Lupus nephritis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.

Systemic lupus erythematosus (SLE, or lupus) is an autoimmune disease. In patients with an autoimmune disease, the immune system cannot tell the difference between harmful substances and healthy ones. As a result, the immune system attacks otherwise healthy cells and tissue. The history of lupus erythematosus can be divided into three periods: classical, neoclassical, and modern.

Lupus Nephritis was first discovered by Osler and Jadassohn, two physicians, in 1948 by the discovery of the LE cell in 1948. The word “lupus” means wolf in Latin, as the destructive injuries SLE causes brought to mind wolf bites. The history of lupus erythematosus can be divided into three periods: classical, neoclassical, and modern. The classical period mostly refers to ancient history, when there was no exact definition of the disease. During the neoclassical lupus era, scientists investigated the manifestations of lupus and worked to define the disease’s action. Modern history is mostly focused on a microscopical understanding of the disease and pathogenesis of SLE.

Lupus nephritis may be classified according to the Renal Pathology Society/International Society of Nephrology (RPS/ISN) classification which includes minimal mesangial lupus nephritis (class I), mesangial proliferative lupus nephritis (class II), focal lupus nephritis (class III), diffuse lupus nephritis (class IV), lupus membranous nephropathy (class V) and advanced sclerosing lupus nephritis (class VI)

Systemic lupus erythematosus (SLE, or lupus) is an autoimmune disease. This means there is a problem with the body’s immune system. Normally, the immune system helps protect the body from harmful substances. But in patients with an autoimmune disease, the immune system cannot tell the difference between harmful substances and healthy ones. As a result, the immune system attacks otherwise healthy cells and tissue.

There are no established direct causes of systemic lupus erythematosus. Common contributory factors in the development of systemic lupus erythematosus include geneticpredisposition, auto-immune diseases, and use of drugs. Less common factors include environmental factors and exposure to ultraviolet (UV) light.

Lupus nephritis must be differentiated from other glomerular diseases that may cause hematuria, proteinuria, or renal failure. The various types of glomerular diseases should be differentiated from each other based on associations, presence of pitting edema, hemeturia, hypertension, hemoptysis, oliguria, peri-orbital edema, hyperlipidemia, type of antibodies, light and electron microscopic features. The following table differentiates between various types of glumerular diseases.

The incidence of lupus nephritis is 34 to 51 percent in Blacks, 31 to 43 percent in Hispanics, 33 to 55 percent in Asians, and 14 to 23 percent in Whites. In 2005, Incidence was fiund to be 5.1 (Overall), 1.9 (Adult men), 8.2 (Adult women).The incidence of Lupus nephritis increases with age upto 50 years; the median age at diagnosis is 25 years.Chronic disease name is usually first diagnosed among middle age patients. African Americans have a higher frequency of developing Lupus nephritis in the United States.

Common risk factors in the development of Lupus nephritis may be occupational, environmental, genetic, and viral.

According to the United States Preventive Services Task Force, screening for systemic lupus erythematosus is not recommended.

Common complications of Lupus nephritis include microscopic hematuria, nephrotic syndrome, celluar casts, elevated creatinine and destruction of more than 50% of glomeruli.

In SLE, nephritis we suspect renal involvment by an abnormal urinalysis and/or increased serum creatinine. Histopathologic findings on renal biopsy confirm the diagnosis.

As a manifestation of SLE, Lupus nephritis shares most of the symptoms with SLE. A positive history of familial lupus, skin rashes (especially photosensitive skin rashes), arthritis, and fatigue may be suggestive of systemic lupus erythematosus. The most common symptoms of SLE include constitutional symptoms like fatigue, fever, myalgia, and weight changes. The organ-specific symptom mostly occur with disease progression. SLE may show a variety of symptoms in different organs depending on its complications. eg.g Foamy urine.

