Highlights
– A 2025 systematic review and meta-analysis (Katsuragawa et al., Lancet Diabetes Endocrinol) pooled data from 24 observational cohorts (6,621 patients) and found that patients with unsuppressed renin after medical therapy for primary aldosteronism had lower cardiovascular event rates (pooled HR 0.43, 95% CI 0.23–0.80).
– The cardiovascular benefit was more pronounced with longer follow-up (≥5 years; pooled HR 0.33, 95% CI 0.19–0.57), while associations with renal outcomes were null and data on mortality were sparse.
– Studies were heterogeneous in design and at moderate-to-high risk of confounding bias; prospective trials are required to determine whether titration of mineralocorticoid receptor antagonists (MRAs) toward renin normalisation improves hard clinical outcomes.
Background: clinical context and unmet need
Primary aldosteronism (PA) is a common, potentially curable cause of secondary hypertension. Autonomous aldosterone excess drives hypertension, hypokalaemia, and end-organ injury through mineralocorticoid receptor activation. Patients with PA have higher rates of cardiovascular events and mortality compared with patients with essential hypertension of similar blood pressure, highlighting disease-specific risk beyond pressure load.
When PA is managed medically — typically because disease is bilateral or the patient is not a surgical candidate — MRAs (spironolactone or eplerenone) are used to antagonise the mineralocorticoid receptor. Adequate blockade should reduce aldosterone-mediated effects, but residual biochemical evidence of mineralocorticoid excess can persist. Plasma renin (measured as plasma renin activity [PRA] or direct renin concentration) is a readily available biomarker that is usually suppressed in PA and that typically rises when mineralocorticoid signalling is effectively blocked. Whether post-treatment renin status predicts long-term cardiovascular, renal, and survival outcomes has important implications for defining treatment targets and monitoring strategies.
Study design and methods (overview)
Katsuragawa and colleagues performed a systematic review and meta-analysis (PROSPERO CRD42024598737) of studies that evaluated associations between post-treatment renin status and clinical outcomes among medically treated patients with PA. Four databases were searched to May 5, 2025. Eligible studies included patients treated with MRAs and reporting post-treatment renin (most commonly PRA) categorised as suppressed versus unsuppressed. Primary outcomes were incident cardiovascular events, renal events, and all-cause mortality. Risk of bias was assessed using QUIPS, and random-effects models were used to pool hazard ratios (HRs).
Key findings and detailed results
Study selection and characteristics
Of 3,814 records screened, 24 studies (6,621 patients) met inclusion criteria; five contributed data to the pooled analyses of primary outcomes. Most studies classified post-treatment renin using PRA with a cut-off of 1.0 ng/mL/h to distinguish suppressed from unsuppressed renin. Follow-up durations, outcome definitions, and renin measurement protocols varied across studies.
Cardiovascular outcomes
In the primary meta-analysis (four studies, 874 patients), unsuppressed post-treatment renin was associated with a substantially lower risk of cardiovascular events versus suppressed renin (pooled HR 0.43, 95% CI 0.23–0.80; I2 = 37%), though the certainty of evidence was graded low. A subgroup analysis restricted to longer follow-up (≥5 years; three studies, 754 patients) showed an even larger relative risk reduction (pooled HR 0.33, 95% CI 0.19–0.57; I2 = 0%), with moderate certainty. These findings suggest a durable association between renin normalisation and reduced cardiovascular risk that becomes clearer with longer observation.
Renal outcomes
Two studies contributed renal outcome data; pooled estimates showed no significant association (pooled HR 0.95, 95% CI 0.51–1.77; I2 = 0%), though the evidence was of very low certainty. Heterogeneity in renal outcome definitions (e.g., decline in eGFR thresholds, need for dialysis) and potential competing effects of MRAs (which may transiently reduce eGFR) complicate interpretation.
All-cause mortality
Only one study reported mortality with an adjusted HR favouring unsuppressed renin (HR 0.29, 95% CI 0.09–0.98; 201 patients), but this single-study result was judged low certainty and requires replication.
Risk of bias and limitations across studies
No included study was rated low risk of bias across all QUIPS domains. Many studies had high risk of bias from confounding (QUIPS Domain 5). Observational designs, incomplete adjustment for determinants of outcomes (e.g., baseline comorbidity, blood pressure control, adherence), differences in MRA dosing strategies, and selection bias limit causal inference. Measurement variability (PRA vs direct renin concentration, timing relative to medication, potassium status, concurrent antihypertensives) and inconsistent cut-offs further weaken conclusions.
Biological plausibility and mechanistic considerations
The association between higher post-treatment renin and better outcomes is biologically plausible. In PA, suppressed renin reflects autonomous aldosterone excess; effective mineralocorticoid receptor antagonism should restore renin towards normal by removing negative feedback. Unsuppressed renin therefore serves as an integrated marker of effective blockade of aldosterone action, beyond simple blood pressure control. Persistent renin suppression despite MRA therapy could reflect underdosing, poor adherence, limited tissue penetration, or ongoing autonomous aldosterone production—conditions that would permit continuing aldosterone-mediated cardiovascular damage.
