesity, podocyte injur

25、y, genetical defects of cytoskeletal proteins, circulating cytokinesChanges of podocyte phenotypeIncreased permeability of GBMEntrapment of plasma proteins and lipids HyalinosisHallmarkClinical features 1. More common in adults 2. Nephrotic syndrome ( nonselective proteinuria ) 3. Often accompanied

26、with hematuria hypertension azotemia 4. Poor response to corticosteroid therapy 5. Slowly progressiveMorphology LM: Focal / segmental sclerosis with hyalinosisInitially juxtamedullary glomeruli affectedWith sever injury of tubules and interstitiumPAS stainingIF: Segmental IgM + , C3+EM: Hyalinosis l

27、esion Segmental increase of mesangial matrix and thickened GBM Effacement of foot processesConsequence Poor prognosis, especially in adults Renal failure after 10 years ( about 50% ) Recurrences in 25% to 50% patients receiving allografts Circulating mediatorsMembranoproliferative GN (MPGN, 膜性增生性肾炎）

28、膜性增生性肾炎） Membrano Proliferative Thickened GBMHypercellularityMsC & En proliferationInfiltrating leukocytesOther terms: Lobular GN Mesangiocapillary GN Typing Type I - Circulating immune complex EM: predominantly subendothelial deposits Type II - Dense deposit disease (DDD) Complement abnormality Exc

29、essive activation of alternative complement pathway ( Persistently low serum level of C3; IF: C3 deposition ) EM: intramembranous deposits Type III - A “variant” of type I EM: subepithelial & subendothelial depositsClinical features 1. Nephrotic syndrome ( 2/3 patients ) A combined nephrotic-nephric

30、 picture 2. Slowly progressive Morphology Gross: Enlarged pale kidneys LM: Hypercellularity MsC & En proliferationInfiltrating leukocytes Thickened GBM: Irregular Subendothelial deposits of immune complexes Mesangial interposition An accentuated lobular appearance “ 分 叶 状 ” Silver staining: “double

31、contour” or “tram track”IF: Type I IgG +, C3 +, C1q +, C4 + Type II IgG +, C3 +, no C1q , C4 Type III IgG +, C3 + A granular pattern along the glomerular capillaries EM: Type I Subendothelial deposits Type II ( DDD) Intramembranous deposit ( ribbon-like) Type III Subepithelial, subendothelial and me

32、sangial deposits Type IMesangial interpositionType IIType IIIPrognosis Slowly progressive Generally poor (especially DDD) Recurrence in 90% DDD patients after kidney transplantationThe nephritic syndrome Hematuria - injury of capillary walls Necrosis, derangement of GBM, broken Dysmorphic red blood

33、cells in urine Oliguria & azotemia - hypercellularity GFR serum BUN / Creatine Hypertension - fluid retention & augmented renin release Proteinuria & edema - not severeAcute Postinfectious GN (APGN) APGN follows infections Other terms: Acute diffuse proliferative GN Endocapillary proliferative GNPos

34、tstreptococcal acute GNHypercellularity: MsC & Endothelial cellsThe most common and best understood GNClinical features 1. More common in children and young adults 2. Infection history of streptococcal ( pharynx, skin) 3. Abrupt onset 4. Nephritic syndrome 5. Elevated serum anti-streptomysin O Ab ti

35、ter low complement level , formation of CIC Morphology Gross :Enlarged with congestion With tiny red speckles ( flea-bite hemorrhage) LM: Diffuse Hypercellularity Necrosis, crescent formation ( in 50% glomeruliAnother term - Rapidly progressive GNClinical features 1. Mainly in adult 2. Acute renal f

36、ailure 3. Typing - Based on immunologic findings Type I (anti-GBM) - anti-GBM disease (Goodpasture syndrome) Type II (immune complex) - Idiopathic, postinfectious GN, LN, IgA nephropathy, H-S purpura Type III ( pouci-immune) - ANCA +, vasculitis, idiopathic Morphology Gross: Enlarged pale kidneys of

37、ten with red petechial hemorrhages LM: Crescents (50%) Proliferation of parietal cells & migration of monocytes and macrophages into the urinary space cellular cell-fibrous fibrous with fibrinoid necrosis with proliferation of MsC and EnC with severe tubular and interstitial lesion CrescentCircumfer

38、ential IF: type I IgG + linear pattern type II Ig, complement granular pattern type III Usually negative Fibrinogen / fibrin in crescentsEM: Wrinkling of GBM with focal disruptions No electron-dense deposit ( Type I / III) Electron-dense deposits ( Type II ) Prognosis Poor (especially crescents in 8

39、0% glomeruli) Dependent on the number of crescentsChronic GN The end stage of a variety of GNs ( End stage kidneys ) Pathological basis of chronic renal failure Clinical features 1. Most in adults 2. Chronic renal failure 3. Treated with renal dialysis and renal transplantation Morphology Gross: sym

40、metrically contracted, diffusely granular an increase in peripelvic fat LM: Glomerulosclerosis (75%) Atrophy and dropout of tubules Interstitial fibrosis Thickening of arterial wall4种肾结构均有变化IF: Usually negative varies with different kinds of GNEM: Increased glomerular matrix with deposited fibrous c

41、ollagenClinicopathological correlations 1. Changes of urination - Loss of tubular function Polyuria, nocturia, low osmotic urine 2. Hypertension - fluid overload, renin 3. Anemia - inhibition of marrow function, EPO 4. Azotemia, uremia - most glomeruli obliterated Consequence Very poor prognosis Tre

42、atment with renal dialysis or transplanted kidney Emphasis Pathologic morphology of GN Changes of tubules and interstitium are usually not specific for glomerular diseases. Pathogenesis (mechanisms) underlies pathologic morphology. Pathologic changes underlies clinical manifestations. Gross LMIF EMD

