Editorial
Usefulness of an specific out patient clinic on hereditary kidney diseases: A different approach based on the family tree
Utilidad de una consulta de enfermedades renales hereditarias: un enfoque diferente basado en el árbol genealógico
Víctor Martínez Jiménez
, Fernanda Ramos Carrasco, Concepción Alcázar Fajardo, Juan Bernardo Cabezuelo Romero
Corresponding author
Servicio de Nefrología, Hospital Reína Sofía, Murcia, Spain
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To create a hypertonic medullary interstitium, adequate function of all the tubular sodium transporters is necessary, for example, NHE3 (<span class="elsevierStyleItalic">type 3 Na<span class="elsevierStyleSup">+</span>/H<span class="elsevierStyleSup">+</span> exchanger</span>), NaPi-2, (<span class="elsevierStyleItalic">type 2 Na-Pi cotransporter</span>), BSC-1 (<span class="elsevierStyleItalic">type 1 bumetanide-sensitive Na-K-2Cl cotransporter</span>), or TSC (<span class="elsevierStyleItalic">thiazide-sensitive cotransporter</span>) in the lumen side of the tubule (mechanism 1). A defect in its function would cause a loss of saline with an accompanied loss of water that would cause a less hypertonic medullary interstitium. Furthermore, adequate function of the urea transporters (UT-A1, UT-A2, UT-A3) is necessary to increase the medullary interstitium osmolality (mechanism 2). In the presence of this hypertonic medullary interstitium, vasopressin can concentrate the urine thanks to the stimulus it exercises on the aquaporins (AQP), which enables the tubular lumen content to become equilibrated with the hypertonic medullar interstitium (mechanism 3).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Víctor M. García-Nieto, Maria Isabel Luis-Yanes, Pedro Arango-Sancho, Jorge V. Sotoca-Fernandez" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Víctor M." "apellidos" => "García-Nieto" ] 1 => array:2 [ "nombre" => "Maria Isabel" "apellidos" => "Luis-Yanes" ] 2 => array:2 [ "nombre" => "Pedro" "apellidos" => "Arango-Sancho" ] 3 => array:2 [ "nombre" => "Jorge V." "apellidos" => "Sotoca-Fernandez" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0211699516300029" "doi" => "10.1016/j.nefro.2016.01.009" "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/S0211699516300029?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251416300499?idApp=UINPBA000064" "url" => "/20132514/0000003600000003/v3_201704140402/S2013251416300499/v3_201704140402/en/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "Usefulness of an specific out patient clinic on hereditary kidney diseases: A different approach based on the family tree" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "217" "paginaFinal" => "221" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Víctor Martínez Jiménez, Fernanda Ramos Carrasco, Concepción Alcázar Fajardo, Juan Bernardo Cabezuelo Romero" "autores" => array:4 [ 0 => array:4 [ "nombre" => "Víctor" "apellidos" => "Martínez Jiménez" "email" => array:1 [ 0 => "victormj80@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Fernanda" "apellidos" => "Ramos Carrasco" ] 2 => array:2 [ "nombre" => "Concepción" "apellidos" => "Alcázar Fajardo" ] 3 => array:2 [ "nombre" => "Juan Bernardo" "apellidos" => "Cabezuelo Romero" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Nefrología, Hospital Reína Sofía, Murcia, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Utilidad de una consulta de enfermedades renales hereditarias: un enfoque diferente basado en el árbol genealógico" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2291 "Ancho" => 2584 "Tamanyo" => 255961 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Hereditary kidney disease out patient clinic planning. AD, autosomal dominant; AR, autosomal recessive; HKD, hereditary kidney diseases; GFR, glomerular filtration rate; XL, linked to the X-chromosome; IM, internal medicine.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Hereditary kidney diseases (HKDs) are a heterogeneous group of kidney diseases that account for 10% to 15% of patients who start renal replacement therapy (RRT), and could account for an even greater percentage in the paediatric population.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">1</span></a> HKDs require a diagnostic approach that is different from other nephropaties since its pathogenesis is due to a mutation. The diagnosis goes beyond the affected patients, it includes the family. Ait is necessary to construct a family tree including both affected and non affected individuals.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Autosomal dominant polycystic kidney disease (ADPKD), which is due to a mutation in the PKD1 or PKD2<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">2</span></a> gene, is the most common hereditary kidney disease and accounts for 6–10% of patients in RRT. It is characterised by the growth of kidney cysts that lead to a decline in kidney function until RRT is required.