Joint European League Against Rheumatism and European Renal AssociationEuropean Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis

Objectives To develop recommendations for the management of adult and paediatric lupus nephritis (LN). Methods The available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus.

# Introduction
Approximately 50% of patients with systemic lupus erythematosus (SLE) will develop lupus nephritis (LN), which increases the risks for renal failure, cardiovascular disease and death. In 2008, we published the first European League Against Rheumatism (EULAR) recommendations on the management of SLE. [bib_ref] Report of a Task Force of the EULAR Standing Committee for International..., Bertsias [/bib_ref] Since then, several controlled trials have been published upon which updated recommendations can be based. The realisation that in the care of patients with LN internists/ rheumatologists and nephrologists are involved, prompted us to develop recommendations for LN under the joint auspices of the EULAR and the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA), with experts from both disciplines. The panel was enriched with renal pathologists and paediatricians with expertise on LN.

# Methods
We followed the EULAR standardised operating procedures 2 and the Appraisal of Guidelines Research and Evaluation instrument. We selected a list of questions by a modified Delphi method further edited for literature search, followed by a systematic search of the PubMed database (web-only appendix tables 1 and 2); all English language publications up to December 2011 were considered. We further refined retrieved items based on abstract and/or full-text content, and the number of patients (requiring n30 for diagnosis, monitoring, prognosis; n  10 for treatment). A detailed presentation of the literature review is provided in web-only appendix table 3. Evidence was categorised based on the design and validity of available studies and the strength of the statements was graded. After discussions, the committee arrived at 28 final statements rated individually by each member (tables 1 and 2).

## Indications for first renal biopsy in sle
Any sign of renal involvement-in particular, urinary findings such as reproducible proteinuria 0.5 g/24 h especially with glomerular haematuria and/or cellular casts-should be an indication for renal biopsy. Renal biopsy is indispensable since in most cases, clinical, serological or laboratory tests cannot accurately predict renal biopsy findings. [bib_ref] Persistent proteinuria and dyslipidemia increase the risk of progressive chronic kidney disease..., Reich [/bib_ref].7 (0. [bib_ref] Lupus nephritis: clinical and pathological correlation, Leaker [/bib_ref] 10 (1) 2. Pathological assessment of kidney biopsy The use of the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification system is recommended with assessment of active and chronic glomerular and tubulointerstitial changes, and of vascular lesions associated with anti-phospholipid antibodies/ syndrome 9.6 (0. [bib_ref] Association between serum total cholesterol level and renal outcome in systemic lupus..., Tisseverasinghe [/bib_ref] 10 (1) 3. Indications and goals of immunosuppressive treatment in lupus nephritis (LN) 3.1. Initiation of immunosuppressive treatment should be guided by a diagnostic renal biopsy. Immunosuppressive agents are recommended in class III A or III A/C (V) and IV A or IV A/C (V) nephritis, and also in pure class V nephritis if proteinuria exceeds 1 g/24 h despite the optimal use of renin-angiotensin-aldosterone system blockers 9.4 (0. [bib_ref] Association between serum total cholesterol level and renal outcome in systemic lupus..., Tisseverasinghe [/bib_ref] 10 (1) 3.2. The ultimate goals of treatment in LN are long-term preservation of renal function, prevention of disease flares, avoidance of treatment-related harms, and improved quality of life and survival. Treatment should aim for complete renal response with UPCR <50 mg/mol and normal or near-normal (within 10% of normal GFR if previously abnormal) renal function. Partial renal response, defined as 50% reduction in proteinuria to subnephrotic levels and normal or near-normal renal function, should be achieved preferably by 6 months but no later than 12 months following initiation of treatment 9.6 (0. [bib_ref] Treatment with cyclophosphamide delays the progression of chronic lesions more effectively than..., Grootscholten [/bib_ref] 10 (1) 4. Treatment of adult LN Initial treatment 4.1. For patients with class III A or III A/C (V) and class IV A or IV A/C (V) LN, mycophenolic acid (MPA) (mycophenolate mofetil (MMF) target dose: 3 g/day for 6 months, or MPA sodium at equivalent dose) or low-dose intravenous cyclophosphamide (CY) (total dose 3 g over 3 months) in combination with glucocorticoids, are recommended as initial treatment as they have the best efficacy/toxicity ratio 9.3 (0.8) 9 (1) 4.2. In patients with adverse prognostic factors (acute deterioration in renal function, substantial cellular crescents and/or fibrinoid necrosis), similar regimens may be used but CY can also be prescribed monthly at higher doses (0.75-1 g/m 2 ) for 6 months or orally (2-2.5 mg/kg/day) for 3 months
[formula] 8.8 (1.3) 9 (2) 4.3. [/formula]
To increase efficacy and reduce cumulative glucocorticoid doses, treatment regimens should be combined initially with three consecutive pulses of intravenous methylprednisolone 500-750 mg, followed by oral prednisone 0.5 mg/kg/day for 4 weeks, reducing to 10 mg/day by 4-6 months 9.0 (1.1) 9 (2) 4.4. In pure class V nephritis with nephrotic-range proteinuria, MPA (MMF target dose 3 g/day for 6 months) in combination with oral prednisone (0.5 mg/kg/day) may be used as initial treatment based on better efficacy/toxicity ratio. CY or calcineurin inhibitors (ciclosporin, tacrolimus) or rituximab are recommended as alternative options or for non-responders.
