FGF23: a key player in mineral and bone disorder in CKD
FGF23: a key player in mineral and bone disorder in CKD
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Erselcan, Z. Hasbek, I. Tandogan, C. Gumus, I. Akkurt" "autores" => array:5 [ 0 => array:2 [ "Iniciales" => "T." "apellidos" => "Erselcan" ] 1 => array:2 [ "Iniciales" => "Z." "apellidos" => "Hasbek" ] 2 => array:2 [ "Iniciales" => "I." "apellidos" => "Tandogan" ] 3 => array:2 [ "Iniciales" => "C." "apellidos" => "Gumus" ] 4 => array:2 [ "Iniciales" => "I." 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Sánchez-López, R. Rodríguez Díez, J. Rodríguez Vita, S. Rayego Mateos, R. R. Rodríguez Díez, E. Rodríguez García, C. Lavoz Barria, S. Mezzano, R. Selgas, J. Egido, A. Ortiz, Marta Ruiz Ortega" "autores" => array:12 [ 0 => array:2 [ "Iniciales" => "E." "apellidos" => "Sánchez-López" ] 1 => array:2 [ "Iniciales" => "R." "apellidos" => "Rodríguez Díez" ] 2 => array:2 [ "Iniciales" => "J." "apellidos" => "Rodríguez Vita" ] 3 => array:2 [ "Iniciales" => "S." "apellidos" => "Rayego Mateos" ] 4 => array:2 [ "Iniciales" => "R. R." "apellidos" => "Rodríguez Díez" ] 5 => array:2 [ "Iniciales" => "E." "apellidos" => "Rodríguez García" ] 6 => array:2 [ "Iniciales" => "C." "apellidos" => "Lavoz Barria" ] 7 => array:2 [ "Iniciales" => "S." "apellidos" => "Mezzano" ] 8 => array:2 [ "Iniciales" => "R." "apellidos" => "Selgas" ] 9 => array:2 [ "Iniciales" => "J." "apellidos" => "Egido" ] 10 => array:2 [ "Iniciales" => "A." "apellidos" => "Ortiz" ] 11 => array:2 [ "nombre" => "Marta" "apellidos" => "Ruiz Ortega" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "X2013251409003613" "doi" => "10.3265/Nefrologia.2009.29.5.5429.en.full" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251409003613?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699509003616?idApp=UINPBA000064" "url" => "/02116995/0000002900000005/v0_201502091404/X0211699509003616/v0_201502091404/es/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "titulo" => "FGF23: a key player in mineral and bone disorder in CKD" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "392" "paginaFinal" => "396" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "H. Komaba, M. Fukagawa" "autores" => array:2 [ 0 => array:3 [ "Iniciales" => "H." "apellidos" => "Komaba" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] 1 => array:4 [ "Iniciales" => "M." "apellidos" => "Fukagawa" "email" => array:1 [ 0 => "fukagawa@med.kobe-u.ac.jp" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:3 [ "entidad" => "Division of Nephrology and Kidney Center, Kobe University School of Medicine, Kobe, Kobe, Japan, " "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "FGF23: a key player in mineral and bone disorder in CKD" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "408527_fig1.jpg" "Alto" => 499 "Ancho" => 710 "Tamanyo" => 31185 ] ] ] ] "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION</span></p><p class="elsevierStylePara">Disorders of mineral and bone metabolism are common complications of chronic kidney disease (CKD)<span class="elsevierStyleSup">1</span>. Abnormal mineral metabolism occurs early in the course of CKD, which can result in significant consequences even in patients not yet on dialysis<span class="elsevierStyleSup">2-4</span>. Traditionally, these abnormalities have been investigated mainly in association with the development of secondary hyperparathyroidism, where phosphate retention, hypocalcemia, and a progressive decline in 1,25-dihydroxyvitamin D [1,25(OH)<span class="elsevierStyleInf">2</span>D], have been considered to be the main factors for abnormal parathyroid hormone (PTH) secretion<span class="elsevierStyleSup">5-7</span>.</p><p class="elsevierStylePara">Recently, a novel phosphaturic hormone FGF23 has been identified, initially as a pathogenic factor in rare hypophosphatemic syndromes disorders<span class="elsevierStyleSup">8,9</span>. Studies since then have shown that this hormone plays an important role in normal physiology<span class="elsevierStyleSup">10</span> as well as in the pathogenesis of alterations in mineral metabolism such as that seen in patients with CKD<span class="elsevierStyleSup">11-13</span>. In this brief review, we summarize recent findings about the role of FGF23 in the  pathogenesis of mineral and bone disorders in CKD.