The Management of Lupus Nephritis as Proposed by EULAR/ERA 2019 Versus KDIGO 2021

Hans-Joachim Anders; Jerome Loutan; Annette Bruchfeld; Gema M. Fernández-Juárez; Jürgen Floege; Dimitrios Goumenos; Kultigin Turkmen; Cees van Kooten; Eleni Frangou; Kate I. Stevens; Andreas Kronbichler; Mårten Segelmark; Vladimir Tesar

Disclosures

Nephrol Dial Transplant. 2023;38(3):551-561.

Abstract and Introduction

Abstract

In 2019 and 2021, the European League for Rheumatism (EULAR) jointly with the European Renal Association (ERA) and the Kidney Disease: Improving Global Outcomes (KDIGO), respectively, released updated guidelines on the management of lupus nephritis (LN). The Immunology Working Group of the ERA reviewed and compared both updates. Recommendations were either consistent or differences were of negligible clinical relevance for: indication for kidney biopsy, kidney biopsy interpretation, treatment targets, hydroxychloroquine dosing, first-line initial immunosuppressive therapy for active class III, IV (±V) LN, pregnancy in LN, LN in paediatric patients and LN patients with kidney failure. Relevant differences in the recommended management relate to the recognition of lupus podocytopathies, uncertainties in steroid dosing, drug preferences in specific populations and maintenance therapy, treatment of pure class V LN, therapy of recurrent LN, evolving alternative drug options and diagnostic work-up of thrombotic microangiopathy. Altogether, both documents provide an excellent guidance to the growing complexity of LN management. This article endeavours to prevent confusion by identifying differences and clarifying discrepancies.

Introduction

Lupus nephritis (LN) is a frequent complication of systemic lupus erythematosus (SLE), a systemic autoimmune disease affecting mostly young women.^[1] LN has significant impact on the morbidity and mortality of SLE, in particular when a late diagnosis or insufficient control of disease activity leads to chronic kidney disease (CKD) or ultimately kidney failure.^[1] In addition, LN and LN-related CKD affect fertility and pregnancy outcomes and cardiovascular morbidity and mortality later in life. Therefore, early diagnosis, rapid and effective treatment, and sustaining an immunological response are essential to improve both short- and long-term outcomes of patients with LN.

Multiple stakeholders have sought to improve management and to expand treatment options for patients with LN. Indeed, the last decade has seen numerous clinical trials, biomarker studies and longitudinal outcome analyses in these areas. Furthermore, several organizations and societies have released recommendations for the management of LN, and periodically update them based on evolving scientific evidence.

The European League Against Rheumatism (EULAR) and the European Renal Association (ERA, formerly ERA-EDTA) joined forces and originally released recommendations for the management of adult and paediatric LN in 2012;^[2] these were updated in 2019 (published in 2020).^[3] To reach a consensus, 11 rheumatologists, 11 nephrologists (including one paediatric), 1 allied health professional and 2 patient representatives followed a Delphi-based methodology with dedicated staff who performed a systematic review of the literature on 15 pre-selected questions regarding the topic. The panel discussed the available evidence before assessing the level of agreement for each topic. The guideline consists of a list of overarching principles and specific recommendations equipped with the respective levels of evidence, grading of recommendations and levels of agreement.

The Kidney Disease: Improving Global Outcomes initiative (KDIGO) released a guideline for the management of the various forms of glomerulonephritides, including LN, in 2012,^[4] with an update produced in 2021.^[5] KDIGO gathered a global panel of multidisciplinary clinical and scientific experts who first convened in 2017 at a Controversy Conference to identify key questions, which were published to gain broad feedback of the community. A designated Evidence Review Team systematically reviewed and analysed the evidence and used the GRADE approach to analyse certainty of the evidence and the strength of the guideline recommendations. A draft was made available for public review, and the feedback was implemented into the final version. The guideline lists 'recommendations' based on clear evidence as well as 'practice points' to provide guidance where sufficient evidence is missing.

Of note, KDIGO 2021 considered scientific evidence that was not yet available at the time of EULAR/ERA 2019 and the EULAR-ERA expert panel included 50% rheumatologists, whereas at KDIGO, rheumatology was less well represented. In addition, the three organizations target different audiences: EULAR and ERA address mostly aspects related to European patient populations and healthcare systems, whereas KDIGO has a global mission and outreach and therefore received input from experts from all world regions.

The board of the Immunonephrology Working Group of the ERA reviewed the two guidelines to establish if and how some of the differences may impact upon clinical practice.

