Prognostic and Therapeutic Implications of Alamandine Receptor MrgD Expression in Clear Cell Renal Cell Carcinoma with Development of Metastatic Disease

Abstract

Despite advances in the management of advanced clear cell renal cell carcinoma (ccRCC), robust biomarkers for prognosis and therapeutic response prediction remain elusive. Dysregulation of the intrarenal renin-angiotensin system (RAS) has been implicated in renal carcinogenesis but little explored, particularly regarding biomarker discovery and therapeutic innovation. Consequently, this study investigates the immunohistochemical expression and clinical relevance of the Mas-related G-protein-coupled receptor D (MrgD) in patients with ccRCC who developed metastatic disease (mccRCC). A cohort of 132 patients treated between 2008 and 2018 with nephrectomy and tyrosine kinase inhibitor (TKI)-based sequential therapy was analyzed. Treatment response was assessed using both the MASS and RECIST scoring systems. High MrgD expression in primary tumors was significantly associated with larger size, advanced stage, higher histological grade, and worse overall survival. Among 81 patients with metachronous metastases, high MrgD expression independently predicted shorter disease-free survival. High MrgD staining intensity correlated with poorer TKI responses in first-line therapy but improved outcomes with second-line mTORC1 inhibitors. These findings suggest that MrgD may be a useful biomarker of RAS linked to tumor aggressiveness in ccRCC. MrgD holds potential for identifying high-risk patients and guiding treatment selection in advanced disease. Further research is needed to unlock its clinical potential.

Keywords: Alamandine; MrgD; biomarker; clear cell renal cell carcinoma; immunohistochemistry; metastatic; prognostic; renin–angiotensin system; tyrosin kinase inhibitors.

Figure 1

MrgD expression in advanced clear cell renal cell carcinoma (mccRCC). (a) Hematoxylin-eosin (H&E) staining of the non-tumor part of the nephrectomized kidney shows proximal convoluted tubules with granular eosinophilic cells (arrows) and glomeruli (asterisks) but also distal nephron tubules (arrowheads). (b) MrgD staining of the non-tumor tissue reveals an intense granular cytoplasmic staining of the proximal tubules (arrows) and weak staining of the distal tubules (arrowheads). Notice that glomeruli can be used as internal negative control (asterisk). (c,d) Low-grade ccRCC shows weak MrgD staining, whereas the high-grade tumor (e,f) shows intense staining. Original magnification ×250.

Figure 2

Immunohistochemical staining of MrgD in mccRCC tumors based on clinical and pathological variables grouped according to histological grade (a), size (b), local invasion (pT) (c), lymph node (N) (d), distant metastasis (M) (e), and NCCN stage at diagnosis (f). IMDC risk criteria (g) and ECOG performance status (h) were evaluated at the time of initiating TKI-therapy. MrgD staining intensity was grouped as negative and positive. The “%” symbol on the Y-axis of the graph represents the percentage of cases that were MrgD positive or negative. The χ² test was used for data analysis. N0: No lymph node metastasis; N1: lymph node metastasis; M0: No distant metastasis; M1: synchronous distant metastasis.

Figure 3

Immunohistochemical staining of MrgD in mccRCC tumors according to patients’ response to first- and second-line therapies. MrgD expression was significantly higher in mccRCCs treated with TKIs as first-line therapy with unfavorable responses (MASS) but lower in cases treated with mTORC1 inhibitors as second-line therapy. The “%” symbol on the Y-axis of the graph represents the percentage of cases that were MrgD positive or negative. CR: Complete response; PR: partial response; SD: stable disease. MrgD staining intensity was grouped as negative or positive. The χ² test was used for data analysis.

Figure 4

MrgD expression in mccRCC and patients’ survival. Kaplan–Meier curves and log–rank test demonstrated the significant association between MrgD positivity and 10-year overall (a) and disease-free (b) survival. The number of patients at risk is shown at specific time points throughout the follow-up period.