Lupus Nephritis

Dr.B.P.Gaminda
Systemic lupus erythematosus (SLE) is an autoimmune
disorder characterized by antibodies to nuclear and
cytoplasmic antigens, multisystem inflammation and a
relapsing and remitting course.
Global Situation and Genetics
 Worldwide, the prevalence of SLE varies. The highest rates of prevalence
have been reported in Italy, Spain, Martinique, and the United Kingdom
Afro-Caribbean population.
 The disease appears to be more common in urban than rural areas
 In children, in whom sex hormonal effects are presumably minimal, the
female-to-male ratio is 3:1
 In adults, especially in women of childbearing years, the ratio ranges
from 7:1 to 15:1
 In "older" individuals, especially post-menopausal women, the ratio is
approximately 8:1
 At least 3 predisposing gene variants are located on X chromosomes
(IRAK1, MECP2, TLR7). In XXY (Klinefelter's syndrome) prevalance is
increased 14-fold in men, whereas XO (Turner's syndrome) SLE is
underrepresented.
 Men tend to have worse outcomes.
 65% of patients with SLE have disease onset between the ages 16 and 55.
Of the remaining cases, 20% present before age 16 and 15% after age 55.
Diagnostic Criteria
EULAR/ACR
2019
Lupus Nephritis
Lupus nephritis typically develops early in the disease course.
Clinically evident kidney disease eventually occurs in up to
one-half of patients with SLE.
10% of patients with LN will develop ESKD.
 In one cohort of 1827 patients with newly diagnosed SLE, LN
occurred in 700 (38 %) Patients followed for a mean of 4.6
years. The overall 10-year incidence of ESKD was 4 % and, in
patients with LN, 10%. In this cohort, LN was also associated
with a threefold increased risk of death.
Greater risk for progressive kidney disease includes African or
Hispanic ancestry, male sex, paediatric onset, frequent
relapses or incomplete remission, and proteinuria >4
g/day at diagnosis.
When to suspect LN
The presence of lupus nephritis should be suspected in
patients developing an active urinary sediment with
persistent heamaturia (5 or more RBC, most of
which are dysmorphic) and/or cellular casts,
proteinuria, and/or an elevated serum creatinine
(or decrease in eGFR). Elevated anti-dsDNA titers
and low complement (C3 and C4) levels often indicate
active SLE
Role of kidney biopsy
Urine protein excretion greater than 500 mg/day.
An active urinary sediment with persistent hematuria
A rising serum creatinine that is not clearly
attributable to another mechanism.
Histopathologic classification of LN
Minimal mesangial LN (class I) –
Normal urinalysis, no or minimal proteinuria, and a
normal serum creatinine.
Mesangial immune deposits that are identified by
immunofluorescence alone or by both
immunofluorescence and electron microscopy, but
such patients do not have light microscopic
abnormalities.
 Mesangial proliferative LN (class II)
Microscopic haematuria and/or
proteinuria. Hypertension is uncommon,
and nephrotic syndrome and kidney
function impairment are very rare.
Light microscopy reveals mesangial
hypercellularity or mesangial matrix
expansion. A few isolated subepithelial
or subendothelial deposits may be seen
on immunofluorescence or electron
microscopy.
Focal LN (class III)
Haematuria and proteinuria, and some patients will also
have hypertension, a decreased GFR, and/or nephrotic
syndrome.
Less than 50 percent of glomeruli are affected by light
microscopy.
Active or inactive endocapillary or extracapillary
glomerulonephritis is almost always segmental.
Electron microscopy usually reveals immune deposits
in the subendothelial space of the glomerular capillary
wall as well as the mesangium.
Diffuse LN (class IV)
Most severe form of lupus nephritis.
Hematuria and proteinuria are present in
virtually all patients. Nephrotic
syndrome, hypertension, and reduced
GFR are all frequently seen. Affected
patients typically have
hypocomplementemia (especially C3)
and elevated anti-dsDNA levels,
especially during active disease.
More than 50 percent of glomeruli are
affected by light microscopy
Affected glomeruli display endocapillary
with or without extracapillary
glomerulonephritis. Mesangial
abnormalities may also be observed.