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Abstract and Introduction
Recommendation Topics
Conclusions
References

Table 1. Recommendations for the management of LN by EULAR/ERA 2019 and KDIGO 2021
Topic	EULAR/ERA-EDTA 2019 overarching principles/recommendations	KDIGO 2021 practice points/recommendations	Clinical impact of differences between the two guidelines
Indication for kidney biopsy	• To be considered with persistent proteinuria ≥0.5 g/24 h (or UPCR ≥0.5 g/g in morning first void urine) and/or an unexplained decrease in GFR • Kidney biopsy is indispensable and no other clinical or laboratory variables can substitute for it	Consider biopsy if either • Dipstick protein ≥2+ (any level of specific gravity) or 1+ if urine diluted or spot UPCR >0.5, ±sediment positive for acanthocytes (≥5%), red blood cells or white blood cells, confirm proteinuria >0.5 g/day in 24-h urine collection, OR • eGFR <60 mL/min/1.73 m² or decreasing if attributable to SLE
Kidney biopsy interpretation	ISN/RPS 2003 classification is recommended with additional assessment of activity and chronicity indices as well as of thrombotic and vascular lesions	Kidney biopsies should be read by an experienced kidney pathologist and classified according to the ISN/RPS scheme and EM (where available) and note features of activity and chronicity
Treatment targets	• Preservation (or improvement) of kidney function plus a reduction in proteinuria of ≤25% by 3, ≤50% by 6, a UPCR <0.5–0.7 g/g by 12 months (nephrotic-range proteinuria at baseline by 18–24 months), keep therapy, if proteinuria is improving • Additional target: remission or low-disease activity of extrarenal domains	• ≥25% proteinuria reduction + normal complement at 2 months = good outcome predictor • CRR within >6–12 months: proteinuria reduction to <0.5 g/g as UPCR from 24-h urine AND stabilization or improvement in kidney function (± 10–15% of baseline) • PRR within 6–12 months: proteinuria reduction >50% and <3 g/g as UPCR from 24-h urine AND stabilization or improvement in kidney function (±10–15% of baseline) OR <0.7–0.8 g/24 h within 12 months
Hydroxychloroquine	• For all patients without contraindication • Max. 5 mg/kg/day adjusted for GFR • 50% dose reduction in GFR <30 mL/min • Eye monitoring upon 5 years of therapy, then yearly or yearly from the start if risk factors (e.g. GFR <30 mL/min)	• For all patients or an equivalent antimalarial unless contraindicated • Initially 6.5 mg/ideal weight/day or 400 mg/day • During maintenance 4–5 mg/kg/day • ≥25% dose reduction if eGFR <30 mL/min/1.73 m² • Baseline retinal exam and annually, especially after 5 years of use • HCQ toxicity is a rare cause of persistent proteinuria in LN	Despite different ways of calculating the HCQ starting dose for most adults the maximal dose will not exceed 400 mg Several cases of HCQ toxicity with Fabry-like 'zebra bodies' in podocytes have been reported as a cause of persistent proteinuria in LN
Therapy LN class I/II	• No need for specific immunosuppression beyond treatment for extrarenal manifestations • Repeat biopsy in significant proteinuria to detect class switch	• Low-level proteinuria: Immuno-suppressive treatment guided by extrarenal manifestations • If nephrotic-range proteinuria (lupus podocytopathy), treat like MCD/FSGS: consider maintenance combination therapy with low-dose steroids and another immunosuppressive agent	LN I/II plus nephrotic-range proteinuria is suggestive of a concomitant podocytopathy with a low threshold for proteinuria triggered even by a mild LN. May benefit from specific diagnostic work-up
Induction therapy active class III/IV (±V), steroids	IV pulses methylprednisolone (total dose 0.5–2.5 g, depending on disease severity) followed by oral prednisone (0.3–0.5 mg/kg/day) for up to 4 weeks, tapered to ≤7.5 mg/day by 3–6 months	• Initial IV methylprednisolone 0.25–0.5 g/day for 1–3 days • Oral prednisolone at start 0.6–1 mg/kg (max. 80 mg) tapering to <5–7.5 mg/day over a few months • If satisfactory improvement in kidney AND extrarenal disease to initial therapy, moderate-dose oral steroids (0.6–0.7 mg/kg to <5 mg after week >25) or reduced-dose oral steroids (0.5–0.6 mg/kg to <2.5 mg after week >25) can be considered	Recent studies suggest that less oral steroids (lower starting dose and faster taper) can be as efficient as traditional doses
Induction therapy active class III/IV (±V)	MMF (2–3 g/day, or MPA at equivalent dose) or low-dose IV CYC (6× 0.5 g every 2 weeks)	• MMF (2–3 g/day) or MPA (1.44–2.16 g/day) for >6 months • Low-dose CYC IV (0.5 g/2 weeks for 6 doses) (efficacy data in mainly in Caucasians) • MMF/MPA is preferred in patients at risk of infertility, Asian, Hispanic, African ancestry or prior exposure to CYC • CYC preferred, if suboptimal adherence is anticipated	Certain preferences apply to specific populations
