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![GENETICFACTORS
Genetic predisposition plays an important role in thedevelopment
of both SLEand lupus nephritis. Multiple genes, many of which are
not yet identified, mediate this genetic predisposition [Human
leukocyte antigen (HLA)classII genes, Complement genes, FcγR
genesand others]](https://image.slidesharecdn.com/lupusnephritis-190810152541/75/Lupus-nephritis-9-2048.jpg)
![LABORATORYTESTS
• Blood urea nitrogen (BUN)
• Serum creatinine
• Urine R/M/E (to check for protein, red blood cells [RBCs],
and cellular casts)
• Aspot urine test for creatinine and proteinconcentration
(normal creatinine excretion is 1000 mg/24 h/1.75 m 2;
normal protein excretion is 150-200 mg/24 h/1.75 m 2;
normal urinary protein-to-creatinine ratio is<0.2)
• A24-hour urine test for creatinine clearance andprotein
excretion](https://image.slidesharecdn.com/lupusnephritis-190810152541/75/Lupus-nephritis-18-2048.jpg)
![• ANA[for diagnosis SLE]
• Antibodies to double-stranded DNA(dsDNA),↑
• Complement (C3,C4, and CH50), ↓
• Erythrocyte sedimentation rate (ESR), ↑
• C-reactive protein (CRP)levels. ↔
• Anti-C1q antibodies ↑ [less sensitive thenAnti
dsDNA,but more specific]
LABORATORYTESTS](https://image.slidesharecdn.com/lupusnephritis-190810152541/75/Lupus-nephritis-19-2048.jpg)
![ACRCRITERIA
ACRcriteria
Persistent proteinuria >0.5
gmper dayor greaterthan
3+by dipstick, and/or
Cellular castsincluding red
blood cells [RBCs],
hemoglobin, granular,
tubular, or mixed
Review of the
ACRcriteria
Spot urine
protein/creatinine ratio of
>0.5
Active urinary sediment(>5
RBCs/HPF,>5WBCs/HPFin
the absence of infection,or
cellular castslimited to RBC
or WBCcasts](https://image.slidesharecdn.com/lupusnephritis-190810152541/75/Lupus-nephritis-22-2048.jpg)
![ADJUNCTIVETREATMENTS
Drugs Cause
Hydroxychloroquine
[Max 6–6.5 mg/kg bodyweight]
All SLEpatients with; unless there isa
contraindication:
• Lower rates of Flare
• Reducedrenal damage
• Lessclottingevents
ACEi/ARBs Patients with proteinuria >0.5gm/day
• Reducesproteinuria by 30%,and
• Significantly delays doubling of serum
creatinine
• Delaysprogression to ESRD
Antihypertensive Targetof ≤130/80mmHg
• Significant delay in progressionof
renal disease
Statin therapy Patients with LDL>100mg/dl
• AsGFR<60ml/min/1.73m2& SLEitself
accelerated atherosclerosis
Calcium supplementation Prevent osteoporosis if the patientis on
long-term corticosteroidtherapy](https://image.slidesharecdn.com/lupusnephritis-190810152541/75/Lupus-nephritis-28-2048.jpg)
![REGIMENSFORINITIALTHERAPYIN CLASSIII/CLASS
IVLN[INTERNATIONALSOCIETYOFNEPHROLOGY-KIDNEYDISEASEIMPROVING GLOBAL
OUTCOME]](https://image.slidesharecdn.com/lupusnephritis-190810152541/75/Lupus-nephritis-36-2048.jpg)
![DEFINITIONSOFRESPONSETOTHERAPY
• Complete response: Return of SCrto previous baseline, plusa
decline in the uPCRto <500 mg/g (<50mg/mmol).
• Partial response: Stabilization (±25%),or improvement of SCr,
but not to normal, plus a≥50%decrease in uPCR.Ifthere was
nephrotic-range proteinuria (uPCR≥3000mg/g [≥300
mg/mmol]), improvement requires a≥50%reduction inuPCR,
and auPCR<3000 mg/g [<300mg/mmol].
