This document discusses lupus nephritis, a manifestation of systemic lupus erythematosus where the kidneys are affected. It first describes how lupus nephritis develops due to autoimmune mechanisms like the production of autoantibodies against nuclear elements. These autoantibodies can form immune complexes that deposit in the glomeruli and cause inflammation. The document then covers the clinical features, investigations including renal biopsy classification, treatment approaches like immunosuppressive induction and maintenance therapies, and factors that influence treatment response.

1. LUPUSNEPHRITIS

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 lupus erythematosus is an
autoimmune diseasein which organs and
cells undergo damage initially mediatedby
tissue binding autoantibodies andimmune
complexes.

4. LUPUSNEPHRITIS
• Lupusnephritis is histologically evident in most
patients with SLE.
• One of the most serious manifestations of SLE.
• Usually arises within 5 yearsof diagnosis.

5. PATHOPHYSIOLOGY
Autoimmunity plays amajor role in the
pathogenesis of lupusnephritis.
Immunologic
mechanisms
Production of
autoantibodies
Againstnuclear
elements

6. Thecharacteristics of the nephritogenicautoantibodies
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
deposited in 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 multiple susceptibility factors, which
result in abnormal immune responses, whichvary
among different patients.
Thesefactors include:
• Genetic factors
• Immunologic factors
• Environmental factors

9. 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]

10. IMMUNOLOGICFACTORS
• Patients with SLEhave 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. Symptoms of 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 diffuse lupus 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 studies havefocused 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. INVESTIGATIONS

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 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

19. • 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

20. Urinary biomarkers canaccurately identify active
lupus nephritis in children:
• Alpha-1-acid glycoprotein (AGP)
• Ceruloplasmin
• Lipocalin-like prostaglandin Dsynthase(LPGDS)
• Transferrin
LABORATORYTESTS

21. Features %
Proteinuria 100
Miroscopic hematuria 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
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

23. RENALBIOPSY
All patients with clinical 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
• Increasing serum 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 of Nephrology/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. TREATMENT

27. TREATMENT
Theprincipal goal of therapy 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 6–6.5 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

29. IMMUNOSUPPRESSIVEAGENTS
• Depends upon classof 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 asdictated by the extrarenalclinical
manifestations of lupus
• ClassI LNhasno clinical kidneymanifestations.
• ClassI LNis not associated withlong-term
impairment of kidneyfunction

31. • May require treatment 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)
• At high 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. INITIAL/INDUCTION
THERAPY

34. INITIAL/INDUCTIONPHASE
• Initial therapy with 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. REGIMENSFORINITIALTHERAPYIN CLASSIII/CLASS
IVLN[INTERNATIONALSOCIETYOFNEPHROLOGY-KIDNEYDISEASEIMPROVING GLOBAL
OUTCOME]

38. MMF CYC
• Non Asian =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 8 week: ≥ 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. IFTHEPATIENTNOT
IMPROVED??
SWITCHREGIMEN

45. OTHERINITIALREGIMENS
Regimens
Rituximab • When treatment 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. MAINTENANCE
THERAPY

49. • Azathioprine (1.5–2.5 mg/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
Continued for 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 is no 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 treated with 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 with corticosteroids and
immunosuppressives only asdictated by the
extrarenal manifestations of systemiclupus.
• Dialysis and
• Kidney transplantation

54. LIFESTYLECHANGESFORLUPUSNEPHRITIS
• Drink enough fluids 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 withthe initial 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 syndrome occurs 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 for antiphospholipid 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 with systemic lupus and thrombotic
thrombocytopenic purpura (TTP)receive plasma
exchange asfor patients with TTPwithoutsystemic
lupus.
SYSTEMICLUPUSANDTHROMBOTIC
MICROANGIOPATHY

61. SYSTEMICLUPUSANDPREGNANCY
• Women be counseled 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 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

63. MONITORINGACTIVITYOFLN

64. PROGNOSIS
10year
73%85%
5year
1950
5-year
survival
rate
wa
s close
to
0%

65. THANKYOU