1 Service de Néphrologie-Hémodialyse-Transplantation, Hôpital de la Conception, 2 Centre dInvestigation Clinique, Hôpital Sainte Marguerite and 3 Service de Médecine Nucléaire, Hôpital de la Timone, Marseille, France
Correspondence and offprint requests to: Professeur Bertrand Dussol, Service de Néphrologie-Hémodialyse-Transplantation, Hôpital de la Conception, 147 Bd Baille, 13385 Marseille Cedex 5, France. Email: bdussol{at}mail.ap-hm.fr
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Abstract |
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Methods. We compared the efficacy of long-acting furosemide (60 mg/day) and hydrochlorothiazide (25 mg/day) in a double-blind, randomized crossover trial in seven patients with severe renal failure and hypertension (seven men, 54±10 years old). The primary end-points were sodium and chloride fractional excretions after 1 month of each diuretic and then after their combination. During the trial, other treatments and the diet were controlled.
Results. A trend towards an increase in the fractional excretion of sodium and of chloride was observed with furosemide, but the difference did not reach the level of statistical significance (P = NS). Hydrochlorothiazide significantly increased fractional excretion of sodium and chloride from 3.7±0.9 to 5.5±0.3 and from 3.9±0.19 to 6.5±0.3, respectively (P<0.05). The combination of the two diuretics had no additional effect on the increase in sodium and chloride fractional excretion. Furosemide, hydrochlorothiazide and the combination of the two diuretics decreased mean arterial blood pressure by the same extent from 112 to 97, 99 and 97 mmHg, respectively (P<0.05).
Conclusions. Hydrochlorothiazide increased the fractional excretion of sodium and chloride more than furosemide did in hypertensive severe renal failure patients. Mean arterial blood pressure decreased by the same amount with both diuretics. Combining furosemide and hydrochlorothiazide did not increase the efficacy of hydrochlorothiazide.
Keywords: fractional excretion; furosemide; hydrochlorothiazide; hypertension; renal failure; sodium
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Introduction |
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For these reasons, diuretics are widely used in the management of hypertension in patients with chronic renal failure (CRF). In this setting, loop diuretics are the drugs of choice because they can increase the sodium fractional excretion by 20% and because they are efficient whatever the glomerular filtration rate (GFR) [4]. Conversely, thiazides are rarely used in patients with CRF because they lose their effectiveness if the GFR is lower than 40 ml/min.
The efficacy of loop diuretics may decrease with time because of the so-called braking phenomenon [5]. This phenomenon results from the adaptive changes in the distal nephron that are due to the chronically increased delivery of sodium in this segment [5]. These pathological and functional changes increase sodium reabsorption below Henle's loop [6,7]. Increased sodium reabsorption is even more pronounced in CRF patients in whom endogenous factors inhibit sodium reabsorption in proximal nephron segments so that a high sodium load is delivered to the distal tubule [4]. Another cause of resistance to loop diuretics is due to their short half-life. The compensatory increase in sodium reabsorption after the action of the diuretic has waned is called the rebound phase and may be sufficient to nullify the prior natriuresis [8].
While the general belief is that thiazides are not efficient in CRF, various authors have demonstrated that they are efficient in patients with low GFR [9,10]. Furthermore, the long-lasting action of thiazides precludes them from rebound antinatriuresis.
The purpose of the present study was to compare the fractional excretion of sodium and chloride following chronic administration of furosemide (FUR) and hydrochlorothiazide (HCTZ).
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Methods |
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Among the patients with Cockcroft clearances lower than 40 ml/min attending the clinics of the Nephrology Unit, seven were randomly recruited. They were under steady-state conditions and aged between 18 and 75 years (Table 1). Primary renal diseases were diabetes (n = 1), polycystic kidney (n = 2), nephroangiosclerosis (n = 3) and undetermined (n = 1). All patients had antihypertensive medications before the study, including ß-blockers (n = 5), angiotensin-converting enzyme (ACE) inhibitors (n = 5), angiotensin 1 (AT1) receptor inhibitors (n = 2), calcium channel blockers (n = 3), loop diuretics (n = 1) and vasodilatators (n = 1). No patients had recombinant human erythropoietin. All participants were Caucasians.
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We used a double-blind, randomized crossover trial. The scheme of the study is depicted in Figure 1. The study was preceded by a 2 month run-in period during which diuretics were withheld at least 1 month prior to the start of the study. Other antihypertensive agents were not washed out, but their dosage was kept unchanged throughout the study. Erythropoietin was not allowed during the study. Pills were prepared at the Central Pharmacy and were indistinguishable. The patients were allocated to the different treatment sequences by using random numbers.
