Fabry's disease: a form of chronic renal disease that may be diagnosed and treated
Enfermedad de Fabry: una forma de enfermedad renal crónica diagnosticable y tratable
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"apellidos" => "Gutiérrez Solís" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "X0211699508033350" "doi" => " " "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699508033350?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251408033358?idApp=UINPBA000064" "url" => "/20132514/0000002800000001/v0_201502091616/X2013251408033358/v0_201502091616/en/main.assets" ] "en" => array:10 [ "idiomaDefecto" => true "titulo" => "Fabry's disease: a form of chronic renal disease that may be diagnosed and treated" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "13" "paginaFinal" => "19" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "José A. Herrero Calvo" "autores" => array:1 [ 0 => array:4 [ "nombre" => "José A." "apellidos" => "Herrero Calvo" "email" => array:1 [ 0 => "jaherrero2@telefonica.net" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Clínico San Carlos, Madrid, Madrid, " "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Enfermedad de Fabry: una forma de enfermedad renal crónica diagnosticable y tratable" ] ] "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION</span></p><p class="elsevierStylePara">Fabry¿s disease is a hereditary disorder of the catabolism of glycosphingolipids produced by a deficit of lisosomal enzyme α-galactosidase A (α-GAL A), which leads to intracellular deposition, especially globotriaosylceramide (Gb3), within the vascular endothelium and other tissues. It is transmitted through the X chromosome and more than 400 mutations have been described so far (Human Gene Mutation Database, Institute of Medical Genetics, Cardiff http://archive.uwcm.ac.uk/uwcm/mg/hgmg0.html). Traditionally it has been considered recessively transmitted so that heterozygous women would be carriers and only 1% would develop the disease due to random inactivation of one of the X chromosomes (known as the Lyon¿s effect); however, there is more and more evidence that a great percentage of heterozygous women have partial enzymatic deficits and clinical manifestations with varying expression.<span class="elsevierStyleSup">1-5</span></p><p class="elsevierStylePara">It is a progressive disease that causes manifestations derived from dysfunction of the organ affected by the deposits, mainly the kidney, heart, nervous system, gastrointestinal tract, and the skin, although any organ or system of the body may be implicated.<span class="elsevierStyleSup">4, 6, 7</span> Clinical<span class="elsevierStyleSup">8,9</span> and experimental<span class="elsevierStyleSup">10</span> studies have shown that Fabry¿s disease conditions a vascular inflammatory and pro-thrombotic state. In fact, the cardiovascular events, mainly ischemic heart disease<span class="elsevierStyleSup">11</span> and cerebrovascular accidents,<span class="elsevierStyleSup">12</span> are an important cause of morbimortality in these patients.</p><p class="elsevierStylePara">The diversity in the clinical presentation has been verified in recent years, with late partial presentation forms diagnosed by chance or through targeted studies, highlighting the fact that although it is a «rare» disease given its low frequency, the prevalence is higher than that initially thought, and thus there exists the suspicion that an undetermined number of affected families are not diagnosed. On the other hand, the availability of enzymatic replacement therapy (ERT) has opened new and encouraging expectations, of course accompanied by a certain level of confusion about the type and administration regimens of the two enzymes commercially available.</p><p class="elsevierStylePara"><span class="elsevierStyleBold">VARIANTS IN THE CLINICAL EXPRESSION</span></p><p class="elsevierStylePara">Fabry¿s disease manifests with high phenotypic variability, not only within a same mutation but also even within a same family.