Review
Reduction of cardiovascular risk in chronic kidney disease by mineralocorticoid receptor antagonism

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Summary

Cardiovascular disease is the leading cause of death and morbidity in people with chronic kidney disease, but there are few evidence-based treatments for reducing cardiovascular events in these patients. The failure of novel drug candidates to delay progression to end-stage renal disease and limit or abrogate cardiovascular morbidity and mortality has led to increased interest in a mineralocorticoid receptor (MR) antagonist-based treatment model to reduce cardiovascular risk in patients with chronic kidney disease and end-stage renal disease. Aldosterone concentrations and MR signalling are associated with an enhanced risk of cardiovascular injury and the incidence of sudden death, and MR blockade decreases the risk of cardiovascular events and sudden death in patients with reduced glomerular filtration rate. Since evidence from clinical trials shows that treatment with MR antagonists confers a morbidity and mortality advantage for patients with cardiovascular disorders, similar benefits might also accrue in patients with chronic kidney disease. Large prospective trials are urgently needed to answer this question. In this Review, I argue that despite differences in the pathophysiology and clinical features of cardiovascular disease in patients with and without chronic kidney disease, MR antagonists could provide cardiovascular benefit in patients with chronic kidney disease.

Introduction

Cardiovascular disease is the leading cause of death and morbidity in people with chronic kidney disease.1, 2 The Global Burden of Disease study identified chronic kidney failure as one of the three causes of death with the greatest increase from 1990 to 2010.1 Patients with chronic kidney disease have up to a three to five times increased risk of cardiovascular events,1 and cardiovascular disease is the most common cause of mortality and morbidity in these patients.

The rates of cardiovascular events and mortality consistently increase as kidney function deteriorates.3 Patients on dialysis have mortality rates up to 40 times higher than the general population,4 with cardiovascular disease causing up to 50% of these deaths.5 The increase in cardiovascular risk for a young patient (aged 25–34 years) with end-stage renal disease on dialysis is 100–1000 times greater than for age-matched healthy people, and this falls to about ten times for patients older than 85 years.6

Chronic kidney disease is common worldwide, affecting up to 16% of the population.2, 7, 8, 9 As a consequence of the increasing prevalence of this condition and of dialysis-dependent end-stage renal disease, the number of people at high risk of cardiovascular events will increase, with growing demands on health services worldwide. These observations emphasise the need to define and establish therapeutic initiatives to modify cardiovascular risk. Addressing this unmet need is a clinical priority.

In this Review, I first discuss the pathophysiology of cardiovascular disease in chronic kidney disease, and briefly consider recent global clinical trials designed to reduce cardiovascular outcomes in patients with chronic kidney disease. I then discuss the several studies that have clearly shown beneficial effects of mineralocorticoid receptor (MR) antagonists on cardiovascular outcomes in patients with chronic heart failure and post-myocardial infarction without concomitant kidney disease. Finally, I argue that, despite differences in the pathophysiology and clinical features of cardiovascular disease in patients with and without chronic kidney disease, MR antagonists might also be effective in attenuating cardiovascular events in patients with chronic kidney disease.

Section snippets

Cardiovascular disease in chronic kidney disease

Cardiovascular disease in chronic kidney disease can be attributed to two distinct but overlapping pathological processes—namely, atherosclerosis and arteriosclerosis.10 Although the risk of atherothrombotic events such as myocardial infarction is raised, arteriosclerosis is the predominant pathophysiological process, which involves fibrosis and thickening of the medial arterial layer. The subsequent increase in arterial stiffness leads to left ventricular hypertrophy and fibrosis, thereby

Cardiovascular risk markers and treatment for cardiovascular events in kidney disease

In chronic kidney disease established markers of cardiovascular disease, such as raised cholesterol19 and blood pressure,20 do not always have the same log-linear association with cardiovascular events as in the general population. In end-stage renal disease there is an inverse association between cardiovascular event rates and conventional risk factors such as total cholesterol, obesity, and even blood pressure. These paradoxical associations might, at least in part, be explained by reverse

Aldosterone and MR antagonism: a rational approach to reduce cardiovascular risk

It is now realised that the traditional concepts governing aldosterone and the MR are wrong:42 angiotensin is not the major driver of aldosterone secretion; aldosterone is merely one of several physiological ligands for the MR; and, although the sodium-retaining effects of aldosterone are clearly relevant in maintaining volume homoeostasis in the setting of hypovolaemia, aldosterone increases blood pressure mainly by actions on the vasculature and CNS.

