Lupus nephritis update, classification, approach according to guidelines, different case scenarios with stress on algorithmic management of different presentations Ahmed Yehia

1. LUPUS NEPHRITIS,
CASE-BASED
APPROACH
AHMED YEHIA, MD
IMMUNOLOGY, ALLERGY &
RHEUMATOLOGY

3. CASE 1
• A 22 years old female patient presented with malar
rash and alopecia.
• Her ANA is pending.
• S. C4 is 5 (10-14 mg/dl)
• CBC is normal
• Direct coomb’s test is positive.

4. SLE 1997 ACR CLASSIFICATION
CRITERIA

5. NO ALOPECIA OR
HYPOCOMPLEMENTEMI
A

6. THERE IS ALWAYS NEW.

7. SLICC CRITERIA FOR
SLE
* A patient is classified as having SLE using four criteria (with at least
one of the clinical criteria and one of the immunologic
criteria).

9. *Other causes for clinical and immunological manifestations must be ruled out
before attributing them to SLE.
Frequency, chance of occurrence at any time during the patient’s illness.

10. MALAR RASH

11. DISCOID RASH

12. ORAL ULCERS

13. butterfly rash
Finger turns
Skin rashes

15. MALAR OR BUTTERFLY RASH

16. Acute Cutaneous: Malar Rash
Note Sparing of Nasolabial Folds

17. Chronic
Cutaneous:
Discoid
Note Scarring,
Hyperpigment
-ation

18. DISCOID RASH – STIMULATED BY UV
LIGHT

19. LIVEDO RETICULARIS

22. 2012 SLICC CRITERIA FOR SLE
(AHMED YEHIA MNEMONIC)
CLINICAL
Acute & chronic
cutaneous
lupus
Alopecia & oral
and nasal
ulcers
Synovitis
&
serositis
Neurological
&
Nephrologic
al
Hematological
IMMUNOLOGICAL
• 1. ANA
• 2. Anti-dsDNA
• 3. Anti-Smith
• 4. Antiphospholipid antibody
positivity as determined by any of
the following:
- Positive test for lupus anticoagulant
- False positive test result for rapid
plasma regain
- Medium or high-titer ACL(IgG, IgM,
or IgA)

23. (
SLICC 2012 (RASH ON SCALP
- Renal
- Alopecia, nonscarring
- Serositis
- Hemolytic anemia
- Oral and nasal ulcers
- Neurologic
- Synovitis
- Chronic cutaneous lupus (discoid)
- Acute and subacute cutaneous lupus
- Leucopenia/lymphopenia
- Platelets, low

24. CASE 2
•A 22 years old female patient
presented with AKI with new onset
HTN, s.creatinine: 1.6 mg/dl
(?glomerulonephritis“ how to
confirm?”)

26. • Her ANA is negative.
• Anti-dsDNA is positive,
• Proteinuria is 1200mg/ 24 hours.
• S. C3, C4 are normal.
• U/S abdomen is normal.
•What is your next

27. INDICATIONS FOR RENAL BIOPSY

28. RENAL BIOPSY
•Diffuse proliferative GN
• What is your diagnosis?
• How to manage?
lupus
nephritis
Class IV
Later
‫هللا‬ ‫شاء‬ ‫إن‬
But exclude
other
causes.

29. SLICC CRITERIA FOR SLE
*A patient is classified as having SLE using lupus nephritis as a
stand-alone criterion (in the setting of ANAs or
anti-dsDNA antibodies) or four criteria (with at least one of
the clinical criteria and one of the immunologic criteria).

30. SERONEGATI
VE LUPUS??
eight ANA-negative cases from
165 SLE patients. These patients
presented with predominant
dermatological and
rheumatological symptoms. They
remained persistently negative to
ANA testing on rat liver and mouse
kidney substrate. These findings
are consistent with the estimate of
5% of active SLE patients at that
time having no detectable ANA.
Ferreiro & colleagues felt that the
true prevalence of ANA-negative
lupus might well exceed 5%,
because of the likelihood of
underdiagnosis of lupus due to

31. CASE 3
•A 24 years old female patient with SLE
presents with AKI with new onset
HTN, s.creatinine: 1.6 mg/dl.
•Her baseline creatinine 3 weeks ago
was 1.0.
•What is the next step?

