Biomarkers for Lupus Nephritis: A Critical Appraisal

Kidney disease is one of the most serious manifestations of systemic lupus erythematosus (SLE). Despite the improvement in the medical care of SLE in the past two decades, the prognosis of lupus nephritis remains unsatisfactory. Besides exploring more effective but less toxic treatment modalities that will further improve the remission rate, early detection and treatment of renal activity may spare patients from intensive immunosuppressive therapies and reduce renal damage. Conventional clinical parameters such as creatinine clearance, proteinuria, urine sediments, anti-dsDNA, and complement levels are not sensitive or specific enough for detecting ongoing disease activity in the lupus kidneys and early relapse of nephritis. Thus, novel biomarkers are necessary to enhance the diagnostic accuracy and sensitivity of lupus renal disease, prognostic stratification, monitoring of treatment response, and detection of early renal flares. This paper reviews promising biomarkers that have recently been evaluated in longitudinal studies of lupus nephritis.

[1]  Feng-qi Wu,et al.  C1q and anti-C1q antibody levels are correlated with disease severity in Chinese pediatric systemic lupus erythematosus , 2011, Rheumatology International.

[2]  C. Mok Update on emerging drug therapies for systemic lupus erythematosus , 2010, Expert opinion on emerging drugs.

[3]  D. Isenberg,et al.  Urinary neutrophil gelatinase-associated lipocalin as a novel biomarker for disease activity in lupus nephritis. , 2010, Rheumatology.

[4]  D. Isenberg,et al.  Relationship between anti-dsDNA, anti-nucleosome and anti-alpha-actinin antibodies and markers of renal disease in patients with lupus nephritis: a prospective longitudinal study , 2009, Arthritis research & therapy.

[5]  L. Magder,et al.  Urine Osteoprotegerin and Monocyte Chemoattractant Protein-1 in Lupus Nephritis , 2009, The Journal of Rheumatology.

[6]  B. Rovin,et al.  Urinary TWEAK as a biomarker of lupus nephritis: a multicenter cohort study , 2009, Arthritis research & therapy.

[7]  C. Silva,et al.  Anti‐C1q Antibodies in Juvenile‐Onset Systemic Lupus Erythematosus , 2009, Annals of the New York Academy of Sciences.

[8]  L. Bianchi,et al.  Anti‐C1q Autoantibodies in Lupus Nephritis , 2009, Annals of the New York Academy of Sciences.

[9]  E. Pipi,et al.  Relevance of Anti‐C1q Autoantibodies to Lupus Nephritis , 2009, Annals of the New York Academy of Sciences.

[10]  E. Silverman,et al.  Neutrophil gelatinase-associated lipocalin is a predictor of the course of global and renal childhood-onset systemic lupus erythematosus disease activity. , 2009, Arthritis and rheumatism.

[11]  Gang Wang,et al.  Urinary FOXP3 mRNA in patients with lupus nephritis--relation with disease activity and treatment response. , 2009, Rheumatology.

[12]  P. Dieudé,et al.  Anti-C1q antibodies antedate patent active glomerulonephritis in patients with systemic lupus erythematosus , 2009, Arthritis research & therapy.

[13]  N. Hirankarn,et al.  Decreased renal expression of vascular endothelial growth factor in lupus nephritis is associated with worse prognosis. , 2009, Kidney international.

[14]  D. Webb,et al.  Urinary endothelin-1 in chronic kidney disease and as a marker of disease activity in lupus nephritis. , 2009, American journal of physiology. Renal physiology.

[15]  A. Sanz,et al.  Considering TWEAK as a target for therapy in renal and vascular injury. , 2009, Cytokine & growth factor reviews.

[16]  Jun Ying,et al.  Initial Validation of a Novel Protein Biomarker Panel for Active Pediatric Lupus Nephritis , 2009, Pediatric Research.

[17]  Irene Jarchum,et al.  TNF-like weak inducer of apoptosis (TWEAK) induces inflammatory and proliferative effects in human kidney cells. , 2009, Cytokine.

[18]  Mimi Y. Kim,et al.  Expression of endothelial protein C receptor in cortical peritubular capillaries associates with a poor clinical response in lupus nephritis. , 2008, Rheumatology.

[19]  Min Chen,et al.  Autoantibodies against monomeric C-reactive protein in sera from patients with lupus nephritis are associated with disease activity and renal tubulointerstitial lesions. , 2008, Human immunology.

[20]  D. Seligson,et al.  MAGE-B2 Autoantibody: A New Biomarker for Pediatric Systemic Lupus Erythematosus , 2008, The Journal of Rheumatology.

