This is a presentation on Lupus nephritis, based on ACR guideline.

1. LUPUS NEPHRITIS
DR. TALHA-SAMI-UL-HAQUE
HMO
MU-VA
DHAKA MEDICAL COLLEGE HOSPITAL

2. In 1941, Klemperer, Pollack and Baehr first
described systemic lupus erythematosus (SLE)
as one of the Connective Tissue Disease.
19th-
century
• The term “lupus
erythematosus” was
introduced to describe skin
lesions
almost
100 years
later
• the disease is systemic and
spares no organ

3. SYSTEMIC LUPUS ERYTHEMATOSUS
Systemic lupus erythematosus is an
autoimmune disease in which organs and
cells undergo damage initially mediated by
tissue binding autoantibodies and immune
complexes.

4. LUPUS NEPHRITIS
• Lupus nephritis is histologically evident in most
patients with SLE.
• One of the most serious manifestations of SLE.
• Usually arises within 5 years of diagnosis.

5. PATHOPHYSIOLOGY
Autoimmunity plays a major role in the
pathogenesis of lupus nephritis.
Immunologic
mechanisms
Production of
autoantibodies
Against nuclear
elements

6. The characteristics of the nephritogenic autoantibodies
associated with lupus nephritis are as follows :
i. Antigen specificity directed against nucleosome or double-
stranded DNA (dsDNA) - Some anti-dsDNA antibodies cross-
react with the glomerular basement membrane.
ii. Higher-affinity autoantibodies may form intravascular
immune complexes, which are deposited in glomeruli.
iii. Cationic autoantibodies have a higher affinity for the anionic
glomerular basement membrane.
iv. Autoantibodies of certain isotypes (immunoglobulin IgG 1 and
IgG 3) readily activate complement.

7. Autoantibodies
Form pathogenic immune
complexes intravascularly
Immune complexes
deposited in glomeruli
Bind to antigens already
located in the glomerular
basement membrane
Immune complexes in situ
Activating complement and attracting inflammatory cells, including
lymphocytes, macrophages, and neutrophils
Promote an inflammatory
response
The histologic type of lupus nephritis that develops depends on
numerous factors, including the antigen specificity and other
properties of the autoantibodies and the type of inflammatory
response that is determined by other host factors.

8. ETIOLOGY
There are multiple susceptibility factors, which
result in abnormal immune responses, which vary
among different patients.
These factors include:
• Genetic factors
• Immunologic factors
• Environmental factors

9. GENETIC FACTORS
Genetic predisposition plays an important role in the development
of both SLE and lupus nephritis. Multiple genes, many of which are
not yet identified, mediate this genetic predisposition [Human
leukocyte antigen (HLA) class II genes, Complement genes, FcγR
genes and others]

10. IMMUNOLOGIC FACTORS
• Patients with SLE have poor clearance mechanisms for
cellular debris. Nuclear debris from apoptotic cells induces
plasmacytoid dendritic cells to produce interferon-α, which
is a potent inducer of the immune system and
autoimmunity.
• Autoreactive B lymphocytes, which are normally inactive,
become active in SLE because of a malfunction of normal
homeostatic mechanisms, resulting in escape from
tolerance. This leads to the production of autoantibodies.
• Anti-dsDNA antibodies, develop through a process of
epitope spreading.

11. ENVIRONMENTAL FACTOR
• UV light
• EBV
• Smoking
• Alcohol
• Silica dust

12. EPIDEMIOLOGY
50–60% developing nephritis during the first
10 years of disease.
35% adults having SLE have clinical
evidence of nephritis at time of diagnosis.
African Americans and
Hispanics
Whites

13. 9 1
20-40

14. BANGLADESH
Lupus nephritis was the most prevalent
among secondary GN
common histological type
was found Class IV [40%]
Female 73.2% 21-40
year age
ANA positive
63%
Anti-ds DNA
was positive
100%

15. CLINICAL FEATURES: SYMPTOMS
1. Asymptomatic
2. Symptoms of active systemic lupus erythematosus (SLE),
including fatigue, fever, rash, arthritis, serositis, or central
nervous system (CNS) disease.
3. Symptoms related to active nephritis may include peripheral
edema secondary to hypertension or hypoalbuminemia.
4. Other symptoms directly related to hypertension that are
commonly associated with diffuse lupus nephritis include
headache, dizziness, visual disturbances, and signs of cardiac
decompensation.