32. ACTIVITY ASSESSMENT

33. COMPLETE BLOOD PICTURE :
2.7 M/ul
RBC
7.1 g/dl
HGB
20.3%
HCT
74.3
MCV
26.1
MCH
353000
PLT
15.2
WBC
2.1% .
Reticulocytes Absolute count 34015.8

34. ESR : 80
ANA by IF positive , 1/640,
homogenous
•(It was 1/160 on diagnosis)
Anti-ds DNA positive, 100
C3 29
C4 7
Anti cardiolipin IgG 19 (n:<10 )
Anticardiolipin IgM 5.3 (n:<10)

35. LUPUS ACTIVITY MEASURES (AHMED
YEHIA MNEMONIC)
• Anemia , Arthritis (ANA)
• Proteinuria
• C3 & C4 - - , Cytopenia (CRP)
• dsDNA++
• ESR

36. Renal
biops
y

37. BUT THE PATIENT REFUSED
• Her s. creatinine ++ to 2.7. So, you decided
to…….
• Start pulse Solumedrol 1 gm IV for 3 days but after
the 3rd pulse, s. creatinine is still rising till it became
6.0
• You advised the patient again to take a renal
biopsy and she accepted this time as she was
told that she is approaching dialysis.
• Biopsy was done and she continued
immunosuppression & supportive care and
dialysis.

38. THE BIOPSY REVEALED

39. BUT, CAN WE DIAGNOSE TMA
WITHOUT THROMBOCYTOPENIA &
FRAGMENTED RBCS ?
Yes, for example,
Renal-limited
TMA by
histopathology

40. • Consider TMA in resistant lupus nephritis.
• Not every renal affection in SLE is LN.
• Renal affection in SLE:
1. Lupus nephritis (GN)
2. TIN
3. APLN
4. Vasculitis
5. TMA
6. RVT
There are multiple histologic
subtypes of LN & the optimal
treatment varies with the
subtype. Although the clinical
presentation, urinalysis & eGFR
may suggest a specific
subtype, renal biopsy is

41. BIOPSY….BIOPSY….BIOPSY
Kidney biopsy is considered sine qua non in the
management of LN

42. CASE 4
• A 24 years old female patient with SLE, pregnant, 10
weeks presents with AKI with new onset HTN,
s.creatinine: 1.6 mg/dl.
• Her baseline creatinine 3 weeks ago was 0.8.
• What is the next step?

45. PREGNANCY AND LUPUS NEPHRITIS
EULAR/ERA-EDTA and KDIGO, pregnancy may be planned in stable patients
with inactive lupus for 6-months.
Acceptable drugs during pregnancy are HCQ, low-dose prednisone, AZA and
CNI.
Acetylsalicylic acid should be considered to reduce the risk of preeclampsia
 HCQ has been found helpful in reducing maternal and foetal complications .
MMF Suspend at least 10 weeks before pregnancy.
Rituximab Suspend 6 months
Predictors of worse outcomes pregnancy
• Lupus anticoagulant–positive.
• Using antihypertensive medications .
• Prior lupus nephritis also predicts higher rates of preeclampsia and HELLP .
• Aja Jaryal and Sanjay Vikrant J med Res 2017
45

47. PERSISTENT STERILE PYURIA

48. TRANSFORMATION OF
HISTOLOGIC APPEARANCE AND
“SILENT” LUPUS NEPHRITIS
•
The ISN/RPS class found at diagnostic kidney biopsy for LN is not fixed for an
individual’s entire clinical course. Those successfully treated for proliferative (class
III/IV) LN may transform to a less serious histology, such as class II, or have resolution
of inflammatory lesions with scarring and move from an active to a chronic histologic
pattern. Conversely, patients initially diagnosed with class II or V LN may transform to
proliferative LN, usually class IVG (global).
•
This class switch is often heralded by increasing proteinuria and activity of the urine
sediment.28 Switching between class IVS (segmental) and G subtypes is not seen and
may reflect different pathogenic mechanisms.
•
The concept of silent LN has been proposed based on kidney biopsies done in patients
with SLE but no clinically obvious kidney involvement.29 A few hundred such patients
have been reported, with normal kidney function and no hematuria or proteinuria but
with immune complexes in their glomeruli and a histologic pattern most often
consistent with class I/II LN. A few such patients even display class III, IV, or V LN.
Silent LN may represent a preclinical stage in the evolution of LN.

