Outcomes Associated with Serum Calcium Level in Men with Non-Dialysis-Dependent Chronic Kidney Disease
01 Mar 2010-Clinical Journal of The American Society of Nephrology (American Society of Nephrology)-Vol. 5, Iss: 3, pp 468-476
TL;DR: Clinical trials are warranted to determine whether maintaining normal serum calcium can improve outcomes in patients with NDD CKD, and higher serum calcium is associated with increased long-term mortality, and lower calcium isassociated with increased short-term death in patients in the time-varying models.
Abstract: Background and objectives: Elevated serum calcium has been associated with increased mortality in dialysis patients, but it is unclear whether the same is true in non-dialysis-dependent (NDD) chronic kidney disease (CKD). Outcomes associated with low serum calcium are also not well-characterized. Design, setting, participants, & measurements: We examined associations of baseline, time-varying, and time-averaged serum calcium with all-cause mortality in a historic prospective cohort of 1243 men with moderate and advanced NDD CKD by using Cox models. Results: The association of serum calcium with mortality varied according to the applied statistical models. Higher baseline calcium and time-averaged calcium were associated with higher mortality (multivariable adjusted hazard ratio (95% confidence interval): 1.31 (1.13, 1.53); P Conclusions: Higher serum calcium is associated with increased long-term mortality (as reflected by the baseline and time-averaged models), and lower serum calcium is associated with increased short-term mortality (as reflected by the time-varying models) in patients with NDD CKD. Clinical trials are warranted to determine whether maintaining normal serum calcium can improve outcomes in these patients.
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TL;DR: A major role is suggested for elevated P in promoting osteogenic/chondrogenic differentiation of VSMC, whereas elevated Ca has a predominant role in promoting VSMC apoptosis and vesicle release.
Abstract: Vascular calcification contributes to the high risk of cardiovascular mortality in chronic kidney disease (CKD) patients. Dysregulation of calcium (Ca) and phosphate (P) metabolism is common in CKD patients and drives vascular calcification. In this article, we review the physiological regulatory mechanisms for Ca and P homeostasis and the basis for their dysregulation in CKD. In addition, we highlight recent findings indicating that elevated Ca and P have direct effects on vascular smooth muscle cells (VSMCs) that promote vascular calcification, including stimulation of osteogenic/chondrogenic differentiation, vesicle release, apoptosis, loss of inhibitors, and extracellular matrix degradation. These studies suggest a major role for elevated P in promoting osteogenic/chondrogenic differentiation of VSMC, whereas elevated Ca has a predominant role in promoting VSMC apoptosis and vesicle release. Furthermore, the effects of elevated Ca and P are synergistic, providing a major stimulus for vascular calcification in CKD. Unraveling the complex regulatory pathways that mediate the effects of both Ca and P on VSMCs will ultimately provide novel targets and therapies to limit the destructive effects of vascular calcification in CKD patients.
759 citations
TL;DR: FGF23 has recently emerged as one of the most powerful predictors of adverse outcomes in patients with CKD and ESRD and its physiology and pathophysiology is reviewed, and putative mechanisms of action responsible for its negative effects are described and potential therapeutic strategies to treat these are described.
Abstract: Traditional risk factors of cardiovascular morbidity and mortality such as hypertension, hypercholesterolemia and obesity are paradoxically associated with better outcomes in dialysis patients, and the few trials of interventions targeting modifiable traditional risk factors have yielded disappointing results in this patient population. Non-traditional risk factors such as inflammation, anemia and abnormalities in bone and mineral metabolism have been proposed as potential explanations for the excess mortality seen in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD), but without clear understanding of what the most important pathophysiologic mechanisms of these risk factors are, which ones might be ideal treatment targets and which therapeutic interventions may be effective and safe in targeting them. Among the novel risk factors, fibroblast growth factor-23 (FGF23) has recently emerged as one of the most powerful predictors of adverse outcomes in patients with CKD and ESRD. FGF23 is a hormone produced by osteoblasts/osteocytes in bone that acts on the kidney to regulate phosphate and vitamin D metabolism through activation of FGF receptor/α-Klotho co-receptor complexes. It is possible that elevated FGF23 may exert its negative impact through distinct mechanisms of action independent from its role as a regulator of phosphorus homeostasis. Elevated circulating FGF23 concentrations have been associated with left ventricular hypertrophy (LVH), and it has been suggested that FGF23 exerts a direct effect on the myocardium. While it is possible that ‘off target’ effects of FGF23 present in very high concentrations could induce LVH, this possibility is controversial, since α-klotho is not expressed in the myocardium. Another possibility is that FGF23's effect on the heart is mediated indirectly, via ‘on target’ activation of other humoral pathways. We will review the physiology and pathophysiology of FGF23, the outcomes associated with elevated FGF23 levels, and describe putative mechanisms of action responsible for its negative effects and potential therapeutic strategies to treat these.
