Thiazide Diuretics and Risk of Colorectal Cancer: A Population-Based Cohort Study.

Evidence from clinical trials and observational studies on the association between thiazide diuretics and colorectal cancer risk is conflicting. We aimed to determine whether thiazide diuretics are associated with an increased colorectal cancer risk compared with dihydropyridine calcium channel blockers (dCCBs). A population-based, new-user cohort was assembled using the UK Clinical Practice Research Datalink. Between 1990-2018, we compared thiazide diuretic initiators with dCCB initiators and estimated hazard ratios (HR) with 95% confidence intervals (CIs) of colorectal cancer using Cox proportional hazard models. Models were weighted using standardized morbidity ratio weights generated from calendar time-specific propensity scores. The cohort included 377,760 thiazide diuretic initiators and 364,300 dCCB initiators, generating 3,619,883 person-years of follow-up. Compared with dCCBs, thiazide diuretics were not associated with colorectal cancer (weighted HR = 0.97, 95% CI: 0.90, 1.04). Secondary analyses yielded similar results, although an increased risk was observed among patients with inflammatory bowel disease (weighted HR = 2.45, 95% CI: 1.13, 5.35) and potentially polyps (weighted HR = 1.46, 95% CI: 0.93, 2.30). Compared with dCCBs, thiazide diuretics were not associated with an overall increased colorectal cancer risk. While these findings provide some reassurance, research is needed to corroborate the elevated risks observed among patients with inflammatory bowel disease and history of polyps.

Proximal versus distal diuretics in congestive heart failure.

Volume overload represents a hallmark clinical feature linked to the development and progression of heart failure (HF). Alleviating signs and symptoms of volume overload represents a foundational HF treatment target that is achieved using loop diuretics in the acute and chronic setting. Recent work has provided evidence to support guideline-directed medical therapies, such as sodium glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor (MR) antagonists, as important adjunct diuretics that may act synergistically when used with background loop diuretics in people with chronic HF. Furthermore, there is growing interest in understanding the role of SGLT2 inhibitors, carbonic anhydrase inhibitors, thiazide diuretics, and MR antagonists in treating volume overload in patients hospitalized for acute HF, particularly in the setting of loop diuretic resistance. Thus, the current review demonstrates that: 1) SGLT2 inhibitors and MR antagonists confer long-term cardioprotection in chronic HF patients but it is unclear if natriuresis or diuresis represents the primary mechanisms for this benefit, 2) SGLT2 inhibitors, carbonic anhydrase inhibitors, and thiazide diuretics increase natriuresis in the acute HF setting, but implications on long-term outcomes remain unclear and warrants further investigation, and 3) a multi-nephron segment approach, using agents that act on distinct segments of the nephron, potentiate diuresis to alleviate signs and symptoms of volume overload in acute HF.

Use of drugs for hypertension or heart failure and the risk of death in COVID-19: association with loop-diuretics.

PURPOSE: To study the association between the use of drugs for hypertension or heart failure, particularly diuretics, and risk of death in COVID-19. METHODS: We conducted a cohort study, based on record linked individual-based data from national registers, of all Swedish inhabitants 50 years and older (n = 3,909,321) at the start of the first SARS-CoV-2 wave in Sweden. The association between use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), thiazides, loop diuretics, aldosterone antagonists, beta blocking agents and calcium channel blockers at the index date 6 March 2020, and death in COVID-19 during 7 March to 31 July 2020, was analysed using Cox-proportional hazards regression, adjusted for a wide range of possible confounders. RESULTS: Use of loop diuretics was associated with higher risk [adjusted hazard ratio (HR) 1.26; 95% confidence interval (95% CI) 1.17-1.35] and thiazides with reduced risk (0.78; 0.69-0.88) of death in COVID-19. In addition, lower risk was observed for ACEI and higher risk for beta-blocking agents, although both associations were weak. For ARB, aldosterone antagonists and calcium channel blockers no significant associations were found. CONCLUSION: In this nationwide cohort of nearly 4 million persons 50 years and older, the use of loop diuretics was associated with increased risk of death in COVID-19 during the first SARS-CoV-2 wave in Sweden. This contrasted to the decreased risk observed for thiazides. As treatment with loop diuretics is common, particularly in the elderly, the group most affected by severe COVID-19, this finding merit further investigation.

