The Clinical Application of Urine Soluble CD163 in ANCA-Associated Vasculitis
Authors: Moran Sarah M. , Scott Jennifer , Clarkson Michael R. , Conlon Niall , Dunne Jean , Griffin Matthew D. , Griffin Tomas P. , Groarke Elizabeth , Holian John , Judge Conor , Wyse Jason , McLoughlin Kirsty , O’Hara Paul V. , Kretzler Matthias , Little Mark A. ,   Nephrotic Syndrome Study Network (NEPTUNE)
Published: September 2021

Significance Statement
In ANCA-associated vasculitis (AAV), noninvasive biomarkers of active renal inflammation, such as urinary soluble CD163, are needed for early detection of active disease before irreversible end organ damage occurs. Clinical translation requires a diagnostic-grade assay, prospective assessment of its diagnostic utility in AAV flare, and assessment of its utility in proteinuric states. The authors report use of an accredited, diagnostic-grade assay for urinary soluble CD163, derivation of cutoff values, and application of the assay to a prospective cohort of patients with potential renal vasculitis flare. They found that urinary soluble CD163 displays high precision in separating RV flare from flare mimics. They also observed increased false-positive results in the setting of high-grade proteinuria, which they demonstrated can be effectively corrected by normalization to the urine protein value, thereby restoring diagnostic accuracy.

Background
Up to 70% of patients with ANCA-associated vasculitis (AAV) develop GN, with 26% progressing to ESKD. Diagnostic-grade and noninvasive tools to detect active renal inflammation are needed. Urinary soluble CD163 (usCD163) is a promising biomarker of active renal vasculitis, but a diagnostic-grade assay, assessment of its utility in prospective diagnosis of renal vasculitis flares, and evaluation of its utility in proteinuric states are needed.

Methods
We assessed a diagnostic-grade usCD163 assay in (1) a real-world cohort of 405 patients with AAV and 121 healthy and 488 non-AAV disease controls; (2) a prospective multicenter study of 84 patients with potential renal vasculitis flare; (3) a longitudinal multicenter cohort of 65 patients with podocytopathy; and (4) a cohort of 29 patients with AAV (with or without proteinuria) and ten controls.

Results
We established a diagnostic reference range, with a cutoff of 250 ng/mmol for active renal vasculitis (area under the curve [AUC], 0.978). Using this cutoff, usCD163 was elevated in renal vasculitis flare (AUC, 0.95) but remained low in flare mimics, such as nonvasculitic AKI. usCD163’s specificity declined in patients with AAV who had nephrotic-range proteinuria and in those with primary podocytopathy, with 62% of patients with nephrotic syndrome displaying a “positive” usCD163. In patients with AAV and significant proteinuria, usCD163 normalization to total urine protein rather than creatinine provided the greatest clinical utility for diagnosing active renal vasculitis.

Conclusions
usCD163 is elevated in renal vasculitis flare and remains low in flare mimics. Nonspecific protein leakage in nephrotic syndrome elevates usCD163 in the absence of glomerular macrophage infiltration, resulting in false-positive results; this can be corrected with urine protein normalization.