X
UnivadisfromMedscape
processing....
Lupus nephritis is clinically evident in 50-60% of patients with systemic lupus erythematosus (SLE), and it is histologically evident in most SLE patients, even those without clinical manifestations of kidney disease. (See the image below.) Evaluating kidney function in SLE patients is important because early detection and treatment of kidney involvement can significantly improve renal outcome.
Advanced sclerosis lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class VI (×100, hematoxylin-eosin).Patients with lupus nephritis may report 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
Active nephritis
Nephritic symptoms related to hypertension and poor kidney function (typical of diffuse lupus nephritis):
Nephrotic symptoms related to proteinuria (ypical of membranous lupus nephritis):
Physical findings
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
SeePresentation for more detail.
Laboratory tests to evaluate kidney function in SLE patients include the following:
Laboratory tests for SLE disease activity include the following:
Kidney 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:
SeeWorkup for more detail.
The principal goal of therapy in lupus nephritis is to normalize kidney function or, at least, to prevent the progressive loss of kidney 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 kidney 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 kidney function worsens or a proliferative component is present on kidney biopsy samples.
Newer therapies for lupus nephritis include the following:
Investigational therapies for lupus nephritis and SLE include the following:
Patients with end-stage renal disease require dialysis and are good candidates for kidney transplantation. Hemodialysis is preferred to peritoneal dialysis.
SeeTreatment andMedication for more detail.
For patient education information, see Lupus Nephritis.
Autoimmunity plays a major role in the pathogenesis of lupus nephritis. The immunologic mechanisms include production of autoantibodies directed against nuclear elements. 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 withantiphospholipid antibody syndrome, and is believed to be the result of antibodies directed against negatively charged phospholipid-protein complexes. [2]
Specific strains of a gut commensal may contribute to the immune pathogenesis of lupus nephritis. Azzouz and colleagues analyzed blood and fecal samples from 61 women with SLE and 17 healthy women. On rRNA amplification analysis, patients with SLE displayed a fivefold higher number of Gram-positive fecal bacteria, specifically Ruminococcus gnavus (RG). When the researchers stratified patients with SLE according to organ involvement, those with a history of kidney disease demonstrated an abundance of RG-specific amplicon sequence variant compared with those who had no renal impairment. [5]
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). [6,7,8,9,4,10]
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:
Complement genes include the following:
C1Q, C1R, andC1S deficiencies are associated with SLE, lupus nephritis, and production of anti-dsDNA
C2 andC4 deficiencies are associated with SLE or lupus-like syndrome
C4A andC4B (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 theIL10 gene (high producers) and possibly theIL1RN andTNFA 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, includingCD95 (Fas) andCD178 (FasL)
The initial autoantibody response appears to be directed against the nucleosome, which arises from apoptotic cells. [4,11,12]
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. [13,14,15]
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. [16]
In a multi-ethnic international cohort of patients enrolled within 15 months (mean, 6 months) after SLE diagnosis and assessed annually, lupus nephritis occurred in 700 of 1827 patients (38.3%). Lupus nephritis was frequently the initial presentation of SLE; it was identified at enrollment in 80.9% of cases. Patients with nephritis were younger, more frequently men and of African, Asian, and Hispanic race/ethnicity. [17]
In a study of a large Spanish registry, lupus nephritis was histologically confirmed in 1092 of 3575 patients with SLE (30.5%). The mean age at lupus nephritis diagnosis was 28.4 years. The risk for lupus nephritis development was significantly higher in men, in younger individuals, and in Hispanics. Patients receiving antimalarials had a significantly lower risk of developing lupus nephritis. [18]
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. [19]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. [20,21,22]
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. [19]
SLE is more common in African Americans and Asians than in white people, with the highest prevalence in Caribbean people. The prevalence of lupus nephritis is much higher in Asians than in Whites with SLE, but the 10-year renal outcome and renal survival rate appear to be better in Asians. [23]Particularly severe lupus nephritis may be more common in African Americans and Asians than in other ethnic groups. [19]
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. [24]
Mortality in patients with end-stage renal disease due to lupus nephritis has declined significantly in recent decades. The mortality rate per 100 patient-years declined from 11.1 in 1995-1999 to 6.7 in 2010-2014. Deaths due to cardiovascular disease declined by 44% and deaths due to infection declined 63%. [25]
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. [26]
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. [27]
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.