Association between immune checkpoint inhibitor-induced myocarditis and concomitant use of thiazide diuretics.

Although an association has been reported between diuretics and myocarditis, it is unclear whether the risk of immune checkpoint inhibitor (ICI)-induced myocarditis is affected by concomitant diuretics. Thus, the aim of this work was to evaluate the impact of concomitant diuretics on ICI-induced myocarditis. This cross-sectional study used disproportionality analysis and a pharmacovigilance database to assess the risk of myocarditis with various diuretics in patients receiving ICIs via the analysis of data entered into the VigiBase database through December 2022. Multiple logistic regression analysis was performed to identify risk factors for myocarditis in patients who received ICIs. A total of 90 611 patients who received ICIs, including 975 cases of myocarditis, were included as the eligible dataset. A disproportionality in myocarditis was observed for loop diuretic use (reporting odds ratio 1.47, 95% confidence interval [CI] 1.02-2.04, P = .03) and thiazide use (reporting odds ratio 1.76, 95% CI 1.20-2.50, P < .01) in patients who received ICIs. The results of the multiple logistic regression analysis showed that the use of thiazides (odds ratio 1.67, 95% CI 1.15-2.34, P < .01) was associated with an increased risk of myocarditis in patients who received ICIs. Our findings may help to predict the risk of myocarditis in patients receiving ICIs.

The impact of different diuretics on regression of myocardial reperfusion injury in spontaneously hypertensive rats.

The study's objective was to ascertain the results of sub-chronic therapy of various diuretics on the ischemia/reperfusion dysfunction of the heart in hypertensive rats by a global ischemia in an isolated rat heart model. The research included 40 spontaneously hypertensive male rats (Wistar Kyoto strain, body mass 250 ± 30 g, 8 weeks old) grouped into four groups. The animals were treated for 4 weeks with 10 mg/kg of hydrochlorothiazide, indapamide, or spironolactone per os. After a period of sub-chronic treatment, we analyzed hemodynamic measurements, echocardiography, and myocardial function according to the Langendorff retrograde perfusion method. The hearts were subjected to 20 min of global ischemia and then reperfused for 30 min (I20:R30). Cardiovascular parameters that depict the left ventricle functions were continuously monitored, while flowmetry was used to determine coronary flow values. Markers of oxidative stress were estimated from coronary venous effluent using spectrophotometry. All three examined diuretics (hydrochlorothiazide, spironolactone, indapamide) lowered the production of the majority of the detected prooxidants, reducing myocardial oxidative damage. The cardiological examination of heart function in vivo demonstrated that treatment with indapamide and spironolactone mitigates left ventricular hypertrophy but without significant lowering of blood pressure or increment in ejection fraction. Additionally, monitoring of cardiac function ex vivo indicated the cardiodepressant effect of spironolactone in spontaneously hypertensive rats.

Na-Cl Co-transporter (NCC) gene inactivation is associated with improved bone microstructure.

Gitelman syndrome (GS) is the disease model of the inactivation of thiazide-sensitive sodium chloride cotransporter (NCC), which is believed to benefit bone mass and reduce fracture risk. In this study, we found that GS patients have superior bone microarchitecture, which is associated with the disease status. Several decreased bone parameters with aging in healthy controls were reversed in GS patients to a certain extent. PURPOSE: To evaluate the impact of the inactivation of NCC on bone turnover and microarchitecture in Gitelman syndrome patients. METHODS: A cross-sectional study was conducted in 45 GS patients (25 males and 20 females). Serum procollagen type 1 N-terminal propeptide (P1NP), ß-carboxy-terminal crosslinked telopeptide of type 1 collagen (ß-CTX), and osteocalcin were measured. High-resolution peripheral quantitative computed tomography (HR-pQCT) was conducted to evaluate bone microarchitecture in GS patients and age- and sex-matched healthy controls. Areal bone mineral density (aBMD) was measured by dual-energy X-ray absorptiometry (DXA) simultaneously. RESULTS: GS patients had a relatively lower level of ß-CTX. aBMD at several skeletal sites was improved in GS patients. HR-pQCT assessment revealed that GS patients had slightly thinner but significantly more compact trabecular bone (increased trabecular number and decreased thickness), notably decreased cortical porosity, and increased volume BMD (vBMD) at both the radius and tibia compared with controls. The disease severity, represented as the relationship with the minimum level of magnesium during the course and standard base excess, was associated with bone microarchitecture parameters after adjusting for age, sex, and BMI. The decreased vBMD and Tb.BV/TV, and increased Tb.Sp and Ct.Po with aging, were reversed in GS patients to a certain extent. CONCLUSION: GS patients have superior bone microarchitecture, which suggests that the inactivation of NCC might be beneficial for avoiding osteoporosis.