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">3</span></a> In addition, it is associated with other manifestations: hypertension (HTN),<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">4</span></a> polycystic liver disease, brain aneurysms and valve diseases.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">5</span></a> Alport syndrome (AS) is classified according to its pattern of inheritance: 85% X-linked owing to a mutation in COL4A5<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">6</span></a> and 15% autosomal recessive owing to a mutation in COL4A3 or COL4A4.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">7</span></a> In AS, an abnormal glomerular basement membrane causes microhaematuria, proteinuria and progressive CKD, which may be associated with eye abnormalities and hearing loss.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">8</span></a> Benign familial microhaematuria (BFM), which may affect up to 1% of the population, and recessive AS have a common pathogenesis.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">9</span></a> Tubulopathies are another group of HKDs, by which the mutation of a protein involved in tubular reabsorption fosters the excretion of certain ions in the urine.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a> In addition, there are other hereditary syndromes with kidney disease in a context of significant multi-organ involvement such as tuberous sclerosis<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</span></a> and Bardet–Biedl syndrome.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">12</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Our objective was to create a specific practice for the follow-up of patients with HKD. These diseases tend not to be very prevalent, and so it is necessary to group them in a practice followed up by the same physician to increase his or her clinical experience. Below we present the steps that we followed, the difficulties that arose and our results after 3 years of follow-up.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Study design and patient screening</span><p id="par0020" class="elsevierStylePara elsevierViewall">In February 2012, a specific practice was created for the follow-up of patients with HKD in our department, which covers a population of nearly 300,000 inhabitants and has approximately 1500 outpatient visits per year. Our hospital is a tertiary hospital. Patients with kidney disease and a prior family history with a high clinical probability of HKD or with a positive genetic test were enrolled. Patients with a glomerular filtration rate lower than 25<span class="elsevierStyleHsp" style=""></span>ml/min were excluded.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Patients were referred from Primary Care, Paediatric Nephrology and other Nephrology practices and by other specialists to an HKD-specific practice followed up by the same nephrologist. They were discharged from this practice if HKD was ruled out, and relatives with kidney diseases were enrolled after careful screening was performed. Follow-up lasted 3 years. The study ended in January 2015 (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">All the patients underwent blood and urine testing, a kidney ultrasound, measurement of blood pressure and preparation of a family tree that gathered family relationships with proband, healthy relatives and relatives with kidney disease (microhaematuria, proteinuria, kidney cysts, chronic kidney disease and requirement for RRT). With these data, 3 basic clinical patterns were established: tubulointerstitial, subdivided into cystic (cystic diseases by ultrasound diagnosis) and tubulopathic (ion abnormalities due to increase in urinary excretion); glomerular (proteinuria and microhaematuria); and syndromic (kidney disease in a context of significant multi-organ abnormality). The clinical patterns, together with the pattern of inheritance (autosomal dominant [AD], autosomal recessive [AR] and linked to the X chromosome [XL]), guided the physician towards an initial suspected clinical diagnosis in each patient (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><p id="par0035" class="elsevierStylePara elsevierViewall">At the end of the study, the following data were collected: age, gender, performance of a kidney biopsy or genetic study, departments having referred the patient to the HKD practice, existence of a prior diagnosis, follow-up by other specialists owing to his or her HKD, performance of complete family screening, HTN, treatment with renin–angiotensin system inhibitors, diabetes mellitus, dyslipidaemia and whether the subject was a smoker.