Biomarkers of renal outcome in lupus nephritis include proteinuria and serum albumin. Studies have shown that a proteinuria cut-off of less than 0.7 or 0.8 g/day at 12 months predicts good long-term renal outcome. Domingues et al reported that serum albumin > 3.7 g/dL at 12 months predicts favorable renal outcome at 48 months. [28]
Yung S, Chan TM. Anti-DNA antibodies in the pathogenesis of lupus nephritis--the emerging mechanisms.Autoimmun Rev. 2008 Feb. 7(4):317-21.[QxMD MEDLINE Link].
Davidson A, Berthier C, Kretzler M. Pathogenetic mechanisms in lupus nephritis. Wallace DJ, Hahn BH, eds.Dubois' Lupus Erythematosus and Related Syndromes. 8th ed. Philadelphia, PA: Elsevier Saunders; 2013. 237-55.
Grande JP. Mechanisms of progression of renal damage in lupus nephritis: pathogenesis of renal scarring.Lupus. 1998. 7(9):604-10.[QxMD MEDLINE Link].
Lisnevskaia L, Murphy G, Isenberg D. Systemic lupus erythematosus.Lancet. 2014 Nov 22. 384 (9957):1878-1888.[QxMD MEDLINE Link].
Azzouz D, Omarbekova A, Heguy A, Schwudke D, Gisch N, Rovin BH, et al. Lupus nephritis is linked to disease-activity associated expansions and immunity to a gut commensal.Ann Rheum Dis. 2019 Feb 19.[QxMD MEDLINE Link].[Full Text].
Mohan C, Putterman C. Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis.Nat Rev Nephrol. 2015 Jun. 11 (6):329-41.[QxMD MEDLINE Link].
Harley JB, Kelly JA, Kaufman KM. Unraveling the genetics of systemic lupus erythematosus.Springer Semin Immunopathol. 2006 Oct. 28(2):119-30.[QxMD MEDLINE Link].
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. 2008 Feb. 40(2):204-10.[QxMD MEDLINE Link].
Crow MK. Collaboration, genetic associations, and lupus erythematosus.N Engl J Med. 2008 Feb 28. 358(9):956-61.[QxMD MEDLINE Link].
Kaiser R, Criswell LA. Genetics research in systemic lupus erythematosus for clinicians: methodology, progress, and controversies.Curr Opin Rheumatol. 2010 Mar. 22(2):119-25.[QxMD MEDLINE Link].
Mohan C, Adams S, Stanik V, Datta SK. Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus.J Exp Med. 1993 May 1. 177(5):1367-81.[QxMD MEDLINE Link].
Muller S, Dieker J, Tincani A, Meroni PL. Pathogenic anti-nucleosome antibodies.Lupus. 2008. 17(5):431-6.[QxMD MEDLINE Link].
Crow MK. Interferon pathway activation in systemic lupus erythematosus.Curr Rheumatol Rep. 2005 Dec. 7(6):463-8.[QxMD MEDLINE Link].
Rönnblom L, Eloranta ML, Alm GV. The type I interferon system in systemic lupus erythematosus.Arthritis Rheum. 2006 Feb. 54(2):408-20.[QxMD MEDLINE Link].
Rönnblom L, Pascual V. The innate immune system in SLE: type I interferons and dendritic cells.Lupus. 2008. 17(5):394-9.[QxMD MEDLINE Link].
Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus.N Engl J Med. 2003 Oct 16. 349(16):1526-33.[QxMD MEDLINE Link].
Hanly JG, O'Keeffe AG, Su L, Urowitz MB, Romero-Diaz J, et al. The frequency and outcome of lupus nephritis: results from an international inception cohort study.Rheumatology (Oxford). 2016 Feb. 55 (2):252-62.[QxMD MEDLINE Link].
