Lupus Nephritis - 2021.pptx

Lupus Nephritis
Ibrahim Sandokji

A 15-year-old Hispanic female presents with 3 days of
cola-colored urine. Her temperature is 37°C, blood
pressure is 140/85 mm Hg, and heart rate is 80
beats/min. On physical examination, she has generalized
body edema. Her laboratory workup is notable for a BUN
of 29 mg/dL (10.4 mmol/L) and creatinine of 1.9 mg/dL
(168 μmol/L). Her urinalysis has a specific gravity of
1.020 with 300 mg/dL of protein and large blood with 35
RBC/hpf. She undergoes a renal biopsy, which has the
finding depicted in the Figure in 18 out of 22 glomeruli.
Immunofluorescence demonstrates:
Immunoglobulin A, 2+ Immunoglobulin G, 3+
Immunoglobulin M, 1+ C3, 2+
C1q, 3+ C4, 1+
Of the following, the MOST important factor in
determining the appropriate therapy for this patient is:
A. findings on light microscopy
B. level of proteinuria
C. level of serum creatinine
D. percent of glomeruli affected
E. positive immunofluorescence
for immunoglobulin A

Background
•Epidemiology
•Pathogenesis
•Presentation
•Classification
Treatment
•Class I/I
•Class III/IV
•Induction
•Maintenance
•New agents
•Class V

Epidemiology
Renal involvement occurs in 2/3 of patients with childhood-onset SLE
Males with SLE tend to have more aggressive disease than females
Lupus nephritis typically develops early in the disease course (first 6 to 36
months), and may be present at initial diagnosis
Development of lupus nephritis is associated with higher mortality
Parikh et al. Update on Lupus Nephritis. AJKD. 2020
Levy et al. Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis, UpToDate, 2020

Epidemiology
Risk factors for the development of lupus nephritis include:
Younger age
Male sex
Non-European ancestry
In the United States, the incidence of LN is higher in black (34%-51%), Hispanic
(31%-43%), and Asian (33%-55%) compared with white (14%-23%) patients
Black and Hispanic patients have worse outcomes than white patients (even
after adjustment for socioeconomic status)
LN occurs in 50% of Arab SLE patients
Levy et al. Childhood-onset systemic lupus erythematosus (SLE). UpToDate. 2020
Haider. Lupus Nephritis among Arabs - Differences with other Races;
Emphasis on Clinicopathological and Serological Perspectives. 2000

Lupus nephritis in Saudi Arabia
Al-Mayouf SM, AlAmeer A, Alfattani A, Alsonbul A. Outcome of childhood lupus nephritis in Saudi children. Saudi J Kidney Dis Transpl. 2017
•.

Genetics
Kher et al (2016). Clinical Pediatric Nephrology, 3rd Edition

Genetics
Genome-wide association studies (GWAS) have identified risk genes in LN
that are not otherwise seen in patients with SLE without nephritis:
Apolipoprotein L1 (APOL1)
Platelet-derived growth factor receptor alpha (PDGFRA)
Hyaluronan synthase 2 (HAS2)
Genetic modifications in HLA alleles are also associated with LN:
HLA-DR4 and HLA-DR11 appear to protect against LN
HLA-DR3 and HLA-DR15 increase risk of LN

Pathogenesis
Anders et al. A pathophysiology-based approach to the diagnosis and treatment of lupus nephritis. Kidney International. 2016.

Davidson. Lupus nephritis: lessons from murine models. Nat. Rev. Rheumatol. 2009

Presentation
Almaani. Update on Lupus Nephritis. CJASN. 2017
All SLE patients should
be evaluated for renal
involvement:
At the diagnosis
At disease flares
Routine screening q3-6 mo
(at least annually)

2019 EULAR/ACR revised
diagnostic criteria
Required a positive ANA at least once as
obligatory entry criterion
Weighted criteria grouped in 7 clinical and
3 immunological domains
Patients accumulating ≥10 points are
classified
Aringer. Ann Rheum Dis 2019

Kidney biopsy
The gold standard for diagnosis and
classification of LN
A biopsy is required when:
Urine protein excretion > 500 mg/d
↓GFR not attributed to another cause
Active sediments, dysmorphic RBCs,
and/or urinary casts
Dysmorphic red blood cells (acanthocytes)
red blood cell cast

Almaani et al. Update on Lupus Nephritis. CJASN. 2017
Re-biopsy

Histological classification
• WHO classification (1974)
Only addressed glomerular lesions
• ISKDC modified WHO classification in 1982 and again in 1995
• International Society of Nephrology / Renal pathology Society
(ISN/RPS) 2003
– includes activity, chronicity, qualitative and quantitative
lesions (Class III/IV)

Detailed
International
Society Of
Nephrology/Renal
Pathology Society
2003 classification
of lupus nephritis

ISN/RPS LN Classification
2018 revisions
Definition for mesangial hypercellularity adjusted
The term endocapillary proliferation is replaced by endocapillary hypercellularity
Elimination of segmental and global subdivisions of class IV
Modification of the NIH lupus nephritis activity and chronicity scoring system to be used instead of
the old A, C, and A/C parameters
M Bajema et al.: Revision of lupus nephritis classification. Kidney Int, 2018.

