Circulating Levels of Dickkopf-Related Protein 1 Decrease as Measured GFR Declines and Are Associated with PTH Levels

2020 ◽  
Vol 51 (11) ◽  
pp. 871-880
Author(s):  
Corey M. Forster ◽  
Christine A. White ◽  
Mandy E. Turner ◽  
Patrick A. Norman ◽  
Emilie C. Ward ◽  
...  
Keyword(s):  
Bone Disease ◽  
Mineral Metabolism ◽  
Early Stage ◽  
Fibroblast Growth Factor 23 ◽  
Vitamin D Metabolites ◽  
Related Protein ◽  
Clinical Indicators ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Fgf 23

<b><i>Background:</i></b> The Wnt/β-catenin pathway has been implicated in the development of adynamic bone disease in early-stage chronic kidney disease (CKD). Dickkopf-related protein 1 (DKK1) and sclerostin are antagonists of the Wnt/β-catenin pathway yet have not been widely used as clinical indicators of bone disease. This study characterized levels of DKK1, sclerostin, and other biomarkers of mineral metabolism in participants across a spectrum of inulin-measured glomerular filtration rate (GFR). <b><i>Methods:</i></b> GFR was measured by urinary inulin clearance (mGFR) in 90 participants. Blood samples were obtained for measurement of circulating DKK1, sclerostin, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), calcium, phosphate, α-klotho, and vitamin D metabolites including 25-hydroxyvitamin D<sub>3</sub> and 1,25-dihydroxyvitamin D<sub>3</sub>. Spearman correlations and linear regressions were used where appropriate to examine the associations between measured values. <b><i>Results:</i></b> The median [IQR] age was 64 years [53.0–71.0], and the median [IQR] mGFR was 32.6 [21.7–60.6] mL/min. DKK1 decreased (<i>r</i> = 0.6, <i>p</i> &#x3c; 0.001) and sclerostin increased (<i>r</i> = −0.4, <i>p</i> &#x3c; 0.001) as kidney function declined, and both were associated with phosphate, PTH, FGF-23, and 1,25-dihydroxyvitamin D<sub>3</sub> in the unadjusted analysis. After adjustment for age and mGFR, DKK1 remained significantly associated with PTH. <b><i>Conclusion:</i></b> The results of this study demonstrate opposing trends in Wnt/β-catenin pathway inhibitors, DKK1 and sclerostin, as mGFR declines. Unlike sclerostin, DKK1 levels decreased significantly as mGFR declined and was independently associated with PTH. Future studies should determine whether measurement of Wnt signaling inhibitors may be useful in predicting bone histomorphometric findings and important clinical outcomes in patients with CKD.

scholarly journals PENGARUH PEMBERIAN 1,25 DIHYDROXYVITAMIN D (CALCITRIOL) TERHADAP KADAR FIBROBLAST GROWTH FACTOR-23 DAN ALBUMINURIA PADA PASIEN PENYAKIT GINJAL KRONIK STADIUM V YANG MENJALANI HEMODIALISIS

Biomedika ◽  
2017 ◽  
Vol 9 (1) ◽  
Author(s):  
Intan Herlina ◽  
Bambang Purwanto ◽  
Sugiarto Sugiarto
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Drop Out ◽  
Fibroblast Growth ◽  
Angiotensin I ◽  
Chi Square ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Fgf 23

