cholecalciferol and Hypercalciuria

Since the previous Cochrane Review on this topic in 2016, debate has continued surrounding a potential role for vitamin D in reducing risk of asthma exacerbation and improving asthma control. We therefore conducted an updated meta-analysis to include data from new trials completed since this date.. To evaluate the effectiveness and safety of administration of vitamin D or its hydroxylated metabolites in reducing the risk of severe asthma exacerbations (defined as those requiring treatment with systemic corticosteroids) and improving asthma symptom control.. We searched the Cochrane Airways Group Trial Register and reference lists of articles. We contacted the authors of studies in order to identify additional trials. Date of last search: 8 September 2022.. We included double-blind, randomised, placebo-controlled trials of vitamin D in children and adults with asthma evaluating exacerbation risk or asthma symptom control, or both.. Four review authors independently applied study inclusion criteria, extracted the data, and assessed risk of bias. We obtained missing data from the authors where possible. We reported results with 95% confidence intervals (CIs). The primary outcome was the incidence of severe asthma exacerbations requiring treatment with systemic corticosteroids. Secondary outcomes included the incidence of asthma exacerbations precipitating an emergency department visit or requiring hospital admission, or both, end-study childhood Asthma Control Test (cACT) or Asthma Control Test (ACT) scores, and end-study % predicted forced expiratory volume in one second (FEV1). We performed subgroup analyses to determine whether the effect of vitamin D on risk of asthma exacerbation was modified by baseline vitamin D status, vitamin D dose, frequency of dosing regimen, form of vitamin D given, and age of participants.. We included 20 studies in this review; 15 trials involving a total of 1155 children and five trials involving a total of 1070 adults contributed data to analyses. Participant ages ranged from 1 to 84 years, with two trials providing data specific to participants under five years (n = 69) and eight trials providing data specific to participants aged 5 to 16 (n = 766). Across the trials, 1245 participants were male and 1229 were female, with two studies not reporting sex distribution. Fifteen trials contributed to the primary outcome analysis of exacerbations requiring systemic corticosteroids. The duration of trials ranged from three to 40 months; all but two investigated effects of administering cholecalciferol (vitamin D3). As in the previous Cochrane Review, the majority of participants had mild to moderate asthma, and profound vitamin D deficiency (25-hydroxyvitamin D (25(OH)D) < 25 nmol/L) at baseline was rare. Administration of vitamin D or its hydroxylated metabolites did not reduce or increase the proportion of participants experiencing one or more asthma exacerbations treated with systemic corticosteroids (odds ratio (OR) 1.04, 95% CI 0.81 to 1.34; I. In contrast to findings of our previous Cochrane Review on this topic, this updated review does not find evidence to support a role for vitamin D supplementation or its hydroxylated metabolites to reduce risk of asthma exacerbations or improve asthma control. Participants with severe asthma and those with baseline 25(OH)D concentrations < 25 nmol/L were poorly represented, so further research is warranted here. A single study investigating effects of calcidiol yielded positive results, so further studies investigating effects of this metabolite are needed.. Desde la revisión Cochrane anterior sobre este tema en 2016, ha continuado el debate en torno a una posible función de la vitamina D en la reducción del riesgo de exacerbación del asma y la mejora de su control. Por lo tanto, se realizó un metanálisis actualizado para incluir los datos de los nuevos ensayos completados desde esta fecha.. Evaluar la eficacia y seguridad de la administración de vitamina D o sus metabolitos hidroxilados para reducir el riesgo de exacerbaciones graves del asma (definidas como aquellas que requieren tratamiento con corticosteroides sistémicos) y mejorar el control de sus síntomas. MÉTODOS DE BÚSQUEDA: Se buscó en el registro de ensayos del Grupo Cochrane de Vías respiratorias (Cochrane Airways Group) y en las listas de referencias de los artículos. Se estableció contacto con los autores de los estudios para identificar ensayos adicionales. Fecha de la última búsqueda: 8 de septiembre de 2022. CRITERIOS DE SELECCIÓN: Se incluyeron los ensayos doble ciego, aleatorizados, controlados con placebo de vitamina D en niños y adultos con asma que evaluaron el riesgo de exacerbación o el control de los síntomas del asma, o ambos. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Cuatro autores de la revisión aplicaron de forma independiente los criterios de inclusión de los estudios, extrajeron los datos y evaluaron el riesgo de sesgo. Cuando fue posible, se obtuvieron los datos faltantes a través de los autores de los estudios. Los resultados se informaron con intervalos de confianza (IC) del 95%. El desenlace principal fue la incidencia de exacerbaciones graves del asma que requirieron tratamiento con corticosteroides sistémicos. Los desenlaces secundarios incluyeron la incidencia de exacerbaciones del asma que precipitaron acudir al servicio de urgencias o requirieron ingreso hospitalario, o ambas, las puntuaciones de la childhood Asthma Control Test (cACT) o la Asthma Control Test (ACT) al final del estudio, y el % previsto de volumen espiratorio forzado en un segundo (VEF1) al final del estudio. Se realizaron análisis de subgrupos para determinar si el efecto de la vitamina D sobre el riesgo de exacerbación del asma se veía modificado por el estado inicial de vitamina D, la dosis de vitamina D, la frecuencia de la posología, la formulación de la vitamina D administrada y la edad de los participantes.. En esta revisión se incluyeron 20 estudios; 15 ensayos con un total de 1155 niños y cinco ensayos con un total de 1070 adultos aportaron datos para los análisis. Las edades de los participantes variaron entre 1 y 84 años, con dos ensayos que proporcionaron datos específicos de participantes menores de 5 años (n = 69) y ocho ensayos que proporcionaron datos específicos de participantes de 5 a 16 años (n = 766). En todos los ensayos, 1245 participantes eran hombres y 1229 mujeres, y dos estudios no informaron acerca de la distribución por sexos. Quince ensayos contribuyeron al análisis del desenlace principal: exacerbaciones que requirieron corticosteroides sistémicos. La duración de los ensayos fue de entre 3 y 40 meses; todos menos dos investigaron los efectos de la administración de colecalciferol (vitamina D3). Al igual que en la revisión Cochrane anterior, la mayoría de los participantes presentaban asma de leve a moderada y la deficiencia importante de vitamina D (25‐hidroxivitamina D [25(OH)D] < 25 nmol/l) al inicio del estudio fue poco frecuente. La administración de vitamina D o sus metabolitos hidroxilados no redujo ni aumentó la proporción de participantes que presentaron una o más exacerbaciones del asma tratada con corticosteroides sistémicos (odds ratio [OR] 1,04; IC del 95%: 0,81 a 1,34; I. En contraposición con los hallazgos de la revisión Cochrane anterior sobre este tema, esta revisión actualizada no encuentra evidencia que respalde una función de los suplementos de vitamina D o sus metabolitos hidroxilados en la reducción del riesgo de exacerbaciones del asma o la mejoría del control del asma. Los participantes con asma grave y aquellos con concentraciones iniciales de 25(OH)D < 25 nmol/l estuvieron escasamente representados, por lo que se justifica la realización de más estudios de investigación. Un único estudio que investigó los efectos del calcidiol proporcionó resultados positivos, por lo que se necesitan más estudios que investiguen los efectos de este metabolito.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Anti-Asthmatic Agents; Asthma; Calcifediol; Child; Child, Preschool; Cholecalciferol; Disease Progression; Female; Humans; Hypercalciuria; Infant; Male; Middle Aged; Randomized Controlled Trials as Topic; Vitamin D; Vitamins; Young Adult

