Overarching principles and recommendations for the management of patients with LN
| Overarching principles | ||
| Kidney involvement in SLE, a major cause of morbidity and mortality that leads to high medical and societal costs, is best managed by interdisciplinary care with shared patient–physician decisions. | ||
| Vigilance for symptoms and signs suggestive of kidney involvement, histological assessment by nephropathologists and input from specialised centres ensure optimal outcomes. | ||
| Goals of treatment include patient survival, long-term preservation of kidney function, prevention of disease flares, prevention of organ damage, management of comorbidities and improvement in disease-related quality of life. | ||
| Management of active phases of LN includes an initial period of intense immunosuppressive therapy to control disease activity, followed by a longer period of usually less intensive therapy to consolidate response and prevent relapses. | ||
| Recommendation/statement | LoE/GoR | LoA, mean (SD) |
| 1. Investigation of the patient with suspected LN | ||
| 1.1 Kidney biopsy should be considered when there is evidence of kidney involvement, especially in the presence of persistent proteinuria ≥0.5 g/24 hours (or UPCR ≥500 mg/g in morning first void urine), | 2b/B | 9.84 (0.54) |
| and/or an unexplained decrease in GFR. | 2b/C | |
| 1.2 Kidney biopsy remains indispensable and its diagnostic and prognostic value cannot be substituted by other clinical or laboratory variables. | 2b/B | 9.96 (0.20) |
| 2. Pathological assessment of kidney biopsy | ||
| 2.1 The use of the International Society of Nephrology/Renal Pathology SocietyISN/RPS 2003 classification system is recommended, | 2a/B | 9.56 (0.94) |
| with additional assessment of activity and chronicity indices, | 1b/A | |
| as well as of thrombotic and vascular lesions associated with aPL/syndrome. | 2b/C | |
| 3. Indications for immunosuppressive treatment | ||
| 3.1 Immunosuppressive agents, administered in combination with glucocorticoids, are recommended in class IIIA or IIIA/C (±V) and IVA or IVA/C (±V) nephritis. | 1a/A | 9.96 (0.20) |
| 3.2 In pure class V nephritis, glucocorticoids and immunosuppression are recommended in cases of nephrotic-range proteinuria, | 2b/B | 9.04 (1.80) |
| or when UPCR exceeds 1000 mg/g despite the optimal use of renin–angiotensin–aldosterone system blockers. | 5/D | |
| 4. Treatment of adult LN | ||
| Goals of treatment | ||
| 4.1 Treatment aims for optimisation (preservation or improvement) of kidney function, accompanied by a reduction in proteinuria of at least 25% by 3 months, | 2b/D | |
| 50% by 6 months, | 2a/B | 9.60 (0.63) |
| and a UPCR target below 500–700 mg/g by 12 months (complete clinical response). | 2a/B | |
| 4.2 Patients with nephrotic-range proteinuria at baseline may require an additional 6–12 months to reach complete clinical response; in such cases, prompt switches of therapy are not necessary if proteinuria is improving. | 2a/C | 9.68 (0.68) |
| Initial treatment | ||
| 4.3 For patients with class III or IV (±V) LN, MMF(target dose: 2 to 3 g/day, or MPA at equivalent dose) | 1a/A | 9.84 (0.37) |
| or low-dose intravenous CY (500 mg every 2 weeks for a total of 6 doses) | 1a/A | |
| in combination with glucocorticoids, are recommended as they have the best efficacy/toxicity ratio. | ||
| 4.4 Combination of MMF (target dose: 1 to 2 g/day, or MPA at equivalent dose) with a CNI (especially TAC) is an alternative, particularly in patients with nephrotic-range proteinuria. | 1a/B | 9.32 (0.93) |
| 4.5 Patients at high risk for kidney failure (reduced GFR, histological presence of crescents or fibrinoid necrosis or severe interstitial inflammation) can be treated as in 4.3–4.4, | 2b/B | 8.88 (1.56) |
| but high-dose ntravenous CY (0.5–0.75 g/m2 monthly for 6 months) can also be considered. | 1a/B | |