16. • Focal and diffuse lupus nephritis: evidence of
generalized active SLE with the presence of a rash, oral
or nasal ulcers, synovitis, or serositis. Signs of active
nephritis are also common.
• Active lupus nephritis: hypertension, peripheral edema,
and, occasionally, cardiac decompensation.
• Membranous lupus nephritis: signs of an isolated
nephrotic syndrome are common. These include
peripheral edema, ascites, and pleural and pericardial
effusions without hypertension.
CLINICAL FEATURES: SIGNS

17. • Several studies have focused on the
discrepancy between clinical presentation
and pathologic findings at renal biopsy in
patients with SLE.
• Silent LN has been reported not only in
class II but also in class IV.
• Even patients with low-level proteinuria
(<1g/24h) have demonstrated significant
renal involvement with proliferative LN
(classes III or IV).

18. DIFFERENTIAL DIAGNOSES
• Chronic Glomerulonephritis
• Diffuse Proliferative Glomerulonephritis
• Granulomatosis with Polyangiitis (Wegener
Granulomatosis)
• Membranous Glomerulonephritis
• Polyarteritis Nodosa
• Rapidly Progressive Glomerulonephritis

19. INVESTIGATIONS

20. INVESTIGATIONS:
Evaluating renal function
• To detect any renal involvement early.
Renal biopsy
• Classification is based on light microscopy,
immunofluorescence, and electron microscopy
findings from renal biopsy specimens.

21. LABORATORY TESTS
• Blood urea nitrogen (BUN)
• Serum creatinine
• Urine R/M/E (to check for protein, red blood cells [RBCs],
and cellular casts)
• A spot urine test for creatinine and protein concentration
(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)
• A 24-hour urine test for creatinine clearance and protein
excretion

22. • 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 then Anti
dsDNA, but more specific]
LABORATORY TESTS

23. Urinary biomarkers can accurately identify active
lupus nephritis in children:
• Alpha-1-acid glycoprotein (AGP)
• Ceruloplasmin
• Lipocalin-like prostaglandin D synthase (LPGDS)
• Transferrin
LABORATORY TESTS

24. 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

25. ACR CRITERIA
ACR criteria
Persistent proteinuria >0.5
gm per day or greater than
3+ by dipstick, and/or
Cellular casts including red
blood cells [RBCs],
hemoglobin, granular,
tubular, or mixed
Review of the
ACR criteria
Spot urine
protein/creatinine ratio of
>0.5
Active urinary sediment (>5
RBCs/HPF, >5 WBCs/HPF in
the absence of infection, or
cellular casts limited to RBC
or WBC casts

26. RENAL BIOPSY
All patients with clinical evidence of active LN,
previously untreated, undergo renal biopsy (unless
strongly contraindicated) for
• Classified by current ISN/RPS classification
• Disease evaluated for activity and chronicity
• Identify additional or alternative causes of renal
disease
• Determining prognosis and treatment

27. INDICATIONS FOR RENAL BIOPSY IN PATIENTS
WITH SYSTEMIC LUPUS ERYTHEMATOSUS
• Increasing serum creatinine without compelling alternative
causes (such as sepsis, hypovolemia, or medication)
• Confirmed proteinuria of 1.0 gm per 24 hours (either 24-
hour urine specimens or spot protein/creatinine ratios are
acceptable)
• Combinations of the following, assuming the findings are
confirmed in at least 2 tests done within a short period of
time and in the absence of alternative causes:
• Proteinuria 0.5 gm per 24 hours plus hematuria,
defined as 5 RBCs per hpf
• Proteinuria 0.5 gm per 24 hours plus cellular casts

