-
1.
Gallbladder Dyskinesia Is Associated With an Impaired Postprandial Fibroblast Growth Factor 19 Response in Critically Ill Patients.
Koelfat, KVK, Plummer, MP, Schaap, FG, Lenicek, M, Jansen, PLM, Deane, AM, Olde Damink, SWM
Hepatology (Baltimore, Md.). 2019;(1):308-318
Abstract
Critical illness is associated with a disturbed regulation of gastrointestinal hormones resulting in functional and metabolic anomalies. Fibroblast growth factor 19 (FGF19) is an ileum-derived metabolic hormone induced by bile salts upon gallbladder emptying after enteral nutrient stimulation. Our aim was to study the nutrient-stimulated FGF19 response in 24 patients admitted to the intensive care unit (ICU) compared with 12 healthy controls. All subjects received intraduodenal high-lipid nutrient infusion for 120 minutes. Blood was collected every 30 minutes until 1 hour after infusion, and gallbladder emptying was studied by ultrasound. Serum levels of bile salts and FGF19 were assessed. ICU patients had significantly higher fasting bile salt serum levels compared with controls, whereas FGF19 serum levels were similar. In both groups, nutrient infusion elicited substantial bile salt elevations (P < 0.001), peaking at 90 minutes, albeit with a significantly lower peak in the ICU patients (P = 0.029). In controls, FGF19 was significantly elevated relative to baseline from 120 minutes onward (P < 0.001). In ICU patients, the FGF19 response was blunted, as reflected by significantly lower FGF19 elevations at 120, 150, and 180 minutes (P < 0.05) and significantly lower area under the curve (AUC) values compared with controls (P < 0.001). Gallbladder dysmotility was associated with the impaired FGF19 response in critical illness. The gallbladder ejection fraction correlated positively with FGF19 AUC values (ρ = +0.34, P = 0.045). In 10 of 24 ICU patients, gallbladder emptying was disturbed. These patients had significantly lower FGF19 AUC values (P < 0.001). Gallbladder emptying and the FGF19 response were respectively disturbed or absent in patients receiving norepinephrine. Conclusion: The nutrient-stimulated FGF19 response is impaired in ICU patients, which is mechanistically linked to gallbladder dysmotility in critical illness. This may contribute to disturbed liver metabolism in these patients and has potential as a nutritional biomarker.
-
2.
Serum 25-hydroxyvitamin D level is negatively associated with serum phosphorus level among stage 3a-5 chronic kidney disease patients.
Fayed, A, El Nokeety, MM, Heikal, AA, Marzouk, K, Hammad, H, Abdulazim, DO, Salem, MM, Sharaf El Din, UA, ,
Nefrologia. 2018;(5):514-519
Abstract
BACKGROUND Serum 25-hydroxyvitamin D (25(OH)D) negatively correlates with serum phosphorus level of stage 3a-5 chronic kidney disease (CKD) patients. So far, no explanation has been provided for this negative association. OBJECTIVE To confirm this negative association and determine if this relationship is mediated through other known co-morbid factors. CASES AND METHODS One hundred (57 male and 43 female) pre-dialysis stage 3a-5 CKD patients were selected. Estimated glomerular filtration rate (eGFR), serum calcium (Ca), phosphorus (P), 25(OH)D, parathyroid hormone (PTH), and intact fibroblast growth factor-23 (FGF23) were assessed. A correlation analysis between serum 25(OH)D and the different parameters studied was performed. Multivariate linear regression analysis was carried out to determine predictors of 25(OH)D. RESULTS The negative association between serum 25(OH)D and serum P was confirmed in univariate and multivariate correlation analysis. On the other hand, we failed to detect a significant association between 25(OH)D and serum FGF23. Serum P is the most important independent predictor of 25(OH)D in these patients (partial R2=0.15, p<0.0001). CONCLUSION Serum P is likely to have a direct negative impact on serum 25(OH)D. Further studies are needed to determine the underlying mechanism.
-
3.
Effect of essential amino acid кetoanalogues and protein restriction diet on morphogenetic proteins (FGF-23 and Кlotho) in 3b-4 stages chronic кidney disease patients: a randomized pilot study.