Induction therapy active class III/IV (±V), alternatives	• In patients at high risk for kidney failure (reduced GFR, histological presence of crescents or fibrinoid necrosis or severe interstitial inflammation) consider high-dose IV CYC (0.5–0.75 g/m² monthly for 6 months)	• Pulse IV CYC (0.5–1 g/m²) for 6 months (efficacy data in different ethnicities) • Oral CYC 1–1.5 mg/kg/day max. 150 mg for 2–6 months (efficacy data in different ethnicities) • Belimumab: can be added to standard therapy • RTX: consider for repeated flares • AZA (accepted in pregnancy) or leflunomide if patient intolerant, other unavailable or expensive)	Recently, belimumab was approved by FDA and EMA for the initial treatment of active LN and further alternatives exist as listed by KDIGO
Induction therapy active class III/IV (±V), CNI + reduced dose MMF	MMF (1–2 g/day) or MPA at equivalent dose) with a CNI (especially TAC), particularly in nephrotic-range proteinuria	Only, in patients not tolerating MPAA regimen or unfit for CYC or refuse CYC • Voclosporin (23.7 mg ×2) can be added to MMF/MPA and steroids for 1 year in eGFR >45 mL/min/1.73 m²	Previous trials exclusively from Asia with remaining concerns about rate of adverse effects and nephrotoxicity. Recently, voclosporin confirmed rapid and strong effect on proteinuria control in patients on MMF from all world regions with a GFR >45 mL/min/1.73 m²
Maintenance therapy class III/IV (±V): steroids	• Low-dose prednisone (2.5–5 mg/day) when needed to control activity • Gradual withdrawal of steroids after ≥3–5 years therapy in complete clinical response	• Taper to lowest possible dose except if required for extrarenal manifestations • Can consider to stop after CRR for ≥12 months
Maintenance therapy class III/IV (±V), first-line agents	• Upon improvement with initial treatment with MMF: MMF/MPA (dose: 1 to 2 g/day) • Upon improvement of initial treatment with CYC: MMF/MPA as before or AZA (2 mg/kg/day) • AZA is preferred if pregnancy is contemplated • Gradual withdrawal of MMF or AZA upon steroid withdrawal and ≥3–5 years therapy in complete clinical response • HCQ to be continued long term	• MMF (1.5–2 g/day) or MPA (1080–1440 mg/day) (initial + maintenance therapy not <36 months in CRR and no extrarenal manifestations for >36 months	• EULAR/ERA considers MMF/MPA and AZA as equipotent after CYC induction based on the results of the MAINTAIN trial with European patients. The extended ALMS trial across all world regions found AZA inferior to MMF Cytopenias were more common with AZA. AZA is less costly than MMF and has benefits if pregnancy is contemplated • A kidney biopsy can help the decision whether it is safe or not to stop therapy. In patients with residual LN activity therapy should be continued
Maintenance therapy class III/IV (±V), second-line agents	• AZA 2 mg/kg/day (particularly for pregnancy/cost) • Belimumab can be considered as add-on therapy to reduce extrarenal SLE activity and the risk for flares	• AZA 1.5–2 mg/kg/day if intolerant/unavailable MMF/MPA or considering pregnancy • Alternatives: CNI (preferred if considering pregnancy) or mizoribine if MMF/MPA or AZA cannot be used • Caution when adding a CNI to reduce proteinuria (evidence of podocytopathy desirable)
Pure class V: indication immunosuppressive therapy	Immunosuppression plus steroids for nephrotic-range proteinuria or when UPCR exceeds 1 g/g despite the optimal use of RAS inhibitors	Only for nephrotic syndrome or nephrotic-range proteinuria or guided by extrarenal manifestations; consider immunosuppression if worsening of proteinuria and/or complications of proteinuria (thrombosis, oedema) under conservative therapy
Induction therapy pure class V: first line	• Initial IV methylprednisolone 0.5–2.5 g followed by oral prednisone 20 mg tapered to ≤5 mg by 3 months plus MMF 2–3 g/day or MPA at equivalent dose	• At low-level proteinuria: immunosuppression guided by extrarenal SLE, HCQ, RAAS inhibition • At nephrotic-range proteinuria: combined immunosuppression with steroids AND MMF/MPA (reasonable first choice) or CYC (for <6 months) or CNI (if prior CYC or intolerant) or RTX (if prior CYC or intolerant) or AZA • HCQ, RAAS inhibition	The prognosis of pure class V depends on the level of proteinuria and the presence or absence of nephrotic syndrome
Induction therapy pure class V: second line	• CYC • CNI (especially TAC) monotherapy • CNI + MMF/MPA in patients with nephrotic-range proteinuria
Maintenance therapy pure class V	Continuation, switching to or addition of CNIs (especially TAC) can be considered at the lowest effective dose and after considering nephrotoxicity risks
