内科学肾小球疾病（英文版）GlomerularDiseases

1、内科学肾小球疾病（英文版）Glomerular DiseasesThe peripheral portion of a glomerular lobuleGlomerular Diseases ClassificationPrimarySecondaryHereditaryPathogenesisImmunologic glomerular injuryHumoral antibody-mediatedCellular antibody-independent Antibody-mediatedCirculating autoantibodies with intrinsic autoanti

2、gens: eg. anti-GBM diseaseIn situ formation of immune complexs/ circulationg antibodies with extrinsic antigens that have been “planted” within the glomerulus: eg. Postinfectious glomerulonephritisANCA/AECA associated: no disernible immune complexes in the glomerular parenchymaCellular antibody-inde

3、pendent glomerular injuryLess well definedInitiators of injury in pauci-immune glomerulonephritis, which share the downstream mediators with the antibody-dependent injurySoluble factors from T cells: in MCD and primary FSGSNonimmunologic glomerular injuryMetabolicHemodynamictoxic immunologichumoralc

4、ellularnon-immunologicinflammationGlomerular injuryClinicopathologic correlates in glomerular diseaseMajor clinicopathologic entities (contd)Nephrotic syndromeGlomerular filtration barrier affectedHypoalbuminemia, edema, hyperlipidemia, and lipiduria, and a prothrombotic stateMembranous glomerulopat

5、hyMinimal change disease (MCD)FSGSMembranoproliferative: hybrid lesion of nephritic and nephrotic featuresOthersGlomerular deposition diseases: extravascular deposition of paraprotein or fibrillar materialThrombotic microangiopathies: thrombi within the renal microvasculaturePrimary insultInflammato

6、ryMetabolic Hemodynamic or mechanic ToxicInfectiousMay overlapMay induce similar clinicopahtologic presentations病变部位 系膜 mesangium 系膜细胞 mesangial cell 系膜基质 mesangial matrix 基膜 basement membrane 上皮细胞 足细胞 podocyte、 足突 foot process 内皮细胞The peripheral portion of a glomerular lobule 基本病变 增生 proliferation

7、硬化 sclerosis1.轻微肾小球病变（Minor Lesion) 无特异性病变 光镜下可见轻度系膜细胞增生和 系膜基质增多轻微病变肾病 minimal change disease，MCD轻度系膜增殖性肾小球肾炎毛细血管内增殖性肾小球肾炎恢复期其它MCD （左）正常，（右）上皮细胞足突广泛融合、消失2. 局灶节段性病变(1)局灶节段性增殖性肾小球肾炎 focal and segmental proliferative glomerulonephritis (2)局灶节段性肾小球硬化 focal and segmental glomerulosclerosis, FSGS局灶性肾小球肾炎

8、3.弥漫性肾小球肾炎 (diffusive glomerulonephritis)(1)膜性肾病 membranous nephropathy, MN 肾小球基底膜 membranous nephropathy （左）正常，（右）上皮下免役复合物沉积（D），GBM增厚，钉突形成（S），上皮细胞足突融合(2)增殖性肾小球肾炎 proliferative glomerulonephritis系膜增殖性肾小球肾炎 mesangial proliferative glomerulonephritis MsPGN 肾小球系膜IgA肾病 IgA nephropathy非IgA肾病 IgG沉积为主 IgM肾

9、病mesangial proliferative glomerulonephritis（左）正常，（右）系膜细胞和基质增生，电子致密物（D）沉积 毛细血管内增殖性肾小球肾炎 endocapillary proliferative glomerulonephritis 系膜+内皮细胞endocapillary proliferative glomerulonephritis （左）正常，（右）内皮（E）和系膜（M）细胞增生，上皮下驼峰状电子致密物（D）沉积 系膜毛细血管性肾小球肾炎 mesangiocapillary glomerulonephritis 又称膜增殖性肾小球肾炎 membrano

10、proliferative glomerulonephritis 系膜+基底膜致密沉积物性肾小球肾炎 dense desposit glomerulonephritis 电子致密沉积物mesangiocapillary glomerulonephritis （左）正常，（右）系膜增生（M），电子致密物（D），广泛插入（I） 新月体性肾小球肾炎 cresentic glomerulonephritis 又称毛细血管外肾小球肾炎 extracapillary glomerulonephritis 肾小球囊上皮细胞(3) 硬化性肾小球肾炎 sclerosing glomerulonephritisc

