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C4d staining in renal allografts and treatment of antibody-mediated rejection

Christina L Klein, MD
Daniel C Brennan, MD, FACP
Section Editor
Barbara Murphy, MB, BAO, BCh, FRCPI
Deputy Editor
Albert Q Lam, MD


Detection of the complement split product C4d in renal allograft biopsies is an important adjunctive tool to help understand the alloimmune response and, in particular, to diagnose antibody-mediated rejection (AMR). C4d is a degradation product of the classic complement pathway. After an antigen-antibody complex fixes complement, a cascade of events follows, with activation of several complement proteins. The complement protein C4 is split into C4a and C4b. C4b is then converted to C4d. A unique feature of C4d is that it binds covalently to the endothelial and collagen basement membranes, thereby avoiding removal and raising the possibility of serving as an immunologic footprint of complement activation and antibody activity. (See "Complement pathways" and "Clinical manifestations and diagnosis of acute renal allograft rejection".)

In normal kidneys, C4d is detectable in the glomerular mesangium and at the vascular pole. This emphasizes that there is constitutive turnover of immune complexes. When the burden of immune complexes increases with immune complex deposition diseases, C4d deposition overflows from the mesangium and vascular pole to the glomerular capillaries (GCs) [1].

C4d deposition in the glomerular mesangium, the glomerular basement membrane, the tubular basement membrane, arterioles, and arterial intima in both native and transplanted kidneys can be demonstrated by monoclonal antibody staining and immunofluorescence of frozen tissue sections [2,3]. Of note, deposition in the peritubular capillaries (PTCs) has only been described in renal allografts and is thought to represent antidonor humoral activity (picture 1).

In transplanted kidneys, the reason for the specificity of C4d staining in the PTC is not entirely clear. Donor-specific antibody (DSA) directly engages human leukocyte antigens (HLAs), which are present in the glomerulus as well as the PTC. It is known that anticomplement protection in the PTC is weaker than in the glomerulus. Part of the reason for this is that the glomerulus has at least four cell-surface complement inhibitors: decay accelerating factor-CD55, membrane cofactor protein-CD46, complement receptor 1 (CR1)-CD35, and protectin-CD59. By comparison, only protectin (CD59) is actively expressed in the PTC. Protectin inhibits the formation of complement membrane attack complex (C5-9), and, therefore, the generation of C4d is relatively uninhibited [2]. (See "Regulators and receptors of the complement system".)

Despite the association between C4d and immune complex deposition, immunoglobulin has not been detected in PTC where C4d is detectable. The reason for this is unclear and an important question. As humoral rejection probably results from direct antibody attack on the target endothelial cell, modulation from the surface may make antibody detection difficult. Endothelial cells dislodge surface antibody through "capping," "shedding," or "internalization" [4]. C4d resists modulation from the surface due to its covalent binding to tissue structures [5].


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Literature review current through: Jul 2017. | This topic last updated: Nov 09, 2016.
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