CHAPTER 10. LUPUS NEPHRITIS

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10.1. Diagnosis

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* Practice Point 10.1.1. Approach to the diagnosis of kidney involvement in systemic lupus erythematosus (SLE) (Figure 1).

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Figure 1 | Diagnosis of kidney involvement in systemic lupus erythematosus.

<em><strong><span style="color: #2c7db7;">Figure&nbsp;1 | Diagnosis of kidney involvement in systemic lupus erythematosus.</span></strong></em>
anti-dsDNA, anti-double-stranded deoxyribonucleic acid; eGFR, estimated glomerular filtration rate.
10.2. Treatment
10.2.1. General management of patients with lupus nephritis

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* Recommendation 10.2.1.1: We recommend that patients with SLE, including those with lupus nephritis (LN), be treated with hydroxychloroquine or an equivalent antimalarial unless contraindicated (1C).

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* Practice Point 10.2.1.1: Adjunctive therapies to manage LN and attenuate complications of the disease or its treatments should be considered for all patients, as outlined in Figure 3.

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Figure 3 | Measures to minimize the risk of complications related to lupus nephritis or its treatment.

<strong><em><span style="color: #2c7db7;">Figure&nbsp;3 | Measures to minimize the risk of complications related to lupus nephritis or its treatment.</span></em></strong>
HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; RAS, renin–angiotensin system.
10.2.2. Class I or Class II lupus nephritis

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* Practice Point 10.2.2.1: Approach to immunosuppressive treatment for patients with Class I or Class II LN (Figure 4)

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Figure 4 | Immunosuppressive treatment for patients with Class I or Class II lupus nephritis.

<em><strong><span style="color: #2c7db7;">Figure&nbsp;4 | Immunosuppressive treatment for patients with Class I or Class II lupus nephritis.</span></strong></em>
10.2.3. Class III or Class IV lupus nephritis
10.2.3.1. Initial therapy of active Class III/IV lupus nephritis

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* Recommendation 10.2.3.1.1: We recommend that patients with active Class III or IV LN, with or without a membranous component, be treated initially with glucocorticoids plus either one of the following:

i.  mycophenolic acid analogues (MPAA) (1B); or

ii. low-dose intravenous cyclophosphamide (1B); or

iii. belimumab and either MPAA or low-dose intravenous cyclophosphamide (1B); or

iv. MPAA and a calcineurin inhibitor (CNI) when kidney function is not severely impaired (for example estimated glomerular filtration rate [eGFR] ≤45 ml/min per 1.73 m2) (1B).

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* Practice Point 10.2.3.1.1: A regimen of reduced-dose glucocorticoids following a short course of methylprednisolone pulses may be considered during the initial treatment of active LN when both the kidney and extrarenal disease manifestations show satisfactory improvement (Figure 6).

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Figure 6 | Example of glucocorticoid regimens for lupus nephritis.

<em><strong><span style="color: #2c7db7;">Figure&nbsp;6 | Example of glucocorticoid regimens for lupus nephritis.</span></strong></em>

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* Practice Point 10.2.3.1.2: Intravenous cyclophosphamide should be used as the initial therapy for active Class III and Class IV LN in patients who may have difficulty adhering to an oral regimen.

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* Practice Point 10.2.3.1.3: An MPAA-based regimen is the preferred initial therapy of proliferative LN for patients at high risk of infertility, patients who have a moderate to high prior cyclophosphamide exposure.

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* Practice Point 10.2.3.1.4: Initial therapy with an immunosuppressive regimen that includes a CNI (voclosporin, tacrolimus, or cyclosporine) may be preferred in patients with relatively preserved kidney function and nephrotic-range proteinuria likely due to extensive podocyte injury, as well as patients who cannot tolerate standard-dose MPAA or are unfit for or will not use cyclophosphamide-based regimens.

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* Practice Point 10.2.3.1.5: A triple immunosuppressive regimen of belimumab with glucocorticoids and either MPAA or reduced-dose cyclophosphamide may be considered in patients with repeated renal flares or at high-risk for progression to kidney failure.

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* Practice Point 10.2.3.1.6: Other therapies, such as azathioprine or leflunomide combined with glucocorticoids, may be considered in lieu of the recommended initial drugs for proliferative LN in situations of patient intolerance, lack of availability, and/or excessive cost of standard drugs, but these alternatives may be associated with inferior efficacy, including increased rate of disease flares and/or increased incidence of drug toxicities.

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* Practice Point 10.2.3.1.7. Newer biologic and non-biologic therapies are under development and may offer future options for the treatment of active LN. Rituximab may be considered for patients with persistent disease activity or inadequate response to initial standard-of-care therapy.

10.2.3.2. Maintenance therapy for Class III and Class IV lupus nephritis

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* Recommendation 10.2.3.2.1: We recommend that after completion of initial therapy, patients should be placed on MPAA for maintenance (1B).

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* Practice Point 10.2.3.2.1: Azathioprine is an alternative to MPAA after completion of initial therapy in patients who do not tolerate MPAA, who do not have access to MPAA, or who are considering pregnancy.