<span class="elsevierStyleSup">13,14</span> In addition to environmental factors and maybe the participation of other genes, the severity or degree of involvement has been related with the residual activity of the α-GAL A enzyme. The classical form of the disease is usually characterized by a complete deficit of the enzymatic activity (less than 1%), with multisystemic implication, starting at childhood, reaching severe involvement by the third or fourth live decades<span class="elsevierStyleSup">4,7,13,14</span> (table I). Partial enzymatic defects (1-30%) give rise to incomplete forms of late onset (from the age of 20-30 years), with predominantly heart and/or kidney involvement, and scarcity or absence of the classical manifestations of the disease. In this sense, the «heart variant», in which left ventricular hypertrophy (LVH) would predominate,<span class="elsevierStyleSup">15</span> and the «kidney variant» manifested by proteinuria and progressive renal failure often accompanied also by LVH<span class="elsevierStyleSup">16-18</span> have been described (table I).</p><p class="elsevierStylePara">In the kidney there is deposition of Gb3 within the podocytes, mesangium, glomerular capillary endothelium, tubular epithelium, endothelial cells, the muscular layer of the arteries and arterioles, and in the interstitial cells.<span class="elsevierStyleSup">19-21</span> The deposits progress and leads to glomerulosclerosis and interstitial fibrosis.<span class="elsevierStyleSup">19,20</span> The initial data of renal involvement are isosthenuria, microalbuminuria and occasionally sings of proximal tubular dysfunction; later on proteinuria develops that in 20% of the cases may be higher than 3 g/24 h as well as renal failure, with or without arterial hypertension.<span class="elsevierStyleSup">22</span> On the other hand, it has been reported that up to 10% of the patients with Fabry¿s disease have associated glomerular lesions for other reasons.<span class="elsevierStyleSup">20</span></p><p class="elsevierStylePara">The rate of progression of the nephropathy from the initial stages is not well known. In the classical form progression to severe end-stage chronic renal disease (CRD) (stage 5 of NKF-DOQI) is usual between the third an fifth decades of life,<span class="elsevierStyleSup">22, 23</span> whereas in the incomplete forms this may happen at advanced ages.<span class="elsevierStyleSup">15, 18</span> The progression of the renal involvement has been related to the stage of the enzymatic deficit.<span class="elsevierStyleSup">22</span> Once renal failure is established, progression to a severe stage may be rapid, similar to diabetic nephropathy. In the series by Branton et al. a subgroup of 14 patients is described in whom progression of the renal function was known ending up in dialysis, having an average loss of glomerular filtration rate of -12mL/min/1.73 m<span class="elsevierStyleSup">2</span> per year, once the serum creatinine reached 1.5 mg/dL.22 In another series of 447 patients (62% men), the mean time to double the serum creatinine value from a baseline value of 1.5 mg/dL was 39 months.<span class="elsevierStyleSup">24</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">EPIDEMIOLOGY AND DIAGNOSIS</span></p><p class="elsevierStylePara">It is estimated that the incidence of the classical form is 1 in 40,000-60,000 male liveborns (approximately 0.002%),<span class="elsevierStyleSup">25</span> although the global incidence in both genders is unknown, which would include the late onset incomplete forms in both males and females. An Italian study on 37,104 male newborns has been published in which 12 (0.03%) were diagnosed with Fabry¿s disease, which was not previously known in the family and may correspond to late forms,<span class="elsevierStyleSup">26</span>  enderscoring that the incomplete forms are more common that the classical form of the disease. In fact, prospective studies have shown that Fabry¿s disease is present in 3%-4% of the patients with LVH<span class="elsevierStyleSup">15,27</span> and in 5% of a series of patients with acute cerebrovascular accidents of unknown etiology.<span class="elsevierStyleSup">28</span></p><p class="elsevierStylePara">The prevalence of Fabry¿s disease in patients with renal involvement is mainly based on the study of patients submitted to renal replacement therapy. While the European and American registries show a prevalence of 0.018% and 0.016%, respectively, (12% in both registries are women), studies done on dialysis patients have shown a much higher prevalence. When the activity of α-GALA was used for initial screening by means of fluorescence in dry blood on a filter paper, the prevalence in male patients on dialysis with de novo diagnosis of Fabry¿s disease was 0.22-0.30%<span class="elsevierStyleSup">31-33</span> (table II). The main problem with the dry drop method is the existence of false negative results,<span class="elsevierStyleSup">34</span> especially in women.