Milovanova, L, Fomin, V, Moiseev, S, Taranova, M, Milovanov, Y, Lysenko Kozlovskaya, L, Kozlov, V, Kozevnikova, E, Milovanova, S, Lebedeva, M, et al
Clinical and experimental nephrology. 2018;(6):1351-1359
Abstract
BACKGROUND A low protein diet (LPD) with essential amino acid ketoanalogue supplementation (KA) may contribute in improving of chronic kidney disease (CKD), while the exact mechanisms of KA's effect are not established yet. We have conducted a prospective, randomized, controlled comparative study of LPD + KA and LPD alone in relation to serum Klotho, FGF-23 levels in CKD patients. METHODS 79 non-diabetic CKD 3b-4 stage patients, compliant with LPD diet (0.6 g/kg of body weight/day), had been selected. The patients were randomized into two groups. The first group (42 patients) received LPD + КA. The second group (37 patients) continued the LРD alone. In addition to routine tests, serum Klotho, FGF-23 levels, as well as bioimpedance analysis, sphygmography (stiffness (augmentation) indices (AI), central (aortal) blood pressure) with a «SphygmaCor» device; echocardiography (valvular calcification score (VCS) and LVMMI), were performed. RESULTS There were body mass indices' decrease (p = 0.046), including muscle body mass in men (p = 0.027) and woman (p = 0.044) in the LPD group to the end of study (14th month). In addition, lower FGF-23 (p = 0.029), and higher sKlotho (p = 0.037) were detected in the LPD + KA group compared to the LPD one. The increase in AI (p = 0.034), VCS (p = 0.048), and LVMMI (p = 0.023) was detected more often in the LPD group at the end of study. CONCLUSION LPD + KA provides support for nutrition status and contributes to more efficient correction of FGF-23 and Klotho abnormalities that may result in cardiovascular calcification and cardiac remodeling decreasing in CKD. At the same time, a prolonged LPD alone may lead to malnutrition.
-
4.
Lamivudine, Entecavir, or Tenofovir Treatment of Hepatitis B Infection: Effects on Calcium, Phosphate, FGF23 and Indicators of Bone Metabolism.
Saeedi, R, Mojebi-Mogharar, A, Sandhu, SK, Dubland, JA, Ford, JA, Yousefi, M, Pudek, M, Holmes, DT, Erb, SR, Peter Kwan, W, et al
Annals of hepatology. 2017;(2):207-214
Abstract
BACKGROUND Patients with chronic hepatitis B virus (HBV) are often treated with nucleoside/nucleotide antiviral agents and metabolic bone toxicity is a possible concern. OBJECTIVE To determine the relationships between fibroblast growth factor 23 (FGF23), a phosphaturic hormone, bone mineral density (BMD), and bone biochemical abnormalities in these patients. MATERIAL AND METHODS This is a cross-sectional observational study comparing HBV-infected subjects treated for at least one year with tenofovir (TDF), lamuvidine (LVD), entacavir (ETV), or not treated (CON). Patients with abnormalities in either calcium (Ca), phosphate (PO4), intact parathyroid hormone (iPTH) or FGF23 were further evaluated with BMD by DXA. RESULTS No difference in liver enzymes or renal function seen among groups, but hypophosphatemia was seen in all groups with the highest incidence with TDF-treatment (14%). FGF 23 levels were found to be elevated in 11.1% of TDF patients, 2.77% amongst controls. No elevations were found in the LVD or ETV groups. Among a subset of subjects (FGF23, PO4, and/or Ca abnormalities) who underwent further evaluation, 67% had insufficient 25-OH vitamin D, and 30% had elevated 24 h urinary Ca or PO4 excretion. No patients with FGF23 abnormalities had urine abnormalities. 40% had low DXA Z-score (<-2) at spine or hip but there was no difference between control and antiviral treatment groups and the mean FRAX score was 2.33% for major osteoporotic fractures and 0.29% for hip fracture. CONCLUSION Abnormalities in bone metabolism, particularly involving vitamin D insufficiency, in HBV-treated subjects were observed with a small increased likelihood in TDF treated patients.
-
5.
Effects of lanthanum carbonate and calcium carbonate on fibroblast growth factor 23 and hepcidin levels in chronic hemodialysis patients.
