Urine Chemokines as Biomarkers of Human Systemic Lupus Erythematosus Activity

Abstract

The purpose of this study was to evaluate urine monocyte chemoattractant protein-1 (MCP-1) and IL-8 as biomarkers of SLE flare. Urine was collected every 2 mo from patients who were followed prospectively in the Ohio SLE Study. Renal and nonrenal flares were identified and MCP-1 and IL-8 were measured by specific ELISA in samples that were collected at flare. When available, MCP-1 and IL-8 were also measured in urine samples before and after flare. For comparison, MCP-1 and IL-8 were measured in the urine of healthy individuals and in renal and nonrenal SLE patients with stable disease activity (disease controls). Most patients were receiving maintenance immunosuppressive therapy before flare. At renal flare, mean urine MCP-1 (uMCP-1) was significantly greater than uMCP-1 at nonrenal flare and from healthy volunteers and renal disease controls. The level of uMCP-1 correlated with the increase in proteinuria at flare and was higher in patients with proliferative glomerulonephritis and in patients with impaired renal function. Urine MCP-1 was increased beginning 2 to 4 mo before flare. Patients who responded to therapy showed a slow decline in uMCP-1 over several months, whereas nonresponders had persistently high uMCP-1. In contrast, uIL-8 did not change with disease activity and was not elevated at renal or nonrenal flare compared with disease controls. In conclusion, uMCP-1 but not uIL-8 is a sensitive and specific biomarker of renal SLE flare and its severity, even in patients who receive significant immunosuppressive therapy. Persistently elevated uMCP-1 after treatment may indicate ongoing kidney injury that may adversely affect renal prognosis. S ubstantial animal and human evidence suggests that chemokines, in particular monocyte chemoattractant protein-1 (MCP-1) and IL-8, contribute to kidney injury in the glomerulonephritis (GN) of SLE (reviewed in 1,2). In murine models of SLE GN, genetic deletion or pharmacologic blockade of MCP-1 attenuates glomerular and interstitial inflammation and reduces kidney damage (3-5). In humans with SLE GN, MCP-1 and IL-8 are expressed in the kidneys, and their transcripts can be detected by in situ hybridization, confirming intrarenal chemokine production (6 -8). Furthermore, urine MCP-1 and IL-8 (uMCP-1, uIL-8) levels are increased in SLE patients during active renal disease and in some reports decrease with treatment-induced disease remission (6,7,9 -11). Thus, uMCP-1, uIL-8, or both may be clinically relevant biomarkers of SLE GN. To date, however, the association of urine chemokines with renal and nonrenal SLE activity has not been examined rigorously through serial measurement of chemokine levels before, during, and after disease flares. This study was undertaken to investigate the relationship of uMCP-1 and uIL-8 to the onset, severity, and resolution of SLE flare in a cohort of well-characterized patients who were followed in the Ohio SLE Study (OSS), a prospective longitudinal investigation of risk factors for SLE flare in patients with renal or nonrenal SLE. Mate...

Biomarkers in systemic lupus erythematosus: challenges and prospects for the future

“…Several more recent studies, both cross-sectional and longitudinal, have confirmed those findings [Kiani et al 2009;Rovin et al 2005;Tian et al 2007;Tucci et al 2004]. For example, in a study conducted by Rovin and colleagues [Rovin et al 2005], it was shown that uMCP-1 level was a sensitive indicator for renal flare, with 73% of the uMCP-1 levels measured at renal flares higher than the 95th percentile of the disease controls. uMCP-1 levels did not correlate with extrarenal disease activity.…”

Mathematical model of renal interstitial fibrosis

“…Tubulointerstitial fibrosis involving less than 10% of the renal cortex was considered mild, fibrosis involving between 10% and 25% of the cortex was considered moderate, and fibrosis involving over 25% of the cortex was considered severe. Urine MCP-1 was measured by specific ELISA as we have described previously (38). Urine TGF-β was also measured by specific ELISA obtained from R&D Systems.…”

Renal Flare as a Predictor of Incident and Progressive CKD in Patients with Lupus Nephritis

“…The OSS has been described previously (11,12). Patients in the OSS were followed from 2001 to 2009, with a median duration of follow-up of 6 years.…”

“…The specific changes of disease activity (proteinuria, SCr, and urine sediment) required to diagnose a flare have been previously published (11). In the OSS, flares were divided into mild, moderate, and severe, and specific treatment guidelines were applied to each level of flare (11,12). Flares were not divided into nephritic and proteinuric, and treatment was not based on the nephritic/ proteinuric designation.…”

“…We, therefore, consider all LN flares to be potentially detrimental to long-term renal health. To test this theory, we examined the association of LN flares with new or progressive CKD in the Ohio Systemic Lupus Erythematosus Study (OSS), a prospectively followed observational cohort that has been clinically and phenotypically well characterized (11).…”