Abstract Introduction We present a case of a patient with osteoporosis and chronic kidney disease... more Abstract Introduction We present a case of a patient with osteoporosis and chronic kidney disease (CKD)-induced secondary hyperparathyroidism who developed severe hypophosphatemia and increasing parathyroid hormone (PTH) level after receiving Denosumab. Clinical Case 90-year-old male with CKD stage 3 presented for hyperparathyroidism evaluation in 2015. Baseline GFR was 39 - 47 ml/min/1.73 m2. PTH was 320 pg/ml (8 - 97 pg/ml) with normal calcium and low vitamin D (25-D) 14 ng/ml (30 - 100 ng/ml). Repeat PTH was 299 pg/ml; 25-D 23 ng/ml and 24-hr urine calcium was 8 mg (100 - 300 mg). Hyperparathyroidism was concluded to be due to CKD and Vitamin D deficiency. Vitamin D was replaced and PTH decreased to 262 pg/ml. With fragility fracture history, dual-energy X-ray absorptiometry (DXA) scan was obtained and resulted with a T-score of -2.8 SD at the femoral neck. Denosumab (60 mg) was started after 25-D normalized in 3/2016. Follow-up laboratory analysis in 8/2016 revealed PTH 512 pg/ml, calcium 8.9 mg/dl (8.5 - 10.1 mg/dl), 25-D 44.7 ng/ml and phosphate 1.3 mg/dl (2.5 - 4.5 mg/dl), previously 2.1 mg/dl. Alkaline phosphate 104 U/l (45 - 117 U/l), calcitriol 63.9 pg/ml (19.9 - 79.3 pg/ml) and fibroblast growth factor 23 (FGF-23) 188 RU/ml (44 - 215 RU/ml). 24-hr urine calcium was 27 mg and phosphate >90 mg/dl. Serum phosphate improved with supplementation and Cinacalcet started for high PTH. After the second Denosumab injection, low phosphate (1.2 mg/dl) recurred and PTH remained high (510 pg/ml). With recurrent effects, Denosumab was switched to bisphosphonate as GFR was stable >40 ml/min/1.73 m2. PTH normalized to 78 pg/ml and phosphate stable (2-2.4 mg/dl) on Cinacalcet and off Denosumab. Discussion Hypophosphatemia is a rare side effect of Denosumab, a monoclonal antibody to RANK-L. PTH mildly increase with Denosumab secondary to hypocalcemia. In our patient, there was a significant rise in PTH level and a decline in phosphate following Denosumab administration with no effect on calcium level. There are very few reports of these combined adverse events in the literature. The proposed mechanism is that the irreversible blockade by Denosumab results in low bone turnover which then causes increase in PTH and then increase urinary phosphate excretion. This mechanism can apply to CKD patients with secondary hyperparathyroidism when given a blocking agent like Denosumab, there is a further increase in PTH in the setting of low bone turnover. If not closely monitored, it can be detrimental. Elevated FGF-23 can downregulate 1-alpha-hydroxylase and increase urinary phosphate but unlikely in our patient given its normal level. Conclusion Severe hypophosphatemia may be a rare side effect of Denosumab, particularly in CKD patient with secondary hyperparathyroidism. Therefore, phosphate and PTH should be monitored closely after Denosumab administration to prevent adverse events.
Hypertonic saline infusion is used to correct hyponatremia with severe symptoms. The selection of... more Hypertonic saline infusion is used to correct hyponatremia with severe symptoms. The selection of the volume of infused hypertonic saline (V Inf ) should address prevention of overcorrection or undercorrection. Several formulas computing this V Inf have been proposed. The limitations common to these formulas consist of (1) failure to include potential determinants of change in serum sodium concentration ([Na]) including exchanges between osmotically active and inactive sodium compartments, changes in hydrogen binding of body water to hydrophilic compounds, and genetic influences and (2) inaccurate estimates of baseline body water entered in any formula and of gains or losses of water, sodium, and potassium during treatment entered in formulas that account for such gains or losses. In addition, computing V Inf from the Adrogué-Madias formula by a calculation assuming a linear relation between V Inf and increase in [Na] is a source of errors because the relation between these two variables was proven to be curvilinear. However, these errors were shown to be negligible by a comparison of estimates of V Inf by the Adrogué-Madias formula and by a formula using the same determinants of the change in [Na] and the curvilinear relation between this change and V Inf . Regardless of the method used to correct hyponatremia, monitoring [Na] and changes in external balances of water, sodium, and potassium during treatment remain imperative.
