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Lupus Nephritis

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

Practice Essentials

Lupus nephritis is histologically evident in most patients with systemic lupus erythematosus (SLE), even those without clinical manifestations of renal disease. Evaluating renal function in SLE patients is important because early detection and treatment of renal involvement can significantly improve renal outcome. See the image below.

Advanced sclerosis lupus nephritis. International Advanced sclerosis lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class VI (×100, hematoxylin-eosin).

Signs and symptoms

Patients with lupus nephritis may report the following:

  • Other symptoms of active SLE (eg, fatigue, fever, rash, arthritis, serositis, or central nervous system [CNS] disease); these are more common with focal proliferative and diffuse proliferative lupus nephritis
  • Asymptomatic lupus nephritis – During regular follow-up, laboratory abnormalities suggest active lupus nephritis; this is more typical of mesangial or membranous lupus nephritis
  • Active nephritis – Peripheral edema secondary to hypertension or hypoalbuminemia; extreme peripheral edema is more common with diffuse or membranous lupus nephritis
  • Diffuse lupus nephritis – Headache, dizziness, visual disturbances, or signs of cardiac decompensation

Physical findings may include the following:

  • Focal and diffuse lupus nephritis – Generalized active SLE with the presence of a rash, oral or nasal ulcers, synovitis, or serositis; signs of active nephritis
  • Active lupus nephritis – Hypertension, peripheral edema, and, occasionally, cardiac decompensation
  • Membranous lupus nephritis – Peripheral edema, ascites, and pleural and pericardial effusions without hypertension

See Presentation for more detail.

Diagnosis

Laboratory tests to evaluate renal function in SLE patients include the following:

  • Blood urea nitrogen (BUN) testing
  • Serum creatinine assessment
  • Urinalysis (to check for protein, red blood cells [RBCs], and cellular casts)
  • Spot urine test for creatinine and protein concentration
  • 24-hour urine test for creatinine clearance and protein excretion

Laboratory tests for SLE disease activity include the following:

  • Antibodies to double-stranded DNA (dsDNA)
  • Complement (C3, C4, and CH50)
  • Erythrocyte sedimentation rate (ESR)
  • C-reactive protein (CRP)

Renal biopsy should be considered in any patient with SLE who has clinical or laboratory evidence of active nephritis, especially upon the first episode of nephritis.

Lupus nephritis is staged according to the classification revised by the International Society of Nephrology (ISN) and the Renal Pathology Society (RPS) in 2003, as follows:

  • Class I – Minimal mesangial lupus nephritis
  • Class II – Mesangial proliferative lupus nephritis
  • Class III – Focal lupus nephritis (active and chronic; proliferative and sclerosing)
  • Class IV – Diffuse lupus nephritis (active and chronic; proliferative and sclerosing; segmental and global)
  • Class V – Membranous lupus nephritis
  • Class VI – Advanced sclerosis lupus nephritis

See Workup for more detail.

Management

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.

Key points of American College of Rheumatology guidelines for managing lupus nephritis are as follows:

  • Patients with clinical evidence of active, previously untreated lupus nephritis should have a renal biopsy to classify the disease according to ISN/RPS criteria
  • All patients with lupus nephritis should receive background therapy with hydroxychloroquine, unless contraindicated
  • Glucocorticoids plus either cyclophosphamide intravenously or mycophenolate mofetil orally should be administered to patients with class III/IV disease; patients with class I/II nephritis do not require immunosuppressive therapy
  • Angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers should be administered if proteinuria reaches or exceeds 0.5 g/day
  • Blood pressure should be maintained at or below 130/80 mm Hg

Patients with class V 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.

Investigational therapies for lupus nephritis and SLE include the following:

  • Rituximab
  • Other anti-CD20 monoclonal antibodies (eg, ocrelizumab, ofatumumab, epratuzumab, and TRU-015)
  • Belimumab
  • Atacicept
  • Abetimus
  • Anticytokine therapies (eg, monoclonal antibodies directed against interferon alfa, interleukin [IL]-1, IL-6, IL-10, and tumor necrosis factor alpha [TNF-α])

Patients with end-stage renal disease require dialysis and are good candidates for kidney transplantation. Hemodialysis is preferred to peritoneal dialysis.

See Treatment and Medication for more detail.

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Background

Lupus nephritis, one of the most serious manifestations of systemic lupus erythematosus (SLE), usually arises within 5 years of diagnosis; however, renal failure rarely occurs before American College of Rheumatology criteria for classification are met.

