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BACKGROUND AND OBJECTIVE: Thiazide diuretics are first-line drugs for the treatment of hypertension, but hypertension treatment guidelines have systematically discouraged their use in patients with advanced chronic kidney disease (CKD). For the first time, a systematic review and random-effects meta-analysis were performed to assess the effectiveness of thiazides and thiazide-like diuretics to treat hypertension in patients with stages 3b, 4, and 5 CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A systematic review and random-effects meta-analysis that included a literature search using the following databases were performed: MEDLINE through PubMed, Cochrane Database of Systematic Reviews (CDSR) and Cochrane Central Register of Controlled Trials (CENTRAL) through the Cochrane Library, Embase, and ISI - Web of Science (all databases). Prospective studies that evaluated the effectiveness of thiazide and thiazide-like diuretics in individuals with a GFR < 45 mL/min/1.73 m2 were included. RESULTS: Five clinical trials, totaling 214 participants, were included, and the mean GFR ranged from 13.0 ± 5.9 mL/min/1.73 m2 to 26.8 ± 8.8 mL/min/1.73 m2. There was evidence of a reduction in mean blood pressure and in GFR, as well as in fractional sodium excretion and fractional chloride excretion. CONCLUSION: Thiazide and thiazide-like diuretics seem to maintain their effectiveness in lowering blood pressure in patients with advanced chronic kidney disease. These findings should spur new prospective randomized trials and spark discussions, particularly about upcoming hypertension guidelines.

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BACKGROUND: Hypercalciuria is the most common metabolic risk factor for calcium urolithiasis and is associated with bone loss in adult patients. Reduced bone mineral density (BMD) was already described in idiopathic hypercalciuria (IH) children, but the precise mechanisms of bone loss or inadequate bone mass gain remain unknown. Life-long hypercalciuria might be considered a risk to change bone structure and determine low bone mass throughout life. The peak of bone mass should occur without interferences. A beneficial effect of citrate formulations and thiazides on bone mass in adult and pediatric patients with IH have been shown. AIM: To evaluate whether pharmacological therapy has a beneficial effect on bone mass in children and adolescents with IH. METHODS: This retrospective cohort study evaluated 40 hypercalciuric children non-responsive to lifestyle and diet changes. After a 2-mo run-in period of citrate formulation (Kcitrate) usage, the first bone densitometry (DXA) was ordered. In patients with sustained hypercalciuria, a thiazide diuretic was prescribed. The second DXA was performed after 12 mo. Bone densitometry was performed by DXA at lumbar spine (L2-L4). A 24-h urine (calcium, citrate, creatinine) and blood samples (urea, creatinine, uric acid, calcium, phosphorus, magnesium, chloride, hemoglobin) were obtained. Clinical data included age, gender, weight, height and body mass index. RESULTS: Forty IH children; median age 10.5 year and median time follow-up 6.0 year were evaluated. Nine patients were treated with Kcitrate (G1) and 31 with Kcitrate + thiazide (G2). There were no differences in age, gender, body mass index z-score and biochemical parameters between G1 and G2. There were no increases in total cholesterol, kalemia and magnesemia. Calciuria decreased in both groups after treatment. Lumbar spine BMD z-score increased after thiazide treatment in G2. There was no improvement in G1. CONCLUSION: Results point to a beneficial effect of thiazide on lumbar spine BMD z-score in children with IH. Further studies are necessary to confirm the results of the present study.

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BACKGROUND: Thiazide diuretics have demonstrated favorable blood pressure lowering efficacy, but the equivalent doses of their more common agents, chlorthalidone and hydrochlorothiazide, are still unclear. Further, concerns exist regarding adverse metabolic effects, which may be attenuated with the concomitant administration of a potassium-sparing diuretic, such as amiloride. This trial aims to investigate the efficacy of chlorthalidone and hydrochlorothiazide, in combination with amiloride at different doses, for initial management of patients with primary hypertension. METHODS/DESIGN: This is a factorial (2 × 2) randomized double-blinded clinical trial comparing the association of a thiazide diuretic (chlorthalidone 25 mg/day or hydrochlorothiazide 50 mg/day) with a potassium-sparing diuretic (amiloride 10 mg/day or amiloride 20 mg/day) in patients with primary hypertension. The primary outcome will be the mean change from baseline in 24-h systolic and diastolic blood pressure measured by ambulatory blood pressure monitoring. The secondary outcomes will be the mean change from baseline in daytime and nighttime systolic and diastolic blood pressure measured by ambulatory blood pressure monitoring, mean change from baseline in systolic and diastolic blood pressure measured by office blood pressure, incidence of adverse events, variation of laboratory parameters, and proportion of patients who achieved blood pressure control. The follow-up will last 12 weeks. For a P alpha of 0.05, power of 80%, standard deviation of 9 mmHg, and absolute difference of 6 mmHg on systolic blood pressure on 24-h ambulatory blood pressure monitoring, it will be necessary to study a total of 76 patients. The sample size will be increased by 10% to compensate for losses, resulting in 84 patients being randomized. DISCUSSION: Diuretics are pivotal drugs for the treatment of hypertension. Chlorthalidone and hydrochlorothiazide, in combination with amiloride in multiple doses, will be tested in terms of blood pressure lowering efficacy and safety. Since the intensity of blood pressure reduction is the major determinant of reduction in cardiovascular risk in hypertensive patients, this study will help to determine which combination of diuretics represents the most appropriate treatment for this population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03928145. Registered on 25 April 2019. Last update on 29 April 2019.

