Lupus nephritis post fff

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  • The word lupus, meaning wolf, derives from this characteristic rash that was thought to resemble wolf's markings; erythematosus is derived from the Latin word for redness .
  • Photosensitivity refers to the development of a rash after exposure to UV-B radiation found in sunlight or fluorescent lights [45]. It occurs in 60 to 100 percent of patients with SLE. Some patients are also sensitive to UV-A (as from a photocopier [48]), and may even be sensitive to the visible light spectrum. Glass protects individuals sensitive to UV-B, but only partially protects those sensitive to UV-A. Blonde, blue eyed, fair skinned individuals are much more photosensitive than brunettes or individuals with pigmented skin; the incidence is also greater in those with anti-Ro antibodies [49 ].
  • Neoral, sandimmune prograf

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  • 1. Prof. Abdel-Azim AlhefnyProf. of Internal Medicine, Rheumatology& Clinical ImmunologyDirector of Rheumatology UniteAin Shams University
  • 2.  A multi-system autoimmune connectivetissue disease that occurs most commonly inwomen during their reproductive ageThe most serious life threateningfrequent complication is lupus nephritis.
  • 3. AlopeciaOral ulcers&Urinary abnormalitiesNonerosive>4000>100,000Lymphopenia <1500Systemic LupusErythematosus
  • 4. Sparing the nasolabial foldsMalar rash
  • 5. 1) Malar rash2) Discoid rash3) Photosensitivity(rash after exposure to UV-B radiation found in sunlight orfluorescent lights.It occurs in 60 – 100% of SLE patients)
  • 6. Malar / Butter fly rash Erythema in a malar distribution overthe cheeks and bridge of the nose(DD: sunburn, Chloasma ). The rash may precede or accompanyother manifestations of lupus. The involved skin feels warm andedematous. The rash may last for hours or days, andoften recurs, particularly with sunexposure (UV).Spare the nasolabialfold
  • 7. Discoid rashSub acute Cutaneous Lupus
  • 8. 4) Oral ulcers 5) Arthritis4) Oral ulcers 5) Arthritis (nonerosive)(nonerosive)
  • 9. 6) Serositis: Pleurisy pericarditisCXR : pleurisyCXR : pleurisy
  • 10. 7) Renal:Proteinuria >0.5gm/d,Cellular castsRed cell castsGranular castGlomerulonephritis
  • 11. 8) Neurological:Seizures or psychosis9) Hematological:Hemolytic anemiaLeucopenia < 4000Lymphopenia < 1500Thrombocytopenia < 100 000cerebral vasculitis
  • 12. 10) Immunological:Anti dsDNA abAnti –Sm abaCL ab11) ANA antibodiesANA testANA testAnti dsDNA ab test (IFAnti dsDNA ab test (IF((
  • 13. ACRaCL -Antiboy)1982with a 1997 revision(
  • 14. Other common manifestations notOther common manifestations notin the SLE classification criteriain the SLE classification criteria
  • 15. Localized alopecia Wide spread non scaringSLE- Clinical PresentationSLE- Clinical Presentation
  • 16. SLE- ClinicalSLE- ClinicalPresentationPresentationVasculitisRaynaud’s
  • 17. 18Pulmonary Involvement In SLEPleural diseaseAcute lupus pneumonitisChronic interstitial lung diseasePulmonary hemorrhagePulmonary embolismPulmonary vascular diseaseDiaphragmatic dysfunction
  • 18. 19Cardiac manifestation of SLEPericardium :• Pericarditis with orwithout effusion• Cardiac tamponade(rare)• Constrictive perecarditisMyocardium :• MyocarditisEndocardium :• Libman-SacksendocarditisCoronary artery :• Acceleratedatherosclerosis• Vasculitis
  • 19. Possible causes ofleukopenia in SLEPossible causes ofanemia in SLE Immune destruction Marrow suppression Hypersplenism Drugs Auto-immune hemolyticanemia Anemia of chronicdisease Marrow suppression Blood loss due tothrombocytopenia orNSAID use Hypersplenism Anemia of renal failure
  • 20. 22Serological Tests to Aid Diagnosis of SLESerological Tests to Aid Diagnosis of SLE
  • 21.  SLICC group revised and validated the ACRSLE classification criteria in order to: improve clinical relevance, meet efficient methodology requirements, incorporate new knowledge regarding theimmunology of SLE. The SLICC classification criteria providealternative classification criteria for use inSLE clinical care and research.
