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Expression of endothelial protein C receptor in cortical peritubular capillaries associates with a poor clinical response in lupus nephritis

December 29, 2009

The contribution of the vascular endothelium to the pathogenesis
of renal injury has not been emphasized in lupus nephritis (LN).
Despite potential biological insights and treatment strategies to
be gained by studying the endothelium in LN, neither historic
WHO classification, National Institutes of Health chronicity and
activity indices (CI and AI, respectively) [1], nor recent International
Society of Nephrology/Renal Pathology Society (ISN/
RPS) 2003 pathological classifications of LN [2] specifically
address the state of the microvasculature in their definitions.
However, recent murine data based on microarray analysis
suggest that endothelial activation is a feature observed in progressive
glomerulosclerosis but not in non-progressive glomerulosclerosis
The membrane endothelial protein C receptor (mEPCR), an
integral membrane protein with both anti-inflammatory and
anti-thrombotic properties, is expressed on endothelial cells and
regulates the conversion of protein C to activated protein C by
presenting it to the thrombin–thrombomodulin complex [4, 5].

mEPCR is shed in a pathological state to a soluble form, sEPCR,
increased levels of which have been reported in two lupus cohorts
[6, 7]. Patients with LN had significantly higher levels of sEPCR
than those without nephritis [7].
mEPCR expression in kidney disease has been evaluated in
models of sepsis and diabetes [8, 9] but never addressed in LN.
Accordingly, the current study was initiated to test the hypothesis
that the presentation and course of LN is influenced by the renal
microvasculature, as reflected by mEPCR expression. This was
approached by immunohistological analysis of mEPCR expression
in kidney biopsies in patients with all classes of LN, and by
correlating the results of the immunostaining with response to

The study was approved by the Institutional Review Board of
New York University (NYU) School of Medicine. The twelve
subjects followed prospectively signed NYU IRB approved consent
forms for the study. A total of 301 biopsies from 242 patients
with a diagnosis of LN between January 2000 and April 2008 were
identified. Patients were selected based on the following criteria.
Inclusion criteria: (i) confirmation of a diagnosis of SLE as per the
ACR [10]; (ii) confirmation of a diagnosis of LN based on renal
biopsy; (iii) availability of renal biopsy tissue in the paraffin block
for immunohistochemical analysis; (iv) at least 10 glomeruli in the
renal biopsy; and (v) access to medical records. Exclusion criteria:
inappropriate fixation of the renal tissue determined by the
absence of staining of CD31 in PTCs or mEPCR in renal medulla
and/or arterial endothelium. Fifty-nine formalin-fixed, paraffinembedded
renal biopsies from 49 patients were available. Ten
patients had two biopsies.


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