Chronic kidney disease-mineral and bone disorder: a complex scenario
El complejo escenario de las alteraciones de metabolismo óseo y mineral en la enfermedad renal crónica
Natalia Mejiaa, N.. Mejíab, Pablo Roman-Garciac, P.. Roman-Garcíad, Ana Belen Miare, A.B.. Miarf, Beatriz Tavirag, B.. Tavirah, Jorge B Cannata-Andíac, J.B.. Cannata-Andíad
a Servicio de Nefrología Pediátrica, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain,
b Servicio de Nefrología Pediátrica, Hospital Universitario Central de Asturias, Oviedo, Asturias,
c Servicio de Metabolismo Óseo y Mineral, Hospital Universitario Central de Asturias. Instituto Reina Sofía de Investigación. REDinREN del ISCIII. Universidad de Oviedo, Oviedo, Asturias, Spain,
d Servicio de Metabolismo Óseo y Mineral, Hospital Universitario Central de Asturias. Instituto Reina Sofía de Investigación. REDinREN del ISCIII. Universidad de Oviedo, Oviedo, Asturias,
e Departamente de Biología Funcional y Celular, Universidad de Oviedo, Oviedo, Asturias, Spain,
f Departamente de Biología Funcional y Celular, Universidad de Oviedo, Oviedo, Asturias,
g Laboratorio de Genética Molecular, Hospital Universitario Central de Asturias. (REDinREN, Red de investigación renal del Instituto de Salud Carlos III, Fondos FEDER), Oviedo, Asturias, Spain,
h Laboratorio de Genética Molecular, Hospital Universitario Central de Asturias. (REDinREN, Red de investigación renal del Instituto de Salud Carlos III, Fondos FEDER), Oviedo, Asturias,
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Universidad de Oviedo, Oviedo, Asturias, Spain, " "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] 3 => array:3 [ "entidad" => "Servicio de Metabolismo Óseo y Mineral, Hospital Universitario Central de Asturias. Instituto Reina Sofía de Investigación. REDinREN del ISCIII. Universidad de Oviedo, Oviedo, Asturias, " "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "affd" ] 4 => array:3 [ "entidad" => "Departamente de Biología Funcional y Celular, Universidad de Oviedo, Oviedo, Asturias, Spain, " "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "affe" ] 5 => array:3 [ "entidad" => "Departamente de Biología Funcional y Celular, Universidad de Oviedo, Oviedo, Asturias, " "etiqueta" => "<span class="elsevierStyleSup">f</span>" "identificador" => "afff" ] 6 => array:3 [ "entidad" => "Laboratorio de Genética Molecular, Hospital Universitario Central de Asturias. (REDinREN, Red de investigación renal del Instituto de Salud Carlos III, Fondos FEDER), Oviedo, Asturias, Spain, " "etiqueta" => "<span class="elsevierStyleSup">g</span>" "identificador" => "affg" ] 7 => array:3 [ "entidad" => "Laboratorio de Genética Molecular, Hospital Universitario Central de Asturias. (REDinREN, Red de investigación renal del Instituto de Salud Carlos III, Fondos FEDER), Oviedo, Asturias, " "etiqueta" => "<span class="elsevierStyleSup">h</span>" "identificador" => "affh" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "El complejo escenario de las alteraciones de metabolismo óseo y mineral en la enfermedad renal crónica" ] ] "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION </span></p><p class="elsevierStylePara">In healthy individuals kidneys regulate calcium and phosphorus homeostasis through tubular reabsorption mechanisms. Patients with chronic kidney disease have seriously compromised homeostatic mechanisms, giving rise to different adaptive changes in calcium (Ca), phosphorus (P), parathyroid hormone (PTH), vitamin D and fibroblastic growth factor (FGF-23) levels.</p><p class="elsevierStylePara">Among all the CKD disorders, those related to bone and mineral metabolism have a significant impact on morbidity and mortality. Traditionally, these abnormalities are included within the term ‘renal osteodystrophy’.