  • 22.  The new SLICC classification criteriaperformed well in a large set of patientscenarios rated by experts. According to the SLICC rule for theclassification of SLE, the patient must satisfyat least 4 criteria, including at least: one clinical criterion and one immunologiccriterionOR the patient must have biopsy-proven lupusnephritis in the presence of ANA or anti-dsDNAantibodies. Criteria are cumulative and need not bepresent concurrently.
  • 23. *** Clinical Criteria1.Acute or subacute cutaneous lupus2.Chronic cutaneous lupus3.Oral/Nasal ulcers4.Nonscarring alopecia5.Inflammatory synovitis with physician-observed swelling OR tenderness of > 2joints+ MS > 30min6.Serositis (pleural, pericardial)7.Renal: Urine protein/creatininerepresenting at least 500 mg protein/24hr or RBC casts8.Neurologic: seizures, psychosis,mononeuritis multiplex, myelitis,peripheral or cranial neuropathycerebritis (acute confusional state)1.Hemolytic anemia2. Leukopenia (<4000/mm3 at least once)OR Lymphopenia (<1000/mm3 at leastonce)3.Thrombocytopenia (<100,000/mm3) at*** Immunologic Criteria• ANA above laboratory referencerange• Anti-dsDNA above laboratoryreference• Anti-Sm• Antiphospholipid antibodylupus anticoagulant,false-positive test for syphilis,anticardiolipin– at least 2xnormal or medium-high titer,anti- b2 glycoprotein 1• Low complementlow C3,low C4,low CH50• Direct Coombs test in absence ofhemolytic anemia
  • 24.  Renal involvement is common in SLE. The most frequently observed abnormality inpatients with lupus nephritis is proteinuria. In the US 35% of adults with SLE have clinicalevidence of nephritis at the time of diagnosis, 50–60% will develop nephritis during the first 10years of disease. It is more severe in blacks than it is in whites& in men than in women.
  • 25.  General Patients with active lupus nephritis often have other symptoms ofactive SLE, including fatigue, fever, rash, arthritis, serositis, or CNSdisease. These are more common with Class III & IV L. nephritis. Occasionally, patients are asymptomatic (mesangial); yet, laboratoryabnormalities may be essential for diagnose. Nephritis   Symptoms related to active nephritis may include peripheral edemasecondary to hypertension or hypoalbuminemia. Extreme peripheral edema is more common in persons with diffuseproliferative or membranous lupus nephritis because of heavyproteinuria (NS). Other symptoms directly related to hypertension that are commonlyassociated with class II & IV lupus nephritis include headache,dizziness, visual disturbances, and signs of cardiac decompensation.
  • 26.  Patients with SLE should undergo testing for renalinvolvement at regular intervals. Urinalysis with examination of the urinary sediment (≥5red blood cells /HPF, casts), Urine protein excretion >0.5 g/day or 3+ on dipstick(a spot urine protein/creatinine ratio>0.2), An elevated serum creatinine by at least 0.8 mg/dLfrom pt. base line or to≥1.5 mg/dL Low estimated glomerular filtration rate ( or cr cl.). Elevated anti-DNA titers and Low complement (C3 and C4, anti-C1q antibodies )levels often indicate active lupus, particularly LN. The diagnosis is confirmed by histopathologicfindings on renal biopsy.
  • 27. 1. Increasing serum creatinine without alternativecauses (such as sepsis, hypovolemia, or medication)2. Confirmed proteinuria of >1.0 gm/24 hours (either 24-hour urine specimens or spot protein/creatinine ratios).3. Combinations of the following, assuming the findingsare confirmed in at least 2 tests done within a shortperiod of time and in the absence of alternative causes:a. Proteinuria > 0.5 gm/24 hours plus hematuria,defined as > 5 RBCs/hpfb. Proteinuria > 0.5 gm/24 hours plus cellular castsRBCs: red blood cells; HPF: high-power field. (Hahn et al., 2012)
  • 28. To detect transformation from one histologic pattern to another the emergence of an active sediment, a new elevation in serum creatinine, and/or worsening of proteinuria despite treatmentAmong patients with membranous lupus:- Development of an active sediment since (transformation to aproliferative lesion) which usually requires different treatmentIn patients with treated proliferative LN Nephrotic syndrome may reflect a concurrent membranouslesion Combined active sediment and a rapidly rising serumcreatinine, which might reflect crescentic disease thatrequires more aggressive initial therapy.Suspicion of possible renal disease unrelated to lupus(eg, drug-induced acute interstitial nephritis).
