Our results demonstrated the effect of combined bumetanide and chlorthalidone therapy in patients with advanced chronic kidney disease. Among the significant findings, a direct effect of combined therapy with respect to total body water levels and blood pressure was found throughout the study. Trials up to the time of this study evaluating the efficacy and safety of bumetanide plus chlorthalidone treatment with diuretics in patients with chronic kidney disease are limited (6). Current KDIGO guidelines do not recommend thiazide diuretic use in advanced chronic kidney disease, arguing that the efficacy of this type of diuretic diminishes proportionally with the glomerular filtration rate, suggesting the substitution of thiazide diuretics with a loop diuretic when the glomerular filtration rate dips below 30 ml/min (7). This recommendation originated from a study conducted in 1961, in which a poor natriuretic effect of thiazides was observed in two patients with glomerular filtration rates below 15 ml/min (14). Hoshino et al. found that the combination of HCTZ and loop diuretics improved BP levels and decreased proteinuria in eleven advanced stage type 2 DKD patients with severe edema (15). Previously, in the nineties, Fliser et al. showed that the combination of torsemide with a thiazide diuretic significantly increased urinary sodium and chloride elevation in ten patients (16). Recently, Agarwal et al. showed in an excellent clinical trial the positive impact on blood pressure of adding chlorthalidone in patients with stage 4 CKD (17). The results obtained in our study not only demonstrate the antihypertensive effect of thiazide diuretics in advanced chronic kidney disease but also demonstrate the benefit of combined therapy in treating volume overload. Szu-Chun Hung et al. employed a model to predict mortality based on patients’ volume status. Patients were classified into two groups based on the extracellular water to total body water ratio with a cutoff of ± 48%, and after four years of follow-up, they observed twice the mortality rate in those with levels ≥ 48% (18). These results could be of particular interest when applied to this trial since, before the intervention, both groups had an ECW/TBW ratio > 50%; however, at the end of follow-up, only the combined treatment group exhibited a reduction to 46%, which could be impactful as a possible benefit in terms of mortality in this population.
Another finding was that treatment with loop diuretics alone was insufficient for blood pressure and volume overload control compared with bumetanide plus chlorthalidone. This was evidenced by the fact that in our trial, all patients had a history of chronic loop diuretic use (most were on furosemide); however, when they were randomized, furosemide was changed to bumetanide, a more potent loop diuretic with a dose equivalent to 160 mg furosemide QD (19). This protocol, along with our findings, allowed us to demonstrate that high doses of loop diuretics are not sufficient by themselves to achieve adequate blood pressure and volume overload in patients with advanced chronic kidney disease without renal replacement therapy. When employing high doses of bumetanide, the possibilities of poor efficacy of the loop diuretic secondary to pharmacokinetic processes associated with diuretic resistance, such as insufficient dosage, reduced absorption, low bioavailability, and interaction with uremic toxins, are diminished (20). We consider that this difference could be explained by chronic loop diuretic use and previously described adaptive changes at the distal convoluted tubule, in which patients exhibit higher sodium reabsorption, lower natriuresis, and, as a consequence, loss of loop diuretic efficacy (21, 22).
Thiazide diuretic use, particularly chlorthalidone, seems to provide additional benefits; chlorthalidone has a potency at least threefold that of hydrochlorothiazide, as well as a longer half-life (23). A recent meta-analysis demonstrated that chlorthalidone has a larger antihypertensive effect than hydrochlorothiazide with a comparable safety profile (24). Other studies have demonstrated that chlorthalidone may be superior to hydrochlorothiazide with respect to inducing regression of left ventricular hypertrophy and preventing cardiovascular events (25, 26). As described in other studies, our results suggest that the effect of bumetanide plus chlorthalidone therapy on blood pressure levels could be related to the natriuretic effect with subsequent volume depletion produced by thiazide diuretics (27). Even studies conducted in anuric patients failed to demonstrate an antihypertensive effect of thiazides independent of natriuresis and volume depletion (28). Regarding the dose of chlorthalidone used in our study, we recognize that these doses are higher than the 12.5 to 25 mg/day dose that is usually recommended in patients with arterial hypertension (29); however, doses > 50 mg (optimal doses) have been evaluated and defined in the context of high-dose diuretic therapy, as derived from studies that evaluated the dose–response curve of thiazide diuretics (30). The pharmacokinetics of chlorthalidone doses between 50 and 200 mg reveal optimal erythrocyte half-life values and urinary excretion in patients with CKD (11). In addition, we considered pharmacokinetic adjustment according to the deterioration in the glomerular filtration rate present in our patients to achieve the expected natriuretic effect (12). We must recognize that there are no update pharmacokinetic studies of chlorthalidone in patients with advanced chronic kidney disease, which represents a challenge and a weakness of our study. Based on the above and based on the results of our work, it would be important to design pharmacokinetic studies of chlorthalidone with or without loop diuretics in patients with advanced chronic kidney disease as a future area of research.