In the earlier stages of the disease, patients appear well, while in the late stages of the disease, patients are clearly ill with multi-organ involvement. The patient may show a wide range of skin manifestations including urticaria, bullous lesions, malar rash, and scarring alopecia. The patient may develop nasal and oral ulcers. Arthritis may lead to a decreased range of motion, joint effusion, and arthralgia. Neurological manifestations including psychosis, cognitive impairment, and hallucinations, may also be present. 

Laboratory findings consistent with the diagnosis of systemic lupus erythematosus include autoantibody elevation of ANA, anti-dsDNA antibody, anti-SM antibody, and antiphospholipid antibodies, and a decrease in complement levels. Nonspecific laboratory findings include mild pancytopenia, elevated levels of creatinine and proteinuria due to renal failure (secondary to nephritis), elevated levels of ESR and CRP as acute phase reactants, decreased level of complements, and positive direct Coombs test.

The most common and important ECG findings associated with systemic lupus erythematosus (SLE) include sinus tachycardia, ST segment changes, and ventricular conduction disturbances. Other ECG findings are related to late complications of SLE and may range based on the complication.

On X-ray imaging, systemic lupus erythematosus (SLE) may be characterized by different features regarding the present complication. The most common characteristic findings of SLE in X-ray include thumb printing sign in the abdominal X ray, blunting of the costophrenic angle due to pleural effusion, cardiomegaly, hepatomegaly, osteoprosis, tenosinovitis, and other manifestations based on the complications.

On abdominal CT-scan, systemic lupus erythematosus (SLE) may be characterized by hepatosplenomegaly, pancreatic parenchymal enlargement, and ascites. On cardiac CT-scan, SLE may be characterized by enhancement of the thickened pericardium. On brain CT-scan, SLE may be characterized by brain atrophy, stroke patterns like cortical hypodensity, and increased attenuation of the cortex.

On abdominal MRI, systemic lupus erythematosus (SLE) may be characterized by hepatomegaly, pancreatic parenchymal enlargement, and hypervascularity of mesentery. On cardiac MRI, SLE may be characterized by mitral leaflet thickening, pericardial thickness, and pericardial effusions. On brain MRI, SLE may be characterized by white matter lesions, changes in blood circulation of the brain, and patchy areas of enhancement. On musculoskeletal MRI, SLE may be characterized by intramuscular edema, proliferative tenosynovitis, and bone marrow edema.

Another imaging modality that can be used for the diagnosis of systemic lupus erythematosus complications is the double-contrast technique for gastritis evaluation. Another imaging technique that can be helpful in the diagnosis of SLE complications, especially early manifestations, is the Technetium-99m scan. It can be used in different ways, including bone scintigraphy and bone scans to evaluate early and late bone complications, and for early evaluation of other organ complications including cardiac, hepatobiliary, and pulmonary complications.

Renal biopsy may be helpful in the diagnosis of Lupus nephritis.

The mainstay of therapy for systemic lupus erythematosus (SLE) is to control disease activity and prevent organ damage. The treatment of choice for systemic lupus erythematosus (SLE) varies based on the severity of the disease and symptoms. Generally, all the patients with any type of SLE manifestation should be treated with hydroxychloroquine regardless of the level of their disease. Other pharmacologic medical therapies for SLE include glucocorticoids like oral prednisone or intravenous methylprednisolone, NSAIDs like celecoxib, and immunosuppressive therapy with mycophenolate, cyclophosphamide, or rituximab, particularly in severe cases. Cutaneous lupus erythematosus (CLE), if presented separately without any other system involvement, can be treated with topical corticosteroids. Other organ-related complications of SLE should be treated separately.

Surgical intervention is not recommended for the management of systemic lupus erythematosus.

There is no established method for the primary prevention of systemic lupus erythematosus.

Secondary prevention strategies following systemic lupus erythematosus include using aspirin, ACE inhibitors, and statins to reduce atherosclerotic diseases, and using cancer screenings.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

Lupus Nephritis was first discovered by Osler and Jadassohn, two physicians, in 1948 by the discovery of the LE cell in 1948. The word “lupus” means wolf in Latin, as the destructive injuries SLE causes brought to mind wolf bites. The history of lupus erythematosus can be divided into three periods: classical, neoclassical, and modern. The classical period mostly refers to ancient history, when there was no exact definition of the disease. During the neoclassical lupus era, scientists investigated the manifestations of lupus and worked to define the disease’s action. Modern history is mostly focused on a microscopical understanding of the disease and pathogenesis of SLE.

