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The effect of trichlormethiazide in autosomal dominant polycystic kidney disease patients receiving tolvaptan: a randomized crossover controlled trial.
Uchiyama, K, Kitayama, C, Yanai, A, Ishibashi, Y
Scientific reports. 2021;(1):17666
Abstract
The vasopressin V2 receptor antagonist tolvaptan delays the progression of autosomal dominant polycystic kidney disease (ADPKD). However, some patients discontinue tolvaptan because of severe adverse aquaretic events. This open-label, randomized, controlled, counterbalanced, crossover trial investigated the effects of trichlormethiazide, a thiazide diuretic, in patients with ADPKD receiving tolvaptan (n = 10) who randomly received antihypertensive therapy with or without trichlormethiazide for 12 weeks. The primary and secondary outcomes included amount and osmolarity of 24-h urine and health-related quality-of-life (HRQOL) parameters assessed by the Kidney Disease Quality of Life-Short Form questionnaire, renal function slope, and plasma/urinary biomarkers associated with disease progression. There was a significant reduction in urine volume (3348 ± 584 vs. 4255 ± 739 mL; P < 0.001) and a significant increase in urinary osmolarity (182.5 ± 38.1 vs. 141.5 ± 38.1 mOsm; P = 0.001) in patients treated with trichlormethiazide. Moreover, trichlormethiazide improved the following HRQOL subscales: effects of kidney disease, sleep, emotional role functioning, social functioning, and role/social component summary. No significant differences were noted in renal function slope or plasma/urinary biomarkers between patients treated with and without trichlormethiazide. In patients with ADPKD treated with tolvaptan, trichlormethiazide may improve tolvaptan tolerability and HRQOL parameters.
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Do Thiazide Diuretics Increase the Risk of Skin Cancer? A Critical Review of the Scientific Evidence and Updated Meta-Analysis.
Bendinelli, B, Masala, G, Garamella, G, Palli, D, Caini, S
Current cardiology reports. 2019;(9):92
Abstract
PURPOSE OF REVIEW We reviewed the hypothesised mechanisms of skin cancerogenesis for thiazide diuretics; conducted an updated meta-analysis of studies focusing on their association with skin cancer risk; critically appraised the quality of available studies and identified knowledge gaps; and discussed implications for health professionals and patients. RECENT FINDINGS Thiazide diuretics possess well-described photosensitizing properties and a causal association with skin cancer is biologically plausible. The epidemiological evidence is stronger for squamous cell cancer; however, diversity in design among studies, methodological concerns potentially affecting the validity of results, and scarcity of data on dose-relation relationship suggest caution in drawing conclusions. Only few, unbalanced, and/or heterogeneous data exist to date for melanoma and basal cell cancer. Patients effectively treated with thiazide diuretics are currently not advised to stop treatment, but encouraged to limit exposure to sunlight and regularly check their skin. While endorsing these recommendations, we believe that well-designed studies are urgently needed to overcome persistent knowledge gaps.
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Thiazide therapy is not related to any changes in cognitive function in older hypertensive patients with or without dementia: a 26-week follow-up study.
Kocyigit, SE, Soysal, P, Ates Bulut, E, Dokuzlar, O, Isik, AT
Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society. 2019;(1):16-22
Abstract
AIM: The study aimed to evaluate the effect of thiazide diuretics, a first-line antihypertensive therapy, on cognitive function in elderly hypertensive patients with or without cognitive impairment. METHODS This retrospective and observational study assessed 286 elderly patients with hypertension. Patients were divided based on thiazide diuretic usage and then into dementia and non-dementia groups. The comprehensive geriatric assessment was performed for all patients. All participants were re-evaluated after a 26-week period. RESULTS In total, 133 patients, including 62 with dementia, took thiazide. There were no significant differences between baseline and follow-up laboratory findings, comprehensive geriatric assessment parameters, including detailed neurocognitive assessment, or electrolytes in the thiazide group, the non-thiazide group, and the dementia group (P > 0.05). CONCLUSION Thiazide therapy does not show any effect on cognitive function in older hypertensive adults regardless of dementia status.
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Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry.
Irvin, MR, Sitlani, CM, Noordam, R, Avery, CL, Bis, JC, Floyd, JS, Li, J, Limdi, NA, Srinivasasainagendra, V, Stewart, J, et al
The pharmacogenomics journal. 2019;(1):97-108
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Abstract
We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10-8) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10-8; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.
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Genome Wide Association Study Identifies the HMGCS2 Locus to be Associated With Chlorthalidone Induced Glucose Increase in Hypertensive Patients.
