Galectin-3 and Cardio-Kidney Outcomes: A Bit of History Repeating

Cardiovascular disease (CVD) and chronic kidney diseases (CKDs) are linked through overlapping mechanisms of inflammation, fibrosis, and hemodynamic stress.¹ Identification of a unifying biomarker for both conditions would be of clinical importance for risk prediction and management; at population level, it could influence prevention strategies, guide resource allocation, and ultimately improve outcomes for over 400 million people living with concomitant CVD and CKD.²

First identified in the 1980s as a β-galactoside-binding lectin in macrophages, galectin-3 was subsequently found to be widely distributed across various tissues and cell types, in which it plays roles in cell adhesion, proliferation, apoptosis, inflammation, and fibrosis.³ The protein’s multifunctionality has led to its investigation in numerous physiological and pathological states, including cardiovascular and kidney diseases, cancer, and immune responses.³ By stabilizing TGF-β receptor 2 and amplifying TGF-β1 signaling, galectin-3 drives fibroblast activation, myofibroblast differentiation, and extracellular matrix expansion, producing myocardial and tubulointerstitial fibrosis.4, 5, 6 In addition, galectin-3 sustains immune cell recruitment and activation, perpetuating chronic inflammation.^4,7 These combined processes promote adverse ventricular remodeling and heart failure in the myocardium, whereas in the kidney, they accelerate CKD progression and loss of renal function.^4,8, 9, 10

Persistently elevated or increasing galectin-3 levels over time have been repeatedly associated with adverse cardiovascular outcomes, including incident heart failure, coronary heart disease, stroke, and all-cause mortality.11, 12, 13 Similarly, elevated galectin-3 levels have been associated with kidney outcomes, including incident CKD, accelerated decline in renal function, and progression of nephropathy in both diabetic and general population.^9,10,14 In advanced kidney disease and dialysis populations, higher galectin-3 levels were found to be independently associated with increased risk of all-cause mortality, cardiovascular events, and infections.¹⁵

The study by Banerjee et al¹⁶ provides additional, novel data on the association between plasma galectin-3 level and major CVD and kidney outcomes. In an observational cohort of 882 ambulatory Veterans referred for outpatient echocardiogram for various clinical indications, the authors demonstrated that plasma galectin-3 levels were independently associated with 54%, 81%, and 92% greater risk of major adverse cardiac events (MACEs; hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.02-2.32), all-cause death (HR, 1.81; 95% CI, 1.41-2.33), and major adverse kidney events (MAKEs; HR, 1.92; 95% CI, 1.20-3.08), defined as initiation of renal replacement therapy or ≥40% decline in estimated glomerular filtration rate, respectively. Each doubling of galectin-3 level was associated with more than 3 times higher risk of having both MACEs and MAKEs (HR, 3.57; 95% CI, 1.63-7.84). Interestingly the association with heart failure or acute coronary syndrome was not significant after adjusting for confounders. This warrants further study because multiple cohort studies have demonstrated associations between galectin-3 and heart failure events, and experimental models show that its inhibition mitigates fibrosis and improves cardiac function.^5,12,13,17

The timing for reconsidering galectin-3 as a dual biomarker for heart and kidney health is particularly relevant. Recent updates in cardiovascular and kidney disease guidelines have renewed emphasis on cardio-kidney outcomes and the role of fibrosis and inflammation as therapeutic targets.¹ The current study reaffirms galectin-3 associations with major adverse CVD, kidney disease progression, and mortality in a contemporary population, reinforcing that galectin-3 is not an incidental finding but a persistent pattern. This may be an opportune moment to ask whether galectin-3 is more than a signal of risk and whether its biology can be used to advance prediction and therapy. The plausibility of galectin-3 as a unifying biomarker rests on its biology, with elevated circulating levels likely reflecting systemic fibrotic activation across multiple organ systems.

