Guideline sources The following summarized guidelines for the evaluation and management of lupus nephritis (LN) are prepared by our editorial team based on guidelines from the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2021), the European Dialysis and Transplant Association (ERA- EDTA/EULAR 2020), the Royal College of Ophthalmologists (RCOphth 2020), and the American College of Rheumatology (ACR 2012). 1 2 3 5 Calculator Classification criteria for lupus n https://web.pathway.md/diseases/recrc0K5l9trrzGaD 1/11 6/29/23, 5:55 AM Lupus nephritis Pathway Guidelines 1. Screening and diagnosis Classification criteria: define LN according to the ACR classification criteria. 2. Diagnostic investigations Initial evaluation: Obtain the following baseline investigations in patients with active LN: BP measurement serum creatinine urinalysis UPCR C3/C4 levels anti-DNA levels. B 3. Diagnostic procedures Kidney biopsy: As per EULAR 2020 guidelines, consider performing kidney biopsy if there is evidence of kidney involvement, especially in the presence of persistent proteinuria 0.5 g/24 hours or urine protein-to-creatine ratio 500 mg/g in morning first void urine C and/or an unexplained decrease in GFR. C Show 2 more As per ACR 2012 guidelines, obtain a renal biopsy in all patients in whom a first episode of active LN is suspected, unless strongly contraindicated, so that glomerular disease can be classified by current International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification: class I - minimal mesangial glomerulonephritis class II - mesangial proliferative LN class III - focal proliferative nephritis class IV - diffuse proliferative nephritis class V - membranous nephritis. B 4. Medical management Goals of treatment: Set the following as goals of treatment: patient survival https://web.pathway.md/diseases/recrc0K5l9trrzGaD 2/11 6/29/23, 5:55 AM Lupus nephritis Pathway long-term preservation of kidney function prevention of disease flares prevention of organ damage management of comorbidities improvement in disease-related quality of life. B Show 3 more Immunosuppressive therapy, class I-II LN: As per KDIGO 2021 guidelines: Initiate immunosuppressive treatment in patients with class I or II LN with low-level proteinuria guided by extrarenal manifestations of SLE. B Evaluate for lupus podocytopathy (electron microscopy would be useful) in patients with class I or II LN and nephrotic syndrome. Treat these patients as for minimal change disease. Consider initiating maintenance combination therapy with low-dose corticosteroids and another immunosuppressive agent. B As per ACR 2012 guidelines, avoid using immunosuppressive therapy for the treatment of class I-II LN. D Immunosuppressive therapy, class III and IV LN: As per KDIGO 2021 guidelines, initiate corticosteroids plus either low-dose IV cyclophosphamide or mycophenolic acid analogs as initial therapy in patients with active class III or IV LN, with or without a membranous component. B Show 11 more As per ERA-EDTA/EULAR 2020 guidelines, initiate immunosuppressive agents in combination with corticosteroids in patients with class IIIA or IIIA/C ( V) and IVA or IVA/C ( V) nephritis. A Show 5 more As per ACR 2012 guidelines, treat patients with class III and IV LN using corticosteroids in combination with either mycophenolate mofetil (2-3 g PO total daily) or intravenous cyclophosphamide. A Show 2 more Landmark trials: ALMS In patients with class III to V lupus nephritis undergoing induction treatment, mycophenolate mofetil was not superior to intravenous cyclophosphamide with respect to the percentage of patients achieving urine protein/creatinine ratio reduction and stabilization or reduction in serum creatinine. Appel GB et al. J Am Soc Nephrol. 2009 May. Immunosuppressive therapy, class V LN: https://web.pathway.md/diseases/recrc0K5l9trrzGaD 3/11 6/29/23, 5:55 AM Lupus nephritis Pathway As per KDIGO 2021 guidelines, initiate RAAS blockade and control BP in patients with pure class V LN. B Show 4 more As per ERA-EDTA/EULAR 2020 guidelines, initiate corticosteroids and immunosuppression in patients with pure class V nephritis with nephrotic-range proteinuria (2b/B) or if urine protein-to- creatine ratio exceeds 1,000 mg/g despite the optimal use of RAAS blockers. B Show 2 more As per ACR 2012 guidelines, initiate prednisone (0.5 mg/kg PO total daily dose) plus mycophenolate mofetil (2-3 g PO total daily dose) in patients with pure class V LN and nephrotic range proteinuria. A Hydroxychloroquine: As per KDIGO 2021 guidelines, initiate hydroxychloroquine or an equivalent antimalarial in patients with SLE, including patients with LN, unless contraindicated. B As per EULAR 2020 guidelines, coadminister hydroxychloroquine B at a dose not exceeding 5 mg/kg/day and adjusted for the GFR