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Updated: Mar 7, 2026
Assessment of Kidney Function in Mouse Models of Glomerular Disease
Published on: June 30, 2018
Glomerular C4d deposits can mark structural capillary wall remodelling in thrombotic microangiopathy and transplant
Adil H Gasim1, Jamie S Chua1,2, Ron Wolterbeek3
1Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Insights
Glomerular basement membrane C4d (GBM-C4d) can indicate active antibody-mediated rejection or structural GBM changes. Isolated GBM-C4d in kidney biopsies may signal glomerular remodeling or rejection.
Area of Science:
- Nephrology
- Immunopathology
- Transplant Medicine
Background:
- Peritubular capillary C4d (ptc-C4d) typically signifies active antibody-mediated rejection.
- The diagnostic significance of pseudolinear glomerular capillary C4d (GBM-C4d), especially in isolation, remains unclear.
Purpose of the Study:
- To correlate GBM-C4d with structural glomerular basement membrane (GBM) abnormalities and active antibody-mediated rejection.
- To investigate the diagnostic implications of isolated GBM-C4d in kidney biopsies.
Main Methods:
- Analysis of 319 renal transplant and 35 control native kidney biopsies.
- Correlation of GBM-C4d staining (immunofluorescence microscopy and immunohistochemistry) with ptc-C4d, transplant glomerulopathy, Banff scores, GBM duplication, and thrombotic microangiopathies.
Main Results:
- In kidney transplants, GBM-C4d frequently co-occurred with ptc-C4d but was also observed in isolation with transplant glomerulopathy.
- Isolated GBM-C4d correlated with GBM duplication in transplant and native kidneys, and with thrombotic microangiopathies in controls.
- GBM-C4d staining intensity correlated with Banff glomerulopathy scores.
Conclusions:
- Pseudolinear GBM-C4d staining can represent either structural GBM changes (duplication) or active antibody-mediated rejection.
- Isolated strong GBM-C4d may indicate glomerular architectural remodeling, distinct from the etiologic role of ptc-C4d in active antibody-mediated rejection.
Abstract:
Peritubular capillary C4d (ptc-C4d) usually marks active antibody-mediated rejection, while pseudolinear glomerular capillary C4d (GBM-C4d) is of undetermined diagnostic significance, especially when seen in isolation without concurrent ptc-C4d. We correlated GBM-C4d with structural GBM abnormalities and active antibody-mediated rejection in 319 renal transplant and 35 control native kidney biopsies. In kidney transplants, ptc-C4d was associated with GBM-C4d in 97% by immunofluorescence microscopy (IF) and 61% by immunohistochemistry (IHC; P < 0.001). Transplant glomerulopathy correlated with GBM-C4d (P < 0.001) and presented with isolated GBM-C4d lacking ptc-C4d in 69% by IF and 40% by IHC. Strong isolated GBM-C4d was found post year-1 in repeat biopsies with transplant glomerulopathy. GBM-C4d staining intensity correlated with Banff cg scores (rs = 0.45, P < 0.001). Stepwise exclusion and multivariate logistic regression corrected for active antibody-mediated rejection showed significant correlations between GBM duplication and GBM-C4d (P = 0.001). Native control biopsies with thrombotic microangiopathies demonstrated GBM-C4d in 92% (IF, P < 0.001) and 35% (IHC). In conclusion, pseudolinear GBM-C4d staining can reflect two phenomena: (i) structural GBM changes with duplication in native and transplant kidneys or (ii) active antibody-mediated rejection typically accompanied by ptc-C4d. While ptc-C4d is a dynamic 'etiologic' marker for active antibody-mediated rejection, isolated strong GBM-C4d can highlight architectural glomerular remodelling.