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The thiazide-sensitive Na+-Cl- cotransporter (NCC) is the major pathway for salt reabsorption in the distal convoluted tubule, serves as a receptor for thiazide-type diuretics, and is involved in inherited diseases associated with abnormal blood pressure. The functional and structural characterization of NCC from different species has led us to gain insights into the structure-function relationships of the cotransporter. Here we present an overview of different studies that had described these properties. Additionally, we report the cloning and characterization of the NCC from the spiny dogfish (Squalus acanthias) kidney (sNCC). The purpose of the present study was to determine the main functional, pharmacological and regulatory properties of sNCC to make a direct comparison with other NCC orthologous. The sNCC cRNA encodes a 1033 amino acid membrane protein, when expressed in Xenopus oocytes, functions as a thiazide-sensitive Na-Cl cotransporter with NCC regulation and thiazide-inhibition properties similar to mammals, rather than to teleosts. However, the Km values for ion transport kinetics are significantly higher than those observed in the mammal species. In summary, we present a review on NCC structure-function relationships with the addition of the sNCC information in order to enrich the NCC cotransporter knowledge.

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We have previously shown that an association of losartan and hydrochlorothiazide, initiated 1 mo after 5/6 nephrectomy (Nx), reversed hypertension and albuminuria and promoted lasting renoprotection. In this new study, we investigated whether equal or even better protection could be obtained by combining losartan and furosemide. Nx was performed in 58 Munich-Wistar rats. One month later, tail-cuff pressure and albuminuria were markedly elevated. At this time, Nx rats were distributed among the following four groups: untreated Nx rats, Nx rats that received losartan, Nx rats that received losartan + hydrochlorothiazide, and Nx rats that received losartan + furosemide. Seven months later, Nx rats exhibited high mortality, severe hypertension, albuminuria, glomerulosclerosis, and interstitial fibrosis. Losartan treatment limited mortality and attenuated the renal and hemodynamic abnormalities associated with Nx. As previously shown, the losartan + hydrochlorothiazide association normalized tail-cuff pressure and albumin, prevented renal injury, and reduced mortality to zero. The losartan + furosemide treatment failed to reduce tail-cuff pressure or albumin to normal and prevented renal injury less efficiently than the losartan and hydrochlorothiazide regimen. The reasons for the differing efficacies of the losartan + furosemide and losartan + hydrochlorothiazide schemes are unclear and may include beneficial nondiuretic actions of thiazides, such as vasorelaxation and antiproliferative activity. These results refute the established concept that thiazides and thiazide-like diuretics are ineffective at advanced chronic kidney disease stages. Rather, they suggest that, in view of their renoprotective action, these compounds may even be preferable to loop diuretics in the management of hypertension in advanced chronic kidney disease.

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Background: Decreased bone mineral density and increased prevalence of bone fractures have been found in patients with idiopathic hypercalciuria. It is not yet clear if thiazide treatment prevent these events. Methods: We retrospectively evaluated bone mass and biochemical markers of bone turnover in response to thiazide therapy in 52 consecutive female patients with idiopathic hypercalciuria and nephrolithiasis. Patients were divided in two subgroups according to their menopausal status: 25 were pre-menopausal (Group I) and 27 were postmenopausal (Group II). Results: Osteoporosis was found in 12 patients at baseline, 9 at the lumbar spine and 6 at the femoral neck. Two were pre-menopausal and 10 were postmenopausal. Patients with osteoporosis were analyzed separately (Group III). There was a significant and persistent reduction in urinary calcium with preservation of bone mass in all the groups after a median follow-up of 51 months. Few adverse effects were found using low doses of hydrochlorothiazide / amiloride. Only in the group III we found a statistcally significant an increase in BMD at the lumbar spine of 9.5% and an increase in BMD at femoral neck of 4.4% that did not reach statistical significance. Conclusions: We conclude that correction of hypercalciuria during long term treatment with low-dose hydrochlorothiazide//amiloride in women with nephrolithiasis prevents bone loss and in those with osteoporosis can lead to a significant increase in bone mineral density at the lumbar spine. Few adverse effects were seen during treatment and no interruption of therapy was necessary.(AU)