Actual estimates indicate that nearly 40% of patients diagnosed with advanced chronic kidney disease decide not to start renal replacement therapy, choosing conservative treatment instead (31). Our results support the notion that bumetanide plus chlorthalidone therapy could be an alternative in patients with advanced chronic kidney disease who have not yet accepted the initiation of renal replacement therapy to reduce volume overload and optimize blood pressure control, with the aim of achieving a better quality of life. However, this pharmacological therapy with diuretics will always be limited by the prerequisite of residual uresis in patients subject to this treatment modality.
On the other hand, BNP has been correlated with volume overload in patients with chronic kidney disease measured by bioimpedance (32, 33); however, in our trial, BNP levels did not behave in a manner that reflected a reduction in volume overload, as evidenced by bioimpedance vector analysis. This result can be explained by results obtained in other studies in patients subject to renal replacement therapy in which it was demonstrated that a significant reduction in BNP levels (< 100 pg/dL, only attainable after multiple hemodialysis sessions) is associated with ECW/TBW ratios < 40% (34, 35). For this reason, we consider that even though our patients exhibited decreased ECW/TBW ratio, at the end of follow-up, none achieved the ideal dry weight, and vectors had not relocated to the ellipse corresponding to ideal body water. Therefore, the reduced volume overload observed in the bumetanide plus chlorthalidone group was not sufficient to diminish cardiac muscle stress or achieve a significant reduction in BNP levels.
We observed the same phenomenon in plasma urea levels and glomerular filtration rate (GFR), both associated with a nonsignificant deterioration in patients on bumetanide plus chlorthalidone treatment compared with bumetanide plus placebo. The proportion of patients in the bumetanide plus chlorthalidone group who experienced an increase in plasma creatinine levels could be conceptually defined as having acute kidney injury (36). Nevertheless, grading by AKIN or RIFLE classifications (utilized for acute kidney failure diagnosis) has not been applied in advanced chronic kidney disease populations (37). Among the reasons for not applying these criteria to diagnose acute kidney failure in patients with advanced chronic kidney disease and chronic diuretic use is the fact that urinary volume measurements, considered part of the diagnostic criteria for acute kidney failure, cannot be applied because urinary volume in this population is variable and dependent on residual renal tubular function (38). Employing serum creatinine elevation as a diagnostic criterion for acute kidney failure, considering that basal creatinine levels in the patients included in our study were near 4 mg/dL, would not be adequate, as serum creatinine in these stages of kidney disease is more a marker of nutritional status than of kidney function.
One of the main adverse effects reported in the literature associated with thiazide use is hydroelectrolytic imbalance, hyperuricemia or an increased diabetes risk (39, 40, 41) and hyperuricemia. Our results did not show any significant differences in uric acid risk, blood glucose, potassium or sodium levels at the end of follow-up. There was one case of acute myocardial infarction in the intervention group, which required endoprosthesis insertion via catheterization. Cardiovascular function improved significantly following intervention; however, kidney function remained unchanged, with final GFR readings similar to baseline.
This study has some others limitations. First, the follow-up in our study was short; therefore, further prospective trials are needed to assess the long-term safety and efficacy of this regimen. Second, there was patient noncompliance with dietary recommendations, even though all patients were evaluated and counseled in terms of renal nutrition, with an emphasis on sodium dietary restriction, as it is known that sodium excretion is directly proportional to kidney function and sodium dietary intake (42). Finally, most of our patients did not have a basal echocardiogram at the time of enrollment. Having an estimate of ventricular function beforehand may have allowed us to identify the presence of cardiac failure or changes in left ventricle ejection fraction or telediastolic volume, which may have explained the observed BNP behavior.
In conclusion, our study demonstrated the efficacy of chlorthalidone and bumetanide on volume overload and blood pressure reduction in advanced chronic kidney disease patients. Our results suggest that at the one-month follow-up, bumetanide plus chlorthalidone therapy is effective in patients with advanced chronic kidney disease. Volume overload reduction was adequately tolerated in this population; however, further studies with larger samples and longer follow-up periods are warranted. Based on this trial and those conducted previously on thiazide use for advanced chronic kidney disease, we propose that current guidelines should be reviewed to perhaps change the notion that thiazides should not be used in advanced CKD patients, as it has been demonstrated that this class of diuretics can be helpful in the treatment of this population.