<span class="elsevierStyleSup">35</span> By quantifying the enzymatic activity in whole blood, plasma and/or leukocytes, studies carried out in the USA, Europe and Japan yield a prevalence rate of the disease in male patients on dialysis of around 0.20%-1.2%<span class="elsevierStyleSup">16, 36-41</span> (table II). The three series published including female patients show a prevalence of 0%,<span class="elsevierStyleSup">32</span> 0.05%, and 0.33%.<span class="elsevierStyleSup">40</span> The mentioned data underscore that the prevalence of Fabry¿s disease in male patients on dialysis is 15-80 times higher than that expected according to the registries. These patients not diagnosed before the dialysis onset often present incomplete forms, with few or none extrarenal clinical manifestations of the disease but cardiac involvement, mainly LVH.<span class="elsevierStyleSup">16, 31</span></p><p class="elsevierStylePara">The prevalence of Fabry¿s disease in CRD patients not submitted to renal replacement therapy is unknown. Undoubtedly, early diagnosis would be of great relevance for several reasons. On the one hand, because of the instauration of ERT, which may prevent or delay the disease progression, and on the other hand because it allows for performing a family study leading to early diagnosis and genetic counseling. In this sense, a multicenter study is being conducted in Spain targeting male patients with stages 1-5 CRD of unknown origin (not submitted to dialysis), in which the screening method is based on the measurement of plasma α-GAL A activity.<span class="elsevierStyleSup">42</span> The preliminary results on 229 patients yield a prevalence of 0.9%. This represents two male patients aged 25 and 74 years, both with incomplete forms and with α-GAL A activity > 1% and absence of the classical clinical manifestations.</p><p class="elsevierStylePara">Thus, it is necessary to diagnose patients with Fabry¿s disease as early as possible. In the classical form, the multisystemic symptomatic complex may put on alert during childhood although more commonly the diagnosis is made in the second or third decades of life by means of renal biopsy and/or determination in the blood the α-GAL A activity, with confirmation by means of a genetic study. The incomplete forms arriving to the nephrology unit are more difficult to detect if programs are not established since, according to the experience in published studies, these patients cannot be biopsied given their characteristics.<span class="elsevierStyleSup">16, 31-33, 36-41</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">MANAGEMENT</span></p><p class="elsevierStylePara">The main goals in the management of Fabry¿s disease are symptoms relief, tissular damage reduction, and late complications prevention.<span class="elsevierStyleSup">34, 43-47</span> From the renal point of view, the actions will be focused on preventing renal disease or slowing its progression by means of the earliest intervention possible for which we count on ERT and general prevention measures for CRD.</p><p class="elsevierStylePara">From the year 2001, two recombinant human enzymes are available, alpha agalasidase produced from human fibroblasts (Replagal®, Shire Human Genetic Therapies, Inc), and beta agalasidase (Fabrazyme®, Genzyme Corp) produced from ovary cells of Chinese hamster. Phase I/II studies<span class="elsevierStyleSup">48, 49</span> led to marketing doses of alpha agalasidase of 0.2 mg/kg infused fortnightly, and 1 mg/kg of beta agalasidase also infused fortnightly at a similar cost of about 210.000 ¿ per patient/year for an individual of 70 kg. Several clinical studies have evaluated the efficacy and safety of both formulations, and two trends with supporters of one or the other therapeutic strategies have emerged. Both products are able to reduce tissular deposition of Gb3,<span class="elsevierStyleSup">50, 51</span> and reduce LVH,<span class="elsevierStyleSup">52, 53</span> although the different inclusion criteria and study designs did not allow a direct comparison.