[formula] 8.9 (1.2) 9 (2) [/formula]
4.5. Azathioprine (AZA) (2 mg/kg/day) may be considered as an alternative to MPA or CY in selected patients without adverse prognostic factors (as defined in 4.2), or when these drugs are contraindicated, not tolerated or unavailable. Azathioprine use is associated with a higher flare risk.
8.6 (1.3) 9 (2) Subsequent treatment 4.6. In patients improving after initial treatment, subsequent immunosuppression is recommended with either MPA at lower doses (initial target MMF dose 2 g/day) or AZA (2 mg/kg/day) for at least 3 years, in combination with low dose prednisone (5-7.5 mg/day). Gradual drug withdrawal, glucocorticoids first, can then be attempted. 6. Monitoring and prognosis of LN 6.1. Active LN should be regularly monitored by determining at each visit body weight, blood pressure, serum creatinine and eGFR, serum albumin, proteinuria, urinary sediment (microscopic evaluation), serum C3 and C4, serum anti-dsDNA antibody levels and complete blood cell count. Anti-phospholipid antibodies and lipid profile should be measured at baseline and monitored intermittently. 6.4. Repeat renal biopsy may be used in selected cases, such as worsening or refractoriness to immunosuppressive or biological treatment (failure to decrease proteinuria by 50%, persistent proteinuria beyond 1 year and/or worsening of GFR), or at relapse, to demonstrate change or progression in histological class, change in biopsy chronicity and activity indices, to provide prognostic information, and detect other pathologies 9.2 (1.4) 10 (1)

## Continued

## Results and discussion indications for first renal biopsy in sle
Because of the potentially aggressive nature of LN, the thresholds for performing a renal biopsy should be low. Any sign of renal involvement-in particular, reproducible proteinuria 0.5 g/24 h especially with glomerular haematuria and/or cellular casts-can be an indication for biopsy. Clinical, serological or laboratory tests cannot accurately predict histological findings.
Although clinically relevant biopsy findings are more common in the presence of significant proteinuria, a biopsy may also be considered in cases of persisting isolated glomerular haematuria, isolated leucocyturia (after other causes, such as infection or drugs are excluded), and the rare occurrence of unexplained renal insufficiency with normal urinary findings. Lower glomerular filtration rate (GFR) is associated with chronic histological lesions and faster rate of decline in GFR. [bib_ref] Lupus nephritis: clinical and pathological correlation, Leaker [/bib_ref] [bib_ref] Contribution of renal biopsy data in predicting outcome in lupus nephritis. Analysis..., Nossent [/bib_ref] [bib_ref] Association between serum total cholesterol level and renal outcome in systemic lupus..., Tisseverasinghe [/bib_ref] [bib_ref] Treatment with cyclophosphamide delays the progression of chronic lesions more effectively than..., Grootscholten [/bib_ref] [bib_ref] Persistent proteinuria and dyslipidemia increase the risk of progressive chronic kidney disease..., Reich [/bib_ref] Methods for estimating GFR such as the Cockcroft-Gault and the Modification of Diet in Renal Disease equations in adults or the Schwartz formula in children, although not fully validated in SLE, are acceptable in clinical practice. For GFR <30 ml/min the decision for biopsy should be based on normal kidney size (>9 cm length in adults) and/or evidence of renal disease activity, in particular proteinuria and active urinary sediment (dysmorphic red blood cells (glomerular haematuria), white blood cells and/or cellular casts). Biopsy should be performed within the first month after disease onset, preferably before the institution of immunosuppressive treatment, unless contraindicated. [bib_ref] The clinical and renal biopsy predictors of long-term outcome in lupus nephritis:..., Esdaile [/bib_ref] [bib_ref] Withdrawal of therapy in patients with proliferative lupus nephritis: long-term follow-up, Moroni [/bib_ref] [bib_ref] Prognostic factors in lupus nephritis: diagnostic and therapeutic delay increases the risk..., Faurschou [/bib_ref] Treatment with high-dose glucocorticoids should not be delayed if a renal biopsy cannot be readily performed.