49. CASE 5
•A 21-year-old African American woman presents for
initial therapy of LN. She was diagnosed with SLE 1
year ago, when she was found to have alopecia,
malar rash & arthralgias with ANA & dsDNS
antibodies. At that time, urine sediment was
unremarkable, serum creatinine was 0.6 mg/dl with
no proteinuria. She was treated with low-dose
steroids & HCQ, with resolution of her symptoms.
Over the past month, she noticed foamy urine &
mild ankle swelling.

50. CASE 5
• A 21-year-old African American woman presents for initial therapy of LN. She
was diagnosed with SLE 1 year ago, when she was found to have alopecia,
malar rash & arthralgias with ANA & dsDNS antibodies. At that time, urine
sediment was unremarkable, serum creatinine was 0.6 mg/dl with no
proteinuria. She was treated with low-dose steroids & HCQ, with resolution of
her symptoms. Over the past month, she noticed foamy urine & mild ankle
swelling.
• Evaluation showed blood on urine dipstick, 24-hour
urine with 4 g protein, serum creatinine of 1 mg/dl, & a
rising dsDNA titer with both C3 & C4 now newly
decreased.

51. CASE 5
• A 21-year-old African American woman presents for initial
therapy of LN. She was diagnosed with SLE 1 year ago, when
she was found to have alopecia, malar rash & arthralgias with
ANA & dsDNS antibodies. At that time, urine sediment was
unremarkable, serum creatinine was 0.6 mg/dl with no
proteinuria. She was treated with low-dose steroids & HCQ, with
resolution of her symptoms. Over the past month, she noticed
foamy urine & mild ankle swelling. Evaluation showed blood on
urine dipstick, 24-hour urine with 4 g protein, serum creatinine of
1 mg/dl, & a rising dsDNA titer with both C3 & C4 now newly
decreased.
•Kidney biopsy revealed ISN class IVA LN,
25% cellular crescents & areas of
glomerular capillary necrosis. The
patient is young & may want children
in the future.

52. Revision of the International Society of
Nephrology/Renal Pathology Society
classification
for lupus nephritis: clarification of
definitions, and
modified National Institutes of Health
activity and
chronicity indices

53. WHAT IS NEW?
1. New definitions are provided for mesangial
hypercellularity & for cellular, fibrocellular &
fibrous crescents.
2. The term “endocapillary proliferation” is
eliminated & the definition of endocapillary
hypercellularity considered in some detail.
3. Class IV-S and IV-G subdivisions of class IV LN
are eliminated.
4. The active and chronic designations for class
III/IV lesions are replaced by a proposal for
activity and chronicity indices that should be

54. 5. In the activity index, they
included fibrinoid necrosis as a
specific descriptor.
6. They made recommendations
on issues for which there are
limited data at present and that
can best be addressed in future

55. • Many renal lesions encountered in lupus nephritis also are
present in other renal diseases, providing a rationale for
harmonizing definitions for lesions irrespective of the
disease context.
•As a general rule, 10
seems to be the
appropriate number of