Public concern over vitamin D deficiency has led to widespread use of over the counter (OTC) vitamin D (-D3 or -D2) supplements, containing up to 10,000 IU/unit dose (400 IU=10μg). Overzealous use of such supplements can cause hypercalcemia due to vitamin D toxicity. Infants are particularly vulnerable to toxicity associated with vitamin D overdose. OTC supplements are not subject to stringent quality control regulations from FDA and high degree of variability in vitamin D content in OTC pills has been demonstrated. Other etiologies of vitamin D induced hypercalcemia include hyperparathyroidism, granulomatous malignancies like sarcoidosis and mutations in the CYP24A1 gene. The differential diagnosis of hypercalcemia should include iatrogenic and genetic etiologies. C24-hydroxylation and C3-epimerization are two important biochemical pathways via which 25-hydroxyvitamin D3 (25(OH)D3) is converted to its metabolites, 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) or its C3 epimer, 3-epi-25-OH-D3 respectively. Mutations in the CYP24A1 gene cause reduced serum 24,25(OH)2D3 to 25(OH)D3 ratio (<0.02), elevated serum 1,25-dihydroxyvitamin D (1,25(OH)2D3), hypercalcemia, hypercalciuria and nephrolithiasis. Studies in infants have shown that 3-epi-25(OH)D3 can contribute 9-61.1% of the total 25(OH)D3. Therefore, measurements of parathyroid hormone (PTH) and vitamin D metabolites 25(OH)D3, 1,25(OH)2D3, 3-epi-25(OH)D3 and 24,25(OH)2D3 are useful to investigate whether the underlying cause of vitamin D toxicity is iatrogenic versus genetic. Here we report a case of vitamin D3 associated toxicity in a 4-month-old female who was exclusively breast-fed and received an oral liquid vitamin D3 supplement at a dose significantly higher than recommended on the label. The vitamin D3 content of the supplement was threefold higher (6000 IU of D/drop) than listed on the label (2000 IU). Due to overdosing and higher vitamin D3 content, the infant received ∼50,000 IU/day for two months resulting in severe hypercalcemia, hypercalciuria and nephrocalcinosis. We also review the relevant literature on vitamin D3 toxicity in this report.

