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 Clinical.)
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.)
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] G1 and IgG3) 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]
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 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 African Americans
- FcγRIIIa 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
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]
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]
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]
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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| 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. | ||
| 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. | ||
| 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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