Nephrotic SyndromePurpose and Requirement oMaster the definition of NSoMaster the clinical types of NSoMaster the treatment principles of NS Nephrotic SyndromeoDefinition:n1. Massive proteinurian2. Hypoalbuminemia With or withoutn3. Hypercholesterolemian4. Edema-50 mg / kg / d or 3.5 gm/day)-+,2周周3次次-尿蛋白尿蛋白/肌酐肌酐2.05.72mmol/L Nephrotic Syndromen1. Primaryn2. Secondaryn3. Congenital Nephrotic Syndromen90 % - primary glomerular abnormality (Idiopathic)nRest part of renal involvement in different diseases Nephrotic SyndromeoIncidence of Idiopathic Formn2 to 7 / 100,000 nMale-to-female 2-4:1 in children 1:1 in adolescents and adultsnMCNS : 2 and 5 years of agen92% remissionnAdolescents : aggressiveClassificationo1.ClinicalnSimplenNephriticoHematuriaoHypertensionoAzotemiaoComplement decreaseClassificationo2. Pathological1.MinimalChangeNS2.MesangialProliferationGlomeruerNephritis3.FocalSegmentalGlomerulosclerosis4.Membranousnephropathy(1%)5.MembranousProliferativeGlomeruerNephritis Pathological Types MCNS Nephrotic Syndromeo76% MCNSo No glomerular abnormalities in light microscopeo Effacement of foot processes in electron microscopyo Minimal deposition of mesangial matrixo Serum complement (C3) normalo Circulating immune complexes absent Pathogenesis of NS In MCNS : T Cell dysfunction leads to alteration of cytokines which causes a loss of negatively charged glycoproteins within capillary wall In FSGS: A plasma factor produced by lymphocytes responsible Mutations in podocyte proteins (podocin, a actinin 4) In Steroid resistant NS: Mutations in NPHS 1(nephrin) & 2(podocin) and WT1 or ACTN4 (-actinin) genes Increased permeability of glomerular capillary wall, which leads to massive proteinuria and hypoalbuminemia.Massive Proteinuria - Mechanism Loss of negatively charged sialoproteins and glycoproteins Increased size of pores Loss of foot processes Increased excretion or decreased absorption Protein Losso Albumino Thyroxine-binding proteino Cholecalciferol-binding proteino Transferrino Metal binding proteinso Anti Thrombin III, Proteins C & S Hypoproteinemia - MechanismoIncreased lossoInadequate synthesisoIncreased catabolism Hyperlipidemia - MechanismoLoss of lipoprotein lipase enzyme in urineo synthesis of lipoproteins Oedema - MechanismoMassive proteinuria hypoalbuminemia - plasma oncotic pressure - transudation of fluid from intravascular compartment to interstitial space.oPrimary retention of water and sodium Clinical Featureso Age of onset : 85 - 90% 3.5 gm or 50 mg/kgoUrine protein / creatinine ratio : 2.0oUrine protein selectivityoHyaline castsoMicroscopic hematuria in 20% Hyaline Cast in urine BloodoS.CholesteroloS.AlbuminoS. A/G ratio - reversaloS.CreatinineoBl. UreaoS . C3 and C4 levelsDiagnosiso4 characteristicsRenal Biopsy - indicationsoAge of onset 15 yrs.oFeatures suggestive of disease other than MCNS macroscopic hematuria, HTN, Low C 3, renal failureoSteroid non-responderoFrequent relapsesoSteroid dependencyoSecondary steroid resistanceoPrior cytotoxic therapyoDDn Protein losing enteropathyn Hepatic failuren CHFn Acute or chronic GNn PEM Secondary Nephrotic Syndromeo Vasculitides SLE, Sarcoidosis, HSP, Rheumatoid arthritis, Wageners granulomatosis Goofpasteur syndromeo Metabolic Amyloidosis, Myxoedema, DMo Infections Syphilis, Shunt nephritis, Hepatitis B and C, CMV, HIVo Parasitic Plasmodium malariae, Toxoplasma, Syphiliso Drugs Gold, Mercury, Penicillamine, Lithium, Ethosuccimide, NSAIDSo Malignancies Lymphomas, Carcinomaso Congenital / Inherited Alport syndrome, Nail - Patella syndromeMINIMALCHANGENEPHROTICSYNDROMEFOCALSEGMENTALGLOMERULOSCLEROSISMEMBRANOUSNEPHROPATHYMEMBRANOPROLIFERATIVEGLOMERULONEPHRITISTypeITypeIIFREQUENCYChildren75%10% 30% calories from fatsnAvoid saturated fatsnReduction in salt intake (1-2 g/d) for those with persistent edemanCalcium and Vitamin D supplementationoEnsure physical activity? Diuretic Therapy Treatment of Initial EpisodeoSteroid TherapynPrednisaloneo2mg / kg / d in 2-3 divided doses for 6 weeks the most dosage 80 mg / doAfter 4-8 wks, reduce dose 1.5 mg/kg/d as a single dose every other day morningoslowly tapering in 2-3 months/ 6 mons/ 9oThen discontinuenShorter duration of initial therapy is not recommended. ISKDC TerminologyoRemissionn Urine albumin : Nil or