Use of Thiazides to Treat Hypertension and Advanced CKD.

PURPOSE OF REVIEW: Hypertension is often difficult to control in patients with CKD as manifested by suboptimal control rates in this population. Use of thiazides in CKD patients has been limited as these agents are thought to be ineffective in reducing blood pressure in people with advanced CKD. This review summarizes recent studies impacting indications and safety of use of thiazide in patients with CKD and discusses the mechanism of how thiazides reduce blood pressure. RECENT FINDINGS: Chlorthalidone reduces blood pressure compared to placebo in patients with advanced CKD, challenging the belief that thiazide diuretics lose efficacy at lower levels of GFR. Recent clinical trial data indicate that thiazides are effective in patients with advanced kidney disease for blood pressure lowering. However, monitoring of electrolytes and kidney function is important to ensure patient safety when prescribing these agents in patients with CKD.

Antihypertensive medication use and ovarian cancer survival.

OBJECTIVE: Although experimental models suggest that use of beta-blockers, a common antihypertensive agent, may improve survival in ovarian cancer patients, results from clinical studies have been mixed. METHODS: We evaluated the associations of pre-diagnostic (n = 950) and post-diagnostic (n = 743) use of antihypertensive medications with survival among patients with invasive, epithelial ovarian cancer in the Nurses' Health Study (NHS; 1994-2016) and NHSII (2001-2017), with follow-up until 2018 and 2019, respectively. Cox proportional hazards models were used to estimate hazard ratios (HR) for ovarian cancer mortality according to antihypertensive medication use before and after diagnosis, considering multiple drug classes (beta-blockers, calcium-channel blockers, thiazide diuretics, angiotensin-converting enzyme [ACE] inhibitors). RESULTS: After adjusting for age, BMI, smoking status and tumor characteristics, pre-diagnostic use versus non-use of calcium-channel blockers was associated with higher ovarian cancer mortality (HR: 1.49; 95% CI: 1.13, 1.96), which was primarily due to polytherapy involving calcium-channel blockers (HR: 1.61; 95% CI: 1.15, 2.26). Pre-diagnostic use of beta-blockers, thiazide diuretics, or ACE inhibitors was not associated with ovarian cancer mortality. No association was observed for post-diagnostic antihypertensive medication use individually or in combination, except for lower mortality associated with polytherapy involving ACE inhibitors (HR: 0.53; 95% CI: 0.31, 0.91). CONCLUSION: Overall, we did not find clear relationships between antihypertensive medication use and ovarian cancer mortality. However, given the limitation of the data, we cannot determine whether the association may differ by type of beta-blockers. The reasons underlying the observed associations with pre-diagnostic calcium-channel blocker use and post-diagnostic ACE inhibitor use require further investigation.

Thiazide diuretics and the rate of disease progression in autosomal dominant polycystic kidney disease: an observational study.

BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD), hypertension is prevalent and cardiovascular events are the main cause of death. Thiazide diuretics are often prescribed as second-line antihypertensives, on top of renin-angiotensin-aldosterone system (RAAS) blockade. There is a concern, however, that diuretics may increase vasopressin concentration and RAAS activity, thereby worsening disease progression in ADPKD. We aimed to investigate the validity of these suggestions. METHODS: We analysed an observational cohort of 533 ADPKD patients. Plasma copeptin (surrogate for vasopressin), aldosterone and renin were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively. Linear mixed models were used to assess the association of thiazide use with estimated glomerular filtration rate (eGFR) decline and Cox proportional hazards models for the association with the composite kidney endpoint of incident end-stage kidney disease, 40% eGFR decline or death. RESULTS: A total of 23% of participants (n = 125) used thiazide diuretics at baseline. Compared with non-users, thiazide users were older, a larger proportion was male, they had lower eGFRs and similar blood pressure under more antihypertensives. Plasma copeptin was higher, but this difference disappeared after adjustment for age and sex. Both renin and aldosterone were higher in thiazide users. There was no difference between thiazide users and non-users in the rate of eGFR decline {difference -0.35 mL/min/1.73 m2 per year [95% confidence interval (CI) -0.83 to -0.14], P = 0.2} during 3.9 years of follow-up (interquartile range 2.5-4.9). This did not change after adjustment for potential confounders [difference final model: 0.08 mL/min/1.73 m2 per year [95% CI -0.46 to -0.62], P = 0.8). In the crude model, thiazide use was associated with a higher incidence of the composite kidney endpoint [hazard ratio (HR) 1.53 (95% CI 1.05-2.23), P = 0.03]. However, this association lost significance after adjustment for age and sex and remained unassociated after adjustment for additional confounders [final model: HR 0.80 (95% CI 0.50-1.29), P = 0.4]. CONCLUSIONS: These data do not show that thiazide diuretics have a detrimental effect on the rate of disease progression in ADPKD and suggest that these drugs can be prescribed as second-line antihypertensives.

Update on Treatment of Hypertension After Renal Transplantation.

PURPOSE OF REVIEW: To incorporate novel findings on pathophysiology and treatment of posttransplant hypertension. RECENT FINDINGS: (1) The sodium retaining effects of CNIs are mediated by stimulation of the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule and in this regard chlorthalidone was proven to be an effective antihypertensive drug in renal transplantation. (2) Local and not systemic activation of the renin-angiotensin-aldosterone system plays a crucial role in the pathogenesis of posttransplant hypertension. (3) Recent randomized controlled trials failed to prove the presumed superiority of renin-angiotensin blockers in kidney transplantation. (4) Steroid-free and mammalian target of rapamycin-based immunosuppressive drug combinations did not show favorable effects on blood pressure control. (5) In a recent report the risk of non-melanoma skin cancer was higher with thiazide diuretics. But the increased cancer risk in transplant recipients is mainly attributed to comorbidities, such as diabetes and hypertension and of course to the transplantation condition itself or the obligatory application of immunosuppression, and has little to do with the antihypertensive medication Actual recommendations about BP targets in adult renal transplant recipients are coming from a post hoc analysis of a large randomized trial with another primary endpoint. Unless convincing studies on treatment of hypertension after renal transplantation are available, the ESC/ESH Guidelines 2018 should apply for these patients.

Use of thiazide diuretics for the prevention of recurrent kidney calculi: a systematic review and meta-analysis.

BACKGROUND: Thiazide diuretics reduce the risk of recurrent kidney calculi in patients with kidney calculi or hypercalciuria. However, whether thiazide diuretics can definitely prevent recurrent kidney calculi remains unclear. We aimed to evaluate the effect and safety of thiazide diuretics on recurrent kidney calculi. METHODS: The PubMed, Cochrane Library, and EMBASE databases were systematically searched using the keywords thiazide diuretics and kidney calculi to identify randomized controlled trials (RCTs). The primary outcome was the incidence of recurrent kidney calculi, and the secondary outcome was the 24-h urinary calcium level. The pooled risk ratio (RR), risk difference (RD), standardized mean difference (SMD), and 95% confidence interval (CI) were calculated. The evidence quality was graded using the GRADE criteria, and recommendations for recurrent kidney calculus prevention using thiazide diuretics were reassessed. RESULTS: Eight RCTs involving 571 patients were included. The pooled RR for the incidence of kidney calculi in the thiazide diuretic groups was 0.44 (95% CI 0.33-0.58, P < 0.0001) compared to that in the placebo and untreated groups; the pooled RD was - 0.23 (95% CI - 0.30 to - 0.16, P < 0.0001). The pooled SMD for the 24-h urinary calcium level was - 18.59 (95% CI - 25.11 to - 12.08, P < 0.0001). The thiazide diuretic groups had a high incidence of adverse reactions and low tolerance. The evidence quality for decrease in kidney calculus incidence using thiazide diuretics was low, while that for the 24-h urinary calcium level decrease among those with recurrent kidney calculi was moderate, and that for the decrease in kidney calculus incidence using short-acting and long-acting thiazide diuretics was low. The overall strength of recommendation for prevention of recurrent renal calculi using thiazide diuretics was not recommended. The subgroup and sensitivity analysis findings were robust. CONCLUSIONS: Long-term use of thiazide diuretics reduces the incidence of recurrent renal calculi and 24-h urinary calcium level. However, the benefits are insufficient, and the evidence quality is low. Considering the adverse effects, poor patient compliance, and economic burden of long-term medication, their use in preventing recurrent kidney calculi is not recommended.