## Pathological assessment of renal biopsy
We recommend using the International Society of Nephrology/ Renal Pathology Society 2003 classification system [bib_ref] The classification of glomerulonephritis in systemic lupus erythematosus revisited, Weening [/bib_ref] [bib_ref] Interobserver reproducibility and application of the ISN/RPS classification of lupus nephritis-a UK-wide..., Furness [/bib_ref] [bib_ref] Interobserver agreement of scoring of histopathological characteristics and classification of lupus nephritis, Grootscholten [/bib_ref] with assessment of active and chronic glomerular and tubulointerstitial changes, [bib_ref] Tubulointerstitial renal disease in systemic lupus erythematosus, O&apos;dell [/bib_ref] [bib_ref] Predictors of one year outcome in lupus nephritis: the importance of renal..., Esdaile [/bib_ref] [bib_ref] High-risk features of lupus nephritis: importance of race and clinical and histological..., Austin [/bib_ref] [bib_ref] A new morphologic index for the evaluation of renal biopsies in lupus..., Hill [/bib_ref] and of vascular lesions associated with antiphospholipid antibodies/syndrome. An adequate sample of 8 glomeruli should be examined under light microscopy with haematoxylin and eosin, periodic acid-Schiff, Masson's trichrome and silver stain. Immunofluorescence or immunohistochemistry for immunoglobulin and complement deposits (IgG, IgA, IgM, C3, C1q,  and  light chains) is recommended. [bib_ref] The clinical and renal biopsy predictors of long-term outcome in lupus nephritis:..., Esdaile [/bib_ref] Electron microscopy facilitates the recognition of proliferative and membranous lesions and should be performed if possible. Indications and goals of immunosuppressive treatment in LN Ultimate goals of treatment are long-term preservation of renal function, prevention of flares, avoidance of treatment-related harms, and improved quality of life and survival. Treatment must be based on a shared decision between patient and doctor. Immunosuppressive treatment is generally not indicated in classes I and VI LN, unless necessitated by extra-renal lupus activity. [bib_ref] Long-term mortality and renal outcome in a cohort of 100 patients with..., Faurschou [/bib_ref] [bib_ref] Minimal mesangial lupus nephritis: a systematic review, Mok [/bib_ref] [bib_ref] Revised classification of lupus nephritis is valuable in predicting renal outcome with..., Hiramatsu [/bib_ref] Treatment should aim for complete renal response, defined as urine protein:creatinine ratio (UPCR) <50 mg/mmol (roughly equivalent to proteinuria <0.5 g/24 h) and normal or nearnormal (within 10% of normal GFR if previously abnormal) GFR. Partial renal response, defined as 50% reduction in proteinuria to subnephrotic levels and normal or near-normal GFR, should be achieved preferably by 6 months and no later than 12 months following treatment initiation. 9 33-35 Improvement includes any reduction in proteinuria and normalisation or stabilisation of GFR. Although partial response carries worse prognosis than complete response, [bib_ref] Renal flares are common in patients with severe proliferative lupus nephritis treated..., Illei [/bib_ref] it may be an acceptable outcome when all treatments have been exhausted or cannot be used due to high individual risks for toxicity. Following response, patients may experience nephritic or proteinuric flares, the former having more adverse impact on renal outcomes. Nephritic flares include reproducible increase of serum creatinine by 30% (or, decrease in GFR by 10%) and active urine sediment with increase in glomerular haematuria by 10 red blood cells per high power field, irrespective of changes in proteinuria; proteinuric flares include reproducible doubling of UPCR to >100 mg/mmol after complete response or reproducible doubling of UPCR to >200 mg/mmol after partial response. [bib_ref] Renal flares are common in patients with severe proliferative lupus nephritis treated..., Illei [/bib_ref] 1. All methods of renal replacement treatment can be used in patients with lupus, but there may be increased risk of infections in patients on peritoneal dialysis still on immunosuppressive agents and vascular access thrombosis in patients with anti-phospholipid antibodies 9.5 (0. [bib_ref] Treatment with cyclophosphamide delays the progression of chronic lesions more effectively than..., Grootscholten [/bib_ref] 10 (1) 7.2. Transplantation should be performed when lupus activity has been absent, or at a low level, for at least 3-6 months, with superior results obtained with living donor and pre-emptive transplantation. Anti-phospholipid antibodies should be sought during transplant preparation because they are associated with an increased risk of vascular events in the transplanted kidney. 9.4 (0.9)
10 (1) 8. Anti-phospholipid syndrome-associated nephropathy in SLE In patients with lupus and anti-phospholipid syndrome (APS)-associated nephropathy (APSN), hydroxychloroquine and/or antiplatelet/ anticoagulant treatment should be considered 9.0 (1.4) 9 (2) 9. LN and pregnancy 9.1. Pregnancy may be planned in stable patients with inactive lupus and UPCR <50 mg/mmol, for the preceding 6 months, with GFR that should preferably be >50 ml/min. Acceptable medications include hydroxychloroquine, and where needed, low dose prednisone, azathioprine and/or calcineurin inhibitors. The intensity of treatment should not be reduced in anticipation of pregnancy. During pregnancy, acetylsalicylic acid should be considered to reduce the risk of pre-eclampsia. Patients should be assessed at least every 4 weeks, preferably by a specialist physician and obstetrician. Compared to adult-onset disease, LN in children is more severe with increased damage accrual and more common at presentation but the diagnosis, management and monitoring is similar to that of adults. A coordinated transition programme to adult specialists is important in assessing concordance to treatments and optimising long-term outcomes. 9.6 (0.7)
10 (1) *Numbers are mean (SD) and median (IQR) agreement level among experts. A score of 10 represents the highest level of agreement. GFR, glomerular filtration rate; UPCR, urine protein:creatinine ratio. Better outcome when lupus activity is absent or at a low level for 3-6 months 3 C Better outcome with living versus cadaveric donor 2 B Better outcome with pre-emptive transplantation 3 C Increased risk for vascular events in patients with anti-phospholipid antibodies 2 B 8. Treatment of anti-phospholipid syndrome (APS)-associated nephropathy (APSN) Hydroxychloroquine -C Antiplatelet/anticoagulation treatment -C 9. LN and pregnancy Safe in inactive SLE with UPCR <50 mg/mmol for the preceding 6 months 2 B GFR preferably above 50 ml/min -C Safety and efficacy of the following medications Hydroxychloroquine 3 B Low-dose prednisone 4 C Azathioprine 4 C Calcineurin inhibitors 4 C Intensity of treatment should not be reduced in anticipation of pregnancy -C Acetylsalicylic acid to reduce the risk of pre-eclampsia 3 C Assessment every 4 weeks, preferably by a specialist physician and obstetrician -C Flare of nephritis can be treated with same acceptable medications but also with calcineurin inhibitors, intravenous immunoglobulin, immunoadsorption and plasma exchange -C 10. Paediatric LN More common at presentation compared to adult-onset SLE 1 A More severe with increased damage accrual compared to adult-onset disease 2 B Similar monitoring with adults 3 C Similar treatment with adults 3 C Importance of coordinated transition programme to adult specialists -C *Quality of evidence was graded 1-4 and the strength of statements was graded A-C (refer to web-only appendix table 1 for details). MPA refers to either mycophenolate mofetil (MMF) or enteric-coated MPA sodium at equivalent dose based on evidence for comparable efficacy of the two regimens. MMF has been used in most controlled trials in LN. dsDNA, double-stranded DNA; GFR, glomerular filtration rate; UPCR, urine protein:creatinine ratio.