Electron microscopy reveals
subendothelial deposits.
Lupus membranous nephropathy (class V)
Typically present with signs of nephrotic
syndrome, similar to that in primary
membranous nephropathy.
Microscopic hematuria and
hypertension may also be seen at
presentation, and creatinine is usually
normal or only slightly elevated.
Class V disease is characterized by
diffuse thickening of the glomerular
capillary wall on light microscopy and
by subepithelial immune deposits
(either global or segmental
involvement) on immunofluorescence
or electron microscopy . Mesangial
involvement may also be seen.
Advanced sclerosing LN (class VI)
Slowly progressive kidney dysfunction in association
with proteinuria and a relatively bland urine sediment.
Class VI disease is characterized by global sclerosis of
more than 90 % of glomeruli. It represents healing of
prior inflammatory injury, as well as the advanced
stage of chronic class III, IV, or V lupus nephritis.
Therapy
Immunosuppressive therapy is used to treat active focal (class III) or
diffuse (class IV) LN or lupus membranous nephropathy (class V LN),
whereas it is not usually used to treat minimal mesangial (class I),
mesangial proliferative (class II), or advanced sclerosing (class VI) LN.
The treatment has two main components: initial therapy with anti
inflammatory and immunosuppressive agents to control inflammation
and halt kidney injury, followed by long-term subsequent
immunosuppressive therapy to control the chronic autoimmune
processes
The likelihood of a successful initial outcome is greater if therapy is
initiated early in the course of the disease. A single episode of LN can
lead to irreversible nephron loss, and every subsequent LN flare
contributes to organ damage. Early therapy is crucial to prevent
successive decreases in kidney function
Initial therapy with MMF or
cyclophosphamide
MMF-based regimen-[ALMS] compared initial
therapy with MMF or Cyclophosphomide. Complete
renal response, systemic disease activity improvement,
and safety were similar.
Cyclophosphamide-based regimen - Shorter, lower-
dose regimen IV Cyclophosphamide is administered
as 500 mg every two weeks for a total of six doses.
Longer, higher-dose regimen pulse IV
Cyclophosphamide (0.5 to 1 g/m2) is administered
monthly for six to seven months.
ELNT, showed equivalent outcomes at a median of 41
months with the shorter and longer regimens, each
followed by subsequent therapy with Azathioprine
Oral glucocorticoid therapy is typically started at 0.5
to 1 mg/kg per day . In patients with severe active
disease IV pulse Methylprednisolone (250 to 1000 mg
is given over 30 minutes daily for three days) prior to
initiation of oral glucocorticoids to induce a rapid
antiinflammatory effect.
Newer Therapeutic Options
Belimumab, an anti-BAFF monoclonal antibody,
was the first biological agent approved for SLE in
2011. It was subsequently approved for LN in
December 2020. (BLISS)
Voclosporin, a novel oral calcineurin inhibitor,
was approved for LN in January 2021 based on
results from the AURORA trials.
Anifrolumab, an anti-interferon-α mAb, was
approved for moderate to severe SLE in August
2021 making it the only new drug for SLE in over
a decade. It is currently undergoing a phase 3
trial in LN.(TULIP)
Subsequent therapy
MAINTAIN trial confirms similar efficacy between
MMF and Azathioprine as subsequent therapy agents.
Patients who are intolerant to both MMF and
Azathioprine can be treated with Cyclosporine or
Tacrolimus.
Low-dose oral Prednisolone is continued in most
patients receiving subsequent therapy. Patients who
remain asymptomatic can be slowly tapered off
steroids.
General supportive measures in patients
Dietary sodium restriction
Antihypertensive therapy
Lipid lowering
Prevention of Pneumocystis jirovecii pneumonia
Prevention of cyclophosphamide-induced bladder and
gonadal toxicity
Minimizing glucocorticoid-induced bone loss and
other adverse effects
Benefits of HCQ in SLE
Reduce the rate and intensity of flares.
Reduce disease intensity in lupus nephritis.
Improves lipid profile and cardiovascular benefit
Reduce the incidence of neonatal CHB in anti Ro/La +
pregnancies.
Contribute to the maintenance of remission.