Design and Baseline Characteristics of the Chlorthalidone in Chronic Kidney Disease (CLICK) Trial.

BACKGROUND: Hypertension often accompanies chronic kidney disease (CKD), and diuretics are widely prescribed to reduce blood pressure (BP). Chlorthalidone (CTD) is a thiazide-like diuretic and an effective antihypertensive drug, yet little data exist to support its use in treating hypertension in individuals with advanced CKD. METHODS: Chlorthalidone in Chronic Kidney Disease (CLICK) is a phase II, single-institution, multicenter, double-blind randomized control trial to test the hypothesis that CTD improves BP, through reduction of extracellular fluid volume, and results in target organ protection in patients with stage 4 CKD and poorly controlled hypertension. After a single-blind placebo run-in for 2 weeks and confirmation of hypertension by 24-h ambulatory blood pressure (ABP), patients are randomized to either placebo or CTD 12.5 mg once daily (QD) followed by dose escalation. Randomization is stratified by prior loop diuretic use, and the double-blind phase lasts 12 weeks. With a total of 160 patients, the study will have ≥80% power to detect a 6 mm Hg difference in systolic 24-h ABP between the 2 treatment groups. RESULTS: Between June 2016 and October 2019, 131 patients have been randomized. The baseline characteristics are as follows: average age 65.8 years, 79% men, 36% Black, 79% with diabetes, mean eGFR 23.2 mL/min/1.73 m2, median urine albumin/creatinine ratio 923 mg/g, average number of BP medications 3.4, 60% on loop diuretics, and 24-h ABP averaged 141.7/73.8 mm Hg. CONCLUSION: Among patients with stage 4 CKD and uncontrolled hypertension, CLICK should answer the question whether CTD is safe and effective.

Important drug-micronutrient interactions: A selection for clinical practice.

Interactions between drugs and micronutrients have received only little or no attention in the medical and pharmaceutical world in the past. Since more and more pharmaceutics are used for the treatment of patients, this topic is increasingly relevant. As such interactions - depending on the duration of treatment and the status of micronutrients - impact the health of the patient and the action of the drugs, physicians and pharmacists should pay more attention to such interactions in the future. This review aims to sensitize physicians and pharmacists on drug micronutrient interactions with selected examples of widely pescribed drugs that can precipitate micronutrient deficiencies. In this context, the pharmacist, as a drug expert, assumes a particular role. Like no other professional in the health care sector, he is particularly predestined and called up to respond to this task. The following article intends to point out the relevance of mutual interactions between micronutrients and various examples of widely used drugs, without claiming to be exhaustive.

Factors of importance for discontinuation of thiazides associated with hyponatremia in Sweden: A population-based register study.

PURPOSE: In a patient with clinically significant hyponatremia without other clear causes, thiazide treatment should be replaced with another drug. Data describing to which extent this is being done are scarce. The aim of this study was to investigate sociodemographic and socioeconomic factors that may be of importance for the withdrawal of thiazide diuretics in patients hospitalized due to hyponatremia. METHODS: The study population was sampled from a case-control study investigating individuals hospitalized with a main diagnosis of hyponatremia. For every case, four matched controls were included. In the present study, cases (n = 5204) and controls (n = 7425) that had been dispensed a thiazide diuretic prior to index date were identified and followed onward regarding further dispensations. To investigate the influence of socioeconomic and sociodemographic factors, multiple logistic regression was used. RESULTS: The crude prevalence of thiazide withdrawal for cases and controls was 71.9% and 10.8%, respectively. Thiazide diuretics were more often withdrawn in medium-sized towns (adjusted OR, 1.52; 95% CI, 1.21-1.90) and rural areas (aOR, 1.81; 95% CI, 1.40-2.34) compared with metropolitan areas and less so among divorced (aOR, 0.72; 95% CI, 0.53-0.97). However, education, employment status, income, age, country of birth, and gender did not influence withdrawal of thiazides among patients with hyponatremia. CONCLUSIONS: Thiazide diuretics were discontinued in almost three out of four patients hospitalized due to hyponatremia. Educational, income, gender, and most other sociodemographic and socioeconomic factors were not associated with withdrawal of thiazides.