## Treatment of adult ln initial treatment
Patients with LN should be managed, if possible, in experienced centres. [bib_ref] Hospital experience and mortality in patients with systemic lupus erythematosus: which patients..., Ward [/bib_ref] Early trials of immunosuppressive agents have highlighted the importance of long-term (beyond 5 years) follow-up in demonstrating differences in 'hard' outcomes such as doubling of serum creatinine, end-stage renal disease (ESRD) and death. [bib_ref] Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs, Austin [/bib_ref] [bib_ref] Induction treatment of proliferative lupus nephritis with leflunomide combined with prednisone: a..., Wang [/bib_ref] [bib_ref] Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome..., Illei [/bib_ref] Such outcomes, however, are not frequent and may occur late in the course of LN. Intermediate outcome measures, such as renal response and flares, occurring in the majority of patients within the first 2 years after treatment initiation, correlate with hard outcomes in studies with long-term follow-up and are commonly used as endpoints in trials. Correlation does not guarantee surrogacy of these outcomes for all patients, some of whom may still have hard outcomes diverging from their intermediate outcomes.
To date, long-term data are not available for MPA (box 1). Nonetheless, the publication of the Aspreva Lupus Management Study (ALMS) trial, [bib_ref] Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis, Appel [/bib_ref] the largest trial in LN showing comparable response rates between MPA (target mycophenolate mofetil (MMF) dose 3 g/day) and intravenous cyclophosphamide (CY) (monthly pulses 0.5-1 g/m 2 ), both administered for 6 months, together with the ease of administration and the more favourable gonadal toxicity profile of the former, 46-48 formed the basis for recommending MPA as initial treatment for most cases of class III-IV LN. Evidence from transplantation medicine and a single randomised controlled trial (RCT) in LN [bib_ref] Efficacy and safety of enteric-coated mycophenolate sodium in combination with two glucocorticoid..., Zeher [/bib_ref] suggests that MMF and entericcoated mycophenolic acid sodium (eMPA) are likely to be equally efficacious. To this end, and while awaiting further validation, the Committee felt that either MPA formulation can be used in treatment of LN, with 720 mg dose eMPA roughly equivalent to 1 g dose of MMF. We also recommend low-dose intravenous CY (total dose 3 g over 3 months) in combination with glucocorticoids (0.5 mg/kg/day) as initial treatment of class III-IV (V) LN in Caucasians based on better efficacy/ toxicity ratio than high-dose intravenous CY. A single RCT in patients with pure class V LN demonstrated that the combination of glucocorticoids with intravenous CY (6 bimonthly pulses 0.5-1 g/m 2 ) was more efficacious than glucocorticoids alone; the combination of glucocorticoids with ciclosporin was also efficacious but was associated with significantly more relapses of nephrotic syndrome than CY. [bib_ref] Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy, Austin [/bib_ref] Moreover, combined analysis of two other RCTs in the subgroup of patients with pure class V LN showed a comparable antiproteinuric effect of MPA versus high-dose intravenous CY. [bib_ref] Mycophenolate mofetil and intravenous cyclophosphamide are similar as induction therapy for class..., Radhakrishnan [/bib_ref] By extrapolation from these studies, and based on the more favourable gonadal toxicity profile of MPA compared to CY, we recommend MPA as initial treatment for most cases of class V LN and nephrotic-range proteinuria. The low-dose CY regimen has not been tested in pure class V LN.