  • 29.  Most patients with LN have an immune complex-mediatedglomerular disease. Based upon clinicopathologic correlations, a LN classificationsystem was developed by a group of renal pathologists,nephrologists, and rheumatologists in 2004. The ISN classification system divides glomerular disordersassociated with SLE into six different classes. Ideally, the biopsy specimen should contain at least 25glomeruli. In addition, a significant percentage of patients evolve fromone class of LN to another, sometimes after therapy orspontaneously However, no serum or urine marker of disease activityprovides the degree of information that is gained byhistopathology. Thus, classification of LN is determined by kidney biopsy.
  • 30.  Minimal mesangial LN is characterized by mesangial immunedeposits identified either by immunofluorescence alone, or byimmunofluorescence and electron microscopy, but withoutlight microscopic abnormalities. Patients have a normal urinalysis and serum creatinine con. Mesangial proliferative LN is characterized by mesangialhypercellularity or mesangial matrix expansion on LM. A few isolated subepithelial or subendothelial deposits may beseen on IF or EM but no subendothelial deposits visible onLM. Patients present with microscopic hematuria and/orproteinuria; hypertension is uncommon, and NS and renalinsufficiency are virtually never seen.
  • 31. Mild global mesangial hypercellularity within capillary loops
  • 32.  Focal proliferative LN is defined by light microscopicappearance of endocapillary or extracapillaryglomerulonephritis that involves <50 % of glomeruli. Lesions are associated with focal subendothelial depositson EM. Class III disease is further categorized depending on thechronicity of the lesions. Hematuria and proteinuria are seen in almost all patients,some have NS, HTN, and/or an elevated plasma creatinine. < 25% of glomeruli are affected and glomeruli show onlysegmental areas of proliferation without necrosis. Progressive renal dysfunction is uncommon.
  • 33. Focal endocapillary proliferative lesions on a background of focalmesangial hypercellularity (arrow(
  • 34.  Diffuse proliferative LN is defined by >50 % ofglomeruli displaying endocapillary with or withoutextracapillary GN. Class IV disease is further categorized into segmental(IV-S) and global (IV-G) depending on whetheraffected glomeruli have segmental or global lesions. Additional subclasses of class IV disease arecategorized depending on the chronicity of thelesions. Hematuria and proteinuria are present in all patientswith active disease, and NS, HTN, and renalinsufficiency are frequently observed.
  • 35. Glomerular capillary walls are segmentally thickened by wire-loopdeposits. An intraluminal deposit forms a hyaline thrombus in onecapillary, and there is global endocapillary proliferation (arrow(
  • 36.  Membranous LN is characterized by diffusethickening of the glomerular capillary wall onLM and by subepithelial immune deposits onIF or EM. Patients primarily present with NS althoughhematuria and HTN may be seen. The plasma creatinine concentration isusually normal or only slightly elevated.
  • 37. There is regular thickening and rigidity of the glomerular capillarywalls accompanied by global mesangial hypercellularity
  • 38.  Advanced sclerosing LN is characterized byglobal sclerosis involving more than 90% ofglomeruli. It represents healing of prior inflammatoryinjury, as well as the advanced stage ofchronic class III, IV, or V lupus nephritis. Patients display slowly progressive renaldysfunction in association with proteinuriaand a relatively bland urine sediment.
