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Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

Furosemide is the diuretic of choice for the treatment of hypertension in chronic kidney disease but the adaptative changes in the distal nephron may decrease its efficacy. Hydrochlorothiazide is not believed to be efficient in this setting. In a randomized, double-blind, cross-over trial, 23 patients with hypertension and stage 4 or 5 chronic kidney disease received long-acting furosemide (60 mg) and hydrochlorothiazide (25 mg) for 3 months and then both diuretics for 3 months. Sodium and chloride fractional excretions were measured after 3 months of each diuretic and then after their association. A trend towards an increase in the fractional excretion of sodium and chloride was observed with furosemide and hydrochlorothiazide (P=not significant). The association of the two diuretics increased the fractional excretions of sodium and chloride from 3.4±1.8 to 4.9±2.8 and from 3.8±2.0 to 6.0±3.1, respectively (P<.05). Furosemide and hydrochlorothiazide decreased mean blood pressure by the same extent. The association of the two diuretics was more efficient on blood pressure. There were no differences between furosemide and hydrochlorothiazide with respect to natriuresis and blood pressure control in patients with hypertension and chronic kidney disease.

Arterial hypertension is a leading factor for progression to kidney failure in patients with chronic kidney disease (CKD).1 The main mechanism involved in the pathophysiology of hypertension in CKD is the expansion of extracellular fluid because of the decreased capacity of the kidneys to excrete sodium.2 Thus, diuretics are widely used in the management of hypertension in patients with CKD.

Loop diuretics such as furosemide are considered the diuretics of choice in CKD because they can increase the sodium fractional excretion by 20% and because they are efficient regardless of the glomerular filtration rate (GFR). Their efficacy may decrease with time, however, because of the “rebound phase” due to their short half-life and because of the “braking phenomenon.”3–6 The rebound phase is the compensatory increase in sodium reabsorption after the action of the diuretic has waned.3,4 The braking phenomenon results from adaptative changes in the distal nephron due to the chronically increased delivery of sodium in this segment.5,6

Conversely, thiazides such as hydrochlorothiazide (HCTZ) are rarely used in patients with CKD because they can increase sodium fractional excretion by only 5% to 10%.7 Some authors believe thiazides lose their effectiveness as soon as the GFR ranges below 30 mL/min,8,9 and this notion has been widely accepted, but we and other authors have demonstrated in short-term and experimental studies that the natriuretic effect of thiazides is preserved in patients with low GFR.10–14

The purpose of this pilot study was to compare in usual clinical practice the fractional excretion of sodium and chloride after chronic administration of furosemide and HCTZ in hypertensive patients with stage 4 and 5 CKD.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

Study Population

The study protocol was approved by the local ethics committee. All patients gave written informed consent. Study participants were recruited from the Centre de Néphrologie in a University Hospital of Marseille, France. Patients were at least 18 years of age, had hypertension (blood pressure [BP] >130/80 mm Hg or antihypertensive treatments), and had stage 4 or 5 CKD evaluated by the 6-component Modified Diet in Renal Disease formula.15 They were under steady-state conditions, defined as a lack of clinical event during the past 4 months. A clinical event was defined as a >15% increase in serum creatinine or any cardiovascular event.

Exclusion criteria were uncontrolled hypertension, symptomatic congestive heart failure, obvious extracellular overhydration, cirrhosis, urinary tract obstruction, and allergy to sulfa drugs. Thirty patients, all Caucasians, were screened for participation but 23 were included in the study because 3 refused to participate and 4 could not stop diuretics during the run-in period. Baseline demographic and clinical characteristics are shown in Table I. All patients were taking antihypertensive medications before the study. Fifteen patients took furosemide (20–60 mg/d), 2 took HCTZ (12.5–25 mg/d), 5 ramipril (5–15 mg/d), 7 enalapril (10–30 mg/d), 5 losartan (100–200 mg/d), 3 irbesartan (150–300 mg/d), 10 atenolol (50–100 mg/d), 2 bisoprolol (5–10 mg/d), 6 amlodipine (5–10 mg/d), 3 prazosine (5–10 mg/d), and 1 clonidine (0.15 mg/d). Six patients took recombinant human erythropoietin.