57. TREATMENT OF PROLIFERATIVE LUPUS
NEPHRITIS

59. From Prof. Hussein Sheashaa

60. THE POINT SYSTEM USED TO CALCULATE
LUPUS NEPHRITIS BIOPSY ACTIVITY &
CHRONICITY INDICES*

61. CASE 1
• A 21-year-old African American woman presents for initial
therapy of LN. She was diagnosed with SLE 1 year ago, when
she was found to have alopecia, malar rash & arthralgias with
ANA & dsDNS antibodies. At that time, urine sediment was
unremarkable, serum creatinine was 0.6 mg/dl with no
proteinuria. She was treated with low-dose steroids & HCQ, with
resolution of her symptoms. Over the past month, she noticed
foamy urine & mild ankle swelling. Evaluation showed blood on
urine dipstick, 24-hour urine with 4 g protein, serum creatinine of
1 mg/dl, & a rising dsDNA titer with both C3 & C4 now newly
decreased.
•Kidney biopsy revealed ISN class IVA LN,
25% cellular crescents & areas of
glomerular capillary necrosis. The
patient is young & may want children
in the future.
Considering options for initial therapy for
her LN, which of the following is correct?
A. She should be treated with intravenous
rituximab for initial therapy.
B. She should be treated with high-dose
steroids & azathioprine for initial therapy.
C. MMF or cyclophosphamide is an
appropriate choice. Ovarian protection or
cryopreservation of eggs should be
considered if cyclophosphamide is to be
used.
D. She should not receive MMF because
she wants to get pregnant in the future.

62. DID RENAL BIOPSY
CHANGE TREATMENT
PLAN?

63. LET’S REVISE LN CLASSES

64. EULAR/EDTA 2013
INITIAL TREATMENT (INDUCTION
THERAPY)
4.1. For patients with class IIIA or
IIIA/C (±V) and class IVA or IVA/C
(±V) LN,
a)mycophenolic acid (MPA)
(mycophenolate mofetil (MMF) target
dose: 3 g/day for 6 months, or MPA
sodium at equivalent dose) or
b)low-dose intravenous
cyclophosphamide (CY) (total dose 3
g over 3 months) in combination with
glucocorticoids, are recommended as

65. 4.2. In patients with adverse
prognostic factors (acute
deterioration in renal function,
substantial cellular crescents
and/or fibrinoid necrosis),
similar regimens may be used but
CY can also be prescribed monthly
at higher doses (0.75–1 g/m2) for
6 months or orally (2–2.5
mg/kg/day) for 3 months.
EULAR/EDTA 2013
INITIAL TREATMENT (INDUCTION
THERAPY)

66. EULAR 2019
•3.4.2 Mycophenolate (1a/A) or
low-dose IV cyclophosphamide
(2a/B) are recommended as initial
(induction) treatment, as they have
the best efficacy/toxicity ratio.

67. EULAR 2019
•3.4.3 In patients at high risk for renal
failure:
1. reduced glomerular filtration rate,
2. histological presence of :
1) fibrous crescents or
2) fibrinoid necrosis, or
3) tubular atrophy/interstitial fibrosis],
similar regimens may be considered but
high-dose IV cyclophosphamide can also be

68. • 4.3. To increase efficacy and reduce
cumulative glucocorticoid doses, treatment
regimens should be combined initially with
three consecutive pulses of intravenous
methylprednisolone 500–750mg,
followed by oral prednisone 0.5
mg/kg/day for 4 weeks, reducing to ≤10
EULAR/EDTA 2013
INITIAL TREATMENT (INDUCTION
THERAPY)

69. Hahn BH, ArthCare Res 2012
Plus : IV pulse steroids (500-1000 mg methyl prednisolone daily for 3 doses) .
Or KIDIGO:initial dose of oral prednisone 1 mg/kg, taper according to clinical response
over 6-12 months.

70. TREATMENT OF RESISTANT SEVERE
PROLIFERATIVE LUPUS NEPHRITIS

71. CASE 6
• 2. A 24-year-old African American female has been
treated for the last 6 months with MMF (2 to 3 g/day) &
a tapering dose of corticosteroids for active focal
proliferative lupus nephritis (ISN class IIIA). Her initial
proteinuria decreased from 3.4 g daily to 1.2 g daily,
urine sediment is inactive, and serum creatinine
decreased from 1.6 to 0.9 mg/dl over the 6 months of
therapy while anti-dsDNA titer declined and serum
complement values returned to normal. What is your

72. T2T

73. EULAR/EDTA 2013
3.2. Treatment should aim for:
A)complete renal response with UPCR
<50 mg/mmol and normal or near-
normal (within 10% of normal GFR if
previously abnormal) renal function.
B)Partial renal response, defined as
≥50% reduction in proteinuria to
subnephrotic levels and normal or
near-normal renal function,
C)should be achieved preferably by 6
months but no later than 12 months
following initiation of treatment

