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Clinical CaseClinical CaseMs. SM a 44 yr old female was referred to MAW on the Ms. SM a 44 yr old female was referred to MAW on the 16/11/2007 with the following symptoms:16/11/2007 with the following symptoms:
Major joints pain Major joints pain –– 11/12 (no morning stiffness)11/12 (no morning stiffness)Joints affected: elbows, hands, knees and anklesJoints affected: elbows, hands, knees and anklesJoint pain was on and offJoint pain was on and off
DyspneaDyspnea grade IIgrade II--III III –– 3/123/12Assoc: Assoc: orthopneaorthopnea (2 pillows), dry cough sometimes, (2 pillows), dry cough sometimes, palpitationspalpitations
Pedal edema (pitting edema) Pedal edema (pitting edema) –– 2/122/12Rash on the face Rash on the face -- ? Duration? Duration
Systems Review: nothing of noteSystems Review: nothing of note
Clinical CaseClinical CasePMH : hypertension ?durationPMH : hypertension ?duration
previous admission in NDH for arthritis in Jan previous admission in NDH for arthritis in Jan 20072007
Medications: Medications: HdrochlorothiazideHdrochlorothiazide, , EnalaprilEnalapril, , BrufenBrufenCompliance: goodCompliance: goodNo No hxhx. of herbal ingestion. of herbal ingestion
Allergies : dry meat, dairy productsAllergies : dry meat, dairy productsdrugs nonedrugs none
Family Family HxHx: hypertension: hypertension--mothermotherdeaths: fatherdeaths: father--asthma; brotherasthma; brother-- cause cause unknown unknown
Clinical ExaminationClinical ExaminationVitals: P 90, BP 161/83, t 37 C, wt 75.1 kgVitals: P 90, BP 161/83, t 37 C, wt 75.1 kgGeneral: pallor, cervical LN and pitting bipedal edemaGeneral: pallor, cervical LN and pitting bipedal edemaSkin: Skin: malarmalar rash, no oral ulcers. Later developed rash, no oral ulcers. Later developed
uraemicuraemic frostfrostNails: Nails: leukonychialeukonychiaRaynaudRaynaud’’ss phenomenon phenomenon
RepiratoryRepiratory SystSyst..Not distressed, trachea centralNot distressed, trachea centralHarsh breath sounds , left mid and lower zone Harsh breath sounds , left mid and lower zone
crepitationscrepitations
Clinical CaseClinical CaseCardiovascular Cardiovascular SystSyst..JVP: not raisedJVP: not raisedApex beat: displaced to the 5Apex beat: displaced to the 5thth ICS MCLICS MCLPositive signs for pulmonary hypertensionPositive signs for pulmonary hypertensionEnd systolic murmur 2/6 at apex radiating to the End systolic murmur 2/6 at apex radiating to the axillaaxillaNo friction rubNo friction rubAbdomenAbdomenSoft, nonSoft, non--pulsatilepulsatile 2cm 2cm hepatomegalyhepatomegaly, no , no splenomegalysplenomegalyMusculoMusculo--SkeletalSkeletal: No stigmata for RA: No stigmata for RA
SummarySummary
Ms SM a 44 yr, a known hypertensive Ms SM a 44 yr, a known hypertensive patient on treatment who presents with patient on treatment who presents with signs and symptoms that suggest signs and symptoms that suggest connective tissue diseaseconnective tissue disease
InvestigationsInvestigations1.1. Urine Urine dipstixdipstix: blood 4+, : blood 4+, protprot 3+3+2.2. UrinalysisUrinalysisleuco+leuco+--10, RBC+10, RBC+--200, epithelial cells+200, epithelial cells+--7, 7, casts:granularcasts:granular
and hyaline, Alb 3+and hyaline, Alb 3+24hr urine: 24hr urine: CreatCreat. . ClCl 13ml/min, TP 3.74g/24hrs13ml/min, TP 3.74g/24hrs3. Radiological Studies3. Radiological Studiesu/su/s heart and abdomen:heart and abdomen:Chest: bilateral effusions notedChest: bilateral effusions notedHeart: small pericardial effusion at RV level 9mmHeart: small pericardial effusion at RV level 9mmKidneys: L 12.3cm, R 12cm. Both kidneys are Kidneys: L 12.3cm, R 12cm. Both kidneys are
echogenicechogenic, no , no hydronephrosishydronephrosis..