| 4.6 To reduce cumulative glucocorticoid dose, the use of intravenous pulses methylprednisolone (total dose 500–2500 mg, depending on disease severity) is recommended, followed by oral prednisone (0.3–0.5 mg/kg/day) for up to 4 weeks, tapered to ≤7.5 mg/day by 3 to 6 months. | 2b/C | 9.48 (0.90) |
| 4.7 In pure class V nephritis, MMF (target dose 2 to 3 g/day; or MPA at equivalent dose), | 2a/B | |
| in combination with pulse intravenous methylprednisolone (total dose 500–2500 mg, depending on disease severity) followed by oral prednisone (20 mg/day, tapered to ≤5 mg/day by 3 months) | 2b/C | 9.28 (0.96) |
| is recommended as initial treatment due to best efficacy/toxicity ratio. | ||
| 4.8 Alternative options for class V nephritis include intravenous CY, | 2b/B | 9.28 (0.92) |
| or CNIs (especially TAC) in monotherapy | 2b/B | |
| or in combination with MMF/MPA, particularly in patients with nephrotic-range proteinuria. | 1b/B | |
| 4.9 HCQ should be coadministered, | 2a/B | 9.28 (1.40) |
| at a dose not to exceed 5 mg/kg/day and adjusted for the GFR. | 3b/C | |
| Subsequent treatment | ||
| 4.10 If improvement after initial treatment is achieved, subsequent immunosuppression is recommended with either MMF/MPA (dose: 1 to 2 g/day)—especially if it was used as initial treatment— | 1a/A | 9.80 (0.49) |
| or AZA (2 mg/kg/day)—preferred if pregnancy is contemplated—in combination with low-dose prednisone (2.5–5 mg/day) when needed to control disease activity. | 1a/A | |
| 4.11 Gradual withdrawal of treatment (glucocorticoids first, then immunosuppressive drugs) can be attempted after at least 3 to 5 years therapy in complete clinical response. HCQ should be continued long-term. | 2b/C | 9.40 (0.75) |
| 4.12 Continuation, switching to or addition of CNIs (especially TAC) can be considered in pure class V nephritis at the lowest effective dose and after considering nephrotoxicity risks. | 2b/B | 9.28 (1.15) |
| Non-responding/refractory disease | ||
| 4.13 In case of failure to achieve the treatment goals, thorough evaluation of the possible causes is recommended, including assessment of adherence to treatment and therapeutic drug monitoring. | 5/D | 9.84 (0.46) |
| 4.14 For active non-responding/refractory disease, treatment may be switched to one of the alternative initial therapies mentioned above, | 2b/B–C | 9.64 (0.62) |
| or RTX (1000 mg on days 0 and 14) may be given. | 2b/C | |
| 5. Adjunct treatment | ||
| 5.1 Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are recommended for all patients with UPCR >500 mg/g or arterial hypertension. | 5/D | 9.84 (0.37) |
| 5.2 Statins are recommended on the basis of lipid levels and estimated 10-year cardiovascular disease risk using the Systematic Coronary Risk Evaluation or other validated tools. | 5/D | 9.52 (0.75) |
| 5.3 Bone protection (calcium/vitamin D supplementation and/or antiresorptive agents) and immunizations with non-live vaccines may reduce treatment-related and disease-related comorbidities and are recommended. | 5/D | 9.68 (0.61) |
| 5.4 If aPL (defined as in the international consensus statement for definite antiphospholipid syndrome classification criteria) are positive, and based on aPL profile, acetyl-salicylic acid (80–100 mg/day) may be used after balancing benefits and bleeding risk. | 2a/C | 9.28 (1.25) |
| 5.5 Anticoagulant treatment should be considered in cases of nephrotic syndrome with serum albumin <20 g/L. | 5/D | 9.76 (0.43) |
| 5.6 Belimumab may be considered as add-on treatment, to facilitate glucocorticoid sparing, control extra-renal lupus activity and decrease the risk for extra-renal flares. | 2a/C | 8.48 (1.92) |
| 6. Monitoring and prognosis of LN | ||
| 6.1 Visits should be scheduled every 2–4 weeks during the first 2–4 months after diagnosis or flare, and subsequently, according to response to treatment. Monitoring for renal, extra-renal disease activity and comorbidities is lifelong. | 5/D | 9.40 (0.69) |
