Disordered calcium homeostasis of sepsis: association with calcitonin precursors

Müller, Beat; Becker, Kenneth L.; Kränzlin, Marius; Schächinger, Hartmut; Huber, Peter; Nylen, Eric; Snider, Richard H.; White, Jon; Schmidt-Gayk, H; Zimmerli, Werner; Ritz, R

doi:10.1046/j.1365-2362.2000.00714.x

Cited by 108 publications

(89 citation statements)

References 52 publications

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“…Circulating levels of calcitonin, mainly high molecular weight procalcitonin forms, are elevated in critically ill patients (19). The levels are higher in septic (especially septic shock) than in nonseptic patients and are related to the severity of illness.…”

Section: Discussionmentioning

confidence: 99%

“…However, the hypoparathyroidism is persistent following magnesium repletion in burn-injured children, making this explanation unlikely (17). Calcitonin precursors are increased in the circulation of critically ill patients with sepsis and could contribute to the hypocalcemia (16,18,19). In addition, the serum concentra-tions of proinflammatory cytokines such as interleukin-1␤ (IL-1␤) and tumor necrosis factor-␣ (TNF-␣) are markedly increased in patients with burn injury or sepsis and are inversely related to the calcium concentration (16).…”

mentioning

confidence: 99%

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Calcium-sensing Receptor Gene Transcription Is Up-regulated by the Proinflammatory Cytokine, Interleukin-1β

Canaff¹,

Hendy

2005

Journal of Biological Chemistry

101

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The calcium-sensing receptor (CASR) in parathyroid, thyroid, and kidney is essential for calcium homeostasis. Hypocalcemia is common in critically ill patients having increased circulating proinflammatory cytokines, although the causes are unknown. We hypothesized that the cytokines increase CASR expression and reduce the set point for parathyroid hormone suppression by extracellular calcium, leading to hypocalcemia and hypoparathyroidism. Here, we show in vivo in the rat that parathyroid, thyroid, and kidney CASR mRNA and protein increased after injection of interleukin-1␤. This was associated with decreased circulating parathyroid hormone, calcium, and 1,25-dihydroxyvitamin D levels. Interleukin-1␤ stimulated endogenous CASR gene transcripts and transfected promoter reporter activity in human thyroid C-cells (TT cells) and kidney proximal tubule (HKC) cells. Cotransfection of NF-B proteins enhanced activity of the reporter constructs, whereas cotransfection with inhibitor-B or application of an NF-B nuclear localization sequence peptide abrogated responsiveness to cytokine or NF-B proteins. Mutagenesis of some, but not all, of the potential B elements in the 5 part of the CASR gene led to loss of responsiveness to cytokine. These elements conferred cytokine responsiveness to a heterologous promoter, and in electrophoretic mobility shift assays, NF-B complexes formed on the same three B elements. In summary, the CASR gene has several functional B elements that mediate its upregulation by proinflammatory cytokines and probably contribute to altered extracellular calcium homeostasis in the critically ill.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Calcium-sensing Receptor Gene Transcription Is Up-regulated by the Proinflammatory Cytokine, Interleukin-1β

Canaff¹,

Hendy

2005

Journal of Biological Chemistry

101

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“…Some of the decrease in calcium concentrations was considered to be because of a decrease in the protein (albumin) bound fraction, and some was considered to be because of sepsis. 27 Increases in a-2-macroglobulin concentrations were first detected on day 3 after exposure, and these were markedly increased by day 5 after exposure. The increases in a-2-macroglobulin were considered to be because of the acute phase response to F. tularensis.…”

Section: Clinical Pathologymentioning

confidence: 93%

The Natural History of Pneumonic Tularemia in Female Fischer 344 Rats after Inhalational Exposure to Aerosolized Francisella tularensis Subspecies tularensis Strain SCHU S4

