SYSTEMIC DISEASE AND THE KIDNEY

Lupus nephropathy and Key points

vasculitis Lupus nephritis:
C Lupus nephritis is common in patients with systemic lupus
Dominic McGovern erythematosus and can be asymptomatic
Lisa Willcocks
C The development of lupus nephritis strongly influences renal
Rachel Jones and patient survival

C Current treatments are glucocorticoids with an immunosup-

Abstract pressive agent, mycophenolate mofetil, or cyclophosphamide
Multisystem autoimmune diseases, including systemic lupus erythe- plus hydroxychloroquine
matosus (SLE) and vasculitis, are inflammatory conditions of unknown
cause. Renal involvement occurs in a variety of forms and usually rep- C Other treatment options include calcineurin inhibitors (voclo-
resents a severe disease manifestation. SLE is complicated by renal sporin, tacrolimus, ciclosporin) and B cell therapies (rituximab,
involvement (lupus nephritis) in over one-third of individuals. Small belimumab) or azathioprine
vessel vasculitides, including antineutrophil cytoplasmic antibody-
associated vasculitis, also frequently affect the kidneys, causing a
rapidly progressive glomerulonephritis. Histologically, this manifests ANCA-associated vasculitis:
as a necrotizing, crescentic glomerulonephritis. This is potentially
reversible but if left untreated generally results in end-stage renal fail- C Antineutrophil cytoplasmic antibody (ANCA)-associated
ure and death within days to weeks. A crescentic glomerulonephritis vasculitis (AAV) is the most common cause of rapidly pro-
can also be seen in SLE, but this is not the typical pattern of lupus gressive glomerulonephritis (RPGN)
nephritis, which is usually characterized by immune complex deposi-
tion causing a diffuse, proliferative glomerulonephritis. Lupus nephritis C If untreated, RPGN secondary to ANCA-associated vasculitis
and renal vasculitis are the most frequent causes of renal failure in progresses rapidly to end-stage renal failure
multisystem autoimmune disease.
C Haematuria and proteinuria, deteriorating renal function and
Keywords Antineutrophil cytoplasmic antibody-associated vascu-
ANCA positivity point to the diagnosis of renal AAV. If detected
litis; autoimmune disease; granulomatosis with polyangiitis; immuno-
early, haematuria and proteinuria can be present with normal
suppression; lupus nephritis; microscopic polyangiitis; rapidly
renal function, highlighting the importance of urinalysis and
progressive glomerulonephritis; systemic lupus erythematosus; sys-
ANCA testing
temic vasculitis

C About 90% of patients respond well to treatment, and early

detection and treatment is associated with improved renal
outcomes
Lupus nephritis
Epidemiology
C Current standard initial treatment includes high-dose cortico-
Systemic lupus erythematosus (SLE) has a prevalence of 97 per steroids with rituximab or cyclophosphamide
100,000 in the UK, with the incidence peaking in the sixth
decade. Female sex and Black Caribbean ancestry greatly in-
C Renal impairment at presentation and older age are the
crease the risk of developing SLE. Overt renal disease occurs in strongest predictors of mortality; mortality at 1 year is 10%
up to 40% of individuals with SLE and is the most common se- and treatment toxicity is a major early contributor
vere manifestation. In the 2012 Systemic Lupus International
Collaborating Clinics diagnostic criteria, lupus nephritis in the
C Life-long follow-up is recommended in view of the high relapse
presence of antinuclear antibodies (ANA) or anti-double- rate and late complications of the disease and its treatment

Dominic McGovern BM BCh MRCP is an Academic Research Fellow at

the University of Cambridge, UK. He has a research interest in ANCA stranded DNA antibodies (anti-dsDNA) is sufficient to make a
vasculitis. Competing interests: none declared. diagnosis of SLE.
The development of nephritis is closely linked to reduced
Lisa Willcocks PhD FRCP is a Consultant in Nephrology and Vasculitis
survival and chronic morbidity: 10e20% of patients die and 10
at Addenbrooke’s Hospital, Cambridge, UK. She has a research
interest in immune-mediated glomerulonephritis. Competing e25% reach end-stage kidney disease (ESKD) within 10 years.
interests: none declared. However, there is considerable variation in the presentation,
pathology, course and outcome. Lupus nephritis responds to
Rachel Jones MD FRCP is a Consultant in Nephrology and Vasculitis
corticosteroid and immunosuppressive therapy, but drug toxicity
at Addenbrooke’s Hospital, Cambridge, UK. She has a research
interest in ANCA vasculitis. Competing interests: none declared. contributes to the morbidity and mortality.

