Effect of Spironolactone on Blood Pressure and the Renin-Angiotensin-Aldosterone System in Oligo-Anuric Hemodialysis Patients

doi:10.1053/j.ajkd.2005.03.005

American Journal of Kidney Diseases

Volume 46, Issue 1, July 2005, Pages 94-101

https://doi.org/10.1053/j.ajkd.2005.03.005 Get rights and content

Background: Through its actions on nonepithelial tissues, including brain, blood vessels, and heart, aldosterone may mediate hypertension, cardiac hypertrophy, and fibrosis. Whether aldosterone has a direct pathogenic role in the development of cardiovascular complications in patients with end-stage renal disease is unknown. Oligo-anuric dialysis patients provide a clinical setting to study the effects of the mineralocorticoid receptor blocker spironolactone that are independent of the diuretic properties of the drug. We performed a randomized, double-blinded, placebo-controlled, crossover study to assess the effect of spironolactone on blood pressure and the renin-angiotensin-aldosterone system in oligo-anuric hemodialysis patients. Methods: Eight hemodialysis patients were administered either spironolactone, 50 mg, or placebo orally twice daily for 2 weeks, followed by a 3-week washout period, after which patients crossed over in their treatment arms for 2 more weeks. Results: Administration of spironolactone for 2 weeks decreased predialysis systolic blood pressure from 142.0 ± 19.6 to 131.4 ± 18.2 mm Hg (P < 0.05). Compared with placebo, a 2-week course of spironolactone had no effect on predialysis and postdialysis plasma potassium or aldosterone concentrations or renin activity. Conclusion: When administered for 2 weeks, spironolactone, 50 mg twice daily, reduced predialysis systolic blood pressure, but did not produce hyperkalemia in oligo-anuric hemodialysis patients.

Section snippets

Participants

We selected study participants from adult hemodialysis patients treated thrice weekly at Barnes-Jewish Dialysis Center, St Louis, MO. Men and women qualified for the study if they were on hemodialysis therapy for more than 3 months, had an average predialysis plasma potassium concentration less than 6 mEq/L (mmol/L) at the time of enrollment, were not administered angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and had nil or minimal urine output (<500 mL/24 h).

Results

Table 1 lists baseline patient demographic and clinical characteristics, and Table 2 lists antihypertensive regimens for each individual patient. After dialysis, as expected, we observed a statistically significant decline in systolic blood pressure (143 ± 20 versus 130 ± 22 mm Hg; P < 0.05), weight (89.6 ± 26.1 versus 86.6 ± 25.4 kg; P < 0.05), and potassium concentration (4.5 ± 0.4 versus 3.6 ± 0.5 mEq/L [mmol/L]; P < 0.05; Table 1). There was no significant change in diastolic blood pressure

Discussion

Results of our study indicate that administration of spironolactone decreases predialysis systolic blood pressure in oligo-anuric hemodialysis patients by a nondiuretic mechanism. There are several plausible explanations for this finding. First, aldosterone mediates hypertension centrally.8, 9, 10, 11 In a rat model, intracerebral infusion of aldosterone at doses that do not increase serum levels to greater than normal produces hypertension.8, 21 Blockade of mineralocorticoid receptors in the

