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.
Yung S, Chan TM. Anti-DNA antibodies in the pathogenesis of lupus nephritis--the emerging mechanisms. Autoimmun Rev. Feb 2008;7(4):317-21. [Medline].
D'Agati VD, Appel GB. Lupus Nephritis: Pathology and Pathogenesis. In: Wallace DJ, Hahn BH, eds. Dubois' Lupus Erythematosus. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:1094-111.
Grande JP. Mechanisms of progression of renal damage in lupus nephritis: pathogenesis of renal scarring. Lupus. 1998;7(9):604-10. [Medline].
Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med. Feb 28 2008;358(9):929-39. [Medline].
Tsao BP. Update on human systemic lupus erythematosus genetics. Curr Opin Rheumatol. Sep 2004;16(5):513-21. [Medline].
Nath SK, Kilpatrick J, Harley JB. Genetics of human systemic lupus erythematosus: the emerging picture. Curr Opin Immunol. Dec 2004;16(6):794-800. [Medline].
Wong M, Tsao BP. Current topics in human SLE genetics. Springer Semin Immunopathol. Oct 2006;28(2):97-107. [Medline].
Harley JB, Kelly JA, Kaufman KM. Unraveling the genetics of systemic lupus erythematosus. Springer Semin Immunopathol. Oct 2006;28(2):119-30. [Medline].
Harley JB, Alarcón-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet. Feb 2008;40(2):204-10. [Medline].
Crow MK. Collaboration, genetic associations, and lupus erythematosus. N Engl J Med. Feb 28 2008;358(9):956-61. [Medline].
Kaiser R, Criswell LA. Genetics research in systemic lupus erythematosus for clinicians: methodology, progress, and controversies. Curr Opin Rheumatol. Mar 2010;22(2):119-25. [Medline].
Mohan C, Adams S, Stanik V, Datta SK. Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J Exp Med. May 1 1993;177(5):1367-81. [Medline].
Muller S, Dieker J, Tincani A, Meroni PL. Pathogenic anti-nucleosome antibodies. Lupus. 2008;17(5):431-6. [Medline].
Crow MK. Interferon pathway activation in systemic lupus erythematosus. Curr Rheumatol Rep. Dec 2005;7(6):463-8. [Medline].
Rönnblom L, Eloranta ML, Alm GV. The type I interferon system in systemic lupus erythematosus. Arthritis Rheum. Feb 2006;54(2):408-20. [Medline].
Rönnblom L, Pascual V. The innate immune system in SLE: type I interferons and dendritic cells. Lupus. 2008;17(5):394-9. [Medline].
Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. Oct 16 2003;349(16):1526-33. [Medline].
Rus V, Maury EE, Hochberg MC. Epidemiology of Systemic Lupus Erythematosus. In: Wallace DJ, Hahn BH, eds. Dubois' Lupus Erythematosus. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:34-44.
Dooley MA. Clinical and laboratory features of lupus nephritis. In: Wallace DJ, Hahn BH, eds. Dubois' Lupus Erythematosus. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:1112-30.
Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus. 2006;15(5):308-18. [Medline].
Gloor JM. Lupus nephritis in children. Lupus. 1998;7(9):639-43. [Medline].
Brunner HI, Gladman DD, Ibañez D, Urowitz MD, Silverman ED. Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus. Arthritis Rheum. Feb 2008;58(2):556-62. [Medline].
Bogdanovic R, Nikolic V, Pasic S, Dimitrijevic J, Lipkovska-Markovic J, Eric-Marinkovic J. Lupus nephritis in childhood: a review of 53 patients followed at a single center. Pediatr Nephrol. Jan 2004;19(1):36-44. [Medline].
Faurschou M, Mellemkjaer L, Starklint H, et al. High risk of ischemic heart disease in patients with lupus nephritis. J Rheumatol. Nov 2011;38(11):2400-5. [Medline].
Pisetsky DS, Gilkeson G, St. Clair EW. Systemic lupus erythematosus. Diagnosis and treatment. Med Clin North Am. Jan 1997;81(1):113-28. [Medline].
Grande JP, Balow JE. Renal biopsy in lupus nephritis. Lupus. 1998;7(9):611-7. [Medline].
Simón JA, Cabiedes J, Ortiz E, Alcocer-Varela J, Sánchez-Guerrero J. Anti-nucleosome antibodies in patients with systemic lupus erythematosus of recent onset. Potential utility as a diagnostic tool and disease activity marker. Rheumatology (Oxford). Feb 2004;43(2):220-4. [Medline].
Su Y, Jia RL, Han L, Li ZG. Role of anti-nucleosome antibody in the diagnosis of systemic lupus erythematosus. Clin Immunol. Jan 2007;122(1):115-20. [Medline].
Bigler C, Lopez-Trascasa M, Potlukova E, Moll S, Danner D, Schaller M, et al. Antinucleosome antibodies as a marker of active proliferative lupus nephritis. Am J Kidney Dis. Apr 2008;51(4):624-9. [Medline].
Marto N, Bertolaccini ML, Calabuig E, Hughes GR, Khamashta MA. Anti-C1q antibodies in nephritis: correlation between titres and renal disease activity and positive predictive value in systemic lupus erythematosus. Ann Rheum Dis. Mar 2005;64(3):444-8. [Medline].