Penyebab utama morbiditas dan mortalitas pada pasien Penyakit Ginjal Kronik adalah insiden kardiovaskuler yang didasari oleh proses aterosklerosis yang menyebabkan meningkatnya morbiditas dan mortalitas. Ginjal merupakan tempat utama sintesa 1,25 Dihydroxyvitamin D (Calcitriol), sehingga dengan adanya kerusakan ginjal menyebabkan defisiensi 1,25 Dihydroxyvitamin D (Calcitriol). Pada pasien Penyakit Ginjal Kronik terjadi peningkatan Fibroblast Growth Factor-23 dan Albuminuria akibat dari aktifitas Renin Angiotensin Aldosteron Sistem. Aktifitas RAAS mempengaruhi 1,25 Dihydroxy vitamin D (Calcitriol), Fibroblast Growth Factor-23 melalui Angiotensin 2 dengan cara menghambat reseptor Angiotensin I (AT1) melalui Nicotinmide Adenine Dinucleotide Phosphate Oxidase (NADPH Oksidase) dan Stress Oxidativ. Beberapa penelitian menyimpulkan pemberian 1,25 Dihydroxyvitamin D (Calcitriol) mempunyai efek renoprotektif, anti inflamasi dan antiproteinuric dengan cara menghambat reseptor Angoitensin I (AT1) sehingga mengakibatkan menurunnya albuminuria. Tujuan Penelitian ini adalah untuk membuktikan pemberian 1,25 Dihydroxyvitamin D (Calcitriol) dapat menurunkan kadar Fibroblas Growth Factor-23 dan albuminuria pada pasien Penyakit Ginjal Kronik stadium V yang menjalani hemodialisis. Penelitian ini merupakan penelitian eksperimen dengan randomisasi, subyek penelitian 30 orang, dibagi dalam dua kelompok sampel, kelompok plasebo 15 orang dan kelompok perlakuan 15 orang. Dalam perjalanan, kelompok placebo drop out 4 pasien karena keluarga pasien tidak menyetujui untuk melanjutkan penelitian dan satu lagi mengalami perburukan, sehingga jumlah sampel menjadi 26 orang, terbagi menjadi kelompok placebo sebanyak 11 orang yang diberi placebo dan kelompok perlakuan 15 orang diberi calcitriol 1x0,5 μg peroral selama 4 minggu. Karakteristik penelitian yang berupa variabel kualitatif, uji homogenitas dilakukan menggunakan uji Chi Square. Uji beda dua Rerata menggunakan uji t pada p<0.005. Pada kelompok plasebo (n=11) ; Kadar Fibroblast Growth Factor-23 sebelum dan sesudah perlakuan (876,24±795,93 RU/mL vs 1235,69±791,71 RU/mL; p=0,059) dan Albuminuria (72,30±195,06 μg/ mg vs 320,14±208,90 μg/mg; p=0,001). Pada kelompok perlakuan (n=15); Kadar Fibroblast Growth Factor-23 sebelum dan sesudah perlakuan (1210,96±845,97 RU/mL vs 612,33±487,32 RU/mL; p=0,002) dan Albuminuria (206,63±327,25 μg/mg vs 192,89±316,00 μg/mg; p=0,001). Terdapat perbedaan yang bermakna pada selisih ratarata kadar Fibroblast Growth Factor-23 (Delta-FGF-23) sebelum dan sesudah perlakuan pada kelompok placebo vs kelompok perlakuan (-359,45±560,23 RU/mL vs 598,63±608,27 RU/mL; p=0,001) dan selisih rata-rata Albuminuria (Delta-albuminuria) sebelum dan sesudah perlakuan pada kelompok placebo vs kelompok perlakuan (-247,84±189,48 μg/mg vs 13,73±23,15μg/mg;p=0,001. Pemberian suplementasi 1,25 Dihydroxyvitamin D (calcitriol) menurunkan kadar FGF-23 albuminuria secara bermakna pada pasien penyakit ginjal kronik stadium V yang menjalani hemodialisisKata Kunci: Penyakit Ginjal Kronis Stadium V, 1,25 Dihydroxyvitamin D (Calcitriol), Fibroblast Growth Factor-23, Albuminuria

Measurement of Plasma 1,25 Dihydroxyvitamin D Using a Novel Immunoextraction Technique and Immunoassay with Iodine Labelled Vitamin D Tracer

1997 ◽  
Vol 34 (6) ◽  
pp. 632-637 ◽  
Author(s):  
W D Fraser ◽  
B H Durham ◽  
J L Berry ◽  
E B Mawer
Keyword(s):  
Vitamin D ◽  
Solid Phase ◽  
Plasma Concentrations ◽  
Sample Volume ◽  
Cross Reactivity ◽  
Regression Equations ◽  
Vitamin D Metabolites ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
High Concentrations