InvestigationsInvestigationsAscites: minimal free fluid inf. To liver and surrounding Ascites: minimal free fluid inf. To liver and surrounding
spleenspleenPelvis: uterus normal, R ovary Pelvis: uterus normal, R ovary echogenicechogenic and enlarged and enlarged
measuring 4.2x3.7cmmeasuring 4.2x3.7cm4. HRCT4. HRCTBilateral large pleural effusionsBilateral large pleural effusionsPulmonary Pulmonary conusconus and arteries are prominent in keepingand arteries are prominent in keepingwith PHT. with PHT. FibroticFibrotic changes noted in both apiceschanges noted in both apicesBronchiectasisBronchiectasis with bronchial wall thickening noted with bronchial wall thickening noted
bilaterallybilaterally
InvestigationsInvestigations
Coarse linear bands seen in middles zones bilaterallyCoarse linear bands seen in middles zones bilaterallyAreas of honeycombing and ground glass appearances Areas of honeycombing and ground glass appearances
are seen in the right upper zoneare seen in the right upper zoneConclusion: Bilateral pleural effusions with features Conclusion: Bilateral pleural effusions with features
suggestive of pulmonary SLE suggestive of pulmonary SLE 5.5. Doppler EchocardiogramDoppler EchocardiogramEF 54%, FS 24%, PAS 50mmHgEF 54%, FS 24%, PAS 50mmHgMild MR, TRMild MR, TRDilated RV, LADilated RV, LAPericardium minimal effusionPericardium minimal effusion
InvestigationsInvestigations6.6. Blood Work UpBlood Work UpFBC: FBC: WccWcc 4.7 4.7 HbHb 7.7 MCV 74.9 PLT 2997.7 MCV 74.9 PLT 299U/E: Na 141, K 5.83, U/E: Na 141, K 5.83, ClCl 120, CO2 14.4, U 22.2 120, CO2 14.4, U 22.2
CreCre 307 Ca 1.86, PO4 2.46, Mg 1.24 307 Ca 1.86, PO4 2.46, Mg 1.24 CK 143, TG 4.08, Chol 6.12, HDLD 0.59CK 143, TG 4.08, Chol 6.12, HDLD 0.59CRP 23.3CRP 23.3PT 10.1, APTT 28.0, INR 0.97PT 10.1, APTT 28.0, INR 0.97HIV and HIV and HepHep B negativeB negativeANF + , ANF + , titretitre 1:32001:3200ANF HEP 2 cells + (homogeneous pattern noted)ANF HEP 2 cells + (homogeneous pattern noted)
InvestigationsInvestigations
ASOT + , ASOT + , titretitre to followto followDNA antibody +DNA antibody +ENA ELISA screen +ENA ELISA screen +SSaSSa (Ro) antibody +(Ro) antibody +Complement: C3: 0.53, C4: 0.08Complement: C3: 0.53, C4: 0.087. R Kidney Biopsy7. R Kidney Biopsy::IMMUNOFLUORESCENCEIMMUNOFLUORESCENCEDemonstrates IgA,G,M,C1,C3, and C4 deposition.Demonstrates IgA,G,M,C1,C3, and C4 deposition.Histology report pendingHistology report pending
Lupus NephritisLupus Nephritis
IntroductionIntroductionLupus Nephritis (LN) most serious manifestations of Lupus Nephritis (LN) most serious manifestations of SLESLEArises within 5 yrs of diagnosisArises within 5 yrs of diagnosisHistological evidence of LN is present in most patient Histological evidence of LN is present in most patient with SLE, even without clinical manifestations of renal with SLE, even without clinical manifestations of renal diseasediseaseAggressive Aggressive immunosuppresiveimmunosuppresive and supportiveand supportivetherapy use, the renal involvement and patient survival therapy use, the renal involvement and patient survival rate improvesrate improves
EpidemiologyEpidemiologyUSAUSAPrevalence (SLEPrevalence (SLE):):--1 case/ 2000 in general population (underestimation due 1 case/ 2000 in general population (underestimation due
to diagnosis difficulty)to diagnosis difficulty)1 case/ 5001 case/ 500--1000 population (researchers) 1000 population (researchers) Renal involvement: 30Renal involvement: 30--90% published studies90% published studiesTrue prevalence of clinical L.N. approximately being True prevalence of clinical L.N. approximately being
more common in certain ethnic groups and in childrenmore common in certain ethnic groups and in children
EpidemiologyEpidemiologyIn 1950In 1950’’s : 5 yr survival rate of patient with LN s : 5 yr survival rate of patient with LN
approximately 0%approximately 0%Recently: 5 and 10 yr survival rate 85% and 73% Recently: 5 and 10 yr survival rate 85% and 73%
respectively (addition of respectively (addition of immunosupppressiveimmunosupppressive) ) Morbidity due to: disease and its complicationsMorbidity due to: disease and its complications
cormorbiditiescormorbiditiesthromboticthrombotic eventseventstreatment related complicationstreatment related complications
EpidemiologyEpidemiologyRaceRaceSLE more common in Black and Hispanic people than in SLE more common in Black and Hispanic people than in
White peopleWhite peopleBlack and Asian people: higher prevalence of more Black and Asian people: higher prevalence of more
severe LN than other ethnic groupssevere LN than other ethnic groupsSexSexLN more common in females (SLE prevalence higher in LN more common in females (SLE prevalence higher in
females with F:M of 9:1)females with F:M of 9:1)Males with SLE have increased prevalence of clinical Males with SLE have increased prevalence of clinical
renal disease with worse prognosisrenal disease with worse prognosis
EpidemiologyEpidemiologyAgeAgeSLE : more common in 3SLE : more common in 3rdrd decade of life of femaledecade of life of femaleLN : 20LN : 20--40 yrs40 yrs
PathophysiologyPathophysiologyAUTOIMMUNITY major role in pathogenesis of LNAUTOIMMUNITY major role in pathogenesis of LNImmunologic mechanism:Immunologic mechanism:Production of Production of autoantibodiesautoantibodies against nuclear elementsagainst nuclear elementsAutoantibodiesAutoantibodies form pathogenic immune complexesform pathogenic immune complexesDeposition of immune complexes in kidneys then Deposition of immune complexes in kidneys then