The word “lupus” means wolf in Latin, as the destructive injuries SLE causes brought to mind wolf bites. The history of lupus erythematosus can be divided into three periods: classical, neoclassical, and modern.^[1] The classical period mostly refers to ancient history, when there was no exact definition of the disease. During the neoclassical lupus era, scientists investigated the manifestations of lupus and worked to define the disease’s action. Modern history is mostly focused on a microscopical understanding of the disease and pathogenesis of SLE.

• In ancient times, it was believed that lupus patients could turn into wolves, especially when exposed to sunlight. This false belief was later found to be related to lupus photosensitivity.^[2]
• Hippocrates was the first to use the phrase “herpes esthiomenos,” which was a definition for lupus lesions. Thus, Hippocrates is considered the first to have described cutaneous ulceration of the disease.^[3][4]

• In 1230 A.D., Rogerius Frugardi was the first to describe erosive facial lesions and used the term “lupus” for the first time scientifically.^[3]
• In 1530 A.D., Giovanni Manardi used the same pattern of ulceration to describe lower extremity lesions and also called it lupus.
• In the late 18th century, Robert Willan, a British dermatologist, was the first to describe the destructive lesions of the face and nose under the heading of lupus. Lupus willani, which is cutaneous tuberculosis or lupus vulgaris, is named after him.
• In 1833, Laurent Theodore Biett was the first one to describe lupus erythematosus, although he called it “erythema centrifugum.” Later, his student Pierre Louis Alphee Cazenave published his work.^[5]
• In 1845, Ferdinand von Hebra described an aggressive skin lesion with tissue destructive characteristics. Later, in 1866, Ferdinand von Hebra used the term “butterfly” to describe what is known as malar rash. He initially named the condition “seborrhea congestiva.”^[6]
• In 1851, Cazenave was the first to complete the description of discoid lupus. He called it “lupus erythematosus.”
• In 1872, Kaposi was the first to describe the systemic signs of the disorder, including arthritis, fever, anemia, lymphadenopathy, and weight loss.
• Kaposi and Cazenave were the first ones who clearly distinguished lupus erythematosus from lupus vulgaris or cutaneous tuberculosis, though both diseases coexist in some patients.
• In the late 19th century, Sir William Osler was the first to coin the term “systemic lupus erythematosus.” He discussed systemic complications of “erythema exsudativum multiforme,” including cardiac, pulmonary, and renal problems as well as cutaneous lesions.^[6]
• In the late 19th century, Jonathan Hutchinson was the first to describe the photosensitive nature of malar rash.
• In 1902, Sequira and Balean were the first to describe acroasphyxia, or the Raynaud phenomenon, and lupus nephritis.
• In 1908, Alfred Kraus and Carl Bohac were the first to describe pulmonary involvement in lupus.
• In 1923, Emanuel Libman and Benjamin Sacks were the first to describe noninfectious endocarditis due to lupus.^[7]

