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

h.wilson16@imperial.ac.uk

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.