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Medical Associates  ·  Department of Nephrology ← urinenephrology.org
Clinical Mastery Series

HFpEF as a Cardiorenal-Metabolic Disease

A Nephrology-Focused Clinical Review: From Phenomapping to FINEARTS-HF
Andrew Bland, MD, FACP, FAAP UICOMP · UDPA · Butler COM 2026-07-03 5 min read

The Kidney Sits at the Pathophysiological Heart of HFpEF

The Paulus-Tschope paradigm established that comorbidities—obesity, diabetes, CKD, hypertension—drive HFpEF through coronary microvascular endothelial inflammation rather than ischemia-mediated cardiomyocyte death. This inflammatory cascade begins when elevated IL-6, TNF-alpha, and CRP provoke endothelial dysfunction, reducing nitric oxide bioavailability, ultimately causing titin hypophosphorylation and increased cardiomyocyte stiffness.

Mineralocorticoid Receptor Overactivation

Perhaps the most therapeutically actionable pathway linking CKD to HFpEF. MRs expressed in cardiomyocytes, fibroblasts, vascular endothelium, and immune cells stimulate TGF-beta, IL-6, and PAI-1, promoting fibrosis in both organs simultaneously. Critically, obesity and hyperglycemia cause ligand-independent MR activation even without elevated aldosterone.

Galectin-3

Central mediator of bidirectional cardiorenal injury. Reduced eGFR correlates strongly with increased galectin-3 (r = −0.71, p = 0.01). Kidney injury upregulates galectin-3, which then initiates cardiac inflammatory and fibrotic processes.

Hemodynamic Consequences

Reduced GFR decreases sodium filtration capacity while RAAS activation prevents compensatory reductions in tubular reabsorption. Elevated central venous pressure from HFpEF reduces the arteriovenous pressure gradient across the kidney, creating “renal tamponade” that further decreases GFR.

Albuminuria Predicts Heart Failure with Striking Consistency

ARIC Study (10,975 participants, 8.3 years): Continuous graded relationship between UACR and HF incidence, extending even within the “normal” range:

UACR Category HR for Incident HF
Optimal (<5 mg/g)Reference
Intermediate-normal (5–9 mg/g)HR 1.54
High-normal (10–29 mg/g)HR 1.91
Microalbuminuria (30–299 mg/g)HR 2.49
Macroalbuminuria (≥300 mg/g)HR 3.47

HOPE study: Every 0.4 mg/mmol UACR increase raises HF hospitalization risk by 11%. TOPCAT: 50% albuminuria reduction decreased HF hospitalization by approximately 30–70%.

Shah's Phenomapping: CKD as the Highest-Risk HFpEF Phenotype

The 2016 Circulation study by Shah et al. analyzed 397 HFpEF patients using 67 continuous phenotypic variables, identifying three distinct phenogroups through unbiased hierarchical clustering.

High-Risk Phenotype

Phenogroup 3—the “CKD-vascular aging” phenotype—demonstrated HR 4.2 (95% CI 2.0–9.1, p<0.001) for HF hospitalization. Characterized by older age (median 75), CKD as the defining feature, 43% AF prevalence, pulmonary hypertension, and RV dysfunction.

Clinical Pearl

The TOPCAT phenogroup analysis identified a similar cluster with the best response to spironolactone (NNT 14). CKD-associated HFpEF represents both the highest-risk phenotype and the subgroup most likely to benefit from targeted therapy.

The CKM Syndrome Framework (AHA 2023)

Formally defined by Ndumele et al. (October 2023 AHA Presidential Advisory) as “a systemic disorder characterized by pathophysiological interactions among metabolic risk factors, CKD, and the cardiovascular system.”

StageDefinitionKey Actions
0No CKM risk factorsPrevention
1Excess/dysfunctional adiposityScreen with eGFR + UACR even here
2Metabolic risk factors or moderate-high CKDSGLT2i for CKD, HF, or T2D (eGFR ≥20)
3Subclinical CVD or risk equivalent; KDIGO G4/G5 (eGFR <30) = automatic Stage 3Intensive prevention; add finerenone for DKD with UACR >300 on ACEi/ARB
4a/4bEstablished CVD ± kidney failureFull cardiorenal GDMT
Clinical Pearl

KDIGO Stage G4/G5 CKD (eGFR <30) is now treated as a cardiovascular risk equivalent under the CKM framework, warranting intensive prevention even without overt CVD.

SGLT2 Inhibitors: Class I, Level A for HFpEF

EMPEROR-Preserved

5,988 patients, LVEF >40%: empagliflozin HR 0.79 (95% CI 0.69–0.90; p<0.001), NNT 30 over 26.2 months. Consistent benefit regardless of diabetes status.

DELIVER

6,263 patients, LVEF >40%: dapagliflozin HR 0.82 (95% CI 0.73–0.92; p<0.001). Benefit maintained even with LVEF ≥60%.

Pooled Meta-Analysis (n=12,251)

Consistent benefit across all prespecified subgroups including LVEF ≥60%. The 2023 ESC Focused Update upgraded SGLT2i to Class I, Level A for HFmrEF and HFpEF.

FINEARTS-HF: Finerenone as Definitive HFpEF Therapy

6,001 patients, LVEF ≥40%, across 634 sites in 37 countries: primary composite rate ratio 0.84 (95% CI 0.74–0.95; p=0.007) — 16% relative risk reduction. Remarkably consistent across the EF spectrum (p for interaction = 0.75).