</p><p class="elsevierStylePara">According to some information, it may be inferred that alpha agalasidase and beta agalasidase are similar, since they have the same specific activity per milligram of product administered, determined in vitro by Gb3 clearance in fibroblasts from the skin of patients with Fabry¿s disease,<span class="elsevierStyleSup">54</span> and there is complete cross-reaction of IgG antibodies between these products.<span class="elsevierStyleSup">55</span> Recently, Vedder et al. have published a single clinical comparative study which results also support the similarity between both formulations.<span class="elsevierStyleSup">56</span> Alpha agalasidase and beta agalasidase were prospectively and randomly administered to 18 and 16 patients, respectively, at the same dose (0.2 mg/kg fortnightly), with a followup period of 24 months. No differences were observed between both treatments in the parameters studied: proteinuria, glomerular filtration (GF), LVH, neuropathic pain, plasma and urinary levels of Gb3, and occurrence of IgG antibodies.<span class="elsevierStyleSup">56</span></p><p class="elsevierStylePara">In 2001, two prospective controlled and randomized phase III studies with agalasidase alpha<span class="elsevierStyleSup">50</span> and beta agalasidase<span class="elsevierStyleSup">51</span> were published, and in both, phase IV extension studies were done, which allowed assessing the long-term renal function. Fifty-eight patients were included with beta agalasidase, 29 treated at standard doses (1 mg/kg/14 days) for 20 weeks, with the primary end-point of assessing the Gb3 deposits within the renal microvascular endothelium. A marked reduction in Gb3 deposits was observed at the kidney, skin, and heart.<span class="elsevierStyleSup">51</span> With an extension to 11 months, in which all patients received ERT (the placebo group from week 20), it was verified that renal deposits were close to the null value.<span class="elsevierStyleSup">57</span> These patients continued being assessed in two extension studies to 358 and 4.5 years.<span class="elsevierStyleSup">59</span> The average values for proteinuria and GF remained with no significant changes although 6 patients experienced renal function deterioration. The main progression factors were proteinuria > 1 g/24 h and a percentage of glomerular sclerosis > 50% at baseline. It should be underscored that only 10 out of 58 patients had a GF rate < 90mL/min/ 1.73 m<span class="elsevierStyleSup">2</span> at the study beginning, of which 4 had renal function worsening and 6 remained in a stable situation.</p><p class="elsevierStylePara">The phase 3 study with alpha agalasidase included 26 patients, 14 treated at a dose of 0.2 mg/kg fortnightly for 24 weeks,50 which was followed by a phase 4 study for 4.5 years, in which all patients received ERT from the sixth month and on.<span class="elsevierStyleSup">61</span> The treatment did not change proteinuria, and the average GF rate significantly decreased at the end of the study period.<span class="elsevierStyleSup">60</span> However, this decrease essentially occurred at the expense of the loss of renal function in all patients presenting stage 3 CRD at baseline, and some patients at stage 2.</p><p class="elsevierStylePara">Other observational studies highlight that ERT may stabilize the renal function in patients with stage 2 CRD, although it does not prevent progression in stage 3 CRD or less.<span class="elsevierStyleSup">61, 62</span> In the larger series with 201 men and women treated with alpha agalasidase it was observed that in a subgroup of 12 patients with stage 2 CRD the mean GF rate had decreased from 83.7 to 71.9 mL/min/1.73 m<span class="elsevierStyleSup">2</span> in the year before starting with ERT, which was unchanged one year after from the ERT onset.<span class="elsevierStyleSup">61</span> In the subgroup of 8 patients with stage 3 CRD, the ERT did not modify the renal failure progression rate.<span class="elsevierStyleSup">61</span> One interesting study recently published showed how 11 male patients with the classical form of Fabry¿s disease and presenting renal function loss > -5 mL/min/1.73 m<span class="elsevierStyleSup">2</span>/year experienced a slowing in their progression when switched from a conventional regimen (0.2 mg/kg fortnightly) to a weekly regimen of 0.2 mg/kg (from -8.0 to -3.3 mL/min/1.73 m<span class="elsevierStyleSup">2</span> per year, p < 0.01).