We evaluated a novel assay for the measurement of 1,25 dihydroxyvitamin D (1,25 (OH)2D). Immunoextraction of 1,25 (OH)2D is performed using a mini column containing a solid-phase monoclonal antibody followed by radioimmunoassay (RIA) using an 125I-labelled 1,25 (OH)2D derivative tracer and Sac-cell separation. The mean recovery of 1,25(OH)2D3 was 101%, linearity was excellent, inter- and intra-assay coefficients of variation were 9, 8 and 13% and 11, 10 and 14% at low, medium and high concentrations of 1,25(OH)2D3, respectively. The cross-reactivity of vitamin D metabolites was <0·0015% for 25-hydroxyvitamin D3, 24, 25 dihydroxyvitamin D3 and dihydrotachysterol and 0·54% for lα calcidol. 1,25 dihydroxyvitamin D2 cross-reactivity was 79%. The detection limit of the assay was 5pmol/L. Comparison with a commercial radio receptor assay (RRA) and an in-house RIA gave regression equations of y = 0·94x+11·8 ( r = 0·98) and y = 0·91x-1·7 ( r = 0.95), respectively, with no major discrepancies between the methods in all patient groups studied. Plasma concentrations of 1,25 (OH)2D obtained with the assay were as follows: normal, unsupplemented subjects: mean 88, range 48–155 pmol/L, n = 68, patients with chronic renal failure: mean 11, range 3–36 pmol/L, n = 27, primary hyperparathyroidism: mean 198, range 130–299 pmol/L, n = 23, Paget's disease: mean 92, range 42–149 pmol/L, n = 24, osteomalacia: mean 43, range 27–61 pmol/L, n = 9. A minimum sample volume of 300 μL is required, the hands-on time is significantly less than other commercial assays and the measuring procedure is gamma counting rather than scintillation counting. The assay offers several advantages over previous methods and should allow more laboratories to offer measurement of 1,25 (OH)2D as part of their repertoire.

scholarly journals Mechanistic study of the cause of decreased blood 1,25-Dihydroxyvitamin D in sepsis

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Chih-Huang Li ◽  
Xiaolei Tang ◽  
Samiksha Wasnik ◽  
Xiaohua Wang ◽  
Jintao Zhang ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Vitamin D ◽  
Growth Factor ◽  
Kidney Failure ◽  
Mechanistic Study ◽  
Blood Levels ◽  
Biological Functions ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Fgf 23

Abstract Background Vitamin D deficiency, determined by blood levels of 25-hydroxyvitamin D [25(OH) D, i.e. the major vitamin D form in blood], has been shown to associate with all-cause mortalities. We recently demonstrated that blood levels of 1,25-dihydroxyvitamin D [1,25(OH)2D, i.e. the active vitamin D] were significantly lower in non-survivors compared to survivors among sepsis patients. Unexpectedly, despite the well documented roles of 1,25(OH)2D in multiple biological functions such as regulation of immune responses, stimulation of antimicrobials, and maintenance of barrier function, 1,25(OH)2D supplementation failed to improve disease outcomes. These previous findings suggest that, in addition to 1,25(OH)2D deficiency, disorders leading to the 1,25(OH)2D deficiency also contribute to mortality among sepsis patients. Therefore, this study investigated the mechanisms leading to sepsis-associated 1,25(OH)2D deficiency. Methods We studied mechanisms known to regulate kidney 25-hydroxylvitamin D 1α-hydroxylase which physiologically catalyzes the conversion of 25(OH) D into 1,25(OH)2D. Such mechanisms included parathyroid hormone (PTH), insulin-like growth factor 1 (IGF-1), fibroblast growth factor 23 (FGF-23), and kidney function. Results We demonstrated in both human subjects and mice that sepsis-associated 1,25(OH)2D deficiency could not be overcome by increased production of PTH which stimulates 1α-hydroxylase. Further studies showed that this failure of PTH to maintain blood 1,25(OH)2D levels was associated with decreased blood levels of IGF-1, increased blood levels of FGF-23, and kidney failure. Since the increase in blood levels of FGF-23 is known to associate with kidney failure, we further investigated the mechanisms leading to sepsis-induced decrease in blood levels of IGF-1. Our data showed that blood levels of growth hormone, which stimulates IGF-1 production in liver, were increased but could not overcome the IGF-1 deficiency. Additionally, we found that the inability of growth hormone to restore the IGF-1 deficiency was associated with suppressed expression and signaling of growth hormone receptor in liver. Conclusions Because FGF-23 and IGF-1 have multiple biological functions besides their role in regulating kidney 1α-hydroxylase, our data suggest that FGF-23 and IGF-1 are warranted for further investigation as potential agents for the correction of 1,25(OH)2D deficiency and for the improvement of survival among sepsis patients.