Introduction: Renin-Angiotensin System (RAS) induces oxidative stress and contributes to various ... more Introduction: Renin-Angiotensin System (RAS) induces oxidative stress and contributes to various pathological conditions including insulin resistance and the metabolic syndrome. Recent studies have shown the role of PPARδ-agonist in attenuation of Angiotensin II induced oxidative stress.The aim of this study was to explore the effectiveness of a PPARδ-agonist in the prevention of Ang II-induced vascular and adipocyte dysfunction and the possible interaction between PPARδ and HO-1 system in a model of enhanced oxidative stress, the Goldblatt 2K1C model. Methods: We first established a direct stimulatory effect of the PPARδ-agonist (GW 501516) on the HO-1 gene by demonstrating increased luciferase activity in COS-7 cells transfected with a luciferase-HO-1 promoter construct. SD rats were divided in 4 groups: sham operated animals, 2K1C rats and 2K1C rats treated with GW 501516, in the absence or presence of the HO activity inhibitor, stannous mesoporphyrin (SnMP). Results: 2K1C animals had increased blood pressure, visceral adiposity, adipocyte hypertrophy, increased inflamatory cytokines, increased circulatory and adipose tisssue levels of renin and Ang II along with increased adipose tissue gp91 phox expression (p<0.05) when compared to sham operated animals. Treatment with GW 501516 increased adipose tissue HO-1 and adiponectin levels (p<0.01) along with enhancement of Wnt10b and β-catenin expression. HO-1 induction was accompanied by the decreased expression of Wnt 5b, Mest and C/EBPα levels and an increased number of small adipocytes (p<0.05). These effects of GW501516 were reversed in 2K1C animals exposed to SnMP (p<0.05). Conclusion: This novel study corroborates the existence of a PPARδ-HO-1 axis whose direct stimulation via the administration of an exogenous PPARδ-agonist induces HO-1 expression, abates RAS associated adipocyte and vascular dysfunction and induces adipocyte remodeling with smaller adipocytes while decreasing inflammation and increasing adiponectin secretion.
ObjectiveThe triad of obesity, a high‐protein diet from animal sources, and disturbed gut microbi... more ObjectiveThe triad of obesity, a high‐protein diet from animal sources, and disturbed gut microbiota have been linked to poor clinical outcomes in patients with COVID‐19. In this report, the effect of oxidative stress resulting from the Na+/K+‐ATPase transporter signaling cascade is explored as a driver of this poor clinical outcome.MethodsProtein–protein interactions with the SARS‐CoV‐2 proteome were identified from the interactome data for Na+/K+‐transporting ATPase subunit α‐1 (ATP1A1), epidermal growth factor receptor, and ERB‐B2 receptor tyrosine kinase 2, using the curated data from the BioGRID Database of Protein Interactions. Data for the gene expression pattern of inflammatory response were from the Gene Expression Omnibus database for cardiomyocytes post SARS‐CoV‐2 infection (number GSE151879).ResultsThe ATP1A1 subunit of the Na+/K+‐ATPase transporter is targeted by multiple SARS‐CoV‐2 proteins. Furthermore, receptor proteins associated with inflammatory response, including epidermal growth factor receptor and ERB‐B2 receptor tyrosine kinase 2 (which interact with ATP1A1), are also targeted by some SARS‐CoV‐2 proteins. This heightened interaction likely triggers a cytokine release that increases the severity of the viral infection in individuals with obesity.ConclusionsThe similarities between the effects of SARS‐CoV‐2 proteins and indoxyl sulphate on the Na+/K+‐ATPase transporter signaling cascade suggest the possibility of an augmentation of gene changes seen with COVID‐19 infection that can result in a hyperinduction of cytokine release in individuals with obesity.
