GLOMERULOPATHY-clinical-课件

1、GLOMERULOPATHYclinical categoriesAcute nephritic syndrome: haematuria, red blood cell casts, proteinuria, oliguria, hypertension, edema, circulatory congestionRapidly progressive nephritic syndrome: relentlessly progressive glomerulonephritis resulting in ESRF within weeksRecurrent gross haematuria

2、GLOMERULOPATHYclinical categoriesAsymptomatic glomerulopathy: proteinuria, haematuria, or both without clinical symptomsChronic nephritic (glomerular) syndrome: glomerular disease that progress in chronic renal failureNephrotic syndromeGLOMERULOPATHYstructural characteristicsAcute damage (diffuse or

3、 segmental): - proliferation of epithelial, endothelial and mesangial cells; - exudation of polymorphonuclear leukocytes in the glomerulus; - necrosis of glomerular capillaries GLOMERULOPATHYstructural characteristicsChronic damage: - proliferation of cellular elements (epithelium, endothelium, mesa

4、ngium); - membranous involvement with thickening of glomerular basement membrane (GBM); - sclerosis of the glomerulus; - tubular atrophy, nephrosclerosis, interstitial scarring (in ESRF)GLOMERULOPATHYpathogenesisImmunologic reactionsVascular diseases Abnormalities in coagulationMetabolic defectsHere

5、ditary factorsUnknown factorsGLOMERULOPATHYimmunologic mechanismCirculating immune complex mediated diseaseAntitissue antibody mediated diseaseCell- mediated diseaseDisease associated with activation of alternative complement pathwayPhysiology of protein excretionProtein filtration through the glome

6、rulus is dependent on the protein size, shape and electrical charge Physiology of protein excretionProtein chargeAt physiological pH, most proteins are negatively chargedSince the basement membranes are also negatively charged, most proteins are retainedPhysiology of protein excretionProtein sizePro

7、teins greater than 40kDa are almost completely retainedThus, only small proteins, e.g. retinol-binding protein, 2 microglobulin, passes into the ultrafiltratePhysiology of protein excretionHowever, most of the filtered proteins are reabsorbed by the proximal tubules.Consequently, very little plasma

8、protein appears in the urineNormally 40kDa can escape into the urineThe most common form of proteinuriaGlomerular proteinuriaCausesGlomerulonephritisDiabetes mellitusMultiple myelomaAmyloidosisSLEPre-eclampsiaPenicillamine, goldDefinitionsProteinuriaUrine protein excretion 150mg/dayMicroalbuminuriaU

9、rine albumin 30mg/day but not detectable by urine dipstickNephrotic syndromeUrine protein excretion 3.5g/day (with hypoalbuminaemia, oedema and hyperlipidaemia) Nephrotic Syndrome (NS)uIs not a disease but a group of signs and symptoms seen in patients with heavy proteinuriaupresents with oedemaupro

10、teinuria usually 3.5g / 24hrs (0.05g / kg / 24hrs in children)userum albumin 30g/luother features: hyperlipidaemia, and hypercoaguable stateNS pathophysiologyuproteinuria: due to an increase in glomerular permeabilityuhypoalbuminuria: occurs when liver synthesis cannot keep up with urine lossesuoede

11、ma mechanism is complex and still in dispute: primary salt and water retention associated with reduced renal function as well as reduced plasma oncotic pressure are primary factors (overfill and underfill)uhyperlipidaemia: increased liver synthesisuhypercoagulation: increased fibrinogen and loss of

12、antithrombin IIIClinical Features in NS - ThrombosisSerious risk of thrombosisIncreased fibrinogen concentrationAntithrombin III concentration reducedNS patients resistant to heparinPlatelets hyperaggregableIncreased blood viscosityNS - laboratory FeaturesHct may be elevatedHyponatremia is commonPla

13、sma creatinine is elevated in 33% of patientsNS laboratory- Plasma ProteinAlbuminHypoalbuminemia due to loss via the kidneyUrinary excretionProximal tubular cells catabolismImmunoglobulinsIgG levels reducedIgM levels elevatedIgM-IgG-SwitchingNS laboratory- HyperlipidemiaIncreased synthesis of choles

14、terol, triglycerides and lipoproteinsDecreased catabolism of lipoproteinsDecreased activity of lipoprotein lipaseDecreased LDL receptor activityIncreased urinary loss of HDLLp(a) levels are elevatedPrimary glomerular diseases commonly causing the nephrotic syndromeuminimal change diseaseufocal and s

15、egmental glomerulosclerosisumembranous glomerulonephritisuproliferative glomerulonephritis (various histology and less common cause)umembranoproliferative (mesangiocapillary)ufocal proliferativeudiffuse proliferativeumesangial proliferative Other causes of the nephrotic syndrome 1uSystemic diseasesu

