Lupus Nephritis Treatment & Management
- Author: Lawrence H Brent, MD; Chief Editor: Vecihi Batuman, MD, FACP, FASN more...
The principal goal of therapy in lupus nephritis is to normalize renal function or, at least, to prevent the progressive loss of renal function. Therapy differs depending on the pathologic lesion.[19, 36] It is important to treat extrarenal manifestations and other variables that may affect the kidneys.
Corticosteroid therapy should be instituted if the patient has clinically significant renal disease. Use immunosuppressive agents, particularly cyclophosphamide, azathioprine, or mycophenolate mofetil, if the patient has aggressive proliferative renal lesions, as they improve the renal outcome. They can also be used if the patient has an inadequate response or excessive sensitivity to corticosteroids.[36, 37, 38]
Treat hypertension aggressively. On the basis of beneficial effects in other nephropathies, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have been routinely used to treat proteinuria in lupus nephritis.
Alter the diet according to the presence of hypertension, hyperlipidemia, and renal insufficiency. Restrict fat intake or use lipid-lowering therapy such as statins for hyperlipidemia secondary to nephrotic syndrome. Restrict protein intake if renal function is significantly impaired.
Administer calcium supplementation to prevent osteoporosis if the patient is on long-term corticosteroid therapy, and consider adding a bisphosphonate (depending on renal function).
Avoid drugs that affect renal function, including nonsteroidal anti-inflammatory drugs (NSAIDs), especially in patients with elevated creatinine levels. Nonacetylated salicylates can be used to safely treat inflammatory symptoms in patients with renal disease.
Patients with active lupus nephritis should avoid pregnancy, because it may worsen their renal disease and because certain medications used in the treatment may be teratogenic.[39, 40, 41]
Patients with end-stage renal disease (ESRD), sclerosis, and a high chronicity index based on renal biopsy findings are unlikely to respond to aggressive therapy. In these cases, focus therapy on extrarenal manifestations of systemic lupus erythematosus (SLE) and on possible kidney transplantation.
The first guidelines for managing lupus nephritis have been issued by the American College of Rheumatology. Key points of the guidelines are as follows:
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
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 
Glucocorticoids plus either cyclophosphamide intravenously (IV) or mycophenolate mofetil orally for induction in patients with ISN class III/IV disease; patients with ISN/RPS class I and II nephritis do not require immunosuppressive therapy
Administer ACE inhibitors or angiotensin-receptor blockers if proteinuria is 0.5 g/24 h or more
Maintain blood pressure at or below 130/80 mm Hg
Joint guidelines for the management of adult and pediatric lupus nephritis have also been issued by European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA). The EULAR/ERA-EDTA recommendations include the following :
Any sign of renal involvement can be an indication for biopsy, which should be performed within the first month after disease onset, preferably before the institution of immunosuppressive treatment
Use mycophenolate mofetil or or low-dose IV cyclophosphamide plus glucocorticoids as the initial treatment for patients with ISN class III–IV A disease
In patients with adverse clinical or histological features, cyclophosphamide can be prescribed at higher doses, while azathioprine is an alternative for milder cases
For pure class V lupus nephritis LN with nephrotic-range proteinuria, use mycophenolate mofetil in combination with oral glucocorticoids for initial immunosuppressive therapy
Patients who improve after initial treatment should receive mycophenolate mofetil or azathioprine for at least 3 years; patients who start on mycophenolate mofetil should continue on that agent
Patients in whom mycophenolate mofetil or cyclophosphamide therapy fails should be switched to the other agent or to rituximab
Pharmacotherapy for Lupus Nephritis Based on Stage
Classes I and II
Minimal mesangial (class I) lupus nephritis requires no specific therapy.
Mesangial proliferative (class II) lupus nephritis may require treatment if proteinuria is greater than 1000 mg/day. Consider prednisone in low-to-moderate doses (ie, 20-40 mg/day) for 1-3 months, with subsequent taper.
