The Spectrum of C4d Deposition in Renal Biopsies of Lupus Nephritis Patients

Abstract

Objectives: This study aimed to determine the prevalence and localization of complement factor C4d in renal biopsies from patients with lupus nephritis (LN), as well as its associations with the disease's clinico-pathological features. The correlation between arteriolar C4d deposition and renal microvascular lesions (RVLs) was further analyzed.

Methods: A total of 325 biopsy-proven LN patients were enrolled, and their clinico-pathological data were collected. C4d staining of renal biopsies was performed by immunohistochemistry. The associations between C4d deposition and the clinico-pathological features were further analyzed.

Results: C4d deposition was present in most (98.8%) renal specimens in our cohort. These deposits were localized in the glomeruli (98.2%), tubular basement membrane (TBM) (43.7%), arterioles (31.4%), and peritubular capillary (33.8%). Patients with TBM C4d staining had higher disease activity (measured with the Systemic Lupus Erythematous Disease Activity Index) and higher National Institutes of Health pathological activity and chronicity indices (all P < 0.01). Patients with arteriolar C4d deposition were more likely to develop RVLs (91.2%) compared to those with no arteriolar C4d deposition (78.0%; P = 0.004), especially with two or more types of RVLs (P < 0.001). During the mean follow-up of 55.8 months, arteriolar C4d was related to worse renal outcomes [hazard ration (HR): 2.074, 95% confidence interval (CI) 1.056-4.075, P = 0.034]. Multivariate Cox hazard analysis showed that co-deposition of arteriolar C4d and C3c was an independent risk factor (HR: 3.681, 95% CI 1.519-8.921, P = 0.004) for predicting renal outcomes.

Conclusions: C4d deposition was common in renal tissues from LN patients. TBM C4d deposition was related to the disease activity, and arteriolar C4d deposition was associated with RVLs and worse renal outcomes.

Keywords: C4d; complement; lupus nephritis; prognosis; renal microvascular lesions.

Figure 1

(A) was negative control from a living kidney donor which showed scanty granular mesangial C4d deposition; C4d was negative along tubular basement membrane (TBM) and peritubular capillary wall (PTC) (×200); (B) showed glomerular C4d granular deposition along the capillary wall and in the mesangial area (×400); (C) showed C4d deposition along the tubular basement membrane (red arrow) (×400); (D) showed C4d deposition along peritubular capillary wall (red arrow) (×400); (E) showed that C4d was negative in the arteriolar wall (red arrow) (×400); (F) showed C4d segmental arteriolar wall deposition (red arrow) (×400); (G) showed C4d deposition in the arteriolar wall (red arrow) (×400).

Figure 2

The distribution or intensity of C4d staining between different lupus nephritis sub-classes. (A) showed the intensity of glomerular C4d staining; (B) showed distribution of arteriolar C4d staining; (C) showed distribution of PTC-C4d staining; (D) showed distribution of TBM-C4d staining. Glom, glomerular; A, arteriolar; PTC, peritubular capillary; TBM, tubular basement membrane. Bonferroni’s correction for multiple correlations: statistical significance was considered at P < 0.008 (0.05/6).

Figure 3

Comparison of renal microvascular lesion types between patients with and without arteriolar C4d deposition in the ensemble (A), in subgroup class II (B), in subgroup class III (C), in subgroup class IV (D), and in subgroup class V (E). NRVL, no renal microvascular lesions.

Figure 4

(A) Comparison of renal outcomes between patients with and without arteriolar C4d deposition. (B) Comparison of renal outcomes between patients with and without arteriolar C4d and C3c deposition.