<span class="elsevierStyleSup">1 </span>Recently, the collection of biochemical abnormalities such as calcium, phosphorus, vitamin D and PTH disorders, changes in bone morphology such as variation in turnover, volume and bone mineralisation, and vascular or other soft-tissue calcifications, have been included under the definition of “chronic kidney disease mineral and bone disorders” (CKD-MBD).<span class="elsevierStyleSup">2-4 </span>There are various clinical signs, although secondary hyperparathyroidism (SHPT), fractures, bone pain, vascular calcification and cardiovascular events are highlighted as causing lower quality of life with a high morbidity and mortality.<span class="elsevierStyleSup">5 </span></p><p class="elsevierStylePara">This review pays special attention to the Ca-P-PTH-vitamin D-FGF-23 axis, SHPT, vascular calcifications and their relationship with bone-mineral density (BMD) in CKD-MBD.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">CA-P-PTH-VITAMIN D-FGF-23 AXIS </span></p><p class="elsevierStylePara">The most important factors that regulate bone and mineral metabolism are PTH, Ca, P, FGF-23 and the vitamin D related compounds. These factors are also totally interrelated and their effects depend on the target organ studied. The progression of CKD is associated with an early increase in FGF-23 and with a reduced functioning kidney mass; both factors favour the decrease in alpha-1-hydroxylase, the enzyme responsible for calcitriol synthesis, a physiologically active form of vitamin D. The final result is that this hormone’s levels are found frecuently decreased.<span class="elsevierStyleSup">6 </span>The decrease in calcitriol significantly affects the intestinal Ca absorption, favouring the serum calcium to decrease and stimulating PTH.<span class="elsevierStyleSup">7 </span>In the bone, PTH stimulates Ca and P release, whilst in the kidney, it stimulates Ca reabsorption and inhibits phosphate reabsorption. Furthermore, PTH increases alpha-1-hydroxylase expression, therefore favouring calcitriol synthesis which increases intestinal Ca and P absorption.<span class="elsevierStyleSup">8 </span>As a result of these changes, serum Ca increases and P decreases.<span class="elsevierStyleSup">9 </span></p><p class="elsevierStylePara">Reduced renal function also directly affects P reabsorption. The kidney is not capable of filtering enough P, and its high level in blood directly stimulates the parathyroid gland which, in turn, stimulates FGF-23 synthesis and secretion by the osteocytes.<span class="elsevierStyleSup">10-13 </span>In principle, FGF-23 was described to inhibit renal P reabsorption and calcitriol production; these effects are synergic and contrary to those of PTH, respectively.<span class="elsevierStyleSup">14 </span>However, previous studies have shown that FGF-23 not only has an effect on renal tissue but also on the parathyroid gland, which under normal conditions activates the mitogen-activated protein kinase (MAPK) pathway, reducing PTH synthesis and secretion.<span class="elsevierStyleSup">15 </span>To do so, it needs to bind to its FGFR-1 and 3 receptors, and its co-receptor <span class="elsevierStyleItalic">Klotho</span>. The <span class="elsevierStyleItalic">Klotho </span>gene codes for a transmembrane protein whose deficiency in rats results in a premature ageing-like phenotype, characterised by atherosclerosis, osteoporosis, hyperphospatemia, calcifications in the vascular medial layer, cardiac muscle and other tissues.<span class="elsevierStyleSup">16 </span><span class="elsevierStyleItalic">Klotho </span>expression determines the tissue-specificity of FGF-23 and is increased by FGF-23 in a feedback mechanism.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">SECONDARY HYPERPARATHYROIDISM </span></p><p class="elsevierStylePara">The parathyroid gland is the main organ responsible for Ca homeostasis in the organism, it senses serum Ca concentration via the Ca receptor (CaR), and also has vitamin D receptors (VDR). Its main action is PTH production.