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Sequeira-Antunes, B.; Ferreira, H.A. Urinary Biomarkers for Early Diagnosis of Disease. Encyclopedia. Available online: (accessed on 23 April 2024).
Sequeira-Antunes B, Ferreira HA. Urinary Biomarkers for Early Diagnosis of Disease. Encyclopedia. Available at: Accessed April 23, 2024.
Sequeira-Antunes, Beatriz, Hugo Alexandre Ferreira. "Urinary Biomarkers for Early Diagnosis of Disease" Encyclopedia, (accessed April 23, 2024).
Sequeira-Antunes, B., & Ferreira, H.A. (2023, April 18). Urinary Biomarkers for Early Diagnosis of Disease. In Encyclopedia.
Sequeira-Antunes, Beatriz and Hugo Alexandre Ferreira. "Urinary Biomarkers for Early Diagnosis of Disease." Encyclopedia. Web. 18 April, 2023.
Urinary Biomarkers for Early Diagnosis of Disease

Urinary biomarkers are molecules found in urine that can be used as indicators of certain diseases or health conditions. The presence or absence of these biomarkers can help in the early detection of diseases, allowing for timely intervention and treatment, improving patients outcomes.

urine biomarkers proteins nucleic acids

1. Urine Metabolites and Their Role as Biomarkers

According to the World Health Organization (WHO), biomarkers are defined as “any substance, structure, or process that can be measured in the body or its products and influence or predict the incidence of outcome or disease” [1]. One of the many advantages of using biomarkers is that, unlike disease symptoms, which are subjective, biomarkers provide an objective and measurable way to characterise the disease [2]. They can often be measured by analysing blood or urine samples, helping clinicians avoid complex invasive procedures [3].
Urine is a rich source of cellular metabolites and an important, easily accessible biological fluid, and one of the most useful biofluids for routine testing [4]. Metabolomics is a novel field of science that seeks to quantitatively describe the fluctuations of numerous metabolites within organisms. It offers significant benefits in identifying disease biomarkers because certain metabolites can vary among individuals, indicating their unique metabolic traits and the underlying manifestations of their disease [5][6][7]. However, the normal reference values of various urine metabolites have not been established yet, and further clinical validation is necessary.
Metabolomic studies typically begin with sampling, followed by sample analysis. There are several techniques to do this analysis, although the most common used is nuclear magnetic resonance spectroscopy (NMR) [8][9]. This technique is non-destructive in nature, quantitative, and has a safe metabolite identification that provides detailed information on the molecular structure. Other techniques are used, such as gas chromatography mass spectrometry (GC-MS), liquid chromatography mass spectrometry (LC-MS), and the enzyme-linked immunosorbent assay (ELISA) [8].
Currently, approximately 4500 metabolites have been documented in urine, showing connections to approximately 600 human conditions including, for example, obesity, cancer, inflammation, and neurological diseases [10].

1.1. Arterial Hypertension

Hypertension, which is characterized by elevated blood pressure in systemic circulation arteries, is among the most widespread of chronic diseases [7][11]. According to statistics, the global prevalence of hypertension was 26.4% by 2000, and it is anticipated to climb to 29.2% by 2025 [7]. This disease can lead to other several diseases, such as stroke, heart disease, and kidney failure [11]. In this way, it can be said that hypertension is a key modifiable risk factor for cardiovascular morbidity and mortality [12] for which it is important to find urinary biomarkers that would allow for an early diagnosis.
Previous metabolomic studies on hypertension have been mainly based on blood and urine samples. The study carried out by Loo et al. [13] had as the identification of a panel of urinary metabolites whose changes are related to risk factors of cardiovascular disease (CVD) as its main objective. The results indicated that there are six urinary metabolites associated with blood pressure (proline-betaine, carnitine, hippurate, 4-cresyl sulphate, phenylacetylglutamine, and N-methyl-2-pyridone-5-carboxamide).
In recent years, trimethylamine-N-oxide (TMAO) has also emerged as a potential biomarker for the development of CVD [14][15][16]. This metabolite is a small, organic, gut microbiome-generated compound whose concentration increases after ingesting dietary L-carnitine and phosphatidylcholine rich foods such as red meat, eggs, and fish [16].

