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: Elevations of normalized alkaline phosphatase were significantly associated with several comorbid conditions, increased fractures, parathyroidectomy, risk of hospitalization due to major adverse cardiac events, higher all-cause cardiovascular, and infection-related mortality risk.
133 citations
"Outcomes Associated with Serum Calc..." refers background in this paper
...only had data on PTH levels in a subgroup of patients; hence, we could not account for the confounding effects of it in the entire population, but we were able to use instead serum ALP as a marker of increased bone formation and an independent risk factor of mortality in maintenance hemodialysis patients (41,42)....
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TL;DR: Coronary calcification is highly prevalent in pre-dialysis patients and correlates with traditional and non-traditional risk factors for CVD.
Abstract: Background. Coronary heart disease (CHD) is the leading cause of death among end-stage renal disease patients. There is evidence that coronary calcification is a marker of atherosclerotic vascular disease and is predictive of cardiovascular events, especially in patients on renal replacement therapy. It has recently been suggested that CHD begins in the pre-dialysis period. However, data regarding coronary calcification in this population is scarce. This study was aimed at evaluating such coronary calcification and identifying related factors. Methods. A total of 96 chronic kidney disease outpatients who were not on dialysis were included. Patients presenting neoplastic, infectious or inflammatory diseases were excluded. Demographic characteristics, clinical profiles, laboratory test results and multislice computed tomography scans were evaluated. Results. The median age was 55 years (range 20–69 years), 67% were men and the median creatinine clearance was 37 ml/min/1.73 m 2 . Coronary calcification, defined as a coronary artery calcification score (CACS) >0 Agatston units (AU), was seen in 61 patients (median 89.1 AU, range 0.37–2299.3 AU). On average, these patients were older, more often had diabetes, higher body mass indices and higher Framingham risk indices, as well as presenting higher proteinuria, intact parathyroid hormone (iPTH), blood glucose and triglyceride levels compared with those without calcification. Multiple logistic regression analysis, adjusted for age and diabetes, identified iPTH and triglyceride levels as independent determinants of calcification. Severe calcification (CACS >400 AU) was seen in 22 patients, who were also older and more frequently had a history of cardiovascular disease (CVD), as well as having higher levels of phosphorus, blood glucose and soluble Fas (sFas).
127 citations
Additional excerpts
...7 Smoking, n (%) 59 (22) 66 (24) 92 (29) 86 (27) 0....
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TL;DR: Lower blood pressure is associated with higher mortality in patients with moderate to severe CKD, but interactions with kidney function and with ASCVD suggest that blood pressure may play a surrogate rather than a causative role in this association.
Abstract: Background. Blood pressure shows an inverse association with mortality in patients with chronic kidney disease (CKD) on dialysis. It is unclear if the same phenomenon exists in patients with CKD not yet on dialysis. Methods. We examined the association of systolic (SBP) and diastolic (DBP) blood pressure with allcause mortality in a historical prospective cohort of 860 patients (age 68.1±10.1 years, 99.1% male, 24.4% black) with estimated glomerular filtration rate (GFR) 170 mmHg, compared with 86 mmHg, compared with <65 mmHg: 0.85 (0.62–1.18), 0.72 (0.52–1.00) and 0.60 (0.41–0.86)]. The same association was present for both SBP and DBP only in subgroups with GFR � 30 ml/min/1.73 m 2 and for DBP only in the subgroup with ASCVD. Conclusions. Lower blood pressure is associated with higher mortality in patients with moderate to severe CKD, but interactions with kidney function and with ASCVD suggest that blood pressure may play a surrogate rather than a causative role in this association.
114 citations
Additional excerpts
...Future calcitriol use, n (%) 101 (35) 96 (33) 97 (29) 95 (28) 0....
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...7 Smoking, n (%) 59 (22) 66 (24) 92 (29) 86 (27) 0....
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...005 Race (black), n (%) 55 (19) 66 (23) 81 (25) 98 (29) 0....
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TL;DR: This first such study of nondialyzed individuals with DN suggests that, unlike ESRD patients, the high CAC burden seen at earlier stages of diabetic chronic kidney disease is probably unrelated to disordered mineral metabolism.
108 citations
Additional excerpts
...7 Smoking, n (%) 59 (22) 66 (24) 92 (29) 86 (27) 0....
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TL;DR: The understanding of the relationship between altered mineral metabolism and mortality outcomes is expanded, showing slightly stronger associations with cardiovascular causes than observed for all‐cause mortality.
Abstract: Abnormalities in mineral metabolism have been linked to mortality in hemodialysis (HD) patients. We postulated that these abnormalities would have a particularly large deleterious impact on deaths due to cardiovascular causes in Japan. This study describes the recent status of abnormal mineral metabolism, significant predictors, and potential consequences in the Dialysis Outcomes and Practice Patterns Study (DOPPS), Phases 1 and 2, in Japan. Major predictor variables were patient demographics, comorbidities, and laboratory markers of mineral metabolism such as albumin-adjusted serum calcium (calciumAlb), phosphorus, and intact PTH (iPTH). In a cross section of 3973 Japanese HD patients in DOPPS I and II, a large faction had laboratory values outside of the recommended Kidney Disease Outcomes Quality Initiative (K/DOQI) guideline range for serum concentrations of phosphorus (51% of patients above upper target range), calciumAlb (43.7% above), calcium-phosphorus (Ca x P) product (41.1% above), and iPTH (18.6% above). All-cause mortality was significantly and independently associated with calciumAlb (relative risk [RR]=1.22 per 1 mg/dL, p=0.0005) and iPTH (RR=1.04 per 100 pg/mL, p=0.04). Cardiovascular mortality was significantly associated with calciumAlb (RR=1.28, p=0.02), phosphorus (RR=1.13 per 1 mg/dL, p=0.008), Ca x P product (RR=1.07 per 2 mg(2)/dL(2), p=0.002), and PTH (RR=1.08, p=0.0001). This study expands our understanding of the relationship between altered mineral metabolism and mortality outcomes, showing slightly stronger associations with cardiovascular causes than observed for all-cause mortality. These findings have important therapeutic implications for Japanese HD patients.
102 citations