High Aldosterone Levels Increase Risk for CKD Progression

Higher serum aldosterone levels among patients with chronic kidney disease (CKD) are independently associated with an increased risk for CKD progression and end-stage kidney disease (ESKD) regardless of whether or not patients have concomitant diabetes, a prospective study shows.

"Recent randomized controlled trials have shown that a drug called finerenone (Kerendia) is effective in delaying CKD progression and adverse cardiovascular outcomes in patients with CKD and diabetes," Ashish Verma, MD, assistant professor, Boston University School of Medicine, Massachusetts, said in a statement.

"Since excessive levels of aldosterone are very common — yet mostly unrecognized — we hypothesized that one reason why finerenone (a mineralocorticoid receptor [MR] antagonist) was effective in lowering the risk of CKD progression was that it was treating unrecognized high concentrations of the hormone," he added.

"This study provides evidence for the mechanism by which MR antagonists could delay CKD progression and supports investigating their value in patients without diabetes," Verma said.

The study was published online on August 9 in the European Heart Journal.

Chronic Renal Insufficiency Cohort

The association between aldosterone concentrations in the blood and CKD progression was examined among 3680 participants in the Chronic Renal Insufficiency Cohort study. Participants were 21-74 years of age and the study took place between 2003 and 2008. Baseline estimated glomerular filtration rate (eGFR) ranged from 20 to 70 mL/min/1.73m² and patients were not taking any aldosterone antagonists.

"The primary outcome was CKD progression, defined as the composite of a 50% decline in eGFR or incident ESKD, whichever came first," Verma and colleagues observe. Over a median follow-up of 9.6 years, 1412 participants, or slightly over 38% of the cohort, developed the composite outcome of CKD progression while 1129 patients developed ESKD.

Median baseline serum aldosterone concentrations, at 10.6 ng/dL, were significantly higher in patients who developed the composite outcome compared with those who did not, at 9.6 ng/dL (P < .001), the authors report. Higher serum aldosterone concentrations were also associated with lower serum potassium levels, greater urinary potassium levels, and greater protein excretion.

Indeed, for each doubling of serum aldosterone, there was an 11% increased risk of patients developing CKD progression. Moreover, patients in the highest quartile of serum aldosterone had a 45% increased risk of CKD progression compared with those in the lowest quartile.

Those in the highest quartile of serum aldosterone also had a 46% increased risk of developing ESKD compared with those in the lowest quartile.

Increased Risk of Death, Coronary Events

Over a median follow-up of 11.5 years, 1293 participants died. During the median follow-up of 9.1 years, 1088 participants developed the composite outcome of a major acute coronary event. Again, patients in the highest quartile of serum aldosterone had a 22% higher risk for all-cause mortality compared with patients in the lowest quartile, although as a continuous variable, the association between serum aldosterone and all-cause mortality was not statistically significant.

"We found no evidence of interaction of diabetes mellitus with CKD progression or ESKD as outcomes, nor any interaction between the use of ACE inhibitors and angiotensin receptor blockers and outcomes," the authors emphasize. As investigators explain, one of the factors that increase aldosterone synthesis is higher serum potassium concentrations. An increase in serum potassium with worsening kidney function may well stimulate aldosterone secretion.

"However, this is contrary to what we observed," investigators caution. Higher baseline serum aldosterone concentrations in the study were associated with lower rather than higher serum potassium and higher rather than lower urinary potassium excretion, findings that support the pathologic aldosterone production and MR activation, as the authors suggest.

Current study findings also support prior studies linking aldosterone with CKD and provide supportive evidence for the use of MR antagonists for preventing CKD progression, investigators suggest. Given that the study indicates that pathogenic aldosteronism has a role in CKD progression in patients without diabetes, they also suggest that MR antagonist therapy should be investigated as a method to slow CKD progression in patients without diabetes.

Assess Aldosterone Levels in All Patients

Commenting on the study, George Bakris, MD, University of Chicago Medicine, Illinois, and Frederic Jaisser, MD, PhD, French National Institute of Health and Medical Research (INSERM), Paris, France, point out that while plasma aldosterone is adequate to measure the hormone level, it should be done in the context of plasma renin activity to fully assess activation of the axis.

"Moreover, due to increased platelet adherence of aldosterone, 24 h urine aldosterone corrected for creatinine is a more accurate way to determine aldosterone levels," they add. Now that there is a new class of nonsteroidal MR antagonists, it is safe to treat advanced CKD with a drug like finerenone, they add.

Indeed, an analysis of over 13,000 patients treated in two randomized trials of patients with advanced diabetic kidney disease showed that finerenone reduced heart failure hospitalizations by 22% and led to a 20% reduction in the risk of progression to dialysis.

Furthermore, after a median follow-up of 3 years, fewer than 2% of over 6500 patients developed hyperkalemia compared with 0.6% of placebo controls. Hyperkalemia was a risk factor for long-term use of the older steroidal MR antagonists. "Taken together these studies suggest that aldosterone levels need to be assessed in all patients at risk for and/or in the presence of cardiorenal disease, especially if they have central obesity and/or resistant hypertension," Bakris and Jaisser write.

"We now have relatively safe and better-tolerated agents than traditional steroidal agents that can and should be used to reduce cardiorenal risk in these groups of patients," they advise.

Verma has reported receiving consulting fees from Concept Therapeutics, Mineralys, and HRA Pharma. Bakris has reported being a consultant for or serving on steering committees for clinical trials for Bayer, KBP Biosciences, Ionis, Alnylam, AstraZeneca, Quantum Genomics, Horizon, Novo Nordisk, DiaMedica Therapeutics, and inRegen. Jaisser has reported no relevant financial relationships.

Eur Heart J. Published online August 9, 2022. Abstract, Editorial

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