initiating an initiating an inflammmatoryinflammmatory response by activating the response by activating the complement cascade complement cascade
Recruitment of inflammatory cells (seen in biopsy Recruitment of inflammatory cells (seen in biopsy specimens)specimens)
EtiologyEtiologyGENETIC FACTORSGENETIC FACTORSGenetic predisposition plays major role in development Genetic predisposition plays major role in development
of SLE and LN of SLE and LN Multiple genes (many not identified) mediate genetic Multiple genes (many not identified) mediate genetic
predispositionpredispositionSLE more common in 1SLE more common in 1stst degree relatives of patients degree relatives of patients
with SLE (familial prevalence of 10with SLE (familial prevalence of 10--12%)12%)Concordance rate higher (24Concordance rate higher (24--58%) monozygotic twins 58%) monozygotic twins
than in than in dizygoticdizygotic twin (2twin (2--5%)5%)Concordance rate of monozygotic twins not 100% Concordance rate of monozygotic twins not 100%
suggesting that suggesting that enviromentalenviromental factors trigger the factors trigger the development of the clinical diseasedevelopment of the clinical disease
EtiologyEtiologyHLA Class II GenesHLA Class II GenesHLAHLA--DR2 and HLADR2 and HLA--DR3 associated with SLEDR3 associated with SLEHLAHLA--DR4 associated lower prevalence of SLE and DR4 associated lower prevalence of SLE and
appears to be protectiveappears to be protectiveComplement genesComplement genesC1Q, C1R, and C1S deficiencies associated SLE, LN, C1Q, C1R, and C1S deficiencies associated SLE, LN,
and production of antiand production of anti--double stranded DNA (antidouble stranded DNA (anti--dsDNAdsDNA))
C2 and C4 deficiencies associated with SLE or lupus C2 and C4 deficiencies associated with SLE or lupus like syndromelike syndrome
C4A and C4B (possibly) gene deletions associated with C4A and C4B (possibly) gene deletions associated with SLESLE
EtiologyEtiologyFcyRFcyR genesgenesMediate binding of immunoglobulin G (Mediate binding of immunoglobulin G (IgGIgG) and ) and IgGIgG
containing immune complexes to cells containing immune complexes to cells egeg. . macrophages, mononuclear phagocytesmacrophages, mononuclear phagocytes
FcyRIIaFcyRIIa binds to IgG2 and is encoded by 2 binds to IgG2 and is encoded by 2 codominantcodominantalleles (H131alleles (H131--high affinity and R131 low affinity)high affinity and R131 low affinity)
Low affinity phenotype (homozygous for R131 allele, Low affinity phenotype (homozygous for R131 allele, 131 R/R) associated with LN in Black population131 R/R) associated with LN in Black population
FcyRIIIaFcyRIIIa binds to binds to IgGIgG, and is encoded by 2 concomitant , and is encoded by 2 concomitant alleles which are V158 (high affinity) and F158 (low alleles which are V158 (high affinity) and F158 (low affinity)affinity)
Low affinity phenotype ( homozygous for F158 allele, Low affinity phenotype ( homozygous for F158 allele, 158 F/F) associated with SLE158 F/F) associated with SLE
EtiologyEtiologyCytokines GenesCytokines GenesCertain polymorphism IL 10 gene (high producers) and Certain polymorphism IL 10 gene (high producers) and
possibly IL 1 RN and TNFA genes (low producers) possibly IL 1 RN and TNFA genes (low producers) associated SLEassociated SLE
MannoseMannose--binding binding LectinLectin GenesGenesPolymorphism associated with increased risk of SLEPolymorphism associated with increased risk of SLE
Apoptosis GenesApoptosis GenesDefects incl. CD95 (Defects incl. CD95 (FasFas) and CD178 () and CD178 (FasLFasL) associated ) associated
with lupus like syndromes in mice and rarely, SLE in with lupus like syndromes in mice and rarely, SLE in humans humans
EtiologyEtiologyImmunological FactorsImmunological FactorsInitial autoantibody response is directed against the Initial autoantibody response is directed against the
nucleosomenucleosome arising from apoptotic cellsarising from apoptotic cellsPoor clearance mechanisms for cellular debris is seen in Poor clearance mechanisms for cellular debris is seen in
SLE patientsSLE patientsNuclear debris (apoptotic cells) induce Nuclear debris (apoptotic cells) induce antiferonantiferon--alpha alpha
by plasma by plasma cytoidcytoid dendriticdendritic cells (potent inducer of cells (potent inducer of immune system and autoimmunity)immune system and autoimmunity)
AutoreactiveAutoreactive B lymphocytes (normally inactive) become B lymphocytes (normally inactive) become active in SLE because of malfunction in normal active in SLE because of malfunction in normal homeostatic homeostatic mechanimsmechanims losing tolerance then leading losing tolerance then leading to production of auto antibodiesto production of auto antibodies
EtiologyEtiologyOther autoOther auto--antibodies (antibodies (egeg. Anti. Anti--dsDNAdsDNA antibodies) antibodies)
develop through a process of develop through a process of epitopeepitope spreadingspreadingThese autoThese auto--antibodies develop over time in an orderly antibodies develop over time in an orderly
fashion (months to years) prior to the onset of SLEfashion (months to years) prior to the onset of SLELN associated with production of LN associated with production of nephritogenicnephritogenic autoauto--
antibodies with the characteristics as follows:antibodies with the characteristics as follows:--Antigen specificity directed against Antigen specificity directed against nucleosomenucleosome or or