Development of a hyponatremia screening tool (ABCDF-S score) for patients with hypertension using thiazide diuretic agents.

WHAT IS KNOWN AND OBJECTIVE: Hyponatremia is a common side effect of thiazide diuretics that can lead to increased mortality and hospitalization. A rapid and accurate screening tool is needed for rapid and appropriate management. In this study, we report on the development of a simple clinical screening tool for hyponatremia using thiazide diuretics. METHODS: This nested case-control study was performed by collecting data from 1 January 2015 to 30 June 2017. Univariable and multivariable logistic regressions were used to identify potential risk factors. The regression coefficients were converted into item scores by dividing each regression coefficient with the minimum coefficient in the model and rounding to the nearest integer. This value was then summed to the total score. The prediction power of the model was determined by the area under the receiver operating characteristic curve (AuROC). RESULTS AND DISCUSSION: Six clinical risk factors, namely age ≥65 years, benzodiazepine use, history of a cerebrovascular accident, dose of hydrochlorothiazide ≥25 mg, female sex and statin use, were included in our ABCDF-S score. The model showed good power of prediction (AuROC 81.53%, 95% confidence interval [CI]: 78%-84%) and good calibration (Hosmer-Lemeshow X2  = 23.20; P = .39). The positive likelihood ratios of hyponatremia in patients with low risk (score ≤ 6) and high risk (score ≥ 8) were 0.26 (95% CI: 0.21-0.32) and 3.89 (95% CI: 3.11-4.86), respectively. WHAT IS NEW AND CONCLUSION: The screening tool with six risk predictors provided a useful prediction index for thiazide-associated hyponatremia. However, further validation of the tool is warranted prior to its utilization in routine clinical practice.

The effect of indapamide vs. bendroflumethiazide for primary hypertension: a systematic review.

The aims of the current review were to compare the efficacy of monotherapy with bendroflumethiazide vs. indapamide on mortality, cardiovascular outcomes, blood pressure, need for intensification of treatment and treatment withdrawal. Two authors independently screened the results of a literature search, assessed the risk of bias and extracted relevant data. Randomized clinical trials of hypertensive patients of at least a 1-year duration were included. When there was disagreement, a third reviewer was consulted. Risk ratio (RR) and mean differences were used as measures of effect. Two trials comparing bendroflumethiazide against placebo, one comparing indapamide with placebo and three of short duration directly comparing indapamide and Bendroflumethiazide, were included. No statistically significant difference was found between indapamide and bendroflumethiazide for all deaths [RR 0.82; 95% confidence interval (CI) 0.57, 1.18], cardiovascular deaths (RR 0.82; 95% CI 0.55, 1.20), noncardiovascular deaths (0.81; 95% CI 0.54, 1.22), coronary events (RR 0.73; 95% CI 0.30, 1.79) or all cardiovascular events (RR 0.89; 95% CI 0.67, 1.18). Indapamide performed worse for stroke (RR 2.21; 95% CI 1.19, 4.11), even though a reduction in RR compared with placebo was observed in both groups. There was no statistically or clinically significant difference between indapamide and bendroflumethiazide in blood pressure reduction (mean absolute difference <1 mmHg). The present review highlights a lack of studies to answer the review question but also a lack of evidence of superiority of one drug over the other. Therefore, there is a clear need for new studies directly comparing the effect of these drugs on the outcomes of interest.

Risk factors for vancomycin nephrotoxicity and time course of renal function during vancomycin treatment.