Table I.   Clinical Data of the Patients at Entry in the Study
  1. Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers; BMI, body mass index; FE, fractional excretion; FF, filtration fraction; GFR, glomerular filtration rate; MDRD, Modification of Diet in Renal Diseases; RPF, renal plasma flow; RVR, renal vascular resistance.

Sex (men/women)16/7
Age, y62±13
Causes of chronic kidney diseaseChronic glomerulonephritis (n=5)
Diabetic nephropathy (n=5)
Polycystic kidney disease (n=4)
Hypertension (n=3)
Ischemic nephropathy (n=2)
Interstitial nephritis (n=1)
Undetermined (n=3)
Weight, kg76±19
BMI, kg/m227±5
Mean blood pressure, mm Hg101±13
Antihypertensive medications, No.2.5±1.3
Antihypertensive class, No.Diuretics n=17
ACE inhibitors or ARB n=20
β-blockers n=12
Calcium channel blockers n=6
Other n=4
Diabetes mellitus, No.7
Estimated GFR by MDRD, mL/min24.6±13
Cockcroft and Gault, mL/min/1.73 m226.7±15
GFR, mL/min/1.73 m225±10
RPF, mL/min/1.73 m295±35
RVR, mm Hg/mL/min/1.73 m22.0±1.0
FF, %27±8
FE Na+, %3.4±1.8
FE Cl, %3.8±2.0

Study Design

The design was a randomized, fixed-dose, double-blind, single-center, cross-over trial. The scheme of the study is depicted in Figure. All participants were studied under outpatient conditions. 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 and nonsteroidal anti-inflammatory drugs were prohibited.

image

Figure FIGURE.  Scheme of the study. The study was double-blinded until day 240 (D240) and then opened from D240 until day 330 (D330). After a run-in period of 2 months (from day 60 [D60] to day 0 [D0]), patients were randomized to receive either long-acting furosemide (FUR) (60 mg) or hydrochlorothiazide (HCTZ) (25 mg) for 3 months (until day 90 [D90]). After a 1-month washout (day 120 [D120]), patients received the other diuretic for 3 months (until day 210 [D210]). After a second washout period of 1 month (D240), patients received the combined regimen (both diuretics) for 3 months (D330). The fractional excretions of sodium and chloride and the renal parameters were determined at D0, D90, D210, and D330.

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Pills were prepared at the Central Pharmacy of the Assistance Publique and were undistinguishable. Long-acting furosemide has a 3-hour half-life and is specifically indicated for hypertension according to the manufacturer.

The patients were allocated to the different treatment sequences by using random numbers. At day 0 (D0), the patients were randomized to start either long-acting furosemide 60 mg once a day or HCTZ 25 mg once a day for 3 months (until day 90 [D90]). These doses were chosen because they are those recommended (and usually given in European countries) by the French Society of Arterial Hypertension. A 30-day washout period until day 120 [D120] preceded the second sequence, during which patients had furosemide or HCTZ for 3 months (until day 210 [D210]). The double-blind phase of the study ended at D210. After a second washout period until day 240 (D240), patients had, during an open phase, both diuretics (combined regimen) for 3 months (until day 330 [D330]). Compliance with treatments was monitored during the protocol by telephone calls.

Dietary counseling by a nutritionist was given to all participants, who were advised to consume a diet containing 70 mmol of sodium chloride (4 g), 50 mmol of potassium chloride, and 0.8 g/kg of protein per day. They were advised not to make any dietary changes during the study. Patients were thoroughly instructed on how to collect a 24-hour urine sample in order to assess electrolytes and urea excretion.

At D60, D0, D90, D120, D210, D240, and D330, patients were examined in the Centre d’Investigation Clinique. Weight, heart rate, BP, and adverse effects of treatments were collected. Patients collected their urine during the 24 hours before measurement of urinary sodium, chloride, potassium, urea, protein, and volume. Blood tests were performed for serum electrolytes, urea, creatinine, uric acid, hemoglobin, calcium, phosphorus, and proteins. On the same days, GFR and renal plasma flow (RPF) were determined.