1.2. Oxidative Stress and Inflammatory Disease

Oxidative stress is caused by a production imbalance between reactive oxygen species (ROS) and antioxidant defences [17][18]. That phenomenon, if uncontrolled, initializes numerous intracellular signaling pathways that trigger apoptosis or excessive cell growth, which can lead to organ dysfunction in the heart, pancreas, kidneys, and lungs. As a consequence, hypertension, diabetes, chronic kidney disease, and pulmonary disorders can develop [19].
Inflammation is a natural defence mechanism of the immune system that can be triggered by a variety of factors [20]. Oxidative stress has the ability to activate several transcription factors that cause specific genes involved in inflammatory pathways to be expressed differentially [19]. Therefore, there is evidence that oxidative stress and inflammation are coincident phenomena that exert an influence on each other [21].
If the level of ROS exceeds the antioxidant capacity of a cell, cellular biomolecules such as DNA, lipids, and proteins are oxidized. This leads to the creation of compounds that can serve as biomarkers of oxidative stress. The most commonly used urinary oxidative stress biomarkers are 8-hydroxy-2′-deoxyguanosine (8-OHdG) [19][22][23], phenylacetylglutamine, adenine, glycine [24], lactate [9], 8-isoprostane [22][25], malondialdehyde (MDA), F2-isoprostanes, and dityrosine (diY) [23].

1.3. Chronic Kidney Disease

Chronic kidney disease (CKD) is a condition that occurs when the kidney gradually loses its function or when a glomerular filtration rate (GFR) is less than 60 mL/min per 1.73 m2 for 3 or more months, regardless of the cause [26]. The prevalence of CKD is increasing worldwide, and the mortality rate continues to be unacceptably high [27]. This disease is a complex one because can it affect multiple organ systems and often coexists with numerous associated conditions, such as CVD, diabetes mellitus, and chronic inflammation [28]. GFR estimation and albuminuria are commonly utilized to diagnose and predict the prognosis of CKD in clinical practice. GFR estimation correlates with the severity of kidney malfunction, whereas albuminuria indicates the existence of kidney damage [27].
Detecting CKD early is a crucial and unsatisfied medical requirement, not only for forecasting and impeding CKD progression, but also for enhancing patient survival and decreasing associated morbidities. That can be accomplished through the identification of suitable biomarkers [27]. Some new possible biomarkers of the diagnosis of CKD and its prediction of outcomes have been identified, such as creatinine [28][29].

1.4. Urinary Tract Infection

Urinary tract infections (UTI) affect 150 million people each year worldwide, with an annual incidence of 12.6% in women and 3% in men [30]. It appears due to microbial pathogens invading the urinary tract, which can lead to several clinical manifestations [31].
Currently, urine culture is the standard method in the diagnostics of UTI [32]. However, this method is slow, and therefore the diagnosis happens with a considerable delay, which is not desirable [31]. Also, urine test strips can be used for rapid UTI screening. These strips evaluate several biomarkers, although only nitrite and leukocyte esterase show an independent relation with UTI. Nonetheless, there are reports of considerable variations in the test performances, which limit their further use, and as such new biomarkers that allow for a quick diagnosis are warranted [32]. Several promising urine biomarkers of UTI such as agmatine and N6-methyladenine have already been identified [33].