Pinheiro. Pediatric lupus nephritis. J Bras Nefrol, 2019

Characteristic LN deposits on IF
• Polyclonal (kappa and lambda) IgG
• Complement components (C3, C1q)
When all three immunoglobulin
isotypes, IgG, IgM and IgA are present,
the pattern is often referred to as
“full house” staining.

Treatment
General management of
patients with lupus nephritis
KDIGO Draft. 2020

Antimalarial therapy
Hydroxychloroquine
Prevent lupus flares
Increase long-term survival
Generally minimal side effects
Safe during pregnancy
Regular examination by an ophthalmologist (ocular toxicity)
Antimalarials are immunomodulators -> act on the innate
immune system by blocking TLR signaling on dendritic cells
-> reduce production of IFN-α and downstream
proinflammatory cytokines
Ruiz-Irastorza, et al. Antimalarials in SLE: a systematic review. Annals of the Rheumatic Diseases 2010
KDIGO Draft. 2020
Pinheiro. Pediatric lupus nephritis. J Bras Nefrol, 2019

Clinicopathological treatment protocols
LN Class I
Treatment of extrarenal
manifestations
Prednisone/prednisolone
< 0.5 mg/kg/day – max 30 mg/day
HCQ is generally not needed
LN Class II
Treatment of extrarenal
manifestations
Prednisone/prednisolone
0.25-0.5 mg/kg/day – max 30 mg/day
HCQ is generally needed
Pinheiro. Pediatric lupus nephritis. J Bras Nefrol. 2019
Kher. Clinical Pediatric Nephrology. 3rd Edition. 2016

Treatment approach

Mesangial hypercellularity Endocapillary hypercellularity
Fibrous crescent Fibrocellular crescent
Cellular crescent
Identify the
pathology

Cyclophosphamide
Landmark NIH study
Compared Steroid-only induction to
Steroid plus IV CYC induction
Dose of IV CYC: 0.5-1 g/m2 monthly pulses
for 6 months, total dose exposure of 9-12 g
But cyclophosphamide -> significant toxicities
(e.g. ovarian failure, BM suppression, & malignancies)
The addition of IV cyclophosphamide to
corticosteroid treatment improved kidney
outcomes and reduced kidney failure risk
beyond corticosteroids alone

High vs low-dose cyclophosphamide
Arthritis & Rheumatism. 2002
High-dose (NIH)
IV 0.5-1 g/m2 monthly
pulses for 6 months
Low-dose (Euro-Lupus)
IV 500 mg every 2 weeks
for 6 doses
Each followed by AZA
n=90
>14y
There was no significantly
greater cumulative
probability of treatment
failure in patients given
low-dose than in those
given a high-dose
Higher rate of severe
infections in high-dose
group (not significant)
P = 0.64

High vs low-dose cyclophosphamide
The 2 regimens were equally effective for short-term remission induction & long-term renal
preservation
There were fewer adverse events in low-dose group
BUT
Study population of
European, primarily
Caucasian, might not be
generalizable to other
populations that tend to
have more severe nephritis
(e.g., black and Hispanic)

Comparing different populations in different
trials
ACCESS
North American population
37% black & 41% Hispanic
>16y
The addition of Abatacept did not improve
response to low-dose cyclophosphamide
ALMS
88 centers in 20 countries in North America, Latin
America, Asia, Australia, and Europe
Comparing MMF to high-dose cyclophosphamide
12 to 75 yr
Low-dose IV CYC is closely comparable to high-dose in different patient populations
-> Low-dose IV CY
-> Low-dose IV CY
-> High-dose IV CY
-> High-dose IV CY

MMF vs cyclophosphamide
Aspreva Lupus Management Study
(ALMS)
88 centers in 20 countries in North
America, Latin America, Asia, Australia,
and Europe
12 to 75 yr
N=370
Compared MMF (3 g/d) with NIH-
regimen cyclophosphamide for LN
induction
Mostly black or
Latin American
mixed race
JASN 2009
-> High-dose
(NIH protocol)
Equal efficacy at 6 months and after
3.5 years in all groups except in

The Journal of Rheumatology 2011
Leucopenia
Infections
Gastrointestinal
Herpes Zoster
Amenorrhea
Alopecia
ESRD
Death
MMF was not superior to cyclophosphamide for renal remission