Sinico RA, Radice A, Ikehata M, Giammarresi G, Corace C, Arrigo G, et al. Anti-C1q autoantibodies in lupus nephritis: prevalence and clinical significance. Ann N Y Acad Sci. Jun 2005;1050:193-200. [Medline].
Sinico RA, Rimoldi L, Radice A, Bianchi L, Gallelli B, Moroni G. Anti-C1q autoantibodies in lupus nephritis. Ann N Y Acad Sci. Sep 2009;1173:47-51. [Medline].
Mok CC, Ho LY, Leung HW, Wong LG. Performance of anti-C1q, antinucleosome, and anti-dsDNA antibodies for detecting concurrent disease activity of systemic lupus erythematosus. Transl Res. Dec 2010;156(6):320-5. [Medline].
Weening JJ, D'Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. Feb 2004;15(2):241-50. [Medline].
Houssiau FA, Ginzler EM. Current treatment of lupus nephritis. Lupus. 2008;17(5):426-30. [Medline].
Dooley MA, Falk RJ. Immunosuppressive therapy of lupus nephritis. Lupus. 1998;7(9):630-4. [Medline].
Dooley MA, Ginzler EM. Newer therapeutic approaches for systemic lupus erythematosus: immunosuppressive agents. Rheum Dis Clin North Am. Feb 2006;32(1):91-102, ix. [Medline].
Khamashta MA. Systemic lupus erythematosus and pregnancy. Best Pract Res Clin Rheumatol. Aug 2006;20(4):685-94. [Medline].
Petri M. The Hopkins Lupus Pregnancy Center: ten key issues in management. Rheum Dis Clin North Am. May 2007;33(2):227-35, v. [Medline].
Witter FR. Management of the high-risk lupus pregnant patient. Rheum Dis Clin North Am. May 2007;33(2):253-65, v-vi. [Medline].
Chan TM, Li FK, Tang CS, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med. Oct 19 2000;343(16):1156-62. [Medline].
Ginzler EM, Dooley MA, Aranow C, Kim MY, Buyon J, Merrill JT. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. Nov 24 2005;353(21):2219-28. [Medline].
Contreras G, Pardo V, Leclercq B, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med. Mar 4 2004;350(10):971-80. [Medline].
Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. May 2009;20(5):1103-12. [Medline]. [Full Text].
Gourley MF, Austin HA 3rd, Scott D, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med. Oct 1 1996;125(7):549-57. [Medline].
Ciruelo E, de la Cruz J, Lopez I, Gomez-Reino JJ. Cumulative rate of relapse of lupus nephritis after successful treatment with cyclophosphamide. Arthritis Rheum. Dec 1996;39(12):2028-34. [Medline].
Somers EC, Marder W, Christman GM, Ognenovski V, McCune WJ. Use of a gonadotropin-releasing hormone analog for protection against premature ovarian failure during cyclophosphamide therapy in women with severe lupus. Arthritis Rheum. Sep 2005;52(9):2761-7. [Medline].
Dooley MA, Jayne D, Ginzler EM, et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med. Nov 17 2011;365(20):1886-95. [Medline].
Mok CC, Ying KY, Yim CW, Ng WL, Wong WS. Very long-term outcome of pure lupus membranous nephropathy treated with glucocorticoid and azathioprine. Lupus. Oct 2009;18(12):1091-5. [Medline].
Silverman GJ. Anti-CD20 therapy in systemic lupus erythematosus: a step closer to the clinic. Arthritis Rheum. Feb 2005;52(2):371-7. [Medline].
Looney RJ, Anolik JH, Campbell D, Felgar RE, Young F, Arend LJ. B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum. Aug 2004;50(8):2580-9. [Medline].
Leandro MJ, Cambridge G, Edwards JC, Ehrenstein MR, Isenberg DA. B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology (Oxford). Dec 2005;44(12):1542-5. [Medline].
Ng KP, Leandro MJ, Edwards JC, Ehrenstein MR, Cambridge G, Isenberg DA. Repeated B cell depletion in treatment of refractory systemic lupus erythematosus. Ann Rheum Dis. Jul 2006;65(7):942-5. [Medline].
Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. Jan 2010;62(1):222-33. [Medline].
Looney RJ, Anolik J, Sanz I. New therapies for systemic lupus erythematosus: cellular targets. Rheum Dis Clin North Am. Feb 2006;32(1):201-15, xi. [Medline].
Furie R. Abetimus sodium (riquent) for the prevention of nephritic flares in patients with systemic lupus erythematosus. Rheum Dis Clin North Am. Feb 2006;32(1):149-56, x. [Medline].
Kirou KA, Salmon JE, Crow MK. Soluble mediators as therapeutic targets in systemic lupus erythematosus: cytokines, immunoglobulin receptors, and the complement system. Rheum Dis Clin North Am. Feb 2006;32(1):103-19, ix. [Medline].
Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. Sep 15 2009;61(9):1168-78. [Medline]. [Full Text].
Jacobi AM, Huang W, Wang T, et al. Effect of long-term belimumab treatment on B cells in systemic lupus erythematosus: extension of a phase II, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum. Jan 2010;62(1):201-10. [Medline]. [Full Text].
Dall'Era M, Chakravarty E, Wallace D, et al. Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial. Arthritis Rheum. Dec 2007;56(12):4142-50. [Medline].
| 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 |