Hyperkalemia Monitoring

K+ >5.5 mmol/L: 14.3% finerenone vs. 6.9% placebo (2.6-fold increase). By eGFR: eGFR ≥60 (0.3% vs 0.1% hospitalization), eGFR 45–<60 (0.4% vs 0.3%), eGFR <45 (1.2% vs 0.4%). No deaths attributable to hyperkalemia.

Finerenone Advantages Over Steroidal MRAs

  • No affinity for androgen or progesterone receptors — eliminates gynecomastia, breast pain, menstrual irregularities
  • ARTS trial: hyperkalemia 5% (finerenone) vs. 12% (spironolactone), p=0.05
  • Balanced heart-kidney tissue distribution vs. steroidal MRAs (kidney-concentrated)
  • AMBER trial: spironolactone caused hyperkalemia in 64.2% vs. 11.6% with finerenone in FIDELITY

FIDELIO/FIGARO/FIDELITY for DKD

  • FIDELIO-DKD: Renal composite HR 0.82 (p=0.001); CV composite HR 0.86 (p=0.03)
  • FIGARO-DKD: CV composite HR 0.87 (p=0.03); HF hospitalization HR 0.71 (29% reduction); new-onset HF reduced by 32%
  • FIDELITY pooled (n=13,171): CV composite HR 0.86, kidney composite HR 0.77, HF hospitalization HR 0.82

CONFIDENCE Trial: Simultaneous Initiation

Phase II trial (NEJM 2025): simultaneous finerenone + empagliflozin achieved 52% UACR reduction — 29% greater than finerenone alone and 32% greater than empagliflozin alone. SAEs similar across groups (~6–7%).

Clinical Pearl

Hyperkalemia with finerenone was substantially lower in SGLT2i users: 8.1% vs. 18.7% without SGLT2i. This suggests SGLT2i may mitigate finerenone-associated hyperkalemia through natriuretic and kaliuretic effects.

KDIGO 2024 Sequential Approach

  1. Optimize ACEi/ARB to maximum tolerated dose
  2. Add SGLT2i regardless of diabetes status if eGFR ≥20
  3. Add finerenone if persistent UACR ≥30 despite RAASi + SGLT2i (eGFR ≥25, K+ ≤5.0)
  4. Consider GLP-1 RA if additional glycemic control, CV risk reduction, or weight management needed

Finerenone Dosing

eGFRStarting DoseTarget
≥6020 mg daily20–40 mg
25–<6010 mg daily20 mg
<25Not recommended for initiation

Monitor K+ and eGFR at 4 weeks post-initiation. Uptitrate if K+ ≤4.8 and eGFR stable. If K+ >5.5: hold until ≤5.0, then restart at lower dose.

HFpEF Screening in Nephrology Practice

ADA 2024: Screen for asymptomatic HF in diabetics using BNP or NT-proBNP. In CKD (eGFR <60), higher thresholds of 200–400 pg/mL may be appropriate.

Practical Nephrology Screening Algorithm

  1. All T2D + CKD patients: annual NT-proBNP
  2. NT-proBNP ≥125 pg/mL (≥200 if eGFR <45): trigger echocardiography
  3. Combine symptoms + elevated NP + echo abnormalities → HFA-PEFF scoring
  4. Scores 2–4: cardiology referral
  5. Scores ≥5: confirm diagnosis; initiate SGLT2i + consider finerenone

The Four Pillars of Cardiorenal Protection

  1. RAASi (ACEi/ARB) — foundation of cardiorenal therapy
  2. SGLT2i — Class I, Level A for HFpEF
  3. Finerenone — definitive MRA for HFpEF and DKD
  4. GLP-1 RA — complementary CV, renal, and metabolic benefits

References

  1. Shah SJ, et al. Phenomapping for novel classification of HFpEF. Circulation. 2015;131(3):269-279. PubMed
  2. Ndumele CE, et al. Cardiovascular-kidney-metabolic health: AHA Presidential Advisory. Circulation. 2023;148(20):1606-1635. PubMed
  3. Anker SD, et al. Empagliflozin in HFpEF (EMPEROR-Preserved). N Engl J Med. 2021;385(16):1451-1461. PubMed
  4. Solomon SD, et al. Dapagliflozin in HFmrEF/HFpEF (DELIVER). N Engl J Med. 2022;387(12):1089-1098. PubMed
  5. Bakris GL, et al. Finerenone reduces kidney failure events (FIDELIO-DKD). N Engl J Med. 2020;383(23):2219-2229. PubMed
  6. Pitt B, et al. Cardiovascular events with finerenone in DKD (FIGARO-DKD). N Engl J Med. 2021;385(24):2252-2263. PubMed
  7. Solomon SD, et al. Finerenone in HFmrEF and HFpEF (FINEARTS-HF). N Engl J Med. 2024;391(16):1475-1485. PubMed
  8. Green JB, et al. CONFIDENCE trial: finerenone + empagliflozin in DKD. N Engl J Med. 2025;392(6):533-543. PubMed
  9. Arnott C, et al. Albuminuria and risk of incident heart failure: ARIC Study. Eur Heart J. 2020;41(27):2558-2567. PubMed Search
  10. Paulus WJ, Tschope C. A novel paradigm for HFpEF: comorbidities drive myocardial dysfunction. J Am Coll Cardiol. 2013;62(4):263-271. PubMed

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