Subgroup analysis suggests that MPA may have greater efficacy in patients of African descent; further confirmation is needed before issuing a recommendation favouring MPA in these patients. Post hoc analysis in 32 patients in ALMS with baseline GFR<30 ml/min/1.73 m 2 , [bib_ref] Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis, Appel [/bib_ref] and evidence from 2 controlled studies in severe histological forms of LN, support the use of MPA in patients with impaired renal function or crescents. Only high-dose intravenous CY has demonstrated efficacy in a RCT specifically designed to include severe nephritic cases with GFR 25-80 ml/min or with crescents/necrosis in >25% of glomeruli. [bib_ref] Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in..., Boumpas [/bib_ref] Data from a RCT 59 and the 10-year follow-up 60 suggest that azathioprine can be used in class III-IV LN albeit at an increased risk for renal relapse (HR 4.5), thus the committee recommends it for milder cases ( preserved renal function and no adverse histological findings).
Intravenous methylprednisolone (MP) pulses are recommended as part of the initial treatment regimen by extrapolation from controlled studies, to decrease cumulative glucocorticoid dose and associated harms. Higher initial glucocorticoid dose (oral prednisone 0.7-1 mg/kg/day) may be used in severe renal or extra-renal lupus, or when intravenous MP treatment is not feasible. Clinical experience suggests that a further course of three intravenous MP pulses can be considered in patients failing to improve within the first 3 months.
For class II LN with proteinuria >1 g/24 h despite renin-angiotensin-aldosterone system (RAAS) blockade, especially in the presence of glomerular haematuria, we recommend low-to-moderate doses of glucocorticoids ( prednisone 0.25-0.5 mg/kg/day) alone or in combination with azathioprine (1-2 mg/kg/day), if needed, as steroid-sparing agent. Glucocorticoids alone or in combination with immunosuppressive agents may also be considered in cases of class I LN with podocytopathy on the electron microscopy (minimal change disease) or interstitial nephritis. 

## Subsequent treatment
For patients improving after initial treatment, we recommend subsequent immunosuppression to consolidate renal response and prevent flares. Although among patients from European ancestries azathioprine and MPA were equivalent after initial treatment with low-dose intravenous CY, 67 a larger RCT suggested a difference between the two drugs in favour of MPA after initial response to either MPA or intravenous CY (monthly pulses 0.5-1 g/m 2 ). [bib_ref] Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis, Dooley [/bib_ref] In this trial, sequential use of azathioprine after MPA resulted in more treatment failures as compared to

## Box 1 research agenda
- Special training sessions for renal pathologists to improve the interpretation of renal biopsy findings in lupus nephritis (LN) and enhance interobserver agreement - Development and validation of biomarkers which will better reflect kidney biopsy findings and renal disease activity and severity - Long-term (beyond 5 years) efficacy and safety data for mycophenolic acid - Provide data to guide duration of immunosuppressive treatment beyond 3 years - Define the role of adding calcineurin inhibitors, rituximab or belimumab to standard immunosuppressive treatment in cases with residual renal disease - Need for more data on switching regimens in cases of treatment failure - Larger studies with extended follow-up are needed to assess the prognostic significance of anti-phospholipid syndrome (APS)-associated nephropathy (APSN) and coexistence of anti-phospholipid antibodies in LN - Need for controlled trials to assess the role of antiplatelet/ anticoagulant regimes in APSN - Need for randomised controlled trials (RCTs) in paediatric LN and the need to have very long follow-up (beyond 10-15 years) to fully assess the impact of the various treatment strategies and modalities in children MPA followed by MPA. The committee therefore recommends continuation of MPA if the drug was successful as initial treatment. Calcineurin inhibitors can be considered in selected cases with preserved renal function based on evidence from RCTs. [bib_ref] A randomized pilot trial comparing cyclosporine and azathioprine for maintenance therapy in..., Moroni [/bib_ref] [bib_ref] Cyclosporine treatment of lupus membranous nephropathy, Radhakrishnan [/bib_ref] [bib_ref] Irreproducibility of the activity and chronicity indices limits their utility in the..., Schwartz [/bib_ref] Intravenous CY, pulsed every 3 months, may be used in selected cases but exposure to CY should be minimised, especially in women at risk for amenorrhoea and infertility 73 or men planning to father children.
There is no data to guide duration of treatment beyond 3 years; continuing treatment for longer time periods should be individualised with an effort first to withdraw glucocorticoids before immunosuppressive agents. Gradual drug dosage titration may be attempted to ensure the best possible efficacy/toxicity ratio. MPA dose often needs titration to reduce toxicity (doses 1-2 g/day can be effective for long-term treatment). Monitoring MPA blood levels to minimise harm and increase efficacy is under investigation [bib_ref] Pharmacokinetics of mycophenolate mofetil for autoimmune disease in children, Filler [/bib_ref] [bib_ref] Pharmacokinetics of mycophenolic acid in severe lupus nephritis, Lertdumrongluk [/bib_ref] [bib_ref] Mycophenolic acid area under the curve correlates with disease activity in lupus..., Zahr [/bib_ref] but it should be considered in cases with GFR <30 ml/min.