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 SYSTEMIC DISEASE AND THE KIDNEY

Pathology Management
Immune deposits in the glomeruli and mesangium are charac- The treatment of lupus nephritis is governed by the ISN/RPS
teristic of lupus nephritis and stain positive on immunofluores- histological stage. Most data suggest that class I and class II lupus
cence for immunoglobulin (Ig) G, IgM, IgA and complement nephritis have benign courses, and treatment in the absence of
components C3, C1q and C4. Circulating autoantibodies to other indications (e.g. significant extra-renal manifestations) is
cellular antigens (particularly anti-dsDNA, anti-Ro and anti-C1q) usually not required. Immunosuppressive treatment is recom-
and complement activation (with correspondingly reduced mended in active ISN/RPS class III/IV disease. The best treat-
serum C3, C4 and C1q) are typical of lupus nephritis. ment for class V disease is under debate, but the emerging
After the appearance of immune complexes, an inflamma- consensus is that if individuals have significant proteinuria
tory reaction develops, leading to mesangial cell proliferation, (nephrotic range or >1 g/24 hour despite an optimal use of renin
expansion of the mesangial matrix and the infiltration of in- eangiotensinealdosterone system blockers), they should be
flammatory leucocytes. Other pathogenic mechanisms include given immunosuppressive treatment.
the infarction of glomerular segments, thrombotic micro- The first phase of treatment (known as induction) aims to
angiopathy, vasculitis and glomerular sclerosis. Extra- induce disease remission, and this is achieved with a combina-
glomerular features of lupus nephritis include tubulo-interstitial tion of corticosteroids and another immunosuppressive agent.
nephritis (70% of individuals with nephritis), which involves Induction therapy aims for a response by 3e6 months, although
lymphoid follicle formation and T cell tubulitis, renal vein complete remission can take over 24 months. There is a growing
thrombosis and renal artery stenosis. Thrombotic manifesta- awareness of the adverse effect burden of corticosteroids, and the
tions are associated with autoantibodies to phospholipids, cumulative corticosteroid dose should be limited as much as is
which are detectable as circulating anticardiolipin autoanti- clinically safe to do (initial total intravenous methylprednisolone
bodies or lupus anticoagulant. doses of 500 -3000 mg (in 1-3 doses, maximum of 1000mg per
dose) are used according to disease severity by practitioners
Clinical features and prognosis experienced in treating lupus nephritis, with lower dose oral
Nephritis is the first manifestation of disease in 25% of SLE pa- prednisolone thereafter).2
tients. In approximately 5% of cases, renal abnormalities occur In addition to corticosteroids, low-dose intravenous cyclo-
several years before other diagnostic criteria or serological ab- phosphamide (six intravenous infusions of 0.5 g given every 2
normalities. Patients can present with asymptomatic urinary weeks) or mycophenolate mofetil (MMF; 2 -3 g/day) are rec-
abnormalities on routine testing (microscopic haematuria or ommended first-line therapies;1 MMF is preferred in patients of
proteinuria; 40%). Less commonly, lupus nephritis presents as Hispanic, Latin American or African ancestry and in women
acute renal failure, which can be accompanied by other severe where preservation of fertility is important. Higher dose cyclo-
manifestations, such as myocarditis or cerebritis. Poor prognostic phosphamide dosing can be considered in individuals with
factors to be considered when evaluating individuals with lupus reduced kidney function or histological predictors of severe dis-
nephritis include: ease (crescents or necrosis in >25% of the glomeruli). Hydrox-
 demography (black or Hispanic race and ethnicity; delay in ychloroquine is recommended for all individuals with lupus
diagnosis or starting therapy) nephritis to prevent relapse. However, it can cause retinal
 impaired renal function (elevated serum creatinine, toxicity so regular ophthalmic screening is essential.
nephrotic range proteinuria, hypertension) Many individuals with lupus nephritis fail to achieve complete
 anaemia with haematocrit <26% proteinuric remission with MMF or cyclophosphamide. These
 histopathology (severity of acute and chronic tubulo- patients may require either a switch between cyclophosphamide
interstitial disease and interstitial inflammation; presence and MMF or the addition of another therapy. Calcineurin in-
of cellular crescents) hibitors (tacrolimus, voclosporin, ciclosporin) can be used with
 higher relapse rate and failure to achieve partial or com- low-dose MMF for patients with preserved renal function.
plete remission B lymphocytes play an important role in the pathogenesis of
 suggestions from recent trial evidence that proteinuria at SLE and lupus nephritis. Belimumab, which blocks the action of
12 months is the single best predictor of ESKD. B-cell activating factor (BAFF) is safe and effective as add-on
The histological appearance of glomerular disease has been therapy to cyclophosphamide or MMF in lupus nephritis. The B
classified according to the pattern and extent of immune depo- cell-depleting therapy rituximab is also widely used in addition to
sition and inflammation by the International Society of either MMF or cyclophosphamide, while another B cell-depleting
Nephrology/Renal Pathology Society (ISN/RPS) (Table 1, therapy e obinutuzumab e is being investigated alongside MMF
Figure 1). Transformation to a more or less severe histological in clinical trials of lupus nephritis.
class is well documented; this can result from treatment or be A failure to reach complete remission with induction therapy,
part of the disease’s natural history. The activity and chronicity or early withdrawal of immunosuppression, increases relapse
of lesions identified at renal biopsy are used to assess whether rates, so longer term maintenance therapy with MMF or azathi-
treatment should be intensified, and chronicity indices predict oprine (alongside low-dose prednisolone) is commonly used.
long-term renal outcomes.1 MMF is more effective at preventing relapse than azathioprine.
The risk of cardiovascular disease is greatly increased in SLE Voclosporin, ciclosporin and tacrolimus can also be used to
and is a major cause of late mortality; secondary prevention maintain remission. The optimum duration of therapy is debated
therapy for cardiovascular disease should be considered. e continuing treatment for at least 36 months is recommended,