</p><p class="elsevierStylePara"><span class="elsevierStyleBold">ROLE OF FGF23 IN PHOSPHATE AND VITAMIN D HOMEOSTASIS</span></p><p class="elsevierStylePara">FGF23 is a 32-kDa protein with 251 amino acids that is secreted mainly by osteocytes in bone<span class="elsevierStyleSup">14,15</span>. FGF23 was first cloned in mice as a new member of FGF family<span class="elsevierStyleSup">16</span> and identified as a causative humoral factor for autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR)<span class="elsevierStyleSup">8</span> and tumor-induced osteomalacia (TIO)<span class="elsevierStyleSup">9</span> that are characterized by severe hypophosphatemia, inappropriate phosphaturia, low levels of 1,25(OH)<span class="elsevierStyleInf">2</span>D, and rickets or osteomalacia. Dysregulated secretion of FGF23 is also involved in a number of other diseases with abnormal phosphate and vitamin D homeostasis, such as X-linked hypophosphatemia (XLH)<span class="elsevierStyleSup">17</span>, autosomal recessive hypophosphatemic rickets/osteomalacia (ARHR)<span class="elsevierStyleSup">18</span>, and McCune-Albright syndrome<span class="elsevierStyleSup">19</span>.</p><p class="elsevierStylePara">In accordance with human diseases, functional in vivo studies have shown that FGF23 is one of the most potent phosphatonins that induces renal phosphate wasting and reduction of 1,25(OH)<span class="elsevierStyleInf">2</span>D. Administration of recombinant FGF23 results in phosphaturia and hypophosphatemia by suppressing the expression of sodium-phosphate  cotransporter that mediates physiological phosphate uptake in proximal tubular epithelial cells<span class="elsevierStyleSup">20</span>. Excess FGF23 also suppresses 1,25(OH)<span class="elsevierStyleInf">2</span>D via inhibition of 1α-hydroxylase (CYP27B1) which converts 25-hydroxyvitamin D [25(OH)D] to 1,25(OH)<span class="elsevierStyleInf">2</span>D and stimulation of 24-hydroxylase (CYP24) which converts 1,25(OH)<span class="elsevierStyleSup">2</span>D to more hydrophilic metabolites with lesser biological activity<span class="elsevierStyleSup">20</span>.</p><p class="elsevierStylePara">In keeping with these observations, transgenic mice that overexpress either wild-type or a mutant form of FGF23 that is resistant to cleavage developed hypophosphatemia, low serum 1,25(OH)<span class="elsevierStyleInf">2</span>D levels, and rickets and osteomalacia<span class="elsevierStyleSup">21,22</span>. Conversely, targeted ablation of FGF23 leads to the opposite renal phenotype, consisting of hyperphosphatemia and elevated production of 1,25(OH)<span class="elsevierStyleInf">2</span>D23. Subsequent studies highlighted the physiologic role of FGF23 in maintaining normal serum phosphate levels in the setting of dietary phosphate variation<span class="elsevierStyleSup">10</span>, although the precise mechanism by which phosphate loading mediates FGF23 production remains unknown.</p><p class="elsevierStylePara"><span class="elsevierStyleBold">FGF23-KLOTHO AXIS</span></p><p class="elsevierStylePara">Another unique characteristic of FGF23 is that this molecule derives from bone and exerts its hormonal effects in the kidney despite the ubiquitous presence of its receptors (FGFRs). This is in sharp contrast to other FGF family members that are thought to regulate various cell functions at a local level<span class="elsevierStyleSup">24</span>. This mystery has been progressively unraveled by a recent major breakthrough that FGF23 requires Klotho, an anti-aging protein, as a cofactor in FGF23-FGFR1c interaction<span class="elsevierStyleSup">25,26</span>. This fact clearly explains why Klotho mutant mice<span class="elsevierStyleSup">27</span> display a phenotype identical to that of FGF23 null mice<span class="elsevierStyleSup">23</span>, both of which are characterized by premature agingrelated phenotypes associated with hyperphosphatemia and paradoxically high 1,25(OH)<span class="elsevierStyleInf">2</span>D levels.