Dietary sodium intake and cardiovascular outcomes have a reported J‐shaped curve relationship. Th... more Dietary sodium intake and cardiovascular outcomes have a reported J‐shaped curve relationship. This study analyzes the relationship between dietary sodium and sugar intake as a potential mechanism to explain this association. The authors examined cross‐sectional data from the National Health and Nutrition Examination Survey (NHANES) 2001‐2016 where dietary sodium, carbohydrate, fat, cholesterol, and sugar intakes were assessed by 24‐hour dietary recall and were standardized to a total daily intake of 2000 calories. Sodium intake was categorized into sodium quintiles (SQ) as follows: SQ1(0.06‐2.6 g/d); SQ2(2.6‐3.0 g/d); SQ3(3.0‐3.4 g/d); SQ4(3.4‐4.0 g/d); and SQ5(4.0‐29.3 g/d). Simple and multivariate linear regression using SQ3 as reference were used to assess associations between daily sodium intake and the other nutrients. Our results showed that among 38 722 participants that met our study criteria, the mean age was 43.6 years (SD 16.8 years) and sex was equally distributed (48.8% male vs 51.2% female). Sugar intake went down across increasing SQs and was significantly higher in SQ1 (141.2 g/d) and SQ2 (118.6 g/d) and significantly lower in SQ4 (97.9 g/d) and SQ5 (85.6 g/d) compared to SQ3 (108.6 g/d; all P < .01). These same trends remained unchanged and significant in the fully adjusted multivariate model. In conclusion, NHANES study participants reporting low sodium intake on 24‐hour dietary recall have a higher consumption of sugar. The negative impact of low sodium diet on cardiovascular health may be explained at least partially by the associated high sugar intake.
There is an increased risk of cardiovascular disease and higher rate of hypertension in post-meno... more There is an increased risk of cardiovascular disease and higher rate of hypertension in post-menopausal (compared to pre-menopausal women). We analysed the cross-sectional National Health and Nutritional Examination and Survey 2007–2012 to look at the factors that affect systolic blood pressure in post-menopausal women. We also performed a linear regression with systolic blood pressure as the dependent variable and age, body mass index, total cholesterol, triglycerides, A1C and serum creatinine as independent variables. In the regression model, only body mass index was a significant predictor of systolic blood pressure (adjusted r2 of 0. 100, F(6, 740) = 14.74, standard error β = 0.08, standardized coefficient B = 0.31, p &lt; 0.01).
Abstract Introduction We present a case of a patient with osteoporosis and chronic kidney disease... more Abstract Introduction We present a case of a patient with osteoporosis and chronic kidney disease (CKD)-induced secondary hyperparathyroidism who developed severe hypophosphatemia and increasing parathyroid hormone (PTH) level after receiving Denosumab. Clinical Case 90-year-old male with CKD stage 3 presented for hyperparathyroidism evaluation in 2015. Baseline GFR was 39 - 47 ml/min/1.73 m2. PTH was 320 pg/ml (8 - 97 pg/ml) with normal calcium and low vitamin D (25-D) 14 ng/ml (30 - 100 ng/ml). Repeat PTH was 299 pg/ml; 25-D 23 ng/ml and 24-hr urine calcium was 8 mg (100 - 300 mg). Hyperparathyroidism was concluded to be due to CKD and Vitamin D deficiency. Vitamin D was replaced and PTH decreased to 262 pg/ml. With fragility fracture history, dual-energy X-ray absorptiometry (DXA) scan was obtained and resulted with a T-score of -2.8 SD at the femoral neck. Denosumab (60 mg) was started after 25-D normalized in 3/2016. Follow-up laboratory analysis in 8/2016 revealed PTH 512 pg/ml, calcium 8.9 mg/dl (8.5 - 10.1 mg/dl), 25-D 44.7 ng/ml and phosphate 1.3 mg/dl (2.5 - 4.5 mg/dl), previously 2.1 mg/dl. Alkaline phosphate 104 U/l (45 - 117 U/l), calcitriol 63.9 pg/ml (19.9 - 79.3 pg/ml) and fibroblast growth factor 23 (FGF-23) 188 RU/ml (44 - 215 RU/ml). 24-hr urine calcium was 27 mg and phosphate >90 mg/dl. Serum phosphate improved with supplementation and Cinacalcet started for high PTH. After the second Denosumab injection, low phosphate (1.2 mg/dl) recurred and PTH remained high (510 pg/ml). With recurrent effects, Denosumab was switched to bisphosphonate as GFR was stable >40 ml/min/1.73 m2. PTH normalized to 78 pg/ml and phosphate stable (2-2.4 mg/dl) on Cinacalcet and off Denosumab. Discussion Hypophosphatemia is a rare side effect of Denosumab, a monoclonal antibody to RANK-L. PTH mildly increase with Denosumab secondary to hypocalcemia. In our patient, there was a significant rise in PTH level and a decline in phosphate following Denosumab administration with no effect on calcium level. There are very few reports of these combined adverse events in the literature. The proposed mechanism is that the irreversible blockade by Denosumab results in low bone turnover which then causes increase in PTH and then increase urinary phosphate excretion. This mechanism can apply to CKD patients with secondary hyperparathyroidism when given a blocking agent like Denosumab, there is a further increase in PTH in the setting of low bone turnover. If not closely monitored, it can be detrimental. Elevated FGF-23 can downregulate 1-alpha-hydroxylase and increase urinary phosphate but unlikely in our patient given its normal level. Conclusion Severe hypophosphatemia may be a rare side effect of Denosumab, particularly in CKD patient with secondary hyperparathyroidism. Therefore, phosphate and PTH should be monitored closely after Denosumab administration to prevent adverse events.