The figure and panel summarise the new

Risks of available MR antagonists

Pharmacological differences between spironolactone and eplerenone include lower affinity of eplerenone for progesterone, androgen, and glucocorticoid receptors, and the presence of longacting metabolites for spironolactone.74, 75

Both agents produce dose-dependent increases in potassium concentrations. However, caution is needed when comparing the rates of hyperkalaemia between spironolactone and eplerenone. Struthers and colleagues74 speculated that the extended half-life of the active

Aldosterone and cardiovascular events in patients on haemodialysis

When end-stage renal disease is reached, the prevalence of cardiac comorbidities is extremely high.4, 5 Several investigators have assessed whether increased concentrations of aldosterone correlate with these dire cardiovascular outcomes. In the CRIC study, Deo and colleagues86 reported that in participants with chronic kidney disease, higher aldosterone concentrations were independently associated with the development of congestive heart failure, but not with death, end-stage renal disease, or

Evidence from trials of MR antagonists in heart failure

The evidence presented above suggests that renal disease is associated with a high risk of cardiovascular disease and that aldosterone concentrations and MR activation are increased in patients with renal disease. Additionally, it suggests that activation of these systems can contribute to the pathophysiological mechanisms behind increased cardiovascular disease in these patients, and that blockade of these systems prevents cardiovascular disease morbidity and mortality in other cardiovascular

Continuing and recently completed MR antagonist clinical trials

Of the eight MR antagonist clinical trials, three (PHASE,94 MiREnDa,95 and ALCHEMIST [NCT018448639]) are in patients with end-stage renal disease undergoing dialysis, three (ARTS-DN,73 FIGARO-DKD [NCT02540993], and FIDELIO-DKD [NCT02545049]) are in patients with chronic kidney disease, and two (ARTS-HF85 and FINESSE-HF) are in patients with chronic heart failure (table). The pilot study in patients with end-stage renal disease (PHASE)94 is now complete and has shown the safety of eplerenone

Hyperkalaemia associated with MR antagonist treatment

Most clinicians are reluctant to prescribe MR antagonists in patients with chronic kidney disease, and in patients with end-stage renal disease on haemodialysis, because of the risk of hyperkalaemia.47, 97, 98 MR antagonists are contraindicated in patients with an eGFR of less than 30 mL/min/1·73m2, including patients on haemodialysis. A recent study99 that did an in-depth analysis of de-identified medical records from a large database of electronic health records (initially screening 1·7

Conclusion

Enhanced MR activation complicates the clinical course of chronic kidney disease and end-stage renal disease, and contributes to progression of disease, maintenance of hypertension, and importantly associated cardiovascular complications.49, 50, 51, 52, 53, 54, 55, 57 Compelling evidence from clinical trials in the general population without chronic kidney disease has shown that treatment with MR antagonists confers a morbidity and mortality advantage for patients with cardiovascular disorders

Search strategy and selection criteria

I searched MEDLINE and the Cochrane Database of Systematic Reviews for articles published between Jan 1, 2005, and Aug 31, 2015, and reviewed original publications, review articles, and abstracts in published in English. Additionally, I searched my personal literature libraries. I used the following search terms: “chronic kidney disease”, “dialysis patients”, “end-stage renal disease”, “ESRD”, “angiotensin-converting enzyme inhibitor”, “ACE-I”, “angiotensin II receptor blocker”, “ARB”,

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