Failure to achieve treatment goals/refractory disease	• Thorough evaluation of the possible causes, including assessment of drug-adherence and therapeutic drug monitoring • For active disease: switch to one of the alternative initial therapies or RTX (1 g on days 0 and 14) • Mentioned: obinutuzumab, belimumab, IVIGs, plasma exchange (rarely indicated)	• Evaluate compliance and adequate dosing (drug levels) • Repeat biopsy, if concern for chronicity/other diagnoses (TMA) • Switch MMF/MPA to CYC, CYC to MMF/MPA • If refractory, combine MMF/MPA + CNI OR add RTX (or another biologic agent) OR extend IV CYC • Mentioned: obinutuzumab, belimumab	Switching drugs makes sense only when drug non-adherence is an unlikely cause. There is little experience with belimumab as a rescue therapy of LN but is has benefits as early add-on to standard of care in active LN
Therapy of relapse		• Use initial therapy that achieved original response or an alternative first-line agent • Mind cumulative dose of CYC	In case of drug non-adherence or recent dose reductions recurrent active LN should respond again to the initial treatment
Follow-up screening	• Visits every 2–4 weeks during first 2–4 months after diagnosis or flare, then according to response • At each visit: body weight, BP, GFR, albumin, UPCR/24 h-U • Urine red cell count or sediment and blood cell count if active nephritis • aPL, C3/C4, anti-dsDNA periodically, anti-C1q, if available • Repeat biopsy if: refractory, worsening, relapse	• Visit frequency and tests not specified • Repeat biopsy considered, if concerns for chronic damage or other diagnosis	Follow-up intervals can be individualized depending on the response to therapy
Adjunctive therapies	• RAAS inhibition, if UPCR >0.5 g/g or arterial hypertension • BP target: <130/80 mmHg • Statin depending on CVRF-score • Avoid nephrotoxins (no NSAIDs) • Bone protection: general measures, Vit D/Ca/antiresorptives) • Vaccination: influenza, pneumococci, VZV (based on individual RF) • If aPL+, ASA (80–100 mg/day) after balancing benefits/bleeding risks • Anticoagulants considered if nephrotic syndrome with albumin <20 g/L	• RAAS inhibition, BP control • BP target: <130/80 mmHg • Avoidance of high-sodium diet • Dislipidemia management • Bone protection: general measures Vit D/Ca/bisphosphonates when appropriate • Vaccination: influenza, pneumococci, HBV, VZV (based on individual RF) • Screening for HBV, HCV, HIV • Pneumocystis jirovecii prophylaxis Based on individual risk constellation • Contraception, gonadal preservation • Age-adjusted cancer screening • Limit CYC exposure to <36 g • Full anticoagulation in case of thrombembolic events in nephrotic syndrome, prophylactic anticoagulation based on individual risk–benefit assessment	The use of anticoagulants, pneumocystis prophylaxis, contraception and age-adjusted cancer screening are all important considerations. Risks for thromboembolism versus serious bleeding should be balanced for prophylactic anticoagulation in nephrotic syndrome
Pregnancy	• Planned in stable, inactive LN • Ideally UPCR <0.5 g/g for 6 months + GFR >50 mL/min • Compatible medications: HCQ, prednisone, AZA and/or CNIs (especially TAC) 3 to be continued at safe dosages (pregnancy/lactation) • Stop MMF and switch 3–6 months before pregnancy to test efficacy of new therapy • ASA to avoid pre-eclampsia • Controls every 4 weeks, preferably with experienced obstetrician • Flares treated with acceptable medications as stated above or IV pulses of MPA	• Advice patients to avoid pregnancy if active LN OR treatment with teratogenic drugs is ongoing AND for ≥6 months after LN becomes inactive • HCQ continued (to reduce the risk of complications), start low-dose aspirin <16 weeks of gestation • Only steroids, HCQ, AZA and CNI are considered safe • Low-dose ASA
Paediatric	• Diagnosis, management and monitoring similar to adults • Coordinated transition programme	Paediatric patients are treated similar to adults but need to consider issues relevant to this population (dose adjustments, growth, fertility, psychological factors)
Kidney failure	• All kidney replacement modalities can be used • Transplantation preferred after 6 months of clinically and ideally serologically inactive SLE • Outcomes better with living donation or pre-emptive Tx • HD and PD identical outcomes • Immunosuppressive therapy guided by extrarenal manifestations • aPL testing before transplantation	• Transplantation is preferred to long-term dialysis, as soon as disease is quiescent • HD and PD similar outcomes • If aPL positive, consider prophylactic anticoagulation
Anti-phospholipid antibodies and TMA	• ASA may be used upon balancing risks in high-risk profiles • aPL-related nephropathy: ASA/anticoagulant can be considered + HCQ	• TMA should be managed according to the underlying aetiology (TTP, aHUS, aPL-related nephropathy) • Long-term anticoagulants are reasonable to treat aPL-related nephropathy	Presence of TMA in patients with SLE does not necessarily relate to aPL. It is reasonable to consider also other causes of TMA treatments are different for the various forms of TMA