Galindo-Izquierdo M, Rodriguez-Almaraz E, Pego-Reigosa JM, et al. Characterization of Patients With Lupus Nephritis Included in a Large Cohort From the Spanish Society of Rheumatology Registry of Patients With Systemic Lupus Erythematosus (RELESSER).Medicine (Baltimore). 2016 Mar. 95 (9):e2891.[QxMD MEDLINE Link].
Lim SS, Drenkard C. The Epidemiology of Lupus. Wallace DJ, Hahn BH, eds.Dubois' Lupus Erythematosus and Related Syndromes. 8th ed. Philadelphia, PA: Elsevier Saunders; 2013. 8-24.
Gloor JM. Lupus nephritis in children.Lupus. 1998. 7(9):639-43.[QxMD MEDLINE Link].
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. 2008 Feb. 58(2):556-62.[QxMD MEDLINE Link].
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. 2004 Jan. 19(1):36-44.[QxMD MEDLINE Link].
Yap DY, Chan TM. Lupus Nephritis in Asia: Clinical Features and Management.Kidney Dis (Basel). 2015 Sep. 1 (2):100-9.[QxMD MEDLINE Link].
Dooley MA. Clinical and epidemiologic features of lupus nephritis. Wallace DJ, Hahn BH, eds.Dubois' Lupus Erythematosus and Related Syndromes. 8th ed. Philadelphia, PA: Elsevier Saunders; 2013. 438-54.
Jorge A, Wallace ZS, Zhang Y, Lu N, Costenbader KH, Choi HK. All-Cause and Cause-Specific Mortality Trends of End-Stage Renal Disease due to Lupus Nephritis from 1995 to 2014.Arthritis Rheumatol. 2018 Sep 18.[QxMD MEDLINE Link].
Faurschou M, Mellemkjaer L, Starklint H, et al. High risk of ischemic heart disease in patients with lupus nephritis.J Rheumatol. 2011 Nov. 38(11):2400-5.[QxMD MEDLINE Link].
Rianthavorn P, Buddhasri A. Long-term renal outcomes of childhood-onset global and segmental diffuse proliferative lupus nephritis.Pediatr Nephrol. 2015 Nov. 30 (11):1969-76.[QxMD MEDLINE Link].
Domingues V, Levinson BA, Bornkamp N, Goldberg JD, Buyon J, Belmont HM. Serum albumin at 1 year predicts long-term renal outcome in lupus nephritis.Lupus Sci Med. 2018. 5 (1):e000271.[QxMD MEDLINE Link].[Full Text].
Pisetsky DS, Gilkeson G, St. Clair EW. Systemic lupus erythematosus. Diagnosis and treatment.Med Clin North Am. 1997 Jan. 81(1):113-28.[QxMD MEDLINE Link].
Grande JP, Balow JE. Renal biopsy in lupus nephritis.Lupus. 1998. 7(9):611-7.[QxMD MEDLINE Link].
Smith EM, Jorgensen AL, Midgley A, Oni L, Goilav B, Putterman C, et al. International validation of a urinary biomarker panel for identification of active lupus nephritis in children.Pediatr Nephrol. 2016 Sep 3.[QxMD MEDLINE Link].
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). 2004 Feb. 43(2):220-4.[QxMD MEDLINE Link].
Su Y, Jia RL, Han L, Li ZG. Role of anti-nucleosome antibody in the diagnosis of systemic lupus erythematosus.Clin Immunol. 2007 Jan. 122(1):115-20.[QxMD MEDLINE Link].
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. 2008 Apr. 51(4):624-9.[QxMD MEDLINE Link].
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. 2005 Mar. 64(3):444-8.[QxMD MEDLINE Link].
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. 2005 Jun. 1050:193-200.[QxMD MEDLINE Link].
Sinico RA, Rimoldi L, Radice A, Bianchi L, Gallelli B, Moroni G. Anti-C1q autoantibodies in lupus nephritis.Ann N Y Acad Sci. 2009 Sep. 1173:47-51.[QxMD MEDLINE Link].
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. 2010 Dec. 156(6):320-5.[QxMD MEDLINE Link].
Parikh SV, Almaani S, Brodsky S, Rovin BH. Update on Lupus Nephritis: Core Curriculum 2020.Am J Kidney Dis. 2020 Aug. 76 (2):265-281.[QxMD MEDLINE Link].
