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Stopping RAS Inhibitors in Advanced Chronic Kidney Disease and Cardiorenal Outcomes—Several Unanswered Questions Remain

  • Macaulay Amechi Chukwukadibia Onuigbo
    Correspondence
    Requests for reprints should be addressed to Macaulay Amechi Chukwukadibia Onuigbo, MD, Division of Nephrology, Department of Medicine, The Robert Larner, M.D. College of Medicine, University of Vermont, UHC Campus, 1 South Prospect Street, Burlington, VT 05401.
    Affiliations
    The Robert Larner, M.D. College of Medicine, University of Vermont, Burlington
    College of Business, University of Wisconsin MBA Consortium, Eau Claire
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      We read with fascination the recent Swedish study of cardiorenal outcomes after stopping renin-angiotensin system inhibitors (RASi) in 10,524 prevalent RASi users with advanced chronic kidney disease.
      • Fu EL
      • Evans M
      • Clase CM
      • et al.
      Stopping renin-angiotensin system inhibitors in patients with advanced CKD and risk of adverse outcomes: a nationwide study.
      Compared with continuing RASi, stopping RASi was associated with a higher absolute 5-year risk of death and major adverse cardiovascular events, but with a lower risk of kidney replacement therapy.
      • Fu EL
      • Evans M
      • Clase CM
      • et al.
      Stopping renin-angiotensin system inhibitors in patients with advanced CKD and risk of adverse outcomes: a nationwide study.
      We were the first to report a large prospective nonrandomized study of RASi withdrawal in progressive chronic kidney disease at the Mayo Clinic Health System in Northwestern Wisconsin.
      • Onuigbo MA
      • Onuigbo NT
      Late onset renal failure from angiotensin blockade (LORFFAB): a prospective thirty-month Mayo Health System clinic experience.
      ,
      • Onuigbo MA
      • Onuigbo NT
      Late-onset renal failure from angiotensin blockade (LORFFAB) in 100 CKD patients.
      This single-center experience of discontinuing RASi in chronic kidney disease patients with recent >25% increase in baseline serum creatinine demonstrated clearly improved renal outcomes without increased cardiovascular mortality.
      • Onuigbo MA
      • Onuigbo NT
      Late onset renal failure from angiotensin blockade (LORFFAB): a prospective thirty-month Mayo Health System clinic experience.
      ,
      • Onuigbo MA
      • Onuigbo NT
      Late-onset renal failure from angiotensin blockade (LORFFAB) in 100 CKD patients.
      Coincidentally, another recent Journal of the American Society of Nephrology report on 2738 patients with moderate to severe chronic kidney disease, participants in the CRIC Study, demonstrated that slower estimated glomerular filtration rate declines, or indeed, improved estimated glomerular filtration rate over time, were associated with lower risks of death and cardiovascular events.
      • Orlandi PF
      • Xie D
      • Yang W
      • et al.
      Slope of kidney function and its association with longitudinal mortality and cardiovascular disease among individuals with CKD.
      Furthermore, in a just-published Canadian population-based retrospective cohort study of RASi discontinuation in 49,571 older adults who developed hyperkalemia, RASi discontinuation was not associated with a higher risk of 1-year cardiovascular events (hazard ratio 0.96; 95% confidence interval, 0.91-1.02) or all-cause mortality (hazard ratio 1.05; 95% confidence interval, 0.96-1.15), compared with no intervention.
      • Hundemer GL
      • Talarico R
      • Tangri N
      • et al.
      Ambulatory treatments for RAAS inhibitor-related hyperkalemia and the 1-year risk of recurrence.
      The Swedish authors rightly acknowledged that, despite their sophisticated analytical design and very large population studied, residual confounding cannot be excluded.
      • Fu EL
      • Evans M
      • Clase CM
      • et al.
      Stopping renin-angiotensin system inhibitors in patients with advanced CKD and risk of adverse outcomes: a nationwide study.
      Most importantly, and again acknowledged by the authors, the precise reasons for stopping RASi remain unknown and may have impacted study outcomes.
      • Fu EL
      • Evans M
      • Clase CM
      • et al.
      Stopping renin-angiotensin system inhibitors in patients with advanced CKD and risk of adverse outcomes: a nationwide study.
      The unknown interplay of residual confounding remains the Achilles’ heel of the Swedish report. Besides, the likely very huge impacts of ecological fallacy on the findings of this study remain unresolved.
      We remain optimistic that the ongoing European STOP-ACEi Trial (trial registration: current controlled trials, ISRCTN62869767), an investigator-led, multicenter, open-label randomized controlled trial of 410 participants with advanced (Stage 4 or 5) progressive chronic kidney disease receiving angiotensin-converting enzyme inhibitor, angiotensin receptor blockers, or both, due to be completed in 2022, would shed further light on these vexing questions.

      References

        • Fu EL
        • Evans M
        • Clase CM
        • et al.
        Stopping renin-angiotensin system inhibitors in patients with advanced CKD and risk of adverse outcomes: a nationwide study.
        J Am Soc Nephrol. 2021; 32: 424-435
        • Onuigbo MA
        • Onuigbo NT
        Late onset renal failure from angiotensin blockade (LORFFAB): a prospective thirty-month Mayo Health System clinic experience.
        Med Sci Monit. 2005; 11 (CR462-9)
        • Onuigbo MA
        • Onuigbo NT
        Late-onset renal failure from angiotensin blockade (LORFFAB) in 100 CKD patients.
        Int Urol Nephrol. 2008; 40: 233-239
        • Orlandi PF
        • Xie D
        • Yang W
        • et al.
        Slope of kidney function and its association with longitudinal mortality and cardiovascular disease among individuals with CKD.
        J Am Soc Nephrol. 2020; 31: 2912-2923
        • Hundemer GL
        • Talarico R
        • Tangri N
        • et al.
        Ambulatory treatments for RAAS inhibitor-related hyperkalemia and the 1-year risk of recurrence.
        Clin J Am Soc Nephrol. 2021; 16: 365-373