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 SYSTEMIC DISEASE AND THE KIDNEY

ISN/RPS 2004 classification of lupus nephritis4

Class I: Minimal mesangial lupus nephritis
C Normal glomeruli on light microscopy with mesangial immune deposits on immunofluorescence
Class II: Mesangial lupus nephritis
C Mesangial hypercellularity with mesangial immune deposits on immunofluorescence
Class III: Focal proliferative lupus nephritis
C Focal proliferative glomerulonephritis involving <50% of the glomeruli, typically with focal subendothelial immune deposits and leucocyte
infiltration
Class IV: Diffuse proliferative lupus nephritis
C Diffuse proliferative glomerulonephritis involving 50% of the glomeruli, typically diffuse subendothelial immune deposits
Class V: Membranous lupus nephritis
C Thickening of the capillary walls and global or segmental subepithelial immune deposits
Class VI: Advanced sclerosis lupus nephritis
C 90% glomeruli globally sclerosed

Table 1

and repeat biopsy to assess for disease activity can be used to Pregnancy and lupus nephritis
predict the risk of flare if immunosuppression is withdrawn. SLE and its treatment can impair fertility, and pre-existing renal
Cyclophosphamide, MMF and azathioprine are associated impairment, proteinuria or hypertension increases the risks of
with severe adverse effects. Cyclophosphamide is associated pregnancy for both mother and fetus. Secondary anti-
with infertility and premature menopause, myelosuppression, an phospholipid syndrome frequently occurs in individuals with
increased risk of severe infections and (with total cumulative lupus nephritis and is associated with recurrent miscarriage.
doses >20 g) bladder malignancy. The risk of infection during Lupus nephritis can relapse during pregnancy, and treatment
treatment with MMF and cyclophosphamide is similar. Both should therefore not be reduced before or during pregnancy e
MMF and cyclophosphamide are teratogenic and should be azathioprine, hydroxychloroquine and corticosteroids are all
avoided in pregnancy. Long-term azathioprine use is associated used during pregnancy. Pregnancy is not recommended when
with an increased risk of non-melanoma skin cancer. The effects lupus nephritis is active and for at least 6 months after complete
of rituximab on B cells can last for over a year, impairing sub- remission has been achieved. Antiplatelet therapy with aspirin
sequent vaccine responses e if possible coronavirus disease and low-molecular-weight heparin is used to reduce the risk of
(COVID-19), pneumococcal and influenza vaccination should placental failure in higher risk cases. The immediate postpartum
be performed before rituximab administration. period is associated with a high risk of relapse, and closer

Figure 1 Renal histology in class IV lupus nephritis on (a) light microscopy and (b) immunofluorescence. Antineutrophil cytoplasmic antibody-
associated ‘pauci-immune’ vasculitis on (c) light microscopy and (d) immunofluorescence. Source: Kindly provided by Dr Franco Ferrario, S. Carlo
Borromeo Hospital, Milan, Italy.

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 SYSTEMIC DISEASE AND THE KIDNEY

monitoring is required. Management by a specialist team before enzyme-linked immunosorbent assay (ELISA); the antigenic
conception and during pregnancy is important in optimizing fetal targets are myeloperoxidase (MPO-ANCA) and proteinase 3
and maternal renal outcomes. (PR3-ANCA) on ELISA. Indirect immunofluorescence assays are
less useful because of their lower sensitivity and specificity.
Systemic vasculitis and rapidly progressive PR3-ANCA with cytoplasmic (c-)ANCA is present in 80% of