</p><p class="elsevierStylePara">Of note, Klotho is expressed in limited tissues such as the kidney, parathyroid gland, and pituitary gland. It is intriguing that such limited expression pattern corresponds to the target tissues for FGF23 as functionally defined by the induction of early growth-responsive 1 (Egr-1) expression after intravenous administration of recombinant FGF23 to rats<span class="elsevierStyleSup">25</span>. It is, however, still unclear how in the kidney FGF23 exerts its physiological effects on the proximal tubule despite the highest expression of Klotho-FGFR complexes in the distal tubule. Several investigators hypothesize that FGF23 actions on the proximal tubule may be indirectly mediated by FGF23 stimulation of the distal tubule and subsequent release of paracrine factors<span class="elsevierStyleSup">28</span>, but further researches are needed to confirm this attracting hypothesis.</p><p class="elsevierStylePara"><span class="elsevierStyleBold">ELEVATED LEVELS OF FGF23 IN CKD</span></p><p class="elsevierStylePara">Insights into the role of FGF23 in mineral homeostasis have launched a new field of clinical research in CKD patients. Several studies have measured circulating FGF23 levels in predialysis <span class="elsevierStyleSup">11</span> and dialysis <span class="elsevierStyleSup">29</span> patients using an enzyme-linked immunosorbent assay (ELISA) that detects the carboxylterminal portion of FGF23, and reported progressively elevated FGF23 levels as serum creatinine or phosphate levels increase, suggesting its physiologic response to chronic phosphate retention. However, the possibility of accumulation of carboxyl-terminal fragments due to decreased renal function cannot be excluded in these studies.</p><p class="elsevierStylePara">Accordingly, a subsequent study measured intact FGF23 levels in CKD patients using a sandwich ELISA system that exclusively detects full-length human FGF23, and found similar increase in FGF23 levels along with decline in glomerular filtration rate (GFR)<span class="elsevierStyleSup">12</span>. Furthermore, serum FGF23 levels were negatively associated with 1,25(OH)<span class="elsevierStyleInf">2</span>D levels and maximal tubular reabsorption of phosphate (TmP/GFR) correlated negatively with serum FGF23 levels, consistent with the physiological action of FGF23 to inhibit phosphate reabsorption in the proximal tubule. However, patients with more advanced CKD exhibited impaired urinary phosphate excretion despite extremely high FGF23 levels.</p><p class="elsevierStylePara">Taken together, it is suggested that in early stage of CKD, serum FGF23 is elevated to maintain normal serum phosphate levels by promoting urinary phosphate excretion, but in advanced stage, overt phosphate loading may overcome such compensation for decreased GFR despite markedly elevated FGF23 levels, which in turn results in decreased renal production of 1,25(OH)<span class="elsevierStyleInf">2</span>D, possibly thereby worsening secondary hyperparathyroidism<span class="elsevierStyleSup">30</span>. Another group further supported this hypothesis by elegantly showing that increased FGF23 was an independent predictor of decreased 1,25(OH)<span class="elsevierStyleInf">2</span>D levels and the effects of renal function and hyperphosphatemia on serum 1,25(OH)<span class="elsevierStyleInf">2</span>D levels were completely extinguished by adjusting for FGF23, suggesting that FGF23 is a central factor in the early pathogenesis of secondary hyperparathyroidism<span class="elsevierStyleSup">13</span>.