dsDNAdsDNA. Some anti. Some anti--dsDNAdsDNA antibodies cross react with antibodies cross react with glomerularglomerular basement membrane (BM)basement membrane (BM)
--Higher affinity Higher affinity autoantibodiesautoantibodies may form intravascular may form intravascular immune complexes, which are deposited in immune complexes, which are deposited in glomeruliglomeruli
EtiologyEtiologyCationic Cationic autoantibodiesautoantibodies have higher affinity for anionic have higher affinity for anionic
glomerularglomerular BMBMAutoantibodiesAutoantibodies of certain of certain isotypesisotypes (IgG1 and IgG3) (IgG1 and IgG3)
readily activate complementreadily activate complementIntravascular immune complexes are deposited in Intravascular immune complexes are deposited in
glomeruliglomeruliAlternatively Alternatively autoantibodiesautoantibodies may bind to antigen already may bind to antigen already
located in the located in the glomerularglomerular BM forming immune BM forming immune complexes in situcomplexes in situ
Immune complexes promote inflammatory response Immune complexes promote inflammatory response through activation of complement and attracting through activation of complement and attracting inflammatory cells inflammatory cells egeg. lymphocytes, macrophages and . lymphocytes, macrophages and neutrophilsneutrophils
EtiologyEtiologyHistologicHistologic type of LN depends on:type of LN depends on:Antigen specificityAntigen specificityProperties of Properties of autoantibodiesautoantibodiesType of inflammatory response ( which is determined by Type of inflammatory response ( which is determined by
other host factors)other host factors)
ClinicalClinicalGENERALGENERALAsymptomaticAsymptomaticDuring follow upDuring follow up-- increased serum increased serum creatininecreatinine levels, low levels, low
Albumin or urinary protein/sediment suggest active LNAlbumin or urinary protein/sediment suggest active LNSLE SymptomsSLE SymptomsFatigue, fever rash arthritis Fatigue, fever rash arthritis serositisserositis, or CNS disease, or CNS diseaseActive NephritisActive NephritisPeripheral edema secondary to hypertension or Peripheral edema secondary to hypertension or
hypoalbuminemiahypoalbuminemiaOther symptoms related to hypertension: headache, Other symptoms related to hypertension: headache,
dizziness, visual disturbance and signs of cardiac dizziness, visual disturbance and signs of cardiac decompensationdecompensation
ClinicalClinicalIsolated Isolated NephroticNephrotic SyndromeSyndromePeripheral edema, ascites, and pleural and pericardial Peripheral edema, ascites, and pleural and pericardial
effusions without hypertensioneffusions without hypertensionDIFFERENTIAL DIAGNOSISDIFFERENTIAL DIAGNOSIS
GolmerulonephritisGolmerulonephritis (GN), Chronic(GN), ChronicGN, Diffuse GN, Diffuse ProliferativeProliferativeGN, MembranousGN, MembranousGN, GN, RappidlyRappidly ProgressiveProgressivePolyarteritisPolyarteritis NodosaNodosaWegenerWegener GranulomatosisGranulomatosis
ClinicalClinical
MesangialMesangial glomerulosclerosisglomerulosclerosisGlomerulosclerosisGlomerulosclerosis
Laboratory StudiesLaboratory Studies1.1. Renal FunctionRenal FunctionBlood urea nitrogenBlood urea nitrogenSerum Serum creatininecreatinine levellevelUrinalysis (check protein, Urinalysis (check protein, RBCsRBCs, and cellular casts), and cellular casts)Spot urine test (Spot urine test (creatininecreatinine and protein conc.)and protein conc.)24 hr urine test24 hr urine test-- creatininecreatinine clearance and protein clearance and protein
excretionexcretion
Laboratory studiesLaboratory studies
2. Tests of SLE Disease Activity2. Tests of SLE Disease ActivityAntiAnti--dsDNAdsDNAComplement (C3,C4, and CH50)Complement (C3,C4, and CH50)ESR, CESR, C--reactive Protein (raisedreactive Protein (raised--arthritis or infection)arthritis or infection)Active NephritisActive Nephritis-- elevated ESR and antielevated ESR and anti--dsDNAdsDNA, low C3 , low C3
and C4 levels , 30% decrease in and C4 levels , 30% decrease in creatininecreatinine clcl., ., proteinuriaproteinuria>1000 mg/d>1000 mg/d
AntiAnti--nucleosomenucleosome antibodies:antibodies:Appear early in response to SLEAppear early in response to SLEHigh sensitivity and specificityHigh sensitivity and specificityTiters correlate with disease activityTiters correlate with disease activity
Laboratory StudiesLaboratory StudiesAntiAnti--C1q antibodies associated with LNC1q antibodies associated with LNHigher titers correlate with active renal diseaseHigher titers correlate with active renal disease
3. RENAL BIOPSY3. RENAL BIOPSYIndicated in SLE patients with clinical or lab. Evidence of Indicated in SLE patients with clinical or lab. Evidence of
active nephritis (esp. 1active nephritis (esp. 1stst episode)episode)Useful to:Useful to:Establish histological patternEstablish histological patternStaging of the disease (activity and Staging of the disease (activity and chronicitychronicity))Determine prognosis and treatmentDetermine prognosis and treatment
Laboratory StudiesLaboratory StudiesSampling error occur. Therefore biopsy results to be Sampling error occur. Therefore biopsy results to be
evaluated for consistency with clinical and laboratory evaluated for consistency with clinical and laboratory presentation of the patientpresentation of the patient
Pathologist experience to read biopsy specimens vary Pathologist experience to read biopsy specimens vary considerablyconsiderably