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. 2004 Feb. 15(2):241-50.[QxMD MEDLINE Link].
Bajema IM, Wilhelmus S, Alpers CE, Bruijn JA, Colvin RB, Cook HT, et al. Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices.Kidney Int. 2018 Apr. 93 (4):789-796.[QxMD MEDLINE Link].[Full Text].
Houssiau FA, Ginzler EM. Current treatment of lupus nephritis.Lupus. 2008. 17(5):426-30.[QxMD MEDLINE Link].
Pons-Estel GJ, Alarcón GS, McGwin G Jr, Danila MI, Zhang J, Bastian HM, et al. Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort.Arthritis Rheum. 2009 Jun 15. 61 (6):830-9.[QxMD MEDLINE Link].
Dooley MA, Falk RJ. Immunosuppressive therapy of lupus nephritis.Lupus. 1998. 7(9):630-4.[QxMD MEDLINE Link].
Dooley MA, Ginzler EM. Newer therapeutic approaches for systemic lupus erythematosus: immunosuppressive agents.Rheum Dis Clin North Am. 2006 Feb. 32(1):91-102, ix.[QxMD MEDLINE Link].
Kronbichler A, Neumann I, Mayer G. Moderator's view: the use of calcineurin inhibitors in the treatment of lupus nephritis.Nephrol Dial Transplant. 2016 Sep 1.[QxMD MEDLINE Link].
Mok CC, Jayne D. Pro: The use of calcineurin inhibitors in the treatment of lupus nephritis.Nephrol Dial Transplant. 2016 Sep 1.[QxMD MEDLINE Link].
Fernandez Nieto M, Jayne DR, Mok CC. Con: The use of calcineurin inhibitors in the treatment of lupus nephritis.Nephrol Dial Transplant. 2016 Sep 1.[QxMD MEDLINE Link].
Mike Donnelly. FDA Approves Aurinia Pharmaceuticals’ LUPKYNIS™ (voclosporin) for Adult Patients with Active Lupus Nephritis. PR Newswire. Available athttps://www.prnewswire.com/news-releases/lupus-foundation-of-america-congratulates-aurinia-pharmaceuticals-on-fda-approval-of-lupkynis-voclosporin-to-treat-lupus-nephritis-301213505.html#:~:text=Today%2C%20Aurinia%20Pharmaceuticals%20announced%20they,the%. 1/22/2021; Accessed: 1/22/2021.
Cao H, Rao Y, Liu L, Lin J, Yang H, Zhang X, et al. The Efficacy and Safety of Leflunomide for the Treatment of Lupus Nephritis in Chinese Patients: Systematic Review and Meta-Analysis.PLoS One. 2015. 10 (12):e0144548.[QxMD MEDLINE Link].
Zhang M, Qi C, Zha Y, Chen J, Luo P, Wang L, et al. Leflunomide versus cyclophosphamide in the induction treatment of proliferative lupus nephritis in Chinese patients: a randomized trial.Clin Rheumatol. 2019 Mar. 38 (3):859-867.[QxMD MEDLINE Link].
Lightstone L, Hladunewich MA. Lupus Nephritis and Pregnancy: Concerns and Management.Semin Nephrol. 2017 Jul. 37 (4):347-353.[QxMD MEDLINE Link].
Moroni G, Doria A, Giglio E, Tani C, Zen M, Strigini F, et al. Fetal outcome and recommendations of pregnancies in lupus nephritis in the 21st century. A prospective multicenter study.J Autoimmun. 2016 Aug 2.[QxMD MEDLINE Link].
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. 2000 Oct 19. 343(16):1156-62.[QxMD MEDLINE Link].
Ginzler EM, Dooley MA, Aranow C, Kim MY, Buyon J, Merrill JT. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis.N Engl J Med. 2005 Nov 24. 353(21):2219-28.[QxMD MEDLINE Link].
Contreras G, Pardo V, Leclercq B, et al. Sequential therapies for proliferative lupus nephritis.N Engl J Med. 2004 Mar 4. 350(10):971-80.[QxMD MEDLINE Link].