<span class="elsevierStyleSup">63</span> It is unclear whether this beneficial effect was due to the increase in the frequency of administration or the dose increase, or both. In any case, these results would apparently be in contradiction with the observation that nor the dose not the frequency of administration had an influence on the magnitude of reduction in plasma Gb3 in a randomized study evaluating 18 patients with 5 different administration regimens of alpha agalasidase (0.1, 0.2, or 0.4 mg/kg/week, or 0.2 mg/kg fortnightly, or 0.4 mg/kg fortnightly).<span class="elsevierStyleSup">64</span> It is likely that the Gb3 levels may not be a marker of severity and response to treatment in Fabry¿s disease, and the authors themselves underline that new studies are required to determine the best treatment regimen to achieve the best clinical outcomes.<span class="elsevierStyleSup">64</span></p><p class="elsevierStylePara">The renal, cardiac and cerebrovascular effects of ERT have been assessed in patients with established chronic renal failure in a prospective, randomized, and controlled study in which 51 patients were treated with beta agalasidase and 31 received placebo, with a mean GF rate of 53 and 52.4 mL/min/ 1.73 m<span class="elsevierStyleSup">2</span>, respectively, and a median follow-up time of 18.5 months.<span class="elsevierStyleSup">65</span> The average values of GF rate and proteinuria were not significantly different between both groups at the end of the study period. However, the group of treated patients presented a reduction in the risk of occurrence of renal (defined as an increase in creatinine values > 33%, dialysis or transplantation), cardiac and/or cerebrovascular events as compared with the control group. These beneficial effects were more evident in those patients with lower levels of proteinuria (< 1 g/24 h) and lesser renal function impairment (GF rate > 55 mL/min/1.73 m<span class="elsevierStyleSup">2</span>), inferring that both proteinuria and renal function may be considered as markers of the risk for cardiovascular complications and response to ERT in Fabry¿s disease. The importance of early implementation of ERT on both renal function progression and prevention of extrarenal complications has been underscored by Breunig et al. in a prospective study including 23 patients treated with beta agalasidase.<span class="elsevierStyleSup">66</span> It was observed that in those patients with GF rate > 90 mL/min/1.73 m<span class="elsevierStyleSup">2</span> the renal function remained stable and did not present clinical events, whereas in those having stage 2-4 CRD there was progression of renal failure and ERT did not prevent the occurrence of cardiac and cerebrovascular complications.<span class="elsevierStyleSup">66</span></p><p class="elsevierStylePara">About the immune response against the two enzymes, and taking as a reference the phase III studies with their extensions,<span class="elsevierStyleSup">59, 60</span> 90% of the patients treated with beta agalasidase developed IgG antibodies<span class="elsevierStyleSup">59</span> versus 56% with alpha agalasidase.60 These differences may be due to the different dose regimen and/or the method used, and not so much to the difference between both preparations since there is complete cross-reaction between both;<span class="elsevierStyleSup">55</span> moreover, in a comparative study with equal dosing, the rate of sero-conversion was similar.<span class="elsevierStyleSup">56</span> However, there was a decrease in antibody titers with both formulations, which reached undetectable levels in some patients. The importance of the occurrence and maintenance of IgG antibodies in treatment efficacy is unclear. In both studies<span class="elsevierStyleSup">59,60</span> it is reported that sero-conversion has no influence on either Gb3 clearance within the renal tissue<span class="elsevierStyleSup">59</span> or urinary clearance of Gb3 and progression of the GF rate.