109 citations
Cites background from "Outcomes Associated with Serum Calc..."
...Abnormalities of bone and mineral metabolism associated with increased mortality in CKD include hyperphosphatemia [11, 12], hypo- and hypercalcemia [13], hypo- and hyperparathyroidism [14] and hyperphosphatasemia [15]; these have recently been grouped under the umbrella term of CKDrelated mineral and bone disorders (CKD-MBD) [16]....
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TL;DR: By understanding better the molecular pathways and genetic circuitry responsible for the pathological mineralization process novel drug targets may be identified and exploited to combat and reduce the detrimental effects of vascular calcification on human health.
Abstract: Vascular calcification has severe clinical consequences and is considered an accurate predictor of future adverse cardiovascular events, including myocardial infarction and stroke. Previously vascular calcification was thought to be a passive process which involved the deposition of calcium and phosphate in arteries and cardiac valves. However, recent studies have shown that vascular calcification is a highly regulated, cell-mediated process similar to bone formation. In this article, we outline the current understanding of key mechanisms governing vascular calcification and highlight the clinical consequences. By understanding better the molecular pathways and genetic circuitry responsible for the pathological mineralization process novel drug targets may be identified and exploited to combat and reduce the detrimental effects of vascular calcification on human health.
104 citations
Cites background from "Outcomes Associated with Serum Calc..."
...A number of clinical studies have also shown an association between elevated serum calcium and increased risk of myocardial infarction and vascular calcification in both CKD patients and in the general population (Yamada et al., 2007; Kovesdy et al., 2010; Larsson et al., 2010; West et al., 2010)....
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TL;DR: Whereas in hemodialysis patients cumulatively high or low calcium levels are associated with higher death risk, subtle but meaningful interactions with phosphorus, PTH, paricalcitol dose and race exist.
Abstract: Background: The outcome-predictability of baseline and instantaneously changing serum calcium in hemodialysis patients has been examined. We investigated the mortality-predictabilit
82 citations
TL;DR: To improve the overall quality of life of hemodialysis patients, a multidisciplinary intervention that includes medical, dietetic and psychosocial strategies that address factors associated with mental and physical quality ofLife are warranted to reduce further health complications and to improvequality of life.
Abstract: Although hemodialysis treatment has greatly increased the life expectancy of end stage renal disease patients, low quality of life among hemodialysis patients is frequently reported. This cross-sectional study aimed to determine the relationship between medical history, hemodialysis treatment and nutritional status with the mental and physical components of quality of life in hemodialysis patients. Respondents (n=90) were recruited from Hospital Kuala Lumpur and dialysis centres of the National Kidney Foundation of Malaysia. Data obtained included socio-demography, medical history, hemodialysis treatment and nutritional status. Mental and physical quality of life were measured using the Mental Composite Summary (MCS) and Physical Composite Summary (PCS) of the Short-Form Health Survey 36-items, a generic core of the Kidney Disease Quality of Life Short Form. Two summary measures and total SF-36 was scored as 0–100, with a higher score indicating better quality of life. Approximately 26 (30%) of respondents achieved the body mass index (24 kg/m2) and more than 80% (n=77) achieved serum albumin level (>35.0 mg/dL) recommended for hemodialysis patients. The majority of respondents did not meet the energy (n=72, 80%) and protein (n=68,75%) recommendations. The total score of SF-36 was 54.1±19.2, while the score for the mental and physical components were 45.0±8.6 and 39.6±8.6, respectively. Factors associated with a higher MCS score were absence of diabetes mellitus (p=0.000) and lower serum calcium (p=0.004), while higher blood flow (p=0.000), higher serum creatinine (p=0.000) and lower protein intake (p=0.006) were associated with a higher PCS score. To improve the overall quality of life of hemodialysis patients, a multidisciplinary intervention that includes medical, dietetic and psychosocial strategies that address factors associated with mental and physical quality of life are warranted to reduce further health complications and to improve quality of life.
