Dr Kiran Kumar M,Senior Resident,

Dept of Nephrology, NIMS

Management of Lupus Nephritis

Immunosuppressive therapy

Diffuse proliferative LN (Class IV LN) (Class III LN)

Membranous LN (class V LN)

•Severe nephrotic syndrome •Elevated Sr Cr •Asstd proliferative disease

Focal proliferative LN

RISK FACTORS FOR PROGRESSION

At the time of initial presentation

• Elevated Sr Cr• HTN•Nephrotic proteinuria, •Anemia (Hct < 26%)• Black and Hispanic race• Tubulointerstitial disease•Cellular crescents

After initial presentation and during

therapy

• Frequency and severity of relapses (renal flares)

• Complete /partial remission of proteinuria, hematuria

•Severity of azotemia

• Delayed therapy — due to presumed mild disease

– Increased glomerular injury– Progressive tubulointerstitial fibrosis– Glomerulosclerosis – Lesser response to immunosuppressive drugs

• Better long-term prognosis a/w attaining clinical remission

– Complete or partial remission is a/w improved outcome compared to no remission

Complete remission

•Inactive urine sediment

•Sr Cr ≤ 1.4 mg/dL

•Protein excretion ≤330 mg/day

Partial remission

• 50 %reduction in proteinuria to less than 1.5 g/day

•Stable Sr Cr

Predictive of remission

•Lower chronicity index on renal biopsy

•White race

•Lower baseline proteinuria

•Lower Sr Cr

Lower likelihood of remission

•Male gender

•Earlier development of nephritis from the time of diagnosis of lupus

Immunosuppressive therapy for LN

Induction therapy

Administration of potent immunosuppressive drugs to

achieve remission of immunologic disease

Avg duration : 6 months

Maintenance therapy

Given for a prolonged period to prevent relapse

Indications of immunosuppressive therapy in LN

• Proliferative LN at high risk for progressive renal failure

– All pts with diffuse proliferative GN– Most pts with focal proliferative GN – Membranous LN - Rx against the proliferative

component

Focal proliferative GN• Approximately 10 to 20 % of pts • Accuracy of diagnosis – sampling error– 10 to 20 glomeruli may be necessary

Severe involvement on renal biopsy - 40 to 50 % of glomeruli affected with

areas of necrosiscrescent formationsubendothelial deposits

Clinical findingsNephrotic range proteinuria and/orHypertension

Should be treated as if they have

diffuse proliferative

disease

Focal proliferative LN with •< 25 % of the glomeruli involvement •only segmental areas of proliferation without necrosis•no necrotizing or crescentic lesions

Clinical findings

•Normotensive •Subnephrotic proteinuria•Normal serum creatinine

Glucocorticoids alone –Prednisolone 60 mg/day for 1 wk, tapered to 15 mg/day during the first 3 mths of therapy, and then continued for another 3 mths

Glucocorticoids plus Azathioprine

(2mg/kg/day) X 2 years

Therapeutic goals

•Loss of hematuria

•Reduced proteinuria

• Some authors

– Sampling errors- crescents/necrosis missed– Rx- Steroids + MMF

• Standard induction therapy indicated ( in apparently mild disease)

– Do not respond within 3 mths – Develop signs of more severe disease

• Extensive focal necrotizing lesion• Increasing proteinuria • HTN and/or • Rise in Sr Cr

Induction therapy

KDIGO guideline

12.3: Class III LN (focal LN) and class IV LN (diffuse LN)—initial therapy

12.3.1: We recommend initial therapy with corticosteroids(1A), combined with either cyclophosphamide(1B) or MMF (1B).