Therapy of resistant lupus nephritis
In general, Cyclophosphamide-resistant patients are
treated with MMF, and MMF-resistant patients with
Cyclophosphamide.
 The induction and maintenance regimens are same
as those used for primary therapy.
Patients who fail treatment with both
Cyclophosphamide and MMF may be treated with
rituximab.
 Another option is to use "multitargeted therapy" with
a combination of glucocorticoids,MMF, and
tacrolimus. This regimen has been used for both
induction and maintenance therapy.
Therapy of lupus membranous
nephropathy
Non immunosuppressive therapy is the mainstay of
management. All patients should be treated with
antihypertensive, antiproteinuric, and lipid-lowering measures.
Anticoagulation in severe nephrotic syndrome is
individualized.
Indications for immunosuppressive therapy-
1. Nephrotic syndrome or, in the absence of nephrotic
syndrome, persistent proteinuria >3.5 g/day despite non
immunosuppressive therapy.
2. A progressive rise in serum creatinine above baseline.
3. Mixed membranous and proliferative lesions on biopsy
Remission
The 2019 EULAR/ERA-EDTA guidelines
recommend, as goals of therapy, a decrease in
proteinuria of ≥25 percent by three months, ≥50
percent by six months, and proteinuria below 0.5
to 0.7 g/day by 12 months of initial therapy.
Role of kidney transplanttion
 Approximately 10 to 30 %
of patients with
proliferative lupus
nephritis progress to
ESRD.
 Patient survival with
either HD or CAPD
appears to be similar to
that in the general
population of patients
with ESRD.
 Kidney transplantation
has been associated with
improved survival among
patients with ESRD due to
lupus nephritis
Kidney transplantation is associated with a 70%
reduction in all-cause mortality
 It is recommended that all patients with ESRD due to
lupus nephritis be dialysed for at least 3 - 6 months and
be on less than 10 mg/d of prednisone before kidney
transplantation
However, a period of dialysis is not necessary for
patients with a slow, progressive course to ESRD who
have been shown to have only chronic sclerosing lesion
on kidney biopsy and who exhibit no clinical or
serologic activity. Such patients often undergo
preemptive kidney transplantation.
The reported rate of clinically apparent recurrent lupus
nephritis in the kidney transplant is 2 to 11%
Pregnancy and SLE
Fertility in SLE patients does not appear to be altered by
disease itself; however, a decrease in ovarian reserve can
occur in women exposed to cyclophosphamide.
Ovum preservation and GnRH analogues can be used in
patients receiving cyclophosphamide.
The prognosis for both mother and child is best when
SLE has been quiescent for at least six months prior to
the pregnancy.
Antibodies to Ro/La should be assessed prior to
pregnancy, as these antibodies may predispose to
neonatal lupus.
For most pregnant women with SLE, continuation of
HCQ reduces the risk of SLE flares.
Low-dose aspirin in all women with SLE, starting from
approximately 12 weeks gestation, to reduce the risk of
preeclampsia and its sequelae (eg, fetal growth
restriction), regardless of the presence of
antiphospholipid antibodies.
Control of disease with the lowest possible dose of
prednisolone.
Should be off MMF at least 6 weeks.
Azathioprine and cyclosporin are compatible with
pregnancy.
Methyldopa, labetalol, nifedipine, and hydralazine are
the most commonly used antihypertensives in
pregnancy.
There is a small increased risk of oligohydramnios
when NSAIDs are used beyond 20 weeks.FDA
recommends that the lowest dose and shortest
duration of NSAID be used between 20 and 30 weeks
of gestation. Use of NSAIDs after 30 weeks of gestation
may cause premature closure of the ductus arteriosus,
as well as other complications, and should be avoided
altogether from the third trimester on.
Contraindicated in pregnancy
Cyclophosphomide
MMF
Methotrexate
Leflunomide
Although it is generally accepted that pregnancy and
the postpartum period are associated with a higher rate
of SLE disease flares, widely variable rates have been
reported ranging from 25 to 60 percent
The following factors are associated with an increased
risk of SLE flare during pregnancy :
●Active disease during the six months prior to conception
●A history of lupus nephritis
●Discontinuation of HCQ
●Primigravidas
Thank You