Chang, YM, Tsai, SC, Shiao, CC, Liou, HH, Yang, CL, Tung, NY, Hsu, KS, Chen, IL, Liu, MC, Kao, JL, et al
Clinical and experimental nephrology. 2017;(5):908-916
Abstract
BACKGROUND Phosphate binders have an impact on fibroblast growth factor 23 (FGF23); however, the effect of phosphate binders on serum hepcidin has not been explored. We conducted a 24-week multicenter randomized controlled trial to investigate the effects of lanthanum carbonate or calcium carbonate monotherapy on serum phosphate, FGF23, and hepcidin levels in chronic hemodialysis patients. METHODS Forty-six patients were recruited, and daily dietary phosphorus was controlled between 600-800 mg. Serum calcium, phosphate, albumin, alkaline phosphatase (ALP), FGF23, intact parathyroid hormone (iPTH), hepcidin, high-sensitivity CRP (hsCRP), 25(OH)D, 1,25(OH)2D, fetuin-A, and osteopontin were checked as scheduled. RESULTS Twenty-five patients completed the study. Mean serum FGF23 level was significantly decreased after a 24-week treatment with lanthanum (8677.5 ± 7490.0 vs. 4692.8 ± 5348.3 pg/mL, p = 0.013, n = 13), but not with calcium (n = 12). The reduction of serum hepcidin in lanthanum group was positively correlated with the decrement of serum phosphate (r = 0.631, p = 0.021) and serum hsCRP (r = 0.670, p = 0.012) levels, respectively. Serum ALP, iPTH, vitamin D, fetuin-A, and osteopontin revealed no significant inter- or intragroup differences. CONCLUSIONS In summary, a decrease in serum FGF23 levels and a trend of decline in hepcidin levels were observed only in lanthanum group.
-
6.
Effect of Omega-3 Fatty Acid Supplementation on Plasma Fibroblast Growth Factor 23 Levels in Post-Myocardial Infarction Patients with Chronic Kidney Disease: The Alpha Omega Trial.
de Borst, MH, Baia, LC, Hoogeveen, EK, Giltay, EJ, Navis, G, Bakker, SJL, Geleijnse, JM, Kromhout, D, Soedamah-Muthu, SS
Nutrients. 2017;(11)
Abstract
Fibroblast growth factor 23 (FGF23) is an independent risk factor for cardiovascular mortality in chronic kidney disease. Omega-3 (n-3) fatty acid consumption has been inversely associated with FGF23 levels and with cardiovascular risk. We examined the effect of marine n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and plant-derived alpha-linolenic acid (ALA) on plasma FGF23 levels in post-myocardial infarction patients with chronic kidney disease. In the randomized double-blind Alpha Omega Trial, 4837 patients with a history of myocardial infarction aged 60-80 years (81% men) were randomized to one of four trial margarines supplemented with a targeted additional intake of 400 mg/day EPA and DHA, 2 g/day ALA, EPA-DHA plus ALA, or placebo for 41 months. In a subcohort of 336 patients with an eGFR < 60 mL/min/1.73 m² (creatinine-cystatin C-based CKD-EPI formula), plasma C-terminal FGF23 was measured by ELISA at baseline and end of follow-up. We used analysis of covariance to examine treatment effects on FGF23 levels adjusted for baseline FGF23. Patients consumed 19.8 g margarine/day on average, providing an additional amount of 236 mg/day EPA with 158 mg/day DHA, 1.99 g/day ALA or both, in the active intervention groups. Over 79% of patients were treated with antihypertensive and antithrombotic medication and statins. At baseline, plasma FGF23 was 150 (128 to 172) RU/mL (mean (95% CI)). After 41 months, overall FGF23 levels had increased significantly (p < 0.0001) to 212 (183 to 241) RU/mL. Relative to the placebo, the treatment effect of EPA-DHA was indifferent, with a mean change in FGF23 (95% CI) of -17 (-97, 62) RU/mL (p = 0.7). Results were similar for ALA (36 (-42, 115) RU/mL) and combined EPA-DHA and ALA (34 (-44, 113) RU/mL). Multivariable adjustment, pooled analyses, and subgroup analyses yielded similar non-significant results. Long-term supplementation with modest quantities of EPA-DHA or ALA does not reduce plasma FGF23 levels when added to cardiovascular medication in post-myocardial patients with chronic kidney disease.
-
7.
Roux-en-Y Gastric Bypass Surgery Has Unique Effects on Postprandial FGF21 but Not FGF19 Secretion.