Lupus nephritis is histologically evident in most patients with SLE, even those without clinical manifestations of renal disease. The symptoms of lupus nephritis are generally related to hypertension, proteinuria, and renal failure. (See Presentation.)

Evaluating renal function in patients with SLE to detect any renal involvement early is important because early detection and treatment can significantly improve renal outcome. Renal biopsy should be considered in any patient with SLE who has clinical or laboratory evidence of active nephritis, especially upon the first episode of nephritis. (See Workup.)

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. With the advent of more aggressive immunosuppressive and supportive therapy, rates of renal involvement and patient survival are improving. (See Treatment.)

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Pathophysiology

Autoimmunity plays a major role in the pathogenesis of lupus nephritis. The immunologic mechanisms include production of autoantibodies directed against nuclear elements. The characteristics of the nephritogenic autoantibodies associated with lupus nephritis are as follows[1] :

  • Antigen specificity directed against nucleosome or double-stranded DNA (dsDNA) - Some anti-dsDNA antibodies cross-react with the glomerular basement membrane
  • Higher-affinity autoantibodies may form intravascular immune complexes, which are deposited in glomeruli
  • Cationic autoantibodies have a higher affinity for the anionic glomerular basement membrane
  • Autoantibodies of certain isotypes (immunoglobulin [Ig] G 1 and IgG 3) readily activate complement

These autoantibodies form pathogenic immune complexes intravascularly, which are deposited in glomeruli. Alternatively, autoantibodies may bind to antigens already located in the glomerular basement membrane, forming immune complexes in situ. Immune complexes promote an inflammatory response by activating complement and attracting inflammatory cells, including lymphocytes, macrophages, and neutrophils.[2, 3]

The histologic type of lupus nephritis that develops depends on numerous factors, including the antigen specificity and other properties of the autoantibodies and the type of inflammatory response that is determined by other host factors. In more severe forms of lupus nephritis, proliferation of endothelial, mesangial, and epithelial cells and the production of matrix proteins lead to fibrosis.[4]

Glomerular thrombosis is another mechanism that may play a role in pathogenesis of lupus nephritis, mainly in patients with antiphospholipid antibody syndrome, and is believed to be the result of antibodies directed against negatively charged phospholipid-protein complexes.[2]

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Etiology

Genetic factors

As with many autoimmune disorders, evidence suggests that genetic predisposition plays an important role in the development of both SLE and lupus nephritis. Multiple genes, many of which are not yet identified, mediate this genetic predisposition (see Table 1 below).[5, 6, 7, 8, 9, 10, 4, 11]

Table 1. Genes Associated With Systemic Lupus Erythematosus (Open Table in a new window)

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.

SLE is more common in first-degree relatives of patients with SLE (familial prevalence, 10-12%). Concordance rates are higher in monozygotic twins (24-58%) than in dizygotic twins (2-5%), supporting an important role for genetics in the development of SLE. However, the concordance rate in monozygotic twins is not 100%, suggesting that environmental factors trigger development of clinical disease.

Human leukocyte antigen (HLA) class II genes include the following:

  • HLA-DR2 and HLA-DR3 are associated with SLE
  • HLA-DR4 is associated with a lower prevalence of SLE and appears to be protective

Complement genes include the following:

  • C1Q, C1R, and C1S deficiencies are associated with SLE, lupus nephritis, and production of anti-dsDNA
  • C2 and C4 deficiencies are associated with SLE or lupuslike syndrome
  • C4A and C4B (possibly) gene deletions are associated with SLE

FcγR genes include the following:

  • These mediate the binding of IgG and IgG-containing immune complexes to cells such as macrophages and other mononuclear phagocytes
  • FcγRIIa binds to IgG 2 and is encoded by 2 codominant alleles, H131 (or high affinity) and R131 (or low affinity); the low-affinity phenotype (homozygous for R131 allele; 131R/R) is associated with lupus nephritis in African Americans
  • FcγRIIIa binds to IgG 1 and is encoded by 2 codominant alleles, V158 (or high affinity) and F158 (or low affinity); the low-affinity phenotype (homozygous for F158 allele; 158F/F) is associated with SLE

Other relevant genes include the following:

  • Cytokine genes - Certain polymorphisms of the IL10 gene (high producers) and possibly the IL1RN and TNFA genes (low producers) are associated with SLE
  • Mannose-binding lectin genes - These gene polymorphisms are associated with an increased risk of SLE
  • Apoptosis genes - Defects of several apoptosis genes are associated with lupuslike syndromes in mice and, rarely, SLE in humans, including CD95 (Fas) and CD178 (FasL)