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* Practice Point 10.2.3.2.2: Glucocorticoids should be tapered to the lowest possible dose during maintenance, except when glucocorticoids are required for extrarenal lupus manifestations; discontinuation of glucocorticoids can be considered after patients have maintained a complete clinical renal response for ≥12 months.

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* Practice Point 10.2.3.2.3: The dose of MMF in the early maintenance phase is approximately 750–1000 mg twice daily, and for MPA, approximately 540–720 mg twice daily.

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* Practice Point 10.2.3.2.4: The total duration of initial immunosuppression plus combination maintenance immunosuppression for proliferative LN should be ≥36 months.

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* Practice Point 10.2.3.2.5: Patients treated with triple immunosuppressive regimens that include belimumab or a CNI in addition to standard immunosuppressive therapy can continue with the original triple immunosuppressive regimen as maintenance therapy (Figure 9).

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* Practice Point 10.2.3.2.6: If MPAA and azathioprine cannot be used for maintenance, CNIs or mizoribine or leflunomide can be considered (Figure 9).

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Figure 9 | Maintenance immunosuppressive regimens in patients with lupus nephritis.

<em><strong><span style="color: #2c7db7;">Figure&nbsp;9 | Maintenance immunosuppressive regimens in patients with lupus nephritis.</span> </strong></em>
AURORA, Aurinia Renal Response in Active Lupus with Voclosporin; AZA, azathioprine; BLISS-LN, Efficacy and Safety of Belimumab in Patients with Active Lupus Nephritis; CNI, calcineurin inhibitor; LN, lupus nephritis; MPAA, mycophenolate acid analogs.
10.2.4. Class V lupus nephritis

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* Practice Point 10.2.4.1: A suggested approach to the management of patients with pure Class V LN is described in Figure 10.

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Figure 10 | Management of patients with pure Class V lupus nephritis.

<em><strong><span style="color: #2c7db7;">Figure&nbsp;10 | Management of patients with pure Class V lupus nephritis.</span></strong></em>
10.2.4.1. Assessing treatment response in LN 

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* Practice Point 10.2.4.1.1: Definitions of response to therapy in LN are provided in Figure 11.

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Figure 11 | Commonly used definitions of response to therapy in lupus nephritis.

<em><strong><span style="color: #2c7db7;">Figure&nbsp;11 | Commonly used definitions of response to therapy in lupus nephritis.</span></strong></em>
∗For children <18 years old, complete response is defined as proteinuria <0.5 g/1.73 m2/d or <300 mg/m2/d based on a 24-h urine specimen. PCR, protein–creatinine ratio.
10.2.4.2. Management of unsatisfactory response to treatment

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* Practice Point 10.2.4.2.1: An algorithmic approach to patients whose response to therapy is deemed unsatisfactory is provided in Figure 12.

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Figure 12 | Management of patients who show unsatisfactory response to initial therapy for active lupus nephritis.

<em><strong><span style="color: #2c7db7;">Figure&nbsp;12 | Management of patients who show unsatisfactory response to initial therapy for active lupus nephritis.</span></strong></em>
i.v., intravenous
10.2.4.3. Treatment of LN relapse

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* Practice Point 10.2.4.3.1: After a complete or partial remission has been achieved, LN relapse should be treated with the same initial therapy used to achieve the original response, or an alternative recommended first-line therapy.

10.3. Special situations
10.3.1. LN and thrombotic microangiopathy

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* Practice Point 10.3.1.1: Patients with LN and thrombotic microangiopathy (TMA) should be managed according to the underlying etiology of TMA, as shown in Figure 131.

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Figure 13 | Management of patients with lupus nephritis and thrombotic microangiopathy TMA. 

<em><strong><span style="color: #2c7db7;">Figure&nbsp;13 | Management of patients with lupus nephritis and thrombotic microangiopathy TMA.&nbsp;</span></strong></em>
Bendapudi PK, Hurwitz S, Fry A, et al. Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study. Lancet Haematol. 2017;4:e157–e164.1 ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; PLASMIC, Platelet count, combined hemoLysis variable, absence of Active cancer, absence of Stem-cell or solid-organ transplant, MCV, INR, Creatinine.
10.3.2. Pregnancy in patients with lupus nephritis

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* Practice Point 10.3.2.1. Patients with active LN should be counseled 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.

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* Practice Point 10.3.2.2: To reduce the risk of pregnancy complications, hydroxychloroquine should be continued during pregnancy, and low-dose aspirin should be started before 16 weeks of gestation.

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* Practice Point 10.3.2.3: Only glucocorticoids, hydroxychloroquine, azathioprine, tacrolimus, and cyclosporin are considered safe immunosuppressive treatments during pregnancy.

10.3.3. Treatment of lupus nephritis in children

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* Practice Point 10.3.3.1: Treat pediatric patients with LN using immunosuppression regimens similar to those used in adults, but consider issues relevant to this population, such as dose adjustment, growth, fertility, and psychosocial factors, when devising the therapy plan.

10.3.4. Management of lupus patients with kidney failure

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* Practice Point 10.3.4.1: Patients with LN who develop kidney failure may be treated with hemodialysis, peritoneal dialysis, or kidney transplantation; and kidney transplantation is preferred to long-term dialysis.

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