Ytterberg, Steven R.

Abstract Background Prior work has shown that urinary soluble CD163 (usCD163) displays excellent biomarker characteristics for detection of active renal vasculitis using samples that included new diagnoses with highly active renal disease. This study focused on the use of usCD163 in the detection of the more clinically relevant state of mild renal flare and compared results of usCD163 testing directly to testing of urinary monocyte chemoattractant protein-1 (uMCP-1). Methods Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV, n = 88) were identified within a serially sampled, longitudinal and multicentre cohort. Creatinine-normalized usCD163 and uMCP-1 levels were measured by enzyme-linked immunosorbent assay and, both alone and in combination, were compared between times of active renal AAV and during remission and/or active non-renal AAV. Results Samples from 320 study visits included times of active renal vasculitis (n = 39), remission (n = 233) and active extrarenal vasculitis (n = 48). Median creatinine levels were 0.9 mg/dL [interquartile range (IQR) 0.8–1.2] in remission and 1.4 mg/dL (IQR 1.0–1.8) during renal flare. usCD163 levels were higher in patients with active renal vasculitis compared with patients in remission and those with active extrarenal vasculitis, with median values of 162 ng/mmol (IQR 79–337), 44 (17–104) and 38 (7–76), respectively (P < 0.001). uMCP-1 levels were also higher in patients with active renal vasculitis compared with patients in remission and those with active extrarenal vasculitis, with median values of 10.6 pg/mmol (IQR 4.6–23.5), 4.1 (2.5–8.4) and 4.1 (1.9–6.8), respectively (P < 0.001). The proposed diagnostic cut-points for usCD163 and uMCP-1 were 72.9 ng/mmol and 10.0 pg/mmol, respectively. usCD163 and uMCP-1 levels were marginally correlated (r2 = 0.11, P < 0.001). Combining novel and existing biomarkers using recursive tree partitioning indicated that elevated usCD163 plus either elevated uMCP-1 or new/worse proteinuria improved the positive likelihood ratio (PLR) of active renal vasculitis to 19.2. Conclusion A combination of usCD163 and uMCP-1 measurements appears to be useful in identifying the diagnosis of subtle renal vasculitis flare.

ObjectiveTo examine the association between macrophage migration inhibitory factor (MIF) promoter polymorphisms and granulomatosis with polyangiitis (GPA) in human subjects, and to assess the role of MIF in a murine model of granulomatous vasculitis.MethodsThe human study involved 1,077 patients with GPA and healthy controls whose serum was genotyped by capillary electrophoresis for the MIF −794 CATT5−8 promoter microsatellite (rs5844572). MIF promoter, CATT‐length–dependent gene expression in response to β‐glucan was assessed by gene reporter assays. In mouse studies, granulomatous disease was induced by injection of Candida albicans β‐glucan into wild‐type (WT) or Mif‐knockout (Mif‐KO) C57BL/6 mice and C57BL/6 mice transgenically overexpressing Mif in lung epithelium (Mif lung–Tg2.1). Mice were treated with a neutralizing anti‐MIF antibody and analyzed for the density of pulmonary granulomas, expression of inflammatory chemokines, and frequency of mortality.ResultsThe percentage of human subjects carrying >5 CATT repeats in each MIF allele (high genotypic MIF expressers) was 60.2% among patients with GPA and 53.9% among healthy controls (adjusted P = 0.049). In response to granulomatous stimulation, human MIF gene expression increased proportionally with CATT length. Mif lung–Tg2.1 mice exhibited more pulmonary granulomas than WT mice, which in turn showed more granulomas than Mif‐KO mice. A significantly higher percentage of Mif lung–Tg2.1 mice, compared to Mif‐KO or WT mice, died when injected with Candida albicans β‐glucan, and treatment of these mice with an anti‐MIF monoclonal antibody protected against a lethal outcome. Levels of MIF‐dependent neutrophil/macrophage chemokines were elevated in the bronchoalveolar lavage fluid or plasma of Mif lung–Tg2.1 mice.ConclusionPatients with GPA have an increased frequency of high MIF expression CATT alleles. Higher Mif expression increases the incidence of mortality and pulmonary granulomas in Mif lung–Tg2.1 mice, while anti‐MIF treatment protects these mice against death. Blockade of MIF in high genotypic MIF expressers may therefore offer a selective pharmacologic therapy for GPA.