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A randomized controlled trial of the effect of spironolactone on left ventricular mass in hemodialysis patients
2019, Kidney International
Mineralocorticoid receptor antagonists have beneficial effects on left ventricular remodeling, cardiac fibrosis, and arrhythmia in heart failure, but efficacy and safety in dialysis patients is less clear. We evaluated the effect of spironolactone on left ventricular mass (LVM), an independent predictor of all-cause and cardiovascular mortality, in hemodialysis patients. In this placebo-controlled, parallel-group trial, 97 hemodialysis patients (23% female; mean age 60.3 years) were randomized to spironolactone 50 mg once daily (n=50) or placebo (n=47). The primary efficacy endpoint was change in LVM index (LVMi) from baseline to 40 weeks as determined by cardiac magnetic resonance imaging. Safety endpoints were development of hyperkalemia and change in residual renal function. There was no significant change in LVMi in participants randomized to spironolactone compared to placebo (-2.86±11.87 vs. 0.41±10.84 g/m²). There was also no difference in the secondary outcomes of mean 24-hour systolic or diastolic ambulatory blood pressure, left ventricular ejection fraction, 6-minute walk test distance, or New York Heart Association functional class. Moderate hyperkalemia (pre-dialysis potassium levels of 6.0-6.5 mmol/L) was more frequent with spironolactone treatment (155 vs. 80 events), but severe hyperkalemia (≥6.5 mmol/L) was not (14 vs. 24 events). Changes in residual urine volume and measured glomerular filtration rate did not differ between groups. There were no deaths in the spironolactone group and 4 deaths in the placebo group. Thus, treatment with 50 mg spironolactone did not change left ventricular mass index, cardiac function, or blood pressure in hemodialysis patients. Spironolactone increased the frequency of moderate hyperkalemia, but did not increase severe hyperkalemia.
2017 Comprehensive Update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure
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These results do not alter previous recommendations on combination therapy with an ACEi and an ARB. Aldosterone blockade has been evaluated in 3 small cohorts for safety381-383 and 1 small RCT of 16 patients with HF without significant benefits.384 There are limited safety data and no efficacy data favouring digoxin for patients with HF receiving hemodialysis.
Since the inception of the Canadian Cardiovascular Society heart failure (HF) guidelines in 2006, much has changed in the care for patients with HF. Over the past decade, the HF Guidelines Committee has published regular updates. However, because of the major changes that have occurred, the Guidelines Committee believes that a comprehensive reassessment of the HF management recommendations is presently needed, with a view to producing a full and complete set of updated guidelines. The primary and secondary Canadian Cardiovascular Society HF panel members as well as external experts have reviewed clinically relevant literature to provide guidance for the practicing clinician. The 2017 HF guidelines provide updated guidance on the diagnosis and management (self-care, pharmacologic, nonpharmacologic, device, and referral) that should aid in day-to-day decisions for caring for patients with HF. Among specific issues covered are risk scores, the differences in management for HF with preserved vs reduced ejection fraction, exercise and rehabilitation, implantable devices, revascularization, right ventricular dysfunction, anemia, and iron deficiency, cardiorenal syndrome, sleep apnea, cardiomyopathies, HF in pregnancy, cardio-oncology, and myocarditis. We devoted attention to strategies and treatments to prevent HF, to the organization of HF care, comorbidity management, as well as practical issues around the timing of referral and follow-up care. Recognition and treatment of advanced HF is another important aspect of this update, including how to select advanced therapies as well as end of life considerations. Finally, we acknowledge the remaining gaps in evidence that need to be filled by future research.
Depuis la parution des Lignes directrices sur l’insuffisance cardiaque (IC) de la Société canadienne de cardiologie en 2006, les soins aux patients atteints de ce trouble ont connu d’importants changements. Au cours de la dernière décennie, le Comité des lignes directrices sur l’IC a publié des mises à jour périodiques. Toutefois, en raison des changements importants qui sont survenus, le Comité des lignes directrices a jugé qu’il était nécessaire de procéder à une réévaluation exhaustive des recommandations sur la prise en charge de l’IC afin de produire un ensemble complet de lignes directrices à jour. Les membres des comités primaire et secondaire sur l’IC de la Société canadienne de cardiologie, ainsi que des spécialistes externes, ont passé en revue la littérature pertinente afin d’indiquer aux cliniciens la marche à suivre. Les lignes directrices de 2017 donnent des indications sur le diagnostic et la prise en charge (autosoins, traitements pharmacologiques et non pharmacologiques, dispositifs et orientation des patients) destinées à faciliter la prise de décisions quotidiennes en matière de soins aux patients atteints d’IC. Parmi les questions abordées figurent notamment les cotes de risque, les différences de prise en charge selon qu’il s’agit d’IC à fraction d’éjection préservée ou réduite, l’activité physique et la réadaptation, les dispositifs implantables, la revascularisation, la dysfonction ventriculaire droite, l’anémie et la carence en fer, le syndrome cardiorénal, l’apnée du sommeil, les cardiomyopathies, l’IC pendant la grossesse, la cardio-oncologie et la myocardite. Le comité a apporté une attention particulière aux stratégies et aux traitements visant à prévenir l’IC, à l’organisation des soins aux patients atteints d’IC, à la prise en charge des comorbidités, ainsi qu’à des questions pratiques concernant les délais d’orientation du patient et les soins de suivi. La reconnaissance et le traitement de l’IC au stade avancé, et notamment le choix des thérapies à ce stade et les considérations en matière de fin de vie, représentent un autre aspect important de cette mise à jour. Enfin, le comité reconnaît les lacunes dans les données probantes qui subsistent et devront être comblées par les recherches futures.
The Challenges of Blood Pressure Control in Dialysis Patients
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Average age and percent of males of all study participants was 60.2 years and 63.1%, respectively. Five trials included only hemodialysis patients,15,18,20-22 and 4 included only patients undergoing peritoneal dialysis.16,19,23,24 The target population varied between trials, with one trial enrolling only patients with reduced ejection fraction,19 one excluding patients with symptomatic heart failure,25 one including only patients already using 3 antihypertensives,24 and one excluding patients with diabetes or vascular disease.21
Patients who require dialysis are at high risk for cardiovascular mortality, which may be improved by mineralocorticoid receptor antagonists (MRAs).
Systematic review and meta-analysis of randomized controlled trials.
Adults undergoing long-term hemodialysis or peritoneal dialysis with or without heart failure.
Randomized controlled trials evaluating an MRA in dialysis and reported at least one outcome of interest.
Spironolactone (8 trials) or eplerenone (1 trial) compared to placebo (7 trials) or standard of care (2 trials).
Cardiovascular and all-cause mortality, hyperkalemia, serum potassium level, hypotension, change in blood pressure, and gynecomastia.
We identified 9 trials including 829 patients. The overall quality of evidence was low due to methodologic limitations in most of the included trials. The relative risk (RR) for cardiovascular mortality was 0.34 (95% CI, 0.15-0.75) for MRA-treated compared with control patients. The RR for all-cause mortality was 0.40 (95% CI, 0.23-0.69). The RR for hyperkalemia for MRA treatment was 3.05 (95% CI, 1.21-7.70). Sensitivity analyses demonstrated wide variability in RRs for cardiovascular mortality, all-cause mortality, and hyperkalemia, suggesting further uncertainty in the confidence of the primary results.
Trial quality and size insufficient to robustly and precisely identify a treatment effect.
Given the uncertainty of both the benefits and harms of MRAs in dialysis, large high-quality trials are required.
Effects of Renin-Angiotensin-Aldosterone System Blockade in Patients with End-Stage Renal Disease
2016, American Journal of the Medical Sciences
Blockers of the renin-angiotensin-aldosterone system (RAAS), such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are routinely used in patients with chronic kidney disease because of their cardiovascular (CV) and renoprotective effects. However, there are no uniform recommendations about RAAS blockers for CV protection in the end-stage renal disease (ESRD) population other than the preferred drug class for blood pressure control. This uncertainty stems from the fact that patients with ESRD were generally excluded from randomized controlled trials evaluating the cardioprotective benefits of RAAS blockers. It is important to weigh the potential harms associated with the use of RAAS blockers, such as electrolyte disturbances and worsening anemia, with their role in protection of residual kidney function, alleviation of thirst and potential CV benefits. The objective of this review is to summarize the current knowledge about the use of RAAS blockers in patients with ESRD.
Heart Failure and Chronic Kidney Disease: Should We Use Spironolactone?
2015, American Journal of the Medical Sciences
Half of all deaths in patients with chronic kidney disease (CKD) arise from cardiovascular causes. Congestive heart failure (CHF) is specifically more frequent with CKD. Cardiovascular therapies with proven benefit are often withheld from patients with renal disease for fear of adverse events. The renin-angiotensin-aldosterone system (RAAS) has been implicated as an important maladaptive neurohormonal pathway in heart failure. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been shown to suppress it ineffectively. Current guidelines support the use of spironolactone for more comprehensive suppression of the RAAS in heart failure patients. Most supporting trials have however excluded patients with renal dysfunction resulting in a dearth of data to support use of spironolactone in CKD patients with CHF. Several small studies that prospectively interrogated the benefits of augmented RAAS blockade with spironolactone in CKD patients have shown improvement in predictors of cardiovascular mortality. More recently, improved mortality outcomes were demonstrated with the use of spironolactone in hemodialysis patients. Although reduction in glomerular filtration rate and hyperkalemia are potential adverse effects with its use, the available evidence suggests that it is uncommon and serious consequences can be avoided with close monitoring. Studies investigating the optimal spironolactone dosage in such a setting recommend starting with a low dose and careful uptitration. This review attempts to provide a comprehensive insight into the issues associated with the use of spironolactone in the setting of concomitant CHF and CKD.