16、diabetes mellitusuamyloidosisuSLE and other connective tissue diseasesuHIV/AIDSunephrotoxinsunsaidsumercury poisoningupenicillamineugold saltsOther causes of the nephrotic syndrome 2uAllergiesubee stingupollensupoison ivyuCirculatory effectsucongestive cardiac failureuconstrictive pericarditisurenal

17、 vein thrombosis (cause or result?)uNeoplasticuleukaemiausolid tumoursNS epidemiologyNS treatment- DietLow proteinDecreases albuminuriaMalnutritionSalt restriction (Na+0.5 mg/kg/alt day plus:Severe steroid side effectsHigh risk of toxicity- diabetesUnusually severe relapsesRelapses on Prednisone Dos

18、age 1.0 mg/kg/alt dayAcute Nephritic SyndromeuSyndrome characterised in typical cases by:uhaematuriauoliguriauoedemauhypertensionureduced GFRuproteinuriaufluid overloadClinical Features of the Acute Nephritic Syndromeuhaematuria is usually macroscopic with pink or brown urine (like coca cola)uoligur

19、ia may be overlooked or absent in milder casesuoedema is usually mild and is often just peri-orbital- weight gain may be detecteduhypertension common and associated with raised urea and creatinineuproteinuria is variable but usually less than in the nephrotic syndromeEtiology of the Nephritic Syndro

20、meMost common cause is acute post infectious glomerulonephritisgroup A beta haemolytic streptococci of certain serotypes important in NZIgA disease and Henoch-Schonlein purpura, crescentic glomerulonephritis and SLE can also present in this wayComplications of the Nephritic SyndromeuHypertensive enc

21、ephalopathy (seizures, coma)uHeart Failure (pulmonary oedema)uUraemia requiring dialysisAcute poststreptococcal GNArchetype of acute nephritic syndromeProliferative characterOnly certain varietes of beta-hemolytic streptococci (nephritogenic strains) induce abnormalities in kidneysProduction of nons

22、pecific evidence of streptococcal exposure (elevated antistreptolisin titers)Antibody production and immune complexesAcute poststreptococcal GNKidneys are enlarged, edematosus, paleElectron-dense deposits on the epithelial side of GBMReduced GFR Elevation of urea and creatinine is characteristicUrin

23、e: reduced in volume, concentrated, reddish brown; contains as much as 2 to 4 mg/day of protein Acute poststreptococcal GNMore common in males than females and most frequent between the ages of 3 and 7 yearsClassically, 10 days after sore throatAcute nephritic syndromeGross hematuria and feverWorse

24、prognosis in adultsDefinition of glomerulonephritisGlomerulonephritides are supposedly immunologically mediated glomerular diseases, often, but not always, inflammatory in natureGlomerular inflammation1.Exsudation of neutrophils and/or macrophages2. Proliferation of mesangial and/or endothelial cell

25、s Ultrastructural changes in non-proliferative vs. proliferative glomerulonephritidesMechanisms of glomerular damageSimplified classification of primary glomerulonephritides1. Nonproliferative- minimal change disease - focal segmental glomerulosclerosis - membranous nephropathy 2. Proliferative - Ig

26、A nephropathy - membranoproliferative GNUltrastructural changes in glomerular capillaries in different glomerular diseasesPodocytes and slit diaphragmsMajor causes of podocyte effacement1.Slit diaphragm and its lipid raft nephrin, podocin1.Podocyte cytoskeleton -actinin1.Adhesion of podocyte to GBM

27、-dystroglycan, 1-integrins4. Loss of podocyte electronegative charge podocalyxinNon-proliferative glomerulopathiesDamage to the glomerular capillary wall resulting in:1. nephrotic selective proteinuria - minimal change disease2. nephrotic non-selective proteinuria with microscopic hematuria - focal

28、segmental glomerulosclerosis - idiopathic membranous nephropathyPrimary glomerulonephritides as a cause of nephrotic syndrome Korbet et al., Am. J. Kidney Dis., 1996, 27: 647 - 651Role of renal biopsy in glomerular disease1. Diagnosis of glomerulopathy2. Assessment of activity intention to treat3. A

29、ssesment of chronicity outcome of the disease Indications for BiopsyPretreatmentRecommendedOnset age 12 yearsPersistent HTN of hematuriaIndications for BiopsyPost treatmentSteroid resistanceFrequent relapsersMinimal change diseaseMinimal change diseasePathogenesis of minimal change disease1.circulat

30、ing permeability factor(hemopexin?)1.decreased synthesis of glomerular polyanions (heparan sulfate) by podocytes2.impaired adhesion of podocytes to GBM( -dystroglycan, 1-integrins?)4. expression of TGF1 detectable almost only in steroid resistant MCD and FSGSMinimal change disease1.full-blown nephro

