Biomarkers of Organ Reserve Under Multimorbidity: Current Evidence and Clinical Implications

Abstract

Organ reserve, the capacity of an organ to withstand physiological stress, is a critical determinant of clinical outcomes in patients with multimorbidity. As the prevalence of multimorbidity escalates globally, there is a growing need to identify objective biomarkers that can reliably assess organ reserve across various systems. This review synthesizes current evidence on established and emerging biomarkers of organ reserve in the context of multimorbidity, discusses their mechanisms, clinical relevance, and practical applications, and explores future directions for research and practice.

Introduction

The concept of organ reserve refers to the functional capacity available in an organ to respond to increased demands or injury. In individuals with multimorbidity defined as the coexistence of two or more chronic conditions the assessment of organ reserve becomes particularly challenging and clinically significant. Accurate evaluation of organ reserve can inform risk stratification, guide therapeutic decision-making, and optimize patient outcomes. Advances in molecular medicine, imaging techniques, and systems biology have enabled the identification of novel biomarkers that provide insight into organ-specific and systemic reserve under the complex interplay of multiple diseases. This review aims to critically appraise the current landscape of biomarkers for organ reserve within the multimorbid population, integrating pathophysiological understanding with clinical utility.

Epidemiology / Disease Burden

Multimorbidity is a major public health concern, affecting more than one-third of adults in developed nations and increasing in prevalence with age. The burden of multimorbidity is associated with heightened healthcare utilization, polypharmacy, impaired quality of life, and increased mortality. As chronic diseases progress, the cumulative effect on organ systems leads to diminished reserve, predisposing patients to acute decompensation during stressors such as infection, surgery, or medication changes. The lack of readily accessible and validated measures of organ reserve complicates clinical management, emphasizing the need for robust biomarkers that reflect true physiological capacity beyond traditional disease markers.

Pathophysiology

Organ reserve is determined by a complex interplay of factors including tissue architecture, cellular regenerative potential, metabolic flexibility, and vascular supply. In multimorbidity, shared pathogenic mechanisms such as chronic inflammation, oxidative stress, endothelial dysfunction, and mitochondrial impairment converge to erode organ reserve. For example, in cardiac reserve, chronic heart failure and diabetes synergistically promote myocardial fibrosis and reduce contractile responsiveness. Renal reserve is compromised by cumulative insults from hypertension, diabetes, and nephrotoxic exposures, leading to reduced nephron endowment. The interplay of frailty, sarcopenia, and inflammatory cytokines further impairs musculoskeletal and immunological reserve, underscoring the need for integrated biomarkers that capture these multifaceted pathophysiological changes.

Risk Factors

Risk factors for reduced organ reserve in multimorbid patients include advanced age, polypharmacy, persistent low-grade inflammation, poor nutritional status, sedentary lifestyle, and the presence of specific chronic diseases such as chronic kidney disease, heart failure, chronic obstructive pulmonary disease, and neurodegenerative disorders. Genetics and epigenetic modifications may also modulate organ adaptability and susceptibility to decompensation. Understanding these risk factors is vital for selecting appropriate biomarkers and implementing preventive strategies.

Clinical Features

Clinically, diminished organ reserve may manifest as increased vulnerability to stress, reduced exercise tolerance, frequent exacerbations of chronic illness, and prolonged recovery times following acute events. Subtle early features such as orthostatic hypotension, mild cognitive decline, or reduced eGFR may precede overt organ failure. Biomarkers that can detect subclinical decline in reserve are therefore of high value for timely intervention in at-risk populations.

Diagnosis

Diagnosing impaired organ reserve requires a multimodal approach combining clinical assessment, functional testing, and biomarker evaluation. Cardiac reserve can be estimated by brain natriuretic peptide (BNP), N-terminal proBNP, and high-sensitivity troponin assays, alongside echocardiographic parameters (ejection fraction, strain imaging). Renal reserve is best captured by estimated glomerular filtration rate (eGFR), cystatin C, and emerging tubular injury markers such as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). For hepatic reserve, conventional markers (albumin, bilirubin, INR) are complemented by dynamic tests (indocyanine green clearance) and novel fibrosis biomarkers (Hyaluronic acid, ELF score). Skeletal muscle reserve is assessed by serum creatinine, myostatin, and imaging-based measures of muscle mass. Inflammatory markers (CRP, IL-6, TNF-α) and frailty indices further refine risk stratification.

Treatment & Management

Management of patients with reduced organ reserve centers on minimizing further insults, optimizing comorbidity control, and tailoring interventions to physiological capacity. Pharmacological regimens should be regularly reviewed to avoid polypharmacy and adverse drug interactions. Multidisciplinary care, including physiotherapy, nutritional support, and psychosocial interventions, plays a crucial role in preserving functional reserve. Biomarker-guided therapy such as titration of heart failure medications based on natriuretic peptide levels has shown promise in improving outcomes. Early identification of declining reserve enables timely referral for advanced therapies or palliative care when appropriate.

Recent Advances / Emerging Therapies

Recent years have witnessed the emergence of omics-based biomarkers, including transcriptomics, metabolomics, and proteomics, offering unprecedented insights into organ reserve dynamics. Circulating microRNAs and exosomal signatures are being explored as sensitive indicators of early tissue injury and regenerative potential. Machine learning algorithms integrating multi-biomarker panels with clinical and imaging data are enhancing predictive accuracy for organ decompensation. Interventions targeting mitochondrial function, senescence pathways, and inflammatory cascades are under investigation for their potential to restore or preserve organ reserve in multimorbid populations.

Guideline Recommendations

Current guidelines emphasize the importance of individualized care and comprehensive assessment in patients with multimorbidity. The use of validated biomarkers for organ reserve assessment is recommended, particularly in perioperative risk stratification, chronic disease management, and advanced care planning. Integration of biomarker data with frailty measures and patient-reported outcomes is advocated to guide shared decision-making and optimize resource allocation. Ongoing research and consensus development are needed to standardize biomarker use across clinical settings.

Conclusion

Biomarkers of organ reserve represent a vital tool in the management of patients with multimorbidity, offering objective measures for risk stratification, therapeutic targeting, and prognostication. While significant progress has been made in identifying and validating these biomarkers, challenges remain in translating findings into routine clinical practice. Multidisciplinary collaboration and continued research are essential to refine biomarker panels, integrate emerging technologies, and ultimately improve outcomes for this vulnerable patient population.