28. International Society of Nephrology/Renal Pathology Society 2003 classification
of LN
Class I Minimal mesangial LN
Class II Mesangial proliferative LN
Class III Focal LN (50% of glomeruli)
III (A): active lesions
III (A/C): active and chronic lesions
III (C): chronic lesions
Class IV Diffuse LN (50% glomeruli)
Diffuse segmental (IV-S) or global (IV-G)
LN
IV (A): active lesions
IV (A/C): active and chronic lesions
IV (C): chronic lesions
Class V Membranous LN
Class VI Advanced sclerosing LN (90% globally
sclerosed glomeruli without residual
activity)

29. CLASS I
Delicate mesangial positivity for
IgG.
No structural changes by light
microscopy

30. CLASS II
Mesangial cell proliferation,
mesangial matrix expansion.
Granular mesangial positivity of all three
immunoglobulins and both
complements (C1q and C3) (“full house”
pattern)

31. CLASS III
Less than 50% of all glomeruli,
segmental or global, swelling and
proliferation of endothelial and
mesangial cells associated with
leukocyte accumulation, capillary
necrosis, and hyaline thrombi;
extracapillary proliferation,
crescents.
Full house pattern as in class II,
immune deposits also identified in
tubular basement membranes,
interstitial capillary walls,
interstitial collagen, arterial intima,
and media, Fibrinogen positivity

32. CLASS IV
Lesions similar to Class III, but
involves > 50% of glomeruli

33. WIRE LOOP LESIONS

34. HYALINE THROMBI

35. CLASS V
Diffuse thickening of the capillary
walls due to deposition of
subepithelial immune complexes,
increased production of basement
membrane-like material
There are delicate subepithelial
immune deposits staining for IgG
with or without mesangial deposits

36. CLASS VI
Sclerosis of more than 90% of the
glomeruli, end stage renal disease, severe
tubular atrophy, interstitial fibrosis,
inflammation.

37. TREATMENT

38. TREATMENT
The principal 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 the kidneys.
• Adjunctive Treatments
• Primary disease management by immunosuppressive agents
• Induction Therapy
• Maintenance Therapy
• Lifestyle Changes

39. ADJUNCTIVE TREATMENTS
Drugs Cause
Hydroxychloroquine
[Max 6–6.5 mg/kg body weight]
All SLE patients with; unless there is a
contraindication:
• Lower rates of Flare
• Reduced renal damage
• Less clotting events
ACEi/ARBs Patients with proteinuria >0.5 gm/day
• Reduces proteinuria by 30%, and
• Significantly delays doubling of serum
creatinine
• Delays progression to ESRD
Antihypertensive Target of ≤130/80 mmHg
• Significant delay in progression of
renal disease
Statin therapy Patients with LDL >100 mg/dl
• As GFR<60ml/min/1.73m2 & SLE itself
accelerated atherosclerosis
Calcium supplementation Prevent osteoporosis if the patient is on
long-term corticosteroid therapy

40. IMMUNOSUPPRESSIVE AGENTS
• Depends upon class of LN diagnosed on kidney
biopsy along with presence of extra-renal
manifestations of SLE
• Goals of immunosuppressive treatment:
• Long-term preservation of renal function,
• Prevention of flares,
• Avoidance of treatment-related harms, and
• Improved quality of life and survival.

41. CLASS I LN (MINIMAL-MESANGIAL LN)
Treatment as dictated by the extrarenal clinical
manifestations of lupus
• Class I LN has no clinical kidney manifestations.
• Class I LN is not associated with long-term
impairment of kidney function

42. • May require treatment if proteinuria is
greater than 1000 mg/day.
• Consider prednisone in low-to-moderate
doses (ie, 20-40 mg/day) for 1-3 months,
with subsequent taper.
CLASS II LN (MESANGIAL-PROLIFERATIVE LN)

43. CLASS III LN (FOCAL) AND CLASS IV LN (DIFFUSE)
• At high risk of progressing to ESRD
• Require aggressive therapy.
• Therapy for class III and IV LN has 2 phases:
• Initial/Induction phase: to rapidly decrease kidney
inflammation
• Maintenance phase: to consolidate treatment over a
longer time.

44. INITIAL/INDUCTION
THERAPY

45. INITIAL/INDUCTION PHASE
• Initial therapy with corticosteroids , combined with
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 recommended initial
therapy, or a repeat kidney biopsy be performed to
guide further treatment.

