课件：内科学肾小球疾病丁小强.ppt

Glomerular Diseases,For Internal Medicine,The peripheral portion of a glomerular lobule,Glomerular Diseases Classification,Primary Secondary Hereditary,Pathogenesis,Immunologic glomerular injury,Humoral antibody-mediated Cellular antibody-independent,Antibody-mediated,Circulating autoantibodies with intrinsic autoantigens: eg. anti-GBM disease In situ formation of immune complexs/ circulationg antibodies with extrinsic antigens that have been “planted” within the glomerulus: eg. Postinfectious glomerulonephritis ANCA/AECA associated: no disernible immune complexes in the glomerular parenchyma,Cellular antibody-independent glomerular injury,Less well defined Initiators of injury in pauci-immune glomerulonephritis, which share the downstream mediators with the antibody-dependent injury Soluble factors from T cells: in MCD and primary FSGS,Nonimmunologic glomerular injury,Metabolic Hemodynamic toxic,immunologic humoral cellular,non-immunologic,inflammation,Glomerular injury,Clinicopathologic correlates in glomerular disease,Major clinicopathologic entities (contd),Nephrotic syndrome Glomerular filtration barrier affected Nephrotic-range proteinuria =3.5g/24h Hypoalbuminemia, edema, hyperlipidemia, and lipiduria, and a prothrombotic state Membranous glomerulopathy Minimal change disease (MCD) FSGS Membranoproliferative: hybrid lesion of nephritic and nephrotic features,Others,Glomerular deposition diseases: extravascular deposition of paraprotein or fibrillar material Thrombotic microangiopathies: thrombi within the renal microvasculature,Primary insult,Inflammatory Metabolic Hemodynamic or mechanic Toxic Infectious May overlap May 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 硬化 sclerosis,1.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,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 membranoproliferative 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 glomerulonephritis,cresentic 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 glomerulonephritis,Clinical presentations,Clinical classification,Acute glomerulonephritis,AGN Rapidly progressive glomerulonephritis, RPGN Chonic glomerulonephritis,CGN Nephrotic syndrome,NS Latent glomerulonephritis, asymptomatic hematuria and/or proteinuria,Acute nephritic syndrome,Sudden onset (days to weeks) Nephritic urinary sediment Hematuria:Red blood casts, dysmorphic red blood cells Subnephrotic proteinuria (3.0 g/24h) Extracellular fluid volume expansion, edema, and hypertension Acute renal failure and oliguria,Acute nephritic syndrome (contd),Proliferative glomerulonephritis Infiltration of the glomerular tuft by neutropils and monocytes, followed by proliferation of resident endothelial and mesangial cells Endocapillary proliferative GN,Streptococcal infection (PSGN) - symptoms and signs,1-3weeks after pharyngitis or 1-4 weeks after a skin infection (impetigo) Nephritogenic strain of group A beta-hemolytic streptococcus Nephritic syndrome with oliguric ARF, or milder Headache, anorexia, nausea, vomiting, and malaise, flank or back pain,PSGN lab investigations,Serum creatinine often mildly elevated C3 and CH50 depressed within 2 weeks in 90% patients, C4 characteristically normal; return to normal within 6-8 weeks Transient hypergammaglobulinemia and mixed cryoglobulinemia Circulating antibodies against streptococcal exoenzymes such as ASO,PSGN - pathology,Diffuse proliferative GN Crescents uncommon Extraglomerular involvement mild IF microscopy: diffuse granular deposition of IgG and C3 EM: large electron-dense deposits in the subendothelial, subepithelial and mesangial areas,2019/8/23,39,可编辑,PSGN- treatment,Eliminating the streptococcal infection with antibiotics Diuretics and antihypertensive agents to control ECF volume and BP Spontaneous resolution within 6-8 weeks in children 20% adults may have persistent proteinuria and/or compromise of GFR,RPGN,Over weeks to months Nephritic urinary sediment, subnephrotic proteinuria and variable oliguria, hypervolemia, edema, and hypertension Crescentic GN Crenscents can also develop concomitantly with proliferative GN, membranous GN and other GN,RPGN-Immunofluorescence microscopy,anti-GBM dis-more discrete linear deposition of Ig along the GBM immune complex GN-scattered granular deposits of immunoglobulin pauci-immune GN-paucity or absence of Ig,RPGN-Serologic markers,Depressed C3 level -Type II anti-GBM antibody-Type I ANCA-Type III May overlap,Anti-GBM disease (Goodpastures syndrome),Antibody to a3 chain (noncollagenous domain) of type IV collagen, which preferentially expressed in glomerular and pulmonary alveolar basement membrane RPGN/crescentic GN, hematuria, nephritic urinary sediment, subnephrotic proteinuria 50-70% have lung hemorrhage with hemoptysis or severe alveolar hemorrhage,Anti-GBM lab tests,Anti-GBM antibodies Renal biopsy, gold standard for diagnosis of anti-GBM nephritis Diffuse proliferative GN Focal necrotizing lesions Crescents in 50% of glomeruli Linear ribbon-like deposition of IgG along the GBM,pauci-immune RPGN,Idiopathic renal-limited crescentic GN Microsopic polyangiitis nodosa Wegeners granulomatosis Churg-strauss syndrome All-encompassing term: ANCA-associated small vessel vasculitis,ANCA-associated