• Deterioration:There is no definition of deterioration inLNto
define treatment failure. Asustained 25%increase in SCris
widely used but hasnot beenvalidated.](https://image.slidesharecdn.com/lupusnephritis-190810152541/75/Lupus-nephritis-41-2048.jpg)
![• If pregnant patients are receiving corticosteroids or
azathioprine, we suggestthat these drugs not be
tapered during pregnancy or for at least 3 monthsafter
delivery.
• Contraindicated: High-dose glucocorticoid [hypertension
and diabetes mellitus]. MMF, CYC,and methotrexate
should be avoided becausethey are teratogenic.
• Class III or IV with crescents: consideration ofdelivery
after28 weeks fora viable fetus.
• Administration of low-dose aspirin during pregnancyto
decrease the risk of fetalloss.
SYSTEMICLUPUSANDPREGNANCY](https://image.slidesharecdn.com/lupusnephritis-190810152541/75/Lupus-nephritis-62-2048.jpg)
More Related Content
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More from Nilesh Jadhav
Lupus nephritis
- 1.
- 2. In 1941, Klemperer,Pollack and Baehr first described systemic lupus erythematosus (SLE) asone of the Connective TissueDisease. 19th- century • The term “lupus erythematosus” was introduced to describeskin lesions almost 100years later • the disease is systemicand spares no organ
- 3. SYSTEMIC LUPUSERYTHEMATOSUS Systemic lupuserythematosus is an autoimmune diseasein which organs and cells undergo damage initially mediatedby tissue binding autoantibodies andimmune complexes.
- 4. LUPUSNEPHRITIS • Lupusnephritis ishistologically evident in most patients with SLE. • One of the most serious manifestations of SLE. • Usually arises within 5 yearsof diagnosis.
- 5. PATHOPHYSIOLOGY Autoimmunity plays amajorrole in the pathogenesis of lupusnephritis. Immunologic mechanisms Production of autoantibodies Againstnuclear elements
- 6. Thecharacteristics of thenephritogenicautoantibodies associated with lupus nephritis are asfollows: iii. i. Antigen specificity directed against nucleosome or double- stranded DNA(dsDNA) - Someanti-dsDNAantibodies cross- react with the glomerularbasement membrane. ii. Higher-affinity autoantibodies may form intravascular immune complexes, which are deposited inglomeruli. Cationic autoantibodies have ahigher affinity for theanionic glomerular basement membrane. iv. Autoantibodies of certain isotypes (immunoglobulin IgG1and IgG3) readily activate complement.
- 7. Autoantibodies Form pathogenicimmune complexesintravascularly Immune complexes depositedin glomeruli Bind to antigens already located in theglomerular basement membrane Immune complexes in situ Activating complement and attracting inflammatory cells,including lymphocytes, macrophages,andneutrophils Promote an inflammatory response Thehistologic type of lupus nephritis that developsdepends on numerous factors, including the antigen specificity and other properties of the autoantibodies and the type of inflammatory response that is determined by other hostfactors.
- 8. ETIOLOGY There are multiplesusceptibility factors, which result in abnormal immune responses, whichvary among different patients. Thesefactors include: • Genetic factors • Immunologic factors • Environmental factors
- 9. GENETICFACTORS Genetic predisposition playsan important role in thedevelopment of both SLEand lupus nephritis. Multiple genes, many of which are not yet identified, mediate this genetic predisposition [Human leukocyte antigen (HLA)classII genes, Complement genes, FcγR genesand others]
- 10. IMMUNOLOGICFACTORS • Patients withSLEhave poor clearance mechanisms for cellular debris. Nuclear debris from apoptotic cells induces plasmacytoid dendritic cells to produce interferon-α,which is apotent inducer of the immune system and autoimmunity. • Autoreactive Blymphocytes, which are normally inactive, become active in SLEbecauseof amalfunction of normal homeostatic mechanisms, resulting in escapefrom tolerance. Thisleads to the production ofautoantibodies. • Anti-dsDNAantibodies, develop through aprocess of epitope spreading.