<span class="elsevierStyleSup">60</span> Notwithstanding, other authors find that patients developing IgG antibodies had lower Gb3 urine clearance as compared with those without sero-conversion, for both alpha agalasidase and beta agalasidase,<span class="elsevierStyleSup">56</span> which opens questions on these issues. About the adverse events, most of the patients treated with beta agalasidase and 56% of those treated with alpha agalasidase presented at least one episode during the follow-up. Most of these effects were mild, related with the infusion, and decreased with time.<span class="elsevierStyleSup">59,60</span></p><p class="elsevierStylePara">From these works it follows that in those patients with normal GF rate without proteinuria or with proteinuria < 1 g /24 hours, ERT prevents the progression of CRD and the occurrence of complications. In stage 2 CRD patients, the response to ERT is more difficult to predict, proteinuria > 1g/24 h being a factor indicating a worse prognosis. Already established glomerulosclerosis and interstitial damage prevent ERT from avoiding progression of CRD when GF rate is < 60 mL/min/1.73 m<span class="elsevierStyleSup">2</span>, although the treatment is justified by the possible prevention of complications and relieve of some of the symptoms.</p><p class="elsevierStylePara">It is generally observed that proteinuria is not reduced with ERT<span class="elsevierStyleSup">50,51,56,59,60,66</span> in spite of the massive decrease in renal deposition of Gb3, even with normal GF rate.<span class="elsevierStyleSup">50,51,66</span> This indicates the presence of already irreversible structural glomerular and interstitial lesions from the moment that proteinuria is present. However, enzymatic therapy may reduce microalbuminuria,<span class="elsevierStyleSup">67</span> which is another reason for the need for early treatment. In any case, there is the idea that the general measures for every proteinuric nephropathy should be established in Fabry¿s disease with renal involvement, such as are diet, hypertension and hyperlipidemia management, and the use of angiotensin converting enzyme inhibitors (ACEI)/ angiotensin receptor antagonists (ARA II).<span class="elsevierStyleSup">68</span> The benefits from the proteinuriareducing therapy with ACEI and/or ARA II have been showed in a recent work in which a decrease in proteinuria and renal function stabilization in stage 2 CRD patients treated with beta agalasidase was confirmed.<span class="elsevierStyleSup">69</span></p><p class="elsevierStylePara">Groups of experts have elaborated guidelines on the assessment and management of Fabry¿s disease.<span class="elsevierStyleSup">70,71</span> One important issue is the recommendation on when ERT should be started. The Guidelines for the Study and Management of Fabry¿s disease (GSMFD) establish major and minor criteria so that to start on the therapy, 1 major criterion and 2 minor criteria would be needed; among them, proteinuria (> 300 mg/24 h in adults or > 5 mg/kg/day in children) and GF rate < 80 mL/min/1.73 m<span class="elsevierStyleSup">2</span> are major criteria, whereas microalbuminuria falls within the minor criteria.<span class="elsevierStyleSup">70</span> However, other guidelines recommend offering the enzymatic therapy to every adult (older than 16 years) male patient diagnosed with Fabry¿s disease independently of his stage of CRD, in children when symptoms occur, and in women if there are symptoms or signs of organic involvement.<span class="elsevierStyleSup">71</span></p><p class="elsevierStylePara">In dialysis patients, ERT would be indicated to prevent the extrarenal complications of the disease.<span class="elsevierStyleSup">72</span> The administration of beta agalasidase during the hemodialysis session, of both highand low-flow, is well tolerated without losing the enzymatic activity.<span class="elsevierStyleSup">73</span> Although the typical lesions of Fabry¿s disease do not occur in the grafted kidney, ERT would also be justified to treat and prevent multisystemic involvement.