Measurements and Calculations

Plasma and urine chemistry was analyzed by enzymatic methods with spectrophotometric readings on a Hitachi 747 Analyzer (Roche-Boehringer, Mannheim, Germany). GFR was assessed by 99m Technetium (Tc) diethylenetriamine pentaacetate (DTPA) clearance and RPF by 131I-hippuran clearance (Elumatic III and Hippi-131; Shering Cis-Bio International, Gif sur Yvette, France). Replicate measurements of DTPA and hippuran clearances in individuals showed a mean coefficient of variation of <5%. Patients were hydrated orally (10 mL/kg). The labeled compounds were injected as a bolus of 3.7 MBq of 99m Tc-DTPA and 0.3 MBq of 131I-hippuran. To calculate the extraction fraction of 131I-hippuran, peripheric venous blood and urine were sampled every 30 minutes for 3 hours after a period of 1 hour to avoid any washout effect. Plasma and urinary radioactivity of 99mTc-DTPA and 131I-hippuran were measured with an automatic gamma scintillation spectrometer. GFR and RPF were calculated using the following equations:

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Results were expressed in mL/min/1.73 m2.

Mean BP was measured oscillometrically by an automatic BP device (Dinamap; GE Healthcare, Waukesha, WI). We considered the mean of 5 measures taken at 10-minute intervals with the patient in a supine position.

Study End Points

The primary end points were 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:

  • image
  • image

Filtration fraction (FF) was the ratio between GFR and RPF (%). Renal vascular resistance (RVR) was calculated as the ratio between mean arterial BP and RPF:

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Statistical Analysis

The SAS package (SAS Institute Inc, Cary, NC) was used for statistical analysis. The primary efficacy parameters were the differences in FENa+ and in FECl after diuretics. Because each patient was his or her own control, data were analyzed by the nonparametric Wilcoxon test for paired samples. Differences were assumed to be significant at a P level of .05.

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

All the patients completed the first two parts of the study (furosemide then HCTZ or HCTZ then furosemide), but 7 patients had to stop the combined regimen because of low BP and prerenal acute renal failure. The main results are shown in Table II. A nonsignificant increase in the fractional excretions of sodium and of chloride was observed after 3 months of furosemide and of HCTZ. Conversely, the combined regimen significantly increased the fractional excretion of sodium from 3.4±1.8 to 4.9±2.8 and of chloride from 3.8±2.0 to 6.0±3.1 (P<.05). Mean BP decreased by the same extent after furosemide and HCTZ from 101 mm Hg to 93/94 mm Hg, respectively (P<.05). The combined regimen was more effective, with mean BP decreasing to 86 mm Hg (P<.01).

Table II.   Fractional Excretions of Sodium and Chloride and Renal Parameters During the Study
 Basal StateFURHCTZCombined Regimen (FUR + HCTZ)a
  1. Abbreviations: FECl, fractional excretion of chloride; FE Na, fractional excretion of sodium; FF, filtration fraction; FUR, furosemide; GFR, glomerular filtration rate; HCTZ, hydrochlorothiazide; RPF, renal plasma flow; RVR, renal vascular resistance. aOnly 16 patients were included in the analysis. bP<.05 vs basal. cP<.01 vs basal.

FE Na+3.4±1.84.4±2.23.9±2.44.9±2.8b
FE Cl3.8±2.05.1±2.94.6±2.56.0±3.1b
Mean blood pressure, mm Hg101±1393±9b94±7b86±13c
GFR, mL/min/1.73 m225±1021±1022±1018±11c
RPF, mL/min/1.73 m295±3596±3194±3685±41
RVR, mm Hg/mL/min/1.73 m22.0±1.01.7±0.81.9±1.11.8±1.0
FF, %27±822±6b23±7b20±6c

Furosemide and HCTZ decreased the GFR by the same extent from 25±10 to 21±10 mL/min/1.73 m2 and to 22±10 mL/min/1.73 m2, respectively, but the decrease was not significant. The combined regimen significantly decreased GFR to 18 mL/min/1.73 m2 (P<.01). RPF and RVRs were stable with the 3 diuretic regimens. FF decreased significantly with furosemide and HCTZ from 27% to 22% and 23%, respectively (P<.05). The combined regimen decreased FF more, to 20% (P<.01).

No patients had adverse effects with furosemide or HCTZ. With the combined regimen, 7 patients complained of hypotension, asthenia, and polyuria. They had to stop the study and were not included in the analysis. Body weights significantly decreased with furosemide and the combined regimen, while 24-hour diuresis was stable all along the study (Table III).