in patients with LN. B As per ACR 2012 guidelines, initiate hydroxychloroquine in all patients with LN, unless contraindicated. B Belimumab: consider initiating belimumab as add-on treatment to facilitate corticosteroid sparing, control extrarenal lupus activity and decrease the risk for extrarenal flares. C Management after adequate response: continue subsequent immunosuppression with either mycophenolate mofetil/mycophenolic acid (1-2 g/day) - especially if it was used as initial treatment, or azathioprine (2 mg/kg/day) - preferred if pregnancy is contemplated - in combination with low-dose prednisone (2.5-5mg/day) when needed to control disease activity in patients achieved improvement after initial treatment. A Show 2 more Management of inadequate treatment response: As per KDIGO 2021 guidelines: Undertake the following measures in patients with unsatisfactory response to therapy: verify adherence to treatment ensure adequate dosing of immunosuppressive medications by measuring plasma drug levels if applicable or available (check mycophenolic acid level if on mycophenolic acid analogs, check infusion records if on cyclophpsphamide) perform repeat biopsy if concern for chronicity or other diagnosis (such as thrombotic microangiopathy) consider switching to an alternative first-line regimen when there is persistent disease activity (mycophenolic acid analogs to cyclophosphamide-based regimen or vice versa). B Consider initiating the following regimens in patients refractory to first-line treatment: combined mycphenolic acid analogs and calcineurin inhibitor therapy, or addition of rituxomab or other biologic therapies https://web.pathway.md/diseases/recrc0K5l9trrzGaD 4/11 6/29/23, 5:55 AM Lupus nephritis Pathway extended course of IV pulse cyclophosphamide. C As per EULAR 2020 guidelines: Obtain thorough evaluation of the possible causes including assessment of adherence to treatment and therapeutic drug monitoring in patients with failure to achieve the treatment goals. B Consider switching to one of the alternative initial therapies (2b/B-C) or rituximab (1,000 mg on days 0-14) in patients with active nonresponding/refractory disease. C As per ACR 2012 guidelines, monitor most patients for 6 months following the initiation of induction treatment with either cyclophosphamide or mycophenolate mofetil before making major changes in treatment other than alteration of corticosteroid doses, unless there is clear evidence of worsening at 3 months ( 50% worsening of proteinuria or serum creatinine). A Show 2 more Management of relapse after complete or partial remission: treat patients with LN relapse after a complete or partial remission with the same initial therapy used to achieve the original response, or an alternative recommended first-line therapy. B RAAS blocker therapy: As per EULAR 2020 guidelines, initiate ACEIs or ARBs in all patients with urine protein-to- creatine ratio > 500 mg/g or arterial hypertension. B As per ACR 2012 guidelines, initiate RAAS blockers in patients with LN and proteinuria 0.5 g/day or equivalent by protein/creatinine ratios on spot urine samples. A Statin therapy: As per EULAR 2020 guidelines, initiate statins on the basis of lipid levels and estimated 10-year CVD risk using the Systematic Coronary Risk Evaluation or other validated tools. B As per ACR 2012 guidelines, initiate statin therapy in patients with LN and LDL cholesterol 100 mg/dL. B Antithrombotic therapy: as per EULAR 2020 guidelines, consider initiating anticoagulant treatment in patients with nephrotic syndrome with serum albumin < 20 g/L. C Antihypertensive therapy: manage and treat hypertension in patients with LN, with a target BP of < 130/80 mmHg. A Adjunctive therapies: Consider providing the following adjunctive therapies for the management of patients with LN and attenuate complications of the disease or its treatments: Situation Guidance Advise lifestyle modifications, including smoking cessation, body weight optimization, and exercising Cardiovascular risk Manage dyslipidemia Initiate low-dose aspirin during pregnancy https://web.pathway.md/diseases/recrc0K5l9trrzGaD 5/11 6/29/23, 5:55 AM Lupus nephritis Pathway Proteinuria Advise avoiding high sodium diet Control BP Initiate RAAS blockade Assess medical history of zoster and tuberculosis Infection risk Screen for HBV, HCV, human immunodeficiency virus, and offer vaccination against HBV Administer P. jirovecii prophylaxis Offer vaccination against influenza and pneumococcus Individualize offering recombinant zoster vaccine and immunizations against other infectious organisms as dictated by public health concerns at the time of treatment Assess bone mineral density and fracture risk Bone injury Offer calcium and vitamin D supplementation Initiate bisphosphonates when appropriate Advise