Hypertonic saline infusion is used to correct hyponatremia with severe symptoms. The selection of... more Hypertonic saline infusion is used to correct hyponatremia with severe symptoms. The selection of the volume of infused hypertonic saline (V Inf ) should address prevention of overcorrection or undercorrection. Several formulas computing this V Inf have been proposed. The limitations common to these formulas consist of (1) failure to include potential determinants of change in serum sodium concentration ([Na]) including exchanges between osmotically active and inactive sodium compartments, changes in hydrogen binding of body water to hydrophilic compounds, and genetic influences and (2) inaccurate estimates of baseline body water entered in any formula and of gains or losses of water, sodium, and potassium during treatment entered in formulas that account for such gains or losses. In addition, computing V Inf from the Adrogué-Madias formula by a calculation assuming a linear relation between V Inf and increase in [Na] is a source of errors because the relation between these two variables was proven to be curvilinear. However, these errors were shown to be negligible by a comparison of estimates of V Inf by the Adrogué-Madias formula and by a formula using the same determinants of the change in [Na] and the curvilinear relation between this change and V Inf . Regardless of the method used to correct hyponatremia, monitoring [Na] and changes in external balances of water, sodium, and potassium during treatment remain imperative.
Introduction: Renin-Angiotensin System (RAS) induces oxidative stress and contributes to various ... more Introduction: Renin-Angiotensin System (RAS) induces oxidative stress and contributes to various pathological conditions including insulin resistance and the metabolic syndrome. Recent studies have shown the role of PPARδ-agonist in attenuation of Angiotensin II induced oxidative stress.The aim of this study was to explore the effectiveness of a PPARδ-agonist in the prevention of Ang II-induced vascular and adipocyte dysfunction and the possible interaction between PPARδ and HO-1 system in a model of enhanced oxidative stress, the Goldblatt 2K1C model. Methods: We first established a direct stimulatory effect of the PPARδ-agonist (GW 501516) on the HO-1 gene by demonstrating increased luciferase activity in COS-7 cells transfected with a luciferase-HO-1 promoter construct. SD rats were divided in 4 groups: sham operated animals, 2K1C rats and 2K1C rats treated with GW 501516, in the absence or presence of the HO activity inhibitor, stannous mesoporphyrin (SnMP). Results: 2K1C animals had increased blood pressure, visceral adiposity, adipocyte hypertrophy, increased inflamatory cytokines, increased circulatory and adipose tisssue levels of renin and Ang II along with increased adipose tissue gp91 phox expression (p&lt;0.05) when compared to sham operated animals. Treatment with GW 501516 increased adipose tissue HO-1 and adiponectin levels (p&lt;0.01) along with enhancement of Wnt10b and β-catenin expression. HO-1 induction was accompanied by the decreased expression of Wnt 5b, Mest and C/EBPα levels and an increased number of small adipocytes (p&lt;0.05). These effects of GW501516 were reversed in 2K1C animals exposed to SnMP (p&lt;0.05). Conclusion: This novel study corroborates the existence of a PPARδ-HO-1 axis whose direct stimulation via the administration of an exogenous PPARδ-agonist induces HO-1 expression, abates RAS associated adipocyte and vascular dysfunction and induces adipocyte remodeling with smaller adipocytes while decreasing inflammation and increasing adiponectin secretion.