## Refractory disease
Complete renal response can take up to 2 years to reach with <30% to 40% of patients achieving this outcome within the first 6 months of treatment. Switching to an alternative agent is recommended for patients who fail to improve within 3-4 months, or do not achieve partial response after 6-12 months, or complete response after 2 years of treatment. For patients not responding to MPA or CY, evidence from uncontrolled studies suggests that treatment may be switched from MPA to CY, from CY to MPA, or that rituximab (anti-CD20 mAb) may be given either as add-on treatment or as monotherapy. Additional options include calcineurin inhibitors (ciclosporin A, tacrolimus), [bib_ref] Long-term outcomesmycophenolate mofetil treatment for lupus nephritis with addition of tacrolimus for..., Cortes-Hernandez [/bib_ref] [bib_ref] Tacrolimus is an alternative therapeutic option for the treatment of refractory lupus..., Lee [/bib_ref] [bib_ref] Cyclophosphamide in lupus nephritis: a controlled trial, Steinberg [/bib_ref] intravenous immunoglobulin, [bib_ref] Intravenous immunoglobulin treatment of lupus nephritis, Levy [/bib_ref] plasma exchange for rapidly progressive glomerulonephritis, or immunoadsorption for patients who have failed or cannot tolerate other treatments. Data on leflunomide are limited. [bib_ref] Safety and efficacy of leflunomide in the treatment of lupus nephritis refractory..., Tam [/bib_ref] 

## Adjunctive treatment in patients with ln
We recommend control of cardiovascular disease risk factors in a manner similar to patients who do not have SLE with chronic kidney disease, although benefit has not been demonstrated specifically in SLE.Complications of chronic renal insufficiency (anaemia, cardiovascular disease, metabolic bone disease) should also be managed as in patients who do not have SLE. RAAS blockers are recommended as preferred treatment in all patients who are not pregnant with significant proteinuria or hypertension, based on: (a) evidence for their antihypertensive, antiproteinuric and renoprotective effect, [bib_ref] Angiotensin-converting enzyme inhibitors delay the occurrence of renal involvement and are associated..., Duran-Barragan [/bib_ref] [bib_ref] Antiproteinuric effect of ARB in lupus nephritis patients with persistent proteinuria despite..., Kanda [/bib_ref] [bib_ref] Angiotensin inhibition or blockade for the treatment of patients with quiescent lupus..., Tse [/bib_ref] and, (b) lack of data on the comparative efficacy of other classes of antihypertensive agents in LN. Their dose is titrated for maximum antiproteinuric effect while monitoring blood pressure (target level <130/80 mm Hg), serum potassium and GFR levels. Epidemiological studies and the follow-up of a controlled trial 95 demonstrate that hydroxychloroquine use is associated with higher rates of renal response, fewer renal relapses and reduced accrual of renal damage. Hydroxychloroquine (6.5 mg/kg/day or 400 mg/day, whichever is lower) is generally safe in patients with normal baseline ophthalmological examination; dose adjustments may be necessary in patients with GFR <30 ml/min. Annual ophthalmological screening begins after 5 years of treatment or sooner if there are risk factors for retinal damage. [bib_ref] Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy, Marmor [/bib_ref] Patients should also be immunised with non-live vaccines according to the EULAR recommendations. Monitoring and prognosis of LN Patients should be monitored regularly according to EULAR recommendations, [bib_ref] European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus..., Mosca [/bib_ref] including annual examination of cervicovaginal smear in women and measurement of serum immunoglobulins at baseline and then annually in patients who receive immunosuppressive treatment to assess risk of infection. Monitoring of body weight, blood pressure, serum creatinine and estimated GFR, serum albumin, proteinuria, urinary sediment (microscopic evaluation), serum C3/C4, serum anti-dsDNA antibody levels and complete blood cell count are used to define activity and evaluate response to treatment although their individual predictive value for hard outcomes at particular time points is modest.
Spot UPCR measured on first morning void urine sample is a valid and conveniently repeatable measure for measuring proteinuria in children and monitoring within-patient changes in adults. [bib_ref] A prospective study of protein excretion using short-interval timed urine collections in..., Fine [/bib_ref] [bib_ref] Random spot urine protein/ creatinine ratio is unreliable for estimating 24-hour proteinuria..., Hebert [/bib_ref] [bib_ref] Urine protein-to-creatinine ratio in an untimed urine collection is a reliable measure..., Leung [/bib_ref] Timed (12 h or 24 h) urine collections may also be considered at baseline and when major therapeutic changes are considered. Reappearance of urine cellular casts has >80% sensitivity and specificity for renal flares. [bib_ref] Relationship between appearance of urinary red blood cell/white blood cell casts and..., Hebert [/bib_ref] Although serum C3 has generally higher sensitivity than serum C4 (72% to 85% vs 28% to 74%), both tests have modest specificity for active LN. The diagnostic accuracy of serum anti-dsDNA is also modest with positive and negative likelihood ratios ranging from 1.5-4.8 and 0.3-0.8, respectively. Farr and ELISA methods are both acceptable, although the former yields higher sensitivity and specificity rates. Anti-C1q and anti-nucleosome 112-114 antibodies have higher sensitivity and specificity for active nephritis but further standardisation and validation are required. Changes in serological tests are more important predictors of concurrent or impending LN flare than their absolute levels but should be repeated no more than monthly. In the absence of proteinuria, active serology (decreasing C3/C4 and/or increasing anti-dsDNA) and/or urine sediment is not an indication for pre-emptive treatment but dictates closer monitoring of patients. Repeat renal biopsy provides additional prognostic information [bib_ref] A double-blind controlled trial comparing cyclophosphamide, azathioprine and placebo in the treatment..., Steinberg [/bib_ref] [bib_ref] Predictive power of the second renal biopsy in lupus nephritis: significance of..., Hill [/bib_ref] [bib_ref] Outcome of relapse in lupus nephritis: roles of reversal of renal fibrosis..., Hill [/bib_ref] [bib_ref] Clinical and prognostic value of serial renal biopsies in lupus nephritis, Moroni [/bib_ref] and can assist therapeutic decisions in patients with relapse of nephritis after complete renal response, or with refractory disease. It can also be used in the context of a clinical trial to monitor treatment efficacy and changes in chronicity scores. 

