Markus Ketteler, Vincent Brandenburg, Willi Jahnen-Dechent, Ralf Westenfeld, Jürgen Floege, Don’t be misguided by pointers: the calcium × phosphate product could be a Computer virus, Nephrology Dialysis Transplantation, Quantity 20, Difficulty 4, April 2005, Pages 673–677, https://doi.org/10.1093/ndt/gfh734
In recent times, it has grow to be more and more evident that the dramatic cardiovascular mortality of end-stage renal illness (ESRD) sufferers is linked with disturbances in calcium and phosphate homeostasis. Whereas for many years the manifestations of secondary and tertiary hyperparathyroidism had been largely considered explicit types of bone illness, it’s now widespread sense that extraosseous and particularly cardiovascular calcifications could develop as a consequence of an elevated extracellular availability of calcium and phosphate ions on this setting. This ‘paradigm shift’ with regard to renal osteodystrophy led to the publication of the Ok/DOQI pointers in October 2003 which, along with defining goal ranges of intact parathyroid hormone (iPTH) in several phases of kidney failure, now suggest goal ranges for serum phosphate (P), serum calcium (Ca) and the Ca × P product [1]. Whereas these pointers signify a serious step ahead to improved cardiovascular prevention in ESRD sufferers, we want to advise and clarify on this article that some warning could also be essential within the interpretation of serum Ca and P ranges.
Deranged Ca and P homeostasis as a cardiovascular danger issue
It has lengthy grow to be clear that conventional danger elements comparable to arterial hypertension or hypercholesterolaemia don’t clarify the surplus cardiovascular mortality of sufferers on dialysis. The commentary that low blood strain and low serum ranges of low-density lipoprotein (LDL)-cholesterol truly had been related to a worse end result within the dialysis inhabitants led to the time period ‘reverse epidemiology’ in an try to explain this seemingly paradoxical phenomenon [2]. Whereas looking for the important thing determinants of survival in ESRD sufferers, a number of giant registry research indicated that hyperphosphataemia and an elevated Ca × P product signify impartial danger elements for the survival of dialysis sufferers [3–5]. In a latest research, >40 000 sufferers of the FMC North America Affected person Statistical Profile system exhibited, after adjustment for a number of variables, a 25% enhance of mortality at serum phosphate ranges of 6.0–7.0 mg/dl and a 100% enhance of danger when phosphate ranges exceeded 9 mg/dl [5]. The predictive worth of the Ca × P product was related, whereas elevated serum Ca ranges had been a weaker, although nonetheless vital danger predictor.
Hyperphosphataemia and an elevated serum Ca × P product had been additionally discovered to be related to the presence or magnitude of vascular and valvular calcifications in some, however not in all research. For instance, Goodman et al. noticed in younger sufferers on dialysis a correlation of the diploma of coronary artery calcifications with the diploma of serum Ca × P product elevation and the oral Ca load (i.e. consumption of Ca-containing phosphate binders), however not with serum Ca ranges or hyperphosphataemia alone (borderline significance for the latter: P = 0.06) [6]. Related outcomes had been obtained by Wang et al., specifically a major correlation between valvular calcifications and Ca × P product in sufferers on peritoneal dialysis [7]. For the reason that magnitude of vascular and valvular calcifications is a robust predictor of mortality in dialysis sufferers (reviewed in [8]), preventive measures ought to definitely purpose at such apparent development elements.
The opposite facet of the coin
The ‘Treat-to-Goal’ research could serve to display the potential difficulties in decoding the results of Ca load and the position of the Ca × P product measured within the context of uraemic cardiovascular calcifications. This research in contrast the influence of sevelamer vs Ca-containing phosphate binders (calcium acetate or carbonate) on the development of coronary and aortic calcifications in dialysis sufferers [9]. Calcifications progressed in sufferers handled with Ca-containing phosphate binders, whereas sevelamer remedy was related to a halt in development. Within the context of the current dialogue, it’s noteworthy that on the finish of the research, each affected person teams had related serum calcium and phosphate ranges, whereas Ca ranges had been marginally decrease within the sevelamer group (2.3 vs 2.4 mmol/l) throughout the course of the research and related to a decrease incidence of hypercalcaemic episodes (8 vs 17%) as in contrast with the Ca-containing phosphate binder group. Consequently, these laboratory information don’t adequately mirror the truth that sufferers within the Ca-containing phosphate binder group ingested ∼500 g extra elemental Ca throughout 1 yr than the sevelamer-treated sufferers. Whereas it could possibly be argued that almost all of this extra Ca was in all probability excreted within the stools, it seems cheap to estimate {that a} vital proportion underwent intestinal absorption—facilitated by the concomitant vitamin D remedy in near 60% of the sufferers included within the research.