renal disease,Lethargy, malaise, anorexia, weight loss, fever, arthralgias, myalgias Elevated ESR/CRP, leukocytosis, thrombocytosis, normochromic normocytic anemia, complement level typically normal Nephritic urine sediment and subnephrotic proteinuria Renal dysfunction Biopsy: focal segmental necrotizing GN with crescent formation Paucity 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 中、老年,我国多见,treatment,Glucocorticoid, pulse treatment and maintenance treatment CTX or AZA plasmaphereses, immunoadsorption Better prognosis in relatively early cases (Scr 442 mmol/L) Relapses not unusual,Nephrotic syndrome, NS,Proteinuria 3.5 g/24h Hypoalbuminemia 3.0g/L Edema Hyperlipidemia, lipiduria and hypercoagulability,Main entities of NS,Minimal change disease, MCD Focal and segmental glomerulosclerosis, FSGS Membranous glomerulopathy, MN MsPGN Membranoproliferative glomerulonephritis, MPGN Diabetic nephropahy, DN Amyloidosis,MM,Complications-thrombosis deep vein thrombosis renal vein thrombosis,Sudden onset of flank or abdominal pain Gross hematuria A left-sided varicocele Increased proteinuria Acute decline in GFR Paticularly common in MN/MPGN/Amyloidosis,Other complications,Protein malnutrition infection,NS- treatment,Specific treatment of the underlying disease Glucocorticoid, immunosuppression General measures of proteinuria control ACEI/ARB Nephrotic complications control and prevention,Sensetivity of steroid prednisone(prednisolone)1mg/kg/d 8w negetive proteinuria remain positive relapse during taper,sentsetive,Steroid-dependent,resistance,NS complications control,Edema Salt restriction 1-2g/d; judicious use of loop diuretics; Lipid lowering HMG CoA reductase Anticoagulation Indications: deep venous thrombosis, arterial thrombosis, pulmonary embolism,Minimal change disease, MCD,80% of NS in children younger than 16 yo, 20% in adults Glomerular size and architecture normal by light microscopy IF microscopy negative for Ig and C3 EM characteristic diffuse effacement of foot processes of visceral epithelial cells,MCD- proteinuria selectivity,Selective proteinuria in children with albumin principally and minimal amounts of higher molecular weight protiens Selectivity poor in adults suggesting more extensive perturbation of membrane,MCD-treatment,Highly steroid-responsive Generally excellent prognosis Remission after 8 weeks of high-dose oral glucocorticoids: 90% in children and 50% in adults,MCD-treatment (contd),Relapses common following withdrawal of glucocorticoids Alkylating agents reserved for steroid-resistant, steroid-dependent or frequently relapsing: CTX, chlorambucil, azathioprine, cyclosporine,Focal segmental glomerulosclerosis, FSGS,Sclerosis with hyalinosis involving portions (segmental) of fewer than 50% (focal) of glomeruli Idiopathic FSGS: Nephrotic syndrome (2/3) or subnephrotic proteinuria (1/3), nonselective Hypertension, mild renal insufficiency, abnormal urine sediment,FSGS (contd),Idiopathic Secondary: a potential long-term consequence of nephron loss (50%) from any cause Congenital oligomeganephronia, extensive surgical ablation of renal mass, reflux nephropathy, GN, interstitial nephritis, sickle cell disease, ischemia, cyclosporine nephrotoxicity, rejection of allograft,FSGS- treatment,Renal prognosis relatively poor Remission rates for 8 week glucocorticoids: 20-40%, up to 70% for prolonged therapy (16-24 weeks) Immunosuppressants: CTX, cyclosporine, MMF Poor prognostic factors: hypertension, abnormal renal function, persistent heavy proteinuria,Membranous glomerulopathy (membranous nephropathy, MN),Peak incidence 30-50 years of age Male:femal 2:1 Named after light micrscopic: diffuse GBM thickening 80% represents with NS, nonselective Microscopic hematuria 50%,MN- pathology,LM: Diffuse thickening of GBM without inflammation or cellular proliferation IF: granular deposition of IgG, C3 and terminal components of complements along the glomerular capillary wall,MN - pathogenesis,Idiopathic MN incompletely understood Immune deposits suggesting an immune process 1/3 with systemic disease: SLE, infections such as hepatitis B, malignancy, drug (eg. gold and penicillamine),MN- treatment and prognosis,remits spontaneously and completely in up to 40% another 30 to 40% repeated relapses and remissions The final 10 to 20% slow progressive decline in GFR that typically culminates in ESRD after 10 to 15 years Poor prognosis indicators: male gender, older age, hypertension, severe proteinuria and hyperlipidemia, and impaired renal function Controlled 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 in patients with progressive disease in small or uncontrolled studies.,Membranoproliferative glomerulonephritis, MPGN,thickening 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, IgA 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 features,Type I An immune-complex (IC) GN nephrotic syndrome, active urinary 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), malignancies 50% of patients reach ESRD by 10 years,MPGN type II- clinical features,Type II an autoimmune disease with an IgG autoantibody, termed C3 nephritic factor proteinuria and nephrotic syndrome; some with nephritic syndrome, RPGN, or recurrent macroscopic hematuria a variabl