75. CASE 6
• 2. A 24-year-old African American female has been
treated for the last 6 months with MMF (2 to 3 g/day) &
a tapering dose of corticosteroids for active focal
proliferative lupus nephritis (ISN class IIIA). Her initial
proteinuria decreased from 3.4 g daily to 1.2 g daily,
urine sediment is inactive, and serum creatinine
decreased from 1.6 to 0.9 mg/dl over the 6 months of
therapy while anti-dsDNA titer declined and serum
complement values returned to normal.
So, our patient achieved partial rem

76. • A 24-year-old African American female has been treated for the last 6 months with MMF (2
to 3 g/day) and a tapering dose of corticosteroids for active focal proliferative lupus
nephritis (ISN class IIIA). Her initial proteinuria decreased from 3.4 g daily to 1.2 g daily,
urine sediment is inactive, and serum creatinine decreased from 1.6 to 0.9 mg/dl over the 6
months of therapy while anti-dsDNA titer declined and serum complement values returned
to normal. What is the optimal therapy for this patient at this
time?
A. Continue the current dose of MMF for an additional 6 months
and then taper slowly over 1 year.
B. Given the persistent proteinuria, change to IV
cyclophosphamide at 500 mg /2 weeks for 6 doses, then administer
azathioprine at 2 mg/kg daily.
C. Reduce the MMF to 1000 mg bid & plan to continue for 3 years
unless otherwise indicated.
CASE 6

77. • A 24-year-old African American female has been treated for the last 6 months with MMF (2
to 3 g/day) and a tapering dose of corticosteroids for active focal proliferative lupus
nephritis (ISN class IIIA). Her initial proteinuria decreased from 3.4 g daily to 1.2 g daily,
urine sediment is inactive, and serum creatinine decreased from 1.6 to 0.9 mg/dl over the 6
months of therapy while anti-dsDNA titer declined and serum complement values returned
to normal. What is the optimal therapy for this patient at this
time?
A. Continue the current dose of MMF for an additional 6 months
and then taper slowly over 1 year.
B. Given the persistent proteinuria, change to IV
cyclophosphamide at 500 mg /2 weeks for 6 doses, then administer
azathioprine at 2 mg/kg daily.
C. Reduce the MMF to 1000 mg bid & plan to continue for 3 years
unless otherwise indicated.
CASE 6

78. CASE 6 CONTINUED
• 2. A 24-year-old African American female has been
treated for the last 6 months with MMF (2 to 3 g/day) &
a tapering dose of corticosteroids for active focal
proliferative lupus nephritis (ISN class IIIA). Her initial
proteinuria decreased from 3.4 g daily to 1.2 g daily,
urine sediment is inactive, and serum creatinine
decreased from 1.6 to 0.9 mg/dl over the 6 months of
therapy while anti-dsDNA titer declined and serum
complement values returned to normal.
She wants to be pregnant.
What is your advice?

79. CASE 6 CONTINUED
•Now, her GFR became
normal, UPCR is 200mg/gm
on MMF.
She wants to be pregnant.
What is your advice?

80. CASE 6 CONTINUED
•Now, her GFR is normal,
UPCR is 200mg/gm on Aza for
6 months.
She wants to be pregnant.
What is your advice?

81. CASE 7
•A 32-year-old White woman with a
history of LN in the past wants to
become pregnant & is concerned about
flares during the pregnancy.
•In considering medications that have
been used successfully in SLE patients
during pregnancy, you discuss use of
which of the following medications

82. CASE 7
A. Corticosteroids
B. Intravenous cyclophosphamide, but not
oral cyclophosphamide
C. Rituximab
D. Mycophenolate mofetil
E. Tacrolimus
F. Cyclosporin A
G. Azathioprine
H. Hydroxychloroquine

83. CASE 7
A. Corticosteroids
B. Intravenous cyclophosphamide, but not
oral cyclophosphamide
C. Rituximab
D. Mycophenolate mofetil
E. Tacrolimus
F. Cyclosporin A
G. Azathioprine
H. Hydroxychloroquine

84. CASE 8
•A 28-year-old White female
patient presents with proteinuria:
800mg/day, s.cr. 0.9 & is found to
have class V membranous lupus on
renal biopsy.
•How will you manage her LN?