Consistent readers in larger medical centers with Consistent readers in larger medical centers with substantial populations of SLE patientssubstantial populations of SLE patients
StagingStaging
Pathologic ClassificationPathologic ClassificationCLASS 1CLASS 1-- MINIMAL MESANGIAL LUPUS NEPHRITISMINIMAL MESANGIAL LUPUS NEPHRITISLM: normalLM: normalIMFIMF--EM: EM: mesangialmesangial immune depositsimmune depositsClinical: mild Clinical: mild proteinuriaproteinuria
CLASS IICLASS II-- MESANGIAL PROLIFERATIVE LNMESANGIAL PROLIFERATIVE LNLM: LM: mesangialmesangial hypercellularityhypercellularity or or mesangialmesangial matrix matrix
expansion with expansion with mesangialmesangial immune depositsimmune depositsIMIM--EM: EM: mesangialmesangial immune deposits, few immune immune deposits, few immune
deposits in deposits in subepithelialsubepithelial or or subendothelialsubendothelial deposits deposits possiblepossible
StagingStagingClinical: mild renal diseaseClinical: mild renal disease-- asymptomatic asymptomatic hematuriahematuria or or
proteinuriaproteinuria not warranting treatmentnot warranting treatment
CLASS IIICLASS III-- FOCAL LUPUS NEPHRITISFOCAL LUPUS NEPHRITISTypes of lesions: (A) Active, (A/C) active and chronic Types of lesions: (A) Active, (A/C) active and chronic
(focal (focal proliferativeproliferative and and sclerosingsclerosing LN), (C) chronic LN), (C) chronic inactive (focal inactive (focal sclerosingsclerosing LN)LN)
LM: active or inactive focal, segmental, or global LM: active or inactive focal, segmental, or global glomerulonephritisglomerulonephritis involving <50% of all involving <50% of all glomeruliglomeruli
IMIM--EM: EM: subendothelialsubendothelial and and mesangialmesangial immune depositsimmune depositsClinical: active SLE and mild to moderate renal disease Clinical: active SLE and mild to moderate renal disease
with with hematuriahematuria and moderate and moderate proteinuriaproteinuria,,
StagingStaging
Significant minority show worsening renal function and Significant minority show worsening renal function and may progress to class IV LNmay progress to class IV LN
CLASS IVCLASS IV-- DIFFUSE LUPUS NEPHRITISDIFFUSE LUPUS NEPHRITISTypes: Types: IVIV--S (A) active lesions: diffuse segmental S (A) active lesions: diffuse segmental proliferativeproliferativeIVIV--G (A) active lesions: diffuse global G (A) active lesions: diffuse global proliferativeproliferative LNLNIVIV--S (A/C) active and chronic: diffuse global S (A/C) active and chronic: diffuse global proliferativeproliferative
and and sclerosingsclerosing LNLNIVIV--S (C) Chronic inactive lesions: diffuse segmental S (C) Chronic inactive lesions: diffuse segmental
sclerosingsclerosing LNLNIVIV--G (C) Chronic inactive lesions: diffuse global G (C) Chronic inactive lesions: diffuse global
sclerosingsclerosing LN LN
StagingStagingLM: LM: active or inactive diffuse, segmental or global active or inactive diffuse, segmental or global
glomerulonephritisglomerulonephritis involving >= 50% of involving >= 50% of glomeruliglomeruli, , Subdivided into:Subdivided into:Diffuse segmental (class IVDiffuse segmental (class IV--S) when >= 50% of involved S) when >= 50% of involved
glomeruliglomeruli have segmental lesions (involving less than have segmental lesions (involving less than half of half of glomerularglomerular tuft)tuft)
Diffuse global (class IVDiffuse global (class IV--G) when >= 50% of involved G) when >= 50% of involved glomeruliglomeruli have global lesionshave global lesions
IMIM--EM: EM: subendothelialsubendothelial immune depositsimmune depositsClinical: hypertension, edema, active urinary sediment, Clinical: hypertension, edema, active urinary sediment,
worsening renal function and worsening renal function and nephroticnephrotic range range proteinuriaproteinuria. Often with . Often with extrarenalextrarenal features of SLEfeatures of SLE
StagingStaging
CLASS V: MEMBRANOUS LUPUS NEPHRITISCLASS V: MEMBRANOUS LUPUS NEPHRITISLM:LM:Diffuse thickening of Diffuse thickening of glomerularglomerular basement membrane basement membrane
without inflammatory infiltratewithout inflammatory infiltratePossibly Possibly subepithelialsubepithelial deposits and surrounding deposits and surrounding
basement membrane spikes on special stains (incl. basement membrane spikes on special stains (incl. silver and silver and trichrometrichrome))
May occur in combination with class II or IVMay occur in combination with class II or IVMay show advanced sclerosisMay show advanced sclerosis
StagingStaging
IMIM--EM: EM: SubepithelialSubepithelial and and intramembranousintramembranous immune depositsimmune depositsSubendothelialSubendothelial deposits present only when associated deposits present only when associated
proliferativeproliferative component is presentcomponent is presentClinical:Clinical:Clinical and laboratory features of Clinical and laboratory features of nephroticnephrotic syndrome, syndrome,
usually without manifestations of active SLEusually without manifestations of active SLECLASS VI: ADVANCED SCLEROSIS LNCLASS VI: ADVANCED SCLEROSIS LNLMLMAdvanced Advanced glomerularglomerular sclerosis involving >90% of sclerosis involving >90% of
glomeruliglomeruli
StagingStaging
All morphological manifestations of irreversible renal All morphological manifestations of irreversible renal injuryinjury
ClinicalClinicalSignificant renal insufficiency or,Significant renal insufficiency or,End stage renal disease which is unlikely to respond to End stage renal disease which is unlikely to respond to