Classes III and IV
Patients with either focal (class III) or diffuse (class IV) lupus nephritis are at high risk of progressing to ESRD and thus require aggressive therapy.
Administer prednisone 1 mg/kg/day for at least 4 weeks, depending on clinical response. Then, taper it gradually to a daily maintenance dose of 5-10 mg/day for approximately 2 years. In acutely ill patients, intravenous (IV) methylprednisolone at a dosage of up to 1000 mg/day for 3 days may be used to initiate corticosteroid therapy.
In patients who do not respond to corticosteroids alone, who have unacceptable toxicity to corticosteroids, who have worsening renal function, who have severe proliferative lesions, or who have evidence of sclerosis on renal biopsy specimens, use immunosuppressive drugs in addition to corticosteroids.
Both cyclophosphamide and azathioprine are effective in proliferative lupus nephritis, although cyclophosphamide is apparently more effective in preventing progression to ESRD. Mycophenolate mofetil has been shown to be at least as effective as IV cyclophosphamide, with less toxicity, in patients with focal or diffuse lupus nephritis who have stable renal function.[45, 46] It may be used alone[45, 46] or sequentially after a 6-month course of IV cyclophosphamide.
Appel et al studied 370 patients with lupus nephritis in a randomized open-label study and found no significant difference in clinical improvement was observed with mycophenolate mofetil compared with IV cyclophosphamide. The study included induction and maintenance therapy, and both study groups received prednisone.
Administer IV cyclophosphamide monthly for 6 months and every 2-3 months thereafter, depending on clinical response. The usual duration of therapy is 2-2.5 years. Reduce the dose if the creatinine clearance is less than 30 mL/min. Adjust the dose depending on the hematologic response.[49, 50] The gonadotropin-releasing hormone analogue leuprolide acetate has been shown to protect against ovarian failure.
Azathioprine can also be used as a second-line agent, with dose adjustments depending on hematologic response.
Mycophenolate mofetil was found to be superior to azathioprine in maintaining control and preventing relapses of lupus nephritis in patients who have responded to induction therapy.
In a 10-year follow-up of the MAINTAIN Nephritis Trial, which compared azathioprine and mycophenolate mofetil as maintenance therapy of proliferative lupus nephritis, Tamirou and colleagues found that the two treatments resulted in similar outcomes. Two deaths and one case of end-stage renal disease developed in the azathioprine group, versus three deaths and three cases of end-stage renal disease in the mycophenolate mofetil group.
Patients with membranous lupus nephritis are generally treated with prednisone for 1-3 months, followed by tapering for 1-2 years if a response occurs. If no response occurs, the drug is discontinued. Immunosuppressive drugs are generally not used unless renal function worsens or a proliferative component is present on renal biopsy samples. Some clinical evidence indicates that azathioprine, cyclophosphamide, cyclosporine, and chlorambucil are effective in reducing proteinuria. Mycophenolate mofetil may also be effective.
In a study of membranous lupus nephritis, 38 patients were treated with corticosteroids and azathioprine; after 12 months of treatment, 67% of patients had a complete remission and 22% had a partial remission, with only 11% resistant to treatment. Long-term follow-up of 12 years showed 19 episodes of renal flares. Retreatment with corticosteroids and azathioprine showed similar responses.
Investigational Therapies for Lupus Nephritis and SLE
Rituximab, a B-lymphocyte–depleting therapy, appears to be effective in SLE and is being investigated as a treatment for SLE and lupus nephritis. Several small case series of rituximab have shown benefit in SLE and lupus nephritis.[55, 56, 57, 58] More recently, however, a randomized, double-blind, phase II/III trial of rituximab in moderately-to-severely active SLE failed to show differences compared to placebo, although a beneficial effect of rituximab was noted in the African American and Hispanic subgroups.