PURPOSE: Vancomycin (VCM) is used for the treatment of methicillin-resistant Staphylococcus aureus. Although the risk factors for VCM nephrotoxicity have been evaluated, the time course of renal function during VCM treatment is unknown. We assessed risk factors for VCM nephrotoxicity and how renal function varied over time. METHODS: We conducted a retrospective analysis of patients receiving intravenous VCM treatment between June 2015 and August 2017 at Tokyo Women's Medical University, Medical Center East. VCM nephrotoxicity was defined as an increase in serum creatinine levels > 50%. We performed multivariate logistic regression analysis to assess risk factors for VCM nephrotoxicity. The time course of renal function with VCM nephrotoxicity was compared and stratified by risk factors for VCM nephrotoxicity. Clinical course of VCM nephrotoxicity and VCM trough concentration were assessed. RESULTS: In total, 42 (17.3%) of 243 patients developed VCM nephrotoxicity. Risk factors for VCM nephrotoxicity were VCM trough concentration > 20 µg/mL and concomitant use of renal hypoperfusion medications (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, loop/thiazide diuretics, and non-steroidal anti-inflammatory drugs). Although time course of renal function stratified by renal hypoperfusion medications was comparable, the time course of renal function significantly deteriorated in patients with loop/thiazide diuretics. Focusing on patients continuing VCM treatment, VCM nephrotoxicity recovered in 40% of the patients and VCM trough concentration improved to 10-20 µg/mL in 75% of the patients. CONCLUSIONS: VCM trough concentration > 20 µg/mL and concomitant use of renal hypoperfusion medications are associated with VCM nephrotoxicity. Recovery of VCM nephrotoxicity was poor compared to the improvement of VCM trough concentration.

Do Thiazide Diuretics Increase the Risk of Skin Cancer? A Critical Review of the Scientific Evidence and Updated Meta-Analysis.

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.

[Inluence of osteoporosis and its causative factors on the prevention of recurrence of urinary stone disease].

INTRODUCTION: The aim of postoperative examination, treatment and follow-up of patients with urinary stone disease is a prevention of recurrence. A choice of method of prevention is based on the results of postoperative examination with consideration of etiological factors of urinary stone disease. An analysis of influence of osteoporosis and its causative factors on the recurrence of urinary stone disease is presented in the article. AIM: to clarify the influence of osteoporosis and its causative factors on excretion of calcium, uric acid and recurrence of urinary stone disease. MATERIALS AND METHODS: A total of 86 patients after surgical treatment of urinary stone disease were included in the study. A physicochemical analysis of stones and their fragments, excretion of calcium and uric acid were done postoperatively. The risk factors for osteoporosis were identified using specific questionnaire. Bone mineral density (BMD) was assessed by X-ray densitometry. After X-ray phasic analysis of the stones and studying of the daily excretion of calcium and uric acid, 10 and 7 patients were prescribed to thiazide diuretics and allopurinol, respectively. In 69 patients (80.2%) there were no indications to the treatment and all of them were included in control surveillance group. RESULTS: Calcium oxalate stones were predominated in patients who were under surveillance (=0,0254). A prevalence of risk factors for osteoporosis was similar in all groups (=0,2156), as well as rate of decrease in BMD (=0,64). In patients taking thiazide diuretics, a significant decrease in daily calcium excretion was found (=0,0054) without significant changes in excretion of uric acid and diuresis volume. Among patients receiving allopurinol there was a significant decrease in daily uric acid excretion (=0,021), without significant changes in excretion of calcium and diuresis volume. There were no significant changes of these values in the control group. A recurrence of urinary stone disease in treatment group was detected in 4 patients with a decrease of BMD after 381+/-61 days, while in control group there were 5 recurrences in patients with decreased BMD and I recurrence in patient with normal BMD after 836+/-64 days. CONCLUSION: Treatment aimed at prevention of recurrence of urinary stone disease allows to correct detected metabolic disturbances. However, such factor as the decrease in BMD can influence on the rate and frequency of recurrence of urinary stone disease. A clarifying of risk factors for osteoporosis and diagnosis of osteoporosis allow to give reliable recommendations for its treatment and to decrease risk of recurrence of urinary stone disease.

Thiazide diuretic usage and risk of fracture: a meta-analysis of cohort studies.

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.