Tubular Biomarkers and Retinal Microvasculature

The American Heart Association recently introduced the cardiovascular-kidney-metabolic (CKM) syndrome framework1 to emphasize the interconnected risks of cardiovascular disease (CVD), CKD, and metabolic disorders. CKM highlights the urgent need for earlier recognition of subclinical disease and for integrated management strategies across specialties. A key feature of the CKM concept is the cross-talk between organs. The heart, kidneys, and metabolic tissues communicate through hemodynamic, inflammatory, and metabolic pathways, creating a network where dysfunction in one organ can exacerbate injury in others, amplifying risk of adverse cardiovascular and kidney outcomes. Risks associated with the different stages of CKM syndrome are cumulative and synergistic, with each additional CKM component (hypertension, diabetes, CKD, dysfunctional adipose tissue, and hyperlipidemia) amplifying the risk of adverse outcomes such as microvascular dysfunction, atherosclerotic CVD, heart failure, and kidney failure. A large cohort study demonstrated that each additional CKM component increases all-cause mortality risk by 22% and CVD mortality by 37%, with a marked increase in incident ESKD risk, compared with individuals without any CKM components.2 This convergence of metabolic risk factors and CKD highlights the need for early detection and integrated management strategies that address not only glycemic issues, but also cardiovascular and renal health. Early identification of high-risk individuals is clinically important because it allows intervention before irreversible organ damage occurs, particularly in the era of novel disease-modifying therapies that reduce cardiovascular risk, slow kidney disease progression, and lower all-cause mortality.3 Within this organ cross-talk, kidney tubular injury has emerged as a sensitive yet often underrecognized contributor to systemic microvascular health. Although glomerular markers, such as eGFR and albuminuria, have been studied extensively and are commonly used in clinical practice,4 tubular biomarkers remain comparatively less explored and less frequently applied, despite their critical roles in reflecting tubular injury and in serving as indicators of interorgan communication, influencing systemic inflammation and metabolic homeostasis. Key tubular biomarkers, including kidney injury molecule-1 (KIM-1), soluble urokinase plasminogen activator receptor (suPAR), monocyte chemoattractant protein-1, TNF receptors 1 and 2, EGF, α-1 microglobulin, and uromodulin, are involved in systemic processes as well as in local tubular injury.5 Tubular injury biomarkers may also provide unique insights into early CKM pathophysiology. By detecting subclinical tubular injury, these biomarkers can reveal disruptions in interorgan communication. Tubular stress may activate systemic inflammatory pathways, impair endothelial function, and influence vascular tone, ultimately affecting the heart and blood vessels. KIM-1, a transmembrane protein upregulated on proximal tubular epithelial cells under conditions of ischemic or toxic stress, has been associated with left ventricular hypertrophy, decline in renal function, and the progression of both CKD and CVD.5–7 Conversely, suPAR is a circulating signaling glycoprotein and marker of immune activation, thought to be directly involved in the pathogenesis of kidney disease and kidney injury across multiple clinical contexts. Elevated suPAR levels have been associated with structural and functional cardiovascular abnormalities, progression of CKD, and immune-mediated mechanisms contributing to the pathophysiology of cardiorenal disease.5,8 Retinal vascular measurements provide a noninvasive approach to evaluate systemic microvascular function. Changes in retinal arteriolar and venular diameters have been associated with impaired vascular function and an increased risk of CVD and CKD. These changes reflect the influence of vascular disease, metabolic stress, and microvascular dysfunction. Accordingly, associations between retinal arteriolar and venular diameters and tubular biomarkers may indicate microvascular rarefaction, an early feature of endothelial dysfunction. The multiethnic study of atherosclerosis (MESA) is a large, prospective, community-based, cohort study designed to investigate the prevalence, progression, and risk factors of subclinical atherosclerosis and its cardiovascular, renal, and metabolic consequences.9 Notably, MESA also measured tubular biomarkers, providing a unique opportunity to explore the relationship between early kidney tubular injury and systemic microvascular health in a diverse, community-dwelling population.6,8 From July 2000 to July 2002, MESA enrolled 6814 adults age 45–84 years from six US communities, intentionally including a diverse cohort of Asian, Black, Hispanic, and White participants, while excluding individuals with