scholarly journals Successful Treatment for Hypercalcemia due to Cosecretion of Parathyroid Hormone-Related Protein and 1,25-Dihydroxyvitamin D3 in Non-Small-Cell Lung Cancer: A Case Report and Literature Review

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Takunori Ogawa ◽  
Jun Miyata ◽  
Koichi Fukunaga ◽  
Akihiko Kawana ◽  
Takashi Inoue
Keyword(s):  
Lung Cancer ◽  
Case Report ◽  
Parathyroid Hormone ◽  
Serum Calcium ◽  
Successful Treatment ◽  
Related Protein ◽  
Hypercalcemia Of Malignancy ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Parathyroid Hormone Related Protein

Hypercalcemia of malignancy frequently manifests as paraneoplastic syndrome in patients with solid tumors. A 71-year-old man was diagnosed with stage IIIB lung squamous cell carcinoma. Laboratory examination revealed high serum calcium concentration with elevated serum parathyroid hormone-related protein (PTHrP) and 1,25-dihydroxyvitamin D3 levels. As the patient did not respond to the initial treatment with calcitonin, extracellular fluid infusion, and chemotherapy, systemic prednisolone was administered additionally. Thus, the levels of serum calcium normalized and PTHrP and 1,25-dihydroxyvitamin D3 decreased simultaneously. To our knowledge, this is the first case report on the successful treatment of hypercalcemia of malignancy caused by PTHrP and 1,25-dihydroxyvitamin D3 cosecretion in a patient with lung cancer.

Unusual behaviour of an unusual tumour: calcitriol-induced hypercalcaemia in metastatic oesophageal neuroendocrine carcinoma

2020 ◽  
Vol 13 (8) ◽  
pp. e235209
Author(s):  
Filip Ionescu ◽  
Ioana Petrescu ◽  
Maria Marin
Keyword(s):  
Parathyroid Hormone ◽  
Serum Calcium ◽  
Neuroendocrine Carcinoma ◽  
Solid Tumours ◽  
Related Protein ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Parathyroid Hormone Related Protein ◽  
Solid Malignancies ◽  
Osteolytic Metastases

Hypercalcaemia in malignancy is most commonly caused by paraneoplastic secretion of parathyroid hormone-related protein or osteolytic metastases. Very rarely (<1% of cases), the mechanism behind increased serum calcium is increased production of calcitriol (1,25-dihydroxyvitamin D) and even rarer is the occurrence of this phenomenon in solid malignancies, with few such instances reported in the literature. We present a case of a neuroendocrine malignancy originating in the oesophagus associated with calcitriol-induced hypercalcaemia, a phenomenon that has not been previously described. We review the pathophysiology of calcitriol-induced hypercalcaemia and previously reported cases of solid tumours with this presentation.

scholarly journals Impact of Race on the Association of Mineral Metabolism With Heart Failure: the Multi-Ethnic Study of Atherosclerosis

2019 ◽  
Vol 105 (4) ◽  
pp. e1144-e1151
Author(s):  
Cassianne Robinson-Cohen ◽  
Michael Shlipak ◽  
Mark Sarnak ◽  
Ronit Katz ◽  
Carmen Peralta ◽  
...  
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
African Americans ◽  
Ethnic Groups ◽  
Mineral Metabolism ◽  
Fibroblast Growth Factor 23 ◽  
Cox Models ◽  
Ethnic Study ◽  
Potential Risk Factors ◽  
Fgf 23