## Management of esrd in ln
Despite immunosuppressive treatment, 10% to 30% of patients with LN will progress to ESRD within 15 years of diagnosis. Infections (including peritonitis) may occur in patients with active disease still on immunosuppressive treatment, and contribute to morbidity and mortality. [bib_ref] Why do patients with lupus nephritis die, Correia [/bib_ref] [bib_ref] Thrombotic microangiopathy in United States long-term dialysis patients, Perkins [/bib_ref] [bib_ref] Clinical outcomes of systemic lupus erythematosus patients undergoing continuous ambulatory peritoneal dialysis, Siu [/bib_ref] [bib_ref] Peritoneal dialysis and hemodialysis in systemic lupus erythematosus patients: comparison of clinical..., Weng [/bib_ref] Although clinical and serological activity tend to subside in most patients with ESRD on dialysis, flares of renal or extra-renal lupus can occur. [bib_ref] Factors associated with active systemic lupus erythematosus after endstage renal disease, Szeto [/bib_ref] [bib_ref] Analysis of lupus activity in end-stage renal disease treated by hemodialysis, Okano [/bib_ref] [bib_ref] Poor prognosis in end-stage lupus nephritis due to nonautologous vascular access site..., Sires [/bib_ref] [bib_ref] Renal replacement therapy in lupus nephritis, Rietveld [/bib_ref] Comparative studies and cases series support that patients with SLE are good candidates for renal transplantation performed when clinical (and ideally, serological) lupus activity is absent, or at a low level, for at least 3-6 months 135 ; best results are obtained with living donor [bib_ref] Recurrence of lupus nephritis after kidney transplantation, Contreras [/bib_ref] [bib_ref] Outcome of renal transplantation in systemic lupus erythematosus, Stone [/bib_ref] [bib_ref] Factors affecting kidney-transplant outcome in recipients with lupus nephritis, Tang [/bib_ref] and pre-emptive transplantation. [bib_ref] Preemptive kidney transplantation in systemic lupus erythematosus, Naveed [/bib_ref] Patients with moderate to high titres of antiphospholipid antibodies are at increased risk for thrombotic complications and may receive anticoagulants perioperatively. [bib_ref] The long-term prognosis of renal transplantation in patients with lupus nephritis, Moroni [/bib_ref] [bib_ref] Antiphospholipid antibody syndrome in renal transplantation: occurrence of clinical events in 96..., Stone [/bib_ref] [bib_ref] Frequency, potential risk and therapeutic intervention in end-stage renal disease patients with..., Vaidya [/bib_ref] [bib_ref] Relative risk of post-transplant renal thrombosis in patients with antiphospholipid antibodies, Vaidya [/bib_ref] Post-transplantation recurrent LN, although difficult to treat, is a rare cause of renal allograft loss. [bib_ref] Recurrence of lupus nephritis after kidney transplantation, Contreras [/bib_ref] Anti-phospholipid syndrome (APS)-associated nephropathy (APSN) in SLE Anti-phospholipid antibodies (anti-cardiolipin antibodies, anti-2-glycoprotein I antibodies, lupus anticoagulant) may be associated with a distinct type of vascular nephropathy (APSN) with adverse prognostic factors such as hypertension, impaired renal function and interstitial fibrosis. [bib_ref] Antiphospholipid syndrome nephropathy in patients with systemic lupus erythematosus and antiphospholipid antibodies:..., Tektonidou [/bib_ref] [bib_ref] Immunohistochemical detection of intravascular platelet microthrombi in patients with lupus nephritis and..., Galindo [/bib_ref] [bib_ref] IgA antiphospholipid antibodies are an independent risk factor for thromboses, Shen [/bib_ref] [bib_ref] Antiphospholipid antibody profiles in lupus nephritis with glomerular microthrombosis: a prospective study..., Zheng [/bib_ref] Histological lesions of APSN are present in 20% to 30% of patients with SLE and include thrombotic microangiopathy and chronic lesions such as fibrous intimal hyperplasia, organising thrombi with recanalisation, focal cortical atrophy and fibrous occlusions of arteries/arterioles, thus, need to be distinguished from thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome and malignant hypertension. In spite of lack of evidence from controlled studies, hydroxychloroquine and/or antiplatelet/anticoagulant treatment can be considered in combination with immunosuppressive treatment if nephritis is present. Patients with definite APS should receive anticoagulation treatment. [bib_ref] Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid..., Ruiz-Irastorza [/bib_ref] 

## Ln and pregnancy
Pregnancy may be planned in patients with inactive lupus and UPCR <50 mg/mmol for the preceding 6 months, with GFR that should preferably be >50 ml/min. Patients with LN who are pregnant should ideally be followed by a multidisciplinary team. Stable renal disease is treated with the same drugs that are recommended as acceptable during prepregnancy counselling (hydroxychloroquine, prednisone, azathioprine). Hydroxychloroquine should be continued or even instituted if immunosuppressive agents need to be stopped. MPA or CY should not be used in the last 3 months, and biological agents for at least 4 months-dependent upon the agent used before conception. Blood pressure should be controlled without RAAS blockers at the time of conception if possible, due to their potential teratogenic effect during the first trimester, or with switching to other agents such as nifedipine or labetalol as soon as pregnancy is confirmed. Acetyl-salicylic acid is recommended to reduce the risk for pre-eclampsia. [bib_ref] Pregnancy in women with pre-existing lupus nephritis: predictors of fetal and maternal..., Imbasciati [/bib_ref] Patients with APS are at increased risk for adverse pregnancy outcomes and should be considered for anticoagulation with low-molecular-weight heparin and/or acetyl-salicylic acid depending on their history of obstetric and/or thrombotic events. [bib_ref] Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid..., Ruiz-Irastorza [/bib_ref] Warfarin must be discontinued as soon as pregnancy is confirmed. Patients with nephrotic-range proteinuria are also candidates for anticoagulation.
