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.
Glomerulonephritis is one of the commonest and most serious manifestations of systemic lupus erythematosus (SLE) [
Despite the overall improvement in the care of SLE in the past two decades, the prognosis of lupus nephritis remains unsatisfactory. Up to 25% of patients still develop end stage renal failure 10 years after onset of renal disease [
Current laboratory markers for lupus nephritis such as proteinuria, urine protein-to-creatinine ratio, creatinine clearance, anti-dsDNA, and complement levels are unsatisfactory. They lack sensitivity and specificity for differentiating renal activity and damage in lupus nephritis. Significant kidney damage can occur before renal function is impaired and first detection by laboratory parameters. Persistent proteinuria may not necessarily indicate ongoing inflammation in the kidneys and may be contributed by pre-existing chronic lesions or recent damage in the kidneys during the course of the disease. Flares of nephritis can occur without any observable and recent increase in the degree of proteinuria. Renal biopsy is the gold standard for providing information on the histological classes of lupus nephritis and the relative degree of activity and chronicity in the glomeruli. However, it is invasive and serial biopsies that are impractical in the monitoring of lupus nephritis. Thus, novel biomarkers that are able to discriminate lupus renal activity and its severity, predict renal flares, and monitor treatment response and disease progress are clearly necessary.
A biomarker refers to a biologic, biochemical, or molecular event that can be assayed qualitatively and quantitatively by laboratory techniques. The levels of biomarkers should correlate with disease pathogenesis or activity in different organ systems. An ideal biomarker for lupus nephritis should possess the following properties: (
Hitherto, quite a number of serum and urine biomarkers have been studied in lupus nephritis. Most of these markers have only been tested in cross-sectional studies and only a few have been evaluated in longitudinal studies. The number of patients having been tested is relatively small and the results have not been confirmed by independent groups of investigators. Even for biomarkers that have been prospectively evaluated, further validation has to be performed in larger groups of patients with lupus nephritis.
In this paper, biomarkers that have been recently studied in lupus nephritis are systematically reviewed. Information is grouped under three subheadings: (
Monocyte chemoattractant protein-1 (MCP-1) is a leukocyte chemotactic factor that is involved in mediating inflammation and injury in lupus nephritis [
Level of MCP-1 in urine is increased in patients with a variety of glomerulonephritis and correlates with the extent of proteinuria and the severity of glomerular lesions [
Rovin et al. [
Similar findings of uMCP-1 in lupus nephritis were reported by Tian et al. [
Overall, uMCP-1 is a promising biomarker for lupus nephritis. It is specific for renal activity, sensitive to predict renal flares and correlates with severity of flares and proliferative types of lupus nephritis. However, further longitudinal validation of uMCP-1 in larger cohorts of patients with lupus nephritis is necessary.
Lipocalin-2 is a small glycosylated protein produced in many tissues and organs. Lipocalin-2 was first described in human neutrophil granules as neutrophil gelatinase-associated lipocalin (NGAL). NGAL belongs to a family of carrier proteins that are important for cellular iron transport, apoptosis, bacteriostasis, and tissue differentiation. NGAL is constitutively expressed at low levels in the kidneys [
Two cross-sectional studies have examined the relationship between NGAL levels and human lupus nephritis [
Longitudinal data on NGAL in lupus nephritis are recently available. Suzuki et al. [
Another longitudinal study on NGAL was carried out in 111 pediatric SLE patients [
Finally, a more recent longitudinal study confirmed that urine NGAL level was a significant predictor of renal disease activity in SLE patients and a significant predictor for flares in patients with a history of biopsy-proven nephritis [
Tumor necrosis factor- (TNF-) like inducer of apoptosis (TWEAK) is a multifunctional cytokine that belongs to the TNF-ligand superfamily. The main source of soluble TWEAK is believed to be the macrophages. TWEAK binds to its cognate receptor, Fn14, in various tissues and mediates a number of physiological processes such as cellular proliferation, survival, differentiation, migration, and angiogenesis [
It is recently shown that ex vivo stimulation of murine and human kidney cells by TWEAK induces the expression of chemokines and inflammatory mediators such as MCP-1, RANTES, IFN-gamma-induced protein 10 (IP-10), ICAM-1, and VCAM-1 [
A pilot cross-sectional study demonstrated that urinary TWEAK (uTWEAK) levels were significantly higher in SLE patients with active nephritis as compared to those with inactive or no nephritis [
A further multicenter longitudinal study involving 30 biopsy-proven lupus nephritis patients and five control groups (normal, nonrenal SLE, rheumatoid arthritis, osteoarthritis and, non-SLE renal diseases) showed that uTWEAK levels were significantly higher in patients with lupus nephritis than nonrenal SLE, rheumatoid arthritis, and healthy controls [
Thirteen patients with flares of lupus nephritis were longitudinally evaluated. The uTWEAK levels peaked at the time of flares, with an increasing trend before the flares and a decreasing trend after the flare events. The uTWEAK levels were significantly higher during renal flares than those values 4–6 months before and after the flares. A significant association between uTWEAK levels in SLE patients and their renal disease activity scores over time was also found. However, the small increase in the levels of uTWEAK 2 months before renal flares from baseline was not statistically significant.