Singh, S, McDonough, CW, Gong, Y, Alghamdi, WA, Arwood, MJ, Bargal, SA, Dumeny, L, Li, WY, Mehanna, M, Stockard, B, et al
Journal of the American Heart Association. 2018;(6)
Abstract
BACKGROUND Thiazide and thiazide-like diuretics are first-line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide-like diuretic/chlorthalidone-induced glucose change. METHODS AND RESULTS Genome-wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR-2 (Pharmacogenomic Evaluation of Antihypertensive Responses-2). Single-nucleotide polymorphisms with P<5×10-8 were further prioritized using in silico analysis based on their expression quantitative trait loci function. Among blacks, an intronic single-nucleotide polymorphism (rs9943291) in the HMGCS2 was associated with increase in glucose levels following chlorthalidone treatment (ß=12.5; P=4.17×10-8). G-allele carriers of HMGCS2 had higher glucose levels (glucose change=+16.29 mg/dL) post chlorthalidone treatment compared with noncarriers of G allele (glucose change=+2.80 mg/dL). This association was successfully replicated in an independent replication cohort of hydrochlorothiazide-treated participants from the PEAR study (ß=5.54; P=0.023). A meta-analysis of the 2 studies was performed by race in Meta-Analysis Helper, where this single-nucleotide polymorphism, rs9943291, was genome-wide significant with a meta-analysis P value of 3.71×10-8. HMGCS2, a part of the HMG-CoA synthase family, is important for ketogenesis and cholesterol synthesis pathways that are essential in glucose homeostasis. CONCLUSIONS These results suggest that HMGCS2 is a promising candidate gene involved in chlorthalidone and Hydrochlorothiazide (HCTZ)-induced glucose change. This may provide insights into the mechanisms involved in thiazide-induced hyperglycemia that may ultimately facilitate personalized approaches to antihypertensive selection for hypertension treatment. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852.
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Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.
Seyerle, AA, Sitlani, CM, Noordam, R, Gogarten, SM, Li, J, Li, X, Evans, DS, Sun, F, Laaksonen, MA, Isaacs, A, et al
The pharmacogenomics journal. 2018;(2):215-226
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Abstract
Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.
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Thiazide diuretic usage and risk of fracture: a meta-analysis of cohort studies.
Xiao, X, Xu, Y, Wu, Q
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2018;(7):1515-1524
Abstract
UNLABELLED Inconsistent findings in regard to association between thiazide diuretic use and the risk of fracture have been reported during the past decade. This updated meta-analysis, which pooled data from 11 qualified prospective designed studies, found that thiazides have a significant protective effect on fracture risk. INTRODUCTION An updated comprehensive meta-analysis examine the association between thiazide diuretic use and therisk of fracture is needed. METHODS Cohort studies regarding thiazide diuretic exposure and the risk of fracture, published from inception to May 1 2017, were identified through MEDLINE, EMBASE, SCOPUS, and the Cochrane Database of Systematic Reviews. The literature search, study selection, study appraisal, and data extraction were pre-defined in the protocol and were independently conducted by two investigators. Due to the heterogeneity of the original studies, a random effects model was used to pool the confounder-adjusted relative risk (RR). RESULTS Eleven eligible cohort studies involving 2,193,160 participants were included for analysis. Overall, thiazide diuretic users, as compared with non-users, had a significant 14% reduction in the risk of all fractures (relative risk [RR], 0.86; 95% confidence interval [CI], 0.80-0.93; p = 0.009) and an 18% reduction in the risk of hip fracture (RR, 0.82; 95%CI, 0.80-0.93; p = 0.009). However, the effect size associated with thiazide use became slightly weaker when the analysis was limited to only high-quality original studies (quality score > 8) (RR, 0.89; 95%CI, 0.80-0.99; p = 0.005), studies with a larger sample size (> 10,000) (RR, 0.90; 95%CI, 0.80-1.00; p = 0.002), and studies published after 2007 (RR, 0.92; 95%CI, 0.82-1.02; p = 0.001). CONCLUSION Our findings indicate that thiazide diuretic use may convey a decreased risk of fracture and as such, the protective effect of this class of medicine should be considered when prescribing thiazide diuretics in clinical practice.
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Hydrochlorothiazide treatment increases the abundance of the NaCl cotransporter in urinary extracellular vesicles of essential hypertensive patients.