For monitoring, any fall in serum C3/C4 is significant given than levels usually rise during pregnancy; 159 additional investigation may be needed to rule out pre-eclampsia before diagnosing exacerbation of renal disease. [bib_ref] Pregnancy in past or present lupus nephritis: a study of 32 pregnancies..., Huong [/bib_ref] For active disease or pre-eclampsia, combined care with obstetricians is recommended. [bib_ref] A systematic review and meta-analysis of pregnancy outcomes in patients with systemic..., Smyth [/bib_ref] Close surveillance for renal flare post partum is essential. In addition to acceptable medications used in stable LN, refractory cases can also be treated with calcineurin inhibitors, intravenous immunoglobulin, immunoadsorption and possibly plasma exchange, according to disease severity. Management of paediatric LN Children are at increased risk for renal involvement compared to adults with SLE (OR 1.5-2.4), and nephritis often is a presenting feature of paediatric SLE. Together with elevated blood pressure, fever, lymphadenopathy, skin and joint manifestations, [bib_ref] Differences in clinical manifestations between childhood-onset lupus and adult-onset lupus: a meta-analysis, Livingston [/bib_ref] children with LN tend to have more active disease over time, receive more intensive immunosuppressive treatment and accrue more damage, often related to glucocorticoid toxicity, compared to adults. [bib_ref] Risk factors for hypercreatinemia in patients with systemic lupus erythematosus, Rzany [/bib_ref] [bib_ref] Assessment of damage in juvenile-onset systemic lupus erythematosus: a multicenter cohort study, Ravelli [/bib_ref] [bib_ref] Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus, Brunner [/bib_ref] [bib_ref] Clinical and laboratory characteristics and long-term outcome of pediatric systemic lupus erythematosus:..., Hiraki [/bib_ref] [bib_ref] Differences in long-term disease activity and treatment of adult patients with childhood-and..., Hersh [/bib_ref] [bib_ref] Prognostic impact of atypical presentation in pediatric systemic lupus erythematosus: results from..., Taddio [/bib_ref] The diagnosis, management and monitoring is based on extrapolation from evidence in adults, and on the limited, non-randomised, evidence in children with LN. [bib_ref] Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haemopoietic stem-cell..., Traynor [/bib_ref] [bib_ref] Clinical efficacy of cyclosporin a neoral in the treatment of paediatric lupus..., Fu [/bib_ref] [bib_ref] Induction therapy for pediatric focal proliferative lupus nephritis: cyclophosphamide versus mycophenolate mofetil, Lau [/bib_ref] [bib_ref] Outcomes in patients with active lupus nephritis requiring immunosuppressives who never received..., Urowitz [/bib_ref] Additional considerations include the negative effect of disease activity and glucocorticoids on linear growth, and the modification of body image induced by treatment. This may represent major psychological burden especially in adolescents building their self-esteem and affecting treatment compliance.
[fig] .: Flare of LN during pregnancy can be treated with acceptable medications stated above depending on severity of [/fig]
[table] Table 1: Recommendations for the management of patients with systemic lupus erythematosus (SLE) with renal involvement [/table]
[table] Table 2: Category of evidence and strength of statements* Indications for first renal biopsy Diagnostic value of urinary findings (proteinuria 0.5 g/24 h especially with glomerular haematuria and/or cellular casts) 2 C Clinical, serological or laboratory tests correlate modestly with renal biopsy findings 2 B 2. Pathological assessment of kidney biopsy International Society of Nephrology/Renal Pathology Society (ISN/RPS) Immunosuppression for class III A or III A/C (V) and IV A or IV A/C (V) nephritis 1 A Immunosuppression for class V nephritis if proteinuria >1 g/24 h 4 C Target: preservation of renal function, prevention of disease flares, avoidance of treatment-related harms and improved quality of life and survival [/table]