</p><p id="par0040" class="elsevierStylePara elsevierViewall">In ADPKD, there was no radiologist assigned specifically to analyse ultrasound data: kidney size measured in centimetres, description of normal or large kidneys and presence of liver cysts. Familial microhaematuria (FM) was defined as microhaematuria in the patient and at least one of his or her relatives, other causes having been ruled out with immunology, serology and lithiasis studies. The following were included within FM: AS by consistent genetic or histological diagnosis and familial IgA nephropathy by kidney biopsy with a positive family history. In this group, the hearing tests performed were assessed by the otorhinolaryngologist as normal or with hearing loss.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Of the 177 patients followed up in the HKD practice, 73 were men (41.2%) and 104 were women (58.8%). The mean age was: 43.13<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>15.20 (14–84) years. A family tree was prepared for all the patients; family screening was complete in 81 patients (45.8%) and incomplete in 96 patients (54.2%) owing to their relatives’ death or refusal. A total of 117 patients (66.1%) had at least one relative in RRT. Regarding patterns of inheritance: AD in 143 (80.1%), AR in 16 (9%), XL in 11 (6.2%) and unknown in 7 (4%). A genetic study was requested in 34 cases and positive in 21 (61.8%). Of the 8 kidney biopsies performed, only 3 were diagnostic for IgA nephropathy, and the rest were normal. <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a> shows the prevalence of HKD in our practice.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">The origin of the patients followed up in the HKD practice was: 61 (34.5%) from Primary Care; 14 (7.9%) from Paediatric Nephrology; 51 (28.8%) from other Nephrology practices; 17 (9.6%) from other specialists, mainly Urology and Internal Medicine; and 34 (19.2%) from family screening performed in the HKD practice. Only 73 patients (41.2%) were diagnosed before being referred to our practice.</p><p id="par0055" class="elsevierStylePara elsevierViewall">A total of 49 patients (27.7%) were followed up by other specialists owing to abnormalities deriving from their HKD: 19 by Urology, owing to lithiasis, repeated urinary infections or complicated cysts; 11 by Otorhinolaryngology owing to hearing loss; 5 by Cardiology owing to ischaemic cardiomyopathy or mitral valve insufficiency; and 4 by Gastroenterology owing to massive polycystic liver disease or diverticulosis.</p><p id="par0060" class="elsevierStylePara elsevierViewall">An analysis of cardiovascular risk factors revealed that 94 patients (53.1%) were hypertensive, 15 (8.5%) were diabetic, 58 (32.8%) had dyslipidaemia and 42 (23.7%) were smokers. In addition, 104 patients (58.8%) were treated with renin–angiotensin system inhibitors.</p><p id="par0065" class="elsevierStylePara elsevierViewall">The ultrasound data in the ADPKD group were as follows: liver cysts were present in 49 patients (54.44%) and kidney size was only measured in 45 (50%), although in all patients it was determined whether their kidneys were normal or large. Hearing tests were performed in the group with FM in 45 patients (75%), 26 of whom had hearing loss and only 13 of whom were informed by the otorhinolaryngologist.</p><p id="par0070" class="elsevierStylePara elsevierViewall">The majority of patients were referred to our practice owing to a suspicion of HKD, as they had kidney disease and at least one relative in RRT, although nearly 60% were not initially diagnosed. To establish a clinical diagnosis, our main tool was not the genetic study, but the family tree. In addition to examining the patient, it is essential to perform comprehensive family screening, with laboratory testing and a kidney ultrasound, distinguishing between healthy individuals and individuals with kidney disease to identify the type of inheritance and clinical pattern. However, in half of the cases family screening was incomplete owing to some family members’ refusal or death.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Proper diagnosis of HKD is important for managing factors for progression, establishing a multidisciplinary approach, performing suitable recording, offering genetic counselling and, in some cases, starting the appropriate treatment, such as enzyme replacement in Fabry disease<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">13</span></a> or everolimus in tuberous sclerosis.