Determinants and Changes Associated with Aldosterone Breakthrough after Angiotensin II Receptor Blockade in Patients with Type 2 Diabetes with Overt Nephropathy

Abstract

SummaryBackground and objectives Inhibition of the renin-angiotensin-aldosterone system decreases proteinuria and slows estimated GFR decline in patients with type 2 diabetes mellitus with overt nephropathy. Serum aldosterone levels may increase during renin-angiotensin-aldosterone system blockade. The determinants and consequences of this aldosterone breakthrough remain unknown.Design, setting, participants, & measurements This study examined the incidence, determinants, and changes associated with aldosterone breakthrough in a posthoc analysis of a randomized study that compared the effect of two angiotensin II receptor blockers in patients with type 2 diabetes mellitus with overt nephropathy.Results Of 567 of 860 participants included in this posthoc analysis, 28% of participants developed aldosterone breakthrough, which was defined by an increase greater than 10% over baseline values of serum aldosterone levels after 1 year of angiotensin II receptor blocker treatment. Factors independently associated with aldosterone breakthrough at 1 year were lower serum aldosterone and potassium levels at baseline, higher decreases in sodium intake, systolic BP, and estimated GFR from baseline to 1 year, and use of losartan versus telmisartan. Aldosterone breakthrough at 6 months was not sustained at 1 year in 69% of cases, and it did not predict estimated GFR decrease and proteinuria increase between 6 months and 1 year.Conclusions Aldosterone breakthrough is a frequent event 1 year after initiating renin-angiotensin-aldosterone system blockade, particularly in participants exposed to intensive lowering of BP with sodium depletion and short-acting angiotensin II receptor blockers. Short-term serum aldosterone level increases at 6 months are not associated with negative kidney outcomes between 6 months and 1 year.

Cardiovascular actions of mineralocorticoid receptor antagonists in patients with chronic kidney disease: A systematic review and meta-analysis of randomized trials

“…In 10-50% of patients' circulating aldosterone concentrations return to pre-treatment levels (a phenomenon termed 'aldosterone breakthrough'). 45 There are reports that patients who demonstrate aldosterone breakthrough have a worse prognosis than those who do not. 45 It has been suggested that the use of MRA in this context would be beneficial, especially in the context of renal impairment, and there are many animal and human studies to support this.…”

“…45 There are reports that patients who demonstrate aldosterone breakthrough have a worse prognosis than those who do not. 45 It has been suggested that the use of MRA in this context would be beneficial, especially in the context of renal impairment, and there are many animal and human studies to support this. 2 A further important and not unexpected finding of this analysis was that there was a significant increase in serum potassium concentrations and a significant increase in the risk of hyperkalemia.…”

Cardiac hypertrophy in chronic kidney disease—role of Aldosterone and FGF23

“…Furthermore, Hosoya et al [15] have recently demonstrated that the expression of the aldosterone-producing enzyme CYP11B2 in the adipose tissue of 5/6-nephrectomized rats is upregulated, leading to increased tissue aldosterone content. Finally, aldosterone breakthrough phenomenon (i.e., an elevation in plasma aldosterone levels 3-6 months after the administration of RAS inhibitors) could be a possible mechanism for aldosterone dysregulation [32,33]. Taken together, these mechanisms may act in concert to enhance aldosterone activity in CKD.…”

“…Furthermore, the expression of CYP11B2, an aldosterone-producing enzyme, in the adipose tissue of 5/6-nephrectomized rats is upregulated, resulting in increased tissue aldosterone content [15]. Finally, the continued use of ACE inhibitors or ARB may cause paradoxical increases in plasma aldosterone concentrations through aldosterone breakthrough phenomenon [32,33]. These mechanisms would act in concert to elevate plasma aldosterone concentrations as renal function declines.…”

A pilot study of the effects of eplerenone add-on therapy in patients taking renin–angiotensin system blockers

“…Moranne et al found that initial plasma potassium and aldosterone concentrations, as well as higher decreases in sodium intake, systolic BP (SBP), and estimated GFR (eGFR) from baseline to 1 year were factors that influence plasma aldosterone level. 14 The aim of the present study was to determine whether those parameters mentioned above, including initial plasma potassium and aldosterone concentration, higher decreases in sodium intake, SBP, and eGFR from baseline to 1 year, as well as the transtubular K gradient (TTKG) (an index of potassium secretion from the collecting ducts), can predict the clinical effects of Ep add-on therapy on BP and proteinuria in patients already taking ACEis or ARBs.…”