• In the early 20th century, George Belote and H.S. Ratner were the first to describe endocarditis of Libman-Sacks as a manifestation of lupus, even without concurrent cutaneous involvement. They changed the common idea of the necessity of cutaneous involvement for the diagnosis of lupus.
• In 1935, Paul Klemperer, George Baehr, and A.D. Pollack were the first to describe wire loop nephritis.
• In 1959, Leonardt, Arnett, and Schulman were the first to describe the familial aggregation of lupus and concordance in monozygotic twins.
• In 1906, Wasserman, while trying to develop a serologic test for syphilis, was the first to describe a complement-fixing antibody that reacted with extracts from bovine hearts. The corresponding antigen was later identified as cardiolipin.^[7]
• In 1948, Malcolm Hargraves discovered the lupus erythematosus (LE) cell. He observed two unusual phenomena in several bone marrow preparations while adding serum from patients with lupus erythematosus to bone marrow preparations from normal subjects.^[8]
• In 1954, Miescher and Fauconnet observed that absorption of lupus serum with nuclei prevented its ability to induce the LE cell phenomenon, suggesting that a globulin in the serum was reacting with, or destroying, the nuclei.^[8]
• In 1954, researchers at the Cleveland Clinic were the first to describe drug-induced lupus erythematosus, which was induced by the antihypertensive drug hydralazine.^[9]
• in 1958, George Friou discovered that the substance in the serum of patients with lupus erythematosus that reacted to the nuclei of cells was gamma globulin. He also discovered that the target in the nucleus was the complex of DNA and histones. He described the indirect immunoflourescence test to detect antinuclear antibodies. Autoantibodies like nuclear ribonucleoprotein (nRNP), Smith, Ro, La, and anticardiolipin antibodies were discovered based on his primary work.^[9]
• In 1959, the discovery of a lethal kidney disease in Otago Medical School in New Zealand represented a breakthrough in the understanding of lupus. The discovery provided many insights into disease mechanisms in immunopathogenesis of auto-antibody formation, immunologic tolerance, and the development of glomerulonephritis in lupus. The discovery also led to better evaluation of newer therapeutic agents in lupus erythematosus.^[4]
• In 1971, the first classification criteria for lupus was established.
• In 1982, the criteria were revised by the American College of Rheumatology (ACR) to incorporate new advances in serologic testing (ANA and anti-dsDNA) and improved biostatistical techniques.^[4][7]
• In 2012, the Systemic Lupus Collaborating Clinics (SLICC) revised and validated the American College of Rheumatology (ACR) SLE classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge in SLE immunology.^[4]

• Michael Jackson, had both SLE and vitiligo; diagnosed in 1986, and confirmed by his dermatologist, Arnold Klein, who presented legal documents during court depositions.^[10][11]
• Lady Gaga, has been tested borderline positive for SLE;^[12] says she hopes to avoid symptoms by maintaining a healthy lifestyle.^[13][14][11]
• Selena Gomez, American actress and singer was diagnosed with lupus.^[15][11]
• Toni Braxton, hospitalized in Los Angeles in December 2012 because of “minor health issues” related to lupus.^[16][11]
• Louisa May Alcott, American author best known for her novel Little Women; has been suggested to have had SLE.^[17][11]
• Ferdinand Marcos, former Philippine president; died of SLE complications in 1989.^[18][11]
• Hugh Gaitskell, British politician; died of SLE complications in 1963 aged 56.^[19][11]
• Donald Byrne, American chess player; died from SLE complications in 1976.^[20]
• Lauren Shuler Donner, American movie producer was diagnosed with lupus.^[21][11]
• Caroline Dorough-Cochran, died of SLE complications. She was the sister of Howie D. of the Backstreet Boys, who founded the Dorough Lupus Foundation in her memory.^[11]
• Pumpuang Duangjan, “queen of Thai country music”, was diagnosed with lupus.^[11]
• Juli Furtado, champion professional mountain biker was diagnosed with lupus.^[22][11]
• Sophie Howard, British glamour model was diagnosed with lupus.^[23][11]
• J Dilla (also known as Jay Dee), hip-hop producer and beat maker; died of SLE complications in 2006.^[24][11]
• Teddi King, American singer; died of SLE complications in 1977.^[25][11]
• Charles Kuralt, former anchor of CBS Sunday Morning; died of SLE complications in 1997.^[26][11]
• Inday Ba (also known as N’Deaye Ba), Swedish-born actress; died from SLE complications at age 32.^[27][11]
• Mary Elizabeth McDonough, American actress; believes her SLE to be due to silicone breast implants.^[28][11]
• Flannery O’Connor, American fiction writer; died of SLE complications in 1964.^[29][11]
• Tim Raines, former major league baseball player was diagnosed with lupus.^[30][11]
• Ray Walston, character actor who died of SLE complications in 2001 after a six-year battle with the disease.^[31][11]
• Michael Wayne, Hollywood director and producer; part owner of Batjac Productions; son of John Wayne, died of heart failure resulting from SLE complications in 2003.^[32][11]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