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">14</span></a> However, there are familial kidney diseases of unknown origin or with a very atypical clinical presentation that are the subject of research studies, where collaboration between hospitals is required to create a national network that includes more patients with these low-prevalence diseases. The latest next-generation genomic sequencing techniques are contributing to the evolution and optimisation of HKD diagnosis.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">15</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">ADPKD is the most common hereditary kidney disease and our data is consistent with this. Ultrasound is the technique of choice for ADPKD diagnosis, in conjunction with follow-up and screening in first-degree relatives.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">16</span></a> Kidney volume is the best predictor of disease progression.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">17</span></a> However, in half of the cases in our radiological study, kidney size was not assessed precisely. In addition, an ultrasound must be performed to diagnose liver cysts, the most common extrarenal manifestation of ADPKD.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">2</span></a> It is essential that awareness be raised and that imaging tests be performed by a single physician trained in these diseases.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Clinically, it is difficult to distinguish between BFM, AS carrier status and familial IgA, since they may have the same glomerular pattern.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">18</span></a> Although in our study they were grouped together as FM, a definitive diagnosis should be made. The first step in making a differential diagnosis is determining the pattern of inheritance: AD in BFM, AR or XL in AS and polygenic inheritance in familial IgA (although the genes involved are being researched).<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">19</span></a> A definitive diagnosis of AS is made by finding a dysfunctional glomerular basement membrane in electron microscopy or a pathogenic mutation in COL4A5 in XL Alport syndrome, or 2 pathogenic mutations in COL4A3 or COL4A4 in AR Alport syndrome, while in BFM there would only be a mutation in COL4A3/COL4A4.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">9</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">There are characteristic multi-organ abnormalities associated with certain HKDs that may help to identify them. It is essential to take a multidisciplinary approach. In many cases, the nephrologist becomes the coordinator of the other specialties. Patients should be followed up by a single physician with experience so that these low-prevalence diseases do not go undetected. If AS is suspected, a hearing test must be performed to rule out bilateral hearing loss for high frequencies (2000–8000<span class="elsevierStyleHsp" style=""></span>Hz).<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">8</span></a> When we reviewed the hearing tests, we found that hearing loss was only diagnosed in half of the cases, as it was considered to be normal when the impairment was mild: this is a confounding factor. Another added problem is the transition from Paediatrics to Nephrology for adults, in such a difficult stage as adolescence, when the patient may come to deny his or her disease and reject chronic treatment.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">20</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">There is a series of factors that accelerate a decline in kidney function and they should be managed to slow down its progression.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">21</span></a> The factors for progression of ADPKD are: genetic (the PKD1 mutation has a worse prognosis than the PKD2 mutation), kidney volume, HTN,<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">5</span></a> proteinuria, inability to concentrate urine and hyperuricaemia.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">22</span></a> The factors for progression of AS are: type of mutation (truncating mutations are more serious), proteinuria, hearing loss and episodes of macrohaematuria.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">23</span></a> Renin–angiotensin system inhibitors are a first-line treatment, as they manage HTN, decrease proteinuria and delay a decline in kidney function in both ADPKD<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">24</span></a> and AS.