31、tic syndrome with selective proteinuria2.hematuria, hypertension and reduced renal function uncommon3.absence of glomerular abnormalities on LM and IF4.fusion of epithelial cells foot processes on electron microscopyMinimal change disease-prevalence among nephrotic patientsChildren - 85 95%Young adu

32、lts - 50%Adults 40 years - 20 25% Classification of patients with minimal change disease based on response to corticosteroids1.Steroid responsive (sensitive)develop complete remission of proteinuria within 8 12 weeks of treatment (in adults remission should develop within 16 weeks)2. Steroid depende

33、ntdevelop relapse during tapering of steroids or within 2 weeks after cessation of therapy3. Steroid resistant fail to respond to steroid treatment at allDefinitionsSteroid Dependence- Two consecutive relapses occurring during corticosteroid treatment or within 14 days of its cessationSteroid Resist

34、ance- Failure to achieve response in spite of 4 weeks of prednisone 60 mg/m2*dayClinical course of MCD in children1.Remission - 90%a. no relapses - 20%b. infrequent relapses - 40%c. frequent relapses and steroid dependent - 30%2. Resistance to steroids - 10%a. response to alternative treatment- 8% b

35、. refractory to any kind of treatment - 2%In adults, initial response rate is lower, relapses and steroid dependence are less frequentTherapy of MCD in children current recommendations1.Initially course of prednisone 60 mg/m2 for 4-6 weeks with 40 mg/m2 every alternate day for another 4-6 weeks2.Rel

36、apses treated in a similar way, but tapering of prednisone starts when urine becomes protein free3.Frequent relapsers and steroid dependent patients treated either by cyclophosphamide 2 mg/kg/day for 8 weeks or by cyclosporine 5 mg/kg/day for 6-12 months4. Treatment of steroid resistant patients is

37、usually unsatisfactoryTherapy of MCD modifications in adults1.Initially course of prednisone 1mg/kg for 8-16 weeks or for one week after remission is achieved, then several weeks (one month) 1 mg/kg on alternate days, thereafter corticosteroids are slowly tapered during several months 2.Relapses tre

38、ated in a similar way3.Frequent relapsers and steroid dependent patients treated either by CPH 2 mg/kg/day for 8 weeks or by CyA 5 mg/kg/day for 6-12 months4. Treatment of steroid resistant patients is usually unsatisfactoryMild FSGSModerate FSGSTip lesion in early FSGSCollapsing FSGSEtiology of FSG

39、S1.Primary FSGSa. glomerular tip lesionb. collapsing glomerulopathy2. Secondary FSGSa. healing focal lesions (FSGN)b. hyperfiltration in residual nephrons- agenesis of one kidney- vesicoureteral reflux- morbid obesityc. damage to epithelial cells- HIV nephropathy- heroin nephropathyClassification of

40、 FSGS1.Genetic FSGSa. podocinb. -actinin2. Immunologicmechanisms not yet identified3. Viral FSGSa. HIVb. hepatitis C4. Toxic FSGSa. heroinb. pamidronatePathogenesis of primary FSGS1.Late onset congenital FSGSdeficiency of podocyte proteins (podocin, -actinin, CD2AP, et al.) 2.Circulating permeabilit

41、y factorsa. imunoglobulin, or Ig-like moleculeb. protein of MW about 30-50 kDa c. factor inhibiting inducible NO synthase in mesangial cells (hemopexin)3. Deficient inhibitors of permeability factors lost in urineapolipoproteins of HDL complex (e.g. apo J, apo E2 and apo E4)Permeability factors in M

42、CD and FSGSGlassock, J Am Soc Nephrol, 2003, 14: 541 - 5431.Permeability factors in MCD and FSGS may be different2.Among PF described in MCD (e.g. heparanase, VEGF) hemopexin is best characterized (Cheung et al., Kidney Int, 2000, 57: 1512 1520)3.In FSGS 30-50 kD weakly anionic, heat labile, proteas

43、e-sensitive factor inhibiting NO production in mesangial cells was identified with the Palb assay (Sharma et al., Kidney Int, 2000, 58: 1073 - 1079).4.This PF is increased also in pts with genetic mutation of podocin (Carraro et al., JASN, 2002, 13: 1946 - 1952).Serial estimates of permeability fact

44、ors in FSGSCattran et al., J Am Soc Nephrol, 2003, 14: 448 - 4531.Serum permeability activity assessed in 27 pts with FSGS treated either by cyclosporine or placebo before and after 26 weeks of treatment (Cattran et al., Kidney Int., 1999, 56: 2220 2226)2.Proteinuria decreased in cyclosporine treate

45、d patients from 7.2 to 3.1 g/day and did not change in pts on placebo (from 9.5 to 7.4 g/day)3.Serum permeability activity changed neither in cyclosporine (from 0.31 to 0.46), nor in placebo (from 0.41 to 0.36) treated pts4.Antiproteinuric effect of cyclosporine seemed to be independent on changes o