</p><p class="elsevierStylePara">Of note, a recent observational study have shown that in patients who are beginning hemodialysis treatment high FGF23 levels were associated with mortality independently of serum phosphate levels and other known risk factors<span class="elsevierStyleSup">31</span>. Supposing that FGF23 may indicate phosphate retention even in patients with normophosphatemia, its measurements may be useful to identify which of those patients might benefit from more aggressive phosphate management. Whether such strategies for the control of phosphate homeostasis would prolong survival of CKD patients is worthy of further investigation.</p><p class="elsevierStylePara"><span class="elsevierStyleBold">FGF23 AND SECONDARY HYPERPARATHYROIDISM IN CKD</span></p><p class="elsevierStylePara">Serum FGF23 levels are progressively increased as kidney function declines and are markedly elevated once on dialysis therapy<span class="elsevierStyleSup">32,33</span>. Such high levels of FGF23 may be due to persistent phosphate retention or  hyperphosphatemia, while active vitamin D therapy has also been shown to increase serum FGF23 levels in dialysis patients<span class="elsevierStyleSup">34</span>. This observation was further supported by in vivo and in vitro studies showing that 1,25(OH)<span class="elsevierStyleInf">2</span>D directly increases the production of FGF23 by osteoblasts through the vitamin D-responsive elements present in the FGF23 promoter<span class="elsevierStyleSup">35</span>. (Figure 1)</p><p class="elsevierStylePara">In this context, it is an interesting finding that in dialysis patients with secondary hyperparathyroidism high FGF23 levels may predict the future development of refractory hyperparathyroidism<span class="elsevierStyleSup">32,33</span>. Although the mechanism of this finding remains unclear, it is possible that chronic phosphate retention as reflected by elevated FGF23 levels maycontribute to further progression of parathyroid hyperplasia, because high phosphate directly stimulates PTH secretion and parathyroid cell proliferation. Another possibility is that high levels of FGF23 at baseline may be a consequence of prolonged active vitamin D administration for severe hyperparathyroidism<span class="elsevierStyleSup">35</span>, which may be related to future resistance to vitamin D therapy.</p><p class="elsevierStylePara">Besides the above-mentioned indirect effect of FGF23 on parathyroid function via inhibition of 1,25(OH)<span class="elsevierStyleInf">2</span>D production, the abundant expression of Klotho in the parathyroid suggests that FGF23 may directly affect parathyroid function<span class="elsevierStyleSup">25</span>. In fact, a recent study using rats with normal renal function has shown that FGF23 suppresses secretion of PTH in vivo and in vitro<span class="elsevierStyleSup">36</span>. FGF23 also increases parathyroid 1α-hydroxylase expression and partly thereby decreases secretion of PTH in primary cultures of bovine parathyroid cells<span class="elsevierStyleSup">37</span>. Thus, it is likely that FGF23 is a negative regulator of parathyroid function, at least in normal physiology. However, in CKD patients with secondary hyperparathyroidism, PTH secretion remains stimulated despite extremely high FGF23 levels<span class="elsevierStyleSup">32,33</span>. Such resistance of the parathyroid to high FGF23 levels in uremia should be investigated in future studies.</p><p class="elsevierStylePara">Another issue of concern is a recent finding that PTH secretion is regulated in a Klotho- and  Na<span class="elsevierStyleSup">+</span>,K<span class="elsevierStyleSup">+</span>-ATPasedependent manner<span class="elsevierStyleSup">38</span>. It is proposed that when extracellular calcium is low, Na<span class="elsevierStyleSup">+</span>,K<span class="elsevierStyleSup">+</span>-ATPase is quickly recruited to the plasma membrane and an electrochemical gradient created by increased Na<span class="elsevierStyleSup">+</span>,K<span class="elsevierStyleSup">+</span>-ATPase may cause PTH release. However, it remains unclear how such a Klotho- and Na<span class="elsevierStyleSup">+</span>,K<span class="elsevierStyleSup">+</span>-ATPasedependent PTH regulation interacts with the inhibitory