glomerulonephritis (RPGN) patients with granulomatosis with polyangiitis (GPA, formerly
known as Wegener granulomatosis). MPO-ANCA with peri-
Primary systemic vasculitis
nuclear (p)-ANCA is the predominant subtype in microscopic
Primary vasculitides are rare diseases that usually affect multiple
polyangiitis. Around 40% of patients with eosinophilic gran-
organ systems and are characterized by inflammation and ne-
ulomatosis with polyangiitis (eGPA, formerly known as Churg
crosis of the blood vessels. They are classified according to the
eStrauss syndrome) are ANCA positive, usually with MPO-
size of the blood vessel involved (Table 2).3 The most common
ANCA; renal involvement occurs in only 15% of eGPA patients.
subgroup of primary vasculitis is the small vessel subtype of
In addition to their diagnostic role, ANCA titres show some
vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associ-
correlation with disease activity and are routinely measured in
ated (small vessel) vasculitis (AAV). This has an annual inci-
the follow-up of patients with AAV. Drugs such as propylth-
dence of 19 per million population, peaking in the sixth and
iouracil and cocaine are able to induce circulating ANCA and
seventh decades of life.
should be considered in the differential diagnosis of AAV. It is
Renal involvement is common, occurring in 80% of patients
important to note that neutrophils, monocytes, lymphocytes and
with AAV. Renal vasculitis represents a severe disease manifes-
complement have also been implicated in the pathogenesis.
tation, typically progressing over days or weeks to ESKD. Early
recognition and treatment is crucial to preserve renal function Clinical features of ANCA-associated vasculitis
(Table 3). Active renal vasculitis is almost always associated with micro-
scopic haematuria and proteinuria. RPGN occurs in 80% of in-
Causes of rapidly progressive glomerulonephritis
dividuals at first presentation, often without symptoms.
All types of small vessel vasculitis and SLE can cause the syn-
Approximately 30% of patients with RPGN present with ESKD,
drome of RPGN, although AAV is the most common cause. The
requiring dialysis. Milder renal involvement with haematuria and
clinical course of RPGN results from a characteristic underlying
proteinuria but stable renal function can also occur, often iden-
histological process of glomerular capillary inflammation and
tified when patients present with extra-renal disease.
fibrinoid necrosis, which leads to glomerular basement membrane
Because of its multisystem involvement, AAV presents in a
(GBM) rupture and extracapillary proliferation (also known as
variety of ways. Constitutional symptoms such as fatigue, weight
crescent formation; Figure 1c). Clinical features, the presence and
loss and fevers are common. The non-specific symptomatology
pattern of glomerular immune deposits, and an assessment of
and lack of clinical suspicion can unfortunately result in diag-
circulating serology (ANA, ANCA, anti-GBM antibodies, rheuma-
nostic delay for several months, with a major impact on long-
toid factor, serum complement, cryoglobulins) are necessary for
term outcomes. Symptoms of other organ involvement (e.g.
the classification and diagnosis of RPGN (Table 4). In AAV, renal
pulmonary haemorrhage, peripheral neuropathy, skin rash, joint
immune deposits are absent, creating a ‘pauci-immune’ appear-
or ear, nose and throat disease) tend to allow earlier diagnosis.
ance (Figure 1d). Rarer primary causes of RPGN include anti-GBM
The absence of extra-renal symptoms usually results in late
disease, IgA vasculitis (formerly known as HenocheScho €nlein
diagnosis, associated with worse renal function.
purpura) and cryoglobulinaemic vasculitis.