Pathare, G, Tutakhel, OAZ, van der Wel, MC, Shelton, LM, Deinum, J, Lenders, JWM, Hoenderop, JGJ, Bindels, RJM
American journal of physiology. Renal physiology. 2017;(6):F1063-F1072
Abstract
The thiazide-sensitive NaCl cotransporter (NCC), located apically in distal convoluted tubule epithelia, regulates the fine-tuning of renal sodium excretion. Three isoforms of NCC are generated through alternative splicing of the transcript, of which the third isoform has been the most extensively investigated in pathophysiological conditions. The aim of this study was to investigate the effect of different anti-hypertensive treatments on the abundance and phosphorylation of all three NCC isoforms in urinary extracellular vesicles (uEVs) of essential hypertensive patients. In uEVs isolated from patients (n = 23) before and after hydrochlorothiazide or valsartan treatment, the abundance and phosphorylation of the NCC isoforms was determined. Additionally, clinical biochemistry and blood pressure of the patients was assessed. Our results show that NCC detected in human uEVs has a glycosylated and oligomeric structure, comparable to NCC present in human kidney membrane fractions. Despite the inhibitory action of hydrochlorothiazide on NCC activity, immunoblot analysis of uEVs showed significantly increased abundance of NCC isoforms 1 and 2 (NCC1/2), total NCC (NCC1-3), and the phosphorylated form of total NCC (pNCC1-3-T55/T60) in essential hypertensive patients treated with hydrochlorothiazide but not with valsartan. This study highlights that NCC1/2, NCC1-3, and pNCC1-3-T55/T60 are upregulated by hydrochlorothiazide, and the increase in NCC abundance in uEVs of essential hypertensive patients correlates with the blood pressure response to hydrochlorothiazide.
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Urolithiasis: evaluation, dietary factors, and medical management: an update of the 2014 SIU-ICUD international consultation on stone disease.
Jung, H, Andonian, S, Assimos, D, Averch, T, Geavlete, P, Kohjimoto, Y, Neisius, A, Philip, J, Saita, A, Shah, H, et al
World journal of urology. 2017;(9):1331-1340
Abstract
PURPOSE The aim of this review was to provide current best evidence for evaluation, dietary, and medical management of patients with urolithiasis. METHODS Literature addressing evaluation, dietary, and medical management of urolithiasis was searched. Papers were analyzed and rated according to level of evidence (LOE), whereupon a synthesis of the evidence was made. Grade of recommendation (GOR) was judged from individual clinical experience and knowledge of the evidence according to the Oxford Centre for Evidence-based Medicine. RESULTS It is obvious that different stone diseases influence the life of stone-forming individuals very differently, and that evaluation and medical management should be personalized according to risk of recurrence, severity of stone disease, presence of associated medical conditions, and patient's motivation. With regard to evaluation, dietary and medical management of patients with urolithiasis evidence from the literature suggest that selective metabolic evaluation may lead to rational dietary and medical management. Statements based on LOE and GOR are provided to guide clinical practice. CONCLUSION The provided evidence for evaluation of patients with urolithiasis aims at defining patients at high risk for recurrent/complicated stone disease. Based on this approach, evidence-based dietary and medical management regimes are suggested.
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Genome-Wide Prioritization and Transcriptomics Reveal Novel Signatures Associated With Thiazide Diuretics Blood Pressure Response.
Shahin, MH, Sá, AC, Webb, A, Gong, Y, Langaee, T, McDonough, CW, Riva, A, Beitleshees, AL, Chapman, AB, Gums, JG, et al
Circulation. Cardiovascular genetics. 2017;(1)
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BACKGROUND Thiazide diuretics are among the most commonly prescribed antihypertensives. However, <50% of thiazide-treated patients achieve blood pressure (BP) control. Herein, we used different omics (genomics and transcriptomics) to identify novel biomarkers of thiazide diuretics BP response. METHODS AND RESULTS Genome-wide analysis included 228 white hypertensives with BP determined at baseline and after 9 weeks of hydrochlorothiazide. Single-nucleotide polymorphisms with P <5×10-5 were prioritized according to their biological function, using RegulomeDB, haploreg, and Genome-Wide Annotation of Variants. The results from the prioritization approach revealed rs10995 as the most likely functional single-nucleotide polymorphism, among single-nucleotide polymorphisms tested, that has been associated with hydrochlorothiazide BP response. The rs10995 G-allele was associated with better BP response to hydrochlorothiazide versus noncarriers (Δ systolic BP/Δ diastolic BP: -12.3/-8.2 versus -6.8/-3.5 mm Hg, respectively, Δ systolic BP P=3×10-4, Δ diastolic BP P=5×10-5). This association was replicated in independent participants treated with chlorthalidone. In addition, rs10995 G-allele was associated with increased mRNA expression of VASP (vasodilator-stimulated phosphoprotein). Moreover, baseline expression of the VASP mRNA was significantly higher in 25 good responders to hydrochlorothiazide compared with 25 poor responders (P=0.01). This finding was replicated in independent participants treated with chlorthalidone (P=0.04). Last, allelic-specific expression analysis revealed a significant but modest imbalance with rs10995 and rs10156, a single-nucleotide polymorphism in high linkage disequilibrium (r2=0.7) with rs10995, which both could contribute to the observed genetic effects by affecting VASP mRNA expression. CONCLUSIONS This study highlights the strength of using different omics to identify novel biomarkers of drug response and suggests VASP as a potential determinant of thiazide diuretics BP response. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852.