Introducción: Reducción de la densidad mineral ósea y aumento de la prevalencia de fracturas óseas se han encontrado en pacientes con hipercalciuria idiopática. Aún no está claro si el tratamiento con tiazidas prevenir estos eventos. Métodos: Evaluamos retrospectivamente la masa ósea y los marcadores bioquímicos de recambio óseo en respuesta a la terapia con tiazidas en 52 pacientes femeninos consecutivos con hipercalciuria idiopática y nefrolitiasis. Los pacientes fueron divididos en dos subgrupos de acuerdo a su estado de la menopausia : 25 fueron pre-menopáusicas (Grupo I) y 27 eran posmenopáusicas (Grupo II). Resultados: La osteoporosis se encontró en 12 pacientes al inicio del estudio, 9 en la columna lumbar y 6 en el cuello femoral. Dos eran premenopáusicas y 10 eran posmenopáusicas. Los pacientes con osteoporosis se analizaron por separado (Grupo III). Hubo una reducción significativa y persistente en el calcio urinario con la preservación de la masa ósea en todos los grupos después de una mediana de seguimiento de 51 meses. Pocos efectos adversos se encuentran utilizando dosis bajasde hidroclorotiazida / amilorida. Sólo en el grupo III encontramos un aumento estadísticamente significativo en la DMO de la columna lumbar del 9,5% y un aumento de la densidad mineral ósea en el cuello femoral de 4,4% que no alcanzó significación estadística. Conclusión: Llegamos a la conclusión de que la corrección de la hipercalciuria durante el tratamiento a largo plazo con dosis bajas de hidroclorotiazida / / amilorida en mujeres con nefrolitiasis previene la pérdida ósea y en aquellos con osteoporosis puede conducir a un aumento significativo en la densidad mineral ósea en la columna lumbar. Pocos se observaron efectos adversos durante el tratamiento y no hay interrupción de la terapia era necesario.(AU)

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Background: Decreased bone mineral density and increased prevalence of bone fractures have been found in patients with idiopathic hypercalciuria. It is not yet clear if thiazide treatment prevent these events. Methods: We retrospectively evaluated bone mass and biochemical markers of bone turnover in response to thiazide therapy in 52 consecutive female patients with idiopathic hypercalciuria and nephrolithiasis. Patients were divided in two subgroups according to their menopausal status: 25 were pre-menopausal (Group I) and 27 were postmenopausal (Group II). Results: Osteoporosis was found in 12 patients at baseline, 9 at the lumbar spine and 6 at the femoral neck. Two were pre-menopausal and 10 were postmenopausal. Patients with osteoporosis were analyzed separately (Group III). There was a significant and persistent reduction in urinary calcium with preservation of bone mass in all the groups after a median follow-up of 51 months. Few adverse effects were found using low doses of hydrochlorothiazide / amiloride. Only in the group III we found a statistcally significant an increase in BMD at the lumbar spine of 9.5% and an increase in BMD at femoral neck of 4.4% that did not reach statistical significance. Conclusions: We conclude that correction of hypercalciuria during long term treatment with low-dose hydrochlorothiazide//amiloride in women with nephrolithiasis prevents bone loss and in those with osteoporosis can lead to a significant increase in bone mineral density at the lumbar spine. Few adverse effects were seen during treatment and no interruption of therapy was necessary.

Introducción: Reducción de la densidad mineral ósea y aumento de la prevalencia de fracturas óseas se han encontrado en pacientes con hipercalciuria idiopática. Aún no está claro si el tratamiento con tiazidas prevenir estos eventos. Métodos: Evaluamos retrospectivamente la masa ósea y los marcadores bioquímicos de recambio óseo en respuesta a la terapia con tiazidas en 52 pacientes femeninos consecutivos con hipercalciuria idiopática y nefrolitiasis. Los pacientes fueron divididos en dos subgrupos de acuerdo a su estado de la menopausia : 25 fueron pre-menopáusicas (Grupo I) y 27 eran posmenopáusicas (Grupo II). Resultados: La osteoporosis se encontró en 12 pacientes al inicio del estudio, 9 en la columna lumbar y 6 en el cuello femoral. Dos eran premenopáusicas y 10 eran posmenopáusicas. Los pacientes con osteoporosis se analizaron por separado (Grupo III). Hubo una reducción significativa y persistente en el calcio urinario con la preservación de la masa ósea en todos los grupos después de una mediana de seguimiento de 51 meses. Pocos efectos adversos se encuentran utilizando dosis bajasde hidroclorotiazida / amilorida. Sólo en el grupo III encontramos un aumento estadísticamente significativo en la DMO de la columna lumbar del 9,5% y un aumento de la densidad mineral ósea en el cuello femoral de 4,4% que no alcanzó significación estadística. Conclusión: Llegamos a la conclusión de que la corrección de la hipercalciuria durante el tratamiento a largo plazo con dosis bajas de hidroclorotiazida / / amilorida en mujeres con nefrolitiasis previene la pérdida ósea y en aquellos con osteoporosis puede conducir a un aumento significativo en la densidad mineral ósea en la columna lumbar. Pocos se observaron efectos adversos durante el tratamiento y no hay interrupción de la terapia era necesario.

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