Galectin-3 circulates predominantly as a freely filterable 30 kDa monomer. However, high inflammatory states (ie, CKD, diabetes, heart failure, etc.) result in increased levels of circulating glycoproteins and inflammatory mediators that can promote its oligomerization, resulting in higher-order polymers, increasing its effective molecular size, and limiting its glomerular filtration. Plasma galectin-3 levels increase with worsening kidney function: from ∼13 ng/mL at eGFR ≥90 to >50 ng/mL in dialysis cohorts.¹⁵ This is a reflection of impaired renal clearance and increased production from activated fibroblasts/macrophages in advanced CKD. The relative weight of these mechanisms remains unclear, and careful adjustment for kidney function is essential because data on galectin-3 as a prognostic biomarker in CKD cohorts are mixed.^15,18 Beyond eGFR, adjustment for albuminuria, which was not performed in the study by Banerjee et al,¹⁶ would provide greater confidence that kidney function is appropriately accounted for. Complementing plasma measurement, urinary galectin-3 may offer a direct window into intrarenal fibrotic activity. In peripheral artery disease, the ratio of plasma to urinary galectin-3 was independently associated with long-term outcomes.¹⁹ Incorporating urinary with plasma galectin-3 levels could clarify whether the observed increased levels reflect systemic fibrosis, or impaired renal clearance. For kidney outcomes, urinary galectin-3 may ultimately prove more specific, and future studies should test whether combined serum and urinary measures improve prediction of MAKEs.

Current professional societies guidelines acknowledge galectin-3 as a fibrosis biomarker with pathophysiologic relevance to heart failure and cardiorenal interactions but do not recommend serial measurement or timing for reassessment.^17,20 Proponents may argue that the consistent associations of galectin-3 across studies, including the current one,¹⁶ and its strong mechanistic links to fibrosis justify broader clinical use today. Others may argue that a biomarker does not need to guide therapy directly to provide value in risk stratification. Both perspectives hold merit, but the weight of evidence suggests otherwise. Without clear incremental predictive value beyond clinically available biomarkers, such as natriuretic peptide, troponins, eGFR, and albuminuria, routine testing adds little to current practice. Moreover, interpreting elevated galectin-3 levels in patients with reduced kidney function remains problematic. Until robust evidence demonstrates that measuring galectin-3 levels meaningfully improves patient care or that targeting its biology changes outcomes, it will remain a research biomarker rather than a clinical one.

The study’s strengths include a well-characterized cohort followed for an extended time and clinically meaningful outcomes spanning both organ systems. The consistency of these associations with prior evidence reinforces external validity.10, 11, 12, 13^,15 Nevertheless, several considerations warrant caution. Referral for echocardiography may have resulted in selection of participants with a higher baseline CVD risk, potentially inflating the observed associations. Outcomes were determined by medical record abstraction rather than rigorous adjudication, raising the possibility of misclassification. Analytic adjustment for albuminuria, a well-established predictor of renal and CVD outcomes was not specified, leaving residual confounding possible. Missing longitudinal creatinine values may have biased MAKE definitions if excluded patients differed systematically. Finally, long-term stability of galectin-3 under storage and repeated freeze–thaw cycles requires explicit validation for reproducibility.

We have seen a plethora of observational studies on the association between galectin-3 and clinical outcomes in various cohorts. The time is now to clarify mechanism, standardize measurement, and test therapeutic relevance.

The study by Banerjee et al¹⁶ adds to the growing body of evidence linking galectin-3 with adverse clinical outcomes across the cardio-kidney continuum. Its role as a mediator of fibrosis and inflammation makes the associations biologically plausible. However, translation into clinical practice remains limited by modest incremental prognostic value, and the lack of targeted therapies. In many ways, this work reaffirms what prior studies have already shown, a signal that continues to resurface across cohorts and settings. The message is clear, but also familiar: when it comes to galectin-3, it is all just a little bit of history repeating. The critical question ahead is whether this marker will remain a witness to risk or evolve into a tool that shapes the future of cardio-kidney care.