1.5. Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the leading cause of dementia, the incidence of which is rapidly increasing [34]. AD is characterised by the formation of extracellular amyloid plaques which result from the accumulation of amyloid β-proteins, and intracellular neurofibrillary tangles due to the aggregation of tau proteins, leading to neuronal signalling disruption and cell death [35][36]. Thus, the development of the disease involves numerous factors such as amyloid β build-up, oxidative stress, tau phosphorylation, lipid imbalance, mitochondrial dysfunction, and inflammation [37].
AD is an ailment that frequently impacts the elderly population, and its symptoms are discernible only in the advanced stages, rendering early diagnosis a challenging task [38]. Currently, diagnosis is based on subjective neuropsychological tests and by late-stage biomarkers in cerebrospinal fluid (CSF), which require a lengthy and often a painful procedure [36]. Other often used biomarkers include imaging biomarkers such as the uptake of the 11C-Pittsburgh compound B (11C-Pib), as assessed using positron emission tomography (PET), which binds to amyloid plaques, and the atrophy of the hippocampus and mesial temporal structures, as assessed by magnetic resonance imaging (MRI) [39][40]. Nonetheless, these imaging modalities and examination procedures can also be lengthy and very expensive, whilst also using ionising radiation (PET) and high magnetic fields (MRI), which present risks to the patient [41].
The signs of AD pathology may also be found in the urine, so it is important to know which biomarkers can be used. Due to the oscillation of urinary flow, normalisation of the biomarker concentration is recommended in most cases. This is easily achieved through the relationship between the concentration of the biomarker and the concentration of creatinine [34]. Examples of this kind of biomarker are amino acid-conjugated acrolein (AC-Acro/Cre) and 3-hydroxypropyl mercapturic acid (3-HPMA/Cre) [42][43]. Other urinary biomarkers can be associated with AD, such as 8-OHdG [34][38], and knowing the relationship between AD and oxidative stress, 8-isoprostane and glycine can be included as AD biomarkers [34].

1.6. Oncologic Diseases

Cancer is one of the major causes of mortality worldwide, and according to the America Cancer Society, in 2022 there will be an estimated 1.9 million new cancer cases diagnosed and 609,360 cancer deaths in the United States [44]. Its incidence is predicted to increase significantly, with a forecast of 22 million new cancer cases and 13 million cancer-related deaths occurring annually by 2030 [45]. The best chance of reducing these numbers is through early detection. To this end, the use of biomarkers can be useful. However, in recent years the identification of novel biomarkers in biological fluids has increased significantly, although further validation is needed.

1.6.1. Lung Cancer

Lung cancer (LC) has a high mortality rate globally, and in most cases, diagnosis is often made at a late stage when the process of metastization has already begun [46]. To avoid such a scenario, the use of biomarkers may be useful. Some examples of recurrent biomarkers proposed in scientific papers investigating lung cancer were tyrosine and tryptophan [47], hippurate [48][49][50], N-aceglutamide, β-hydroxyisovaleric acid, α-hydroxyisobutyric acid, and creatinine [48], valine, proline betaine, taurine [50], and phenylalanine [47][50].

1.6.2. Breast Cancer

Breast cancer (BC) is the second most common cancer overall and the most frequent type of cancer in women worldwide [51]. The early diagnosis of breast cancer greatly increases the chance of cure and survival from the disease. Mammography is the gold standard for BC screening; however, it has limited sensitivity, involves exposure to ionising radiation, and it has not been shown to significantly contribute to decrease mortality [49][52]. In this way, noninvasive tests for BC with high sensitivity are needed. The use of urinary metabolomics for breast cancer detection at an early stage has increased over the last few years [49]. The major contributing metabolites identified were 8-OHdG, 1-methyladenoside, 1-methylguanosine [53][54][55][56], creatinine, succinate, valine, and isoleucine [49][57]. Nam et al. also identified homovanillate, 4-hydroxyphenylacetate, 5-hydroxyindoleacetate, and urea in urine as biomarkers of BC [58].