85. CASE 8
• A 28-year-old White female patient presents with
nephrotic syndrome & is found to have class V
membranous lupus on renal biopsy.
• Based on randomized controlled trials, which of the
following medications has not been shown to be effective
in treating this pattern of lupus nephritis?
A. Intravenous cyclophosphamide
B. Intravenous rituximab
C. Oral cyclosporine
D. Oral MMF

86. CASE 8
• A 28-year-old White female patient presents with
nephrotic syndrome & is found to have class V
membranous lupus on renal biopsy.
• Based on randomized controlled trials, which of the
following medications has not been shown to be effective
in treating this pattern of lupus nephritis?
A. Intravenous cyclophosphamide
B. Intravenous rituximab
C. Oral cyclosporine

87. TREATMENT OF LUPUS NEPHRITIS V

88. MANAGEMENT OF ESRD AND TRANSPLANTATION
• Although ESRD is often associated with remission of lupus activity,
extrarenal lupus flares in patients with history of haematologic activity,
positive anti-cardiolipin IgM, younger age & low C4 level .
• Haemodialysis is suitable for patients with active disease & on
immune suppression.
• Peritoneal dialysis should only be offered to patients with inactive
disease &/ minimal immunosuppression. ( GEAS )
• aPL antibodies can increase the risk of vascular access thrombosis
during dialysis .
Ana Barrera rheumatology 2016
89

89. • Transplantation should be performed when lupus activity has been
absent, or at a low level, for at least 3– 6 months, (EULAR/ERA-
EDTA) or 6–12 months (GEAS) to be eligible for transplantation.
• Anti-phospholipid antibodies are associated with an increased risk of
vascular events in the transplanted kidney.
Ana Barrera rheumatology 2016
MANAGEMENT OF ESRD AND TRANSPLANTATION
90

90. CLASS VI LN
SCLEROSED LN
• Extrarenal lupus is often quiescent by the time
patients reach ESRD, but those with active
extrarenal disease may require
immunosuppression while receiving renal
replacement therapy. It has been suggested that
patients with LN defer transplantation for 3 to 6
months to allow SLE to become inactive; however,
recent data suggest that there is an increased risk
for allograft failure if LN patients wait more than 3
months before transplantation.
• Recurrent LN after kidney transplantation is rare,
occurring in only about 1% of patients.
‫عارف‬ ‫مش‬
,
‫تزرع‬ ‫بالش‬
‫الكلى‬ ‫هتاكل‬ ‫الذئبة‬ ‫ألن‬

91. IVIG & PLASMAPHARESIS
IVIG indications :
• Refractory cytopenias
• TTP
• Catastrophic antiphospholipid
• Rapidly deteriorating acute confusional state.
Plasmapharesis
• Most impressive results are shown in active disease with minimal
scarring .
• Its role is limited to cases resistant to steroid &immunosuppressives .
• Carrolin et al,. Rheumatology 2018
92

93. 2019 update of the EULAR
recommendations for the
management of systemic
lupus erythematosus

95. 3.4 RENAL DISEASE (EULAR
2019)
• 3.4.1 Early recognition of signs of renal
involvement and—when present—performance of
a diagnostic renal biopsy are essential to ensure
optimal outcomes
• 3.4.2 Mycophenolate (1a/A) or low-dose
intravenous cyclophosphamide (2a/B) are
recommended as initial (induction) treatment, as
they have the best efficacy/toxicity ratio.
• 3.4.3 In patients at high risk for renal failure
(reduced glomerular filtration rate, histological
presence of fibrous crescents or fibrinoid
necrosis, or tubular atrophy/interstitial fibrosis],

96. 3.4 RENAL DISEASE (EULAR
2019)
• 3.4.4 For maintenance therapy, mycophenolate
(1a/A) or azathioprine (1a/A) should be used.
• 3.4.5 In cases with stable/improved renal function
but incomplete renal response (persistent
proteinuria >0.8–1 g/24 hours after at least 1
year of immunosuppressive treatment), repeat
biopsy can distinguish chronic from active kidney
lesions (4/C).
• 3.4.6 Mycophenolate may be combined with low
dose of a calcineurin inhibitor in severe nephrotic
syndrome (2b/C) or incomplete renal response
(4/C), in the absence of uncontrolled

