Urine and serum glycosaminoglycan levels in the diagnosis of urological diseases and conditions: A narrative review of the literature

Abstract

Glycosaminoglycans (GAGs) are sulfated, negatively charged polysaccharides produced in almost every cell of the human body. As GAGs are extracellularly localized, the changes in body fluids such as blood and urine may reflect pathological changes in the urinary system as observed in other pathologies. In this review, we determined the potential of urinary and/or serum GAG levels as a marker for kidney and urothelial system diseases. We performed a search in the PubMed, MEDLINE, and ScienceDirect databases until September 30, 2019. A number of studies reported changes in the urinary and/or plasma GAG levels or composition in urological diseases and conditions, such as renal cell carcinoma, kidney stone, bladder carcinoma, and overactive bladder. GAGs were found to have a predictive biomarker potential that could be limited by generalizability concerns.

Keywords

Glycosaminoglycans urine renal cell carcinoma kidney stone bladder carcinoma overactive bladder

Introduction

Glycosaminoglycans (GAGs) are sulfated, negatively charged polysaccharides produced in almost every cell of the human body.^1,2

GAGs come in two main types. Nonsulfated GAGs include hyaluronic acid (HA), which is the least negatively charged GAG, and sulfated GAGs include chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS), heparan sulfate (HS), and heparin. The molecular sizes and types of sulfation vary with tissue. GAGs play an important role in numerous pathological conditions because of this feature.^1,2

GAGs are important to maintain the functional integrity of the urinary system. Many different GAG domains with a characteristic distribution can be found in the adult urinary tract. HS domains are located in the basement membranes and cell surfaces, and the CS domains are positioned in the interstitium. GAGs are components of the basal lamina of the urothelium that covers the surface of the urinary tract.^3,4 Damage to the GAG layer disrupts the barrier function of the urothelium.⁵

Renal filtration of the glomerulus is performed in the glomerular filtration membrane.^6,7 GAGs play a pivotal role in the molecular organization of the glomerular basement membrane.⁸ The glomerular basement membrane has selective permeability and shows high membrane permeability to small-and medium-sized solutes in plasma while maintaining a relative impermeability of macromolecules.

The bladder is a muscular organ that allows urine to be stored and emptied intermittently when needed. The urothelium is impermeable and plays an important role as a barrier between urine and the underlying bladder.⁹ The umbrella cell layer surface that forms the inner surface of the urothelium is covered with GAGs.⁵ The sulfonated GAG mucous layer protects the transitional epithelium of the bladder against irritants in urine, including microcrystals, proteins, calcium, toxic metabolic products, and carcinogens.^10–12 GAGs are also necessary to inhibit bacterial adhesion and infection and to prevent tumor cell implantation.^5,11,12

GAGs are excreted in urine. The total urinary GAGs are composed of 80% chondroitin sulfate, 20% heparan sulfate, small amounts of dermatan sulfate (1%–2%), and trace amounts of HA and KS.^13,14 Evidence shows that urinary GAGs may be of systemic origin or may originate from the kidney and/or urinary tract.^13,15–17 As GAGs are extracellularly localized, the changes may reflect changes in body fluids such as blood and urine.^13,15,17,18

Materials and methods

A narrative review critically summarizes literature from multiple primary sources to integrate up-to date knowledge.¹⁹ In this narrative review, we focus on the potential of urinary and/or serum GAG levels as a novel marker to detect patients at risk for kidney and urothelial system diseases.

Using the following keywords “glycosaminoglycans,” and “urine,” and “renal cell carcinoma,” “acute kidney injury,” “kidney stone,” “urolithiasis,” “nephrotic syndrome,” “bladder,” “bladder cancer,” “overactive bladder,” “interstisyel cystitis,” “nocturnal enuresis,” and “bladder diseases,” “urinary tract infection” we performed a PubMed, MEDLINE, and ScienceDirect database search until September 30, 2019.