Topics: Cholecalciferol; Dietary Supplements; Female; Humans; Hypercalcemia; Hypercalciuria; Iatrogenic Disease; Infant; Nephrocalcinosis; Vitamins

Chinese PMO women (n = 219) were treated with 12-month ALN/D5600 (n = 111) or calcitriol (n = 108). Changes in 25(OH) D at month 12 were post hoc analyzed by the baseline 25 (OH) D status using the longitudinal analysis. The main safety outcome measures included serum calcium and phosphate and 24-h urine calcium, and the repeated measures mixed model was used to assess the frequencies of the calcium-phosphate metabolic disorders.. Absolute change in mean serum 25(OH) D level was the greatest in VD-deficient patients and least in VD-sufficient patients at months six and 12 (both, P < 0.01). Serum calcium level remained significantly lower in the ALN/D5600 treatment group than in the calcitriol treatment group throughout the 12 months. Mean 24-h urine calcium slightly increased in the ALN/D5600 treatment group and significantly increased in the calcitriol treatment group (+ 1.1 and + 0.9 mmol/L at months six and 12; both, P < 0.05). Calcitriol treatment was associated with more frequent hypercalciuria at month six (9.4% vs. 18.5%, P = 0.05), but not at month 12 (12.3% vs. 13.0%).. Baseline VD status predicted 25(OH) D improvement in PMO patients on 12-month ALN/D5600 treatment. The daily use of 0.25 μg of calcitriol was associated with more frequent hypercalciuria at month six, compared to ALN/5600 treatment, necessitating the safety re-evaluation of calcitriol at a higher dosage.

Topics: Aged; Aged, 80 and over; Alendronate; Biomarkers; Bone Density; Bone Density Conservation Agents; Calcifediol; Calcium Phosphates; China; Cholecalciferol; Female; Humans; Hypercalciuria; Middle Aged; Osteoporosis, Postmenopausal; Treatment Outcome; Vitamin D; Vitamin D Deficiency

In primary hyperparathyroidism, successful parathyroidectomy leads to improved bone mineral density in the majority of cases. Our aim was to further explore the relationship between hypercalciuria, kidney function, and bone recovery after parathyroidectomy.. Bone mineral density, estimated glomerular filtration rate, and 24-hour urinary calcium were analyzed before and one year after parathyroidectomy in a cohort of 150 primary hyperparathyroidism patients (119 women; median age 60 [range 30-80] years) taking part in a clinical trial. The patients were randomized to 1-year daily treatment with either cholecalciferol 1,600 IU and calcium carbonate 1,000 mg or calcium carbonate alone.. Baseline 24-hour urinary calcium correlated directly with s-calcium, parathyroid hormone, 25-OH-D, the bone markers beta C-terminal telopeptide of type 1 collagen and procollagen type 1 amino-terminal propeptide, and estimated glomerular filtration rate (r = 0.19-0.30; P < .05) and inversely with age (r = -0.25; P = .004); 24-hour urinary calcium decreased and bone mineral density in lumbar spine and hip increased similarly in the 2 groups. Baseline 24-hour urinary calcium in the highest quartile (>10 mmol/d) was associated with greater increases in all locations. In a multivariable model adjusting for age, sex, smoking, diabetes, body mass index, estimated glomerular filtration rate, baseline bone mineral density, and vitamin D group, the increase in total hip bone mineral density remained independently associated with baseline 24-hour urinary calcium in the highest quartile (>10 mmol/d) and with plasma parathyroid hormone. Patients with persistent increases in 24-hour urinary calcium at follow-up (14%) had similar bone mineral density improvement.. Overall, 24-hour urinary calcium > 10 mmol/d was an independent determinant of improvement in bone mineral density and should be taken into account when considering parathyroidectomy.

