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Juvenile elastic arteries after 28 years of renal replacement therapy in a patient with complete complement C4 deficiency
© Knoll et al.; licensee BioMed Central Ltd. 2012
Received: 7 August 2012
Accepted: 27 November 2012
Published: 2 December 2012
Complement activation products are present in atherosclerotic plaques. Recently, binding of complement to elastin and collagen in the aortic wall has been demonstrated, suggesting a role of complement in the development aortic stiffness and atherosclerosis. The definitive role of complement in atherosclerosis and arteriosclerosis, however, remains unclear.
We here describe a patient with hereditary complete deficiency of complement C4 suffering from Henoch-Schoenlein purpura and on renal replacement therapy for twenty-eight years. The patient had the full range of risk factors for vascular damage such as hypertension, volume overload, hyperphosphatemia and hyperparathyroidism. Despite that, his carotid artery intima media thickness was below the normal range and his pulse wave velocity was normal. In contrast, the patient’s coronary and peripheral muscular arteries were heavily calcified.
This case supports the hypothesis that complement plays an important role in the development of stiffness of elastic arteries. We speculate that inability to activate complement by the classical or lectin pathways protected the patient from atherosclerosis, arteriosclerosis, stiffening and calcification of the aorta and carotid arteries. Inhibition of complement activation may be a potential target for prophylactic and therapeutic interventions.
Accelerated vascular calcification and vascular stiffening are common in end-stage renal disease (ESRD) [1–3]. Both are associated with mortality in the CKD and ESRD population . No effective therapeutic strategy is available to prevent or slow down vascular calcification und arterial stiffening in patients with chronic kidney disease. It has recently been shown that complement components C3 and C4 bind to elastic and collagen fibers in the mouse aorta, and it was postulated that complement may play a central role in progressive vascular stiffening of elastic arteries . We here describe a patient who, despite having multiple risk factors, does not show any signs of arteriosclerosis or atherosclerosis of his central elastic arteries after 28 years of renal replacement therapy. This unexpected finding is potentially related to the primary disease of the patient: hereditary complete deficiency of complement component C4.
Laboratory values and medication before the patient started hemodialysis 2011
40 μg once weekly
Investigation of arterial vessels
Complement C4 deficiency
The patient’s primary disease is hereditary complete deficiency of complement C4, and C4 was never detected in his serum on multiple occasions. The human complement C4 genes are located on chromosome 6 in the major histocompatibility complex region. They encode for two highly polymorphic isoforms, C4A and C4B. Hereditary complete C4 deficiency is exceptionally rare with less than 30 patients having been reported. Most of them suffered from a lupus-like illness. Our patient is homozygous for the MHC haplotype HLA A30 B18 DR7. This haplotype does not contain C4A genes, but instead two mutant short C4B genes with a 8127 g → a point mutation at the donor site of the intron 28 splice junction, which abrogates correct RNA splicing . Splicing according to a new potential donor site seven nucleotides downstream would lead to a stop codon in exon 29. These results and the absence of C4 from our patient’s serum strongly suggest that he was completely C4-deficient.
Arteriosclerosis of central and peripheral arteries is the hallmark of the vasculopathy of chronic kidney disease. In addition to traditional risk factors, CKD-specific factors such as electrolyte abnormalities seem to drive vascular pathology in these patients. Our patient with almost 30 years of renal replacement therapy does not fit into this scheme. As expected, his coronary and peripheral muscular arteries were heavily calcified. He had, however, well preserved central elastic arteries.
It is highly unusual to find completely normal carotid vessels without intimal hyperplasia or atherosclerotic plaques and without calcification of the media in a patient who has been on renal replacement therapy for so long, including ten years of hemodialysis. The finding of a PWV of 5.2 m/s corresponds to the PWV of a young adult without arteriosclerosis of the aorta and is also unexpected . He had suffered from the whole array of conditions that are thought to cause the vasculopathy of chronic kidney disease. The efficacy of these mechanisms is clearly illustrated by the calcifications of coronary and peripheral vessels. We believe that the patient’s primary disease, complement C4 deficiency, can explain these unusual findings.
C4 and atherosclerosis
How might C4 deficiency protect against atherosclerosis? C4 is a main component of the classical and lectin pathways of complement. Without doubt, complement plays a role in the development of atherosclerosis. Terminal complement complex C5b-9 is regularly detected in atherosclerotic lesions . In animal models, C6 deficiency protects against plaque formation . Classical pathway activation may occur by several mechanisms in atherosclerosis. C-reactive protein, also present in lesions, is a potent activator of the classical pathway . In addition, activation can be triggered by immune complexes containing autoantibodies against oxidized LDL and heat shock proteins .
C4 and arteriosclerosis
Even more intriguing is the total absence of arteriosclerosis of central elastic arteries in this patient with C4 deficiency. Recent studies in mice support a role of complement in arteriosclerosis of these vessels . It has been shown that complement components C3 and C4 are deposited along collagen and elastin fibers in the external elastic lamina of the aorta. These complement components are most likely derived from the perivascular adipose tissue of the aorta. Complement deposition increases with age and parallels vascular stiffening. In atherosclerosis-prone ApE(−/−) mice complement deposition extends into the media and intimal plaques. How C3 and C4 are deposited along collagen and elastin remains unclear. Spontaneously hydrolyzed C3 and C4 may attach covalently to the fibers. Alternatively, fibromodulin and adiponectin, which bind to collagen fibers in vessel walls [16, 17], also bind to C1q and activate the classical complement pathway [18, 19], which then would lead to complement deposition. As C4 is the central component of the classical pathway, the findings in our patient with C4 deficiency would favor the second mechanism and suggest that complement deposition in the vessel wall is mediated by the classical or lectin pathway. How complement activation eventually leads to vascular stiffening and calcification, remains to be determined. Complement fragments may attract leucocytes to the vascular wall, where they may be activated by complement and secrete proinflammatory cytokines. Elevated levels of interleukin-6 and tumor necrosis factor-alpha in the circulation are associated with vascular calcification in patients with chronic kidney disease . They are also associated with low levels of fetuin-a, a potent inhibitor of calcification . Complement activation may create a local environment in the vessel wall that strongly favors calcification. In an animal model of diabetes collagen synthesis and ventricular stiffening in the heart have been shown to be dependent on mannose-binding lectin and activation of the lectin pathway . Likewise, a complement C5a receptor antagonist prevented cellular infiltration, fibrosis and stiffening of the heart in DOCA-salt hypertensive rats . In analogy, complement activation may also accelerate fibrosis and stiffening of the central elastic vessels. Recently C4d deposits in the adventitia have been found in 50% of patients undergoing surgery of the ascending aorta. Lack of C4d staining was associated with aortic dissection. Whether complement may have a protective role against aortic dissection remains speculative .
Our observations – normal central arteries but advanced calcification of coronary and muscular arteries - also would imply that arteriosclerosis of central elastic and peripheral muscular arteries (including coronary arteries) are driven by separate mechanisms. Whereas arteriosclerosis seems to be complement-dependent in elastic arteries, the process might be complement-independent in muscular arteries. Clearly, further research is needed to unravel the role of the complement system in atherosclerosis and arteriosclerosis. In addition, inhibition of complement activation may be a potential target for prophylactic and therapeutic interventions.
The patient gave written informed consent to publication of his case history and all figures.
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