Rituximab
Lupus Nephritis Assessment With
Rituximab (LUNAR) Study
Phase III RCT
n=144
Patients on MMF and steroids were
randomized: rituximab vs placebo
Primary end point: renal response
status at week 52
Arthritis Rheum. 2012
The combination of rituximab with MMF and
corticosteroids did not improve clinical outcomes after 1
year of treatment

Rituximab
n=44
3.5-13.8 (median 8.4) years
Retrospective review
Primary outcome: flare-free survival
Induction:
IV methylpred pulses (15 mg/kg x3 daily)
Followed by
Two RTX infusions (375 mg/m2 weekly)
Or
MMF 1200 mg/m2 daily
Or
Six CYC pulses IV of 500 mg/m2 every fortnight for 1 mo
Maintenance:
Tapering pred and MMF 800 mg/m2/day in 2 doses
p = 0.006
Pediatr Nephrol. 2017
-> 8 AE
-> 10 AE
-> 15 AE (1 death)
Flare-free survival was significantly higher at 36 months
with RTX compared with MMF and CYC

Rituximab
n=19
6–16 (median 14) years
Refractory proliferative LN
Rituximab 750 mg/m2 given
twice, within a 2-week period
In 1 mo, improvement in renal
function, immunological &
hematological parameters
Herpes zoster in 5 pts
Arch Dis Child. 2008 J Pediatr. 2006
n=8
Median age 13.9 years
2 to 12 rituximab infusions
(350-450 mg/m2/infusion)
Remission in 6/8 patients
Arthritis Rheum. 2005
n=7
7.7-16.1 (median 14.8) years
Refractory proliferative LN
Rituximab 750 mg/m2 given
twice, within a 2-week period
In all patients, improvement in
renal function, immunological
& hematological parameters
No serious adverse effects
Rituximab is still a promising treatment, especially in refractory LN

Multi-target therapy (MMF + Tac)
Randomized, open-label,
multicenter study
26 centers in China
n=362
18 to 65 yrs
Tac (4 mg/d) +MMF (1g/d)
Vs
IV cyclophosphamide (NIH
dose)
Both received pulse then
tapering steroids (to 10 mg/d)
Primary end point: complete
remission at 24 wk
Ann Intern Med. 2015
Complete remission:
MTT group 45.9%
IV CYC 25.6%
Incidence of adverse
events was not
statistically different
Multitarget therapy provides superior efficacy compared with intravenous cyclophosphamide as induction therapy

Abatacept
Randomized, double-blind phase II trial
37% black & 41% Hispanic
>16y
The addition of Abatacept did not improve
response to low-dose cyclophosphamide
(Euro‐Lupus (EL))
Arthritis Rheumatol. 2014
Monoclonal antibody
Inhibits T-cell responsiveness by
blocking the second signal from APC

Belimumab (Benlysta)
A human monoclonal antibody
Binds the soluble form of the B-cell survival
factor, B-lymphocyte stimulator (BLyS)
-> prevent it from signaling on B cells -> apoptosis

Primary end point: primary efficacy renal
response at week 104
 a ratio of urinary protein to creatinine of ≤0.7
 an eGFR that was no worse than 20% below
the value before the renal flare (pre-flare
value) or ≥60 ml/min/ 1.73 m2
 no use of rescue therapy
Primary efficacy renal
Belimumab group 43%
Placebo group 32%
Odds ratio, 1.6; 95% CI, 1.0 to 2.3
P=0.03
Phase 3, randomized, double-blind, placebo-controlled trial conducted at 107 sites in 21 countries
In adult patients, Belimumab plus standard therapies for lupus nephritis enhanced renal

Voclosporin
New CNI
Structurally similar to cyclosporine A except for
a single carbon bond extension with a double bond
Approved for lupus nephritis in adults
Better lipid and glucose metabolic profile than other CNIs
Does not impair insulin secretion (less DM than Tac)
Consistent dose-response (potentially does not need drug monitoring)

May 2021
Multicenter, double-blind, randomized phase 3 trial
142 centers in 27 countries
Voclosporin vs placebo
All with MMF 1 g BID and tapered PO steroids
Primary endpoint: Complete renal response at
1 year
Voclosporin: 73 [41%] of 179
Placebo: 40 [23%] of 178

Maintenance therapy for active class III/IV
Mycophenolate
mofetil
Azathioprine
Fewer side effects
Teratogenic
More adverse events (hematological and malignant)
Safe in pregnancy

Ann Rheum Dis. 2010
MMF Vs Aza
n = 105
RCT
Pulse -> tapering steroids + IV CYC
Then randomized to
AZA (target dose: 2 mg/kg/day)
or MMF (target dose: 2 g/day)
White Caucasian 79% of study population
Primary end point: time to renal flare
There was no difference in time to first renal flare between MMF and azathioprine
No difference in adverse events except more hematological cytopenias with AZA (p=0.03)