12.3.2: We suggest that, if patients have worsening LN(rising SCr, worsening proteinuria) during the first 3 months of treatment, a change be made to an alternative recommended initial therapy, or a repeat kidney biopsy be performed to guide further treatment. (2D)

Cyclophosphamide vs MMF• Ancestry –– Black and Hispanic patients may be more likely to

achieve remission with MMF – limited data

• Disease severity – – More severe disease - elevation in Sr Cr

&/or crescents - cyclophosphamide • pts in the MMF trials did not generally have severe

disease

• Patient preference - gonadal toxicity

Glucocorticoids

IV Methypred (500 to 1000 mg given over 30

min daily for 3days)

•Induce a rapid immunosuppressive effect

Oral Prednisolone

•No severe disease- 0.5 to 1 mg/kg per day

• ALMS trial- start 60mg/day

• then tapered every 2 wks by 10 mg/day until 40 mg/day

•Then tapered by 5 mg/day until 10 mg/day was reached

• Further tapering allowed if the pt was stable for 4 wks

Cyclophosphamide

NIH trial

IV Cyclo + Prednisolone

Aza + Prednisolone Prednisolone alone

90% 60% 20%

Follow up for 10-12 years

Probability of avoiding renal failure

Gourley MF, Austin HA 3rd, Scott D, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med 1996; 125:549.

NIH trial (n=82pts)Class IV LN

Mthly IV Methpred X 1 yr

Mthly IV Cyclo X 6 mths f/b 3 mthly X 24

mths Methpred + Cyclo

5 months follow up

Remission : 29%Relapse : 36%

Remission : 62%Relapse : 7%

Adverse events more

Remission : 85%Relapse : 0

Treatment failure less likely

Treatment failure less likelyAfter 11 years

• Treatment failure - significantly less likely with combination therapy

– Doubling of the Sr Cr, requiring supplemental immunosuppression– Death

Illei GG, Austin HA, Crane M, et al. Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med 2001; 135:248

• 2004 meta-analysis – cyclo+steroid vs steroid

– Reduced the risk of doubling of the Sr Cr in 4 trials of 228 pts (24 vs 40%)

– No effect on mortality in 5 trials of 226 pts (21 vs 17 %)– Increased the risk of ovarian failure in 3 trials of 147 pts (47 vs 19

%)

Flanc RS, Roberts MA, Strippoli GF, et al. Treatment for lupus nephritis. Cochrane Database Syst Rev 2004; :CD002922

• Dosing of cyclophosphamide — higher-dose regimen and lower-dose regimen:

• Higher-dose regimen –

– pulse IV cyclophosphamide (0.5 to 1 g/m2) monthly for six to seven mths

– Historically, this initial course was followed by additional IV doses given quarterly for at least 2yrs

• Lower-dose regimen (Euro-Lupus)

– 500 mg IV every 2 weeks for a total of 6 doses

• Oral cyclophosphamide

– 1.0–1.5mg/kg/d (maximum dose 150mg/d) for 2–4 mths– Equivalent efficacy to i.v. cyclo in prospective observational studies– Equivalent to MMF in Chinese pts– More adverse effects

EURO-LUPUS trial

• Comparative trial of primarily white pts

– Mild to moderate renal insufficiency (mean Sr Cr 1.15 mg/dL)

– Low dose Vs higher-dose IV cyclo regimens each followed by maintenance therapy with azathioprine

– Equivalent outcomes at a median of 41 mths• Treatment failure (16 vs 20%)• Renal remissions (71 vs 54%)• Renal flares (27 vs 29%)

– Similarity in outcomes persisted at 10 yrs, regardless of the baseline severity in renal function

• Houssiau FA, Vasconcelos C, D'Cruz D, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002; 46:2121

MMF as Induction agent

• An alternative to cyclophosphamide as initial therapy for proliferative LN

• Several prospective trials – MMF equivalent (but not superior) to cyclophosphamide

• Largest trial – ALMS trial

– MMF provides greater benefit than cyclophophamide among black and Latino pts

– Was comparable to mthly IV cyclophosphamide among white or Asian pts

Mthly IV cyclo (0.75 g/m2 first dose, f/b 5 infusions of 0.5 to 1.0 g/m2)

Aspreva Lupus Management Study (ALMS)

N = 370 Class IV ± V – 68 % Class III ± V - 16 %Pure Class V- 16% Mean urine PCR 4.1

Mean Sr Cr - 1.1 mg/dL

MMF (0.5 g BD in wk 1, 1.0 g BD in wk 2, and a target of 1.5 g BD thereafter or if not tolerated, 1.0 g three times to two times daily)

•At 24 wks - no difference between groups• Pt attaining normal Cr – MMF (70%) vs cyclo (68%)• Proteinuria < 500mg/24hrs – MMF (24%) vs Cyclo (27%)

