PHARMED INSTITUTE OF CYBERNETICS
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PHARMED INSTITUTE OF CYBERNETICS |
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PIC Res. Comm. 3/2009 (rev PRC 4/2008) |
Coronary artery disease in renal dysfunction - a model of a progressive calcification by a mechanism of chemical self-assembly |
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Rainer K. Liedtke. MD PIC, Munich, Germany, liedtke@pharmed.de |
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| Key words | |
| Chronic renal dysfunction, coronary artery disease, energy metabolism, complex calcium phosphate compounds, chemical self-assembly, metatstatic vascular mineralization | |
| Abstract | |
| The cause for the high incidence of coronary artery disease in patients with a chronic renal dysfunction is still unclear. Here we present a biochemical model of a mechanism of a biochemical self-assembly calcification. It shows that impaired cells can lead, due to a defect in their energy metabolism, an increased intracellular production of calcium phosphate products. This leads to an increased export of complex hydroxyapatites, and which create within a process of a chemical self-assembly mineralizing deposits in the vascular media of coronary arteries. CONCLUSIONS: Impaired renal cells can cause a progressive vascular mineralization through deposits of complex calcium phosphates. In order to reduce the complication of a coronary artery disease in renal dysfunction a strict control of serum calcium and phosphorus and of the use of drugs that can inhibit the oxidative phosphorylation are necessary. | |
| Introduction | |
Late stages of chronic kidney disease (CKD), show a progressive vascular calcification with significantly increased cardiovascular (CV) mortality [1] due to a coronary artery disease (CAD). In dialysis, the progression of the coronary calcification correlated with the prevalence of myocardial infarctions (MI) and the serum concentrations of calcium and phosphate, but not with cholesterol and lipoproteins [2]. Since hyperphosphataemia and/or high calcium x phosphate product (CaxP) predispose for progressive calcification, CV mortality was related to it, too [3]. Therefore the therapy of a hyperphosphataemia and CaxP was given a central role for lowering CV risks [4][5], in particular since the coronary calcium score is also a risk predictor in dialysis patients [6]. In the calcification initialized in coronaries, the lipid profiles appear to influence neither their initiation nor the progression [2][7]. It has also been reported that an application of phosphate binders containing calcium in the therapy of hyperphosphataemia led to a higher progression of coronary calcification than calcium-free phosphate binders [8][9]. Moreover, that this therapy route also showed indications, assessed by the study authors as 'anti-atherogenic' [10]. However also in persons with healthy kidneys, there was already found a relation between calcium supplementation and increased rates of MI [11]. Also a form of an intramural calcification, presenting the picture of an early phase of arteriosclerosis, appears to be induced by a number of drugs, such as NSAIDs, that have an antiproliferative mechanism of action [12]. |
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| Deduction of a Model Mechanism of a Progressive Vascular Calcification |
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| Scope and Method. | |
| It was the principal aim to describe a general model and a functional causality on the origin and initial transformation of a clinically relevant calcification process. For this purpose a model that based on the analysis of biochemical consequences due to an impaired mitochondrial oxidative phosphorylation (OXP) was prepared. That was done by a modified Entity Relationship Modeling of relevant literature (i.a. Medline), supported by the application of a newly developed syntax for interactive data configuration (FNS). The following exemplary deductions are limited only to a basic mechanism of an arterial calcification and its dissemination. | |
| Clinical Premises: | |
| The context between too high CaxP in CKD and processes of progressive vascular calcification indicates that a deposit of calcium phosphates is at least co-responsible for an induction of early vascular sclerotic phases. The initialization of that process appears to be prepared by a mineralization by increased deposits in the media layer. That is supported by the finding that, in late stage renal diseases, there is a stronger calcification in the coronary media than in the intima, but also in patients without kidney disease [13][14]). Also uraemic patients show a significantly more pronounced media thickness and coronary calcification [15]. The initial phase often runs in a sub-clinical manner, wherein the mineralizing structural disorder of elastic proteins in the smooth vascular muscle cells only triggers a "hardening of the arteries" first. That may indicate an explanation of the formation of hypertension as an early effect of a vascular micro-calcification. Calcification of the media moreover was also already found in younger patients without traditional arteriosclerosis risk factors and before the commencement of a haemodialysis, while calcification of the intima was rather found in older patients with a case history of arteriosclerosis [14]. In the same way, an increase in the intima-media thickness of the carotid artery could be found in patients of an advanced age and after a longer duration of the disease [16]. A histological examination of the media sclerosis in Mönckeberg’s arteriosclerosis moreover pointed to a process of dystrophic calcification, wherein a higher calcium and phosphor content was found in the compact calcifications [17]. | |