- 11. ENVIRONMENTALFACTOR • UVlight • EBV •Smoking • Alcohol • Silicadust
- 12. CLINICALFEATURES:SYMPTOMS 1. Asymptomatic 2. Symptomsof active systemic lupus erythematosus (SLE), including fatigue, fever, rash, arthritis, serositis, orcentral nervous system (CNS)disease. 3. Symptoms related to active nephritis may includeperipheral edema secondary to hypertension orhypoalbuminemia. 4. Other symptoms directly related to hypertension that are commonly associated with diffuse lupus nephritis include headache, dizziness, visual disturbances, and signsof cardiac decompensation.
- 13. • Focaland diffuselupus nephritis: evidence of generalized active SLEwith the presence of arash,oral or nasal ulcers, synovitis, or serositis. Signsof active nephritis are alsocommon. • Active lupus nephritis: hypertension, peripheral edema, and, occasionally, cardiac decompensation. • Membranous lupus nephritis: signsof an isolated nephrotic syndrome are common. Theseinclude peripheral edema, ascites, and pleural and pericardial effusions without hypertension. CLINICALFEATURES:SIGNS
- 14. • Several studieshavefocused on the discrepancy between clinicalpresentation and pathologic findings at renal biopsy in patients with SLE. • Silent LNhasbeen reported not only in classII but also in classIV. • Evenpatients with low-level proteinuria (<1g/24h) havedemonstrated significant renal involvement with proliferative LN (classesIII or IV).
- 15. DIFFERENTIALDIAGNOSES • Chronic Glomerulonephritis •Diffuse Proliferative Glomerulonephritis • Granulomatosis with Polyangiitis(Wegener Granulomatosis) • Membranous Glomerulonephritis • Polyarteritis Nodosa • Rapidly Progressive Glomerulonephritis
- 16.
- 17. INVESTIGATIONS: Evaluating renal function •Todetect any renal involvementearly. Renal biopsy • Classification is based on light microscopy, immunofluorescence, and electron microscopy findings from renal biopsyspecimens.
- 18. LABORATORYTESTS • Blood ureanitrogen (BUN) • Serum creatinine • Urine R/M/E (to check for protein, red blood cells [RBCs], and cellular casts) • Aspot urine test for creatinine and proteinconcentration (normal creatinine excretion is 1000 mg/24 h/1.75 m 2; normal protein excretion is 150-200 mg/24 h/1.75 m 2; normal urinary protein-to-creatinine ratio is<0.2) • A24-hour urine test for creatinine clearance andprotein excretion
- 19. • ANA[for diagnosisSLE] • Antibodies to double-stranded DNA(dsDNA),↑ • Complement (C3,C4, and CH50), ↓ • Erythrocyte sedimentation rate (ESR), ↑ • C-reactive protein (CRP)levels. ↔ • Anti-C1q antibodies ↑ [less sensitive thenAnti dsDNA,but more specific] LABORATORYTESTS
- 20. Urinary biomarkers canaccuratelyidentify active lupus nephritis in children: • Alpha-1-acid glycoprotein (AGP) • Ceruloplasmin • Lipocalin-like prostaglandin Dsynthase(LPGDS) • Transferrin LABORATORYTESTS
- 21. Features % Proteinuria 100 Miroscopichematuria 80 Tubular abnormalities 60-80 Reduced renal function 40-80 Nephrotic syndrome 45-65 Granular casts 30 Rapidly declining renal function 30 Hypertension 15-50 Hyperkalemia 15 Macroscopic hematuria 1-2 Acute renal failure 1-2
- 22. ACRCRITERIA ACRcriteria Persistent proteinuria >0.5 gmperdayor greaterthan 3+by dipstick, and/or Cellular castsincluding red blood cells [RBCs], hemoglobin, granular, tubular, or mixed Review of the ACRcriteria Spot urine protein/creatinine ratio of >0.5 Active urinary sediment(>5 RBCs/HPF,>5WBCs/HPFin the absence of infection,or cellular castslimited to RBC or WBCcasts