<span class="elsevierStyleSup">17 </span>Extracellular ionic Ca is the main parathyroid regulator; low levels stimulate PTH secretion in a matter of minutes, whilst high levels inhibit hormone release and, furthermore, favour its degradation within the parathyroid cells.<span class="elsevierStyleSup">18-20 </span>The result is a sigmoidal response in the parathyroid gland, in which small extracellular ionic Ca changes provoke large variations in PTH, achieving maximum inhibition in hypercalcaemia. The effects of Ca on PTH are mediated by its specific receptor, CaR,<span class="elsevierStyleSup">21 </span>a receptor belonging to the family of G protein-coupled receptors, which are found at the cell membrane.</p><p class="elsevierStylePara">Calcitriol acts on the parathyroid gland via its specific receptor, VDR, a high affinity and specificity receptor that belongs to the family of steroid/thyroid receptors.<span class="elsevierStyleSup">22 </span>When calcitriol is bound to a receptor, the calcitriol/VDR complex is translocated to the cell nucleus, forming a heterodimer with retinoid-X receptor (RXR). The calcitriol/VDR/RXR complex is bound to <span class="elsevierStyleItalic">vitamin D responsive elements </span>(VDR-E) present in the PTH gene’s promoter region, blocking its transcription. Furthermore, calcitriol is able to indirectly inhibit PTH secretion, increasing intestinal Ca absorption, and at the same time, stimulating the reabsorption of Ca deposits.<span class="elsevierStyleSup">23-25 </span></p><p class="elsevierStylePara">In CKD, the incorrect control of PTH secretion has partly been attributed to the reduced VDR and CaR expression which occurs in parallel to parathyroid gland growth. Parathyroid gland hyperplasia and the consequent increase in PTH secretion are responsible for SHPT observed in CKD. In mild and moderate forms of SHPT, the parathyroid gland is still able to respond to its main regulators, such as Ca, P and FGF-23.<span class="elsevierStyleSup">26,27 </span>On the other hand, in more advanced stages, especially in tertiary HPT, an irreversible form of HPT which is common in patients undergoing dialysis for a long time and kidney transplant patients, the parathyroid gland has a scarce or null response to usual stimuli and presents a high degree of autonomy.<span class="elsevierStyleSup">28 </span></p><p class="elsevierStylePara">FGF-23/<span class="elsevierStyleItalic">Klotho </span>and Ca/CaR act on the parathyroid gland via mechanisms similar to the MAPK pathway,<span class="elsevierStyleSup">15 </span>with the common objective of reducing PTH synthesis and secretion. Under normal conditions, FGF-23 reduces PTH levels, although in chronic renal failure FGF-23 and PTH levels increase. This is due to a reduction in <span class="elsevierStyleItalic">Klotho</span>/FGFR in uremic parathyroid glands so that FGF-23 fails to exert its inhibitory effect likely due to a decrease in MAPK activation.<span class="elsevierStyleSup">29 </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">VASCULAR CALCIFICATIONS </span></p><p class="elsevierStylePara">Soft-tissue calcification occurs in a high percentage of CKD patients and it has been reported since the 19<span class="elsevierStyleSup">th </span>century. Tissues that are frequently affected are blood vessels, lungs, kidneys, myocardium, coronary arteries, the central nervous system and gastric mucosa. Calcifications are associated with many factors such as excessive doses of calcitriol, hyperphosphatemia, tobacco use, arterial hypertension, increase in CaxP product, calcium overload, diabetes and male gender.<span class="elsevierStyleSup">30 </span>In CKD, lesions are mainly observed in the medial layer, but also in the intima layer and may affect the flow and vascular stiffness, with the consequent increase in arterial pressure and pulse wave velocity.