  • 39.  Some patients with renal disease have a histologic patternof injury that is indistinguishable from lupus nephritis, buthave no extrarenal symptoms, signs, or serologiessuggestive of SLE. ANA titers were negative or weakly positive, complementlevels were normal, and anti-DNA titers were negative. Other causes of glomerulonephritis were also excluded. All were treated with glucocorticoids with or without MMFand CYC and, despite immunosuppression, 75% of thepatients required renal replacement therapy. Some patients, mostly children with lesions of class Vnephritis, initially presented with a "lupus-like" lesion and,after a variable period, developed clinical and/or serologicalfeatures of SLE. In those cases, the glomerulonephritissimply heralds the arrival of overt SLE
  • 40.  In addition to the glomerulopathies, thereare three other forms of lupus renal disease:tubulointerstitial nephritis;vascular disease; anddrug-induced lupus
  • 41.  In spite definition of LN according to ACR criteria when level ofproteinuria > 0.5 g / 24 hour (Tan et al., 1982) some Authors found that histopathological changes obtained fromrenal biopsy in patients who have low level of proteinuria < 0.5gram / 24 hour witout heamaturia or active urinary sediment withnormal kidney function and consider renal biopsy is mandatory for those types of patients toimprove outcome those groups are referred to silent lupus nephritis(Mahajan et al., 2009) Renal biopsy is required for definitive diagnosis of LN. In theabsence of (ARF), low levels of proteinuria (below 0.5 g/24 h) havebeen recommended by some to justify biopsy (Alhefny et al., 2010) Several studies, report that a delay in renal biopsy (and therapy) isa strong dependent predictor of poor outcome (Fiehn et al., 2003)
  • 42.  Renal biopsy is an important tool in assessingpatients with lupus nephritis and is often requiredfor definitive diagnosis of histopathologicalsubtypes and direction to proper treatment(Christopher et al., 2007). The optimal treatment regimen in lupus nephritisvaries according to WHO class(Hahn et al., 2012)
  • 43.  Steroid & hydroxychloroquine They may not require the use ofimmunosuppressants, but patients shouldbe monitored for deterioration in renalparameters and may require repeatedbiopsy(Gordon et al., 2009).
  • 44.  The Task Force Panel recommendedMMF=mycophenolate mofetyl (2–3 gm total dailyorally) or IV CYC= cyclophosphamide= endoxan,along with glucocorticoids. MMF and CYC are considered equivalent based onrecent high-quality studies, a meta-analysis, andexpert opinion (Touma et al., 2011). Data showed good results for induction therapywith MMF of 3 gm daily for 6 months, followed bymaintenance with lower doses of MMF for 3 years(Dooley et al., 2011).
  • 45.  For those with class III/IV without cellular crescents andfor those with proteinuria and a stable creatinine forwhom a renal biopsy sample cannot be obtained, both2 gm and 3 gm MMF (cellcept 250, 500mg) total dailydoses were acceptable to the Task Force Panel, While a dose of 3 gm daily was favored for those withclass III/IV and crescents and for those with proteinuriaand a recent significant rise in creatinine (Hahn et al.,2012). Some evidence suggests that Mycophenolic acid(myfortic 180, 360mg) is less likely than MMF to causenausea and diarrhea
  • 46. Low-dose “Euro-Lupus” CYC (500 mg IV onceevery 2 weeks for a total of 6 doses), followed bymaintenance therapy with daily oral AZA. or dailyoral MMF .High-dose CYC (500–1,000 mg/m2 IV once amonth for 6 doses), followed by maintenancetreatment with MMF or AZA(Houssiau et al., 2010) .
  • 47.  CYC was given monthly for 6 doses, thenquarterly for an additional 2 years, wasmore effective in preventing renal flarethan the shorter 6 month regimen. However, the more current 3 to 6monthregimens followed by AZA or MMFmaintenance are showing good long-term results & less gonadal failure(Dooley et al., 2011).
  • 48.  500–1,000 mg methylprednisolone (soluMedrol) dailyfor 3 doses in combination with immunosuppressivetherapy, followed by daily oral glucocorticoids (0.5–1mg/kg/ day), then taper to the minimal amountnecessary to control disease (Hahn et al., 2012). An extended follow up study has suggested benefit ofthe combination of monthly IV methylprednisoloneand IV CYC over IV CYC alone (Illei et al., 2001). AZA treatment to induce improvement was lesseffective than CYC combined with standardglucocorticoid doses in one study (Houssiau et al.,2010).
  • 49.  A recent study showed that after 8 weeks of inductiontreatment with either CYC or MMF, patients with LNwho showed ≥25% reduction in proteinuria and/ornormalization of C3 and/or C4 serum levels were likelyto show good clinical renal responses (Dall’Era et al.,2011). Similarly, after 6 months of treatment, a decrease inserum creatinine and in proteinuria to 1 gm/d predictsa good long-term outcome (Mersereau and Dooley,2010). Approximately 50% of SLE patients with serious LNshowed definite improvement in renal parametersafter 6 months of treatment with either MMF or CYCand the proportion of responders increased to 65–80%between 1-2yrs of treatment (Houssiau et al., 2010).
