Comparative renal effects of angiotensin receptor neprilysin inhibitors and ACEi/ARB: a systematic review and meta-analysis.

Background: Classical renin-angiotensin system inhibitors (RASI), such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), have long been the foundation of treatment for patients with cardiovascular disease (CVD) and chronic kidney disease (CKD). The development of angiotensin receptor neprilysin inhibitors (ARNI) has introduced a valuable therapeutic option for patients with heart failure with reduced ejection fraction (HFrEF), reducing the risk of major cardiovascular events and becoming an essential component of treatment for this population. However, their effects on renal outcomes remain uncertain. Methods: We conducted a systematic review and meta-analysis to compare the renal effects of ARNI and RASI. Relevant studies were searched in the following databases from inception to 30 December 2024: MEDLINE (PubMed), Embase and Scopus. The primary outcomes assessed were: a ≥50% reduction in estimated glomerular filtration rate (eGFR) or progression to end-stage renal disease (ESRD), a composite measure of worsening renal function (serum creatinine increase of ≥0.5 mg/dL from baseline and a 25% decline in eGFR) and renal impairment (an increase of at least 0.3 mg/dL in creatinine levels). Additionally, a subgroup analysis of renal impairment in patients with HFrEF was performed. Secondary outcomes included hyperkalemia. Results: Our results suggested a 31% reduction in renal impairment with ARNI treatment compared with RASI and a 37% reduction in the odds of ≥50% decline in eGFR or ESRD. However, the pooled analysis for worsening renal function and hyperkalemia showed no apparent difference between ARNI and RASI. A subgroup analysis on a population with a reduced ejection fraction suggested a 37% lower odds of renal impairment with ARNI when compared with RASI. This study represents the largest and first systematic review and meta-analysis with clearly defined renal outcomes. Conclusion: Given that ARNI has been explored for indications beyond heart failure, further randomized controlled trials are needed to understand its renal effects better. Future research should determine whether ARNI provides a benefit in a purely CKD population or in a cardio-renal population, given that CVD is the leading cause of mortality in CKD patients.