[21]  N. Sebire,et al.  Glomerular expression of monocyte chemoattractant protein-1 is predictive of poor renal prognosis in pediatric lupus nephritis. , 2008, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[22]  F. Dammacco,et al.  Overexpression of interleukin‐12 and T helper 1 predominance in lupus nephritis , 2008, Clinical and experimental immunology.

[23]  C. Bao,et al.  Association of elevated transcript levels of interferon-inducible chemokines with disease activity and organ damage in systemic lupus erythematosus patients , 2008, Arthritis research & therapy.

[24]  H. Nagaraja,et al.  Biomarkers of lupus nephritis determined by serial urine proteomics. , 2008, Kidney international.

[25]  D. Bolignano,et al.  Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage. , 2008, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[26]  R. Cervera,et al.  Anti-chromatin (anti-nucleosome) antibodies: diagnostic and clinical value. , 2008, Autoimmunity reviews.

[27]  S. Quaglini,et al.  Are laboratory tests useful for monitoring the activity of lupus nephritis? A 6-year prospective study in a cohort of 228 patients with lupus nephritis , 2008, Annals of the rheumatic diseases.

[28]  Ming-hui Zhao,et al.  Anti-C1q antibodies and IgG subclass distribution in sera from Chinese patients with lupus nephritis. , 2008, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[29]  D. Bolignano,et al.  Neutrophil Gelatinase-Associated Lipocalin Reflects the Severity of Renal Impairment in Subjects Affected by Chronic Kidney Disease , 2008, Kidney and Blood Pressure Research.

[30]  J. Winkles The TWEAK–Fn14 cytokine–receptor axis: discovery, biology and therapeutic targeting , 2008, Nature Reviews Drug Discovery.

[31]  M. Klein-Gitelman,et al.  Neutrophil gelatinase-associated lipocalin as a biomarker of disease activity in pediatric lupus nephritis , 2008, Pediatric Nephrology.

[32]  Chandra Mohan,et al.  Elevated Urinary VCAM-1, P-Selectin, Soluble TNF Receptor-1, and CXC Chemokine Ligand 16 in Multiple Murine Lupus Strains and Human Lupus Nephritis1 , 2007, The Journal of Immunology.

[33]  G. Ross,et al.  Identification of a urinary proteomic signature for lupus nephritis in children , 2007, Pediatric Nephrology.

[34]  C. Putterman,et al.  Lipocalin‐2, TWEAK, and Other Cytokines as Urinary Biomarkers for Lupus Nephritis , 2007, Annals of the New York Academy of Sciences.

[35]  C. Putterman,et al.  Anti-alpha-actinin antibodies: a new marker of lupus nephritis. , 2007, Autoimmunity reviews.

[36]  M. Labrador-Horrillo,et al.  Activation of the signal transducer and activator of transcription-1 in diffuse proliferative lupus nephritis , 2007, Lupus.

[37]  L. Wang,et al.  Urinary levels of RANTES and M-CSF are predictors of lupus nephritis flare , 2007, Inflammation Research.

[38]  C. Putterman,et al.  Urinary lipocalin-2 is associated with renal disease activity in human lupus nephritis. , 2007, Arthritis and rheumatism.

[39]  Yoshiya Tanaka,et al.  Activation signal transduction by beta1 integrin in T cells from patients with systemic lupus erythematosus. , 2007, Arthritis and rheumatism.

[40]  G. Sturfelt,et al.  Glomerular apoptotic nucleosomes are central target structures for nephritogenic antibodies in human SLE nephritis. , 2007, Kidney international.

[41]  M. Abdel-Rahim,et al.  Intercellular adhesion molecules in systemic lupus erythematosus patients with lupus nephritis , 2007, Clinical Rheumatology.

[42]  M. Tai,et al.  Elevated serum anti-endothelial cell autoantibodies titer is associated with lupus nephritis in patients with systemic lupus erythematosus. , 2007, Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi.

[43]  J. Małyszko,et al.  Hepcidin in Anemia and Inflammation in Chronic Kidney Disease , 2007, Kidney and Blood Pressure Research.

[44]  M. Davies,et al.  Serum protein oxidation and apolipoprotein CIII levels in people with systemic lupus erythematosus with and without nephritis , 2007, Free radical research.

[45]  B. Rovin,et al.  Urinary TWEAK and the activity of lupus nephritis. , 2006, Journal of autoimmunity.

[46]  R. Edwards,et al.  Urinary proteomic profiles distinguish between active and inactive lupus nephritis. , 2006, Rheumatology.