  • 50.  Along with IV pulses of high-dose glucocorticoid andinitiation of oral glucocorticoids at the higher-range dosage,1 mg/kg/day orally. Experts favored high-dose IV CYC for treatment of LN withcellular crescents (Hahn et al., 2012). In general, the presence of crescents indicates a poorerprognosis, even with appropriate treatment (Yu et al.,2009). MMF (1 gm twice daily) is at least as effective as high dosesof CYC in crescentic class IV LN (Tang et al., 2008)
  • 51.  Patients with pure class V LN and with Nephroticrange proteinuria be started on prednisone (0.5mg/kg/day) plus MMF 2–3 gm total daily dose. for 6months resulted in improvement similar to that withIV CYC (0.5–1.0 mg/kg IV monthly 6 doses) plusprednisone,(Radhakrishnan et al., 2010).
  • 52.  Patients who improved after 6 months of eitherhigh-dose CYC or MMF were randomized to bemaintained on either AZA 2 mg/kg/day or MMF 2gm total daily dose. Prednisone up to 10 mg daily was permitted. Over 3 years of follow-up, MMF was statisticallybetter than AZA (regarding incidence of death,ESRD, doubling of serum creatinine, and renalflare). (Dooley et al., 2011). Severe adverse events occurred in significantlymore patients receiving AZA than receiving MMF.
  • 53.  In patients who fail to respond after 6 months of treatmentwith glucocorticoids plus MMF or CYC, the Task Force Panelrecommends a switch of the immunosuppressive agent fromeither CYC to MMF, or from MMF to CYC, with these changesaccompanied by IV pulses of glucocorticoid 1gram for 3days (Hahn et al., 2012) . In some cases rituximab can be used in patients whosenephritis fails to improve or worsens after 6 months of oneinduction therapy, or after the patient has failed both CYCand MMF treatments (Terrier et al., 2011). The Task Force Panel did not reach consensus regarding theuse of calcineurin inhibitors (Cyclosporin A=sandimmune,Tacrolimus=prograf) in this setting; however, there isevidence for their efficacy as an induction agent and inrefractory disease (Ogawa et al., 2007).
  • 54.  In a recent prospective trial, tacrolimus was equivalent to high-dose IV CYC in inducing complete and partial remissions of LNover a 6-month period (Chen et al., 2011). In another 4 year long prospective trial cyclosporine was similarto AZA in preventing renal flares in patients receivingmaintenance therapy (Moroni et al., 2006). Combinations of MMF and calcineurin inhibitors and ofrituximab and MMF are being studied and might be consideredfor those who have failed the recommended induction therapies(Bao, 2008). If nephritis is worsening in patients treated for 3 months withglucocorticoids plus CYC or MMF, the Task Force Panelrecommended that the clinician can choose any of thealternative treatments discussed (Hahn et al., 2012).
  • 55.  Several types of vascular involvement can occur in renal tissue of SLE,including vasculitis, fibrinoid necrosis, thrombotic microangiopathy, andrenal vein thrombosis (Hahn et al., 2012). In general, vasculitis is treated similarly to LN discussed above. Vasculopathy is highly associated with hypertension; it is not clearwhich comes first, SLE or hypertension. Thrombotic microangiopathy can be associated with a thromboticthrombocytopenia– like picture. The Task Force Panel recommended that thrombotic microangiopathybe treated primarily with plasma exchange therapy (level C evidence)(Kaplan and George, 2011).
  • 56.  Class VI disease has a uniformly poorprognosis for renal survival, reflectingchronic damage; immunosuppressive treatment is notrecommended. Instead, therapies aiming to optimize bloodpressure control and stabilize protienuriawith the use of antihypertensives, ACE-I andARB are used to optimize renal survival(Mangrum and Bakris, 2004).
  • 57.  Approximately 20 % - 30% of patients with LN progressto ESRD over a 10 year follow-up period. Up to 3% of cases of ESRD requiring dialysis ortransplantation, active lupus early in the dialysisperiod may require treatment with CS and/or otherimmuno-suppressive medication. Although controversial, it has been recommendedthat patients with SLE should wait 6 to 12 monthswhile on dialysis prior to transplantation. Recurrence of active lupus nephritis in the transplantoccurs in 10 % to 30% of patients (West et al., 2007).
  • 58.  MMF was preferable to CYC for patients who express a majorconcern with fertility preservation, since high-dose CYC cancause permanent infertility in both women and men (Toumaet al., 2011). 6 months of high-dose IV CYC was associated withapproximately 17% sustained infertility in young women, andhigher rates in older women compared to 64% of thosetreated with the additional quarterly doses (Hahn et al.,2012). the physician should be sure that a patient is not pregnantbefore prescribing MMF or MPA, and the medications shouldbe stopped for at least 6 weeks before pregnancy isattempted (Hahn et al., 2012).
