Urinary biomarkers in lupus nephritis
Introduction
Lupus nephritis is a prominent feature in SLE present in 15–30% of patients with lupus at the time of initial diagnosis and 30–50% during disease progression [1]. Present assessment of SLE patients includes a urinalysis, creatinine clearance (Cr/Cl) and measurement of urinary protein. However, these parameters are not predictive of the classification and severity of nephropathy seen at biopsy [2] nor have they been shown to be reliable in evaluating treatment response. Renal biopsy remains the “gold standard” to assess disease severity but multiple biopsies to gauge treatment efficacy are not feasible due to their invasive nature. It has thus become clear that there is a real need for surrogate markers that can predict the degree of renal inflammation. Such biomarkers could be used for both initial detection of renal involvement in SLE and to gauge response to therapy. In this review we will focus on urinary biomarkers of lupus nephritis.
Section snippets
Considerations for the use of urinary molecules as biomarkers
The most important characteristic of any biomarker is that it needs have the ability to predict a “gold standard”. In the case of urine biomarkers of lupus nephritis this “gold standard” could be renal biopsy scores or longer-term outcome defined as either renal death (dialysis, transplantation) or significant deterioration in renal function. Any urinary marker should be superior to existing standards (proteinuria, hematuria) but show significant association with these. Urine as a biological
IL-6
IL-6 is a pleiotropic cytokine produced by a large variety of cells including monocytes, T cells, B cells, endothelial cells, fibroblasts and mesangial cells [3]. IL-6 induces differentiation of B cells into antibody-producing cells [4], the differentiation of T cells into effector cells [5] and the terminal differentiation of macrophages [6]. IL-6 is also a potent inducer of the production of acute phase proteins [7]. In addition to these proinflammatory effects, IL-6 acts as a growth factor
IL-10
IL-10 is another cytokine that has been intensely studied in the pathogenesis of SLE. IL-10 has been shown to be a key factor in regulating autoantibody-secreting B-cell activity in lupus. It is generally thought that this cytokine is involved in the production of autoantibodies in SLE through stimulating proliferation and differentiation of human B cells [13]. Indeed, levels of serum IL-10 in SLE patients have consistently been shown to be 3–12-fold higher than in healthy controls [14].
IL-8
IL-8 (CXCL8) belongs to CXC chemokine subfamily and is predominantly chemotactic for neutrophils. It has been implicated in the recruitment of leukocytes to the glomerulus during immune renal damage [17]. Some studies reported that urinary IL-8 levels are increased in SLE patients with active renal disease [17], [18]. To assess the potential role of neutrophil infiltration in the pathogenesis of LN we measured urinary levels of IL-8 (CXCL8). This CXC cytokine belongs to the ELR containing group
MCP-1
Evidence in both human and animal studies highlights the importance of MCP-1 for renal injury in lupus nephritis [20], [21]. MCP-1-deficient MRL/lpr mice have prolonged survival when compared to MCP-1+/+MRL/lpr mice as they lack renal macrophage and T cell infiltration and are thus protected from renal damage [22], [23]. In human SLE, urinary levels of MCP-1 are markedly elevated in patients with lupus nephritis and the presence of MCP-1 in urine reflects its intrarenal expression [18], [24],
MIP-1α (CCL3) fractalkine (CX3CL1)
MIP-1α is a proinflammatory chemokine with stem cell inhibitory activity [27] that is expressed within the kidney [28]. Mice deficient in this chemokine show markedly decreased inflammatory responses to viral infections but are unable to effectively clear virus [27]. MIP-1α is expressed in crescentic lesions of patients with glomerulonephritis and urinary levels of MIP-1α are elevated in these individuals [28]. A good correlation between the number of infiltrating macrophages (CD68+), the
Summary
The lack of availability of good biomarkers of lupus nephritis has hampered development of new therapies for this chronic disease. We and others have examined several urinary markers of renal disease activity with a focus on molecules involved in local inflammation within the kidney. To date MCP-1 appears to have the best correlation with renal disease activity whereas the other markers examined are of lesser utility. Urine is an easy to obtain biological sample and levels of MCP-1 can be
Acknowledgements
Supported by the National Institutes of Health (grant NIDDK K08 DK02890-02 and NCRR MO1 RR00082) and the Lupus Research Institute NYC.
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