clinically apparent CVD at baseline. Ahmadi et al. offer a compelling illustration of the relevance of tubular biomarkers to systemic microvascular health represented in retinal microvascular changes.9 In a subset of 470 participants without diabetes, CKD, or CVD, they measured six plasma and six urinary tubular biomarkers, retinal vascular diameters, central retinal arteriolar equivalents (CRAE), and central retinal venular equivalents (CRVEs), using fundus photography. Assessing tubular biomarkers in individuals without overt cardiovascular, renal, or metabolic disease provides critical insights into early pathophysiologic changes and the mechanisms linking subclinical tubular injury to systemic microvascular dysfunction. The authors demonstrated that higher plasma and urinary KIM-1 levels were associated with narrower CRAE, whereas elevated plasma suPAR concentrations were linked to CRAE and CRVE. Importantly, these associations were observed in individuals with preserved kidney function and no albuminuria, indicating that tubular perturbations can manifest in systemic microvascular changes well before traditional renal or cardiovascular markers detect overt clinical disease, even in the absence of diabetes. This cross-organ communication underscores that kidney health cannot be considered in isolation; subtle tubular dysfunction may propagate microvascular and metabolic disturbances that increase future CVD risk, even in individuals without overt CKD or diabetes. This supports the notion of tubular-vascular cross-talk, in which the kidney communicates injury signals to distant vascular beds, amplifying CKM risk even in the absence of overt CKD or diabetes in the very early phase of the CKM syndrome. The integration of tubular biomarkers and retinal imaging offers a conceptual advance, by broadening the understanding of CKM pathophysiology, and a practical advance, by enabling earlier risk detection and assessment of organ cross-talk. First, it identifies subclinical CKM risk; patients with preserved eGFR and absent albuminuria may nonetheless exhibit tubular injury and early microvascular changes. Second, it highlights multiorgan interactions; tubular injury may initiate or exacerbate systemic endothelial dysfunction, which in turn can affect cardiovascular and metabolic outcomes. Clinically, these insights suggest a paradigm shift in risk stratification. Screening for tubular biomarkers could complement traditional measures, allowing earlier intervention in individuals with an elevated risk of CKM. Moreover, combining tubular biomarkers with imaging and other systemic markers could enable an individualized approach for treating CKM by identifying high-risk patients before clinical events occur and thereby guiding multidisciplinary interventions. Additional investigation is needed to determine whether tubular injury actively drives systemic microvascular dysfunction or simply reflects a parallel process of systemic inflammation in early CKM syndrome. Understanding these pathways may identify novel targets for early therapeutic intervention, potentially enhancing the benefits of emerging cardio-renal protective agents with metabolic effects, such as sodium–glucose cotransporter (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists, in at-risk populations. Mechanistically, SGLT2 inhibitors are well-established in reducing proximal tubular workload, lowering intraglomerular pressure, and attenuating inflammation and fibrosis, processes closely associated with elevated KIM-1 expression. Recent studies have demonstrated that SGLT2 inhibition decreases both circulating and urinary levels of KIM-1 in patients with CKD, independent of baseline albuminuria. These are accompanied by reductions in other markers of tubular injury and inflammation, supporting the rationale for early intervention before irreversible organ damage occurs.10 Several limitations of the study merit consideration.9 First, the cross-sectional design limits causal inference. Second, although CRAE and CRVE are validated, they are surrogate markers of microvascular health and do not directly capture clinical events. In addition, the data were collected more than 20 years ago, and information on contemporaneous treatments, including aspirin, renin-angiotensin system inhibitors, and statins, was not presented. BP was measured at a single time point, which may not reflect long-term exposure. The authors noted and explained that the divergent associations observed in their study—specifically, wider CRAE and CRVE correlating with higher suPAR—may reflect complex vessel-specific inflammatory responses that vary according to the stage of injury, hemodynamic conditions, or microvascular territory. Despite these limitations, the study provides novel and important insights into early CKM pathophysiology and highlights the potential of tubular biomarkers to detect subclinical vascular and renal perturbations.