Lupus nephritis may be classified according to the Renal Pathology Society/International Society of Nephrology (RPS/ISN) classification which includes minimal mesangial lupus nephritis (class I), mesangial proliferative lupus nephritis (class II), focal lupus nephritis (class III), diffuse lupus nephritis (class IV), lupus membranous nephropathy (class V) and advanced sclerosing lupus nephritis (class VI)

The Renal Pathology Society/International Society of Nephrology (RPS/ISN) classification:^{[1][2][3][4][5][6]}

• Very rare.^[1]
• No microscopic finding.
• Identified on electron microscopy and immunofluorescence.^[1]

• Microscopic Hematuria
• Proteinuria
• Hypercellularity in mesangium^[1]
• Light microscopy shows subendothelial deposits or segmental scars^[1]
• Immunofluorescence shows subepithelial or subendothelial deposits
• Good prognosis

• Less than 50% glomeruli involved
• Hematuria
• Proteinuria
• Hypertension
• Crescent formation
• Uniform involvement on immunofluorescence^[1][7]
• Subendothelial immune and mesangial deposits on electron microscopy^[1][8].

• Class III (A) called focal proliferative lupus nephritis: Just active lesions.^[8][9]
• Class III (A/C) called focal proliferative and sclerosing lupus nephritis: Active and chronic lesions^[9]
• Class III (C) called focal sclerosing lupus nephritis: Chronic inactive lesions with scarring.

• More than 50% glomeruli involved
• Proteinuria
• Hematuria
• Nephrotic syndrome
• Hypocomplementemia
• Increased anti-DNA antibodies
• Proliferative, necrotizing lesions
• Crescent formation
• Glomerular capillary wall thickening
• Monocytes, suppressor/cytotoxic T cells may be seen
• Subendothelial deposits on electron microscopy

• Class IV-S (A), class IV-S with active lesions called diffuse segmental proliferative nephritis.
• Class IV-G (A), class IV-G associated with active lesions called diffuse global proliferative nephritis.
• Class IV-S (A/C),associated with active and chronic lesions called diffuse segmental proliferative and sclerosing nephritis.
• Class IV-G (A/C), class IV-G with active and chronic lesions called diffuse global proliferative and sclerosing nephritis.
• Class IV-S (C), associated with chronic inactive lesions with scars called diffuse segmental sclerosing lupus nephritis.
• Class IV-G (C), class IV-G with chronic inactive lesions with scars called diffuse global sclerosing lupus nephritis

• Nephrotic syndrome
• Microscopic hematuria
• Hypertension 
• Light microscopy shows diffuse glomerular capillary wall thickening
• Immunofluorescence or electron microscopy shows subepithelial immune depositson
• May present no SLE features/Lab findings

• Proteinuria
• Dull urine sediment
• Greater than 90 percent of glomeruli involvement.
• Presence of all advanced stages of chronic class III, IV, or V lupus nephritis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2], Cafer Zorkun, M.D., Ph.D. [3], Raviteja Guddeti, M.B.B.S. [4] , Aida Javanbakht, M.D.

Systemic lupus erythematosus (SLE, or lupus) is an autoimmune disease. This means there is a problem with the body’s immune system. Normally, the immune system helps protect the body from harmful substances. But in patients with an autoimmune disease, the immune system cannot tell the difference between harmful substances and healthy ones. As a result, the immune system attacks otherwise healthy cells and tissue.

Immune system, genetic, and environmental factors are considered in the pathogenesis of Lupus Nephritis (LN). All tissues of the renal can be involved in LN.

– Immune system ^[1]:

• Plasma cells and B lymphocytes:

plasma cells(PC) and B cells produce autoantibodies.