medical therapymedical therapy
Active and Chronic Active and Chronic GlomerularGlomerularLesionsLesions
Activity IndexActivity IndexEndocapillaryEndocapillary hypercellularityhypercellularity with or without leukocyte with or without leukocyte infiltration, luminal reductioninfiltration, luminal reductionKaryorrhexisKaryorrhexisFibrinoidFibrinoid necrosisnecrosisRupture of Rupture of glomerularglomerular basement membranebasement membraneCellular or Cellular or fibrocellularfibrocellular crescentscrescentsSubendothelialSubendothelial deposits on light microscopydeposits on light microscopyIntraluminalIntraluminal immune aggregatesimmune aggregates
Active and Chronic Active and Chronic GlomerularGlomerularLesionsLesions
ChronicityChronicity IndexIndexGlomerularGlomerular sclerosis, segmental, globalsclerosis, segmental, globalFibrous adhesionsFibrous adhesionsFibrous crescentsFibrous crescentsAbove indices prognostic tool and general guide to Above indices prognostic tool and general guide to therapytherapySigns of activitySigns of activity-- aggressive medical therapyaggressive medical therapyTherapy may arrest or reverse pathologic changesTherapy may arrest or reverse pathologic changesSigns of Signs of chronicitychronicity-- suggest suggest irreversibiltyirreversibiltyAggressive therapy less likely to affect the outcome Aggressive therapy less likely to affect the outcome
ComplicationsComplications
Disease related complications Disease related complications May secondary to hypertension or May secondary to hypertension or nephroticnephrotic syndromesyndromeInclude:Include:Cardiovascular complications Cardiovascular complications StrokeStrokeHyperlipidemiaHyperlipidemiaHypercoagulabilityHypercoagulability with thrombosiswith thrombosis
ManagementManagement
GOAL GOAL : to normalize renal function or prevent progress : to normalize renal function or prevent progress of renal function lossof renal function lossTreat the reversible histological Treat the reversible histological leasiosleasiosTreat extraTreat extra--renal SLE manifestations and other renal SLE manifestations and other variables affecting the kidneysvariables affecting the kidneys
MedicationMedicationLupus nephritis: corticosteroids, immunosuppressive Lupus nephritis: corticosteroids, immunosuppressive
therapytherapyAntihypertensive: ACEI and other agents (treat Antihypertensive: ACEI and other agents (treat
hypertension aggressively)hypertension aggressively)
MedicationMedicationProteinuriaProteinuria: restrict protein intake if renal function : restrict protein intake if renal function significantly significantly impaired.Useimpaired.Use of of AngioAngio II receptor blockerII receptor blockerRestrict fat intakeRestrict fat intakeUse of lipid lowering therapy (Use of lipid lowering therapy (egeg. . StatinsStatins))Calcium supplementation (also use of Calcium supplementation (also use of biphosphonatebiphosphonate) ) espesp to chronic steroid users to prevent osteoporosisto chronic steroid users to prevent osteoporosis
AnalgesicsAnalgesicsAvoid Avoid NSAIDSNSAIDS (affect renal function especially with (affect renal function especially with
increased levels of increased levels of creatininecreatinine))NonacetylatedNonacetylated salicylatessalicylates can be used for inflammatory can be used for inflammatory
symptomssymptomsRenal transplant for ESRD patientsRenal transplant for ESRD patients
ManagementManagementTHERAPIES FOR TYPES OF LNTHERAPIES FOR TYPES OF LNClass IClass I: Minimal : Minimal mesangialmesangial LN requires no specific LN requires no specific
treatmenttreatmentClass IIClass II: : MesangialMesangial proliferativeproliferative LN may require LN may require txtx if if
proteinuriaproteinuria >1000 mg/d. Prednisone 20>1000 mg/d. Prednisone 20--40mg/d for 140mg/d for 1--3 3 months, with subsequent tapermonths, with subsequent taper
Class III and IVClass III and IV: Focal or diffuse LN: Focal or diffuse LN-- high risk to high risk to progress to ESRD hence requires aggressive therapyprogress to ESRD hence requires aggressive therapyPrednisone 1mg/kg/d at least 4 weeksPrednisone 1mg/kg/d at least 4 weeksTaper dose gradually to Taper dose gradually to maintennancemaintennance dose 5dose 5--10 10 mg/d for approx. 2yrsmg/d for approx. 2yrs
ManagementManagement
Acutely ill patientsAcutely ill patientsMethylprednisoneMethylprednisone iviivi up to 1000mg/d for 3 days (to up to 1000mg/d for 3 days (to
initiate the corticosteroid therapyinitiate the corticosteroid therapyUse immunosuppressive therapy in addition to Use immunosuppressive therapy in addition to
corticosteroids if:corticosteroids if:No response to steroids aloneNo response to steroids aloneUnacceptable toxicity to steroidsUnacceptable toxicity to steroidsWorsening renal functionWorsening renal functionSevere Severe proliferativeproliferative lesions with evidence of sclerosis lesions with evidence of sclerosis on renal biopsy specimenon renal biopsy specimen
ManagementManagement
CyclophosphamideCyclophosphamide and and azathioprineazathioprine effective for effective for proliferativeproliferative lesionslesions
CyclophosphamideCyclophosphamide more effective in preventing more effective in preventing progression to ESRDprogression to ESRD
MycophenolateMycophenolate mofetilmofetil (MMF) shown to be effective (MMF) shown to be effective alone or used after 6 months course of alone or used after 6 months course of iviivi cyclocyclo..