•Greater benefit among black and Latino pts •No difference in response rate b/w focal or diffuse proliferative and membranous LN• Rate of adverse events was not different

Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol 2009; 20:1103

• Meta-analysis - 45 trials -2846 pts

– No significant diff b/w cyclo and MMF-based induction therapy with respect to • Mortality • Incidence of ESRD • Relapse during induction

– MMF - numerically higher rate of complete remissions (19.5 vs 13.8%)- not statistically significant

– Major infections - similar with both drugs

– MMF - less ovarian failure and alopecia

• Henderson L, Masson P, Craig JC, et al. Treatment for lupus nephritis. Cochrane Database Syst Rev 2012; 12:CD002922

MMF trials

• MMF induction regimen provides similar efficacy

• MMF may be more effective than cyclophosphamide and therefore preferred in black and Hispanic patients ( weak data)

Limitations of the trials

•Duration of follow-up was short (6 to 12 months)

• pts did not have severe disease• mean Sr Cr -1.1 mg/dL• mean protein excretion - 3 to 4.7 g/day

• Less preferred therapies

• Tacrolimus – Multicenter non-inferiority trial - 61 Chinese – Steroids + tacrolimus (trough level of 5 to 10 ng/mL) vs

Steroids + cyclophosphamide (500 to 1000 mg/m2 mthly for 6 pulses)

– At 6 mths - no diff among groups in the number who achieved complete remission

Chen W, Tang X, Liu Q, et al. Short-term outcomes of induction therapy with tacrolimus versus cyclophosphamide for active lupus nephritis: A multicenter randomized clinical trial. Am J Kidney Dis 2011; 57:235.

• Short term follow up – limited data- not recommended for induction

• May be given for pts who cant tolerate cyclo or MMF

• Rituximab Lupus Nephritis Assessment with Rituximab

(LUNAR) study (n=144)Class III or IV

MMF 1 gm TID X 52 wksIV methpred 1 gm BD X first 3 days

IV infusion of 1 g of rituximab at baseline and at 2, 24, and 26

weeks

IV infusion of placebo on baseline and at 2, 24, and 26 weeks

•Incidence of complete/ partial remission was numerically higher with Rituximab (57 vs 46 %) - not statistically significant•Rituximab - greater reductions in anti-DNA titers and larger improvements in complement level•2 pts died in the Rituximab group - not related to rituximab

Henderson LK, Masson P, Craig JC, et al. Induction and maintenance treatment of proliferative lupus nephritis: a meta-analysis of randomized controlled trials. Am J Kidney Dis 2013; 61:74.

• Proliferative LN + TMA – Cytotoxic therapy beneficial

– Plasmapheresis - no added benefit• significant adverse events, including serious infection

and death

– Plasmapheresis only • antiphospholipid antibody syndrome, • auto-antibodies to ADAMTS1

• Flanc RS, Roberts MA, Strippoli GF, et al. Treatment for lupus nephritis. Cochrane Database Syst Rev 2004; :CD002922

MAINTENANCE IMMUNOSUPPRESSION

• Up to 50 % of pts relapse following reduction in or cessation of immunosuppressive therapy

• Relapse rates – 5 to 15 per 100 pt-yrs– Average - 8 per 100 pt-yrs for the first 5 years of

f/u

• Relapse-more common with partial remission

Choice of maintenance agent

• Optimal choice - not well defined– Preferred agent – MMF

• Optimal duration - not well defined– 12 to 24 mths of oral azathioprine or MMF best studied

• Alternatives to MMF or azathioprine

– Cyclosporin –effective; more adverse– Cyclophosphamide – less effective ;higher rate of

infection and amenorrhea

MMF or AZA or Cyclo

Randomised trial (n=59)(whites=3)

Induction therapy Steroids + 4-7 cycles of

IV Cyclo

Low dose steroid + MMF (500-

3000mg/day)

Low dose steroid + Azathioprine (1 -3

mg/kg/day)