B cells in LN patients have more MicroRNAs (miRNAs) which modulate gene expression ^[2]. Over expression of the miR-30a could lower the level of Lyn (type of protein tyrosine kinases), and lower level of Lyn may cause deposition of immune complexes in the kidney ^[3][4]. 

High number of PCs in the medulla and activation of B cells cause proteinuria and severe damage in LN.

• T lymphocytes:

T cells are considered as coordinators of the adaptive immune response. The T-cell receptor (TCR) complex is a protein receptor composed of TCRα, β, and ζ chains. Decreased TCRζ chain expression may cause LN ^[5]. Th2 cells play role in LN by affecting B-lymphocyte activation. Th17 cells play role in LN by causing inflammation in nephrons. Stat-1 signaling play role on activity of IL-17 which produced by Th17 cells. IL-17–deficient patients are more susceptible to SLE ^[6].

• Autophagy :

Overexpression of apolipoprotein L1 (APOL1), a protein that induce autophagic cell death, may cause fibrosis in renal and ESRD in patients with LN ^{[7] [8]}.

Low level of myotubularin-related phosphatase 3 (MTMR3), types of the phosphatidylinositol 3-phosphate that plays a role in initiating autophagy, may cause LN ^[9].

• Macrophages:

Macrophages play role in presenting antigens, removing of dying cells, and producing cytokines. Increase expression of Sialoadhesin (Sn), a macrophage-restricted adhesion molecule may play a role in causing sever LN ^[10].

• Inflammatory cytokines:

Tumor necrosis factor (TNF) is a cytokine (cell signaling protein) that play role in inflammation process. One of the sub types of TNF is TNF-like weak inducer of apoptosis (TWEAK) which has an important role in causing LN ^[11]. Fn14 ( TWEAK receptor) is interacted with TWEAK on renal mesangial, endothelial, tubular cells and podocytes ^[12]. This interactions produce multiple inflammatory mediators which lead to LN.

Increased expression of interferon alpha (IFN-α) inducible RNA transcripts by mononuclear cells. 

– Repair impairment and Tissue Scarring:

 Impairment in regulation and repair may cause tissue scars like ^[13]:

• Necrosis and extracellular matrix production cause global glomerulosclerosis ^[14].
• Fibrinogen leakage in to Bowman’s space cause epithelial cell hyperproliferation. Accumulation of epithelial cells make glomerular crescent. In severe LN, epithelial cells produce extra amount of matrix in Bowman’s space, which result in glomerulosclerosis ^[15].
• Exaggerated healing response cause hyperproliferation of mesangial and endothelial cells, and podocyte loss cause damage in renal.

– Environmental factors:

• Geographical distribution :

LN is more severe in African, Hispanics and Asian patients with SLE. LN is associated with temperature and season ^[16]. Most flares are happening in spring and hot weather.

• Infections:
  • May cause more antibodies production by B cells.
  • Include:
    • Parvovirus B19
    • Epstein-Barr virus (EBV)
    • Trypanosomiasis
    • Mycobacterial infections
• Ultraviolet (UV) light:
  • Can stimulate B-cells to produce more antibodies
  • May activate macrophages, interfere with antigen processing, and therefore increase the degree of autoimmunity.
• Diet:
  • Vitamin D and vitamin A play role in SLE flare by affecting immunological pathways. The role of them in LN is unknown.

interaction and mutation between below genes from multiple categories may cause severe LN^{[17] [18] [19] [20]}.

• PP2Ac ^[21]: Overexpression of PP2Ac is associated with renal damage by causing neutrophils accumulation.
• IKZF1 ^[22]
• TNFSF4 ^[23]
• TLR9 ^[24]
• TNFAIP3 (A20) ^[25]
• TNIP3 (ABIN3) ^[26]
• ACE D allele ^[27]
• KLK ^[28]
• FCGR2A, 3A, 3B ^[29]
• ITGAM ^{[30] [31] [32]}
• HLA DR and BLK ^[33]

Epigenetic modification ^[34]:

• DNA methylation:

Hypomethylated genes in B lymphocytes activate transcription, and cause production of many anti-DNA antibodies^[35].

