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Lupus Nephritis Treatment & Management

  • Author: Lawrence H Brent, MD; Chief Editor: Vecihi Batuman, MD, FACP, FASN  more...
 
Updated: Sep 28, 2015
 

Approach Considerations

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.

Guidelines

The first guidelines for managing lupus nephritis have been issued by the American College of Rheumatology.[42] 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 [43]
  • 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[44] :

  • 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
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Pharmacotherapy for Lupus Nephritis Based on Stage

Classes I and II

Minimal mesangial (class I) lupus nephritis requires no specific therapy.[19]

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.[47]

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.[48] 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.[51]

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.[52]

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.[53]

Class V

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.[54] Long-term follow-up of 12 years showed 19 episodes of renal flares. Retreatment with corticosteroids and azathioprine showed similar responses.

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Investigational Therapies for Lupus Nephritis and SLE

Rituximab

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.[59]

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])[60]

Belimumab

Belimumab (Benlysta) is an anti–B-lymphocyte stimulator [BLyS] monoclonal antibody).[62] It has been found to have beneficial effects on clinical and laboratory parameters in patients with active SLE.[63] In addition, the number of B cells and serum IgM were reduced over time.[64]

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

Atacicept is a TACI-Ig fusion protein that inhibits BLyS and a proliferation-inducing ligand [APRIL]).[62] 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.[65]

Abetimus

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.[61]

Anticytokine therapies

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.[62]

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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.

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Renal Transplantation

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.

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Consultations

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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Contributor Information and Disclosures
Author

Lawrence H Brent, MD Associate Professor of Medicine, Jefferson Medical College of Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center

Lawrence H Brent, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Physicians, American College of Rheumatology

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Janssen<br/>Serve(d) as a speaker or a member of a speakers bureau for: Abbvie; Genentech; Pfizer; Questcor.

Coauthor(s)

Arati Karhadkar, MBBS Fellow, Division of Rheumatology, Albert Einstein Medical Center

Disclosure: Nothing to disclose.

Eric Bloom, MD Division Chief of Nephrology, Nephrology Fellowship Program Director, Attending Physician, Division of Nephrology, Department of Internal Medicine, Albert Einstein Medical Center

Eric Bloom, MD is a member of the following medical societies: American Society of Nephrology, National Kidney Foundation

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ajay K Singh, MB, MRCP, MBA Associate Professor of Medicine, Harvard Medical School; Director of Dialysis, Renal Division, Brigham and Women's Hospital; Director, Brigham/Falkner Dialysis Unit, Faulkner Hospital

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FACP, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System

Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society of Nephrology

Disclosure: Nothing to disclose.

Additional Contributors

Carlos J Lozada, MD Director of Rheumatology Fellowship Training Program, Professor of Clinical Medicine, Department of Medicine, Division of Rheumatology and Immunology, University of Miami, Leonard M Miller School of Medicine

Carlos J Lozada, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology

Disclosure: Received honoraria from Pfizer for consulting; Received grant/research funds from AbbVie for other; Received honoraria from Heel for consulting.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Irene Viola, MD, to the development and writing of the source article.

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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).
Focal lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class III (×100, hematoxylin-eosin).
Focal lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class III (×200, immunofluorescence).
Diffuse lupus nephritis with hypertensive vascular changes. International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).
Diffuse lupus nephritis with early crescent formation. International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).
Diffuse lupus nephritis with extensive crescent formation (rapidly progressive glomerulonephritis). International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).
Membranous lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class V (×200, hematoxylin-eosin).
Membranous lupus nephritis showing thickened glomerular basement membrane. International Society of Nephrology/Renal Pathology Society 2003 class V (×200, silver stain).
Advanced sclerosis lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class VI (×100, hematoxylin-eosin).
Table 1. Genes Associated With Systemic Lupus Erythematosus
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.
Table 2. International Society of Nephrology/Renal Pathology Society 2003 Classification of Lupus Nephritis
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.
Table 3. Active and Chronic Glomerular Lesions
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



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