Traces or 3 relapses in 1 year ISKDC TerminologyoSteroid DependentnRelapse while on alternate day steroid therapy or within 14 days of stopping prednisone therapy, and response to more steroid .oSteroid Resistant:ndo not respond to the initial treatment with prednisone within 4 weeks of therapy 2mg/kg/d (FSGS= 80%, MPG = 20%, MCNS rarely) Treatment of RelapseoRelapse often precipitated by URInPrednisoneo2 mg/kg/d until the urine is protein free for 3 consecutive daysoThereafter 1.5 mg/kg/d on alternate days for 4 wks and stop. (Total duration of therapy = 5 to 6 wks.)Management ofFrequent Relapses, Steroid Dependence,Steroid resistanceo1. Long term alternate day prednisone:n 0.5 to 0.25 mg/kg/d as a single morning dose on alternate days for 9 18 monthsManagement ofFrequent Relapses, Steroid Dependence,Steroid resistanceo2. Levamisolen2.0 to 2.5 mg/kg on alternate days for 1-2 yearsnCo-treatment with prednisone at 1.5 mg/kg/d on alt. days for 2-4 weeks gradually reducing the dose to 0.15 0.25 mg/kg for 6 or more months.nAdverse Effects :oLeucopeniao Flu like symptomsoLiver toxicityo ConvulsionsoSkin rashesManagement ofFrequent Relapses, Steroid Dependence,Steroid resistanceo3. Cytotoxic drugs nCyclophosphamide (following remission)o2-3 mg/kg/d for 8-12 week regimen with along with prednisone (1-1.5 mg/kg/d)nAdverse Effects :oLeucopeniaoHemorrhagic cystitisoAlopeciaoGonadal toxicityoNausea & vomitingManagement ofFrequent Relapses, Steroid Dependence,Steroid resistanceoCyclosporine :n3-6 mg/kg/d in q 12 h doses (100-150 mg/m2/d) combined initially with alt. day prednisone for 12-24 monthsnAdverse Effects :oNephrotoxicityoHypertensionoHypercholesterolemiaoElevated transaminasesManagement ofFrequent Relapses, Steroid Dependence,Steroid resistanceoMicophenlate mofetil (MMF) :n800 - 1200 mg / m2 along with tapering dose of prednisone for 12-24 monthsnAdverse Effects :oGI discomfortoDiarrhoeaoLeucopeniaManagement of NSOther Drugs UsedoACE Inhibitors : to prevent proteinurianAct by alteration of capillary permeability and reduction in glomerular hydrostatic pressureoHMG coenzyme-A reductase inhibitorsnto reduce s. cholesteroloAlbumin Infusion : controversialnHypotensionnSevere OliguriaoHeperinManagement of NSImmunizationoPatients on prednisone therapy are considered immunosuppressed avoid live attenuated vaccinesoAll patients should receive pneumococcal vaccineInitial Steroid ResistanceoMesangial proliferative GNoFocal segmental glomerulosclerosis (FSGS)oMembrano-proliferaive GN (MPGN)nType 1 : with intact BMnType 2: (30%) with dense deposits, -persistent low serum C3, abundant immunonglobulin & C3 depositsoMembranous nephropathyInitial Steroid ResistanceoTrial of pulse methylprednisone (15-30 mg/kg)oCTX oCyclosporin AoMycophenolate mofetilOutcome of MCNSoMost stop getting relapses by 11 to 15 yrsoFull recoveryoVery small proportion develop late steroid resistanceoMortality : 1-4 % sec. to infections & hypovolemiaPrognosisoRelated to pathological type and response to steroid 90%MCNS 30% non-relapse 20%FSGS responsive 40% 1-2 relapse 50%MsPGN 30% frequent relapse 小结小结肾肾小小球球 大大量量血血浆浆 原发性原发性 滤滤过过膜膜 白白蛋蛋白白 临临床床综综合合征征 继继发性发性通通透透性性 从从尿尿中中丢丢失失 先天性先天性 大量蛋白尿大量蛋白尿大量蛋白尿大量蛋白尿 尿蛋白尿蛋白尿蛋白尿蛋白3+-4+3+-4+3+-4+3+-4+、50mg/kg/d50mg/kg/d、3.5g/d3.5g/d低白蛋白血症低白蛋白血症低白蛋白血症低白蛋白血症 30g/L30g/L高胆固醇血症高胆固醇血症高胆固醇血症高胆固醇血症 5.7mmol/L5.7mmol/L不同程度水肿不同程度水肿不同程度水肿不同程度水肿治疗治疗NephroticFeaturesNephriticFeaturesMinimalchangeglomerulopathy+Membranousglomerulopathy+Focalsegmentalglomerulosclerosis+Fibrillaryglomerulonephritis+Mesangioproliferativeglomerulopathy*+Membranoproliferativeglomerulonephritis+Proliferativeglomerulonephritis*+Acutediffuseproliferativeglomerulonephritis+Crescenticglomerulonephritis+TABLE30-1-ManifestationsofNephroticandNephriticFeaturesbyGlomerularDiseaseHematuriaProteinuria1Creatinine1.5HematuriaProteinuria13Creatinine3Noabnormality30%2%0%Thinbasementnephropathy26%4%0%IgAnephropathy28%24%8%Glomerulonephritiswithoutcrescents*9%26%23%Glomerulonephritiswithcrescents*2%24%44%Otherrenaldisease5%20%25%Total100%n=43100%n=123100%n=255TABLE30-2-RenalDiseaseinPatientswithHematuriaUndergoingRenalBiopsyoBrenner and Rectors The Kidney oNelson Textbook of Pediatrics - 18EdoOxford Textbook of Clinical Nephrology(3rd Ed)ReferenceIgA肾病紫癜性肾炎思考题o肾脏病理与临床的关系