MMF Vs Aza
The Aspreva Lupus Management
Study (ALMS) trial
Randomized, double-blind, double-dummy,
phase 3 study
Multiethnic population
n = 227
MMF (2 g/d) Vs azathioprine (2 mg/kg/day)
Primary end point:
Time to treatment failure:
Death
End-stage renal diseased
Doubling of the sCr
Renal flare
Rescue therapy for lupus nephritis
N Engl J Med 2011
MMF was found to be superior to in preventing treatment failure
(16.4% vs 32.4%, respectively; P = 0.003)

Multi-target therapy (MMF + Tac) vs Aza
Continued trial of multi-target therapy
vs IV CYC
MT patients -> continued
MMF (0.75 g/d for 6 mo -> 0.5 g/d)
Tac (3 mg/d for 6 mo -> 2 mg/d)
IV CYC patients -> Aza (2 mg/kg/d)
All continued PO Pred 10 mg/d
Both groups had similar cumulative renal relapse rates
More adverse events with AZA (40 compared to 19 in MMF+Tac, p=<0.01)
JASN 2017

KDIGO Draft. 2020
Maintenance therapy for active class III/IV

Class V
Class V LN accounts for 5% to 10% of all LN
cases
Less frequent than proliferative LN and well-
powered RCTs of treatment options are lacking
Unlike primary membranous nephropathy, class
V LN does not typically remit spontaneously.

KDIGO Draft. 2020
Therapy for class V LN

Correct answer A. findings on light microscopy
The patient presents with a history and biopsy findings
consistent with lupus nephritis. The finding of proliferative
lesions on light microscopy as shown in Figure will lead to a
classification of either class III (if <50% of glomeruli are
affected) or class IV (if >50% glomeruli are affected) lupus
nephritis.
In the patient in the vignette, more than 50% of glomeruli
had proliferative lesions, giving this patient class IV lupus
nephritis. The class of lupus nephritis is the major factor that
determines prognosis and treatment, and thus response
choice A is the preferred answer.
While the percentage of glomeruli affected in class IV lupus
nephritis reflects more severe disease and potential for worse
outcomes, the choices for therapy do not differ between class
III and class IV lupus nephritis.
In contrast, in pure class V lupus nephritis, therapy is guided
by the level of serum creatinine and proteinuria.
Finally, the positive immunofluorescence for immunoglobulin
G (IgG), immunoglobulin M (IgM), immunoglobulin A (IgA),
C1q, and C3 is characteristic of lupus nephritis, but does not
define the treatment or prognosis.
A. findings on light microscopy
B. level of proteinuria
C. level of serum creatinine
D. percent of glomeruli affected
E. positive immunofluorescence
for immunoglobulin A

Lupus nephritis in Saudi Arabia
Al Arfaj. Lupus nephritis among 624 cases of systemic lupus erythematosus in Riyadh, Saudi Arabia. Rheumatol Int. 2009

Al Arfaj. Lupus nephritis among 624 cases of systemic lupus erythematosus in Riyadh, Saudi Arabia. Rheumatol Int. 2009

M Bajema et al.: Revision of lupus nephritis classification. Kidney Int, 2018.

Classification
Anders. A pathophysiology-based approach to the diagnosis and treatment of lupus nephritis. Kidney International. 2016.

Oni, L. et al. Kidney outcomes for children with lupus nephritis. Pediatr

Treatment strategy
Treatment goals in lupus nephritis
Anders et al. A pathophysiology-based approach to the diagnosis
and treatment of lupus nephritis. Kidney International. 2016.

Treatment for lupus nephritis is
based on the renal biopsy
pathologic findings
Class I and II lupus may respond to
corticosteroids and management of
extrarenal manifestations of SLE
Proliferative lupus nephritis (class
III and IV) requires escalation of
immunotherapy regimen

Induction
Steroid options
IV methylpred (30 mg/kg/dose x3 consecutive days - maximum dose 1g)
followed by oral Pred (0.5-1 mg/kg/day – max 40 mg/day, x4 wks), gradual
withdrawal
High-dose oral Pred (1-2 mg/kg/day – max 60 mg/day, x4 wks), gradual
withdrawal
Plus either
Euro-Lupus: IV cyclophosphamide (500 mg doses, q 15 days x3 mo - total
3000 mg) followed by maintenance therapy with AZA
NIH: IV cyclophosphamide (500 mg/m2, increased to 750 mg/m2 if
tolerated, q 30 days x6 mo – max 1 g) followed by trimestral doses for 18 mo
SHARE: oral MMF (1200 mg/m2/day, for 6 mo – max 3000 mg/day)
Maintenance
Oral AZA
2-3 mg/kg/day
max 150 mg/day
Oral MMF
500-3000 mg/day
Class III/IV
Pinheiro. Pediatric lupus nephritis. J Bras Nefrol. 2019

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