</p><p class="elsevierStylePara">Vascular calcifications in the artery intima layer are often associated with previous atherosclerotic plaques. They affect the medial layer of medium calibre arteries, the aorta, and coronary arteries, with concentric Ca precipitates in vascular smooth muscle cells, causing stiffness and atherosclerosis. A phenotypic differentiation from vascular to bone cells is produced in these calcifications, critically reducing the contractile ability of muscle cells. Vascular complications often precede bone alterations, which occur very late and insidiously.<span class="elsevierStyleSup">31 </span>Although all histological forms of renal osteodystrophy have been associated with a greater prevalence of vascular calcifications, the one with the most impact is that observed in low turnover renal osteodystrophy.</p><p class="elsevierStylePara">There is a large number of promoters and inhibitors involved in vascular calcification. Promoters favour vessel calcification but, under normal conditions, there are more vascular calcification inhibitors circulating in the blood. With older age and CKD, this process is reversed and calcification inhibitors are down-regulated, while promoters are up-regulated.</p><p class="elsevierStylePara">Phosphorus is the most significant and probably the most studied vascular calcification promoter and its action is facilitated by the Na/P cotransporter, called PiT-1. Ca, osteopontin, osteocalcin, bone morphogenetic proteins (BMP-2 and BMP4), bone sialoprotein, type I collagen, and alkaline phosphatase (ALP) and many transcription factors (CbfaI/RUNX2 and MSX-2) have been described as downsctream vascular calcification promoters.<span class="elsevierStyleSup">32-37 </span>Several types of proteins are vascular calcification inhibitors. Fetuin-A is a circulating molecule that inhibits the formation of hydroxyapatite crystals, and there is a correlation between decreased fetuin-A levels and an increased mortality in patients on haemodialysis and patients with heart diseases.<span class="elsevierStyleSup">38 </span>Osteoprotegerin (OPG) also participates in inhibiting vascular calcification. Studies on KO mice for OPG showed calcifications in the aorta, renal arteries and osteoporosis.<span class="elsevierStyleSup">39 </span>Studies on KO mice for bone Gla protein (BGP) found calcification in the medial layer and the cartilage.<span class="elsevierStyleSup">40 </span>Among the bone morphogenetic proteins (BMP), BMP-7 is associated with vascular calcification inhibition. In KO mice studies for low density lipoprotein (LDL), it was shown that the expression of vascular osteocalcin is down-regulated in animals treated with BMP-7.<span class="elsevierStyleSup">41 </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">RELATIONSHIP BETWEEN DEMINERALISATION AND VASCULAR CALCIFICATION </span></p><p class="elsevierStylePara">Although this relationship was first described 20 years ago,<span class="elsevierStyleSup">42 </span>the relationship between osteoporosis and vascular calcification has been underestimated, possibly because demineralisation, osteoporosis and vascular calcification have always been considered as disorders secondary to ageing. Age can not be excluded as a favouring factor, but evidence of a frequent association between bone fragility and vascular calcification further suggests that there may be a causal relationship between the two. The pathogenic factors involved in both processes are still to a large extent unknown.<span class="elsevierStyleSup">43 </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">KEY CONCEPTS </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">1.            </span>FGF-23 has been added to the list of bone metabolism regulators in chronic kidney disease, given its effects on the kidney, parathyroid gland and vitamin D metabolism. <span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">2.            </span>Vascular calcification, an important chronic kidney disease complication, is subject to a complex regulation in which mineralisation promoters and inhibitors intervene. <span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">3.            </span>Epidemiological, clinical and experimental studies have shown a relationship between vascular calcification progres­sion and bone demineralisation, suggesting that between both processes there is an interrelation, involving com­mon mediators, which goes beyond the known effect that age has on both alterations.</p><p class="elsevierStylePara"> </p>" "pdfFichero" => "P1-E524-S3341-A10926-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:5 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec440461" "palabras" => array:1 [ 0 => "Hiperparatiroidismo secundario" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec440463" "palabras" => array:1 [ 0 => "CKD-MBD" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec440465" "palabras" => array:1 [ 0 => "Calcificación vascular" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec440467" "palabras" => array:1 [ 0 => "FGF-23" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec440469" "palabras" => array:1 [ 0 => "Desmineralización ósea" ] ] ] "en" => array:5 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec440462" "palabras" => array:1 [ 0 => "Secondary hyperparathyroidism" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec440464" "palabras" => array:1 [ 0 => "CKD-MBD" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec440466" "palabras" => array:1 [ 0 => "Vascular calcification" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec440468" "palabras" => array:1 [ 0 => "FGF-23" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec440470" "palabras" => array:1 [ 0 => "Bone demineralization" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "<p class="elsevierStylePara">Las alteraciones del metabolismo óseo en el escenario de la enfermedad renal crónica (CKD-MBD) constituyen un dinámico campo de estudio. Al conjunto de reguladores clásicos del metabolismo óseo tales como calcio, fósforo, hormona paratiroidea (PTH) y calcitriol se ha añadido el factor de crecimiento fibroblástico 23 (FGF-23). La calcificación vascular, una de las complicaciones más importantes de la enfermedad renal crónica, está sujeta a una compleja regulación en la que intervienen factores promotores e inhibidores del proceso de mineralización. La asociación entre calcificación vascular, desmineralización ósea y mortalidad y la existencia de factores y vías de señalización comunes está siendo objeto de interesantes investigaciones.</p> <p class="elsevierStylePara"><span class="elsevierStyleBold">           </span></p>" ] "en" => array:1 [ "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleItalic">The chronic kidney disease-bone and mineral disorders (CKD-MBD) represents a dinamic area of research. Recently, new factors such as FGF-23 have been added to the classic list of regulators of bone metabolism, which include calcium, phosphorus, PTH and calcitriol. Vascular calcification, one of the most important complication of CKD-MBD is regulated by a complex variety of  promoters and inhibitors. The relationship between vascular calcification, bone loss and mortality, together with the existence of likely common signaling pathways are subject of interesting investigations.</span></p>" ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:54 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Torregrosa JV, Bover Sanjuán J, Cannata Andía J. Recomendaciones de la Sociedad Española de Nefrologia para el manejo de las alteraciones del metabolismo óseo-mineral en los pacientes con enfermedad renal crónica. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 9 | 6 | 15 |