Prior to the use of Prior to the use of CyclophosphamideCyclophosphamide iviiviResuscitate/hydrate the patientResuscitate/hydrate the patientMesnaMesna pre,peri,postpre,peri,post cyclocyclo use to prevent hemorrhagic use to prevent hemorrhagic cystitiscystitisGonadotropinGonadotropin-- releasing hormone analog (releasing hormone analog (leuprolideleuprolideacetate) protects against ovarian failureacetate) protects against ovarian failure
ManagementManagement
CyclophosphamideCyclophosphamide iviivi::Use monthly for 6 months and every 2Use monthly for 6 months and every 2--3 months 3 months
thereafter, depending on the clinical responsethereafter, depending on the clinical responseDuration of therapy 2Duration of therapy 2--2.5 yrs2.5 yrsReduce dose if Reduce dose if creatininecreatinine clearance < 30ml/minclearance < 30ml/minAdjust the dose depending on hematological responseAdjust the dose depending on hematological response
M a n a g e m e n tM a n a g e m e n t
AzathioprineAzathioprine22ndnd line agentline agentDose adjustments depending on Dose adjustments depending on hematologichematologicresponseresponse
MycophenolateMycophenolate mofetilmofetilIndicated in focal or diffuse LNIndicated in focal or diffuse LNAs effective as As effective as iviivi cyclocyclo with less toxicity in patients with less toxicity in patients with stable renal functionwith stable renal function
ManagementManagementClass V: Membranous LNClass V: Membranous LNPrednisone for 1Prednisone for 1--3 months3 monthsTaper dose for 1Taper dose for 1--2 yr (if response occurs)2 yr (if response occurs)ImmunosuppresiveImmunosuppresive agents: used only if renal function agents: used only if renal function
worsens or worsens or proliferativeproliferative component is present on component is present on renal biopsy specimensrenal biopsy specimens
Other drugs used in LNOther drugs used in LN1.1. RituximabRituximab
B lymphocyte depleting therapyB lymphocyte depleting therapyEffective in SLEEffective in SLEAlthough still being investigated as a treatment of Although still being investigated as a treatment of SLE and LNSLE and LN
ManagementManagement2.2. InfliximabInfliximab
TumourTumour necrosis factor (TNF)necrosis factor (TNF)-- alpha antagonistalpha antagonistBeneficial in small series of SLE patients incl. Beneficial in small series of SLE patients incl. several with LNseveral with LN
3.3. AbemitusAbemitusB lymphocyte B lymphocyte tolerogentolerogenNot effective in a large controlled trial in preventing Not effective in a large controlled trial in preventing flares of LN althoughflares of LN althoughIt reduces the levels of antiIt reduces the levels of anti--DNA antibodiesDNA antibodies
ManagementManagementEnd Stage Renal DiseaseEnd Stage Renal Disease
Requiring dialysis and good candidates for kidney Requiring dialysis and good candidates for kidney transplantationtransplantation1.5% of patients on dialysis in USA are ESRD 1.5% of patients on dialysis in USA are ESRD secondary to SLEsecondary to SLESurvival rate of patients on dialysis is fair Survival rate of patients on dialysis is fair (5yr: 60(5yr: 60--70%)70%)HemodialysisHemodialysis is preferred over peritoneal dialysis (PD) is preferred over peritoneal dialysis (PD) because several studies documented higher antibecause several studies documented higher anti--dsDNAdsDNA levels, more thrombocytopenia and higher levels, more thrombocytopenia and higher steroid requirements in patients with SLE and ESRD steroid requirements in patients with SLE and ESRD on PDon PD
ManagementManagementHemodialysisHemodialysis has antihas anti--inflammatory effects with inflammatory effects with
decrease Tdecrease T--helper lymphocyte levelshelper lymphocyte levelsSLE generally quiescent in patients on SLE generally quiescent in patients on hemodialysishemodialysis
although flares incl. rash, arthritis, fever, and although flares incl. rash, arthritis, fever, and leukopenialeukopenia may occur and require specific treatmentmay occur and require specific treatment
ConsultationsConsultationsNephrologistNephrologist
Early referral for patients with SLE and renal disease Early referral for patients with SLE and renal disease (LN revolving from one stage to another)(LN revolving from one stage to another)
Renal biopsyRenal biopsy
ManagementManagementDieticianDietician
Diet alteration according to the presence of Diet alteration according to the presence of hypertension, hypertension, hyperlipidemiahyperlipidemia and renal insufficiency and renal insufficiency
Adverse EffectsAdverse Effects
1.1. PREDNISONEPREDNISONECI: No absoluteCI: No absolute
severe infection (bacterial, viral or fungal)severe infection (bacterial, viral or fungal)peptic ulcer peptic ulcer dxdx, DM, DM
InteractionsInteractionsWater and salt retention worsening hypertensionWater and salt retention worsening hypertension--
increase the requirement of antihypertensive in increase the requirement of antihypertensive in hypertensive patienthypertensive patient
Aggravate hyperglycemiaAggravate hyperglycemia-- increase increase eequirementeequirement for for hypoglycemic drugs hypoglycemic drugs
Adverse EffectsAdverse EffectsIncrease in corticosteroid when used in Increase in corticosteroid when used in conjuctionconjuction with with
drugs that induce hepatic drugs that induce hepatic microsomalmicrosomal enzymes enzymes egeg. . PhenytoinPhenytoin, , carbamezapinecarbamezapine, , rifampicinrifampicin and and phenobarbitalphenobarbital
Adverse EffectsAdverse EffectsWeight gain hypertensionWeight gain hypertensionDyspepsia DMDyspepsia DMPeptic ulcer disease osteoporosisPeptic ulcer disease osteoporosisGrowth retardation glaucomaGrowth retardation glaucomaAvascularAvascular necrosis adrenal crisisnecrosis adrenal crisis
Adverse EffectsAdverse Effects2.2. CYCLOPHOSPHAMIDECYCLOPHOSPHAMIDECI: hypersensitivity, infection, severely depressed bone CI: hypersensitivity, infection, severely depressed bone
marrow function and severe marrow function and severe cytopeniascytopeniasInteractionsInteractions
Phenobarbital therapy high dose (long term)Phenobarbital therapy high dose (long term)--increase metabolism to its active metabolite thereby increase metabolism to its active metabolite thereby increase toxicityincrease toxicityInhibits cholinesterase activity up to 10 days after an Inhibits cholinesterase activity up to 10 days after an iviivi dose dose potentiatepotentiate effects of effects of succinylcholinesuccinylcholine chloridechloride