ObjectiveThe triad of obesity, a high‐protein diet from animal sources, and disturbed gut microbi... more ObjectiveThe triad of obesity, a high‐protein diet from animal sources, and disturbed gut microbiota have been linked to poor clinical outcomes in patients with COVID‐19. In this report, the effect of oxidative stress resulting from the Na+/K+‐ATPase transporter signaling cascade is explored as a driver of this poor clinical outcome.MethodsProtein–protein interactions with the SARS‐CoV‐2 proteome were identified from the interactome data for Na+/K+‐transporting ATPase subunit α‐1 (ATP1A1), epidermal growth factor receptor, and ERB‐B2 receptor tyrosine kinase 2, using the curated data from the BioGRID Database of Protein Interactions. Data for the gene expression pattern of inflammatory response were from the Gene Expression Omnibus database for cardiomyocytes post SARS‐CoV‐2 infection (number GSE151879).ResultsThe ATP1A1 subunit of the Na+/K+‐ATPase transporter is targeted by multiple SARS‐CoV‐2 proteins. Furthermore, receptor proteins associated with inflammatory response, including epidermal growth factor receptor and ERB‐B2 receptor tyrosine kinase 2 (which interact with ATP1A1), are also targeted by some SARS‐CoV‐2 proteins. This heightened interaction likely triggers a cytokine release that increases the severity of the viral infection in individuals with obesity.ConclusionsThe similarities between the effects of SARS‐CoV‐2 proteins and indoxyl sulphate on the Na+/K+‐ATPase transporter signaling cascade suggest the possibility of an augmentation of gene changes seen with COVID‐19 infection that can result in a hyperinduction of cytokine release in individuals with obesity.
Dietary sodium intake and cardiovascular outcomes have a reported J‐shaped curve relationship. Th... more Dietary sodium intake and cardiovascular outcomes have a reported J‐shaped curve relationship. This study analyzes the relationship between dietary sodium and sugar intake as a potential mechanism to explain this association. The authors examined cross‐sectional data from the National Health and Nutrition Examination Survey (NHANES) 2001‐2016 where dietary sodium, carbohydrate, fat, cholesterol, and sugar intakes were assessed by 24‐hour dietary recall and were standardized to a total daily intake of 2000 calories. Sodium intake was categorized into sodium quintiles (SQ) as follows: SQ1(0.06‐2.6 g/d); SQ2(2.6‐3.0 g/d); SQ3(3.0‐3.4 g/d); SQ4(3.4‐4.0 g/d); and SQ5(4.0‐29.3 g/d). Simple and multivariate linear regression using SQ3 as reference were used to assess associations between daily sodium intake and the other nutrients. Our results showed that among 38 722 participants that met our study criteria, the mean age was 43.6 years (SD 16.8 years) and sex was equally distributed (48.8% male vs 51.2% female). Sugar intake went down across increasing SQs and was significantly higher in SQ1 (141.2 g/d) and SQ2 (118.6 g/d) and significantly lower in SQ4 (97.9 g/d) and SQ5 (85.6 g/d) compared to SQ3 (108.6 g/d; all P < .01). These same trends remained unchanged and significant in the fully adjusted multivariate model. In conclusion, NHANES study participants reporting low sodium intake on 24‐hour dietary recall have a higher consumption of sugar. The negative impact of low sodium diet on cardiovascular health may be explained at least partially by the associated high sugar intake.
There is an increased risk of cardiovascular disease and higher rate of hypertension in post-meno... more There is an increased risk of cardiovascular disease and higher rate of hypertension in post-menopausal (compared to pre-menopausal women). We analysed the cross-sectional National Health and Nutritional Examination and Survey 2007–2012 to look at the factors that affect systolic blood pressure in post-menopausal women. We also performed a linear regression with systolic blood pressure as the dependent variable and age, body mass index, total cholesterol, triglycerides, A1C and serum creatinine as independent variables. In the regression model, only body mass index was a significant predictor of systolic blood pressure (adjusted r2 of 0. 100, F(6, 740) = 14.74, standard error β = 0.08, standardized coefficient B = 0.31, p &lt; 0.01).
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