ANCA-associated vasculitis Management of ANCA-associated vasculitis

The AAV syndromes are distinguished by the type of circulating A high clinical suspicion and prompt diagnosis are vital for a
ANCA, presence or absence of eosinophilia, and characteristic good outcome in renal vasculitis. Early treatment of RPGN can
clinical features. ANCA testing should be performed using reverse inflammation and renal failure, preventing irreversible

Classification of primary systemic vasculitis according to blood vessel size

Vessel involvement ANCA-associated Non-ANCA-associated

Small Granulomatosis with polyangiitis (Wegener Antiglomerular basement membrane disease

granulomatosis)
Microscopic polyangiitis IgA vasculitis (HenocheScho€nlein purpura)
Eosinophilic granulomatosis with polyangiitis Mixed essential cryoglobulinaemia
(ChurgeStrauss syndrome)
Medium Polyarteritis nodosa
Kawasaki disease
Large Giant cell arteritis
Takayasu arteritis

Table 2

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 SYSTEMIC DISEASE AND THE KIDNEY

Diagnosing vasculitis
When vasculitis is suspected the following should be considered:
C Infections, malignancy and vasculitis can present with similar constitutional symptoms
C RPGN and positive ANCA results can occur in infective endocarditis, malignancy and HIV
C Granulomatous conditions, such as tuberculosis and sarcoidosis, can mimic granulomatosis with polyangiitis (Wegener granulomatosis)
C Cavitating lung lesions and lung haemorrhage can be asymptomatic, so a chest X-ray should be performed if vasculitis is suspected
C Blood tests for ANCA, eosinophil count, anti-GBM antibody, ANA, dsDNA, cryoglobulins, immunoglobulins, C3 and C4 are helpful in distinguishing
causes of RPGN
C Haematuria and proteinuria and red cell casts on urine microscopy suggest glomerular bleeding and are highly suggestive of RPGN in patients
with acute or acute-on-chronic kidney injury
C A renal biopsy with both light microscopy and immunofluorescence microscopy is the gold standard diagnostic test for RPGN
C Infections must be excluded before starting immunosuppressive therapy