| 6.2 At each visit, body weight, blood pressure (including out-of-office measures), estimated GFR, serum albumin, proteinuria (UPCR or 24 hours urine collection), urine red cell count or sediment and complete blood cell count should be evaluated when nephritis is active and less frequently if stable. | 2b/B | 9.64 (0.69) |
| Serum C3/C4 and anti-dsDNA antibody levels are monitored periodically. | 2b/C | |
| 6.3 Repeat kidney biopsy should be considered in selected cases, such as worsening of kidney variables, non-responsiveness to immunosuppressive or biologic treatment (as defined above); or at relapse, to demonstrate possible histologic class transition or change in chronicity and activity indices; to provide prognostic information; and detect other pathologies. | 2b/B | 9.84 (0.37) |
| 7. Management of ESKD in LN | ||
| 7.1 All methods of kidney replacement treatment can be used in patients with SLE. | 2b/B | 9.96 (0.20) |
| 7.2 Immunosuppression in ESKD on dialysis should be guided by extra-renal manifestations. | 2b/C | 9.76 (0.59) |
| 7.3 Transplantation may be preferred over other kidney replacement options and should be considered when extra-renal lupus is clinically (and ideally, serologically) inactive for at least 6 months; outcomes are better with living donor and pre-emptive transplantation. | 2b/C | 9.84 (0.37) |
| 7.4 aPLs should be measured during transplant preparation, because they are associated with an increased risk of vascular events in the transplanted kidney. | 2b/C | 9.48 (1.10) |
| 8. Antiphospholipid syndrome and LN | ||
| 8.1 In patients with antiphospholipid syndrome-associated nephropathy, antiplatelet/anticoagulant treatment can be considered, in addition to HCQ. | 2b/C | 9.68 (0.55) |
| 9. LN and pregnancy | ||
| 9.1 Pregnancy may be planned in stable patients with inactive LN. | 1b/A | 9.56 (0.80) |
| Optimally, UPCR should be below 500 mg/g for the preceding 6 months, with GFR >50 mL/min. | 2b/C | |
| 9.2 Compatible medications such as HCQ, | 1b/B | 9.76 (0.51) |
| prednisone, AZA and/or CNIs (especially TAC) | 3b/C for all | |
| should be continued at safe dosages throughout pregnancy and lactation. | ||
| 9.3 MMF/MPA should be withdrawn at least 3–6 months before conception is planned, to ensure that an alternative immunosuppressive agent does not lead to a relapse. | 5/D | 9.29 (0.93) |
| 9.4 During pregnancy, acetylsalicylic acid is recommended to reduce the risk of pre-eclampsia. | 2b/C | 9.64 (0.62) |
| 9.5 Patients should be assessed at least every 4 weeks, preferably by a multidisciplinary team including an obstetrician with expertise in the disease. | 5/D | 9.56 (0.80) |
| 9.6 Flares of LN during pregnancy can be treated with acceptable medications stated above and pulses of intravenous MPA, depending on flare severity. | 3b/C | 9.56 (1.39) |
| 10.Management of paediatric patients | ||
| 10.1 LN in children is more common at presentation and more severe with increased damage accrual; the diagnosis, management and monitoring are similar to that of adults. | 3b/C | 9.68 (0.68) |
| 10.2 A coordinated transition programme to adult specialists is essential to ensure adherence to therapy and optimisation of long-term outcomes. | 5/D | 9.84 (0.37) |
The LoE, GoR and final LoA are shown in bold for each recommendation.
aPL, antiphospholipid antibodies; AZA, azathioprine; CNI, calcineurin inhibitor; CY, cyclophosphamide; ESKD, end-stage kidney disease; GFR, glomerular filtration rate; GoR, grading of recommendation; HCQ, hydroxychloroquine; ISN/RPS, International Society of Nephrology/Renal Pathology Society; LN, lupus nephritis; LoA, level of agreement; LoE, level of evidence; MMF, mycophenolate mofetil; MPA, mycophenolic acid; RTX, rituximab; SLE, systemic lupus erythematosus; TAC, tacrolimus; UPCR, urine protein–creatine ratio.