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Dietary counselling by a nutritionist was given to all participants, who were advised to ingest a diet containing 70 mmol of NaCl (4 g) per day, 50 mmol of KCl per day and 0.8 g/kg protein per day. They were advised not to make any dietary changes during the study. At D0, D30, D60, D90, D120 and D150, patients were examined in a quiet environment. Weight, heart rate, blood pressure and adverse effects of treatments were recorded. Patients collected urine during the 24 h before measurement of urinary electrolytes. Blood tests were done for serum electrolytes and creatinine, and, on the same days, the GFR and renal plasma flow (RPF) were determined.
Measurements and calculations
Plasma and urine chemistry was analysed by enzymatic methods. GFR was assessed by DTPA clearance, and RPF by hippuran clearance. Replicate measurements of DTPA and hippuran clearances in the same individual showed a mean coefficient of variation of <5%. GFR was measured by using a clearance of 99m Technetium-DTPA, and RPF by using a clearance of [131I]hippuran (Elumatic III and Hippi-131, Shering Cis-Bio International, Gif sur Yvette, France).
Mean blood pressure was measured oscillometrically by an automatic blood pressure device (Dinamap, Critikon Co.). We considered the mean of five measures taken at 10 min intervals in the supine position.
Study end points
The primary end-points were the Na+ and Cl fractional excretions. The fractional excretions of sodium (FENa) and chloride (FECl) were calculated as the ratio between urinary Na+ or Cl excretion rates and filtered Na+ or Cl load.
Filtration fraction (FF) was the ratio between the GFR and RPF (%).
Statistical analysis
The SAS package was used for statistical analysis. The primary efficacy parameters were the differences in FENa and in FECl after diuretics. Data were analysed by the non-parametric Wilcoxon test for paired samples. Differences were considered statistically significant at a P level of 0.05.
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Results |
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Body weights and 24 h diuresis were stable throughout the study (Table 3). No patients had adverse effects with FUR or HCTZ. With the combined regimen, two patients complained of asthenia and polyuria, and one of muscular cramps.
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No differences were observed for 24 h urinary urea. Twenty four hour proteinuria significantly decreased with FUR, HCTZ and the combined regimen.
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Discussion |
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In contrast, FUR did not significantly increase FENa and FECl. This unexpected result may be explained by the negative impact of both the rebound and the braking phenomena on the efficacy of the drug [8]. Because of the design of the study, it was not possible to determine the exact cause of the effectiveness of FUR. To determine if effectiveness was due to rebound and/or to brake effects, we should have performed repeated time-controlled urine collections. The alternative explanation is a type 2 statistical error (power defect) due to the low number of patients. To discard a type 2 statistical error, we should have included many more patients, but this was beyond our goal. We considered this study as a pilot preliminary study useful to determine the number of patients needed in further studies seeking to show a statistical difference between the two treatments.
The pharmacodynamics of diuretics and the physiology of sodium reabsorption in CRF make the results of our study not so unexpected. On the one hand, the real efficacy of thiazides in CRF, their long half-life of action and the increased delivery of sodium to the distal tubule in CRF easily explain the increase in FENa and FECl with HCTZ. On the other hand, the braking and the rebound phenomena may account for the loss of efficacy of FUR. We used a long-acting form of FUR but, even with this form, the half-life is not long enough to prevent the rebound phenomenon.
The combined regimen (FUR + HCTZ) was not more potent than HCTZ alone for increasing FENa and FECl. The effectiveness of the combination is speculative, but one can imagine that if furosemide alone is ineffective in increasing sodium chloride excretion, to combine it with any other diuretics would not increase its efficacy.
Mean arterial blood pressure was similarly decreased by the two diuretics. The mechanism of the hypotensive effect of the drugs seems to be different. FUR acts mainly on blood pressure by decreasing peripheral vascular resistance while blood volume depletion seems marginal [11]. HCTZ, in contrast, by increasing FENa and FECl, decreases mainly blood volume, as evidenced by the significant decrease in RPF. It has already been shown that the hypotensive effect of thiazides relies on their ability to induce negative sodium balance [12].
We did not have clear-cut explanations for the stable potassium levels in spite of the increase in fractional excretion of sodium. It is possible that the transtubular potassium gradient in the cortical collecting duct was low because of low availability of aldosterone in severe renal failure.
The decrease in proteinuria may be explained both by the decrease in GFR under diuretic treatments and by some changes in the renal microcirculation induced by prostaglandins or other vasoactive peptides.
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Acknowledgments |
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Conflict of interest statement. None declared.
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References |
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