Dysregulation of the Microvasculature in Nonlesional Non-Sun-exposed Skin of Patients with Lupus Nephritis

Abstract

Objective Membrane endothelial protein C receptor (mEPCR) is highly expressed in peritubular capillaries of kidneys from patients with active and poorly responsive lupus nephritis (LN). We investigated the hypothesis that changes in the microvasculature are widespread with extension to the dermal vasculature. Methods Skin biopsies from uninvolved skin (buttocks) were performed in 27 patients with LN and 5 healthy controls. Sections were stained with specific antibodies reactive with mEPCR, adiponectin, intercellular adhesion molecule-1 (ICAM-1), and CD31; then assessed by enumeration of stained blood vessels (percentage positive blood vessels) blinded to knowledge of clinical information. Results There was a significant increase in the prevalence of blood vessels that stained for mEPCR and ICAM-1 in patients compared to controls [94% vs 59% (p = 0.045) and 81% vs 67% (p = 0.037), respectively]. Adiponectin staining and CD31 staining were similar between the groups (45% vs 43% and 98% vs 92%). Dermal staining for mEPCR was greater in patients with proliferative glomerulonephritis than in those with membranous disease (96% vs 60%; p = 0.029). A composite of poor prognostic renal markers and death was significantly associated with greater expression of mEPCR staining. Conclusion These data are consistent with the notion that in patients with LN, activation of the microvasculature extends beyond the clinically targeted organ. The insidious expression of this widespread vasculopathy may be a contributor to longterm comorbidities.

Single cell RNA sequencing to dissect the molecular heterogeneity in lupus nephritis

“…Furthermore, increased levels were noted in biopsies of nonlesional, non-sun-exposed skin of LN patients, suggesting that alterations in the microvasculature are widespread and extend to the dermal vasculature (9). Thus, analysis of this more readily accessible tissue, even distant from the primary affected organ, may provide an opportunity to explore surrogates for renal tissue analyses (10).…”

Membrane endothelial protein C receptor expression in renal tissue of pediatric lupus nephritis patients

“…There was a higher median level of mEPCR expression in patients with class III and IV and with biopsies with high immune complex deposition versus those of class V (96% versus 60%; P=0.029). This median % increased in patients with active nephritis (96% versus 59%) in comparison to those with inactive LN 27 .…”

“…The same was confirmed by Izmirly and colleagues (2009) who stated that 84.6% of patients with a score of >2 did not respond to treatment versus 28.6% in those with a score of < 2 (P=0.0018) 6 . In addition, Izmirly and colleagues (2012) stated that the median of mEPCR was significantly higher in patients with a renal prognostic score >3 than in those with a score <3 (P=0.036) 27 .…”

Accelerating Medicines Partnership: Organizational Structure and Preliminary Data From the Phase 1 Studies of Lupus Nephritis

“…The concept that skin can reflect the immunologic milieu of SLE dates back to the original demonstration of immunoglobulin and complement deposition at the dermal-epidermal junction in both lesional and nonlesional skin (25). Activation of the microvasculature is found even in non-sun-exposed, nonlesional skin of patients with active lupus (26)(27)(28), and endothelial changes in the kidneys of patients with LN predict poor responses to therapy (29). Thus, serial analysis of noninvolved skin, although distant from the primary affected organ, may provide an opportunity to explore surrogates for renal tissue analyses so as to facilitate early identification critical to renal survival and follow treatment responses.…”