Urinary Soluble CD163: a Novel Noninvasive Biomarker of Activity for Lupus Nephritis

Abstract

Background: Clinical distinction between patients with lupus nephritis who have active inflammation or chronic kidney damage is challenging. Studies have shown soluble CD163, which derives from cleavage of the CD163 M2c macrophage receptor and can be quantified in urine, correlates with active lupus nephritis.

Methods: We measured urine CD163 at lupus nephritis flares in patients from a Mexican cohort and cross-sectional and longitudinal United States cohorts. We also performed serial urine CD163 measurements during the treatment of flares in a subset of patients from the Mexican and longitudinal United States cohorts, and assessed response to therapy at 12 months. In addition, we evaluated urinary CD163 agreement with histologic activity in 19 patients from the Mexican cohort who had repeated kidney biopsies on follow-up.

Results: Urinary CD163 levels were significantly higher in patients with active lupus nephritis than in patients with active extrarenal SLE, inactive SLE, and other glomerular diseases, and correlated with disease clinical severity, histologic class, and the histologic activity index. Urinary CD163 increased from 6 months preflare to flare, diminishing progressively in complete and partial responders, whereas it remained elevated in nonresponders. Urinary CD163 <370 ng/mmol at 6 months predicted complete renal response at 12 months with >87% sensitivity and >87% specificity. Urinary CD163 <370 ng/mmol or >370 ng/mmol perfectly agreed (κ=1.0) with a histologic activity index ≤1 or >1 in repeated biopsies, respectively. Evaluation of urinary CD163 in patients with persistent proteinuria at 6 months improved the prediction of who would achieve complete renal response at 12 months.

Conclusions: Urinary CD163 reflects histologic inflammation in lupus nephritis and is a promising activity biomarker that varies over time with lupus nephritis activity and treatment.

Keywords: CD163 receptor; biomarkers; lupus nephritis; macrophages; soluble CD163; systemic lupus erythematosus.

Graphical abstract

Figure 1.

Urine CD163 levels are higher in active lupus nephritis than in patients with lupus without nephritis and other glomerular diseases. There was no correlation between corticosteroid dose and uCD163 in all patients or in individual groups. AAV, n=23; aLN-MX, active LN Mexican cohort, n=120; aLN-OSU, active LN OSU cohort, n=129; FSGS, n=13; IgAN, IgA nephropathy, n=27; iSLE, n=40; KD, kidney donors, n=30; MN, membranous nephropathy, n=13; sSLE, n=30.

Figure 2.

Urine CD163 levels increase with the clinical and histological severity of lupus nephritis. Urinary CD163 as (A) a function of LN severity and (B) International Society of Nephrology/Renal Pathology Society (ISN/RPS) class.

Figure 3.

Urine CD163 correlates modestly with proteinuria but not with plasma CD163 in lupus nephritis patients. Correlation between (A) plasma and urinary CD163, and (B) between uCD163 and proteinuria.

Figure 4.

Urine CD163 levels during treatment of lupus nephritis are associated with response to therapy. Course of uCD163 in response to therapy in complete (CR), partial (PR), and nonresponders (NR) in (A) the Mexican cohort and (B) the OSS cohort. The graph shows the estimated means and their 95% confidence intervals obtained from the linear mixed model analysis. The gray area identifies the cutoff of uCD163=370 ng/mmol.

Figure 5.

Urine CD163 measurement allows to better identify responders in patients with persisting proteinuria. At 6 months, 27 patients had proteinuria <0.5g/g (left arm); 26 (96%) achieved complete remission (CR) by 12 months. There was little added value of measuring uCD163 in these patients. At 6 months, there were 74 patients with proteinuria >0.5g/g (right arm); 26 (35%) of these patients achieved CR by 12 months. Measuring uCD163 helped correctly identify the 20/26 patients and 42/48 patients who achieved CR and nonresponse (NR), respectively by 12 months. NRI, net reclassification index; NRI_CR, NRI component for complete remission; NRI_NR, NRI component for nonresponders.

Figure 6.

Urine CD163 levels reflect histologic activity in lupus nephritis patients with repeated biopsies. Course of uCD163 in patients with repeated biopsies performed (A) for renal relapse, (B) per protocol at 12 months, or (C) for nonresponse to therapy. The white circle shows the time point where a kidney biopsy was performed and the numbers correspond to uCD163 levels (ng/mmol). The gray area identifies the cutoff of uCD163=370 ng/mmol.