  • 59.  In patients with prior LN but no current evidence ofsystemic or renal disease activity, no nephritismedications are necessary. Patients with mild systemic activity may be treatedwith HCQ; this probably reduces activity of SLEduring pregnancy (Clowse et al., 2007). If clinically active nephritis is present, or there issubstantial extrarenal disease activity, the clinicianmay prescribe glucocorticoids at doses necessary tocontrol disease activity, and if necessary AZA canbe added (Gordon, 2004)
  • 60.  High-dose glucocorticoid therapy in patients withSLE is associated with a high risk of maternalcomplications such as hypertension and DM(Gordon, 2004). MMF, CYC, and methotrexate should be avoidedbecause they are teratogenic in humans though AZAis listed as pregnancy category D, cross sectionalstudies have shown that the risk of fetalabnormalities is low (Gordon, 2004). The dose of AZA should not exceed 2 mg/kg in apregnant woman. For patients with a persistently active nephritiswith documented or suspected class III or IV withcrescents, consideration of delivery is urgent (Hahnet al., 2012).
  • 61.  Rarely indicated nowadays because ofadvances in patients monitoring andavailability of effective treatment, but canbe one of optional lines of therapy whenthere is:-sever lupus flare with major organ involvementnot responding to aggressive management,sever uncontrolled hypertension andvasculitis affecting major organs (Samadirad etal., 2012).
  • 62. Timing Suggested Lab. Tests CommentsPreconceptioncounselingand/or firstprenatal visitUrine analysisDetermination of proteinuriaCBCSerum creatinineAntiphospholipid antibodiesAnti-Ro and anti-La ABAnti-ds DNAComplement studiesLiver function testsObtain protein/creatinineratio, better:24-hour urine proteinIf positive, conduct weeklyfetal HR assessments from16-24w of gestation andevery other week there afteruntil 32 weekEvery month Urine analysisDetermination of proteinuriaSerum creatinineIf these test results areabnormal, obtain lupusserologies and complementstudies; consider a renalbiopsy before 32 weeksgestationEvery trimester CBCAnti-ds DNA - ABComplement studiesLiver functions (forLaboratory testing of LN patients during pregnancy
  • 63. Pre-EclampsiaHELLPSyndromeActive LupusNephritisTiming in pregnancy After 20 wkof gestationAfter 20 wk ofgestationAll gestational agesComplement (C3, C4) N N Typically decreasedThrombocytopenia Absent present PresentNeutropenia Absent Absent PresentActive urine sediment Absent Absent PresentOther organ involvement Absent Absent PresentAnti-ds DNA Absent Absent PresentANA antibodies Absent Absent PresentAnti-C1q antibodies Absent Absent PresentAbnormal liver function Absent present May be highSerum uric acid Increased Increased (may be elevatedwith reduced GFR)Hypertension(BP >140/90 mmHg)present In 10–15% VariableElevation in creatinine(>1.2 mg/dl)TypicallyabsentMay occur in upto 10%Commonly presentDifferentiation of Pre-eclampsia, HELLP syndrome &Active LN
  • 64.  During the 1950s, the 5-year survival rate among patients with lupusnephritis was close to 0%. Recently, with the addition of immunosuppressive agents the 5- and10-year survival rates are as high as 85% and 73%, respectively. Morbidity is related to the renal disease itself, as well as to treatment-related complications and co-morbidities, including CVD andthrombotic events. Progressive renal failure leads to anemia, uremia, and electrolyte andacid-based abnormalities. Hypertension may lead to an increased risk of CAD and stroke. Nephrotic syndrome may lead to edema, ascites, and hyperlipidemia,which add to the risk of CAD and the potential for thrombosis. Therapy with corticosteroids, cyclophosphamide, and otherimmunosuppressive agents leads to increased risk of infection. Long-term corticosteroid therapy may lead to osteoporosis, avascularnecrosis, DM, and HTN, …….. Cyclophosphamide therapy may cause cytopenias, hemorrhagiccystitis, infertility, and an increased risk of malignancy.Mortality/MorbidityMortality/Morbidity
  • 65. Class III/IV induction therapy
  • 66. Treatment of class V without proliferative changesand with nephrotic range proteinuria (>3gm/ day(.