1.6.3. Bladder Cancer

Bladder cancer is the seventh most common cancer, with an average of 356,000 new cases diagnosed worldwide every year [45][59]. It is the second most prevalent malignancy in middle age and in elderly men after prostate cancer [60]. The current standard procedure for bladder cancer detection and monitoring tumour progression and recurrence involves urine cytology, cystoscopy, and biopsy; however, these techniques have a number of limitations, as low sensitivity, in addition to the fact that is expensive, invasive, and painful [45]. Thus, new diagnostic approaches that improve the diagnostic accuracy, reduce pain levels and that are noninvasive are needed.
Screening bladder cancer patients through urine metabolomics biomarker technology is a promising strategy to improve detection and diagnosis [61]. Some of the commonly used biomarkers for bladder cancer include hippurate [59], lactate [62], succinate [62][63], phenylalanine, tyrosine, tryptophan, leucine, uric acid [60], carnitine [61][63], and taurine [59][62].

1.6.4. Prostate Cancer

Prostate cancer is among the most prevalent types of cancer in men across Europe, and its occurrence has surged dramatically over the last twenty years [64]. At present, the detection of prostate cancer is still an imprecise practice. The screening process involves measuring the level of prostate-specific antigen (PSA) in the blood and performing a digital rectal examination [65]. PSA is the only biomarker commonly utilized in the diagnosis of prostate cancer patients; however, its sensitivity and specificity are inadequate, resulting in the occurrence of false-negative and false-positive test outcomes [66]. To reduce incorrect results and increase the accuracy of diagnosis, it is necessary to search for additional prostate cancer biomarkers.
Sreekumar et al. [67] reported that increasing levels of proline, kynurenine, uracil, and glycerol-3-phosphate were significantly correlated with disease progression. The authors also found that sarcosine concentrations increased in patients with prostate cancer [67]. Some studies confirmed the potential of sarcosine as a noninvasive screening tool for prostate cancer [64][66][68][69][70][71][72]. Other identified contributing metabolites identified were leucine [70][72], creatinine [66][68][72], tyrosine, tryptophan, taurine [72][73], and alanine [65][70].

1.6.5. Gastric Cancer

Gastric cancer was estimated to be responsible for over one million new cases in 2018 worldwide and for more than 700,000 deaths [45]. Currently, the standard diagnostic method for gastric cancer is gastroduodenal endoscopy; however, this technique has several drawbacks, such as invasiveness and high-cost [74]. Currently, no diagnostic method is perfect for detecting gastric cancer at an early stage since, in most cases, it is asymptomatic [8]. In recent years, several urinary biomarkers have been identified as new tools for the early screening of gastric cancer. Among the 25 metabolites investigated by Chan et al. [75], only 2-hydroxyisobutyrate, 3-indoxylsufate and alanine provided useful information for gastric cancer diagnosis. Another study conducted by Dong et al. in 2009 [76] concluded that the level of urinary prostaglandin E2 metabolite (PGE-M) was higher in gastric cancer patients than in a control group. Furthermore, arginine, leucine, isoleucine, valine, citric acid, succinate, histidine, methionine, serine, aspartate, taurine, tyrosine, lactate, and phenylalanine [74][77] have been proposed as biomarkers for gastric cancer.

1.6.6. Kidney Cancer

Kidney or renal cancer is among the top ten most prevalent forms of cancer, and it is more frequent in men than in women [45]. According to the American Cancer Society’s projection for 2022, roughly 79,000 new cases of kidney cancer and approximately 13,920 fatalities due to this type of cancer were anticipated [78]. Currently, most kidney cancers are detected before symptoms appear, namely when performing routine examinations, as well as when investigating symptoms such as back or abdominal pain using imaging [79]. However, it remains true that alternative diagnosis methods, particularly those that use urine markers, could be useful in detecting kidney cancer even earlier. Therefore, the identification of a screening biomarker has the potential for substantial health benefits. Promising biomarkers include acylcarnites such as isobrutyrycarnite, suberoylcarnite, and acetylcarnite [80].