However, renin activation also has complex physiology. A rise in renin may reflect volume depletion or reduced sodium load; conversely, in some contexts elevated renin is pathogenic (e.g., heart failure activation of renin–angiotensin system). Hence interpretation must be context-specific and complemented by clinical and biochemical data.
Clinical implications: what should clinicians do now?
These data support the argument that monitoring renin after initiating MRA therapy in PA is clinically informative. Practical considerations include:
- Consider measuring renin (PRA or direct renin concentration per local laboratory standard) after initiating or titrating MRAs to assess biochemical response.
- If renin remains suppressed, evaluate for reversible causes (medication interactions, hypokalaemia, high dietary sodium, adherence) and consider uptitration of MRA dose where safe and tolerated, balancing the risks of hyperkalaemia and renal dysfunction.
- Choose agents thoughtfully: spironolactone is potent but has sex-hormone side effects; eplerenone has a more favourable side-effect profile but may be less potent. Newer nonsteroidal MRAs are under study.
- Maintain careful monitoring: serum potassium and creatinine should be checked after dose changes and periodically thereafter; hyperkalaemia risk limits aggressive up-titration in some patients.
- Individualise decisions: in unilateral PA or when surgery is feasible, adrenalectomy remains the treatment of choice for many patients because it may eliminate the disease driver.
Crucially, while post-treatment renin appears prognostic, it remains unproven whether actively titrating therapy to achieve an unsuppressed renin target causally reduces cardiovascular events. Until RCT evidence emerges, using renin as one element in a broader clinical assessment is reasonable but should not replace judgement about risks of higher MRA doses.
Research agenda and unanswered questions
Key priorities to move from association to practice change include:
- Randomised trials that test a renin-targeted strategy (titration of MRA to renin normalisation) versus usual care, with cardiovascular events, renal outcomes, and safety (hyperkalaemia, kidney injury, adverse effects) as endpoints.
- Standardisation of renin measurement (PRA vs direct renin concentration), pre-analytical conditions, and cut-offs that best predict clinical benefit.
- Identifying subgroups most likely to benefit from aggressive biochemical targeting (e.g., age, baseline cardiovascular risk, degree of aldosterone excess).
- Comparative effectiveness of different MRAs and of combination strategies (e.g., MRA plus potassium binders to enable higher MRA dosing safely).
Expert commentary and limitations
Endocrine and hypertension experts have long recognised that biochemical control in PA does not always map neatly onto blood pressure control. The evidence summarized by Katsuragawa et al. provides a compelling signal that normalising renin might correspond with better long-term cardiovascular health. However, experts caution that confounding by indication and residual bias in observational cohorts can inflate apparent benefits. For example, patients who achieve renin normalisation may be those who are more adherent, have better access to care, or have less severe disease—factors independently associated with better outcomes.
Guideline context: Current clinical practice guidelines (e.g., Endocrine Society 2016) recommend MRAs for bilateral PA and monitoring of potassium and renal function, but they do not mandate routine renin-guided titration to specific thresholds as a standard of care pending stronger interventional evidence.
Conclusions
The 2025 systematic review and meta-analysis provides moderate-quality evidence that unsuppressed post-treatment renin after medical therapy for primary aldosteronism is associated with a substantially lower risk of cardiovascular events, particularly over longer follow-up. Evidence for renal outcomes and mortality is limited. These observational data support the hypothesis that renin normalisation could serve as a therapeutic target, but they do not establish causality. Randomised controlled trials of renin-guided MRA titration with pre-specified safety monitoring are needed before routine adoption of renin targets as a universal management strategy.
Practical takeaways for clinicians
– Consider measuring renin after initiating or adjusting MRAs in patients with PA; use trends in conjunction with clinical response.
– If renin remains suppressed, investigate adherence and reversible influences and consider cautious MRA up-titration with close monitoring for hyperkalaemia and renal dysfunction.
– Refer patients with unilateral disease for surgical evaluation when appropriate, and prioritise RCTs or registries to further define renin-guided management.
Funding and trial registration
The systematic review reported no funding. The review protocol was pre-registered on PROSPERO (CRD42024598737).
References
1) Katsuragawa S, Le MV, Fuller PJ, Yang J. Post-treatment renin status and cardiovascular, renal, and mortality outcomes in medically treated primary aldosteronism: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2025 Dec;13(12):1041-1053. doi: 10.1016/S2213-8587(25)00263-3.
2) Funder JW, Carey RM, Mantero F, et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(5):1889–1916.
3) Milliez P, Girerd X, Plouin PF, et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. Lancet. 2005;366(9483):1620–1625.