97. MAKE SURE THAT PUNISHMENT FITS
THE CRIME.

99. TO CONCLUDE
•Lupus Nephritis
•Not every renal affection in lupus is
LN.

100. ‫خير‬ ‫هللا‬ ‫جزاكم‬
‫ا‬

101. REFRACTORY LUPUS NEPHRITIS
• Is reserved to patients with none or partial response to first-
line therapies, namely CYC or MMF.
• Response criteria for lupus nephritis clinical trials have been
established by the ACR, on the basis of the effects of treatment
on renal function, proteinuria and urinary sediments.

102. COMPLETE RESPONSE
.1
Inactive urinary sediment
.2
Decrease in proteinuria to ≤ 0.2 g/day
.3
Normal or stable renal function.

A sustained response of 3–6 months is considered a remission, but
cannot be judged to be complete remission in the absence of a biopsy.
Partial response
Is a level of improvement defined as an inactive
urinary sediment, proteinuria < 0.5 g/day, with normal or stable renal
function.

103. RENAL FLARE
Increase in proteinuria, serum creatinine, presence of active
sediments or a decrease in creatinine clearance, It may be a
proteinuric, nephritic or severe nephritic flare.

Nephritic flares :

Are common, even in those patients who achieve
complete response .

Higher risk of developing doubling of serum creatinine and
ESRD as compared with those with proteinuric flares

105. NON-RESPONSIVE PATIENTS
We should rule out other diseases
1. APS with thrombotic microangiopathy
2. Nephritis secondary to NSAIDs
3. Ischaemic nephropathy
4. Poor compliance to treatment .

106. RENAL BIOPSY
WHY SHOULD RENAL BIOPSY BE DONE? WHEN DO WE REPEAT RENAL BIOPSY?
.1
Worsening of disease or
disease refractory to treatment
.2
Relapse:
•
To demonstrate change or
progression in histological class,
especially if the first biopsy was
in non- proliferative class.
•
Change in activity and
chronicity (index).
Feng Yu et al,. NATURE REVIEWS 2015
107

107. REPEAT RENAL BIOPSY AFTER INDUCTION ?
108
Persistent glomerular & interstitial inflammation.
Persistent capillary immune complexes.
Persistent macrophages in tubular lumens
 Predict the future of the decrease in kidney function and renal out come.
Eva elal,. J Nephrol Hyper2017

108. REPEAT THE BIOPSY AFTER
MAINTENANCE ???
The correlation of clinical and serologic tests with the histological picture of lupus
nephritis is weak .

One-third of patients have subendothelial immune complexes despite complete
clinical response.

Over half of patients with residual low-level proteinuria (500–1000 mg/d) after
years of therapy do not have active ongoing histological inflammation.
So renal biopsy after the maintenance

Detects patients with histopathological activity .

Good argument to stop immunosuppression safely in patients with low-grade
proteinuria .
•
Eva elal,. J Nephrol Hyper2017
109

109. LUPUS PODOCYTOPATHY
Definition :
• Diffuse foot process effacement of podocytes without
evidence of immune complex deposition ( incidence 1.3%) .
Criteria for diagnosis of lupus podocytopathy:
(1) Clinical presentation of full nephrotic syndrome .
(2) Diffuse and severe foot process effacement.
(3) Absence of subendothelial or subepithelial
immune deposits .
Podocytes may posses immune function as they express molecules that are usually associated with
immune activation , ( caspase 1 and IL-1b ) these molecules represent potentially interesting
novel target therapy
• The incidence of AKI & tubular injury , were reported to be high
• Good response to steroid , may not needs aggressive immunotherapy
Feng et al ,. Nature review2017

110. VASCULAR LESIONS IN LUPUS NEPHRITIS

Vascular immune complex deposits.

Thrombotic microangiopathy,(upto30% incidence)

Arteriosclerosis.

Non-inflammatory necrotizing vasculopathy .

True renal vasculitis.