[47]  Fabian D. G. McGrath,et al.  A prospective study of anti-chromatin and anti-C1q autoantibodies in patients with proliferative lupus nephritis treated with cyclophosphamide pulses or azathioprine/methylprednisolone , 2006, Annals of the rheumatic diseases.

[48]  S. Sadallah,et al.  High prevalence of anti-C1q antibodies in biopsy-proven active lupus nephritis. , 2006, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[49]  O. Rekvig,et al.  Alpha-actinin-binding antibodies in relation to systemic lupus erythematosus and lupus nephritis , 2006, Arthritis research & therapy.

[50]  C. Mok Therapeutic options for resistant lupus nephritis. , 2006, Seminars in arthritis and rheumatism.

[51]  A. Hammad,et al.  Transforming growth factor beta 1 in children with systemic lupus erythematosus: a possible relation with clinical presentation of lupus nephritis , 2006, Lupus.

[52]  D. Witte,et al.  Urinary neutrophil gelatinase-associated lipocalin as a biomarker of nephritis in childhood-onset systemic lupus erythematosus. , 2006, Arthritis and rheumatism.

[53]  C. Putterman,et al.  Association of α-actinin–binding anti–double-stranded DNA antibodies with lupus nephritis , 2006 .

[54]  J. Zavadil,et al.  Nephritogenic anti-DNA antibodies regulate gene expression in MRL/lpr mouse glomerular mesangial cells. , 2006, Arthritis and rheumatism.

[55]  P. Horák,et al.  C1q complement component and -antibodies reflect SLE activity and kidney involvement , 2006, Clinical Rheumatology.

[56]  V. Mai,et al.  Urinary neutrophil gelatinase-associated lipocalcin in D+HUS: a novel marker of renal injury , 2006, Pediatric Nephrology.

[57]  F. Lai,et al.  The effect of immunosuppressive therapy on the messenger RNA expression of target genes in the urinary sediment of patients with active lupus nephritis. , 2006, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[58]  E. Bonfá,et al.  Antibodies to ribosomal P proteins: a potential serologic marker for lupus membranous glomerulonephritis. , 2006, Arthritis and rheumatism.

[59]  S. Bombardieri,et al.  Prevalence and clinico-serological correlations of anti-alpha-enolase, anti-C1q, and anti-dsDNA antibodies in patients with systemic lupus erythematosus. , 2006, The Journal of rheumatology.

[60]  S. Eiam‐Ong,et al.  Measurement of urinary chemokine and growth factor messenger RNAs: a noninvasive monitoring in lupus nephritis. , 2006, Kidney international.

[61]  C. Putterman,et al.  Proinflammatory Effects of Tweak/Fn14 Interactions in Glomerular Mesangial Cells1 , 2006, The Journal of Immunology.

[62]  S. Varghese,et al.  Prediction of urinary protein markers in lupus nephritis. , 2005, Kidney international.

[63]  M. Trendelenburg Antibodies against C1q in patients with systemic lupus erythematosus , 2005, Springer Seminars in Immunopathology.

[64]  M. Petri,et al.  Incidence and risk factors of thromboembolism in systemic lupus erythematosus: a comparison of three ethnic groups. , 2005, Arthritis and rheumatism.

[65]  R. Sinico,et al.  Anti‐C1q Autoantibodies in Lupus Nephritis: Prevalence and Clinical Significance , 2005, Annals of the New York Academy of Sciences.

[66]  Qing Ma,et al.  Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery , 2005, The Lancet.

[67]  R. Voll,et al.  Impaired clearance of dying cells in systemic lupus erythematosus. , 2005, Autoimmunity reviews.

[68]  E. Beutler,et al.  Regulation of hepcidin transcription by interleukin-1 and interleukin-6. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[69]  H. Nagaraja,et al.  Urine chemokines as biomarkers of human systemic lupus erythematosus activity. , 2005, Journal of the American Society of Nephrology : JASN.

[70]  C. Putterman,et al.  Cross-reactivity of human lupus anti-DNA antibodies with α-actinin and nephritogenic potential , 2005 .

[71]  C. Mok Prognostic factors in lupus nephritis , 2005, Lupus.

[72]  C. Mok,et al.  Incidence and predictors of renal disease in Chinese patients with systemic lupus erythematosus. , 2004, The American journal of medicine.

[73]  F. Lai,et al.  Expression of chemokine and fibrosing factor messenger RNA in the urinary sediment of patients with lupus nephritis. , 2004, Arthritis and rheumatism.

[74]  Z. Amoura,et al.  Nucleosomes in the pathogenesis of systemic lupus erythematosus. , 2004, Rheumatic diseases clinics of North America.