Topics: Adult; Aged; Aged, 80 and over; Antacids; Bone Density; Bone Density Conservation Agents; Calcium Carbonate; Cholecalciferol; Cohort Studies; Female; Glomerular Filtration Rate; Humans; Hypercalciuria; Hyperparathyroidism, Primary; Male; Middle Aged; Parathyroidectomy

There is current interest in the maternal-fetal effects of antenatal vitamin D supplementation, yet little data regarding vitamin D's role in neonatal calcium homeostasis. We determined to assess the effect of high-dose antenatal vitamin D supplementation on fetal and neonatal calcium concentrations.. In a double-blinded, placebo-controlled trial in Bangladesh, 160 pregnant women were randomized to oral vitamin D3 (35,000 IU/wk) or placebo from 26 to 29 wk of gestation.. Total serum calcium (Ca) was higher in cord blood of those supplemented vs. placebo (2.66 ± 0.1 vs. 2.61 ± 0.2 mmol/l; P = 0.04), but the difference in albumin-adjusted calcium was not statistically significant. Change in Ca concentration from birth to day 3 of life was attenuated by vitamin D (-0.10 ± 0.17) compared with placebo (-0.22 ± 0.18 mmol/l; P = 0.02). Maternal 25-hydroxyvitamin D (25(OH)D) (P = 0.04) and cord 25(OH)D (P < 0.01) were associated with day 3 infant Ca, suggesting that the effect of supplementation was mediated by change in maternal-infant vitamin D status. Six infants in each of the supplemented and placebo groups had transient hypercalcemia/hypercalcuria; in all the hypercalcemia/hypercalcuria was asymptomatic, spontaneously resolved, and unassociated with nephrocalcinosis at 1 mo of life.. High-dose antenatal third-trimester vitamin D supplementation attenuated the early postnatal calcium nadir, without increasing the risk of postnatal hypercalcemia.

Topics: Administration, Oral; Biomarkers; Calcium; Cholecalciferol; Dietary Supplements; Double-Blind Method; Drug Administration Schedule; Female; Fetal Blood; Fetus; Gestational Age; Homeostasis; Humans; Hypercalcemia; Hypercalciuria; India; Infant, Newborn; Pregnancy; Pregnancy Trimester, Third; Prenatal Care; Prevalence; Time Factors; Treatment Outcome; Vitamin D; Vitamin D Deficiency

To evaluate and compare the effects and safety of high dose intramuscular (IM) or oral cholecalciferol on 25-hydroxyvitamin D [25(OH)D] levels, muscle strength and physical performance in vitamin D deficient/insufficient elderly.. Randomized prospective study.. 116 ambulatory individuals aged 65 years or older living in a nursing home were evaluated. Eligible patients with 25(OH)D levels <30 ng/ml (n=66) were randomized to IM or Oral groups according to the administration route of 600,000 IU cholecalciferol. Demographic and descriptive data were collected. Biochemical response was measured at baseline, 6th and 12th weeks. Muscle strength was measured from quadriceps by using a hand-held dynamometer and physical performance was evaluated by short physical performance battery (SPPB) at the beginning and 12th week.. Among the screened ambulatory elderly only 5.2% (n=6) had adequate vitamin D levels. 37.1% (n=43) were vitamin D deficient and 57.7% (n=67) were insufficient. After administration of one megadose of vitamin D, mean serum 25(OH)D levels increased significantly at 6th week (32.72±9.0 ng/ml) and at 12th week (52.34±14.2 ng/ml) compared with baseline (11.76±7.6 ng/ml) in IM group (p<0.0001). In Oral group levels were 47.57±12.7 ng/ml, 42.94±13.4 ng/ml and 14.87±6.9 ng/ml, respectively (p<0.0001). At 12th week the increase in IM group was significantly higher than Oral group (p=0.003). At the end of the study period, serum 25(OH)D levels were ≥30 ng/ml in all patients in IM group and in 83.3% of the patients in the Oral group. Quadriceps muscle strength and SPPB total score increased significantly in both groups and SPPB balance subscale score increased only in IM group. Six patients (9.6%) developed hypercalciuria, no significant adverse events were observed.. In vitamin D deficient/insufficient elderly, a single megadose of cholecalciferol increased vitamin D levels significantly and the majority of the patients reached optimal levels. Although both administration routes are effective and appear to be safe, IM application is more effective in increasing 25(OH)D levels and balance performance.