Overall, although uTWEAK is a promising biomarker for lupus nephritis because of its high specificity for lupus renal disease and good correlation with renal disease activity, it may not be sensitive enough to predict a renal flare early and cannot replace the need for a renal biopsy.
Suzuki et al. [
Using a similar technique, Mosley et al. [
In a further validation study, Suzuki et al. [
Hepcidin is a low-molecular-weight peptide hormone mainly produced by the liver. Hepcidin has antimicrobial activity, regulates iron metabolism, and is thought to be involved in the pathogenesis of anemia of chronic illness including chronic kidney disease [
C1q is the first component of the classical pathway of the complement system. C1q plays a crucial role in the clearance of immune complexes and apoptotic bodies [
Anti-C1q antibodies are present in 20%–44% of patients with SLE in cross-sectional studies and are associated with the presence of nephritis [
Two recent prospective studies examined the value of anti-C1q antibodies in monitoring of activity of lupus nephritis and predicting flares [
Moroni et al. [
Although an elevation of anti-C1q titer is shown to predict the development of lupus nephritis or renal flares in these studies, its performance is not significantly better than that of anti-dsDNA and complement levels. The high negative predictive value of anti-C1q for severe renal disease may be helpful for prognostic stratification of SLE patients. The usefulness of anti-C1q level in monitoring of lupus activity in patients with negative anti-dsDNA antibodies has to be further explored.
Nucleosomes released by apoptotic cells are major T and B cell autoantigens in SLE [
A recent review summarizes 13 cross-sectional studies of antinucleosome antibodies in lupus [
The change in antinucleosome antibodies over time in 52 patients with active proliferative lupus nephritis treated with high-dose glucocorticoids and either cyclophosphamide or azathioprine in a prospective controlled clinical trial was studied [
In another more recent study, 16 patients with biopsy-confirmed lupus nephritis were prospectively evaluated for the relationship between antinucleosome titers and parameters of renal disease activity [
Alpha-actinin-4 belongs to a family of actin-binding proteins that is expressed by podocytes and mesangial cells in renal tissues [
Two cross-sectional studies have examined the association between anti-
A recent prospective study by Manson et al. [
Although newer autoantibodies are available and useful for the monitoring of lupus nephritis activity, they are generally not more sensitive than conventional markers such as anti-dsDNA and complements in predicting renal flares. The usefulness of these autoantibodies in the monitoring of disease activity in subsets of SLE patients in whom conventional markers are negative has yet to be studied. The performance of a panel of conventional and novel autoantibodies in the diagnosis, monitoring, and prognostic stratification of lupus nephritis has to be evaluated in the future.
Literature search reveals quite a number of cross-sectional studies on the relationship between novel biomarkers and activity of lupus nephritis [
Serum biomarkers that correlate with lupus nephritis activity in cross-sectional studies.
Authors, year | Biomarkers studied | Main findings |
---|---|---|
Hoftman et al., 2008 [ | MAGE-B2 antibodies | Positive melanoma-associated antigen gene B2 (MAGE-B2) antibody associated with higher SLE disease activity score and active lupus nephritis |
Tan et al., 2008 [ | Anti-CRP antibody | IgG autoantibody against monomeric CRP prevalent in patients with lupus nephritis and associated with SLE disease activity score and renal tubulointerstitial lesions |
Tucci et al., 2008 [ | Serum and urine IL-12 | Glomerular expression of IL-12 predominantly occurs in class IV and V lupus nephritis, serum and urine IL-12 higher in lupus nephritis than nonrenal SLE |
Fu et al., 2008 [ | Peripheral blood leukocyte chemokine transcriptional levels | Interferon-inducible chemokines in peripheral blood leucocytes higher in active than inactive lupus nephritis and associated with SLE disease activity score |
Morgan et al., 2007 [ | Serum apoCIII | Total apolipoprotein (apo) CIII levels significantly elevated in lupus nephritis than nonrenal SLE and controls |
Sabry et al., 2007 [ | Serum ICAM-1 | Intracellular adhesion molecule (ICAM)-1 level significantly higher in lupus nephritis than nonrenal SLE and correlates with disease activity score |
Tseng et al., 2007 [ | Antiendothelial cell antibody | Antiendothelial cell antibody titer higher in active lupus nephritis than nonrenal SLE and correlates with disease activity score |
Urine biomarkers that correlate with lupus nephritis activity in cross-sectional studies.