Two authors (YU and KH) reviewed the data from all eligible studies. The search results were then limited according to the following inclusion and exclusion criteria: articles reported in English, studying GAG levels in patients with kidney/urothelial system diseases were included, whereas non-full-text articles and articles about method evaluation, mucopolysaccharidosis or diabetes were excluded. Then duplicates were removed. Disagreements on inclusion were resolved by a third independent reviewer (MG).

Due to limited research of GAG levels as a marker for kidney and urothelial system diseases, the lack of critical evaluation of these studies can be considered as a limitation of this narrative review.

Urinary GAGs in kidney diseases

An increase in urinary GAGs level is associated with various renal diseases.

Renal cell carcinoma (RCC) is the most common form of kidney cancer in adults. RCC is usually asymptomatic until the advanced stages of the disease, and 20% to 40% of cases have an advanced disease or are metastatic at the time of diagnosis.²⁰ Currently, no diagnostic biological marker is available for widespread clinical use.

GAGs can be associated with tumor progression and metastasis because of their roles in extracellular matrix remodeling and signaling cascades.^1,21 A number of studies reported the significant structural changes in GAGs in RCC tissue compared with normal adjacent tissue.^22–24 Batista et al. showed an increase in CS and a decrease in HS and DS in neoplastic tissues in RCC patients. However, the urinary glycosaminoglycan profile did not differ between the RCC patients and the control patients in their study.²⁴ Sarica et al. reported an increased urinary GAG excretion in RCC patients. Patients with larger tumor masses also excreted higher amounts of GAGs.²⁵

Gatto et al.²⁶ demonstrated that in both metastatic and non-metastatic RCC, plasma and urine GAG compositions and levels significantly changed. Plasma GAG changes occurred early and simultaneously with tumor formation as a response.²⁶ The chemical composition (sulfation profile) of CS or HS and the GAG scores (i.e. the mass ratio of 6 sulfated CS to the mass ratio of 4 sulfated CS and the ratio of mass sulfate of N-sulfated HS to HS) in RCC patients significantly differed from those in the control group.²⁶ However, the GAG scores decreased to normal levels only years after the first surgery in patients without evidence of the disease.²⁷ This result may affect the ability of the test to correctly identify patients without the condition, thus making plasma GAGs a non-ideal biomarker.

The limited number of studies on the effects of RCC on GAG compositions is due to the complexity of the plasma GAG extraction. Further research is needed to assess GAGs role as diagnostic biomarkers for RCC.

Acute kidney injury (AKI) is a sudden decrease in glomerular filtration rate (within hours or days). The rapid identification of patients with AKI and the use of biomarkers as an indicator of the initial stage of the disease is urgently needed.²⁸

AKI can be caused by ischemia–reperfusion injury (i.e. the transient reduction of renal blood flow followed by the reconstruction of perfusion), a complex pathophysiological process frequently seen in renal allografts and major vascular surgery.²⁹ In its high molecular form, HA is a protective agent against ischemic lesions by limiting the proinflammatory signaling.²⁹ The low molecular weight fragments (LMW) formed in the fragmentation during that HA turnover are angiogenic. The LMW HA fragments accumulate during tissue damage. These fragments stimulate cell proliferation and migration and may cause many kidney diseases.^29,30

AKI is common in patients undergoing cardiac surgery with cardiopulmonary bypass. Diagnosis as early and as timely as possible is crucial for improving the treatment outcomes. However, changes in the serum creatinine level and/or urine output do not allow the early detection of AKI until 24 to 48 h after surgery. Zarbock et al.³¹ demonstrated that the concentration of urinary HA after cardiopulmonary bypass has the potential to be an extremely useful biomarker for predicting AKI earlier than the currently used clinical parameters.