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: Originally published online as doi:10.1053/j.ajkd.2005.03.005 on April 29, 2005.

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Original investigationDialysis therapyEffect of Spironolactone on Blood Pressure and the Renin-Angiotensin-Aldosterone System in Oligo-Anuric Hemodialysis Patients

Section snippets

Participants

Results

Discussion

Am J Kidney Dis

Kidney Int

Kidney Int

Kidney Int

Kidney Int

Steroids

Kidney Int

Kidney Int

Kidney Int

USRDS 2001 Annual Data ReportThe incidence and prevalence of ESRD

Am J Kidney Dis

Effects of spironolactone and angiotensin-converting enzyme inhibitor on left ventricular hypertrophy in patients with essential hypertension

Hypertens Res

Effect of selective mineralocorticoid receptor antagonist, eplerenone, in a model of aldosterone induced hypertension and cardiac fibrosis

American Society of Hypertension 13th Scientific Meeting

Involvement of aldosterone in left ventricular hypertrophy of patients with end-stage renal failure treated with hemodialysis

Am J Hypertens

Central infusion of aldosterone increases blood pressure by mechanisms independent of Na retention

Clin Exp Hypertens A

The role of mineralocorticoid receptors in hypothalamic-pituitary-adrenal axis regulation in humans

J Clin Endocrinol Metab

Mineralocorticoid receptor also modulates basal activity of hypothalamus-pituitary-adrenocortical system in humans

Neuroendocrinology

Prerequisite for cardiac aldosterone action. Mineralocorticoid receptor and 11 beta-hydroxysteroid dehydrogenase in the human heart

Circulation

Original investigation
Dialysis therapy
Effect of Spironolactone on Blood Pressure and the Renin-Angiotensin-Aldosterone System in Oligo-Anuric Hemodialysis Patients