Adverse EffectsAdverse EffectsADVERSE EFFECTSADVERSE EFFECTSNausea, vomiting alopeciaNausea, vomiting alopeciaLeukopeniaLeukopenia hemmorhagichemmorhagic cystitiscystitisThrombocytopenia infertilityThrombocytopenia infertilityAnemia Anemia teratogenecityteratogenecityInfection risk of malignancyInfection risk of malignancy
Adverse EffectsAdverse EffectsAzathioprineAzathioprineCI: relative CI: relative -- infection, severe infection, severe cytopeniascytopeniasInteractionsInteractionsCoadministrationCoadministration with:with:1.1. AllopurinolAllopurinol –– decrease the dose by 65decrease the dose by 65--75% because 75% because
azathioprineazathioprine is metabolized by is metabolized by xanthinexanthine oxidaseoxidase2.2. ACE inhibitors ACE inhibitors –– anemia or severe anemia or severe leukopenialeukopenia3.3. WarfarinWarfarin –– may reduce the anticoagulant effect of may reduce the anticoagulant effect of
warfarinwarfarin
Adverse EffectsAdverse Effects
ADVERSE EFFECTSADVERSE EFFECTSNausea, vomiting anemiaNausea, vomiting anemiaLeukopeniaLeukopenia infectioninfectionThrombocytopenia abnormal liver functionThrombocytopenia abnormal liver function
Adverse EffectsAdverse EffectsMycophenolateMycophenolate mofetilmofetilCI: hypersensitivity, relative CI: hypersensitivity, relative –– active infection, active infection,
cytopeniascytopeniasInteractionsInteractions1.1. CoadministrationCoadministration with antacids (containing with antacids (containing Mg&AlMg&Al) )
may reduce MMF absorptionmay reduce MMF absorption2.2. Live Live atttenuatedatttenuated vaccines should be avoided during vaccines should be avoided during
therapytherapyAdverse EffectsAdverse EffectsNausea,vomitingNausea,vomiting and other GI symptoms, and other GI symptoms, leukopenialeukopenia,,Anemia, risk of opportunistic infection (most likely viral),Anemia, risk of opportunistic infection (most likely viral),AbnomalAbnomal liver functionsliver functions
ReviewReviewFOLLOW UP VISITSFOLLOW UP VISITS1.1. Schedule close follow after initiation therapy Schedule close follow after initiation therapy
(focal/diffuse/membranous LN)(focal/diffuse/membranous LN)monitoring: therapy responsemonitoring: therapy responsetreatment related toxicitiestreatment related toxicities
2. Monthly visits to the physician recommended in 2. Monthly visits to the physician recommended in patients initiated with high dose corticosteroids, patients initiated with high dose corticosteroids, cyclophosphamidecyclophosphamide, , azathioprineazathioprine or MMFor MMF
3.3. Follow testingFollow testingMonitor SLE disease activityMonitor SLE disease activity-- ESR, antiESR, anti--dsDNAdsDNA, C3 , C3 and C4and C4
ReviewReview
CyclophosphamideCyclophosphamide therapy therapy CBC, urinalysisCBC, urinalysisAzathioprineAzathioprine, MMF, MMFregular regular –– CBCCBCless frequent less frequent –– liver function testliver function test
OTHEROTHERMonthly : renal function, urinalysis, albumin levelsMonthly : renal function, urinalysis, albumin levelsTrimester: spot urine: Trimester: spot urine: creatininecreatinine and protein, and protein, creatininecreatinine
clearance, 24 hr urinary protein excretionclearance, 24 hr urinary protein excretionAs condition stabilizes monitoring may be less frequentAs condition stabilizes monitoring may be less frequent
PrognosisPrognosisPoor Prognostic IndicatorsPoor Prognostic IndicatorsDelay in treatment of more than 5 months from onset of Delay in treatment of more than 5 months from onset of
nephritisnephritisYoung age at onset of nephritisYoung age at onset of nephritisMale sexMale sexBlack racial backgroundBlack racial backgroundHypertensionHypertensionNephroticNephrotic syndromesyndromeElevated Elevated creatininecreatinine level (> 3 mg/level (> 3 mg/dLdL) at presentation) at presentationPersistently elevated antiPersistently elevated anti--dsDNAdsDNA and low C3 and C4 and low C3 and C4
levels levels
PrognosisPrognosisRenal biopsy findings showing diffuse lupus nephritis or Renal biopsy findings showing diffuse lupus nephritis or
high high chronicitychronicity indexindexExcellent PrognosisExcellent PrognosisMinimal Minimal mesangialmesangial LNLN-- typeItypeIMesangialMesangial proliferativeproliferative LN type IILN type IIGood PrognosisGood PrognosisFocal LN type IIIFocal LN type IIIFair prognosisFair prognosisDiffuse LN (class IV) and membranous LN (type V)Diffuse LN (class IV) and membranous LN (type V)-- with with
a significant number of patients developing a significant number of patients developing progressive renal failureprogressive renal failure
PrognosisPrognosisPoor PrognosisPoor Prognosis
Advanced sclerosis LN (class VI) Advanced sclerosis LN (class VI)
Follow UpFollow Up
Patient EducationPatient EducationDisease and its managementDisease and its managementBiopsy: value, risk, diagnosis Biopsy: value, risk, diagnosis dillemadillema if not performed, if not performed, consentconsentTherapyTherapy
Signs of treatment related toxicities Signs of treatment related toxicities egeg. Infection, . Infection, bladder toxicity bladder toxicity –– need immediate evaluation and need immediate evaluation and attentionattention
Follow UPFollow UP
Pregnancy and LNPregnancy and LNAVOID PREGNANCYAVOID PREGNANCY-- aggravates the renal diseaseaggravates the renal diseaseLN patients have 50LN patients have 50--60% chance of renal flare during 60% chance of renal flare during pregnancypregnancyWell controlled SLE patients conceiving after 3Well controlled SLE patients conceiving after 3--6 6 months of remission have 7months of remission have 7--10% chances of renal 10% chances of renal flareflarePregnant patient with LN is prone to ECLAMPSIAPregnant patient with LN is prone to ECLAMPSIASeveral flares during pregnancy may cause ARF, Several flares during pregnancy may cause ARF, maternal and fetal deathmaternal and fetal deathTherefore closely monitor pregnant patients with SLE:Therefore closely monitor pregnant patients with SLE:
Follow UPFollow UPTreat aggressively Treat aggressively exarcebationsexarcebationsCarefully avoid Carefully avoid teratogenicteratogenic drugsdrugs
ReferencesReferencesProvided on requestProvided on request
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