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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