| A Model of Biochemical Self-Assembly. | |
| Principally any impairment of a renal cell, by either endogenous or exogenous factors, negatively affects the energy metabolism, thus the mitochondrial oxidative phosphorylation (OXP) of the respiratory chain. This leads to a reduced synthesis of adenosine triphosphate (ATP), and implies an induction of the apoptic caspase cascade. Functionally, that leads to a reduced activity of all ionic pumps of the renal cell that receive their energy from the ATP hydrolysis. Therefore, it affects also the Ca-ATPases responsible for the maintenance of low intracellular calcium ions (Ca2+). Of particular relevance here are the membrane-bound plasma membrane Ca22+-transporting ATPase and the sarco(endo)plasmic reticulum Ca2+ ATPases. As a consequence of the impaired ATP synthesis, there occurs simultaneously an intracellular excess of the ATP precursors not used for phosphorylation, thus an increase in the concentration of phosphate, and a cytosolic and intramitochondrial accumulation of Ca2+ due to defects in the calcium pumps. Thus an increased concentration of phosphates is available to the increased Ca2+ as reaction partner. According to this status, there are increasingly formed, as primary reaction products, basic calcium phosphates (Ca3(PO4)2). As a consequence of exceeding the saturation conditions, the latter in part deposit in a crystalline form. That again leads, in a further step, to an increased crystalline complex formation of hydroxyapatites (HAP) (Ca5(PO4)3OH). The deposited HAP now serve, in a process of a chemical self assembly, as replicative matrixes for the production of further HAP crystals. By cell disruption, or also exocytosis, an export of HAP can occur. Its crystalline deposit on the vascular tissue then occurs on the collagen of the media layer first where it causes a stiffening of the collagen fibres. Also this externally deposited HAP again serves as replication matrixes. Through that vicious circle, the degenerative process in the collagen of vascular myofibrils extends and induces a further vascular calcification. This progressive mineralization implies also an acceleration of these processes, moreover affects the renal function in a negative feed-back. Figure 1 summarizes the sequence of this calcification process. | |
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| Fig. 1 Simplified schematic representation of the consequences of an impairment of the mitochondrial oxidative phosphorylation (OXP) in a renal cell. Increasingly calcium phosphates (Ca3(PO4)2) are formed from the increased intracellular calcium ions (Ca2+) and phosphates (PO43-). This leads on its part to an increasing formation and crystalline deposition of hydroxyapatites (Ca5(PO4)3OH). These serve as replicative matrixes and in a process of a chemical self-assembly (CSA), for the formation of further hydroxyapatite complexes, causing a progressive collagen-associated media calcification in the coronary arteries. | |
| DISCUSSION | |
| Within the clinical vascular outcome the chemical self-assembly of HAP appears a core step for the progression. This kind of spontaneous formation of supra-molecular structures is primarily known from the material sciences. In the body it obviously represents an own physico-chemical process which includes Ca2 and organic ligands. Some basic processes of the crystalline nucleation and technical in-vitro assessments on the mechanism of the HAP self-assembly in simulated body fluid have been described [18][19][20]. Studies were also made on composites with collagen, which complied biologically with extracellular matrix fibers [21] or bone structures [22][23]. Important parameters for a biological apatite nucleation and its expansion by self-assembly, appear a contribution of extracellular matrix proteins which bind calcium ions [24] or which are linking mineral and collagen phase [25], also the composition of the phosphates [26], conditions of chemical saturation and pH [19]. Altogether this process appears having some similarities with bone mineralization [20][22][27]. | |
| Initially the micro-calcifications only cause a thickening and stiffening of the media, therefore are sub-clinical. This latency complicates an early therapeutic approach. In the course of the extending mineralization, there is to be expected an increasing occurrence of systemic effects with increasing vascular brittleness and intima immigration. That may also result in more intra-vascular processes like plaque formation. Since the progressive phase can be in sum considered a chemical-stoichiometrical process it offers a therapeutic chance for a management via control of serum calcium and phosphorus. However, in this context it should be noted, that also the use of drugs that inhibit the OXP, such as e.g, NSAID analgesics, should be well controlled in these patients since they may intensify a systemic vascular calcification [12]. | |
| Conclusions: | |
| In summary a coronary artery disease in patients with a chronic kidney dysfunction appears originally caused by an increased formation of complex calcium phosphates, which trigger subsequent calcifications through a chemical self-assembly of hydroxyapatites. In order to reduce the complication of a CAD the model presented here confirms a therapeutic value of a strict control of calcium and phosphorus, in addition, emphasizes a control of compounds that may have an inhibitory effect on the OXP of the renal cell. | |
| References | |
[1] Sigrist MK, Taal MW, Bungay P, McIntyre, CW. Progressive vascular calcification over 2 years is associated with arterial stiffening and increased mortality in patients with stages 4 and 5 chronic kidney disease. Clin J Am Soc Nephrol 2007, 72, 124-8 |
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© 2010 Rainer K. Liedtke |