• Histone modifications:

Histone is a protein in chromatin that play role in gene regulation.

Acetylation of histones are concidered targets for autoantibodies in LN.

• MicroRNAs:

Non-coding RNA sequences that play role in gene regulation by degradation of mRNA and protein translation blockage.

Some miRNAs are increased in LN like miR-142-3p and miR-181 and some are decreased like miR-106a, miR-17, miR-20a, miR-92a and miR-203 ^[36].

 These changes cause dysregulation of genes and LN.

Morbidity and mortality are increased in patients with LN because of aggressive immunosuppressive therapy.

Anti-DNA, anti-nucleosome and anti-histone Abs are associated with sever poor prognosis LN ^[37].

• On gross pathology hypertrophy and pallor of the kidney will be seen.

6 classification for LN on microscopy:

Class	Name	Light Microscopy	Light microscopy previews	Electron microscopy
I	Minimal mesangial lupus nephritis	Normal		Immune deposits in mesangial
II	Mesangial proliferative lupus nephritis	Mesangial widening and hypercellularity		Immune deposits in subepithelial or subendothelial
III	Focal lupus nephritis	Necrotizing and sclerosing lesions in < 50% glomeruli		Fibrinoid necrosis and crescents in glomeruli, Immune deposits in subendothelial space of the glomerular capillary and mesangium
IV	Diffuse lupus nephritis	mesangial, endocapillary and mesangiocapillary involvement > 50%		Diffuse wire loop deposits, extensive subendothelial deposits
V	Lupus membranous nephropathy	thickening of capillary of the glomeruli		Global or segmental subepithelial immune deposits
VI	Advanced sclerosing lupus nephritis	Sclerosis of the glomeruli > 90%		Global or segmental subepithelial immune deposits

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

There are no established direct causes of systemic lupus erythematosus. Common contributory factors in the development of systemic lupus erythematosus include geneticpredisposition, auto-immune diseases, and use of drugs. Less common factors include environmental factors and exposure to ultraviolet (UV) light.

• Genetic predisposition:^[1]
  • HLA class polymorphism
  • Complement genes
  • Female sexual gene due to high levels of estrogen and prolactin
• Auto-immune disease^[2]

• Infections
  • Parvovirus B19
  • Epstein-Barr virus (EBV)
  • Trypanosomiasis
  • Mycobacterial infections 

• Exposure to ultraviolet (UV) light^[3]
  • Can exacerbate or induce systemic manifestations of SLE 
• Drug-induced lupus

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

Lupus nephritis must be differentiated from other glomerular diseases that may cause hematuria, proteinuria, or renal failure. The various types of glomerular diseases should be differentiated from each other based on associations, presence of pitting edema, hemeturia, hypertension, hemoptysis, oliguria, peri-orbital edema, hyperlipidemia, type of antibodies, light and electron microscopic features. The following table differentiates between various types of glumerular diseases:

Lupus nephritis must be differentiated from other glomerular diseases that may cause hematuria, proteinuria, or renal failure. The various types of glomerular diseases should be differentiated from each other based on associations, presence of pitting edema, hemeturia, hypertension, hemoptysis, oliguria, peri-orbital edema, hyperlipidemia, type of antibodies, light and electron microscopic features. The following table differentiates between various types of glumerular diseases:

Some infectious diseases such as HIV, HBV, HCV, syphilis, leprosy, malaria, and schistosomiasis may cause glomerular diseases.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

The incidence of lupus nephritis is 34 to 51 percent in Blacks, 31 to 43 percent in Hispanics, 33 to 55 percent in Asians, and 14 to 23 percent in Whites. In 2005, Incidence was fiund to be 5.1 (Overall), 1.9 (Adult men), 8.2 (Adult women).The incidence of Lupus nephritis increases with age upto 50 years; the median age at diagnosis is 25 years.Chronic disease name is usually first diagnosed among middle age patients. African Americans have a higher frequency of developing Lupus nephritis in the United States.