77 citations
Cites background from "Outcomes Associated with Serum Calc..."
...Several studies have reported that elevated serum calcium was associated with increased mortality in dialysis patients because it increased the risk of cardiovascular diseases [50,51]....
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...There are limited studies on the effects of low serum calcium on mental health status or mortality [17,50,52]....
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...Therefore, for patients on HD, serum calcium in the low-normal range is important to minimise the complications associated with high serum calcium and to improve quality of life [49-51]....
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References
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TL;DR: The results indicate that active calcium absorption is markedly depressed in patients with chronic renal disease who are receiving hemodialysis therapy, and passive calcium movement and endogenous calcium secretions are normal.
Abstract: 10 patients with chronic renal disease on hemodialysis and 8 normals were studied by constant jejunal perfusion of calcium gluconate solutions, using polyethylene glycol as a nonabsorbable marker. Results in normals indicated that calcium absorption from 1 and 5 mM calcium solutions is mainly active. Absorption from 5, 15, and 20 mM solutions was a linear function of luminal calcium concentration, suggesting that the active transport carrier is saturated when luminal calcium concentration is greater than 5 mM and indicating that the increment in absorption at higher luminal concentrations is mainly the result of passive absorption. With 1 mM calcium, normals absorbed calcium against a concentration gradient, whereas the patients secreted calcium. Absorption in the patients was much less than normal with 5, 15, and 20 mM luminal calcium concentrations; however, the slope of this linear (passive) portion of the curve was normal. Unidirectional calcium fluxes were measured with calcium-47. Flux out of the lumen was depressed 2.5-fold in the patients, but flux into the lumen was normal. Xylose, urea, and tritiated water were absorbed normally, indicating no generalized abnormality of jejunal transport in these patients. Endogenous calcium secretion, estimated by the amount of calcium added to a calcium-free solution, was normal in the dialysis patients. These results indicate that active calcium absorption is markedly depressed in patients with chronic renal disease who are receiving hemodialysis therapy. On the other hand, passive calcium movement and endogenous calcium secretions are normal.
37 citations
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...005 Race (black), n (%) 55 (19) 66 (23) 81 (25) 98 (29) 0....
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TL;DR: In this paper, the assessment and mechanisms of calcium flux during hemodialysis, choice of dialysate calcium concentration, influence of HD modality, and potential consequences of therapy choices (cardiovascular and skeletal) resulting from an inappropriate intradialytic calcium balance.
Abstract: Calcium balance during hemodialysis (HD) is important in determining short-term cardiovascular function, this influences the hemodynamic tolerability of dialysis. In the longer term, calcium flux during HD is an important determinant of overall calcium balance in a patient and may also influence the development and progression of vascular calcification, with its attendant consequences. This article aims to review the assessment and mechanisms of calcium flux during HD, choice of dialysate calcium concentration, influence of HD modality, and potential consequences of therapy choices (cardiovascular and skeletal) resulting from an inappropriate intradialytic calcium balance.
33 citations
TL;DR: The calcium gradient concentration between plasma and dialysate was found to be the main factor responsible for the calcium variations observed during haemodialysis with high flux membrane.
Abstract: The variations of ionized and total calcium concentrations were studied during haemodialysis with high flux membrane using dialysate calcium concentrations of 1.63 and 1.76 mmol/l. The changes in ionized and total calcium were related to the predialytic calcium concentration difference between plasma and dialysate. The calcium changes were not influenced by the intradialytic pH variations. But the total calcium level increased more with the higher albumin concentration. Compared with previous studies, the calcium gradient concentration between plasma and dialysate was found to be the main factor responsible for the calcium variations observed during haemodialysis with high flux membrane.
9 citations