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Urine Macrophage Migration Inhibitory Factor Reflects the Severity of Renal Injury in Human Glomerulonephritis

Fiona G. Brown^*, David J. Nikolic-Paterson^*, Prudence A. Hill, Nicole M. Isbel^*, John Dowling, Christine M. Metz^¶ and Robert C. Atkins^*

*Department of Nephrology and Department of Anatomical Pathology, Monash University Department of Medicine, Monash Medical Centre, Clayton, Australia; Department of Anatomy and Cell Biology, University of Melbourne, Victoria, Australia; and ^¶The Picower Institute for Medical Research, Manhasset, New York.

Correspondence to Dr. Fiona G. Brown, Department of Nephrology, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. Phone: +61-3-9594 3525; Fax: +61-3-9594 6530; E-mail: Fiona.Brown{at}med.monash.edu.au

Abstract

ABSTRACT. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a pathogenic role in experimental crescentic glomerulonephritis (GN). Renal expression of MIF is also upregulated in human GN and correlates with leukocytic infiltration, histologic damage, and renal dysfunction. The study presented here examined whether MIF can be measured in urine and if so, whether the urine MIF concentration reflects the degree of renal injury. Urine and serum MIF was measured by enzyme-linked immunosorbent assay in 10 normal healthy volunteers and in a cohort of 63 patients with GN (2 thin basement membrane disease [TBM], 15 membranous GN, 10 focal segmental glomerular sclerosis, 20 IgA glomerularnephritis, 11 crescentic GN, 10 systemic lupus erythematosis World Health Organization class IV). Renal MIF expression was assessed by immunostaining of biopsy tissue. MIF was detected in urine from normal volunteers (mean ± SD; 191 ± 132 pg MIF/µmol creatinine). The urine MIF concentration was unchanged in patients with nonproliferative nephropathies (343 ± 397 pg MIF/µmol Cr) but was increased 3.4-fold in proliferative nephropathies (645 ± 527 pg MIF/µmol Cr; P < 0.05 versus normal and nonproliferative). Stratified analysis showed the greatest increase in urine MIF in crescentic GN (4.5-fold). In contrast, serum MIF levels were not different between normal patients and any patient group. Immunostaining demonstrated a significant increase in renal MIF expression in proliferative glomerulonephritides that was associated with macrophage and T cell infiltration. There was a significant correlation between the urine MIF concentration and renal MIF expression, but not with serum MIF, indicating a renal origin for the excreted urine MIF. The urine MIF concentration also correlated with the degree of renal dysfunction, histologic damage, and leukocytic infiltration, but not with the amount of proteinuria. In conclusion, this study shows that the urine MIF concentration is significantly increased in proliferative forms of GN and correlates with the degree of renal injury. Urine MIF levels reflect MIF expression within the kidney and may be a useful noninvasive tool for monitoring patients with crescentic GN, particularly in disease exacerbation.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673