effect of FGF23 on PTH secretion through Klotho-FGFR complexes. Furthermore, it is also a matter of concern whether such a complex mechanism is modulated in dialysis patients in whom phosphate retention is prevalent and hypocalcemic state is rare due to treatment with calcium-based phosphate binders and active vitamin D analogs. Future studies should investigate the possible complex interaction between FGF23-, Klotho- and Na<span class="elsevierStyleSup">+</span>,K<span class="elsevierStyleSup">+</span>-ATPase-dependent pathways regulating PTH secretion and whether these complex mechanisms are modulated in the setting of CKD.</p><p class="elsevierStylePara"><span class="elsevierStyleBold">CONCLUSION</span></p><p class="elsevierStylePara">The recent identification of FGF23 and Klotho as a physiological regulator of phosphate and vitamin D metabolism has considerably advanced our understanding of the mineral and bone disorder in CKD. It is now clear that FGF23 plays a central role in the pathogenesis of altered mineral metabolism and secondary hyperparathyroidism in CKD patients. FGF23 can be used not only as a biomarker for assessing phosphate retention but also as a predictor of mortality and future development of refractory hyperparathyroidism. However, the precise role of extremely elevated FGF23 levels in uremia still emains unclear, especially as to its direct effect on parathyroid function. Further elucidation of the FGF23- Klotho axis will help us to establish a more rational approach for the management of mineral and bone disorder that is associated with high burden of morbidity and mortality in CKD patients<span class="elsevierStyleSup">39,40</span>.</p><p class="elsevierStylePara"><a href="grande/40818078_f1_pag394.jpg" class="elsevierStyleCrossRefs"><img src="40818078_f1_pag394.jpg"></img></a></p><p class="elsevierStylePara">Figure 1. </p>" "pdfFichero" => "P1-E23-S255-A408.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec434011" "palabras" => array:1 [ 0 => "Role of FGF23 in CKD" ] ] ] "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec434012" "palabras" => array:1 [ 0 => "Role of FGF23 in CKD" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "El FGF23 es una hormona de reciente identificación que regula el metabolismo de los minerales y de la vitamina D. En pacientes con insuficiencia renal crónica (IRC), los niveles circulantes de FGF23 se elevan de forma progresiva para compensar la retención renal de fosfato persistente, lo cual provoca una producción renal reducida de 1,25-dihidroxivitamina D y estimula, por tanto, la secreción de la hormona paratifoidea. Este hecho sugiere que su papel es crucial en la patogénesis de la homeostasis mineral alterada en la IRC. Asimismo, se ha demostrado recientemente que el FGF23 actúa directamente en la glándula paratiroidea y media en la secreción de la hormona paratiroidea en presencia del Klotho como cofactor, aunque hasta el momento dichos efectos no se han confirmado en pacientes con IRC. El FGF23 también puede utilizarse como predictor de la mortalidad así como de un futuro desarrollo de hipertiroidismo refractario en pacientes sometidos a diálisis, en los que los niveles de FGF23 son realmente elevados como reacción al tratamiento de hiperfosfatemia y a la actividad de la vitamina D. En este resumen breve se incluyen las aproximaciones más recientes en cuanto al papel del FGF23 en la patogénesis de las alteraciones del metabolismo óseo-mineral en la IRC." ] "en" => array:1 [ "resumen" => "<p class="elsevierStylePara">FGF23 is a recently identified hormone regulating mineral and vitamin D metabolism. In patients with chronic kidney disease (CKD), circulating FGF23 levels are progressively elevated to compensate for persistent phosphate retention, which result in reduced renal production of 1,25-dihydroxyvitamin D and thereby stimulate secretion of parathyroid hormone, suggesting its critical role in the pathogenesis of altered mineral homeostasis in CKD. Furthermore, it has recently been shown that FGF23 directly acts on parathyroid gland and mediate secretion of parathyroid hormone in the presence of Klotho as a cofactor, although such effects are not yet confirmed in patients with CKD. FGF23 can also be used as a predictor of mortality as well as future development of refractory hyperparathyroidism in patients undergoing dialysis therapy, where FGF23 levels are markedly elevated in response to hyperphosphatemia and active vitamin D treatment. This brief review summarizes recent insights into the role of FGF23 in the pathogenesis of mineral and bone disorders in CKD.