It has been suggested that inclusion of a detailed description of renal vascular
lesions in the ISN/RPS classification of LN may strengthen the predictive value for
renal outcome.
Tan, Y.,et al,. Curr. Opin. Nephrol. Hypertens. (2015).
111

111. TREATMENT
OF LUPUS
NEPHRITIS
The ultimate goals of treatment in LN are:
Long-term preservation of renal function.
Prevention of disease flares.
Avoidance of treatment-related harms .
Improveing quality of life and survival.
Treatment should aim for
complete renal response
Proteinuria <0.5 g/d or UPCR <50 mg/mol and
Normal or near-normal (within 10% of normal GFR if previously abnormal) renal function.
Or Partial renal response:
Defined as 50% reduction in proteinuria to subnephrotic levels
Plus stabilization or improvement of renal function.
Should be achieved preferably by 6 months but no later than 12 months following initiation
of treatment.
According Joint European League Against Rheumatism & European Renal Association-
European Dialysis &Transplant Association (EULAR/ERA-EDTA), ACR,BSR 2017

112. TREATMENT OF LUPUS NEPHRITIS
The ultimate goals of treatment in LN are:
Long-term preservation of renal function.
 Prevention of disease flares.
Avoidance of treatment-related harms .
Improveing quality of life and survival.
113

113. REFRACTORY LUPUS NEPHRITIS
Definition
No international consensus on the definition of
refractory LN.
The EULAR/ERA-EDTA
• Failure to improve within 3–4 months .
• No partial response after 6–12 months of
treatment .
• No complete response after 2 years of
treatment .
NIH & ACR
• Worsening of nephritis (i.e. >50% increase in
UPr or serum creatinine ) by 3 months.
• Or no complete response by 6 months.
Treatment
It is generally advised to switch from MMF
to iv CYC or vice versa if induction
treatment fails.
2- Some guidelines also state that three
pulses of intravenous MP should be
administered.
3-If this approach fails, the guidelines
recommend other options:
• Rituximab, as add-on or monotherapy.
• CNIs as multi target therapy .
• Plasmapharesis
• IVIG .
• Belimumab (BSR, 2017 case by cases)
114
Antonis nouriakis,&GeorgeBertsias nephrology 2015

114. KEY POINTS
IN LUPUS
NEPHRITIS
115
Less glucocorticoids !!!!
Early decrease in the proteinuria is mandatory .
Induction and switching to less toxic therapies.
Prolonged maintenance with
immunosuppression .
RTX for refractory cases .
Adjuvant therapy is a must ( hydroxycholoquine
).
Anti-Blys, anti-CD20, low-dose IL-2, MSCs,
have been used clinically.
Anti-CD22, Interferon-α, CTLA-4-Ig, and some
other biologics are in ongoing clinical trials.

115. CPG SUMMARY
• Overall, immunosuppressive treatment should be guided by renal
biopsy, and treatment aimed at complete renal response
(proteinuria <0.5 g/24 h with normal or near normal renal
function). According to ISN/RPS classification of LN, Class I, Class II
(with proteinuria <3 g/day) and Class VI LN do not need any
treatment from renal point of view but should be treated as per
extrarenal indications. All these major guidelines advise
immunosuppression with either CYC or MMF combined with
steroids in Class III/IV LN. ACR guidelines25 advocate to prefer
MMF in Class III/IV LN, especially in African Americans and
Hispanics. The KDIGO24 and EULAR26 guidelines advise dose
target for MMF of 3 g/day, whereas ACR recommends 3 g/day for
non-Asians and 2 g/day for Asians. Euro lupus regimen is
recommended as alternate to MMF by EULAR/ERA-EDTA in severe

116. CPG SUMMARY 2
• Both ACR and EULAR/ERA-EDTA recommend the use of steroids
plus MMF in Class V LN with nephrotic range proteinuria whereas
KDIGO recommends to choose any of CYC/MMF/AZA/CNI along
with steroids in Class V LN.
• Steroids as per MCD are advised for the treatment of lupus
podocytopathy, which has ultra-structural homology with MCD.
There is evidence to use either of MMF or CYC in severe/crescentic
LN, albeit with longer experience for later agent.