11、resentic glomerulonephritis （左）正常，（右）GBM断裂，纤维蛋白漏出(F)，上皮细胞增生(E)，单核巨噬细胞浸润(P)，新月体形成 4.未分类的肾小球肾炎 unclassified glomerulonephritisClinical presentationsClinical classificationAcute glomerulonephritis,AGNRapidly progressive glomerulonephritis, RPGNChonic glomerulonephritis,CGNNephrotic syndrome,NSLatent gl

12、omerulonephritis, asymptomatic hematuria and/or proteinuriaAcute nephritic syndromeSudden onset (days to weeks)Nephritic urinary sedimentHematuria:Red blood casts, dysmorphic red blood cellsSubnephrotic proteinuria (20% adults may have persistent proteinuria and/or compromise of GFRRPGNOver weeks to

13、 monthsNephritic urinary sediment, subnephrotic proteinuria and variable oliguria, hypervolemia, edema, and hypertensionCrescentic GNCrenscents can also develop concomitantly with proliferative GN, membranous GN and other GNRPGN-Immunofluorescence microscopyanti-GBM dis-more discrete linear depositi

14、on of Ig along the GBMimmune complex GN-scattered granular deposits of immunoglobulinpauci-immune GN-paucity or absence of IgRPGN-Serologic markersDepressed C3 level -Type IIanti-GBM antibody-Type IANCA-Type IIIMay overlapAnti-GBM disease (Goodpastures syndrome)Antibody to a3 chain (noncollagenous d

15、omain) of type IV collagen, which preferentially expressed in glomerular and pulmonary alveolar basement membraneRPGN/crescentic GN, hematuria, nephritic urinary sediment, subnephrotic proteinuria50-70% have lung hemorrhage with hemoptysis or severe alveolar hemorrhageAnti-GBM lab testsAnti-GBM anti

16、bodiesRenal biopsy, gold standard for diagnosis of anti-GBM nephritisDiffuse proliferative GNFocal necrotizing lesionsCrescents in 50% of glomeruliLinear ribbon-like deposition of IgG along the GBMpauci-immune RPGNIdiopathic renal-limited crescentic GNMicrosopic polyangiitis nodosaWegeners granuloma

17、tosisChurg-strauss syndromeAll-encompassing term: ANCA-associated small vessel vasculitisANCA-associated renal diseaseLethargy, malaise, anorexia, weight loss, fever, arthralgias, myalgiasElevated ESR/CRP, leukocytosis, thrombocytosis, normochromic normocytic anemia, complement level typically norma

18、lNephritic urine sediment and subnephrotic proteinuriaRenal dysfunctionBiopsy: focal segmental necrotizing GN with crescent formationPaucity or absence of Ig, complement and immune deposits RPGN I型 II型 III型 抗基膜抗体型 免疫复合物型 非免疫复合物型IF 线样、沿基膜 颗粒样、系膜 （-） 区和基膜 GBM抗体（+）C3、CIC 70%-80%为微 血管炎 ANCA阳性 青、中年 中、老年

19、中、老年 我国多见treatmentGlucocorticoid, pulse treatment and maintenance treatmentCTX or AZAplasmaphereses, immunoadsorptionBetter prognosis in relatively early cases (Scr 3.5 g/24hEdemaHyperlipidemia, lipiduria and hypercoagulabilityMain entities of NSMinimal change disease, MCDFocal and segmental glomeru

20、losclerosis, FSGSMembranous glomerulopathy, MNMsPGNMembranoproliferative glomerulonephritis, MPGNDiabetic nephropahy, DNAmyloidosis,MMComplications-thrombosis deep vein thrombosis renal vein thrombosis Sudden onset of flank or abdominal painGross hematuriaA left-sided varicoceleIncreased proteinuria

21、Acute decline in GFRPaticularly common in MN/MPGN/AmyloidosisOther complicationsProtein malnutritioninfectionNS- treatmentSpecific treatment of the underlying diseaseGlucocorticoid, immunosuppressionGeneral measures of proteinuria controlACEI/ARBNephrotic complications control and preventionSensetiv