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "408527_fig1.jpg" "Alto" => 499 "Ancho" => 710 "Tamanyo" => 31185 ] ] ] ] "bibliografia" => array:1 [ "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:40 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Moe S, Drueke T, Cunningham J, et al. 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| 2023 Abril | 23 | 14 | 37 |
| 2023 Marzo | 21 | 27 | 48 |
| 2023 Febrero | 31 | 33 | 64 |
| 2023 Enero | 42 | 28 | 70 |
| 2022 Diciembre | 39 | 40 | 79 |
| 2022 Noviembre | 50 | 33 | 83 |
| 2022 Octubre | 95 | 54 | 149 |
| 2022 Septiembre | 37 | 32 | 69 |
| 2022 Agosto | 42 | 56 | 98 |
| 2022 Julio | 34 | 46 | 80 |
| 2022 Junio | 47 | 34 | 81 |
| 2022 Mayo | 37 | 36 | 73 |
| 2022 Abril | 52 | 36 | 88 |
| 2022 Marzo | 52 | 53 | 105 |
| 2022 Febrero | 41 | 51 | 92 |
| 2022 Enero | 27 | 36 | 63 |
| 2021 Diciembre | 36 | 44 | 80 |
| 2021 Noviembre | 30 | 41 | 71 |
| 2021 Octubre | 39 | 56 | 95 |
| 2021 Septiembre | 29 | 38 | 67 |
| 2021 Agosto | 51 | 27 | 78 |
| 2021 Julio | 53 | 39 | 92 |
| 2021 Junio | 47 | 40 | 87 |
| 2021 Mayo | 37 | 23 | 60 |
| 2021 Abril | 69 | 56 | 125 |
| 2021 Marzo | 55 | 25 | 80 |
| 2021 Febrero | 81 | 19 | 100 |
| 2021 Enero | 58 | 31 | 89 |
| 2020 Diciembre | 36 | 13 | 49 |
| 2020 Noviembre | 44 | 18 | 62 |
| 2020 Octubre | 35 | 12 | 47 |
| 2020 Septiembre | 35 | 25 | 60 |
| 2020 Agosto | 55 | 17 | 72 |
| 2020 Julio | 75 | 12 | 87 |
| 2020 Junio | 61 | 24 | 85 |
| 2020 Mayo | 58 | 22 | 80 |
| 2020 Abril | 53 | 28 | 81 |
| 2020 Marzo | 45 | 21 | 66 |
| 2020 Febrero | 75 | 24 | 99 |
| 2020 Enero | 90 | 36 | 126 |
| 2019 Diciembre | 96 | 34 | 130 |
| 2019 Noviembre | 60 | 25 | 85 |
| 2019 Octubre | 19 | 14 | 33 |
| 2019 Septiembre | 53 | 14 | 67 |
| 2019 Agosto | 19 | 15 | 34 |
| 2019 Julio | 52 | 32 | 84 |
| 2019 Junio | 30 | 30 | 60 |
| 2019 Mayo | 28 | 45 | 73 |
| 2019 Abril | 108 | 27 | 135 |
| 2019 Marzo | 43 | 22 | 65 |
| 2019 Febrero | 25 | 30 | 55 |
| 2019 Enero | 37 | 27 | 64 |
| 2018 Diciembre | 66 | 32 | 98 |
| 2018 Noviembre | 77 | 17 | 94 |
| 2018 Octubre | 74 | 9 | 83 |
| 2018 Septiembre | 72 | 9 | 81 |
| 2018 Agosto | 44 | 13 | 57 |
| 2018 Julio | 49 | 13 | 62 |
| 2018 Junio | 40 | 11 | 51 |
| 2018 Mayo | 50 | 14 | 64 |
| 2018 Abril | 63 | 8 | 71 |
| 2018 Marzo | 47 | 12 | 59 |
| 2018 Febrero | 40 | 3 | 43 |
| 2018 Enero | 36 | 6 | 42 |
| 2017 Diciembre | 41 | 10 | 51 |
| 2017 Noviembre | 45 | 13 | 58 |
| 2017 Octubre | 49 | 10 | 59 |
| 2017 Septiembre | 51 | 19 | 70 |
| 2017 Agosto | 56 | 19 | 75 |
| 2017 Julio | 39 | 18 | 57 |
| 2017 Junio | 59 | 11 | 70 |
| 2017 Mayo | 59 | 23 | 82 |
| 2017 Abril | 35 | 15 | 50 |
| 2017 Marzo | 38 | 14 | 52 |
| 2017 Febrero | 116 | 20 | 136 |
| 2017 Enero | 62 | 13 | 75 |
| 2016 Diciembre | 97 | 11 | 108 |
| 2016 Noviembre | 118 | 6 | 124 |
| 2016 Octubre | 167 | 16 | 183 |
| 2016 Septiembre | 166 | 16 | 182 |
| 2016 Agosto | 239 | 11 | 250 |
| 2016 Julio | 174 | 8 | 182 |
| 2016 Junio | 133 | 0 | 133 |
| 2016 Mayo | 153 | 0 | 153 |
| 2016 Abril | 103 | 0 | 103 |
| 2016 Marzo | 104 | 0 | 104 |
| 2016 Febrero | 124 | 0 | 124 |
| 2016 Enero | 118 | 0 | 118 |
| 2015 Diciembre | 126 | 0 | 126 |
| 2015 Noviembre | 114 | 0 | 114 |
| 2015 Octubre | 88 | 0 | 88 |
| 2015 Septiembre | 88 | 0 | 88 |
| 2015 Agosto | 75 | 0 | 75 |
| 2015 Julio | 64 | 0 | 64 |
| 2015 Junio | 45 | 0 | 45 |
| 2015 Mayo | 81 | 0 | 81 |
| 2015 Abril | 21 | 0 | 21 |
| 2015 Febrero | 2836 | 0 | 2836 |
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