eMedicine Specialties > Rheumatology > Systemic Rheumatic Disease

Nephritis, Lupus

Author: Lawrence H Brent, MD, Associate Professor of Medicine, Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center
Coauthor(s): Fadi Ahmad Hamed, MD, Resident Physician, Department of Internal Medicine, Albert Einstein Medical Center
Contributor Information and Disclosures

Updated: Jun 23, 2009

Introduction

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 classification criteria 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. With the advent of more aggressive immunosuppressive and supportive therapy, rates of renal involvement and patient survival are improving.

Pathophysiology

Autoimmunity plays a major role in the pathogenesis of lupus nephritis. The immunologic mechanisms include production of autoantibodies directed against nuclear elements. These autoantibodies form pathogenic immune complexes. Deposition of these immune deposits in the kidneys initiates an inflammatory response by activating the complement cascade and recruiting inflammatory cells that can subsequently be observed on biopsy specimens.^1,2

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.¹

Frequency

United States

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.³

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 30-90% in published studies. The true prevalence of clinical lupus nephritis in persons with SLE is probably around 50%, being more common in certain ethnic groups and in children.⁴

Mortality/Morbidity

• Over the last 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%. Recently, with the addition of immunosuppressive agents such as intravenous pulse cyclophosphamide, the 5- and 10-year survival rates are documented as high as 85% and 73%, respectively.⁴
• 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 stroke. Nephrotic syndrome may lead to edema, ascites, and hyperlipidemia, adding to the risk of coronary artery disease and the potential for thrombosis.
• 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.

Race

SLE is more common in black people and Hispanic people than in white people. Particularly severe lupus nephritis may be more common in black people and Asian people than in other ethnic groups.³

Sex

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 with a worse prognosis is more common in males with SLE.³

Age

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.³ 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.^5,6

Clinical

History

• General⁷
  • Patients with active lupus nephritis often have other symptoms of active systemic lupus erythematosus (SLE), including fatigue, fever, rash, arthritis, serositis, or CNS disease. These are more common with focal proliferative and diffuse proliferative lupus nephritis.
  • Some patients have asymptomatic lupus nephritis; however, during regular follow-up, laboratory abnormalities such as elevated serum creatinine levels, low albumin levels, or urinary protein or sediment suggests active lupus nephritis. This is more typical of mesangial or membranous lupus nephritis.
• Nephritis⁴
  • Symptoms related to active nephritis may include peripheral edema secondary to hypertension or hypoalbuminemia. Extreme peripheral edema is more common in persons with diffuse proliferative or membranous lupus nephritis, as these renal lesions are commonly associated with heavy proteinuria.
  • Other symptoms directly related to hypertension that are commonly associated with diffuse proliferative lupus nephritis include headache, dizziness, visual disturbances, and signs of cardiac decompensation.

Physical

• Focal proliferative and diffuse proliferative lupus nephritis: The physical examination may reveal evidence of generalized active SLE with the presence of a rash, oral or nasal ulcers, synovitis, or serositis. Signs of active nephritis are also common.
• Active lupus nephritis: Patients have hypertension, peripheral edema, and, occasionally, cardiac decompensation.
• Membranous lupus nephritis: Signs of an isolated nephrotic syndrome are common. These include peripheral edema, ascites, and pleural and pericardial effusions without hypertension.

Causes

• Genetic factors^{8,9,10,11,12,13,14}
  • 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.
  • SLE is more common in first-degree relatives of patients with SLE (familial prevalence of 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.
• HLA class II genes
  • 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
  • C1Q, C1R, and C1S deficiencies are associated with SLE, lupus nephritis, and production of anti–double-stranded DNA (anti-dsDNA).
  • C2 and C4 deficiencies are associated with SLE or lupuslike syndrome.
  • C4A and C4B (possibly) gene deletions are associated with SLE.
• FcgR genes
  • These mediate the binding of immunoglobulin G (IgG) and IgG-containing immune complexes to cells such as macrophages and other mononuclear phagocytes.
  • Fcg RIIa binds to IgG₂ 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 black persons.
  • Fcg RIIIa binds to IgG₁ 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.
• 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).
• Table 1. Genes Associated With Systemic Lupus Erythematosus
  
  

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  Table

  Gene Locus	Gene Name	Gene Product
  1q21-q23	CRP	C-reactive protein
  1q23	FCGR2A, FCGR2B	Fc γ RIIA (R131), Fc γ RIIB
  1q23	FCGR3A, FCGR3B	Fc γ RIIIA (V176), Fc γ RIIIB
  1q31-q32	IL10	Interleukin-10 (IL–10)
  1q36.12	C1QB	Complement component 1, q subcomponent (C1q) deficiency
  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	Tumor necrosis factor (TNF)–alpha (promoter, -308)
  10q11.2-q21	MBL2	Mannose-binding lectin

  Gene Locus	Gene Name	Gene Product
  1q21-q23	CRP	C-reactive protein
  1q23	FCGR2A, FCGR2B	Fc γ RIIA (R131), Fc γ RIIB
  1q23	FCGR3A, FCGR3B	Fc γ RIIIA (V176), Fc γ RIIIB
  1q31-q32	IL10	Interleukin-10 (IL–10)
  1q36.12	C1QB	Complement component 1, q subcomponent (C1q) deficiency
  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	Tumor necrosis factor (TNF)–alpha (promoter, -308)
  10q11.2-q21	MBL2	Mannose-binding lectin

• Immunologic factors
  • The initial autoantibody response appears to be directed against the nucleosome, which arises from apoptotic cells.^14,15,16 Patients with SLE have poor clearance mechanisms for the cellular debris. Nuclear debris from apoptotic cells induces interferon-alpha by plasmacytoid dendritic cells, which are a potent inducer of the immune system and autoimmunity.^17,18,19 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.²⁰ Lupus nephritis is associated with the production of nephritogenic autoantibodies; their characteristics are as follows²¹ :
    • Antigen specificity directed against nucleosome or 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 (IgG₁ and IgG₃) readily activate complement.
  • Immune complexes form intravascularly and 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. 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.¹⁴

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