Topics: Administration, Oral; Aged; Aged, 80 and over; Cholecalciferol; Drug Administration Schedule; Female; Humans; Hypercalciuria; Injections, Intramuscular; Male; Muscle Strength; Physical Fitness; Postural Balance; Prevalence; Prospective Studies; Quadriceps Muscle; Treatment Outcome; Vitamin D; Vitamin D Deficiency

Although vitamin D supplementation is a fundamental part of osteoporosis treatment, many patients do not regularly take adequate amounts. A once-weekly (OW) alendronate (ALN) preparation that includes 2800 IU of vitamin D3 in a single combination tablet (ALN+D2800) is available for treating patients and ensuring intake of vitamin D that is consistent with existing guidelines. This randomized, double-blind study extension was conducted to evaluate the safety and tolerability of ALN+D2800 and ALN+D2800 plus an additional 2800 IU vitamin D3 single tablet supplement (ALN+D5600) administered for 24 weeks in men and postmenopausal women with osteoporosis previously treated OW for 15 weeks with either ALN or ALN+D2800. The primary endpoint was the proportion of participants who developed hypercalciuria (defined as a 24-hour urine calcium >300 mg in women or >350 mg in men and an increase of >25% versus randomization baseline) at week 39. The key secondary endpoint was the proportion of participants with vitamin D insufficiency (serum 25(OH)D <15 ng/mL [37.4 nmol/L]) at the end of the study. Hypercalciuria incidence (4.2% [ALN+D5600] vs. 2.8% [ALN+D2800]), did not differ between groups (p = 0.354). No participants developed hypercalcemia. Among the participants with vitamin D insufficiency at the week 0 baseline, the prevalence of insufficiency at the end of the study was reduced by 92% in the ALN+D5600 group and by 86% in the ALN+D2800 group. The incidences of clinical adverse experiences, including drug-related adverse experiences, were similar in both groups. In subjects previously treated with ALN+D2800 for 15 weeks, the addition of 2800 IU D3 for 24 weeks did not produce hypercalcemia nor increase the risk of hypercalciuria.

Topics: Aged; Alendronate; Bone Density; Bone Density Conservation Agents; Cholecalciferol; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypercalciuria; Male; Osteoporosis; Postmenopause

Topics: Anti-Inflammatory Agents, Non-Steroidal; Back Pain; Calcium-Regulating Hormones and Agents; Cholecalciferol; Humans; Hypercalciuria; Lumbar Vertebrae; Lumbosacral Region; Male; Mastocytosis, Systemic; Middle Aged; Neck Pain; Osteoporosis; Phenalenes; Treatment Outcome

Mutations of the CYP24A1 gene are associated with alterations in the activity of the enzyme 25-OH-D-24-hydroxylase, resulting in dysfunction of the metabolism of vitamin D. This enzymatic deficiency may cause hypercalcemia, low parathyroid hormone levels, hypercalciuria, nephrolithiasis and nephrocalcinosis. The clinical case of a young woman with recurrent renal lithiasis, hypercalcemia and hypercalciuria is described. These features are linked to deficiency of the enzyme 25-OH-D-24-hydroxylase, therefore to a biallelic mutation of the CYP24A1 gene.