Authors, year | Biomarkers studied | Main findings |
---|---|---|
Kiani et al., 2009 [ | Urine osteoprotegerin (OPG) | OPG strongly associated with renal activity descriptors of the SELENA SLEDAI; medium/high levels of OPG predictive of a urine protein/creatinine ratio of |
Wang et al., 2009 [ | FOXP3 mRNA expression in urinary sediments | FOXP3 mRNA expression significantly higher in active than inactive lupus nephritis, and in proliferative than nonproliferative nephritis, FOXP3 mRNA level correlated with proteinuria and histological activity index; persistent elevation associated with poor treatment response |
Dhaun et al., 2009 [ | Urine endothelin-1 | Fractional excretion of endothelin-1 and urinary endothelin-1/creatinine ratio higher in lupus nephritis than other chronic inflammatory renal diseases when renal function is normal |
Enghard et al., 2009 [ | Urine CXCR3+CD4+T cells | Urinary CXCR3+CD4+ T cells are enriched in lupus nephritis and correlated with SLE disease activity; higher concentration of urinary CXCR3+CD4+ T cells is found in active than inactive nephritis |
Tucci et al., 2008 [ | Serum and urine IL-12 | Glomerular expression of IL-12 predominantly occurs in class IV and V lupus nephritis; serum and urine IL-12 higher in lupus nephritis than nonrenal SLE |
Wu et al., 2007 [ | Urine VCAM-1, P-selectin, TNFR-1, and CXCL16 | Urinary VCAM-1, P-selectin, TNFR-1, and CXCL16 elevated in lupus nephritis, correlating with proteinuria and SLE disease activity scores; urinary VCAM-1 and CXCL16 showed superior specificity and sensitivity in distinguishing subjects with active renal disease from the other SLE patients. |
Hammad et al., 2006 [ | Urine TGF | Urinary TGF |
Chan et al., 2004 [ | TGF | Urinary TGF |
Tables
Biomarkers that correlate with histological findings in lupus nephritis.
Authors, year | Biomarkers studied | Main findings |
---|---|---|
Oates et al., 2008 [ | Serum nitrate and nitrite levels | Serum nitrate plus nitrite levels associated with SLE disease activity score; higher nitrate/nitrite levels associated with histological proliferative renal lesions |
Marks et al., 2008 [ | Glomerular MCP-1 expression | Glomerular monocyte chemoattractant protein-1 (MCP-1) expression higher in class III and class IV than other classes of lupus nephritis |
Nakayamada et al., 2007 [ | CD29 expression on T cells upregulated in active SLE, especially in active diffuse proliferative lupus nephritis | |
Avihingsanon et al., 2006 [ | Chemokine and growth factor mRNA levels in urinary sediments | Urine interferon-producing protein 10 (IP-10), CXCR3, TGF- |
do Nascimento et al., 2006 [ | Antiribosomal P antibody | Frequency of antiribosomal P antibody higher in class V than other classes of lupus nephritis |
Oates et al., 2005 [ | Urine glycoprotein panel | An urinary glycoprotein panel may help to differentiate different histological classes of lupus nephritis |
Biomarkers that correlate with prognosis in lupus nephritis.
Authors, year | Biomarkers studied | Main findings |
---|---|---|
Izmirly et al., 2009 [ | mEPCR expression on renal biopsy | Membrane expression of endothelial protein C receptor (mEPCR) in the renal microvasculature in lupus nephritis associated with poor therapeutic response |
Avihingsanon et al., 2009 [ | VEGF expression | Intrarenal vascular endothelial growth factor (VEGF) mRNA expression predicted the deterioration of renal function in lupus nephritis |
Marks et al., 2008 [ | Glomerular MCP-1 expression | Glomerular monocyte chemoattractant protein-1 (MCP-1) expression associated with poor renal prognosis in pediatric lupus nephritis |
Oates et al., 2008 [ | Serum nitrate and nitrite levels | Higher serum nitrate plus nitrite levels associated with renal damage and treatment failure in lupus nephritis |
Martinez-Lostao et al., 2007 [ | STAT-1 expression on renal biopsy | Expression of STAT-1 in renal tissues associated with worse renal function and outcome in class IV lupus nephritis |
Avihingsanon et al., 2006 [ | Chemokine and growth factor mRNA levels in urinary sediments | Persistent elevation or increase of urine interferon-producing protein 10 (IP-10), CXCR3, TGF- |
Although a large number of novel biomarkers have been studied in lupus nephritis, none of them have been rigorously validated in large-scale longitudinal cohorts of patients with different ethnic background. It is unlikely at this juncture that a candidate biomarker stand-alone can replace conventional clinical parameters to monitor disease progress and detect early renal flares. Urine biomarkers appear to be more encouraging than serum biomarkers possibly because they are the direct products or consequences of kidney inflammation or injury. Future directions in SLE biomarker research should focus on a combination of novel markers with conventional clinical parameters to enhance the sensitivity and specificity for the prediction of renal flares and prognosis in lupus nephritis.