Elsevier

Autoimmunity Reviews

Volume 5, Issue 6, July 2006, Pages 383-388
Autoimmunity Reviews

Urinary biomarkers in lupus nephritis

https://doi.org/10.1016/j.autrev.2005.10.006Get rights and content

Abstract

There has long been a need for biomarkers of disease activity in lupus nephritis (LN). Such markers ideally would be capable of detecting early sub-clinical disease and could be used to gauge response to therapy thus obviating the need for serial renal biopsies. Since urine can be readily obtained it lends itself as an obvious biological sample. Much of the focus has been on the measurement of urinary chemokines and cytokines in patients with LN. Elevations in urinary IL-6 and IL-10 had initially been reported to be associated with disease activity in LN but these markers have proven to be less reliable in larger studies. We and others have recently reported that MCP-1, a key chemokine involved in monocyte chemotaxis can be consistently found at high levels in the urine of patients with active LN. Moreover urinary MCP-1 levels decline with treatment of nephritis. In contrast urinary IL-8, a chemokine involved primarily in neutrophil chemotaxis is not a good predictor of disease activity in LN. Further longitudinal studies with larger numbers of patients are needed to determine the utility of urinary biomarkers such as MCP-1 which may act as surrogates of ongoing inflammation in LN.

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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