Table 3

kidney damage. Immunosuppressive therapies are used, and Cyclophosphamide is given as a 3e6 month course, either
treatment is classified as remission induction, remission main- intravenously or as daily oral dosing. Intravenous dosing is as
tenance or relapse therapy. In cases of organ- or life-threatening effective as oral for remission induction (7.5e15 mg/kg, adjusted
disease, immunosuppressive treatment should not be delayed to for age and renal function, given every 2e3 weeks) and allows lower
wait for a kidney biopsy, providing a clinician with experience in cumulative exposure and toxicity (less infection and malignancy).
vasculitis has been consulted. Rituximab induction therapy (four intravenous doses of 375 mg/m2
given weekly or two intravenous doses of 1 g, 2 weeks apart) is
Remission induction therapy: for 40 years, the standard treat- preferred over cyclophosphamide in adolescents, pre-menopausal
ment used to induce remission in patients with renal AAV has women, men with fertility concerns, frail older individuals and pa-
been cyclophosphamide and corticosteroids. However, rituximab tients with PR3-ANCA positive disease. However, cyclophospha-
is now also used routinely as a first-line therapy, as an alternative mide may still be preferred in cases of severe renal impairment as
to cyclophosphamide. there are fewer trial data supporting rituximab in this subgroup.

Differential diagnosis of RPGN

Disease ANCA serology Other diagnostic Renal Granulomas Other common or serious
tests immunofluorescence organ system involvement

Granulomatosis with PR3 > MPO Negative (pauci- Yes Constitutional, ear, nose and
polyangiitis (Wegener immune) throat, joints, skin, lungs,
granulomatosis) peripheral nerves
Microscopic polyangiitis MPO > PR3 Negative (pauci- No Constitutional, joints, skin,
immune) lungs, peripheral nerves
Eosinophilic MPO > PR3 Eosinophilia Negative (pauci- Yes Asthma, peripheral nerves,
granulomatosis with immune) ear, nose and throat (nasal
polyangiitis polyps), myocarditis
(ChurgeStrauss
syndrome)
Anti-GBM disease 30% positive Anti-GBM antibody Linear IgG on GBM No Lung haemorrhage
(overlap with AAV)
Mixed essential Negative 100% Cryoglobulins C3, C4, IgG, IgM, IgA No Skin, joints, peripheral
cryoglobulinaemia rheumatoid factor C1q, C3, C4 nerves
IgA vasculitis (Henoch Negative 100% None IgA No Skin, gut, joints
eScho€ nlein purpura)
SLE Usually negative ANA, dsDNA, ENAs, IgG, IgM, IgA No Skin, joint and many others
C3, C4, C1q, C3, C4
anticardiolipin
antibody, lupus
anticoagulant

ANA, antinuclear antibody; ENA, extractable nuclear antigen.

Table 4

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 SYSTEMIC DISEASE AND THE KIDNEY

Immunosuppressive agents commonly used to treat lupus nephritis (LN) and AAV
Mechanism Dose Adverse effects