46. GLUCOCORTICOIDS
• Pulse IV glucocorticoids (500–1000 mg
methylprednisolone daily for 3 doses) in
combination with immunosuppressive therapy is
recommended.
• Followed by daily oral glucocorticoids (0.5–1
mg/kg/day), followed by a taper to the minimal
amount necessary to control disease.

47. REGIMENS FOR INITIAL THERAPY IN CLASS III/CLASS
IV LN [INTERNATIONAL SOCIETY OF NEPHROLOGY- KIDNEY DISEASE IMPROVING
GLOBAL OUTCOME]

49. MMF CYC
• Non Asian = 3gm/D
• Asian = 2 gm/D
• Class III/IV + crescents = 3gm/D
• Proteinuria + recent significant
rise in creatinine = 3gm/D
• In severe class III/IV LN
• In whites, low- and high-dose regimens were
equivalent in efficacy.
• Serious infections were less frequent with the lower
doses
• Low and high-dose regimens similar rates of LN
flares, end-stage renal disease, and doubling of the
serum creatinine.

50. IMPORTANT CONSIDERATIONS FOR CYC
• The use of sodium-2-mercaptoethane (mesna) will also minimize the
risk of hemorrhagic cystitis when cyclophosphamide is given as i.v.
pulses.
• Lifetime maximum of 36 g cyclophosphamide in patients with
systemic lupus as there is chance of hematologic malignancies later
in life.
• The dose of cyclophosphamide should be decreased by 20% (CrCl
25-50ml/min) or 30% (10–25 ml/min)
• To minimize bladder toxicity with oral cyclophosphamide, suggest
instructing patients to take cyclophosphamide in the morning, and to
drink extra fluid.
• To protect fertility, women should be offered prophylaxis with
leuprolide and men testosterone. Ovarian tissue
cryopreservation/sperm banking are other options.

51. HOW CAN WE PREDICT OUTCOME??
• After 8 week: ≥ 25% reduction in proteinuria
and/or normalization of C3 and/or C4 serum
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

52. DEFINITIONS OF RESPONSE TO THERAPY
• Complete response: Return of SCr to previous baseline, plus a
decline in the uPCR to <500 mg/g (<50 mg/mmol).
• Partial response: Stabilization (±25%), or improvement of SCr,
but not to normal, plus a ≥50% decrease in uPCR. If there was
nephrotic-range proteinuria (uPCR≥3000 mg/g [≥300
mg/mmol]), improvement requires a ≥50% reduction in uPCR,
and a uPCR <3000 mg/g [<300 mg/mmol].
• Deterioration: There is no definition of deterioration in LN to
define treatment failure. A sustained 25% increase in SCr is
widely used but has not been validated.

53. IF THE PATIENT NOT
IMPROVED??
SWITCH REGIMEN

56. OTHER INITIAL REGIMENS
Regimens
Rituximab • When treatment failed with MMF/CYC
Azathioprine • 2nd line protocol
• Less effective than CYC
MPA • Less nausea & diarrhea than MMF
• Should measured 1 hour after a dose
Cyclosporine • (4–5 mg/ kg/d) was used for 9 months, and then
tapered over the next 9 months.
• No differences in responses, relapse rate, Infections and
leukopenia with CYC.
• ACR guideline preferred it for maintenance therapy.
Tacrolimus • Equivalent to high-dose IV CYC in inducing complete
and partial remissions of LN

57. MAINTENANCE
THERAPY

60. • Azathioprine (1.5–2.5 mg/kg/d) or
• MMF (1–2 g/d in divided doses)
±
Low-dose oral corticosteroids
Calcineurin inhibitors with low-dose corticosteroids be
used for maintenance therapy in patients who are intolerant
of MMF and azathioprine.
MAINTENANCE THERAPY

61. Complete remission
is achieved
Repeat
kidney
biopsy
Change in
therapy
Continued for at
least 1 year
Consideration for
tapering
Kidney function
deteriorates and/or
proteinuria worsens
Treatment be increased
to the previous level of
immunosuppression
that controlled the LN
YESNO
After
1 year

62. DURATION OF THERAPY
• There is no evidence to help determine the
duration of maintenance therapy.
• The average duration of immunosuppression was
3.5 years in seven RCTs.
• Immunosuppressive therapy should usually be
slowly tapered after patients have been in
complete remission for a year.