Low dose steroid + IV cyclo (0.5 – 1 gm/m2 every 3

mths

29 months 30 months 24months

Event free survival rate – 90%

Event free survival rate – 80%

Event free survival rate – 45%

More infections, amenorrhoea,

relapses

Contreras G, Pardo V, Leclercq B, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004; 350:971

Azathioprine vs MMF

• Meta-analysis - six trials (n = 514 pts) – 3 trial compared aza with MMF for maintenance – No significant differences in the risk of mortality or

ESRD– MMF - significantly lower rate of renal relapse

(16.4 vs 30.2 %)– Rate of adverse effects was similar with both

drugs

• Henderson L, Masson P, Craig JC, et al. Treatment for lupus nephritis. Cochrane Database Syst Rev 2012; 12:CD002922

MAINTAIN Nephritis Trial• Randomized, open-label trial (n=105 ) - European patients (83 Caucasian)• Class IV - 61, Class III - 33, and class V – 11

• All pts - 3 daily 750 mg doses of IV methpred f/b oral glucocorticoids + six 500 mg IV cyclo over 10 wks

• On wk 12, maintenance therapy was initiated with either azathioprine (2 mg/kg per day) or MMF (2 g/day)

• Renal relapse was defined as one or more of the following: – recurrence or development of nephrotic syndrome– ≥ 33% increase in Sr Cr within 1 mth– threefold increase in proteinuria accompanied by hematuria

• Houssiau FA, D'Cruz D, Sangle S, et al. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis 2010; 69:2083

• At 3 years

– No significant diff b/w MMF and aza groups in • Rate of renal relapse (19 vs 25 %)• Systemic flares• Steroid withdrawal

– Protocol biopsies 2 yrs revealed no significant histologic differences between the groups

– Adverse events were similar

ALMS Maintenance Trial

• Multinational study (N=227) - who had achieved remission with either MMF or Cyclo randomly assigned to MMF (1 g BD) or aza (2 mg/kg per day) as maintenance therapy for 36 mths

– Treatment failure at 36 mnths - significantly lower with MMF (16 vs 32 %)

– Superiority of MMF was independent of the type of induction therapy, race, or region

• Dooley MA, Jayne D, Ginzler EM, et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med 2011; 365:1886

KDIGO guidelines 12.4.1: We recommend that, after initial therapy is complete, patients with class III

and IV LN receive maintenance therapy with azathioprine (1.5–2.5 mg/kg/d) or MMF (1–2 g/d in divided doses), and low-dose oral corticosteroids (r10 mg/d prednisone equivalent). (1B)

12.4.2: We suggest that CNIs with low-dose corticosteroids be used for maintenance therapy in patients who are intolerant of MMF and azathioprine. (2C)

12.4.3: We suggest that, after complete remission is achieved, maintenance therapy be continued for at least 1 year before consideration is given to tapering the immunosuppression. (2D)

12.4.4: If complete remission has not been achieved after 12 months of maintenance therapy, consider performing a repeat kidney biopsy before determining if a change in therapy is indicated. (Not Graded)

12.4.5: While maintenance therapy is being tapered, if kidney function deteriorates and/or proteinuria worsens, we suggest that treatment be increased to the previous level of immunosuppression that controlled the LN. (2D)

DISEASE RESISTANT TO INDUCTION THERAPY

• Defined as the failure to achieve either complete or partial remission

– a/w worse long-term prognosis compared to pts who attain

remission

– Assessment for the development of remission requires a minimum of 3 mths

– A repeat renal biopsy is indicated in selected patients with resistant LN

• clear understanding of the extent of immunologic remission is essential

Treatment of resistant disease

• Treat cyclophosphamide-resistant pts with MMF, and MMF-resistant pts with cyclo

• Induction & maintenance regimens used in resistant LN are the same as those used for primary therapy

• Pts who fail treatment with both cyclo and MMF may be treated with Rituximab

Rituximab for cyclophosphamide and MMF resistance

• Long-term efficacy and toxicity have not been fully defined

• Largest reported experience - 23 pts– Class III or IV LN - persistent disease activity despite a variety of drugs -

cyclo (11 pts) or MMF (12 pts) as well as other drugs (eg, cyclosporine, azathioprine)

– Rituximab (0.5 to 1 g on days 1 and 15) was added to the existing immunosuppressive regime