Table III.   Serum and Urine Parameters During the Study
 Basal StateFURHCTZCombined Regimen (FUR + HCTZ)
  1. Abbreviations: FECl, fractional excretion of chloride; FENa+, fractional excretion of sodium; FUR, furosemide; HCTZ, hydrochlorothiazide. aP<.05 vs basal. bP<.01 vs basal.

Weight, kg76±1972±19a74±1973±20a
24-h diuresis, mL1700±7001800±4001800±6001700±600
Serum Na+, mmol/L141±3140±3139±4138±3
Serum K+, mmol/L4.9±0.74.5±0.7a4.4±1.2a4.1±0.5b
Serum Cl, mmol/L106±3102±4104±5102±4
Serum HCO3, mmol/L24±326±324±325±3
Serum urea, mg/dL100±33132±51b120±48a157±72b
Serum creatinine, mg/dL2.8±0.93.25±1.2b3.02±1.0a3.60±1.32b
Serum uric acid, mg/dL7.1±1.79.0±2.5b8.1±2.1a8.3±3.2a
Serum glucose, mg/dL107±47123±60121±63105±28
24-h urinary urea, g17±517±417±616±7
24-h urinary Na+, mmol108±47117±51115±65111±61
24-h urinary K+, mmol53±3049±2052±2650±27
24-h urinary protein, mg1015±808758±623689±654608±641a

No major alterations of serum electrolytes were observed. Serum sodium, chloride, and bicarbonates stayed in the normal range. A significant decrease in serum potassium was observed with the 3 diuretic regimens (P<.05); the lower value was with the combined regimen. Serum urea, creatinine, and uric acid significantly increased with the 3 diuretic regimens (P<.05). The increase was more pronounced with furosemide and the combined regimen (P<.01 vs basal; Table III). Glycemia did not increase significantly and lipids (not shown) were stable.

No differences were observed in 24-hour urinary urea: 24-hour proteinuria significantly decreased only with the combined regimen, from 1015 mg/d to 608 mg/d (P<.05 vs basal).

Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

The main results of this pilot study in patients with hypertension and stage 4 or 5 CKD include the following: (1) the natriuretic response to standard dose of furosemide and hydrochlorothiazide is similar, (2) the antihypertensive response to each drug is also similar, and (3) the combination of furosemide and hydrochlorothiazide has an additive effect on natriuresis and BP.

No study has so far compared the efficacy of furosemide and HCTZ in patients with hypertension and stage 4 or 5 CKD in usual clinical practice. Our trial demonstrated that furosemide and HCTZ had similar natriuretic and BP effects when administered in a randomized and blinded design. The nonsignificant increase in fractional excretions of sodium and chloride after 3 months of each drug may be explained either by a type 2 statistical error (power defect) due to the low number of patients or by a new sodium chloride balance at a lower level of extracellular volume. The latter explanation is more likely because all of the patients had obvious clinical and biological features of decreased blood volume. In fact, with the 2 drugs, BP was significantly lower than at baseline and the increase in serum urea, creatinine, and uric acid reflected the contraction of blood volume. Thus, the natriuretic effect of a standard dose of furosemide and HCTZ is confirmed in patients with stage 4 or 5 CKD.

This result challenged two old beliefs. The first is the lack of efficacy of thiazides in patients with GFR <30 mL/min. This notion is based on a small study that showed a poor natriuretic effect of chlorothiazide in 2 patients with extremely low GFR (11 mL/min and 6 mL/min).8 Since this study, it has been believed that thiazides are ineffective in patients with low GFR.16,17 Yet a German group, in 3 experimental short-term studies, showed that different thiazides (bemetizide, hydrochlorothiazide, and xipamide) induced a natriuretic effect, even in patients with end-stage renal disease, and had the linear relationship for salt excretion and GFR similar to loop diuretics.11–13 Our study confirms the efficacy of HCTZ under usual clinical practice, ie, long-term administration of a standard dose of the drug. In a short-term (1 month) small study, we demonstrated the efficacy of HCTZ in 7 stage 4 CKD patients.10