using broad-spectrum sunscreen UV light exposure Advise limiting UV light exposure Initiate GnRH agonists (leuprolide) Premature ovarian failure Offer sperm/oocyte cryopreservation Obtain individual evaluation and counsel for contraception type (preference, thrombosis risk, age) Unplanned pregnancy Evaluate individual risk factors for malignancies Malignancy Obtain age-specific malignancy screening Limit lifetime cyclophosphamide exposure to < 36 g. C 5. Therapeutic procedures Plasma exchange: initiate plasma exchange therapy therapy in patients with LN and thrombotic microangiopathy. B Renal replacement therapy: https://web.pathway.md/diseases/recrc0K5l9trrzGaD 6/11 6/29/23, 5:55 AM Lupus nephritis Pathway As per KDIGO 2021 guidelines, consider initiating hemodialysis or peritoneal dialysis in patients with LN developed kidney failure. C As per EULAR 2020 guidelines: Consider using all methods of renal replacement treatment in patients with SLE. C Guide immunosuppression in patients with end-stage kidney disease on dialysis by extrarenal manifestations. B 6. Surgical interventions Kidney transplantation: As per KDIGO 2021 guidelines, consider offering kidney transplantation in patients with LN developed kidney failure. Prefer kidney transplantation over long-term dialysis. C As per EULAR 2020 guidelines: Consider performing transplantation over other renal replacement options when extrarenal lupus is clinically (and ideally, serologically) inactive for at least 6 months, recognizing that outcomes are better with living donor and preemptive transplantation. C Measure antiphospholipid antibodies during transplant preparation because they are associated with an increased risk of vascular events in the transplanted kidney. B 7. Specific circumstances Pregnant patients: As per KDIGO 2021 guidelines: Continue hydroxychloroquin during pregnancy and initiate low-dose aspirin before 16 weeks of gestation to reduce the risk of pregnancy complications. B Recognize that only corticosteroids, hydroxychloroquine, azathioprine, and calcineurin inhibitors are considered safe immunosuppressive treatments during pregnancy. B As per EULAR 2020 guidelines, advise planning pregnancy in stable patients with inactive LN. B Ensure urine protein-to-creatine ratio < 500 mg/g for the preceding 6 months with GFR > 50 mL/min. B Show 5 more As per ACR 2012 guidelines, avoid routinely using immunosuppressive agents in pregnant patients with prior LN, but no current evidence of systemic or renal disease activity. D Show 4 more Pediatric patients: As per KDIGO 2021 guidelines, treat pediatric patients with LN using immunosuppression regimens similar to those used in adult patients, but take into consideration issues relevant to this population, such as dose adjustment, growth, fertility, and psychosocial factors, when devising the therapy plan. B https://web.pathway.md/diseases/recrc0K5l9trrzGaD 7/11 6/29/23, 5:55 AM Lupus nephritis Pathway As per EULAR 2020 guidelines: Diagnose, manage and monitor LN in pediatric patients as in adult patients, recognizing that LN in children is more common at presentation and more severe with increased damage accrual. B Ensure a coordinated transition program to adult specialists for adherence to therapy and optimization of long-term outcomes. B Patients with thrombotic microangiopathy: As per KDIGO 2021 guidelines, obtain the following in patients with LN and suspected thrombotic microangiopathy: ADAMTS13 activity anti-ADAMTS13 antibodies antiphospholipid antibodies TTP risk stratification (using the PLASMIC score). B Show 4 more As per EULAR 2020 guidelines: Consider initiating aspirin (80-100 mg/day) after balancing benefits and bleeding risk, if antiphospholipid antibodies (defined as in the international consensus statement for definite antiphospholipid syndrome classification criteria) are positive, and based on antiphospholipid antibodies profile. C Consider initiating antiplatelet/anticoagulant treatment in addition to hydroxychloroquine in patients with antiphospholipid syndrome-associated nephropathy. C 8. Patient education Pregnancy counseling: As per KDIGO 2021 guidelines, counsel patients with active LN to avoid pregnancy while the disease is active or when treatment with potentially teratogenic drugs is ongoing, and for 6 months after LN becomes inactive. B As per ACR 2012 guidelines, counsel women of child-bearing potential with active or prior LN regarding the pregnancy risks conferred by the disease and its treatments. B 9. Preventative measures Bone protection: offer calcium/vitamin D supplementation and/or antiresorptive agents for bone protection to reduce treatment-related and disease-related comorbidities in patients with LN. B Routine immunizations: offer immunizations with non-live vaccines to reduce treatment-related