Abstract Background Alterations in mineral metabolism, such as high phosphorus, high parathyroid hormone (PTH), and high fibroblast growth factor-23 (FGF-23) have been identified as potential risk factors for heart failure (HF). Important differences in the prevalence of mineral metabolism abnormalities and in the risk of HF have been reported across race and/or ethnic groups. In this study, we evaluated whether the associations of mineral metabolism markers with HF differed by race and/or ethnicity. Methods We included participants free of cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis to quantify rates of HF overall and across race and/or ethnic groups. Using Cox models, we tested associations of baseline higher phosphorus (&gt;4 mg/dL), PTH greater than 65 pg/mL, and FGF-23 greater than 46.5 pg/mL with incident HF, and for interactions by race and/or ethnicity, adjusting for sociodemographic and cardiovascular risk factors. Results Among the 6413 participants, median follow-up time was 14.9 years. The incidence rate for HF was highest for African Americans and lowest for Chinese (4.71 and 2.42 per 1000 person-years, respectively). The prevalence of elevated PTH (18.8% vs 7.4%) but not FGF-23 (23.1% vs 28.8%) was higher in African Americans vs Whites. In multivariable models, the associations of elevated PTH (hazard ratio [HR] 1.50, 95% CI: 1.13-1.99) and FGF-23 (HR 1.37, 95% CI: 1.07-1.75) with incident HF were statistically significant. However, the interactions by race and/or ethnicity were not statistically significant. Conclusions In a multiethnic population, higher PTH and FGF-23 were associated with risk of HF in African American and Hispanic individuals. There is no evidence that race and/or ethnicity modifies the association of altered mineral metabolism with risk of HF.

scholarly journals Clinical Significance of FGF-23 in Patients with CKD

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Domenico Russo ◽  
Yuri Battaglia
Keyword(s):  
Ventricular Hypertrophy ◽  
Vascular Dysfunction ◽  
Left Ventricular ◽  
Vitamin D Metabolism ◽  
Fgf Receptor ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Phosphate Retention ◽  
Fgf 23

FGF23 is a bone-derived hormone that plays an important role in the regulation of phosphate and 1,25-dihydroxy vitamin D metabolism. FGF23 principally acts in the kidney to induce urinary phosphate excretion and suppress 1,25-dihydroxyvitamin D synthesis in the presence of FGF receptor 1 (FGFR1) and its coreceptor Klotho. In patients with chronic kidney disease (CKD), circulating FGF23 levels are progressively increased to compensate for persistent phosphate retention, but this results in reduced renal production of 1,25-dihydroxyvitamin D and leads to hypersecretion of parathyroid hormone. Furthermore, FGF23 is associated with vascular dysfunction, atherosclerosis, and left ventricular hypertrophy. This paper summarizes the role of FGF23 in the pathogenesis of mineral, bone, and cadiovascular disorders in CKD.

scholarly journals The Effect of Extended Release Niacin on Markers of Mineral Metabolism in CKD

2017 ◽  
Vol 13 (1) ◽  
pp. 36-44 ◽  
Author(s):  
Rakesh Malhotra ◽  
Ronit Katz ◽  
Andrew Hoofnagle ◽  
Andrew Bostom ◽  
Dena E. Rifkin ◽  
...  
Keyword(s):  
Extended Release ◽  
Mineral Metabolism ◽  
Controlled Trial ◽  
Fibroblast Growth Factor 23 ◽  
Phosphate Transport ◽  
Serum Phosphate ◽  
Vitamin D Metabolites ◽  
Long Term Effects ◽  
Double Blind ◽  
Low Hdl

Background and objectivesNiacin downregulates intestinal sodium-dependent phosphate transporter 2b expression and reduces intestinal phosphate transport. Short-term studies have suggested that niacin lowers serum phosphate concentrations in patients with CKD and ESRD. However, the long-term effects of niacin on serum phosphate and other mineral markers are unknown.Design, setting, participants, & measurementsThe Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Trial was a randomized, double-blind, placebo-controlled trial testing extended release niacin in persons with prevalent cardiovascular disease. We examined the effect of randomized treatment with niacin (1500 or 2000 mg) or placebo on temporal changes in markers of mineral metabolism in 352 participants with eGFR<60 ml/min per 1.73 m2 over 3 years. Changes in each marker were compared over time between the niacin and placebo arms using linear mixed effects models.ResultsRandomization to niacin led to 0.08 mg/dl lower plasma phosphate concentrations per year of treatment compared with placebo (P<0.01) and 0.25 mg/dl lower mean phosphate 3 years after baseline (3.32 versus 3.57 mg/dl; P=0.03). In contrast, randomization to niacin was not associated with statistically significant changes in plasma intact fibroblast growth factor 23, parathyroid hormone, calcium, or vitamin D metabolites over 3 years.ConclusionsThe use of niacin over 3 years lowered serum phosphorous concentrations but did not affect other markers of mineral metabolism in participants with CKD.

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