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. 1996 Oct 1. 125(7):549-57.[QxMD MEDLINE Link].
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. 1996 Dec. 39(12):2028-34.[QxMD MEDLINE Link].
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. 2005 Sep. 52(9):2761-7.[QxMD MEDLINE Link].
Houssiau FA, Vasconcelos C, D'Cruz D, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide.Arthritis Rheum. 2002 Aug. 46 (8):2121-31.[QxMD MEDLINE Link].
Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.J Am Soc Nephrol. 2009 May. 20(5):1103-12.[QxMD MEDLINE Link].[Full Text].
Dooley MA, Jayne D, Ginzler EM, et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis.N Engl J Med. 2011 Nov 17. 365(20):1886-95.[QxMD MEDLINE Link].
Tamirou F, D'Cruz D, Sangle S, Remy P, Vasconcelos C, Fiehn C, et al. Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis.Ann Rheum Dis. 2015 Mar 10.[QxMD MEDLINE Link].
[Guideline] Fanouriakis A, Kostopoulou M, Cheema K, et al. 2019 Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis.Ann Rheum Dis. 2020 Mar 27.[QxMD MEDLINE Link].[Full Text].
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. 2009 Oct. 18(12):1091-5.[QxMD MEDLINE Link].
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. 2006 Feb. 32(1):103-19, ix.[QxMD MEDLINE Link].
Furie R, Rovin BH, Houssiau F, Malvar A, Teng YKO, Contreras G, et al. Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.N Engl J Med. 2020 Sep 17. 383 (12):1117-1128.[QxMD MEDLINE Link].
Rovin BH, Solomons N, Pendergraft WF 3rd, Dooley MA, Tumlin J, Romero-Diaz J, et al. A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis.Kidney Int. 2018 Nov 5.[QxMD MEDLINE Link].
Frelick M. Dawn of New Lupus Nephritis Treatment After AURORA Trial.Medscape Medical News. March 27, 2020. Available athttps://www.medscape.com/viewarticle/927657.
Cassia M, Alberici F, Gallieni M, Jayne D. Lupus nephritis and B-cell targeting therapy.Expert Rev Clin Immunol. 2017 Oct. 13 (10):951-962.[QxMD MEDLINE Link].[Full Text].
Zhong Z, Li H, Zhong H, Zhou T. Clinical efficacy and safety of rituximab in lupus nephritis.Drug Des Devel Ther. 2019. 13:845-856.[QxMD MEDLINE Link].[Full Text].
Condon MB, Ashby D, Pepper RJ, Cook HT, Levy JB, Griffith M, et al. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids.Ann Rheum Dis. 2013 Aug. 72(8):1280-6.[QxMD MEDLINE Link].
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. 2010 Jan. 62(1):222-33.[QxMD MEDLINE Link].
Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study.Arthritis Rheum. 2012 Apr. 64 (4):1215-26.[QxMD MEDLINE Link].
Haarhaus ML, Svenungsson E, Gunnarsson I. Ofatumumab treatment in lupus nephritis patients.Clin Kidney J. 2016 Aug. 9 (4):552-5.[QxMD MEDLINE Link].
Masoud S, McAdoo SP, Bedi R, Cairns TD, Lightstone L. Ofatumumab for B cell depletion in patients with systemic lupus erythematosus who are allergic to rituximab.Rheumatology (Oxford). 2018 Jul 1. 57 (7):1156-1161.[QxMD MEDLINE Link].
Mysler EF, Spindler AJ, Guzman R, Bijl M, Jayne D, Furie RA, et al. Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: results from a randomized, double-blind, phase III study.Arthritis Rheum. 2013 Sep. 65 (9):2368-79.[QxMD MEDLINE Link].[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. 2007 Dec. 56(12):4142-50.[QxMD MEDLINE Link].
Furie R. Abetimus sodium (riquent) for the prevention of nephritic flares in patients with systemic lupus erythematosus.Rheum Dis Clin North Am. 2006 Feb. 32(1):149-56, x.[QxMD MEDLINE Link].
