Manifestations of lupus in the kidney and how to manage them
Hannah Wilson 1
Liz Lightstone 1
1 Imperial College Lupus Centre, Imperial College London, UK
Correspondence and offprint requests to Dr Hannah Wilson, email
Introduction
Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus
erythematosus (SLE). Both the condition and its treatments are associated with
considerable morbidity and mortality(1) with 33% of those with class IV disease
reaching end stage renal failure (ESRF) at 10 years(2). However, earlier
diagnosis and initiation of treatment are associated with better outcomes(3). In
this digest we will discuss the classification of lupus nephritis, the approaches to
treatment based on guidelines and new evidence suggesting alternative
strategies.
Diagnosis of lupus nephritis
Clinical indicators for suspicion of renal injury in SLE are fairly uncontroversial:
a reduction in renal function; new onset proteinuria of >50 mg/mmol or a
doubling of “baseline” proteinuria to greater than 100mg/mmol and/or an active
urine sediment. Renal biopsy is required to classify the lupus nephritis
histologically as this influences both the treatment and prognosis. A practical
guide to the ISN/RPS classification of LN is displayed in figure one: it is class III
or IV if there are active or sclerotic glomerular lesions with endocapillary
hypercellularity, subendothelial deposits (wire-loops on light microscopy and
seen on electron microscopy (EM)), intraluminal immune aggregates (hyaline
thrombi) or crescents, amongst other features. Immunofluorescence typically
shows “full house” deposition of immunoglobulins and complement. The
nephritis is considered Class III where these changes are present in fewer than
50% of glomeruli or Class IV if in >50%. The activity of the glomerular lesions is
also classified (all active, active/chronic or all chronic). For those with class IV
the glomerular lesions are further described as predominantly segmental (S), if
most glomeruli have <50% tuft involved, or global (G).
Class V LN involves membranous change, with “full house” granular
immunofluorescence and subepithelial immune deposits on EM. Class III/IV LN
can coexist with Class V.
If the biopsy shows only mesangial hypercellularity then it is class II. These
patients are likely to have minimal proteinuria and normal function. In Class I
LN there are immune complexes detected by immunofluorescence or electron
microscopy alone.
It is worth remembering that the classification of LN refers only to glomerular
changes which are a consequence of immune complex deposition. Other
manifestations can however be found including tubulointerstitial inflammation,
vasculopathy and/or thrombotic microangiopathy (usually in association with
antiphospholipid antibodies)(4). The degree of tubulo-interstitial scarring is
also prognostic and should be documented.
Management of lupus nephritis
The treatment of proliferative LN is generally divided into induction and
maintenance phases. Induction with intravenous (IV) cyclophosphamide (CyP)
or mycophenolate mofetil (MMF) (target 2-3g daily) is recommended alongside
corticosteroids (IV then oral)(5), the dose and duration of which are based on
expert opinion rather than trial data. Wherever higher and lower doses of
steroids have been compared, lower doses are associated with just as good or
better outcomes and fewer side effects. We recommend methyl prednisolone IV
pulses of no >500mg each and for oral steroids, a low starting dose (≤40mg/day,
max 0.5mg/kg/day) with rapid taper – these strategies are effective and safer
(6). Preliminary results from the AURA LN trial(7) which added voclosporin or
placebo to MMF and rapidly tapered steroids have been released. Not only did
the trial reach its endpoint, the control data are also of great interest, showing
similar or higher remission rates than previous studies despite much lower
doses of steroids used with MMF.
CyP (as per either the Eurolupus or NIH regimens) and MMF have similar
efficacy; however CyP may reduce fertility, though this is less likely with low
dose regimens. Maintenance treatment is recommended with MMF (1-2g/day)
or Azathioprine (AZA) (1.5-2.5mg/kg/day) alongside low-dose corticosteroids
for at least 1(KDIGO) to 3(EULAR/ERA-EDTA) years following complete
remission(5).