<span class="elsevierStyleSup">74</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">CONCLUSIONS</span></p><p class="elsevierStylePara">To summarize, the prevalence of Fabry¿s disease is higher than that referred by official registries of patients on renal replacement therapy due to the existence of incomplete variants in the clinical expression of late onset, with a predominant involvement of the heart and the kidney and the absence of other typical manifestations. These incomplete forms are difficult to diagnose without the help of established programs. Given the importance of early diagnosis, these detection programs become paramount in the nephrology clinic. Proteinuria higher than 1g/24 h and/or the decrease in GF rate are prognostic factors, both for the occurrence of cardiac and cerebrovascular complications and for the response to ERT. ERT should be applied from early phases in order to prevent the occurrence of structural renal lesions, although some questions are still unanswered about the best treatment regimen regarding the dosing and frequency of administration. In patients with CRD, ERT may slow the progression at stages 1 and 2, and reduce the occurrence of cardiovascular complications at more advanced stages. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 8 | 2 | 10 |
| 2024 October | 79 | 82 | 161 |
| 2024 September | 67 | 45 | 112 |
| 2024 August | 96 | 69 | 165 |
| 2024 July | 52 | 105 | 157 |
| 2024 June | 66 | 47 | 113 |
| 2024 May | 72 | 64 | 136 |
| 2024 April | 53 | 30 | 83 |
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| 2024 February | 50 | 36 | 86 |
| 2024 January | 49 | 32 | 81 |
| 2023 December | 41 | 27 | 68 |
| 2023 November | 66 | 33 | 99 |
| 2023 October | 72 | 33 | 105 |
| 2023 September | 56 | 36 | 92 |
| 2023 August | 53 | 16 | 69 |
| 2023 July | 74 | 32 | 106 |
| 2023 June | 58 | 23 | 81 |
| 2023 May | 82 | 36 | 118 |
| 2023 April | 70 | 25 | 95 |
| 2023 March | 65 | 25 | 90 |
| 2023 February | 49 | 18 | 67 |
| 2023 January | 58 | 34 | 92 |
| 2022 December | 78 | 41 | 119 |
| 2022 November | 85 | 28 | 113 |
| 2022 October | 79 | 53 | 132 |
| 2022 September | 68 | 31 | 99 |
| 2022 August | 92 | 57 | 149 |
| 2022 July | 79 | 49 | 128 |
| 2022 June | 88 | 26 | 114 |
| 2022 May | 78 | 36 | 114 |
| 2022 April | 117 | 48 | 165 |
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| 2021 December | 84 | 43 | 127 |
| 2021 November | 47 | 41 | 88 |
| 2021 October | 47 | 42 | 89 |
| 2021 September | 40 | 40 | 80 |
| 2021 August | 52 | 36 | 88 |
| 2021 July | 54 | 44 | 98 |
| 2021 June | 55 | 31 | 86 |
| 2021 May | 46 | 35 | 81 |
| 2021 April | 87 | 43 | 130 |
| 2021 March | 71 | 43 | 114 |
| 2021 February | 108 | 26 | 134 |
| 2021 January | 70 | 15 | 85 |
| 2020 December | 65 | 23 | 88 |
| 2020 November | 58 | 23 | 81 |
| 2020 October | 45 | 19 | 64 |
| 2020 September | 51 | 8 | 59 |
| 2020 August | 75 | 14 | 89 |
| 2020 July | 57 | 10 | 67 |
| 2020 June | 39 | 14 | 53 |
| 2020 May | 69 | 13 | 82 |
| 2020 April | 45 | 17 | 62 |
| 2020 March | 43 | 14 | 57 |
| 2020 February | 49 | 20 | 69 |
| 2020 January | 59 | 32 | 91 |
| 2019 December | 80 | 20 | 100 |
| 2019 November | 71 | 29 | 100 |
| 2019 October | 80 | 11 | 91 |
| 2019 September | 69 | 17 | 86 |
| 2019 August | 38 | 15 | 53 |
| 2019 July | 61 | 32 | 93 |
| 2019 June | 41 | 5 | 46 |
| 2019 May | 81 | 19 | 100 |
| 2019 April | 97 | 29 | 126 |
| 2019 March | 39 | 20 | 59 |
| 2019 February | 33 | 14 | 47 |
| 2019 January | 20 | 13 | 33 |
| 2018 December | 65 | 32 | 97 |
| 2018 November | 117 | 20 | 137 |
| 2018 October | 78 | 19 | 97 |
| 2018 September | 62 | 15 | 77 |
| 2018 August | 36 | 23 | 59 |
| 2018 July | 34 | 22 | 56 |
| 2018 June | 26 | 18 | 44 |
| 2018 May | 32 | 15 | 47 |
| 2018 April | 87 | 11 | 98 |
| 2018 March | 35 | 13 | 48 |
| 2018 February | 29 | 2 | 31 |
| 2018 January | 32 | 6 | 38 |
| 2017 December | 46 | 19 | 65 |
| 2017 November | 46 | 18 | 64 |
| 2017 October | 36 | 8 | 44 |
| 2017 September | 42 | 17 | 59 |
| 2017 August | 22 | 25 | 47 |
| 2017 July | 38 | 17 | 55 |
| 2017 June | 25 | 14 | 39 |
| 2017 May | 24 | 16 | 40 |
| 2017 April | 23 | 9 | 32 |
| 2017 March | 16 | 8 | 24 |
| 2017 February | 20 | 17 | 37 |
| 2017 January | 13 | 12 | 25 |
| 2016 December | 76 | 7 | 83 |
| 2016 November | 84 | 8 | 92 |
| 2016 October | 100 | 8 | 108 |
| 2016 September | 124 | 8 | 132 |
| 2016 August | 216 | 10 | 226 |
| 2016 July | 161 | 3 | 164 |
| 2016 June | 136 | 0 | 136 |
| 2016 May | 127 | 0 | 127 |
| 2016 April | 86 | 0 | 86 |
| 2016 March | 79 | 0 | 79 |
| 2016 February | 98 | 0 | 98 |
| 2016 January | 107 | 0 | 107 |
| 2015 December | 103 | 0 | 103 |
| 2015 November | 88 | 0 | 88 |
| 2015 October | 81 | 0 | 81 |
| 2015 September | 71 | 0 | 71 |
| 2015 August | 66 | 0 | 66 |
| 2015 July | 60 | 0 | 60 |
| 2015 June | 30 | 0 | 30 |
| 2015 May | 42 | 0 | 42 |
| 2015 April | 5 | 0 | 5 |
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