43、ont learn everything by rote. Dont cram for exam. II Pyelonephritis Caused by bacterial infection A form of tubulointerstitial nephritis (TIN) primarily involving the interstitium and tubules Most are caused by Gram-negative enteric organisms It occurs in two forms, acute & chronic 1. Acute Pyelonep

44、hritis An acute inflammatory processNeutrophils predominateA common suppurative inflammationEtiology and Pathogenesis Source and route of entry of organisms Hematogenous spread Ascending infection - the most common More common in females Organism involved Gram-negative enteric organisms The most com

45、mon E. Coli Predisposing factors:Urethral instrumentationTrauma of lower urinary tractIncompetence of the vesicoureteral orifice Vesicoureteral refluxClinical features 1. Systemic manifestation -abrupt, chills, fever blood WBC 2. Back pain 3. Manifestation of bladder and urethral irritation 4. Urine

46、 changes - pyuria , bacteriuria Morphology Gross: One or both involved Enlarged kidney Discrete, yellowish abscesses with surrounding hyperemiaabscess LM: Abscess formation within the renal parenchyma Neutrophil casts and bacterial colonies in tubules 2. Chronic pyelonephritis Usually with obstructi

47、on to the urinary tract, or Vesicoureteral reflux Clinical features 1. Recurrence of acute pyelonephritis 2. Polyuria, nocturia, low osmotic urine, electrolytes disorders: Loss of tubular function decrease of concentrating ability decrease of reabsorbtion or secretion function 3. Pyelograms: smaller

48、 renal papilla deformity of the calyceal system Morphology Gross: One or both affected Uneven, irregular, coarse, depressed scars 马鞍样 Generalized dilatation of the collecting system LM: Focal scar Atrophic or dilated tubules containing eosinophilic colloid casts “Thyroidization ” Chronic inflammatio

49、n ( lymphoid follicles ) in interstitium Thickening of Bowmans capsule and periglomerular fibrosis Secondary FSGS3. Consequence Acute pyelonephritis mostly recovered Chronic pyelonephritis Poor prognosis - Chronic renal failure (end stage kidney) GN Pylonephritis CauseImmune injuryDirect bacterial i

50、nfectionPathologic changes Both affected; Glomeruli lesions; Glomerular deposits of immunoglobulins, often with various components of complementClinical manifestationsPyuria 脓尿 / bacteriuria;bladder and urethral irritation (dysuria, frequency and urgency)hematuria, proteinuria, hypertention, azotemi

51、a, uremiaOne or both affected; Tubules & interstitium lesions;Suppurative inflammation“Different”III Transplant Rejection Both cell- and antibody- mediated hypersensitivity responses of the host directed against histocompatibility molecules on the donor allograft The target Major Histocompatibility

52、Complex (MHC抗原) Human Leukocyte Antigen (HLA抗原) Polymorphic & highly variableMechanismsT-cell-mediated rejectionAntibody-mediated rejection Classification Hyperacute Rejection (超急性排异反应超急性排异反应) ) Acute Rejection (急性排异反应急性排异反应) ) Chronic Rejection (慢性排异反应慢性排异反应) ) 1. Hyperacute rejection(超急性排异反应超急性排异反

53、应) Occurs within minutes to a few hours In pre-sensitized host: Preformed anti-donor antibodies are present in the circulation of the recipient. Clinical presentation: Anuria, fever, nor perfusion on renal scanGross: Cyanotic, mottled, flabby and soft, swollen Widespread hemorrhagic cortical necrosi

54、s May excrete only a few drops of bloody fluidMORPHOLOGYLM: (1) Widespread acute arteritis and arteriolitis: Fibrinoid necrosis of walls Thrombosis (2) Ischemic necrosis 2. Acute Rejection A combined process: cellular / humoral (antibody) Clinical features Abrupt Scr , clinical signs of renal failur

55、e Distinct pathologic, immunopathologic, clinical features Acute cellular rejection LM: Extensive infiltrate of mononuclear cells in tubules and interstitium Interstitial edema / hemorrhage T-cells & macrophagesInflammatory cells in the interstitium and between epithelial cells of the tubules Inters

56、titial inflammatoryEdema / interstitial hemorrhage Acute humoral rejection （antibody-mediated） LM: (1) Vaculitis: Neutrophilic infiltration Marked thickening of the intima Fibrinoid necrosis Thrombosis IF: Ab, complements, and fibrin C4d + on PTC - The marker for humoral rejection (2) Focal necrosis

57、“ Less acute ”Focal necrosisC4d deposition in peritubular capillaries3. Chronic rejection It progresses slowly because of persistent or recurrent immunologic reaction. Progressive loss of renal function May be considered as ongoing healing responseGlomerulosclerosis & interstitial fibrosis are promi

58、nent.LM: (1) Proliferative arteritis: Pronounced, concentric, fibrous thickening intima “Onion-skin” (2) Chronic glomerulopathy: Duplication of GBM (3) Loss of nephron and interstitial fibrosis (4) Variable mononuclear infiltrateFoam cells lining up along the internal elasticaOcclusive foam cells C4

59、d depositionMethods of increasing graft survival Better matching of MHC molecules before transplantation Immunosuppression of the recipient is a practical necessity Opportunistic infections “ Double-edged sword ” （双刃剑） EBV-induced lymphomasHPV-induced squamous cell carcinomas Kaposi sarcoma IV Diabe

60、tes MellitusGlucose homeostasisThree interrelated processes: Glucose production in the liver Glucose uptake and utilization by peripheral tissues, chiefly skeletal muscles Insulin glucagon 胰高血糖素 epinephrine 肾上腺素 adrenocortical hormones 肾上腺皮质激素 血糖 Normal insulin physiology The insulin gene is express