Guidelines Summary
Guidelines for managing lupus nephritis have been issued by the American College of Rheumatology. [81] Key points of the guidelines are as follows:
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Patients with clinical evidence of active, previously untreated lupus nephritis should have a renal biopsy to classify the disease according to International Society of Nephrology/Renal Pathology Society criteria
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All patients with lupus nephritis should receive background therapy with hydroxychloroquine, unless contraindicated; this recommendation was based on a prospective controlled trial showing lower flare rates in those who continued hydroxychloroquine, compared with those who switched to placebo [82]
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Glucocorticoids plus either cyclophosphamide intravenously (IV) or mycophenolate mofetil orally for induction in patients with ISN class III and IV disease; patients with ISN/RPS class I and II nephritis do not require immunosuppressive therapy
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Administer ACEIs or ARBs if proteinuria is 0.5 g/24 h or more
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Maintain blood pressure at or below 130/80 mm Hg
In 2019, the joint guidelines for the management of adult and pediatric lupus nephritis were updated by the European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA). The EULAR/ERA-EDTA revised recommendations include the following [64] :
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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
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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 ≥ 500mg/g in morning first void urine), and/or an unexplained decrease in glomerular filtration rate (GFR)
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Initial treatment for class III–IV disease: Mycophenolate mofetil or or low-dose IV cyclophosphamide plus glucocorticoids
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Alternate option for class III–IV disease: Combination therapy of mycophenolate mofetil with a calcineurin inhibitor, especially tacrolimus, particularly in patients with nephrotic-range proteinuria
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To reduce cumulative glucocorticoid dose: Intravenous pulses methylprednisolone (total dose 500–2500 mg, 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 to 6 months
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Initial treatment for pure class V disease with nephrotic-range proteinuria: Mycophenolate mofetil in combination with methylprednisolone followed by oral prednisone
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Alternate options for pure class V: IV cyclophosphamide or calcineurin inhibitors, especially tacrolimus, as monotherapy or in combination with mycophenolate mofetil/mycophenolic acid
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In all LN patients: Hydroxychloroquine (HCQ) should be coadministered at a dose not to exceed 5 mg/kg/day and adjusted for the GFR, in the absence of contraindications
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Patients who improve after initial treatment should receive mycophenolate mofetil/mycophenolic acid (especially if it was the initial treatment) or azathioprine (preferred in women who may become pregnant) in combination with low-dose prednisone when needed to control disease activity
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Gradual withdrawal of treatment (glucocorticoids first, then immunosuppressive drugs) can be attempted after at least 3 to 5 years therapy in patients with complete clinical response. HCQ should be continued long-term.
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Continuation, switching to or addition of calcineurin inhibitors, especially tacrolimus, can be considered in pure class V nephritis at the lowest effective dose and after considering nephrotoxicity risks
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Patients in whom initial therapy fails should be switched to one of the alternative initial therapies or to rituximab
A European initiative, the Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) project, has published guidelines on the diagnosis and treatment of childhood-onset lupus nephritis. [83, 84]
Diagnostic recommendations from SHARE include the following [84] :
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Although pediatric patients with lupus nephritis may present with renal dysfunction, hypertension, and macro- or microscopic hematuria and proteinuria, percutaneous renal biopsy is required because symptoms alone do not reflect disease severity
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For patients with proteinuria and/or a low glomerular filtration rate, consult with a pediatric nephrologist to discuss the need for biopsy
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Consult with an experienced renal pathologist to evaluate renal biopsies
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Exclude orthostatic proteinuria, which is the leading cause of proteinuria in teenagers, by collecting a first-morning urine sample; in girls, avoid collecting samples during menstruation
SHARE recommends complete renal response as the treatment goal in lupus nephritis, with an early-morning urinary protein/creatinine ratio of less than 50 mg/mmol and normal renal function. Patients should achieve a partial response within 6 to 12 months after starting treatment. [84] Treatment recommendations include the following:
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Immunosuppressive treatment should be guided by renal biopsy results; when biopsy is not possible, patients with nephrotic syndrome, hypertension, and impaired renal function should be treated as for lupus nephritis class IV.
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In patients with proteinuria, consider adding angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.
Recommendations for management based on the International Society of Nephrology/Renal Pathology Society 2003 classification system include the following [84] :
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Class I: Treatment should be guided by symptoms
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Class II: Low-dose prednisone, followed by a disease-modifying antirheumatic drug in patients who have 3 months of persistent proteinuria or develop prednisone dependency.
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Class III/IV: Induction with mycophenolate mofetil (MMF) or intravenous cyclophosphamide plus steroids; maintenance treatment for at least 3 years with MMF, azathioprine, or both
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Class V: MMF with low-dose prednisone for induction; maintenance treatment with MMF
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Mesangial proliferative lupus nephritis with moderate mesangial hypercellularity. International Society of Nephrology/Renal Pathology Society 2003 class II (×200, hematoxylin-eosin).
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Focal lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class III (×100, hematoxylin-eosin).
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Focal lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class III (×200, immunofluorescence).
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Diffuse lupus nephritis with hypertensive vascular changes. International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).
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Diffuse lupus nephritis with early crescent formation. International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).
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Diffuse lupus nephritis with extensive crescent formation (rapidly progressive glomerulonephritis). International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).
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Membranous lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class V (×200, hematoxylin-eosin).