Gołębiewska J, Dębska-Ślizień A, Bułło-Piontecka B, Rutkowski B. Outcomes in Renal Transplant Recipients With Lupus Nephritis-A Single-Center Experience and Review of the Literature.Transplant Proc. 2016 Jun. 48 (5):1489-93.[QxMD MEDLINE Link].
[Guideline] Hahn BH, McMahon MA, Wilkinson A, Wallace WD, Daikh DI, Fitzgerald JD, et al. American college of rheumatology guidelines for screening, treatment, and management of lupus nephritis.Arthritis Care Res (Hoboken). 2012 Jun. 64(6):797-808.[QxMD MEDLINE Link].[Full Text].
Tsakonas E, Joseph L, Esdaile JM, Choquette D, Senécal JL, Cividino A, et al. A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group.Lupus. 1998. 7(2):80-5.[QxMD MEDLINE Link].
Reuters. New Guidelines Focus on Diagnosing, Treating Lupus Nephritis in Kids. Medscape Medical News. Available athttps://www.medscape.com/viewarticle/885734. September 17, 2017; Accessed: November 16, 2017.
Groot N, de Graeff N, Marks SD, Brogan P, Avcin T, Bader-Meunier B, et al. European evidence-based recommendations for the diagnosis and treatment of childhood-onset lupus nephritis: the SHARE initiative.Ann Rheum Dis. 2017 Dec. 76 (12):1965-1973.[QxMD MEDLINE Link].
[Guideline] Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases.Kidney Int. 2021 Oct. 100 (4S):S1-S276.[QxMD MEDLINE Link].[Full Text].
Garcia J. Gut Microbes May Predict Lupus Flares.Medscape Medical News. February 26, 2019. Available athttps://www.medscape.com/viewarticle/909553.
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. 2009 Sep 15. 61(9):1168-78.[QxMD MEDLINE Link].[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. 2010 Jan. 62(1):201-10.[QxMD MEDLINE Link].[Full Text].
Aurinia Renal Response in Active Lupus With Voclosporin (AURORA). ClinicalTrials.gov. Available athttps://clinicaltrials.gov/ct2/show/NCT03021499. October 25, 2018; Accessed: December 23, 2018.
[Guideline] Bertsias GK, Tektonidou M, Amoura Z, et al. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis.Ann Rheum Dis. 2012 Nov. 71 (11):1771-82.[QxMD MEDLINE Link].[Full Text].
Ward MM. Recent clinical trials in lupus nephritis.Rheum Dis Clin North Am. 2014 Aug. 40 (3):519-35, ix.[QxMD MEDLINE Link].
Rovin BH, Solomons N, Pendergraft WF 3rd, Dooley MA, Tumlin J, Romero-Diaz J, et al. A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis.Kidney Int. 2019 Jan. 95 (1):219-231.[QxMD MEDLINE Link].
Anders HJ, Loutan J, Bruchfeld A, Fernández-Juárez GM, Floege J, Goumenos D, et al. The management of lupus nephritis as proposed by EULAR/ERA 2019 versus KDIGO 2021.Nephrol Dial Transplant. 2023 Feb 28. 38 (3):551-561.[QxMD MEDLINE Link].
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 |
Lawrence H Brent, MD Associate Professor of Medicine, Sidney Kimmel 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: Stock ownership for: Johnson & Johnson.
Arati S Karhadkar, MD Consulting Physician, Rheumatology Associates, Ltd
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.
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.
Vecihi Batuman, MD, FASN Professor of Medicine, Section of Nephrology-Hypertension, Deming Department of Medicine, Tulane University School of Medicine
Vecihi Batuman, MD, FASN is a member of the following medical societies:American College of Physicians,American Society of Hypertension,American Society of Nephrology,Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.
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.
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.
Lupus Rashes: What to Spot, What to Shield
Lupus and Lifestyle: What Patients Can Control
In Lupus, How to Spot Hidden Heart Risk
Identifying Lesions on Skin of Color
Bullous Systemic Lupus Erythematosus (BSLE)
Unmasking Systemic Lupus Erythematosus: Burden of Disease and Unmet Needs in Lupus Management 1.0 CME Credits
Systemic Lupus Erythematosus (SLE)
Pediatric Systemic Lupus Erythematosus