- 23. RENALBIOPSY All patients withclinical evidence of active LN, previously untreated, undergo renal biopsy (unless strongly contraindicated) for • Classified by current ISN/RPSclassification • Disease evaluated for activity andchronicity • Identify additional or alternative causes ofrenal disease • Determining prognosis andtreatment
- 24. INDICATIONSFORRENALBIOPSYIN PATIENTS WITHSYSTEMICLUPUSERYTHEMATOSUS • Increasingserum creatinine without compellingalternative causes(such assepsis,hypovolemia, or medication) • Confirmed proteinuria of 1.0 gmper 24 hours (either 24- hour urine specimens orspot protein/creatinine ratios are acceptable) • Combinations of the following, assuming the findings are confirmed in at least 2 tests done within ashort period of time and in the absence ofalternative causes: • Proteinuria 0.5 gmper 24 hours plushematuria, defined as5 RBCsper hpf • Proteinuria 0.5 gmper 24 hours plus cellularcasts
- 25. International Society ofNephrology/Renal PathologySociety 2003classification of LN ClassI Minimal mesangialLN ClassII Mesangial proliferative LN ClassIII FocalLN(50%of glomeruli) III (A): activelesions III (A/C): active and chroniclesions III (C):chroniclesions ClassIV Diffuse LN(50% glomeruli) Diffuse segmental (IV-S)or global(IV-G) LN IV(A): active lesions IV(A/C): active and chroniclesions IV(C):chronic lesions ClassV Membranous LN ClassVI Advanced sclerosing LN(90%globally sclerosed glomeruli without residual activity)
- 26.
- 27. TREATMENT Theprincipal goal oftherapy in lupus nephritis is to normalize renal function or, at least, to prevent the progressive loss of renal function. Therapy differs depending on the pathologic lesion.It is important to treat extrarenal manifestations and other variables that may affect thekidneys. • Adjunctive Treatments • Primary disease management by immunosuppressive agents • Induction Therapy • Maintenance Therapy • Lifestyle Changes
- 28. ADJUNCTIVETREATMENTS Drugs Cause Hydroxychloroquine [Max 6–6.5mg/kg bodyweight] All SLEpatients with; unless there isa contraindication: • Lower rates of Flare • Reducedrenal damage • Lessclottingevents ACEi/ARBs Patients with proteinuria >0.5gm/day • Reducesproteinuria by 30%,and • Significantly delays doubling of serum creatinine • Delaysprogression to ESRD Antihypertensive Targetof ≤130/80mmHg • Significant delay in progressionof renal disease Statin therapy Patients with LDL>100mg/dl • AsGFR<60ml/min/1.73m2& SLEitself accelerated atherosclerosis Calcium supplementation Prevent osteoporosis if the patientis on long-term corticosteroidtherapy
- 29. IMMUNOSUPPRESSIVEAGENTS • Depends uponclassof LNdiagnosed on kidney biopsy along with presence of extra-renal manifestations of SLE • Goalsof immunosuppressive treatment: • Long-term preservation of renalfunction, • Prevention of flares, • Avoidance of treatment-related harms,and • Improved quality of life andsurvival.
- 30. CLASSI LN(MINIMAL-MESANGIALLN) Treatment asdictatedby the extrarenalclinical manifestations of lupus • ClassI LNhasno clinical kidneymanifestations. • ClassI LNis not associated withlong-term impairment of kidneyfunction
- 31. • May requiretreatment if proteinuriais greater than 1000mg/day. • Consider prednisone in low-to-moderate doses (ie, 20-40 mg/day) for 1-3 months, with subsequenttaper. CLASSII LN(MESANGIAL-PROLIFERATIVELN)
- 32. CLASSIII LN(FOCAL)ANDCLASSIVLN(DIFFUSE) • Athigh risk of progressing to ESRD • Require aggressive therapy. • Therapy for classIII and IVLNhas2phases: • Initial/Induction phase: to rapidly decreasekidney inflammation • Maintenance phase: to consolidate treatment overa longer time.
- 33.