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Membranous lupus nephritis showing thickened glomerular basement membrane. International Society of Nephrology/Renal Pathology Society 2003 class V (×200, silver stain).
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Advanced sclerosis lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class VI (×100, hematoxylin-eosin).
Tables
Gene Locus |
Gene Name |
Gene Product |
1p13.2 |
PTPN22 |
Lymphoid-specific protein tyrosine phosphatase |
1q21-q23 |
CRP |
CRP |
1q23 |
FCGR2A, FCGR2B |
FcγRIIA (R131), FcγRIIB |
1q23 |
FCGR3A, FCGR3B |
FcγRIIIA (V176), FcγRIIIB |
1q31-q32 |
IL10 |
IL-10 |
1q36.12 |
C1QB |
C1q deficiency |
2q32.2-q32.3 |
STAT4 |
Signal transducer and activator of transcription 4 |
2q33 |
CTLA4 |
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) |
6p21.3 |
HLA-DRB1 |
HLA-DRB1: DR2/*1501, DR3/*0301C1q deficiency |
6p21.3 |
C2, C4A, C4B |
C2, C4 deficiencies |
6p21.3 |
TNF |
TNF-a (promoter, -308) |
10q11.2-q21 |
MBL2 |
Mannose-binding lectin |
CRP = C-reactive protein; HLA = human leukocyte antigen; IL = interleukin; TNF = tumor necrosis factor. |
||
Class I Minimal mesangial lupus nephritis |
Light microscopy findings |
Normal |
Immunofluorescence electron microscopy findings |
Mesangial immune deposits |
|
Clinical manifestations |
Mild proteinuria |
|
Class II Mesangial proliferative lupus nephritis |
Light microscopy findings |
Purely mesangial hypercellularity or mesangial matrix expansion with mesangial immune deposits |
Immunofluorescence electron microscopy findings |
Mesangial immune deposits; few immune deposits in subepithelial or subendothelial deposits possible |
|
Clinical manifestations |
Mild renal disease such as asymptomatic hematuria or proteinuria that usually does not warrant specific therapy |
|
Class III Focal lupus nephritis Class III (A) Active lesions - Focal proliferative lupus nephritis Class III (A/C) Active and chronic lesions - Focal proliferative and sclerosing lupus nephritis Class III (C) Chronic inactive lesions - Focal sclerosing lupus nephritis |
Light microscopy findings |
Active or inactive focal, segmental, or global glomerulonephritis involving < 50% of all glomeruli |
Immunofluorescence electron microscopy findings |
Subendothelial and mesangial immune deposits |
|
Clinical manifestations |
Active generalized SLE and mild-to-moderate renal disease with hematuria and moderate proteinuria in many patients; worsening renal function in significant minority, potentially progressing to class IV lupus nephritis |
|
Class IV Diffuse lupus nephritis Class IV-S (A) Active lesions - Diffuse segmental proliferative lupus nephritis Class IV-G (A) Active lesions - Diffuse global proliferative lupus nephritis Class IV-S (A/C) Active and chronic lesions - Diffuse segmental proliferative and sclerosing lupus nephritis Class IV-G (A/C) Active and chronic lesions - Diffuse global proliferative and sclerosing lupus nephritis Class IV-S (C) Chronic inactive lesions with scars - Diffuse segmental sclerosing lupus nephritis Class IV-G (C) Chronic inactive lesions with scars - Diffuse global sclerosing lupus nephritis |
Light microscopy findings |
Active or inactive diffuse, segmental or global glomerulonephritis involving = 50% of all glomeruli; subdivided into diffuse segmental (class IV-S) when = 50% of involved glomeruli have segmental lesions (involving less than half of glomerular tuft) and diffuse global (class IV-G) when = 50% of involved glomeruli have global lesions |
Immunofluorescence electron microscopy findings |
Subendothelial immune deposits |
|
Clinical manifestations |
Clinical evidence of renal disease including hypertension, edema, active urinary sediment, worsening renal function, and nephrotic range proteinuria in most cases; active extrarenal SLE in many patients |
|
Class V Membranous lupus nephritis |
Light microscopy findings |
Diffuse thickening of glomerular basement membrane without inflammatory infiltrate; possibly, subepithelial deposits and surrounding basement membrane spikes on special stains, including silver and trichrome; may occur in combination with class II or IV; may show advanced sclerosis |
Immunofluorescence electron microscopy findings |
Subepithelial and intramembranous immune deposits; subendothelial deposits present only when associated proliferative component is present |
|
Clinical manifestations |
Clinical and laboratory features of nephrotic syndrome, usually without manifestations of active SLE |
|
Class VI Advanced sclerosis lupus nephritis |
Light microscopy findings |
Advanced glomerular sclerosis involving = 90% of glomeruli, interstitial fibrosis, and tubular atrophy, all morphological manifestations of irreversible renal injury |
Clinical manifestations |
Significant renal insufficiency or end-stage renal disease in most cases; unlikely to respond to medical therapy |
|
SLE = systemic lupus erythematosus. |
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Activity Index |
Chronicity Index |
• Endocapillary hypercellularity with or without leukocyte infiltration; luminal reduction • Karyorrhexis • Fibrinoid necrosis • Rupture of glomerular basement membrane • Cellular or fibrocellular crescents • Subendothelial deposits on light microscopy • Intraluminal immune aggregates |
• Glomerular sclerosis; segmental, global • Fibrous adhesion • Fibrous crescents |