Prednisolone Anti-inflammatory, inhibits lymphocyte AAV: 1 mg/kg/day (maximum of 60 mg) Numerous, including infection,
proliferation LN: 0.5 mg/kg/day orally, tapered over diabetes mellitus, osteoporosis, weight
3e6 months to 5e10 mg daily gain, fluid retention, hypertension,
cataracts
Cyclophosphamide Alkylating agent, inhibits DNA LN: 500 mg i.v. every 2 weeks for Infection, bone marrow suppression,
replication 12 weeks infertility, nausea and vomiting,
AAV: 7.5e15 mg/kg i.v., adjusted for haemorrhagic cystitis, alopecia,
age and renal function, 6e10 doses increased malignancy risk (increased
risk of bladder cancer if the cumulative
dose is >20 g)
MMF Pro-drug of mycophenolic acid, inhibits Induction: 2e3 g/day in two or three Infection, bone marrow suppression,
synthesis of guanosine nucleotides, divided doses nausea and diarrhoea, teratogenicity
thus targeting lymphocyte proliferation Maintenance: 1e2 g/day orally in two
divided doses
Azathioprine Pro-drug of mercaptopurine, inhibits 1e2 mg/kg daily oral Infection, bone marrow suppression
cell proliferation, particularly (especially in thiopurine S-
lymphocytes methyltransferase deficiency),
diarrhoea, pancreatitis, hepatotoxicity,
malignancy (non-melanoma skin cancer
with long-term use)
Methotrexate Folate analogue, inhibits synthesis of Maximum dose 25 mg weekly (oral or Infection, bone marrow suppression,
purine and pyrimidine bases i.m.), given with folic acid 5 mg weekly nausea, vomiting, hepatotoxicity,
(on a different day) pneumonitis, teratogenic, renally
excreted, contraindicated if creatinine
>150 micromol/litre
Rituximab Anti-CD20 monoclonal antibody, Induction: 2  1 g i.v. 2 weeks apart, or Infection, infusion reaction,
depletes B cells 4  375 mg/m2 weekly neutropenia,
Maintenance: 0.5e1 g every 4 hypogammaglobulinaemia, impaired
e6 months for 2 years vaccine responses
Belimumab Blocks BAFF, a B-cell stimulating Induction: 10 mg/kg i.v. in weeks 1, 3 Low risk of infection and infusion
cytokine (only in LN) and 5 reaction, depression, diarrhoea
Maintenance: 10 mg/kg i.v. every
4 weeks or 200 mg s.c. weekly
Voclosporin Calcineurin inhibitor (only in LN) 23.7 mg twice daily orally Can cause a reduction in glomerular
filtration rate and should be avoided in
patients with significant renal
impairment
Tacrolimus Calcineurin inhibitor (only in LN) 4 mg daily orally, adjustments guided Infection, tremor, bone marrow
by trough concentrations suppression, paraesthesia
Avacopan C5a receptor inhibitor, inhibits 30 mg twice daily orally Possible derangement of liver function
neutrophil chemotaxis (only in AAV)

i.m., intramuscularly; i.v., intravenously; s.c., subcutaneously.

Table 5

Intravenous methylprednisolone is used with cyclophospha- substantial reduction in prednisolone use, but also a greater
mide or rituximab for organ- or life-threatening disease, followed improvement in glomerular filtration rate recovery in renal AAV.
by a tapering course of oral prednisolone (starting at 1 mg/kg). For individuals with the most severe renal disease or pul-
High-dose prednisolone contributes to infection risk, and recent monary haemorrhage, the additional use of plasma exchange
studies have shown that a more rapid reduction in prednisolone is should be considered. Plasma exchange does not improve mor-
effective and allows a reduction in infection rates. Avacopan (a C5a tality or ESKD rates in all AAV patients but can benefit patients
receptor antagonist) has recently been shown to be an effective presenting with severe renal impairment (creatinine >500 mmol/
alternative to prednisolone. This therapy not only allows a litre) or significant pulmonary haemorrhage.

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 SYSTEMIC DISEASE AND THE KIDNEY

MMF is another potential remission induction agent when methotrexate) can be sufficient, although methotrexate is not
used with high-dose corticosteroids in non-dialysis-dependent safe in patients with significant renal impairment.
renal AAV. MMF is associated with higher subsequent relapse
rates, so is considered a second-line therapy that is reserved for Prognosis: renal prognosis and patient survival depend on the
patients where rituximab or cyclophosphamide is contra- extent of kidney failure at diagnosis. Current treatment regimens
indicated, as well as for patients with the lowest risk of relapse allow remission rates of 80e90%. However, a 1-year mortality of
(e.g. with MPO-ANCA). 10% still exists, largely because of treatment toxicity. Cyclo-
The goal of remission induction therapy is to achieve an phosphamide and high-dose corticosteroids are associated with
improvement and stabilization of renal function. Remission from high infection rates and infertility.
RPGN is supported by the absence or reduction of blood and Good outcomes are usually obtained in individuals presenting
protein on urine dipstick testing, and negative ANCA results. with a serum creatinine <500 micromol/litre, with 90% surviv-
ing with independent renal function. In patients with advanced
Remission maintenance therapy: relapses are common in AAV renal failure, there is 25% mortality at 1 year, and 25e50%
so prolonged immunosuppression is used. After remission in- develop ESKD. Renal histology can predict survival without
duction, either intravenous rituximab or daily oral azathioprine ESKD; individuals presenting with >50% normal glomeruli have
is the first-line treatment to maintain remission. Rituximab the best 5-year renal survival, whereas those with >50% globally
maintenance therapy (0.5e1 g every 4e6 months for 2 years) is sclerosed glomeruli have the worst. Earlier diagnosis and opti-
preferred over azathioprine in patients with relapsing or PR3- mization of the use of conventional agents, as well as the use of
ANCA disease and in frail older adults. newer therapies, is leading to improvements in survival and risk
Immunosuppressive treatment is typically continued for at of ESKD (Table 5). A
least 2 years, usually with low-dose oral corticosteroids. Treat-
ment withdrawal increases relapse risk, as does the re-emergence
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considering repeat courses of cyclophosphamide for relapsing
disease. In individuals with refractory disease (either at diagnosis FURTHER READING
or in relapse) combination therapy with cyclophosphamide and Walsh M, Merkel PA, Peh CA, et al. Plasma exchange and glucocor-
rituximab can be used. ticoids in severe ANCA-associated vasculitis. N Engl J Med 2020;
For minor relapses where major organs are not affected, an 382: 622e31.
increase in corticosteroid dosage or addition/dose change of an
oral immunosuppressive therapy (azathioprine, MMF,