• The incidence of lupus nephritis is different among:^[1]

Blacks: 34 to 51 percent

Hispanics: 31 to 43 percent

Asians: 33 to 55 percent

Whites: 14 to 23 percent

• In 2005, Incidence was fiund to be 5.1 (Overall), 1.9 (Adult men), 8.2 (Adult women)^[1]

• The overall mortality rate of lupus is very high, estimated to have approximately 50,000 deaths per 100,000 cases.

• Patients of all age groups may develop Lupus nephritis.^[3]
• The incidence of Lupus nephritis increases with age upto 50 years; the median age at diagnosis is 25 years.^[3]
• Lupus nephritis commonly affects individuals older than 18 years of age.
• Chronic disease name is usually first diagnosed among middle age patients.^[3]
• Acute disease commonly affects young females.

• In 1995, the incidence of SLE was estimated to be 2.0 in White adults, 0.4 in White men, 3.5 in White women, 5.3 in African American adults, and 0.7 African America men.^[1]

• Females are more commonly affected with Lupus nephritis. With an overall female to male ratio of approximately 8:1 in adults and 4:3 in children.^[3]

• African Americans have a higher frequency of developing Lupus nephritis in the United States.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D. [2]

Common risk factors in the development of Lupus nephritis may be occupational, environmental, genetic, and viral.

• The most potent risk factor in the development of Lupus nephritis include is auto-immunity. Other risk factors include race, gender, infections and drugs.^[1][2]

• Common risk factors in the development of Lupus nephritis may be:^[2]

• African-Americans^[2]

• Females are more likely to develop Lupus nephritis^[2]

• Viruses specially retroviruses

• Hydralazine
• Procainamide

• Fc gamma RIIIA-V/F158^[3]

Less common risk factors in the development of Lupus nephritis include:^[2]

• C4A or C4B
• Hyopcomplementemia
• Low production of Tumor necrosis factor (TNF)^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D. [2]

According to the United States Preventive Services Task Force, screening for systemic lupus erythematosus is not recommended.

According to the United States Preventive Services Task Force, screening for systemic lupus erythematosus is not recommended.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2] Cafer Zorkun, M.D., Ph.D. [2], Raviteja Guddeti, M.B.B.S. [3]

Common complications of Lupus nephritis include microscopic hematuria, nephrotic syndrome, celluar casts, elevated creatnine and destruction of more than 50% of glomeruli.

Lupus nephritis may damage different parts of the kidney. Class I has normal histology and does not show any evidence of disease and class V shows an extensive disease.

• The symptoms of Lupus nephritis usually develop in one half of the patients with SLE and start with symptoms such as proteinuria.^[1][2][3]
• The symptoms of Lupus nephritis typically develop within three years after having SLE.^[3][4][5]
• If left untreated, thirty percent of patients with SLE may progress to develop hematuria, nephrotic syndrome, and hypertension.

Possible complications include:^[3]

• Interstitial nephritis
• Nephrotic syndrome
• Membranous glomerulonephritis^[5]
• Kidney failure – acute and chronic
• End stage renal disease
• Hypertension

• The class of lupus nephritis: Focal lupus nephritis, minimal mesangial lupus nephritis and mesangial proliferative lupus nephritis have better prognosis than other classes. And, advanced sclerosis lupus nephritis carries a poor prognosis.^[4]
• Nephrotic syndrome carries worse prognosis.^[5]
• Creatinine level: Patients with elevated creatinine (>3 mg/dL) at presentation have worse outcomes.^[5]
• Patients with persistently elevated anti-dsDNA and low C3 and C4 levels have poorer outcomes.
• Renal biopsy findings showing diffuse lupus nephritis or high chronicity index suggest worse prognosis.^[5][4]
• Young age onset carries worse prognosis.
• Male gender have poorer outcomes than female.^[4]
• Black race have worse outcomes than other races.^[4]
• Although lupus nephritis may return in a transplanted kidney, it rarely leads to end-stage kidney disease.^[5]

• Prognosis is generally poor for class IV, and the 50% survival is 15/+- 2.5 years.^[6][7]

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