Harris, LLS, Smith, GI, Mittendorfer, B, Eagon, JC, Okunade, AL, Patterson, BW, Klein, S
The Journal of clinical endocrinology and metabolism. 2017;(10):3858-3864
-
-
Free full text
-
Abstract
CONTEXT Fibroblast growth factor (FGF)19 and FGF21 are secreted by the intestine and liver in response to macronutrient intake. Intestinal resection and reconstruction via bariatric surgery may alter their regulation. OBJECTIVE We tested the hypothesis that weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery, but not matched weight loss induced by laparoscopic adjustable gastric banding (LAGB), increases postprandial plasma FGF19 and FGF21 concentrations. DESIGN Glucose kinetics and plasma FGF19 and FGF21 responses to mixed meal ingestion and to glucose-insulin infusion during a hyperinsulinemic-euglycemic clamp procedure, with stable isotope tracer methods, were evaluated in 28 adults with obesity before and after 20% weight loss induced by RYGB (n = 16) or LAGB (n = 12). RESULTS LAGB- and RYGB-induced weight loss increased postprandial plasma FGF19 concentrations (P < 0.05). However, weight loss after RYGB, but not LAGB, increased postprandial plasma FGF21 concentrations (1875 ± 330 to 2976 ± 682 vs 2150 ± 310 and 1572 ± 265 pg/mL × 6 hours, respectively). The increase in plasma FGF21 occurred ∼2 hours after the peak in delivery of ingested glucose into systemic circulation. Glucose-insulin infusion increased plasma FGF21, but not FGF19, concentrations. The increase in plasma FGF21 during glucose-insulin infusion was greater after than before weight loss in both surgery groups without a difference between groups, whereas plasma FGF19 was not affected by either procedure. CONCLUSIONS RYGB-induced weight loss has unique effects on postprandial FGF21 metabolism, presumably due to rapid delivery of ingested macronutrients to the small intestine and delivery of glucose to the liver.
-
8.
Effect of Cinacalcet and Vitamin D Analogs on Fibroblast Growth Factor-23 during the Treatment of Secondary Hyperparathyroidism.
Sprague, SM, Wetmore, JB, Gurevich, K, Da Roza, G, Buerkert, J, Reiner, M, Goodman, W, Cooper, K
Clinical journal of the American Society of Nephrology : CJASN. 2015;(6):1021-30
-
-
Free full text
-
Abstract
BACKGROUND AND OBJECTIVES Cinacalcet and vitamin D are often combined to treat secondary hyperparathyroidism (SHPT) in patients on dialysis. Independent effects on fibroblast growth factor-23 (FGF-23) concentrations in patients on hemodialysis administered cinacalcet or vitamin D analogs as monotherapies during treatment of SHPT are evaluated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A multicenter, randomized, open-label study to compare the efficacy of cinacalcet versus traditional vitamin D therapy for management of secondary hyperparathyroidism among subjects undergoing hemodialysis (PARADIGM) was a prospective, phase 4, multicenter, randomized, open-label study conducted globally. Participants (n=312) were randomized 1:1 to cinacalcet (n=155) or vitamin D analog (n=157) for 52 weeks. Levels of FGF-23 were measured at baseline and weeks 20 and 52. The absolute and percentage changes from baseline in plasma FGF-23, parathyroid hormone (PTH), calcium (Ca), phosphorus (P), and calcium-phosphorus product (Ca×P) were assessed. Correlations and logistic regression were used to explore relationships between changes in FGF-23 and changes in PTH, Ca, P, and Ca×P from baseline to week 52 by treatment arm. RESULTS Median (quartiles 1, 3) decrease in FGF-23 concentrations was observed in the cinacalcet arm (-40%; -63%, 16%) compared with median increase in the vitamin D analog arm (47%; 0%, 132%) at week 52 (P<0.001). Changes in FGF-23 in both arms were unrelated to changes in PTH (cinacalcet: r=0.17, P=0.11; vitamin D analog: r=-0.04, P=0.70). Changes in FGF-23 in the vitamin D analog but not the cinacalcet arm were correlated with changes in Ca (cinacalcet: r=0.11, P=0.30; vitamin D analog: r=0.32, P<0.01) and P (cinacalcet: r=0.19, P=0.07; vitamin D analog: r=0.49, P<0.001). Changes in FGF-23 were correlated with changes in Ca×P in both arms (cinacalcet: r=0.26, P=0.01; vitamin D analog: r=0.57, P<0.001). Independent of treatment arm, participants with reductions in P or Ca×P were significantly more likely to show reductions in FGF-23. CONCLUSIONS During treatment of SHPT, cinacalcet use was associated with a decrease in FGF-23 concentrations, whereas vitamin D analogs were associated with an increase. The divergent effects of these treatments on FGF-23 seem to be independent of modification of PTH. It is possible that effects of cinacalcet and vitamin D analogs on FGF-23 may be mediated indirectly by other effects on bone and mineral metabolism.
-
9.
Impact of parathyroidectomy on serum FGF23 and soluble Klotho in hemodialysis patients with severe secondary hyperparathyroidism.