Other therapies under investigation for SLE and lupus nephritis are discussed below.[38, 60, 61, 62]
Other anti-CD20 monoclonal antibodies
Other anti-CD20 monoclonal antibodies such as ocrelizumab (humanized) and ofatumumab (human), epratuzumab (anti-CD22 monoclonal antibody), and TRU-015 (anti-CD20 small modular immunopharmaceutical [SMIP])
Belimumab (Benlysta) is an anti–B-lymphocyte stimulator [BLyS] monoclonal antibody). It has been found to have beneficial effects on clinical and laboratory parameters in patients with active SLE. In addition, the number of B cells and serum IgM were reduced over time.
Belimumab was approved by the US Food and Drug Administration (FDA) for use in patients with active SLE who are autoantibody-positive and are receiving standard therapy, including corticosteroids, antimalarials, immunosuppressives, and NSAIDs.
Atacicept is a TACI-Ig fusion protein that inhibits BLyS and a proliferation-inducing ligand [APRIL]). In early phase studies, atacicept was demonstrated to have biologic effects in patients with SLE, resulting in a dose-dependent reduction in B cells and immunoglobulin levels.
Abetimus is a B-lymphocyte tolerogen that was found to be ineffective in preventing flares of lupus nephritis in a large controlled trial, although it did reduce levels of anti-DNA antibodies.
Various anticytokine therapies have been proposed, including monoclonal antibodies directed against interferon-α, interleukin (IL)-1, IL-6, IL-10, and tumor necrosis factor alpha (TNF-α), among others.
Management of End-Stage Renal Disease
Patients with ESRD require dialysis and are good candidates for kidney transplantation (see Renal Transplantation). Patients with ESRD secondary to SLE represent 1.5% of all patients on dialysis in the United States. The survival rate among patients on dialysis is fair (5-year survival rate, 60-70%) and is comparable with that among patients on dialysis who do not have SLE.
Hemodialysis is preferred to peritoneal dialysis; several studies have documented higher levels of antibodies to double-stranded DNS (dsDNA), more thrombocytopenia, and higher steroid requirements in patients with SLE and ESRD who are on peritoneal dialysis. Hemodialysis also has anti-inflammatory effects with decreased T-helper lymphocyte levels. SLE is generally quiescent in patients on hemodialysis, although flares, including rash, arthritis, serositis, fever, and leukopenia may occur, necessitating specific treatment.
Patients with SLE account for 3% of all renal transplantations in the United States. It is important ensure that the patient does not have active SLE disease at the time of transplantation. A 3-month period of dialysis is usually prudent in the event of spontaneous renal recovery.
Substantial evidence shows that patients with SLE fare worse than patients without SLE in terms of graft survival. Living-related allografts show better outcomes than cadaveric allografts. In patients with SLE, reasons for a more severe outcome after transplantation include recurrent lupus nephritis and concomitant antiphospholipid antibody syndrome resulting in allograft loss.
It is frequently advisable to consult a nephrologist for renal biopsy or, if desired, for help in the management of renal disease.
The experience of pathologists in reading lupus nephritis biopsy specimens varies considerably. The most consistent readers of these specimens are usually found in larger academic centers that have substantial populations of patients with SLE.
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|Gene Locus||Gene Name||Gene Product|
|1p13.2||PTPN22||Lymphoid-specific protein tyrosine phosphatase|
|1q23||FCGR2A, FCGR2B||FcγRIIA (R131), FcγRIIB|
|1q23||FCGR3A, FCGR3B||FcγRIIIA (V176), FcγRIIIB|
|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)|
|CRP = C-reactive protein; HLA = human leukocyte antigen; IL = interleukin; TNF = tumor necrosis factor.|
Minimal mesangial lupus nephritis
|Light microscopy findings||Normal|
|Immunofluorescence electron microscopy findings||Mesangial immune deposits|
|Clinical manifestations||Mild proteinuria|
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|
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|
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|
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|
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.|
|Activity Index||Chronicity Index|
|• Endocapillary hypercellularity with or without leukocyte infiltration; luminal reduction
• 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