Immunologic factors

The initial autoantibody response appears to be directed against the nucleosome, which arises from apoptotic cells.[4, 12, 13]

Patients with SLE have poor clearance mechanisms for cellular debris. Nuclear debris from apoptotic cells induces plasmacytoid dendritic cells to produce interferon-α, which is a potent inducer of the immune system and autoimmunity.[14, 15, 16]

Autoreactive B lymphocytes, which are normally inactive, become active in SLE because of a malfunction of normal homeostatic mechanisms, resulting in escape from tolerance. This leads to the production of autoantibodies. Other autoantibodies, including anti-dsDNA antibodies, develop through a process of epitope spreading. These autoantibodies develop over time, in an orderly fashion, months to years before the onset of clinical SLE.[17]

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Epidemiology

United States statistics

The prevalence of SLE is 1 case per 2000 in the general population. Because of the difficulty in diagnosis and a probable underestimation of SLE cases, researchers suggest that the prevalence may be closer to 1 case per 500-1000 population.[18]

Histologically, the kidneys are affected to some degree in most patients with SLE. Estimates of the prevalence of clinical renal involvement in persons with SLE range from 30% to 90% in published studies. The true prevalence of clinical lupus nephritis in persons with SLE is probably around 50%, being higher in certain ethnic groups and in children.[19]

International statistics

A literature review of epidemiologic studies of SLE from the United States, Canada, Europe, Asia, and Australia has suggested marked disparities in rates of SLE, with a higher disease burden in the nonwhite populations in the United States, Europe, Canada, and Australia.[20]

A trend towards higher disease burden is noted in Europe and Australia compared with the United States, with an even lower disease prevalence in Japan. In Europe, the highest prevalence of SLE was found in Sweden, Iceland, and Spain. These differences may indicate true variability across populations or may be the result of methodologic differences in the studies.

Age-related demographics

Most patients with SLE develop lupus nephritis early in their disease course. SLE is more common among women in the third decade of life, and lupus nephritis typically occurs in patients aged 20-40 years.[18] Children with SLE are at a higher risk of renal disease than adults and tend to sustain more disease damage secondary to more aggressive disease and treatment-associated toxicity.[21, 22, 23]

Sex-related demographics

Because the overall prevalence of SLE is higher in females (ie, female-to-male ratio of 9:1), lupus nephritis is also more common in females; however, clinical renal disease has a worse prognosis and is more common in males with SLE.[18]

Race-related demographics

SLE is more common in African Americans and Hispanics than in white people. Particularly severe lupus nephritis may be more common in African Americans and Asians than in other ethnic groups.[18]

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Prognosis

Over the past 4 decades, changes in the treatment of lupus nephritis and general medical care have greatly improved both renal involvement and overall survival. During the 1950s, the 5-year survival rate among patients with lupus nephritis was close to 0%. The subsequent addition of immunosuppressive agents such as intravenous (IV) pulse cyclophosphamide has led to documented 5- and 10-year survival rates as high as 85% and 73%, respectively.[19]

Morbidity associated with lupus nephritis is related to the renal disease itself, as well as to treatment-related complications and comorbidities, including cardiovascular disease and thrombotic events. Progressive renal failure leads to anemia, uremia, and electrolyte and acid-based abnormalities. Hypertension may lead to an increased risk of coronary artery disease and cerebrovascular accident.

Nephrotic syndrome may lead to edema, ascites, and hyperlipidemia, adding to the risk of coronary artery disease and the potential for thrombosis. The findings from one study indicate that patients with lupus nephritis, particularly early-onset lupus nephritis, are at increased risk for morbidity from ischemic heart disease.[24]

In a study of 56 children (<18 years) with either global or segmental diffuse proliferative lupus nephritis, long-term renal outcomes were similar. Most patients reached adulthood but sustained significant renal damage. Complete remission rates were 50% and 60% in the global and segmental groups, respectively. Renal survival rates, defined as an estimated glomerular filtration rate of ≥60 mL/min/1.73 m2, were 93%, 78%, and 64 % at 1, 5, and 10 years, respectively, and corresponding patient survival rates were 98%, 96%, and 91%, respectively, with similar rates in the global and segmental groups.[25] n    

Therapy with corticosteroids, cyclophosphamide, and other immunosuppressive agents increases the risk of infection. Long-term corticosteroid therapy may lead to osteoporosis, avascular necrosis, diabetes mellitus, and hypertension, among other complications. Cyclophosphamide therapy may cause cytopenias, hemorrhagic cystitis, infertility, and an increased risk of malignancy.

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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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