– 3 mths f/u

• 5/23 - complete response (normal serum creatinine, inactive urine sediment, and protein excretion <500 mg/day)

• 7/23 - partial response (>40 % improvement in renal parameters)

• Vigna-Perez M, Hernández-Castro B, Paredes-Saharopulos O, et al. Clinical and immunological effects of Rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res Ther 2006; 8:R83

• Melander C et al

– 20 pts ( class IV - 15 pts or Class V - 5 pts)

– 18 pts – resisitant or relapsing

– Rituximab - 375 mg/m2 weekly X 4 weeks

– 10 pts received additional doses of rituximab as maintenance therapy because of an increase in B cell count

– Mean follow-up of 22 mths

• 5/15 class IV achieved complete remission• 5/15 - partial remission, defined as decrease in protein excretion by at least 50

percent and stabilization of the eGFR

• Melander C, Sallée M, Trolliet P, et al. Rituximab in severe lupus nephritis: early B-cell depletion affects long-term renal outcome. Clin J Am Soc Nephrol 2009; 4:579

MMF plus tacrolimus• Cortés-Hernández J et al

• Cortés-Hernández J, Torres-Salido MT, Medrano AS, et al. Long-term outcomes--mycophenolate mofetil treatment for lupus nephritis with addition of tacrolimus for resistant cases. Nephrol Dial Transplant 2010; 25:3939

Observation study (n=17; class IV-15, class V-2)Tacrolimus (.075mg/kg/day) was added to MMF

6 pts (35 %) - complete response

• Protein excretion <0.3 g/day• normal sediment• normal or stable renal function

6 pts (35%) - partial response

• Protein excretion <2.9 g/day

• stable or improved renal function

Relapsing diasease

Incidence –

5 to 15 per 100 patient years

Risk factors

•More severe disease at baseline•Delay in reaching remission•Attainment of partial compared to complete remission

Definition •recurrent immunologic activity• active urine sediment (a "nephritic" relapse)• increases in protein excretion•Increase in Sr Cr

Monitoring - 3-4 mthly

•Urinalysis•urine PCR•Sr CR•Serologic factors (C3, C4 , anti-dsDNA titers )

• Slowly progressive inactive LN should NOT be treated with immunosuppressive agents

– Aggressive antihypertensive and antiproteinuric therapy - RAS blockade

– Target BP < 130/80 mmHg – Target protein excretion < 500 to 1000 mg per day

• Pts - increase in anti-dsDNA titers or new hypocomplementemia following a clinical remission

– Monitored more carefully (particularly over the ensuing 3 months)

– Generally not treated SOLELY for changes in serologic activity

Treatment of relapse

• Mild relapse- increased activity of urine sediment and possibly a modest (< 50%) increase in protein excretion but with a stable Sr Cr

– Not on maintenance - oral prednisone (60 mg/day for one wk, tapered to 30 mg A/D for 3 mths)

– Initially treated with cyclo who are now on aza maintenance therapy - increase the dose of prednisone as well as azathioprine

– initially treated with MMF for induction and who are now off maintenance therapy - MMF may be restarted

– still on maintenance therapy with lower doses of MMF- the MMF dose can be increased to 2 to 3 g/day

• Moderate – severe diasease• Active urine sediment plus a rise in serum creatinine with

or without increased proteinuria

– Cyclo was used for induction and the pt is taking aza for maintenance- MMF is preferred

– MMF was used for induction and the pt is no longer taking maintenance - either MMF or cyclo

• Cyclo is preferred if relapse occurs while the pt is still taking MMF for maintenance

– Pts who continue to relapse, like those with resistant LN - trial of rituximab

Treatment of Class IV + V LN

• More likely to be resistant to standard induction regimens with cyclophosphamide

• Have worse long-term renal outcome

• Respond better to combined induction therapy with MMF + Tacrolimus

Prospective trial (n=40)

Class IV+V LN 3 doses of IV methpred f/b

prednisolone

MMF (0.75 to 1 g/day) +

Tacrolimus (3 to 4 mg/day)

IV cyclophosphamide

Follow up of 9 mths complete remission –

65%

Follow up of 9 mths complete remission –

15%

Glassock RJ. Multitarget therapy of lupus nephritis: base hit or home run? J Am Soc Nephrol 2008; 19:1842

