Visceral Adiposity May Explain Much of CKD Seen in Older Adults With HFpEF

Older adults living with heart failure with preserved ejection fraction (HFpEF) are frequently labeled as having chronic kidney disease (CKD), but a growing body of evidence suggests that much of this perceived overlap reflects age-related physiology, hemodynamic effects of heart failure, and obesity rather than progressive intrinsic kidney injury.

In a comprehensive review and critical analysis published in the Journal of the American College of Cardiology, investigators argued that visceral adiposity is the dominant biological link between HFpEF and reduced kidney function, while the true prevalence of clinically meaningful CKD in this population is substantially lower than commonly reported.¹ The authors concluded that obesity-driven neurohormonal and adipokine pathways—not hypertension or diabetes alone—were the principal drivers of kidney injury among patients with HFpEF.

HFpEF disproportionately affects older adults, with a mean age of 70 to 80 years in clinical trials and community cohorts. In parallel, reduced estimated glomerular filtration rate (eGFR) is common in aging populations, even in the absence of structural kidney disease.² However, CKD in HFpEF has traditionally been defined using a creatinine-based eGFR threshold of less than 60 mL/min/1.73 m², a cutoff that does not account for age-related declines in kidney function.³

According to the authors, this approach likely overestimates CKD prevalence in HFpEF and may obscure the mechanisms truly responsible for kidney-related risk in this population.¹ “The conventional definition of chronic kidney disease does not distinguish physiological aging from intrinsic renal disease,” the investigators wrote.

When age-adjusted thresholds were applied—specifically, defining clinically meaningful kidney disease as an eGFR below 45 mL/min/1.73 m² in adults older than 70 years—the estimated prevalence of impaired glomerular function in HFpEF fell markedly. Across large HFpEF trials, prevalence declined from approximately 45% to 55% using the conventional definition to roughly 15% to 25% with age adjustment.

Importantly, progression to end-stage kidney disease was rare. Long-term follow-up data from HFpEF trials showed annual rates of kidney failure below 0.5%, far lower than competing risks such as cardiovascular death. Even sustained declines in eGFR were often reversible and related to intrarenal hemodynamic changes or heart failure therapies, rather than irreversible kidney injury.

The authors emphasized that commonly used measures of kidney function are particularly problematic in people with obesity, which affects nearly two-thirds of individuals with HFpEF. Creatinine-based eGFR may be confounded by reduced muscle mass in older adults, whereas cystatin C–based estimates can be falsely low because adipose tissue itself secretes cystatin C. In the SUMMIT trial of individuals with HFpEF and obesity, the prevalence of eGFR less than 60 mL/min/1.73 m² increased from about 45% using creatinine to more than 60% when cystatin C was used, despite no evidence of worsened structural kidney disease.

Rather than hypertension or hyperglycemia directly causing kidney disease in HFpEF, the authors pointed to visceral adiposity as the unifying mechanism linking HFpEF, CKD, type 2 diabetes, and hypertension. Expanded visceral fat mass was associated with sympathetic nervous system activation, renin-angiotensin-aldosterone system upregulation, and secretion of proinflammatory adipokines such as leptin, alongside suppression of protective adiponectin signaling.

These changes promoted sodium retention, renal inflammation, and tubulointerstitial fibrosis independent of measured eGFR. Perirenal and renal sinus fat depots, in particular, were implicated in paracrine injury to adjacent kidney tissue and worsening renal hemodynamics.

“Visceral adiposity is not only the prime driver of HFpEF, but it is also the principal determinant of its association with chronic kidney disease,” the authors wrote.

Clinical interventions that reduce visceral adiposity appeared to support this hypothesis. Bariatric surgery and glucagon-like peptide-1 (GLP-1) receptor agonists were associated with improvements in HFpEF symptoms and reductions in major adverse kidney outcomes, even among people without diabetes.

The analysis drew on data from large HFpEF trials and epidemiologic cohorts that predominantly included older adults, many of whom had obesity, hypertension, or type 2 diabetes. Albuminuria—often used as a marker of intrinsic kidney disease—was uncommon in HFpEF in the absence of diabetes, further supporting the notion that structural kidney injury is not the dominant pathology in most patients.

The authors acknowledged that their conclusions were based on a synthesis of observational data, mechanistic studies, and trial results rather than a single prospective investigation. Direct histologic confirmation of kidney pathology in HFpEF was limited, and long-term effects beyond typical trial durations remain uncertain. Additionally, while obesity reduction strategies showed promise, randomized trials specifically powered for kidney outcomes in HFpEF remain sparse.

For payers and clinicians, the findings raise questions about risk stratification, CKD labeling, and treatment priorities in HFpEF. The authors suggested that interventions targeting visceral adiposity may offer greater kidney and cardiovascular benefit than strategies focused solely on blood pressure or glycemic targets.

Recognizing obesity-related mechanisms may help avoid overdiagnosis of CKD, reduce unnecessary care escalation, and better align treatment with underlying disease biology in this growing population.

Reference

1. Packer M, Testani JM, Butler J, et al. Chronic kidney disease in patients with heart failure with a preserved ejection fraction: the underlying role of visceral adiposity. J Am Coll Cardiol. 2025;86(20):1900-1916. doi:10.1016/j.jacc.2025.08.086
2. Bashir Z, Chen EW, Tori K, et al. Insight into different phenotypic presentations of heart failure with preserved ejection fraction. Prog Cardiovasc Dis. 2023;79:80-88. doi: 10.1016/j.pcad.2023.07.003
3. Löfman I, Szummer K, Dahlström U, Jernberg T, Lund LH. Associations with and prognostic impact of chronic kidney disease in heart failure with preserved, mid-range, and reduced ejection fraction. Eur J Heart Fail. 2017;19:1606-1614. doi:10.1002/ejhf.821