- 34. INITIAL/INDUCTIONPHASE • Initial therapywith corticosteroids , combinedwith either cyclophosphamide or MMF. • If patients have worsening LN(rising SCr,worsening proteinuria) during the first 3 months of treatment, a change be made to an alternative recommendedinitial therapy, or arepeat kidney biopsy be performed to guide further treatment.
- 35. GLUCOCORTICOIDS • PulseIV glucocorticoids(500–1000 mg methylprednisolone daily for 3 doses) in combination with immunosuppressive therapyis recommended. • Followed by daily oral glucocorticoids (0.5–1 mg/kg/day), followed by ataper to theminimal amount necessaryto controldisease.
- 36.
- 38. MMF CYC • NonAsian =3gm/D • Asian =2 gm/D • ClassIII/IV +crescents = 3gm/D • Proteinuria +recent significant rise in creatinine =3gm/D • In severe classIII/IV LN • In whites, low- and high-dose regimenswere equivalent in efficacy. • Serious infections were lessfrequent with thelower doses • Low and high-dose regimens similar rates of LN flares, end-stage renal disease, and doubling of the serum creatinine.
- 39. IMPORTANTCONSIDERATIONSFORCYC • Theuseof sodium-2-mercaptoethane(mesna) will also minimizethe risk of hemorrhagic cystitis when cyclophosphamide is given asi.v. pulses. • Lifetime maximum of 36 gcyclophosphamide in patients with systemic lupus asthere is chance of hematologic malignancieslater in life. • Thedose of cyclophosphamide should be decreased by 20%(CrCl 25-50ml/min) or 30%(10–25ml/min) • Tominimize bladder toxicity with oral cyclophosphamide, suggest instructing patients to take cyclophosphamide in the morning, and to drink extrafluid. • Toprotect fertility, women should be offered prophylaxiswith leuprolide and men testosterone. Ovarian tissue cryopreservation/sperm banking are other options.
- 40. HOWCANWEPREDICTOUTCOME?? • After 8week: ≥ 25%reduction in proteinuria and/or normalization of C3and/or C4serum levels =likely to show good clinical renal responses • After 6 months: decrease in serum creatinine and in proteinuria to <1 gm/D predicts a good long-term outcome
- 41. DEFINITIONSOFRESPONSETOTHERAPY • Complete response:Return of SCrto previous baseline, plusa decline in the uPCRto <500 mg/g (<50mg/mmol). • Partial response: Stabilization (±25%),or improvement of SCr, but not to normal, plus a≥50%decrease in uPCR.Ifthere was nephrotic-range proteinuria (uPCR≥3000mg/g [≥300 mg/mmol]), improvement requires a≥50%reduction inuPCR, and auPCR<3000 mg/g [<300mg/mmol]. • Deterioration:There is no definition of deterioration inLNto define treatment failure. Asustained 25%increase in SCris widely used but hasnot beenvalidated.
- 42.
- 45. OTHERINITIALREGIMENS Regimens Rituximab • Whentreatment failed with MMF/CYC Azathioprine • 2nd lineprotocol • Lesseffective thanCYC MPA • Lessnausea& diarrhea than MMF • Should measured 1 hour after adose Cyclosporine • (4–5 mg/ kg/d) wasusedfor9 months, and then tapered over the next 9months. • No differences in responses, relapse rate, Infectionsand leukopenia with CYC. • ACRguideline preferred it for maintenancetherapy. Tacrolimus • Equivalent to high-dose IVCYCin inducingcomplete and partial remissions of LN
- 46.
- 49. • Azathioprine (1.5–2.5mg/kg/d) or • MMF (1–2 g/d in divideddoses) ± Low-dose oral corticosteroids Calcineurin inhibitors with low-dose corticosteroids be used for maintenance therapy inpatients who are intolerant of MMF andazathioprine. MAINTENANCETHERAPY
- 50. Complete remission is achieved Repeat kidney biopsy Changein therapy Continuedfor at least 1 year Considerationfor tapering Kidney function deteriorates and/or proteinuria worsens Treatment be increased to the previous level of immunosuppression that controlled theLN YESNO After 1year
- 51. DURATIONOFTHERAPY • There isno evidence to help determinethe duration of maintenancetherapy. • Theaverage duration of immunosuppressionwas 3.5 years in sevenRCTs. • Immunosuppressive therapy should usually be slowly tapered after patients have been in complete remission for ayear.