63. CLASS V LN (MEMBRANOUS LN)
• Generally treated with prednisone for 1-3 months,
followed by tapering for 1-2 years if a response occurs. If
no response occurs, the drug is discontinued.
• Immunosuppressive drugs are generally not used unless
renal function worsens or a proliferative component is
present on renal biopsy samples.

64. CLASS VI LN (ADVANCED SCLEROSIS LN)
• Treated with corticosteroids and
immunosuppressives only as dictated by the
extrarenal manifestations of systemic lupus.
• Dialysis and
• Kidney transplantation

65. LIFESTYLE CHANGES FOR LUPUS NEPHRITIS
• Drink enough fluids to stay well hydrated.
• Eat a low-sodium diet, especially if hypertension is an
issue.
• Avoid smoking and drinking alcohol.
• Exercise regularly.
• Maintain a healthy blood pressure.
• Limit cholesterol.
• Avoid medications that can affect the kidneys, such as
nonsteroidal anti-inflammatory drugs (NSAIDs).

66. RELAPSE OF LN
• Treated with the initial therapy followed by the
maintenance therapy that was effective in
inducing the original remission
• Consider a repeat kidney biopsy during relapse if
there is suspicion that the histologic class of LN
has changed, or there is uncertainty whether a
rising SCr and/or worsening proteinuria
represents disease activity or chronicity.

68. SYSTEMIC LUPUS AND THROMBOTIC
MICROANGIOPATHY
• Antiphospholipid syndrome occurs when immune
system mistakenly attacks some of the normal proteins
in blood.
• The antiphospholipid anti-body syndrome (APS)
involving the kidney in systemic lupus patients, with or
without LN.

69. 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
To confirm a diagnosis of antiphospholipid syndrome, the
antibodies must appear in your blood at least twice, in tests
conducted at least 12 weeks apart.
SYSTEMIC LUPUS AND THROMBOTIC
MICROANGIOPATHY

70. • Heparin: Typically, first be given as injection, combined
with another blood thinner in pill form, likely warfarin
(Coumadin).
• Warfarin: After several days of combined heparin and
warfarin, discontinue the heparin and continue the
warfarin, possibly for the rest of life.
• Aspirin: In some cases, may recommend adding low-dose
aspirin to treatment plan.
Target INR 2–3
SYSTEMIC LUPUS AND THROMBOTIC
MICROANGIOPATHY

71. • Patients with systemic lupus and thrombotic
thrombocytopenic purpura (TTP) receive plasma
exchange as for patients with TTP without systemic
lupus.
SYSTEMIC LUPUS AND THROMBOTIC
MICROANGIOPATHY

72. SYSTEMIC LUPUS AND PREGNANCY
• Women be counseled to delay pregnancy until a
complete remission of LN has been achieved.
• In patients with prior LN but no current evidence of
systemic or renal disease activity: no nephritis
medications are necessary
• Patients with mild systemic activity: may be treated with
HCQ
• Clinically active nephritis is present, or there is substantial
extrarenal disease activity: glucocorticoids (at doses
necessary to control disease activity) ± AZA

73. • If pregnant patients are receiving corticosteroids or
azathioprine, we suggest that these drugs not be
tapered during pregnancy or for at least 3 months after
delivery.
• Contraindicated: High-dose glucocorticoid [hypertension
and diabetes mellitus]. MMF, CYC, and methotrexate
should be avoided because they are teratogenic.
• Class III or IV with crescents: consideration of delivery
after 28 weeks for a viable fetus.
• Administration of low-dose aspirin during pregnancy to
decrease the risk of fetal loss.
SYSTEMIC LUPUS AND PREGNANCY

74. MONITORING ACTIVITY OF LN

75. PROGNOSIS
10 year
73%
5year
85%
5-year
survival
rate
was
close to
0%
1950

76. THANK YOU