Treatment of pure class V is more controversial due to less robust evidence. It is
worth noting that whilst prognosis is more benign, a significant proportion of
patients reach ESRF by 10 years(2). It is usually treated the same as class III or
IV LN. Most guidelines agree that nephrotic range proteinuria (>3g/24hr or
UPCR >300mg/mmol) warrants immunosuppressive treatment(5).
A significant proportion of patients do not respond to treatment. It is
recommended with refractory disease to switch therapy from MMF to CyP or
vice versa(5). With relapsing disease it is advised to repeat the treatment which
was effective at bringing about remission. In both scenarios a repeat renal
biopsy should be considered as the pathogenic manifestations can change and
may indicate alternative treatment.
We are now 5 years on from the guidelines discussed above and usefully
compared by Wilhelmus et al(5). Whilst they still represent the standard of care,
almost none of the treatments described are licensed for use and there have
been developments, including emerging roles for both biologics and multi-target
therapy. Multi-target refers to the combination of low dose steroid, MMF and a
calcineurin inhibitor (CNI); both the AURA trial(7) and a large phase III study
from China (8) have demonstrated superiority of such a combination as
induction treatment in comparison to standard of care. Disappointingly, the role
of Rituximab is yet to be defined by positive trial data though it is widely used
(and indeed approved by NHSE) for refractory LN whilst cohort data suggest
benefit as primary therapy(9). Several randomised trials in LN are ongoing,
using drugs aimed at key biological pathways including an anti-interferon
receptor blocker, Anifrolumab (NCT02547922), an anti-CD40L antibody
(NCT00001789) and the anti BAFF antibody, belimumab (NCT01639339).
There is very little evidence or agreement amongst guidelines in regards to
treatment of Class II LN except for the use of renin-angiotensin-aldosterone
system (RAAS) inhibitors. Immunosuppression is largely directed towards extra
renal manifestations. Class I LN requires no specific therapy as it has no clinical
manifestations and is not associated with long-term renal impairment(10).
Adjunctive treatments in LN
Various adjunctive treatments are advised by the majority of guidelines
particularly the use of hydroxychloroquine(5), which is associated with
sustained remission(11) and a reduced rate of relapse(12). Screening with an
ophthalmologist for retinopathy at baseline and yearly after 5 years is
recommended(5). RAAS inhibition for proteinuria and blood pressure control
and statins for hyperlipidaemia are consistently recommended, as are
consideration of calcium and vitamin D supplements, bisphosphonates, low-dose
aspirin, anticoagulation in those with albumin <20g/L, ovarian protection with
GnRH analogues if cumulative CyP dose >10g and avoidance of live vaccines (5).
In addition, low dose prophylactic antibiotics can be considered whilst
complement levels are low. Contraception is warranted for all patients on MMF
or cyclophosphamide and pregnancy should be avoided until remission is
sustained for at least 6 months.
Conclusions
With current advances in personalised medicine we may see a change in
approach to treatment in the coming years with therapeutics tailored to specific
pathogenic mechanisms of injury identified by ‘omics analysis of biopsies, blood
and/or urine. Until then, and awaiting new data from the many trials, MMF or
CyP remain standard of care, with growing support for the use of CNI inhibition.
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Figure 1. Flowchart for diagnosing ISN/RPS class of lupus nephritis, from Elliot V
et al.(13). Pictures: (A) Subendothelial deposit as seen in class III and IV (wire
loop lesion); (B) Granular IgG, IgA, IgM, C3 and C1q staining is seen in class V on
immunofluorescence; (C) Subepithelial deposit as seen in class V; (D) Segmental
glomerular lesion; (E) Global glomerular lesion.
Conflict of interest statement:
There are no novel results discussed in this paper. Prof L Lightstone was in
receipt of a grant from Roche towards US sites in the Rituxilup trial and for
provision of Rituximab globally and honouraria from Genentech and GSK.