Proteinuria Reduction Linked to Lower Heart Failure and Mortality Risk in CKD

Patients with chronic kidney disease (CKD) who achieved at least a 30% reduction in proteinuria over 1 year had significantly lower risks of major adverse cardiovascular events (MACE), heart failure (HF), and all-cause mortality, according to research presented at the American Heart Association's (AHA) Epidemiology and Prevention, Lifestyle and Cardiometabolic Health Scientific Sessions 2026 in Boston, Massachusetts. The association remained consistent across diabetes status, highlighting proteinuria as a dynamic biomarker across the cardiovascular-kidney-metabolic (CKM) continuum.¹

Study Findings

Investigators analyzed 3073 participants with established CKD from the Chronic Renal Insufficiency Cohort who had repeated 24-hour urine protein measurements at baseline and 1 year. Participants had a mean age of about 58.2 years, approximately 45.5% were female, and the median baseline 24-hour urine protein was 161 mg. Most participants (68.9%) were receiving angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy. Median follow-up ranged from 10.7 to 13.7 years.¹

Using time-varying Cox proportional hazards models adjusted for demographics, body mass index, smoking, prior cardiovascular disease, laboratory parameters, and baseline proteinuria, researchers found that a reduction in proteinuria of 30% or greater was associated with 22% lower risk of MACE (HR, 0.78; 95% CI, 0.66-0.93), 26% lower risk of HF (HR, 0.74; 95% CI, 0.59-0.94), and 22% lower risk of all-cause mortality (HR, 0.78; 95% CI, 0.68-0.90). The association with atherosclerotic cardiovascular disease events did not reach statistical significance (HR, 0.93; 95% CI, 0.76-1.13).¹

Importantly, restricted cubic spline analysis demonstrated a linear, graded association between greater proteinuria reduction and lower risk of MACE, HF, and mortality. The MACE benefit was primarily driven by reduction in HF events rather than ischemic events, underscoring the cardiorenal coupling of proteinuric injury.¹

Context in CKM Syndrome Management

The findings align with the AHA's CKM syndrome framework, which emphasizes the interconnected nature of metabolic risk factors, kidney disease, and cardiovascular outcomes. Regular screening for albuminuria and proteinuria represents a central element of CKM syndrome assessment, with proteinuria reduction serving as both a treatment target and prognostic indicator.^2,3

ACE inhibitors and ARBs reduce proteinuria by approximately 35% to 40% in controlled trials through reduction of intraglomerular pressure and blockade of angiotensin II-mediated inflammation and fibrosis. Clinical practice guidelines recommend titrating these agents to the maximum tolerated dose to optimize proteinuria reduction and kidney protection. However, real-world data show that only 30% of patients with proteinuria receive maximal ACE inhibitor or ARB doses, representing a significant treatment gap.^4-6

Newer agents, including sodium-glucose cotransporter-2 (SGLT2) inhibitors and the nonsteroidal mineralocorticoid receptor antagonist finerenone (Kerendia; Bayer), provide additional proteinuria reduction beyond renin-angiotensin system inhibition. SGLT2 inhibitors reduce proteinuria through hemodynamic effects and anti-inflammatory mechanisms, with consistent cardiovascular and kidney benefits demonstrated across CKD populations. Finerenone, when added to maximally tolerated ACE inhibitor or ARB therapy in patients with diabetic kidney disease, reduces both cardiovascular events and kidney disease progression, with particular benefits for HF hospitalization reduction.^2,3,7

Clinical Implications for Pharmacists

Pharmacists should recognize proteinuria reduction as a key therapeutic goal in CKD management that extends beyond kidney protection to cardiovascular risk reduction. When reviewing medication regimens for patients with CKD and proteinuria, pharmacists should verify that ACE inhibitors or ARBs are prescribed at guideline-recommended doses. Patients receiving submaximal doses without documented intolerance or contraindications represent opportunities for optimization.

For patients with CKD and diabetes, pharmacists should advocate for SGLT2 inhibitor therapy in addition to ACE inhibitor or ARB treatment. The combination provides complementary mechanisms of proteinuria reduction and has demonstrated synergistic cardiovascular and kidney protection. Patients with persistent proteinuria despite maximally tolerated renin-angiotensin system inhibition may benefit from finerenone, which can be safely initiated when estimated glomerular filtration rate exceeds 25 mL/min/1.73 m² and serum potassium is below 5 mEq/L.

Patient education should emphasize that proteinuria reduction reflects improved disease control and lower future risk of cardiovascular events, kidney failure, and death. Pharmacists can reinforce adherence by explaining that medications controlling proteinuria provide heart and kidney protection even when patients feel well. Regular urine protein monitoring through spot urine albumin-to-creatinine ratio or 24-hour urine collection enables assessment of treatment response and guides therapy intensification when needed.

REFERENCES

1. Verma A, Claudel SE, Zhao R, et al. Proteinuria reduction and cardiovascular and mortality outcomes in chronic kidney disease: evidence across the CKM continuum. Presented at: American Heart Association Epidemiology, Prevention, Lifestyle and Cardiometabolic Health Scientific Sessions 2026; March 19, 2026; Boston, MA. Abstract MPTH68.

2. Ndumele CE, Rangaswami J, Chow SL, et al; American Heart Association. Cardiovascular-kidney-metabolic health: a presidential advisory from the American Heart Association. Circulation. 2023;148(20):1606-1635. doi:10.1161/CIR.0000000000001184

3. Ndumele CE, Neeland IJ, Tuttle KR, et al; American Heart Association. A synopsis of the evidence for the science and clinical management of cardiovascular-kidney-metabolic (CKM) syndrome: a scientific statement from the American Heart Association. Circulation. 2023;148(20):1636-1664. doi:10.1161/CIR.0000000000001186

4. National Kidney Foundation. KDOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;43(suppl 1):11-13. doi:10.1053/j.ajkd.2004.03.003

5. Chu CD, Powe NR, Estrella MM, Shlipak MG, McCoy IE, Tuot DS. Submaximal angiotensin converting enzyme inhibitor and angiotensin receptor blocker dosing among persons with proteinuria. Mayo Clin Proc. 2022;97(11):2099-2106. doi:10.1016/j.mayocp.2022.07.010

6. Qiao Y, Shin JI, Sang Y, et al. Discontinuation of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in chronic kidney disease. Mayo Clin Proc. 2019;94(11):2220-2229. doi:10.1016/j.mayocp.2019.05.031

7. Bakris GL, Agarwal R, Anker SD, et al; FIDELIO-DKD Investigators. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383(23):2219-2229. doi:10.1056/NEJMoa2025845