TEST YOURSELF
To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the
end of the issue or online here.

Question 1 On clinical examination, she was comfortable, with mild ankle

A 71-year-old woman presented with a 6-week history of weight oedema. Her temperature was 37.5 C, heart rate 96 beats/min-
loss, fever and arthralgia. She had a past medical history of a ute, blood pressure 140/80 mmHg, and oxygen saturations 97%
thyroidectomy (at age 23 years) and hypertension. on air.

MEDICINE xxx:xxx 7 Ó 2023 Published by Elsevier Ltd.

Please cite this article as: McGovern D et al., Lupus nephropathy and vasculitis, Medicine, https://doi.org/10.1016/j.mpmed.2023.01.010
 SYSTEMIC DISEASE AND THE KIDNEY

Investigations She does not have any children but this is something she would
 Haemoglobin 98 g/litre (115e165) like in the future.
 C-reactive protein 185 mg/litre (<10)
 Creatinine 711 micromol/litre (60e110) Investigations
 Urea 32 mmol/litre (2.5e7.0)  Haemoglobin 110 g/litre (130e180)
 Potassium 5.8 mmol/litre (3.5e5.5)  White cell count 3.5  109 (4e10)
 Chest X-ray showed clear lung fields  Platelets 105  109 (150e400)
 Urinalysis showed blood 4+ and protein 4+  Creatinine 115 micromol/litre (40e120)
 Albumin 22 g/litre (37e49)
 Estimated glomerular filtration rate 42 ml/min/1.73 m2
What is the most appropriate next action? (>60)
A. Perform immunology screen; ANCA, anti-GBM antibody,  Anti-dsDNA positive, ANA positive 1:640
ANA, C3 & C4  C3 normal, C4 low
B. Perform emergency dialysis line insertion and  Urinalysis showed blood 2+ and protein 4+
haemodialysis  Erythrocyte sedimentation rate 105 mm in first hour (<30)
C. Commence intravenous methylprednisolone
D. Perform plasma exchange therapy What is the next best step in this patient’s management?
E. Administer broad-spectrum intravenous antibiotics A. Stop the methotrexate and switch to mycophenolate
mofetil
Question 2 B. Commence a short course of high-dose oral corticosteroids
A 22-year-old woman presented with significant swelling of her and review in 2 weeks
legs and frothy urine. She had a history of systemic lupus ery- C. Arrange an urgent renal ultrasound and kidney biopsy
thematosus affecting her skin and joints. She was taking meth- D. Commence tacrolimus
otrexate and hydroxychloroquine in line with her prescription. E. Refer for routine renal outpatient follow up

MEDICINE xxx:xxx 8 Ó 2023 Published by Elsevier Ltd.

Please cite this article as: McGovern D et al., Lupus nephropathy and vasculitis, Medicine, https://doi.org/10.1016/j.mpmed.2023.01.010