One other medical instance to display the issue of relating a excessive Ca × P product to extraosseous calcifications is calcific uraemic arteriolopathy (calciphylaxis), which is characterised by in depth calcifications of cutaneous arterioles resulting in tissue ischaemia, ulceration and secondary superinfection. Affected sufferers often exhibit extreme calcifications of bigger arteries as nicely. Whereas preliminary studies steered a hyperlink between calciphylaxis and hyperparathyroidism, hypercalcaemia and hyperphosphataemia, it was more and more reported that many circumstances occurred within the presence of apparently regular serum Ca, P and iPTH ranges, and a few even following parathyroidectomy. Apparently, in some circumstances, an elevated Ca load seems to have triggered or aggravated calciphylaxis, as helpful results of decreasing the dialysate Ca and cessation of Ca carbonate remedy had been reported [10]. In our personal expertise in eight calciphylaxis sufferers, imply serum Ca ranges (2.4±0.2 mmol/l), serum P ranges (1.79±0.25 mmol/l) and the Ca × P product (4.3±0.8 mmol2/l2) had been additionally comparatively low and solely three of the sufferers had a Ca × P product above the Ok/DOQI goal degree [11].
Extraosseous calcification: why are all of us ‘metastable’?
Just lately, it grew to become evident that vascular calcification is not only a passive precipitation course of because of Ca and P ranges exceeding their solubility product within the extracellular area. Certainly, even regular serum Ca and P concentrations in serum exceed their solubility product in an aqueous answer by many orders of magnitude (H2O, 2.1 × 10−33vs extracellular physique fluid: 1.8 × 10−6). Physique temperature, pH and the ionic power (particularly Na+ and Cl− ions) within the extracellular atmosphere compensate largely for that distinction, however serum nonetheless stays a ‘metastable’ answer regarding Ca and P precipitation and requires calcification inhibitors to forestall extraosseous calcifications. This has grow to be clear by experiments in genetically manipulated mice, which demonstrated that deletion of particular person genes brought on in depth gentle tissue and/or vascular calcifications (reviewed in [12]) rendering these genes ‘operational’ calcification inhibitors together with fetuin-A, matrix Gla protein, osteoprotegerin, ank and klotho. For the sake of readability, we want to limit the time period ‘inhibitor’ to referring to kinetic inhibition of the calcification response, which adequately characterizes the properties of fetuin-A. The absence of a number of the different genes is related to gentle tissue calcification as nicely, however their merchandise by no means take part in precipitation reactions as chemical or biochemical ‘inhibitors’ within the kinetic sense.
Deficiencies of kinetic calcification inhibitors could also be further and important determinants of the initiation and development of calcification processes in sufferers with persistent kidney illness. Our latest cross-sectional research displaying that deficiency of the circulating calcification inhibitor fetuin-A was related to impaired all-cause and cardiovascular survival in ESRD sufferers might be considered oblique in vivo proof in people {that a} lack of calcification inhibition could certainly impose a danger to sufferers on dialysis [13]. As well as, within the eight calciphylaxis sufferers talked about above, in whom serum Ca and P ranges weren’t considerably deranged, we constantly noticed very low fetuin-A serum ranges [11]. Deficiencies of calcification inhibitors comparable to fetuin-A could thus enhance the chance of extraosseous calcification even at comparatively regular Ca and P concentrations.
Classes from uraemic calcification-prone mice
As a way to acquire a greater understanding of the connection between uraemia, mineral load and calcification inhibitor deficiencies, we not too long ago carried out an experimental research in fetuin-A-deficient (Ahsg−/−) mice [14]. These research had been carried out in mice carrying the C57BL/6 genetic background, as a result of these animals require exogenous stimuli to develop extraosseous calcifications, in distinction to Ahsg−/− mice on a DBA/2 background, which calcify spontaneously [11]. The C57BL/6-Ahsg−/− mice allowed us to mix variably in vivo fetuin deficiency, renal insufficiency and excessive dietary phosphate load. A complete of eight teams of mice had been investigated. Wild-type mice with or with out renal insufficiency (induced by 5/6 nephrectomy) and on both regular or excessive phosphate eating regimen had been in contrast with fetuin-A−/− mice uncovered to the identical interventions. We then evaluated the affect of those interventions on extraosseous calcifications and the Ca × P product amongst the teams.
In not one of the teams with regular renal operate and in not one of the teams with regular phosphate consumption did extraosseous calcifications develop, and in all of them Ca × P product remained regular. The important thing findings of this experimental research associated to the 2 teams with renal insufficiency plus a excessive phosphate consumption. If mixed with a wild-type, i.e. fetuin-sufficient, background, no tissue calcifications (aside from the kidneys) occurred, though the serum Ca × P product elevated considerably (to 10.1±0.24 mmol2/l2). In distinction, if mixed with a fetuin-A-deficient background, widespread calcifications of the myocardium, lungs and coronary heart valves had been detected, though the Ca × P product in serum remained regular (5.9±0.8 mmol2/l2).