Hutt

Lovchik

Dekonenko

et al. 2017

The American Journal of Pathology

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The inbred Fischer 344 rat is being evaluated for testing novel vaccines and therapeutics against pneumonic tularemia. Although primary pneumonic tularemia in humans typically occurs by inhalation of aerosolized bacteria, the rat model has relied on intratracheal inoculation of organisms because of safety and equipment issues. We now report the natural history of pneumonic tularemia in female Fischer 344 rats after nose-only inhalational exposure to lethal doses of aerosolized Francisella tularensis subspecies tularensis, strain SCHU S4. Our results are consistent with initial uptake of aerosolized SCHU S4 from the nasal cavity, lungs, and possibly the gastrointestinal tract. Bacteremia with hematogenous dissemination was first detected 2 days after exposure. Shortly thereafter, the infected rats exhibited fever, tachypnea, and hypertension that persisted for 24 to 36 hours and then rapidly decreased as animals succumbed to infection between days 5 and 8 after exposure. Tachycardia was observed briefly, but only after the core body temperature and blood pressure began to decrease as the animals were near death. Initial neutrophilic and histiocytic inflammation in affected tissues became progressively more fibrinous and necrotizing over time. At death, as many as 10 10 colony-forming units were found in the lungs, spleen, and liver. Death was attributed to sepsis and disseminated intravascular coagulation. Overall, the pathogenesis of pneumonic tularemia in the female F344 rat model appears to replicate the disease in humans. (Am J Pathol 2017, 187: 252e267; http://dx

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“…Despite raised PTH level was not statistically significant from day one to day five, survivor patients' median PTH levels elevated within normal range but non-survivor patients median PTH levels elevated above the normal range. Proposed mechanism of PTH elevation at nonsurvivors are cytokine dependent receptor resistance, hypocalcemia, low level of vitamin D levels at septic shock patients and end-organ in responsiveness [32][33][34][35]. İn addition to these mechanism, half-life of PTH at plasma is under 5 minutes and most of metabolites are removed by the kupffer cells and 20-30% of metabolites removed by renal tubules [36].…”

Section: A) B)mentioning

confidence: 99%

Sequential vitamin D and parathyroid hormone measurement in patients with septic shock: Could they be prognostic marker in septic shock

Yeter

Aktepe

Topeli

2018

j-ebr

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A B S T R A C T Aim:Hypocalcemia is a common clinical problem in critically-ill patients and it is associated with increased morbidity and mortality. The aim of this study was to investigate serum calcium, vitamin D and parathyroid hormone (PTH) levels in surviving and non-surviving septic shock patients. Method: Patients with septic shock criteria and who were older than 18 years of age were included, whereas patients with diseases influencing calcium homeostasis were excluded. Demographic and laboratory parameters were recorded prospectively. Results: 41 patients, 20 of which were male were included in the study. The median (min-max) age of study population was 67 (19-88) years. Frequency of hypocalcemia in the study population was 29.2% and 68.2% according to corrected calcium and ionized calcium, respectively. On the day septic shock was diagnosed (day 1), median vitamin D levels of survivors and non-survivors were 8.7 ng/ml (4.3-30.4) and 5.3 ng/ml (1.0-21.7), respectively (p=0.05). On the same day, median PTH levels of survivors and non-survivors were 94 ng/L (16.9-1746) and 49 ng/L (6.6-339), respectively (p=0.042). Although vitamin D levels were suppressed and PTH levels were elevated in non-survivors at day 5, this change was not statistically significant (p=0.19 and p=0.187). Conclusion: Hypocalcemia is frequent in septic shock patients, whereas vitamin D levels were low and PTH levels were high in the diagnosis day. These results suggest that vitamin D is suppressed by septic shock at non-surviving patients during course of septic shock. Parathyroid hormone may be a marker for worse outcome in critically ill patients.

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Disordered calcium homeostasis of sepsis: association with calcitonin precursors

Abstract: In critically ill patients with sepsis, markedly elevated circulating calcitonin precursors might play a role in the development of the pronounced hypocalcemia. The specific calcitonin precursor(s) responsible for this effect and the pathophysiological mechanism remain to be elucidated.

Cited by 108 publications

References 52 publications

Calcium-sensing Receptor Gene Transcription Is Up-regulated by the Proinflammatory Cytokine, Interleukin-1β

Calcium-sensing Receptor Gene Transcription Is Up-regulated by the Proinflammatory Cytokine, Interleukin-1β

The Natural History of Pneumonic Tularemia in Female Fischer 344 Rats after Inhalational Exposure to Aerosolized Francisella tularensis Subspecies tularensis Strain SCHU S4

Sequential vitamin D and parathyroid hormone measurement in patients with septic shock: Could they be prognostic marker in septic shock

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