| 2024 October | 57 | 51 | 108 |
| 2024 September | 53 | 57 | 110 |
| 2024 August | 95 | 92 | 187 |
| 2024 July | 60 | 46 | 106 |
| 2024 June | 67 | 74 | 141 |
| 2024 May | 74 | 58 | 132 |
| 2024 April | 92 | 50 | 142 |
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| 2024 February | 65 | 40 | 105 |
| 2024 January | 82 | 43 | 125 |
| 2023 December | 65 | 21 | 86 |
| 2023 November | 52 | 37 | 89 |
| 2023 October | 106 | 47 | 153 |
| 2023 September | 82 | 38 | 120 |
| 2023 August | 50 | 25 | 75 |
| 2023 July | 79 | 37 | 116 |
| 2023 June | 57 | 37 | 94 |
| 2023 May | 60 | 45 | 105 |
| 2023 April | 49 | 23 | 72 |
| 2023 March | 59 | 28 | 87 |
| 2023 February | 50 | 27 | 77 |
| 2023 January | 63 | 36 | 99 |
| 2022 December | 52 | 45 | 97 |
| 2022 November | 85 | 71 | 156 |
| 2022 October | 80 | 120 | 200 |
| 2022 September | 74 | 50 | 124 |
| 2022 August | 73 | 58 | 131 |
| 2022 July | 91 | 76 | 167 |
| 2022 June | 84 | 45 | 129 |
| 2022 May | 95 | 48 | 143 |
| 2022 April | 110 | 73 | 183 |
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| 2022 January | 68 | 37 | 105 |
| 2021 December | 40 | 49 | 89 |
| 2021 November | 53 | 38 | 91 |
| 2021 October | 79 | 51 | 130 |
| 2021 September | 44 | 51 | 95 |
| 2021 August | 42 | 41 | 83 |
| 2021 July | 61 | 51 | 112 |
| 2021 June | 56 | 37 | 93 |
| 2021 May | 89 | 58 | 147 |
| 2021 April | 204 | 81 | 285 |
| 2021 March | 187 | 63 | 250 |
| 2021 February | 122 | 31 | 153 |
| 2021 January | 76 | 38 | 114 |
| 2020 December | 101 | 24 | 125 |
| 2020 November | 89 | 34 | 123 |
| 2020 October | 88 | 33 | 121 |
| 2020 September | 108 | 29 | 137 |
| 2020 August | 85 | 20 | 105 |
| 2020 July | 94 | 26 | 120 |
| 2020 June | 117 | 27 | 144 |
| 2020 May | 114 | 30 | 144 |
| 2020 April | 141 | 29 | 170 |
| 2020 March | 125 | 28 | 153 |
| 2020 February | 125 | 27 | 152 |
| 2020 January | 127 | 37 | 164 |
| 2019 December | 119 | 36 | 155 |
| 2019 November | 80 | 63 | 143 |
| 2019 October | 62 | 20 | 82 |
| 2019 September | 75 | 27 | 102 |
| 2019 August | 93 | 18 | 111 |
| 2019 July | 108 | 50 | 158 |
| 2019 June | 88 | 25 | 113 |
| 2019 May | 97 | 50 | 147 |
| 2019 April | 126 | 66 | 192 |
| 2019 March | 72 | 29 | 101 |
| 2019 February | 51 | 26 | 77 |
| 2019 January | 43 | 19 | 62 |
| 2018 December | 119 | 36 | 155 |
| 2018 November | 171 | 21 | 192 |
| 2018 October | 164 | 25 | 189 |
| 2018 September | 131 | 28 | 159 |
| 2018 August | 55 | 33 | 88 |
| 2018 July | 58 | 21 | 79 |
| 2018 June | 49 | 22 | 71 |
| 2018 May | 54 | 17 | 71 |
| 2018 April | 98 | 14 | 112 |
| 2018 March | 88 | 10 | 98 |
| 2018 February | 106 | 14 | 120 |
| 2018 January | 91 | 17 | 108 |
| 2017 December | 103 | 15 | 118 |
| 2017 November | 87 | 14 | 101 |
| 2017 October | 58 | 20 | 78 |
| 2017 September | 55 | 15 | 70 |
| 2017 August | 74 | 23 | 97 |
| 2017 July | 72 | 10 | 82 |
| 2017 June | 86 | 8 | 94 |
| 2017 May | 71 | 16 | 87 |
| 2017 April | 56 | 6 | 62 |
| 2017 March | 45 | 13 | 58 |
| 2017 February | 58 | 25 | 83 |
| 2017 January | 35 | 13 | 48 |
| 2016 December | 94 | 14 | 108 |
| 2016 November | 95 | 17 | 112 |
| 2016 October | 107 | 13 | 120 |
| 2016 September | 137 | 12 | 149 |
| 2016 August | 273 | 10 | 283 |
| 2016 July | 218 | 12 | 230 |
| 2016 June | 149 | 0 | 149 |
| 2016 May | 131 | 0 | 131 |
| 2016 April | 98 | 0 | 98 |
| 2016 March | 100 | 0 | 100 |
| 2016 February | 124 | 0 | 124 |
| 2016 January | 131 | 0 | 131 |
| 2015 December | 146 | 0 | 146 |
| 2015 November | 120 | 0 | 120 |
| 2015 October | 111 | 0 | 111 |
| 2015 September | 103 | 0 | 103 |
| 2015 August | 95 | 0 | 95 |
| 2015 July | 82 | 0 | 82 |
| 2015 June | 37 | 0 | 37 |
| 2015 May | 54 | 0 | 54 |
| 2015 April | 7 | 0 | 7 |
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