Background/Purpose:  While a consensus is that a high chronicity index (CI) is associated with a greater risk for progression to renal failure in lupus nephritis (LN), it does not explain why patients with a low index can still have a poor response to conventional therapy.  The need to identify novel biomarkers of poor response has never been more pressing as new biologics enter clinical trials. A focus on the endothelium surfaced when membrane endothelial protein C receptor (mEPCR), an integral membrane protein with both anti-inflammatory and anti-thrombotic properties expressed on endothelial cells was found to predict poor outcome.  In accord with this provocative finding suggesting that changes in the renal microvasculature may be important determinants of prognosis and response to therapy, mEPCR was further evaluated. 

Methods:  A retrospective study of 34 patients with LN was performed. Clinical data were collected at biopsy and 1 year following biopsy. Response to therapy was defined as a 50% improvement of creatinine if abnormal and/or proteinuria without worsening of either measure. Histological analyses included ISN/RPS classification, Activity Index (AI), CI and Tubulo-interstitial Damage (TID) scores. mEPCR expression was evaluated by immunohistochemistry by two pathologists independently and blinded to the clinical outcome of the patients. 

Results:  The average age at the time of biopsy was 37. The cohort was comprised largely of females (74%) and minorities (82.4%). Mean baseline creatinine was 1.62 mg/dl, 24% had a GFR <60 and 38% had nephrotic range proteinuria. Proliferative nephritis was diagnosed in 77% and 53% were responders to standard of care therapy at 1 year.  Positive mEPCR staining of >25% of the peritubular capillaries (PTCs) was observed in 12 renal biopsies. One year after biopsy, 75% (9/12) of patients with staining for mEPCR in >25% of the PTCs did not respond to therapy (1 progressing to end-stage renal disease) compared with 7/22 (32%) with mEPCR staining in ≤25% of the PTCs P=0.029.  There was no association between response and baseline age, gender, creatinine, abnormal GFR, nephrotic range proteinuria, microthrombi on biopsy, ISN/RPS classification, AI, CI, or treatment regimen. The only other variables measured that associated with an absence of response included minorities (P=0.019) and TID (p=.018).  However, mEPCR was clearly observed in areas of non-atrophic cortex.  Thus, the extent of mEPCR was not solely accounted for by TID.  After excluding patients with high TID scores, mEPCR remained strongly associated with a poor response to therapy, P=0.028. A subset of patients with LN who presented with a normal creatinine at biopsy were analyzed separately.  At 1 year, 100% (16/16) of these patients with mEPCR staining ≤25% of the PTC maintained a normal creatinine and GFR compared with 2/4 (50%) with positive staining >25% of the PTC, P=0.03. 

Conclusion:  These data suggest that mEPCR staining be added to the evaluation to aid in the overall prognosis of LN.  While the biology is perplexing given the function of mEPCR as generally protective, a high stain may suggest negative feedback reflecting a state of tissue unresponsiveness to be considered in clinical trial design.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/increased-expression-of-membrane-endothelial-protein-c-receptor-associates-with-poor-response-in-lupus-nephritis-independent-of-chronicity-index/