What do the above observations indicate? First, a excessive Ca × P product could also be compensated, no less than quickly, by sufficient calcification inhibitor ranges that preserve the solubility of Ca and P ions within the serum. Secondly, and extra importantly, within the presence of extreme calcification inhibitor deficiencies, calcium and phosphate seem to precipitate and deposit in tissues so quickly {that a} rise in serum Ca and P concentrations is not detectable. Consequently, on this state of affairs, serum Ca and P could also be a deceptive supply to evaluate the chance of calcification.
Is a excessive Ca × P product in serum all the time dangerous?
The reply might be: sure, no less than in many of the circumstances and definitely in these in whom there’s a persistent elevation of the Ca × P product. Experimentally, if a excessive Ca × P product is persisting for extended occasions within the presence of renal insufficiency, calcifications will develop even in affiliation with regular fetuin-A ranges [15]. Secondly, it’s an outdated medical commentary that in dialysis sufferers with extraordinarily elevated Ca × P merchandise, large gentle tissue calcifications spontaneously typically develop inside just a few days [8]. Thirdly, in dialysis sufferers, along with the registry research cited above [3–5], Stevens and associates not too long ago confirmed in >500 research topics {that a} excessive Ca × P product predicted an impairment of cardiovascular survival particularly if related to both very low or very excessive iPTH serum ranges [16]. These observations could level to a different crucial determinant when decoding the position of an elevated Ca × P product in dialysis sufferers, specifically that of the ‘bone buffer’. In sufferers affected by adynamic bone illness in addition to in sufferers with extreme high-turnover bone illness, the bone is unable to buffer out there extracellular Ca and P ions, resulting in an elevated extraosseous Ca and P pool. Per this commentary, Braun et al. famous an inverse relationship between bone density and coronary calcification in dialysis sufferers [17].
Lastly, when contemplating the Ca × P product, serum Ca and P ranges ought to all the time be additionally judged individually. Each hyperphosphataemia and hypercalcaemia could straight induce organic processes comparable to osteogenic differentiation of vascular clean muscle cells, instantly pathophysiogically related to progressive vascular calcification along with simply rising the Ca × P product [18–20]. Nonetheless, whereas hyperphosphataemia often signifies an actual extracellular phosphate overload, the interpretation of hypercalcaemia seems extra sophisticated, since protein-binding, vitamin D-dependent intestinal absorption and the state of bone turnover all quickly regulate the serum ranges. Additional, doubtlessly harmful serum calcium peaks can’t be reliably detected by occasional measurements. In accordance, registry information level rather more clearly to the significance of hyperphosphataemia as an impartial mortality danger predictor in dialysis sufferers than to a task of hypercalcaemia [5]. Measurements of ionized serum Ca ranges could also be no less than {a partially} higher method to overcome such difficulties, however will likely be exhausting to implement in medical apply. Given the out there proof, the cumulative Ca load administered to sufferers ought to due to this fact be assessed along with measurements of serum Ca ranges with a purpose to higher predict particular person hypercalcaemia-associated cardiovascular dangers [6]. The Ca load needs to be restricted in keeping with the suggestions of the present Ok/DOQI pointers (i.e. most elemental Ca consumption by Ca-based P binders, <1.5 g/day; most whole elemental Ca consumption, <2.0 g/day) [1].
Conclusion – “calcium x phosphate product”
Primarily based on a considerable amount of experimental and medical information, an elevated Ca × P product should nonetheless be considered a predictor of cardiovascular danger and calcification within the majority of dialysis sufferers. Nonetheless, in some uraemic people, a ‘guideline-conform’ regular Ca × P product could also be deceptive, since it could outcome from an impaired capability of serum to maintain Ca and P ions in answer, resulting in a fast deposition of Ca and P inside extraosseous calcifications. Primarily based on the above, we require refined instruments to determine people at excessive danger for progressive cardiovascular tissues. Ideally, future remedy suggestions needs to be prolonged to include measurements of fetuin-A, the foremost systemic calcification inhibitor. Since fetuin-A is regulated as a damaging acute-phase reactant, elevated C-reactive protein ranges may function a surrogate marker till fetuin-A measurements grow to be extra extensively out there. This extra full evaluation hopefully will be capable of keep away from conditions through which the Ca × P product turns into a real ‘Trojan horse’, i.e. a formally applicable product suggesting a well-controlled state of affairs, when the truth is issues are uncontrolled.
Battle of curiosity assertion. None declared.
References
Creator notes
1Department of Nephrology and Medical Immunology and 2IZKF BioMAT, College Hospital Aachen, Germany