[75]  B. Croker,et al.  Strong association of a functional polymorphism in the monocyte chemoattractant protein 1 promoter gene with lupus nephritis. , 2004, Arthritis and rheumatism.

[76]  K. Mori,et al.  Neutrophil Gelatinase-Associated Lipocalin: A Novel Early Urinary Biomarker for Cisplatin Nephrotoxicity , 2004, American Journal of Nephrology.

[77]  D. Isenberg,et al.  Is α-actinin a target for pathogenic anti-DNA antibodies in lupus nephritis? , 2004 .

[78]  L. Trouw,et al.  Diagnostic and prognostic significance of anti-C1q antibodies in systemic lupus erythematosus , 2003, Current opinion in nephrology and hypertension.

[79]  M. Mitsnefes,et al.  Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. , 2003, Journal of the American Society of Nephrology : JASN.

[80]  J. Miyazaki,et al.  Antagonist of monocyte chemoattractant protein 1 ameliorates the initiation and progression of lupus nephritis and renal vasculitis in MRL/lpr mice. , 2003, Arthritis and rheumatism.

[81]  M. García-Carrasco,et al.  Anti-chromatin antibodies in systemic lupus erythematosus: a useful marker for lupus nephropathy , 2003, Annals of the rheumatic diseases.

[82]  Elizabeta Nemeth,et al.  Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. , 2003, Blood.

[83]  W. Mccune,et al.  The Apoptotic Ligands TRAIL, TWEAK, and Fas Ligand Mediate Monocyte Death Induced by Autologous Lupus T Cells1 , 2002, The Journal of Immunology.

[84]  C. Putterman,et al.  α-Actinin Is a Cross-Reactive Renal Target for Pathogenic Anti-DNA Antibodies1 , 2002, The Journal of Immunology.

[85]  S. Quaglini,et al.  Anti-C1q antibodies may help in diagnosing a renal flare in lupus nephritis. , 2001, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[86]  G. Burmester,et al.  Nucleosomes are major T and B cell autoantigens in systemic lupus erythematosus. , 2000, Arthritis and rheumatism.

[87]  B. Rollins,et al.  Monocyte Chemoattractant Protein 1–Dependent Leukocytic Infiltrates Are Responsible for Autoimmune Disease in Mrl-Faslpr Mice , 1999, The Journal of experimental medicine.

[88]  R. Falk,et al.  Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Glomerular Disease Collaborative Network. , 1997, Kidney international.

[89]  B. Rovin,et al.  Monocyte chemoattractant protein-1 levels in patients with glomerular disease. , 1996, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[90]  K. Matsushima,et al.  Monitoring urinary levels of monocyte chemotactic and activating factor reflects disease activity of lupus nephritis. , 1996, Kidney international.

[91]  G. Remuzzi,et al.  Monocyte chemoattractant protein-1 is excreted in excessive amounts in the urine of patients with lupus nephritis. , 1995, Laboratory investigation; a journal of technical methods and pathology.

[92]  F. Breedveld,et al.  Predictive value of IgG autoantibodies against C1q for nephritis in systemic lupus erythematosus. , 1993, Annals of the rheumatic diseases.

[93]  A D GUNN,et al.  Case of Anaphylaxis after Anaesthesia , 1943, British medical journal.

[94]  R. Burlingame,et al.  Anti‐C1q antibodies: association with nephritis and disease activity in systemic lupus erythematosus , 2009, Journal of clinical laboratory analysis.

[95]  Andreas Radbruch,et al.  CXCR3+CD4+ T cells are enriched in inflamed kidneys and urine and provide a new biomarker for acute nephritis flares in systemic lupus erythematosus patients. , 2009, Arthritis and rheumatism.

[96]  S. Shaftman,et al.  Association of serum nitrate and nitrite levels with longitudinal assessments of disease activity and damage in systemic lupus erythematosus and lupus nephritis. , 2008, Arthritis and rheumatism.

[97]  C. Putterman,et al.  The novel role of neutrophil gelatinase-B associated lipocalin (NGAL)/Lipocalin-2 as a biomarker for lupus nephritis. , 2008, Autoimmunity reviews.

[98]  H. Nagaraja,et al.  Biomarker discovery in human SLE nephritis. , 2007, Bulletin of the NYU hospital for joint diseases.

[99]  J. Bach,et al.  Presence of antinucleosome autoantibodies in a restricted set of connective tissue diseases: antinucleosome antibodies of the IgG3 subclass are markers of renal pathogenicity in systemic lupus erythematosus. , 2000, Arthritis and rheumatism.