  • 67. Treatment of SLE patientswho are pregnant.
  • 68. currently recommended therapeuticregimens for the different classes of LN(Dolff et al., 2011)
  • 69.  Anti-DNA immune complex formation  The pattern of glomerular injury seen in SLE is primarilyrelated to the site of formation of the immune deposits Deposits in the mesangium and subendothelial spaceare proximal to the glomerular basement membrane(GBM) and communicate with the vascular space. As a result, activation of complement with thegeneration of the chemoattractants C3a and C5a resultsin the influx of neutrophils and mononuclear cells. These changes manifest histologically by a mesangial orfocal or diffuse proliferative glomerulonephritis, and Clinically by an active urine sediment (red cells, whitecells, and cellular and granular casts), proteinuria, andoften an acute decline in renal function.
  • 70.  Although deposits in the subepithelial spacecan also activate complement, there is noinflux of inflammatory cells, since thechemoattractants are separated from thecirculation by the GBM. Thus, injury is limited to the glomerularepithelial cells and the primary clinicalmanifestation is proteinuria, which is oftenin the nephrotic range. Histologically, these patients most commonlyhave membranous nephropathy.
  • 71. Pathogenesis of lupus nephritisAdapted from (Davidson & Aranow, Lupus nephritis, 2009)
  • 72.  A kidney biopsy should be performed in most patients with SLEwho develop evidence for renal involvement in order toestablish the diagnosis and, determine the class of LN. Determining the class of lupus nephritis is important because: Treatment is guided by the histologic subtype (ie,WHO class, thedegree of activity and chronicity, and by complicating lesions suchas interstitial nephritis and thrombotic microangiopathy). The clinical presentation may not accurately reflect the severity ofthe histologic findings. As an example, proliferative lupus may be present even if thepatient has minimal proteinuria and a normal serum creatinine. However, patients with proteinuria <500 mg/day and abland urine sediment do not need to undergo a kidney biopsy;unlikely to have a class of nephritis that warrantsimmunosuppressive therapy.
  • 73.  Although subendothelial deposits can beseen by IF or EM alone, the presence ofsuch deposits as detected by LM warrants acombined diagnosis of class III/IV and Vdisease.
  • 74. Class IClass IIClass IIIIII (A(:III(A/C(:III (C(:Class IV)IV-S) LN)IV-G) LNIV (A(:IV (A/C(:IV (C(:Class VMinimal mesangial LNMesangial proliferative LNFocal proliferative LN (<50% of glomeruli(active lesionsactive and chronic lesionschronic lesionsDiffuse proliferative LN (>50% glomeruli(Diffuse segmentalGlobal LNactive lesionsactive and chronic lesionschronic lesionsMembranous LN†Advanced sclerosing LN (90% globally sclerosedglomeruli without residual activity(
  • 75.  There is significant renal involvement (Class III, IV, orV LN) in SLE patients with < 0.5 g proteinuria with orwithout hematuria. These findings suggest that biopsy be stronglyconsidered in this patient population. (LisaChristopher Stine et al., 2007). Others have recommended biopsy only in patientswith higher levels of proteinuria (> 1000 mg/24 h) andabnormal urine sediment (Salach and Cash,2007). However, several case series have suggested thatsignificant kidney damage may occur in the setting ofactive proliferative LN without clinical signs of renalinvolvement prevent end stage renal failure (Leeheyet al., 2006)
  • 76.  Because early intervention is crucial to prevent pooroutcomes, it is imperative that kidney biopsies beperformed so that diagnoses can be made andappropriate treatment initiated (Esdaile et al., 2010) Among the biopsy findings felt to be prognostic insome studies are the presence of crescentic andsegmental lesions, global proliferative lesions (eitherdiffuse or focal), interstitial fibrosis, and high activityand chronicity indices (Kashgarian, 2002). Several studies, report that a delay in renal biopsy(and therapy) is a strong dependent predictor of pooroutcome (Fiehn et al., 2003)
  • 77.  Patients receiving low-dose CYC, regardlessof initial response, were randomized formaintenance therapy with either AZA, with agoal of 2 mg/kg/day, or MMF, with a goal of2 gm/day. Over a period of 4 years there were nostatistically significant differences in anyoutcome measures, including death, renalflares, end-stage renal disease, or doublingof serum creatinine (Houssiau et al., 2010).
  • 78. ,,,,,,