Thiazide diuretics are “low-ceiling” diuretics since they act under normal circumstances in the distal tubule, where only small amounts of sodium and chloride are delivered.16,17 But if sodium delivery is increased in this part of the nephron, thiazides may be very effective. This is the case in severe renal failure, in which fractional natriuresis is increased to as much as 8% due to the so-called magnification phenomenon.18–20 The mechanisms responsible for this phenomenon are not completely elucidated. It is thought that poorly defined endogenous forces are responsible for the decreased sodium reabsorption.18

The second belief is the possible loss of efficacy of furosemide due to the rebound and braking phenomena when this drug is chronically administered. We did not observe the rebound phenomenon, since once-a-day administration of a long-acting furosemide induced a negative sodium chloride balance. In the same way, we did not observe the braking phenomenon; the natriuretic effect of furosemide did not wane after 3 months of treatment. The adaptative changes of the distal tubule that could account for the braking phenomenon were evidenced in rats, and the implication of this adaptation in humans is not established.21,22

A combined regimen (furosemide + HCTZ) was more potent than HCTZ or furosemide alone for increasing the fractional excretions of sodium and chloride. This result is in keeping with previous studies showing an increased efficacy of the coadministration of loop diuretics and thiazides over loop diuretics alone in patients with moderate reduction of GFR23,24 and with stage 4 or 5 CKD.25 These studies evaluated the short-term natriuretic response to a coadministration of loop diuretics and thiazides. Our study shows that long-term administration of both loop diuretics and thiazides perpetuates the strong natriuretic response.

Mean BP was similarly decreased by furosemide and HCTZ. It seems that the hypotensive effect of the 2 drugs would be the same, ie, a reduction of the extracellular volume, which is the main factor increasing BP in CKD patients.2 RVR did not decrease under diuretic treatment, underlining the role of volume depletion rather than decreased systemic vascular resistances.

As expected, the 2 diuretics decreased GFR while RPF remained stable, leading to a drop in FF. FF reflects glomerular-capillary hydraulic pressure.26 In an experimental model of renal mass reduction, the remaining nephrons undergo hypertrophy and increased glomerular-capillary hydraulic pressure that results in deteriorated renal function.27 The decrease in 24-hour proteinuria is likely the consequence of the diuretic-induced decrease in glomerular-capillary hydraulic pressure.

Study Limitations

Because this was a pilot study, we did not calculate a sample size. So we could not affirm the bioequivalence of the 2 diuretics in stage 4 and 5 CKD patients. According to our results, with the same cross-over design, 156 patients should be included to test the bioequivalence of the 2 diuretics, assuming a true difference of −0.5% and limits of equivalence between −1.5% and +1.5% (risk α 5% and β 90%).

Clinical Implications

In spite of this limitation, we believe that our results may be useful in managing hypertensive CKD patients. In fluid-overloaded patients, either loop diuretics or thiazides can be used. In contrast to loop diuretics, thiazides have pharmacodynamic features that make them safe in long-term treatment. They prevent calcium loss and, by maintaining the tubuloglomerular balance, they impede rapid volume depletion.28,29 Thiazides, however, are potassium-wasting, but in CKD patients this turns into an advantage because these patients are often hyperkalemic due to low GFR and the concomitant use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.30 Furthermore, thiazides do not induce blunt diuresis, so they prevent polyuria.16 In this study, these pharmacodynamic advantages were not evidenced and further studies are necessary to compare the long-term tolerance of thiazides and loop diuretics.

Conclusions

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

Coadministration of a loop diuretic with a thiazide diuretic should be restricted to CKD patients unresponsive to monotherapy. These patients often have a high risk of sodium retention because of congestive heart failure, acute glomerulonephritis, diabetic nephropathy, or ischemic nephropathy with bilateral renal artery stenosis. Clinicians should use this combination therapy in a carefully controlled setting because of its side effects, ie, hypokalemia or low BP. Because of hypotension, 30% of our patients could not tolerate the combined regimen.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

Acknowledgments and disclosures:  The results presented in this paper have not been published previously in whole or in part, except in abstract form (Congress of the American Society of Nephrology, 2008). We are indebted to Albert Darque and to Marie-Claude Bongrand from the Central Pharmacy of the Assistance Publique for their assistance in the study. This work was supported by a grant “Programme Hospitalier de Recherches Cliniques 2004” from the Ministère de la Santé (Paris, France). The authors do not have any conflicts of interest.

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References
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