22、ity of steroid prednisone(prednisolone)1mg/kg/d 8w negetive proteinuria remain positive relapse during taper sentsetiveSteroid-dependentresistanceNS complications controlEdemaSalt restriction 1-2g/d; judicious use of loop diuretics;Lipid loweringHMG CoA reductaseAnticoagulationIndications: deep veno

23、us thrombosis, arterial thrombosis, pulmonary embolismMinimal change disease, MCD80% of NS in children younger than 16 yo, 20% in adultsGlomerular size and architecture normal by light microscopyIF microscopy negative for Ig and C3EM characteristic diffuse effacement of foot processes of visceral ep

24、ithelial cellsMCD- proteinuria selectivity Selective proteinuria in children with albumin principally and minimal amounts of higher molecular weight protiensSelectivity poor in adults suggesting more extensive perturbation of membraneMCD-treatmentHighly steroid-responsiveGenerally excellent prognosi

25、sRemission after 8 weeks of high-dose oral glucocorticoids: 90% in children and 50% in adultsMCD-treatment (contd)Relapses common following withdrawal of glucocorticoidsAlkylating agents reserved for steroid-resistant, steroid-dependent or frequently relapsing: CTX, chlorambucil, azathioprine, cyclo

26、sporineFocal segmental glomerulosclerosis, FSGSSclerosis with hyalinosis involving portions (segmental) of fewer than 50% (focal) of glomeruliIdiopathic FSGS: Nephrotic syndrome (2/3) or subnephrotic proteinuria (1/3), nonselectiveHypertension, mild renal insufficiency, abnormal urine sedimentFSGS (

27、contd)IdiopathicSecondary: a potential long-term consequence of nephron loss (50%) from any causeCongenital oligomeganephronia, extensive surgical ablation of renal mass, reflux nephropathy, GN, interstitial nephritis, sickle cell disease, ischemia, cyclosporine nephrotoxicity, rejection of allograf

28、tFSGS- treatmentRenal prognosis relatively poorRemission rates for 8 week glucocorticoids: 20-40%, up to 70% for prolonged therapy (16-24 weeks)Immunosuppressants: CTX, cyclosporine, MMFPoor prognostic factors: hypertension, abnormal renal function, persistent heavy proteinuriaMembranous glomerulopa

29、thy (membranous nephropathy, MN)Peak incidence 30-50 years of ageMale:femal 2:1Named after light micrscopic: diffuse GBM thickening80% represents with NS, nonselectiveMicroscopic hematuria 50%MN- pathologyLM: Diffuse thickening of GBM without inflammation or cellular proliferationIF: granular deposi

30、tion of IgG, C3 and terminal components of complements along the glomerular capillary wall MN - pathogenesisIdiopathic MN incompletely understoodImmune deposits suggesting an immune process1/3 with systemic disease: SLE, infections such as hepatitis B, malignancy, drug (eg. gold and penicillamine)MN

31、- treatment and prognosisremits spontaneously and completely in up to 40% another 30 to 40% repeated relapses and remissionsThe final 10 to 20% slow progressive decline in GFR that typically culminates in ESRD after 10 to 15 yearsPoor prognosis indicators: male gender, older age, hypertension, sever

32、e proteinuria and hyperlipidemia, and impaired renal functionControlled trials of glucocorticoids have failed to show consistent improvement in proteinuria or renal protection. Cyclophosphamide, chlorambucil, and cyclosporine have each been shown to reduce proteinuria and/or slow the decline in GFR

33、in patients with progressive disease in small or uncontrolled studies. Membranoproliferative glomerulonephritis, MPGNthickening of the GBM and proliferative changes on light microscopy type I MPGN: subendothelial and mesangial deposits on electron microscopy that contain C3 and IgG or IgM; rarely, I

34、gA deposits type II MPGN (dense deposit disease): electron-dense deposits within the GBM and other renal basement membranes (shown by electron microscopy) that stain for C3, but little or no immunoglobulin. MPGN type I- clinical featuresType IAn immune-complex (IC) GNnephrotic syndrome, active urina

35、ry sediment, and normal or mildly impaired GFR. C3 levels usually depressed, and C1q and C4 levels borderline or low Associated with infections, systemic IC diseases (SLE, cryoglobulinemia), malignancies50% of patients reach ESRD by 10 years MPGN type II- clinical featuresType IIan autoimmune disease with an IgG autoantibody, termed C3 nephritic factorproteinuria and n