Membranous Lupus Nephritis• NON-IMMUNOSUPPRESSIVE THERAPY

Angiotensin inhibition – no RCTs• ACE-I or ARB - recommended in

virtually all pts with proteinuric CKD• Lowers intraglomerular pressure

reduce the rate of disease progression

• Target < 1000 mg/day• At least 50 - 60%from the baseline

level+ protein excretion < 3.5 g/day

Control of BP

•Target < 130/80 mm Hg•slow the progression of proteinuric chronic kidney disease• cardiovascular protection

Lipid-lowering •control of serum LDL cholesterol is the main indication

•slow the progression of the underlying renal disease

Anticoagulation•Risk of thrombotic events - DVT, RVT, PE• prophylactic anticoagulation • massive proteinuria• serum albumin < 2.0 g/dL

Indications for immunosuppressive therapy

• One or more of

1. Persistent severe and symptomatic nephrotic syndrome

2. Increased or rising Sr Cr

3. Mixed membranous and proliferative lesions on Bx which may be present at diagnosis or develop late

Nephrotic syndrome

• morbidity - thromboembolism, hyperlipidemia, accelerated atherosclerosis

•higher rate of progressive disease

•lower likelihood of attained remission

Concurrent proliferative LN —

• worse prognosis• more rapid loss of renal

function• higher rate of end-stage renal

disease

NIH trial of cyclophosphamide vs cyclosporine

42 pts with pure membranous LN median protein excretion - was 5.4 g/day

median eGFR - 83 mL/min per 1.73 m2.

A/D prednisone 40 mg/m2 X 8 wks & then tapered to 10 mg/m2)

A/D prednisone + pulse IV cyclo

every other month

A/D prednisone + cyclosporine 200 mg/m2 5

mg/kg] per day in two divided

doses

•Follow up – 1 yr•Complete remission - protein excretion < 0.3 g/day•Partial remission - protein excretion < 2.0 g/day with > 50 % reduction in proteinuria

Austin HA 3rd, Illei GG, Braun MJ, Balow JE. Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy. J Am Soc Nephrol 2009; 20:901

• Pts with remission of proteinuria were followed for up to 10 yrs

– Relapse after cessation of therapy was significantly later and less frequent with cyclophosphamide (20 % within 50 mths vs 60 % within 36 mths with cyclosporine)

– All of the cyclophosphamide relapses occurred four years or more after cessation of therapy.

• Role of MMF

– Current role of MMF in the treatment of patients with pure membranous LN is not clear

– 2 trials – ALMS & another RCT- long term follow up is not reported

• Chlorambucil versus methylprednisolone

– Ponticelli group - Methpred alone (8 pts) and Methpred + chlorambucil alternated every other month for 6 mths

– Intermittent Methpred + chlorambucil –• higher rate of complete or partial remission (90 vs 38 %)• lower rate of renal flares (10 vs 88 %).

Timing of immunosuppressive therapyClass V LN

Severe , symptomatic nephrotic syndrome

(usually with a serum albumin <2.5 g/dL

No or mild to moderate nephrotic syndrome and

a serum albumin > 2.5 g/d

•Immunosuppressive therapy•Angiotensin inhibition •rigorous BP control

maximum angiotensin

inhibition X 3-6 mths

Proteinuria < 3.5 g/dayContinue

ACE-i/ARBs

Proteinuria > 3.5 g/dayContinue

ACE-i/ARBs +

KDIGO guidelines

• 12.5: Class V LN (membranous LN)

• 12.5.1: We recommend that patients with class V LN, normal kidney function, and non–nephrotic range proteinuria be treated with antiproteinuric and antihypertensive medications, and only receive corticosteroids and immunosuppressives as dictated by the extrarenal manifestations of systemic lupus. (2D)

• 12.5.2: We suggest that patients with pure class V LN and persistent nephrotic proteinuria be treated with corticosteroids plus an additional immunosuppressive agent: cyclophosphamide (2C), or CNI (2C), or MMF (2D), or azathioprine (2D).

• Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) - mycophenolate mofetil as first-line therapy

Thank you !!