and disease-related comorbidities in patient with LN. B 10. Follow-up and surveillance https://web.pathway.md/diseases/recrc0K5l9trrzGaD 8/11 6/29/23, 5:55 AM Lupus nephritis Pathway Assessment of treatment response: Define response to treatment in patients with LN as follows: Situation Guidance Reduction in proteinuria < 0.5 g/g (50 mg/mmol) measured as the protein- creatinine ratio from a 24-hour urine collection (proteinuria < 0.5 g/1.73 m /day or < 300 mg/m /day based on a 24-hour urine specimen in pediatric patients) Complete response Stabilization or improvement in kidney function ( 10-15% of baseline) Within 6-12 months of initiating therapy, but could take > 12 months Reduction in proteinuria by at least 50% and to < 3 g/g (300 mg/mmol) measured as the protein-creatinine ratio from a 24-hour urine collection Partial response Stabilization or improvement in kidney function ( 10-15% of baseline) Within 6-12 months of initiating therapy Failure to achieve a partial or complete response within 6-12 months of initiating therapy. B No kidney response Monitoring of hydroxychloroquine/chloroquine treatment: obtain annual monitoring for retinopathy in all patients receiving hydroxychloroquine for > 5 years or chloroquine for > 1 year. B Show 17 more Follow-up: As per EULAR 2020 guidelines, schedule visits every 2-4 weeks during the first 2-4 months after diagnosis or flare, and subsequently according to response to treatment. Obtain life-long monitoring for renal, extrarenal disease activity and comorbidities. B Show 3 more As per ACR 2012 guidelines: Obtain the following investigations in patients with active LN at the onset of treatment: measurement of BP, urinalysis, UPCR, and serum creatinine every month measurement of C3/C4 levels every 2 months measurement of anti-DNA levels every 3 months. B Obtain the following investigations in patients with previously active LN: https://web.pathway.md/diseases/recrc0K5l9trrzGaD 9/11 6/29/23, 5:55 AM Lupus nephritis Pathway measurement of BP, urinalysis, UPCR, serum creatinine, and C3/C4 levels every 3 months measurement of anti-DNA levels every 6 months. B Clinical findings Patient demographics Symptoms African-american race Ankle swelling Asian ethnicity Cloudy urine Hispanic Hematuria Male sex Vital signs Past medical history Hypertension Autoimmune disorders Serological findings SLE ANA Lab findings anti-double stranded deoxyRNA antibodies Urine RBC casts serum creatinine urine protein serum complement C3 serum complement C4 Histological findings RBCs Studies 2009 ALMS In patients with class III to V lupus nephritis undergoing induction treatment, mycophenolate mofetil was not superior to intravenous cyclophosphamide with respect to the percentage of patients achieving urine protein/creatinine ratio reduction and stabilization or reduction in serum creatinine. Appel GB et al. J Am Soc Nephrol. 2009 May. References 1. Hahn BH, McMahon MA, Wilkinson A et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res Hoboken). 2012 Jun;64 6 797 808. Open https://web.pathway.md/diseases/recrc0K5l9trrzGaD 10/11 6/29/23, 5:55 AM Lupus nephritis Pathway 2. Kidney Disease: Improving Global Outcomes KDIGO Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021 Oct;100 4S S1 S276. Open 3. Antonis Fanouriakis, Myrto Kostopoulou, Kim Cheema et al. 2019 Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association EULAR/ERA EDTA recommendations for the management of lupus nephritis. Ann Rheum Dis. 2020 Jun;79 6 713 723. Open 4. Yoshihiro Arimura, Eri Muso, Shoichi Fujimoto et al. Evidence-based clinical practice guidelines for rapidly progressive glomerulonephritis 2014. Clin Exp Nephrol. 2016 Jun;20 3 322 41. Open 5. The Royal College of Ophthalmologists. Hydroxychloroquine and Chloroquine Retinopathy: Recommendations on Monitoring. RCOphth. 2020 Dec. Open 6. Jeff A Simerville, William C Maxted, John J Pahira. Urinalysis: a comprehensive review. Am Fam Physician. 2005 Mar 15;71 6 1153 62. Open 7. KDIGO. Chapter 12 Lupus nephritis. Kidney Int Suppl 2011 . 2012 Jun;2 2 221 232. Open 8. Cheng Lay Teh, Vui Eng Phui, Guo Ruey Ling et al. Causes and predictors of mortality in biopsy-proven lupus nephritis: the Sarawak experience. Clin Kidney J. 2018 Feb;11 1 56 61. Open 9. Paul J Hoover, Karen H Costenbader. Insights into the epidemiology and management of lupus nephritis from the US rheumatologist's perspective. Kidney Int. 2016 Sep;90 3 487 92. Open 10. Fang Yuan, Fenghua Wei, Junjie Wang et al. Clinical aspects and risk factors of lupus nephritis: a retrospective study of 156 adult patients. J Int Med Res. 2019 Oct;47 10 5070 5081. Open 11. Ajay Jaryal, Sanjay Vikrant. Current status of lupus nephritis. Indian J Med Res. 2017 Feb;145 2 167 178. Open https://web.pathway.md/diseases/recrc0K5l9trrzGaD 11/11