Takahashi, H, Komaba, H, Takahashi, Y, Sawada, K, Tatsumi, R, Kanai, G, Suzuki, H, Kakuta, T, Fukagawa, M
The Journal of clinical endocrinology and metabolism. 2014;(4):E652-8
Abstract
CONTEXT Klotho is a transmembrane protein that functions as a coreceptor for fibroblast growth factor 23 (FGF23). Klotho is cleaved and released into the circulation; however, the main site of production, physiological role, and regulation of soluble Klotho in humans are largely unknown. OBJECTIVE The aim of this study was to determine the impact of parathyroidectomy (PTx) on serum FGF23 and soluble Klotho levels in patients with severe secondary hyperparathyroidism. DESIGN AND SETTING This was a prospective, single-arm trial conducted at Tokai University School of Medicine. PATIENTS Thirteen hemodialysis patients with severe secondary hyperparathyroidism who were candidates for PTx participated in the study. INTERVENTIONS All patients underwent total PTx with forearm autotransplantation. MAIN OUTCOME MEASURES We evaluated changes in serum FGF23 and soluble Klotho levels for 90 days after PTx. Other biochemical parameters related to mineral and bone metabolism were also assessed. RESULTS At baseline, serum FGF23 levels were markedly elevated, whereas serum soluble Klotho levels were modestly decreased. PTx resulted in a marked, progressive decline in serum FGF23 levels together with significant reductions in serum calcium, phosphorus, and intact PTH levels. The serum soluble Klotho levels were reduced 13% from baseline on the day after PTx; however, these levels then increased progressively, reaching 34% above the postoperative values. CONCLUSIONS Our results suggest that the parathyroid gland is not the major site of soluble Klotho production in patients with end-stage renal disease, and the production of Klotho by other organ(s) is affected by alterations in mineral metabolism or medications taken after PTx.
-
10.
Decreased conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 following cholecalciferol therapy in patients with CKD.
Stubbs, JR, Zhang, S, Friedman, PA, Nolin, TD
Clinical journal of the American Society of Nephrology : CJASN. 2014;(11):1965-73
-
-
Free full text
-
Abstract
BACKGROUND AND OBJECTIVES Elevated concentrations of fibroblast growth factor 23 (FGF23) are postulated to promote 25-hydroxyvitamin D (25[OH]D) insufficiency in CKD by stimulating 24-hydroxylation of this metabolite, leading to its subsequent degradation; however, prospective human studies testing this relationship are lacking. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS An open-label prospective study was conducted from October 2010 through July 2012 to compare the effect of 8 weeks of oral cholecalciferol therapy (50,000 IU twice weekly) on the production of 24,25(OH)2D3 in vitamin D-insufficient patients with CKD (n=15) and controls with normal kidney function (n=15). Vitamin D metabolites were comprehensively profiled at baseline and after treatment, along with FGF23 and other mineral metabolism parameters. RESULTS Vitamin D3 and 25(OH)D3 concentrations increased equivalently in the CKD and control groups following cholecalciferol treatment (median D3 change, 8.6 ng/ml [interquartile range, 3.9-25.6 ng/ml] for controls versus 12.6 ng/ml [6.9-41.2 ng/ml] for CKD [P=0.15]; 25(OH)D3 change, 39.2 ng/ml [30.9-47.2 ng/ml] for controls versus 39.9 ng/ml [31.5-44.1 ng/ml] for CKD [P=0.58]). Likewise, the absolute increase in 1α,25(OH)2D3 was similar between CKD participants and controls (change, 111.2 pg/ml [64.3-141.6 pg/ml] for controls versus 101.1 pg/ml [74.2-123.1 pg/ml] for CKD; P=0.38). Baseline and post-treatment 24,25(OH)2D3 concentrations were lower in the CKD group; moreover, the absolute increase in 24,25(OH)2D3 after therapy was markedly smaller in patients with CKD (change, 2.8 ng/ml [2.3-3.5 ng/ml] for controls versus 1.2 ng/ml [0.6-1.9 ng/ml] for patients with CKD; P<0.001). Furthermore, higher baseline FGF23 concentrations were associated with smaller increments in 24,25(OH)2D3 for individuals with CKD; this association was negated after adjustment for eGFR by multivariate analysis. CONCLUSIONS Patients with CKD exhibit an altered ability to increase serum 24,25(OH)2D3 after cholecalciferol therapy, suggesting decreased 24-hydroxylase activity in CKD. The observed relationship between baseline FGF23 and increments in 24,25(OH)2D3 further refutes the idea that FGF23 directly contributes to 25(OH)D insufficiency in CKD through stimulation of 24-hydroxylase activity.