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">25</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">In conclusion, it is necessary to create an HKD practice in which these types of kidney disease are followed up by a single physician to ensure a suitable diagnostic and multidisciplinary approach, management of factors for progression and collaboration between hospitals contributing to diagnostic and therapeutic advances in this constantly evolving field. It is necessary to stress the importance of preparing a complete family tree to classify the pattern of inheritance (AD, AR or XL) and the type of kidney injury (cystic, tubular, glomerular or syndromic), which, unlike genetic diagnosis, is available at all hospitals.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Study design and patient screening" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Martínez Jiménez V, Ramos Carrasco F, Alcázar Fajardo C, Cabezuelo Romero JB. Utilidad de una consulta de enfermedades renales hereditarias: un enfoque diferente basado en el árbol genealógico. Nefrología. 2016;36:217–221.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2291 "Ancho" => 2584 "Tamanyo" => 255961 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Hereditary kidney disease out patient clinic planning. AD, autosomal dominant; AR, autosomal recessive; HKD, hereditary kidney diseases; GFR, glomerular filtration rate; XL, linked to the X-chromosome; IM, internal medicine.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1175 "Ancho" => 2225 "Tamanyo" => 143876 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Prevalence of hereditary kidney diseases at the end of the study (number of patients and percentage). 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 17 | 4 | 21 |
| 2024 October | 386 | 34 | 420 |
| 2024 September | 260 | 30 | 290 |
| 2024 August | 207 | 58 | 265 |
| 2024 July | 85 | 27 | 112 |
| 2024 June | 120 | 37 | 157 |
| 2024 May | 102 | 41 | 143 |
| 2024 April | 93 | 31 | 124 |
| 2024 March | 103 | 27 | 130 |
| 2024 February | 73 | 39 | 112 |
| 2024 January | 96 | 33 | 129 |
| 2023 December | 73 | 24 | 97 |
| 2023 November | 71 | 26 | 97 |
| 2023 October | 88 | 37 | 125 |
| 2023 September | 77 | 40 | 117 |
| 2023 August | 49 | 24 | 73 |
| 2023 July | 80 | 23 | 103 |
| 2023 June | 62 | 20 | 82 |
| 2023 May | 76 | 33 | 109 |
| 2023 April | 60 | 15 | 75 |
| 2023 March | 89 | 21 | 110 |
| 2023 February | 65 | 13 | 78 |
| 2023 January | 66 | 12 | 78 |
| 2022 December | 77 | 35 | 112 |
| 2022 November | 80 | 35 | 115 |
| 2022 October | 66 | 42 | 108 |
| 2022 September | 63 | 30 | 93 |
| 2022 August | 88 | 42 | 130 |
| 2022 July | 96 | 54 | 150 |
| 2022 June | 63 | 38 | 101 |
| 2022 May | 108 | 28 | 136 |
| 2022 April | 103 | 52 | 155 |
| 2022 March | 91 | 71 | 162 |
| 2022 February | 62 | 42 | 104 |
| 2022 January | 63 | 29 | 92 |
| 2021 December | 66 | 44 | 110 |
| 2021 November | 74 | 36 | 110 |
| 2021 October | 109 | 39 | 148 |
| 2021 September | 77 | 33 | 110 |
| 2021 August | 89 | 41 | 130 |
| 2021 July | 58 | 34 | 92 |
| 2021 June | 66 | 31 | 97 |
| 2021 May | 70 | 48 | 118 |
| 2021 April | 104 | 71 | 175 |
| 2021 March | 58 | 34 | 92 |
| 2021 February | 72 | 26 | 98 |
| 2021 January | 45 | 27 | 72 |
| 2020 December | 49 | 21 | 70 |
| 2020 November | 48 | 15 | 63 |
| 2020 October | 32 | 21 | 53 |
| 2020 September | 42 | 14 | 56 |
| 2020 August | 60 | 21 | 81 |
| 2020 July | 51 | 14 | 65 |
| 2020 June | 34 | 21 | 55 |
| 2020 May | 59 | 19 | 78 |
| 2020 April | 33 | 8 | 41 |
| 2020 March | 59 | 17 | 76 |
| 2020 February | 71 | 17 | 88 |
| 2020 January | 87 | 24 | 111 |
| 2019 December | 77 | 27 | 104 |
| 2019 November | 56 | 22 | 78 |
| 2019 October | 36 | 17 | 53 |
| 2019 September | 44 | 18 | 62 |
| 2019 August | 46 | 12 | 58 |
| 2019 July | 55 | 22 | 77 |
| 2019 June | 64 | 13 | 77 |
| 2019 May | 65 | 18 | 83 |
| 2019 April | 87 | 28 | 115 |
| 2019 March | 51 | 20 | 71 |
| 2019 February | 39 | 19 | 58 |
| 2019 January | 47 | 12 | 59 |
| 2018 December | 152 | 40 | 192 |
| 2018 November | 352 | 25 | 377 |
| 2018 October | 372 | 43 | 415 |
| 2018 September | 176 | 26 | 202 |
| 2018 August | 140 | 27 | 167 |
| 2018 July | 73 | 11 | 84 |
| 2018 June | 61 | 13 | 74 |
| 2018 May | 72 | 15 | 87 |
| 2018 April | 136 | 6 | 142 |
| 2018 March | 76 | 10 | 86 |
| 2018 February | 130 | 6 | 136 |
| 2018 January | 55 | 10 | 65 |
| 2017 December | 133 | 11 | 144 |
| 2017 November | 59 | 15 | 74 |
| 2017 October | 30 | 6 | 36 |
| 2017 September | 36 | 12 | 48 |
| 2017 August | 30 | 4 | 34 |
| 2017 July | 38 | 12 | 50 |
| 2017 June | 48 | 7 | 55 |
| 2017 May | 66 | 11 | 77 |
| 2017 April | 51 | 9 | 60 |
| 2017 March | 39 | 26 | 65 |
| 2017 February | 54 | 7 | 61 |
| 2017 January | 27 | 6 | 33 |
| 2016 December | 54 | 6 | 60 |
| 2016 November | 67 | 20 | 87 |
| 2016 October | 100 | 10 | 110 |
| 2016 September | 109 | 4 | 113 |
| 2016 August | 91 | 2 | 93 |
| 2016 July | 125 | 1 | 126 |
| 2016 June | 113 | 0 | 113 |
| 2016 May | 88 | 0 | 88 |
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