- 52. CLASSVLN(MEMBRANOUSLN) • Generally treatedwith prednisone for 1-3 months, followed by tapering for 1-2 years ifaresponse occurs. If no response occurs, the drug isdiscontinued. • Immunosuppressive drugs are generally not usedunless renal function worsens or aproliferative component is present on renal biopsysamples.
- 53. CLASSVILN(ADVANCEDSCLEROSISLN) • Treated withcorticosteroids and immunosuppressives only asdictated by the extrarenal manifestations of systemiclupus. • Dialysis and • Kidney transplantation
- 54. LIFESTYLECHANGESFORLUPUSNEPHRITIS • Drink enoughfluids to stay wellhydrated. • Eatalow-sodium diet, especially if hypertension isan issue. • Avoid smoking and drinking alcohol. • Exerciseregularly. • Maintain ahealthy blood pressure. • Limit cholesterol. • Avoid medications that can affect the kidneys, suchas nonsteroidal anti-inflammatory drugs (NSAIDs).
- 55. RELAPSEOFLN • Treated withtheinitial therapy followed by the maintenance therapy that waseffective in inducing the original remission • Consider arepeat kidney biopsy during relapseif there is suspicion that the histologic classof LN haschanged, or there is uncertainty whether a rising SCrand/or worsening proteinuria represents diseaseactivity or chronicity.
- 57. SYSTEMICLUPUSANDTHROMBOTIC MICROANGIOPATHY • Antiphospholipid syndromeoccurs when immune systemmistakenly attacks some of the normal proteins in blood. • Theantiphospholipid anti-body syndrome (APS) involving the kidney in systemic lupus patients, withor without LN.
- 58. Blood tests forantiphospholipid syndrome look for at least one of the following three antibodies in your blood: • Lupus anticoagulant • Anti-cardiolipin • Beta-2 glycoprotein I Toconfirm adiagnosis of antiphospholipid syndrome, the antibodies must appear in your blood at least twice, in tests conducted at least 12 weeksapart. SYSTEMICLUPUSANDTHROMBOTIC MICROANGIOPATHY
- 59. • Heparin: Typically,first be given asinjection,combined with another blood thinner in pill form, likely warfarin (Coumadin). • Warfarin: After several daysof combined heparinand warfarin, discontinue the heparin and continue the warfarin, possibly for the rest oflife. • Aspirin: In some cases,may recommend adding low-dose aspirin to treatmentplan. Target INR2–3 SYSTEMICLUPUSANDTHROMBOTIC MICROANGIOPATHY
- 60. • Patients withsystemic lupus and thrombotic thrombocytopenic purpura (TTP)receive plasma exchange asfor patients with TTPwithoutsystemic lupus. SYSTEMICLUPUSANDTHROMBOTIC MICROANGIOPATHY
- 61. SYSTEMICLUPUSANDPREGNANCY • Women becounseled to delay pregnancy until a complete remission of LNhasbeenachieved. • In patients with prior LN butno current evidence of systemic or renal disease activity: no nephritis medications are necessary • Patients with mildsystemic activity: may be treatedwith HCQ • Clinically active nephritis is present,orthere is substantial extrarenal disease activity: glucocorticoids (at doses necessary tocontrol disease activity) ± AZA
- 62. • If pregnantpatients are receiving corticosteroids or azathioprine, we suggestthat these drugs not be tapered during pregnancy or for at least 3 monthsafter delivery. • Contraindicated: High-dose glucocorticoid [hypertension and diabetes mellitus]. MMF, CYC,and methotrexate should be avoided becausethey are teratogenic. • Class III or IV with crescents: consideration ofdelivery after28 weeks fora viable fetus. • Administration of low-dose aspirin during pregnancyto decrease the risk of fetalloss. SYSTEMICLUPUSANDPREGNANCY
- 63.
- 64.
- 65.