2. Urine Proteins Biomarkers

Apart from metabolites, the presence or absence of proteins in urine can provide valuable information about various medical conditions, including kidney injury and certain types of cancers. 
One of the most common urine proteins used as biomarker is urinary albumin, which is produced in the liver and helps to maintain the balance of fluids in the body. Overall, urinary albumin can be a useful biomarker for a range of diseases and conditions that affect the cardiovascular system, such as hypertension [12][81], the liver [82], and the kidneys, such as chronic kidney disease [27].
Although urinary albumin is useful for assessing kidney function, it is important to look for other indicators of kidney injury other than GFR. Current established filtration markers for the prediction of outcomes in patients with CKD include creatinine and cystatin C [29][83]. Other biomarkers potentially useful to indicate kidney damage are β2-Microglobulin (B2M) and Beta Trace Protein (BTP). These proteins are filtered out of the blood by the kidneys and excreted in the urine, normally in small amounts of less than 20 and 300 micrograms per liter (µg/L), respectively. Thus, elevated levels of BTP and B2M in urine can be an indication of kidney damage or dysfunction, and can be used as biomarkers to diagnose and monitor various kidney-related diseases and conditions [27][84].
Uromodulin is a protein that is produced by the kidney and is the most abundant protein found in urine [85]. This protein can be used as a biomarker, since its concentration gradually decreases with worsening kidney function, so in patients with CKD, its concentration will be lower [27]. Moreover, the Neutrophil Gelatinase-Associated Lipocalin (NGAL) [83][85] and Kidney Injury Disease-1 (KIM-1) [85][86] have also been suggested to be potential biomarkers of CKD.
Inflammation and CKD are closely related, since inflammation can lead to damage of the kidney tissue or exacerbate existing kidney damage and hasten the progression of the disease. Therefore, the study and identification of related biomarkers is essential in the prevention and management of kidney disease. Inflammatory biomarkers such as C-Reactive Protein (CRP) [87], Interleukin-6 (IL-6) [87][88], Tumor Necrosis Factor-alpha (TNF-α)[87][88][89], and Growth Differentiation Factor-15 (GDF-15) [87][90] have been linked to renal function decline. Regarding urinary tract infections, some proteins have been identified as potential biomarkers, such as lactoferrin (LF) [91], xanthine oxidase (XO), and myeloperoxidase (MPO) [32].
Urine protein biomarkers have also shown promise in the detection and monitoring of certain types of cancer. These biomarkers are often produced by cancer cells or by the body in response to cancer. An example is Prostate-Specific Antigen (PSA), which is a protein produced by the prostate gland, whose elevated urinary levels may indicate prostate cancer [68]. Other biomarkers that are being studied for their potential use in the detection and monitoring of cancer include Human Epididymis Protein 4 (HE4) for ovarian cancer [92], Bladder Tumor Antigen (BTA) for bladder cancer [93], and Matrix Metalloproteinases (MMPs) for various types of cancer, such as MMP-9 for breast cancer [94].
The diagnosis and monitoring of neurodegenerative diseases, such as Alzheimer’s disease, using urine biomarkers have been studied over time. One such biomarker is the Beta-Amyloid (βA) protein, which is detected in the urine. Beta-amyloid is a protein that is present in the brains of individuals with Alzheimer’s disease, and may also be present in the urine of these individuals [95].
Other urinary biomarkers can be associated with AD, such as AD-associated Neuronal Thread Protein (AD7c-NTP) [96], osteopontin, gelsolin, and Insulin-like Growth Factor-Binding Protein 7 (IGF BP7) [35].