46、f PalbFocal segmental glomerulosclerosis1.Asymptomatic proteinuria or full blown nephrotic syndrome2.Hypertension, microscopic hematuria and decreased renal function common3.Slowly progressive disease 50% 10-year renal survival4. Sclerosis of segments of glomerular tuftCumulative renal survival in F

47、SGS Korbet, NDT, 1999, 14 (Suppl. 3): 68 - 73Cumulative renal survival in FSGS Korbet, NDT, 1999, 14 (Suppl. 3): 68 - 73 Treatment of primary FSGS current recommendations1.Response to corticosteroids may increase from only 10-30% up to 60% with longer treatment with higher dose (60 mg/m2 at least 3

48、months, patients should be considered steroid resistant after 6 months)2.Cyclosporine may reduce proteinuria and lower the risk of progression to ESRD even in steroid resistant patients, treatment should be long (at least 6 months), relapses after cyclosporine withdrawal common3.Cytotoxics remain on

49、ly second-line therapy, the evidence for their effect in steroid resistant patients is not conclusiveMembranous nephropathyMembranous nephropathyMembranous nephropathyMembranous nephropathy1.Secondary- infections (hepatitis B, syphilis, malaria)- drugs(organic gold, penicillamine, NSAID)- neoplasms(

50、carcinomas, e.g. Colon, lung, or stomach, and lymphomas)- systemic lupus erythematosus2. IdiopathicIdiopathic membranous nephropathy1.Membranous nephropathy represents 15-25% of adult nephrotic syndrome2.Nephrotic proteinuria is present in about 80% of patients, remaining patients have asymptomatic

51、proteinuria3.Microscopic hematuria is common4.Hypertension and chronic renal failure are uncommon at presentation, but may develop during follow-up5.Histology subepithelial deposits along often thickened GBMNatural course of idiopathic membranous nephropathy1.Spontaneous remission may develop in abo

52、ut one third of patients2.Nephrotic syndrome persists in another third of patients3.Only 20-30% of patients progress to ESRD during 20-30 years of follow upCyclosporine in membranous nephropathyGuasch et al., Am. J. Kidney Dis., 1992, 20: 472 - 481 14 previously untreated patients with MN were treat

53、ed for 12 weeks with CyA and compared with similarly treated pts with MCD proteinuria decreased below 3.5 g/day in 10 out of 14 pts, fractional clearance of albumin decreased by 59%, fractional clearance of IgG by 73% (in MCD albuminuria decreased by 99%) glomerular filtration rate did not change si

54、gnificantly antiproteinuric effect of CyA in MN is less pronounced than in MCD, but cannot be explained only by hemodynamic changesCyclosporine in steroid-resistant MNCattran et al., Kidney Int., 2001, 59: 1484 - 1490 complete or partial remission developed after 26 weeks in 75% of pts treated by Cy

55、A vs. in 22% of pts treated by placebo during 52 weeks relapse developed in 43% of pts treated by CyA and 40% of pts treated by placebo at the end of follow-up in remission was 39% of pts treated by CyA and 13% of pts treated by placeboTreatment of idiopathic membranous nephropathy current recommend

56、ations 1.Corticosteroids should not be used a sole therapy2.Azathioprine is not effective in reversing or stabilizing progressive renal insufficiency3.Cytotoxics induce prolonged remission of nephrotic syndrome and improve renal survival, their use should be reserved for patients with progressive di

57、sease4.Cyclosporine seems to be effective in progressive renal insufficiencyGuidelines for the treatment of IMN Cattran, Kidney Int., 2001, 59: 1983 - 1994Proliferative glomerulonephritides1.Microscopic hematuria and/or bouts of macroscopic hematuria - mesangial proliferation (IgA nephropathy) 2. Mi

58、croscopic hematuria with proteinuria - mesangial proliferation with peripheral expansion of mesangium (membranoproliferative GN)Ultrastructural changes in glomerular capillaries in mesangio- and membranoproliferative GNIgA nephropathy mesangioproliferative glomerulonephritisIgA nephropathyPathogenes

59、is of IgA nephropathyGmez-Guerrero et al., Kidney Int, 2002, 62: 715 - 7171.Aberrantly O-glycosylated IgA1 with exposed GalNAc may be recognized as antigens by IgG2.Circulating immune complexes of IgA1 and IgG and/or IgA1 and soluble Fc RI (CD89) were identified in pts with IgA nephropathy3.Except f

60、rom ASGP-R, CD89, Fc / R and TfR mesangial cells may express further, not yet described IgA receptors4.Patients with IgA nephropathy have increased expression of megsin (serine protease inhibitor serpin). Overexpression of megsin leads to progressive mesangial matrix expansionIgA nephropathy1.Common