Topics: Adult; Calcium; Cholecalciferol; Citrates; Female; Genotype; Humans; Hypercalcemia; Hypercalciuria; Kidney Calculi; Mutation, Missense; Parathyroid Hormone; Phosphorus; Recurrence; Sequence Deletion; Vitamin D; Vitamin D3 24-Hydroxylase

While vitamin D (vitD) deficiency is thought to contribute to poor health in a variety of ways and should be corrected, there is still concern about giving vitD supplements to patients with a history of nephrolithiasis. The aim is to study the prevalence of vitD deficiency and the effect on stone risk of cholecalciferol (vitD3) supplementation in a cohort of idiopathic stone formers (ISF). We screened for vitD deficiency and urinary measures of stone risk, comparing vitD deficient (serum 25-OH vitD ≤30 nmol/L; ≤12 ng/mL) with vitD insufficient (31-75 nmol/L; 13-30 ng/mL) or vitD replete (>75 nmol/L; >30 ng/mL); we investigated the effect of giving vitD3 (20,000 IU orally, weekly for 4 months) to 37 of the vitD deficients. Thirty-one percent (142/456) were vitD deficient, 57% (259/456) vitD insufficient, and the rest (12%) vitD replete (55/456). Comparison among the groups showed that baseline 24-h urinary measures related to stone risk expressed as concentration ratios over urine creatinine (Cr), such as U. Calcium/Cr, U. Oxalate/Cr, U. Citrate/Cr, and U. Uric acid/Cr were not significantly different. VitD3 supplementation did significantly increase serum 25-OH vitD levels and U. Phosphate/Cr ratios, as well as reduce serum parathyroid hormone (PTH) concentrations. Following vitD3 supplementation, there was an overall rise in 24-h urine calcium excretion, but it failed to reach statistical significance (p = 0.06). U. Calcium/Cr increased in 22 out of 37 patients (average increase +0.07 mmol/mmol), decreased in 14 (average decrease -0.13 mmol/mmol), and remained unchanged in 1; 6 out of 26 initially normocalciuric ISF developed hypercalciuria; and 6 out of 9 patients who became vitD replete were hypercalciuric after supplementation. It is appropriate to monitor urinary Ca excretion in vitD-supplemented stone formers, because it may reveal underlying hypercalciuria in some treated patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Calcium; Cholecalciferol; Cohort Studies; Creatinine; Dietary Supplements; Female; Humans; Hypercalciuria; Kidney Calculi; Male; Middle Aged; Phosphates; Prevalence; Renal Elimination; Risk Factors; Vitamin D; Vitamin D Deficiency; Young Adult

Thiazide is known to decrease urinary calcium excretion. We hypothesized that thiazide shows different hypocalciuric effects depending on the stimuli causing hypercalciuria. The hypocalciuric effect of hydrochlorothiazide (HCTZ) and the expression of transient receptor potential vanilloid 5 (TRPV5), calbindin-D(28K), and several sodium transporters were assessed in hypercalciuric rats induced by high calcium diet and vitamin D(3). Urine calcium excretion and the expression of transporters were measured from 4 groups of Sprague-Dawley rats; control, HCTZ, high calcium-vitamin D, and high calcium-vitamin D with HCTZ groups. HCTZ decreased urinary calcium excretion by 51.4% in the HCTZ group and only 15% in the high calcium-vitamin D with HCTZ group. TRPV5 protein abundance was not changed by HCTZ in the high calcium-vitamin D with HCTZ group compared to the high calcium-vitamin D group. Protein abundance of NHE3, SGLT1, and NKCC2 decreased in the hypercalciuric rats, and only SGLT1 protein abundance was increased by HCTZ in the hypercalciuric rats. The hypocalciuric effect of HCTZ is attenuated in high calcium and vitamin D-induced hypercalciuric rats. This attenuation seems to have resulted from the lack of HCTZ's effect on protein abundance of TRPV5 in severe hypercalciuric condition induced by high calcium and vitamin D.

Topics: Animals; Calcium; Calcium Channels; Cholecalciferol; Hydrochlorothiazide; Hypercalciuria; Rats; Rats, Sprague-Dawley; Sodium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 1; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Sodium-Potassium-Chloride Symporters; Solute Carrier Family 12, Member 1; TRPV Cation Channels