ISN/RPS, International Society of Nephrology/Renal Pathology Society; MCD/FSGS, minimal change disease/focal segmental glomerulonephritis; eGFR, estimated glomerular filtration rate; FDA, Food and Drug Administration; EMA, European Medicines Agency; Tx, transplantation; TAC, tacrolimus; IVIG, intravenous immunoglobulin G therapy; BP, blood pressure; C3/C4, complement factor 3/4; NSAID, non-steroidal anti-inflammatory drug; CVRF, cardiovascular risk factor; Vit D, vitamin D; Ca, calcium; HBV/HCV, hepatitis B/C virus; HIV, human immunodeficiency virus; PJP, Pneumocystis jirovecii pneumonia; aPL, anti-phospholipid antibodies; TTP, thrombotic thrombocytopenic purpura; aHUS, atypical haemolytic-uremic syndrome; CRR, complete renal response; PRR, partial renal response.

Authors and Disclosures

Hans-Joachim Anders¹, Jerome Loutan¹, Annette Bruchfeld ^2,3, Gema M. Fernández-Juárez ⁴, Jürgen Floege⁵, Dimitrios Goumenos⁶, Kultigin Turkmen⁷, Cees van Kooten⁸, Eleni Frangou⁹, Kate I. Stevens ¹⁰, Andreas Kronbichler¹¹, Mårten Segelmark^3,12 and Vladimir Tesar¹³, on behalf of the Immunonephrology Working Group of the European Renal Association

¹Division of Nephrology, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany, ²Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine, Linköping University, Linköping, Sweden, ³Department of Clinical Science, Intervention and Technology, Division of Renal Medicine, Karolinska Institutet, Stockholm, Sweden, ⁴Department of Nephrology, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain, ⁵Division of Nephrology, RWTH Aachen University Hospital, Aachen, Germany, ⁶Department of Nephrology and Renal Transplantation, Patras University Hospital, Patras, Greece, ⁷Department of Internal Medicine, Division of Nephrology, Necmettin Erbakan University, Konya, Turkey, ⁸Division of Nephrology and Transplant Medicine, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands, ⁹Department of Nephrology, Limassol General Hospital, Limassol, Cyprus, ¹⁰The Renal and Transplant Unit, Queen Elizabeth University Hospital, Glasgow, UK, ¹¹Department of Medicine, University of Cambridge, Cambridge, UK, ¹²Department of Clinical Sciences Lund, Division of Nephrology, Lund University and Skåne University Hospital, Lund, Sweden and ¹³Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia

Correspondence to
Hans-Joachim Anders; E-mail: hjanders@med.uni-muenchen.de

Conflict of Interest Statement
H.-J.A, E.F. and V.T. were part of the EULAR/ERA guideline panel. A.B. reports personal fees from AstraZeneca, Bayer, ChemoCentryx and Vifor. J.F. chaired and V.T. contributed to the revision of the KDIGO guideline on the treatment of glomerular diseases. H.-J.A. has received consultancy fees and speaker honoraria from GlaxoSmithKline (GSK), Janssen, AstraZeneca, Kezar, Otsuka and Novartis. J.F. has received consultancy fees from Calliditas, Retrophin, Omeros and Visterra. A.K. has received consultancy fees from Alexion, Vifor Pharma, Otsuka, UriSalt and Catalyst Biosciences. G.M.F.J. received consultancy fees from GSK. M.S. reports consultancy fees from Vifor Pharma, AstraZeneca, ChemoCentryx and Hansa Biopharma.
The results presented in this paper have not been published previously in whole or part.