3. Urine Nucleic Acids as Biomarkers

In addition to hundreds of proteins, urine also contains exfoliated tumor cells and tumor cell-free amino acids, in addition to tumor-derived DNA, mRNA, and microRNA (miRNA) [97][98].
In recent years, there has been growing interest in the use of urinary methylation-based biomarkers for the diagnosis and monitoring of some types of urogenital cancers, particularly in their early stages, as alterations in DNA methylation are thought to be among the earliest events in the development of tumors. According to Bryzgunova et al., methylation of Glutathione S-Transferase P1 (GSTP1) shows potential as a promising biomarker for prostate cancer, which can be detected in urine samples from affected patients [99].
Apart from alterations in DNA methylation, messenger RNA (mRNA) molecules in urine can be used as biomarkers. An example of that is the two available tests, SelectMDx and ExoDx, for the detection of prostate cancer. The former detects Distal-Less Homeobox 1 (DLX1) and Homeobox C6 (HOXC6) mRNA in urine after prostate massage, while the latter detects Prostate Cancer Antigen 3 (PCA3), Erythroblast Transformation-Specific (ETS)-related gene (ERG) and Sterile alpha Motifpointed Domain-Containing ETS transcription Factor (SPDEF) in urinary exosomes and does not require a digital rectal exam [100][101].
Feng et al. investigated the potential use of C-C Motif Chemokine Ligand 5 (CCL5) and C-X-C Motif Chemokine Ligand 1 (CXCL1) mRNA levels in urinary sediment as prognostic biomarkers for diabetic nephropathy. The results showed that both CCL5 and CXCL1 were upregulated in diabetic nephropathy patients and were associated with a decline in renal function [102]. In addition, low levels of CD2-associated protein (CD2AP) mRNA in urinary exosomes were associated with an increased risk of kidney disease [103].
The concept of liquid biopsy, which involves the detection, analysis, and monitoring of cancer through various bodily fluids such as urine [104], was initially introduced for circulating tumor cells but has since been extended to include circulating tumor DNA [105]. Circulating tumor DNA has been studied as a potential biomarker for various types of cancer, with a particular focus on genitourinary tract cancers, such as bladder cancer. Regarding bladder cancer, Christensen et al. were able to detect urinary cell-free DNA, specifically targeting three hotspot mutations in Phosphatidylinositol-4,5-bisphosphate 3-Kinase Catalytic subunit Alpha, PIK3CA (E545K) and Fibroblast Growth Factor Receptor 3, and FGFR3 (S249C, Y373C) [106]. Other possible biomarkers were identified, such as Long Interspersed Nuclear Element-1 (LINE1) [107] for lung cancer, p53 mutation (codon 249) for hepatic cancer [108], and vimentin hypermethylation for colorectal cancer (Song2012 [109]).
MicroRNA (miRNAs) are small, typically 20–25 nucleotides in length, non-coding RNA molecules that play a crucial role in the regulation of gene expression [98]. miRNAs have emerged as promising biomarkers for the diagnosis and monitoring of various types of cancer. In prostate cancer, several miRNA were identified, such as miR-107, miR-574-3p [110], miR-205, miR-214 [111], and miR-888 [112]. Other miRNA biomarkers that are being studied for their potential use in the detection and monitoring of cancer include miR-144-5p [113], miR-23b/27b [114], and miR-145 [113] for bladder cancer, and miR-96 and miR-214 [115] for urothelial cancer.
Previous studies showed that urinary levels of microRNA correlated with kidney diseases. Lv et al. [116] concluded that miR-29c from urinary exosomes was significantly downregulated in CKD patients. In a study conducted by Szeto et al. [117], miRNA levels were measured in urinary sediment. The researchers observed a correlation between the expression of urinary miR-21 and miR-216a and the rate of decline in renal function, as well as the risk of developing renal failure requiring dialysis [117]. In most cases, kidney diseases are linked with cardiovascular diseases, such as renovascular hypertension, which is high blood pressure caused by renal artery disease. Through their studies, Yang et al. and Know et al. have identified miR-26A [118] and miR-21, miR-93, and miR-200b [119], respectively, as potential markers for diagnosing renovascular hypertension.
Various urine nucleic acid biomarkers described previously are currently under study. Consequently, there are no normal reference values yet and further clinical validation is warranted.


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