Acute renal failure due to glomerular endothelial glycocalyx destruction and endothelial dysfunction may occur during sepsis. An early increase in urinary GAGs in septic shock can predict renal dysfunction within 72 h.³² In a recent study; urinary GAG fragmentation indices predicted acute renal injury in patients with septic shock.³²

Kidney stone formation is a complex process that begins with crystallization and proceeds with crystal growth, crystal aggregation, and adhesion. Normal individuals carry inhibitors of these processes in their urine.^33,34 The concentration of reduced inhibitors (citrate, magnesium, pyrophosphate, macromolecules, and glycosaminoglycans, etc.) may predispose individuals to stone formation.³⁵ GAGs have been shown to be present on all surfaces of the urinary tract and to directly inhibit stone formation.^36–38

The amount of GAGs excreted in urine and the integrity of the GAG layer in various parts of the urinary tract may be involved in the adhesion, formation, and growth of urine crystals.^16,34,39 CS and HS have been shown to inhibit stone formation,^40,41 whereas HA has the opposite effect by promoting crystal growth and retention.⁴²

Although various inhibitory effects of GAGs on stone formation were identified in several in vitro studies, the results of studies comparing urinary GAG levels in patients and control groups are contradictory.^{13,35,39,43–45} Many reports showed low urinary GAGs in adult nephrolithiasis patients.^{38,39,43,45–48} Ombra et al.⁴⁸ separated the patients into subgroups and found a significant difference in the urinary GAG/creatinine ratio between the recurrent stone disease patients and the first-time stone disease patients. Dissayabutra et al. revealed that urinary decrease in GAG and CS excretion and an increase in HS excretion are common in patients with urolithiasis and their family member.⁴⁵

Kidney stones are rare in children. The results of the total GAG excretion in children with different ethnicities and diet compositions are contradictory. Michelacci et al.¹⁶ and Akcay et al.⁴⁹ determined that the GAG/creatinine ratio in the patient group was lower than that in the control group. However, this result was not confirmed by other studies.^50–53

Harangi et al.⁵³ suggested that the role of GAGs in stone formation could be related not only to their level but also to their degree of sulfation in children. Turudic et al.⁵⁴ found that the calcium independent oxalate/(citrate × glycosaminoglycans) ratio could be used as a marker for idiopathic calcium oxalate urolithiasis.

Nephrotic syndrome comprises various signs and symptoms, such as heavy protein loss through the urine, due to the development of kidney damage.

As GAGs play an important role in the regulation of glomerular permeability, the urinary excretion of various types of GAGs may be associated with different glomerular pathophysiological conditions.

Cengiz et al.⁵⁵ found that that urinary GAG/U Cr in steroid-sensitive nephrotic syndrome patients was significantly higher than that in the control subjects.

Vermylen et al.⁵⁶ demonstrated that HS accounted for 59% of the glycosaminoglycan content of glomerular basal membrane in normal infants, but it was significantly reduced in GBM in infants with congenital nephrotic syndrome. Children with congenital nephrotic syndrome had significantly higher HS levels in the urine compared with normal children and those with acquired nephrotic syndrome.⁵⁶

Meanwhile the urinary excretion of total GAG levels was significantly increased in patients with antibody-mediated glomerular injury (e.g. mesangial glomerulonephritis) than the control patients.⁵⁷

Urinary GAGS in bladder diseases

Urine is a suitable choice for the analysis of any bladder-related disease. Urine samples also reflect the histology and molecular modification of bladder urothelial cells.

Bladder cancer is the most common malignant tumor in the urinary system. It has a high tendency to recur and required strict and regular follow-up. The diagnosis of both primary and recurrent bladder tumors is mainly based on urinary cytology and cystoscopy. Many urine-based tumor markers have been investigated, but they have low sensitivity and low specificity. Therefore, finding a method for the diagnosis of bladder cancer is clearly needed.^58,59

HA is a tissue matrix component that regulates cell adhesion and proliferation. Increased HA levels localized in the stroma in tumor tissues in bladder carcinoma have been detected, and high HA levels have been shown in the urine samples of bladder cancer patients.⁶⁰ Furthermore, urinary HA sensitivity has been reported to be over 75% in bladder cancer detection.^60,61 Urine HA concentration is also associated with tumor metastasis.⁶⁰ More invasive tumors produce and secrete more HA than superficial tumors, and thus higher levels of HA indicate a more aggressive disease.⁶²

Hyaluronidase (HA-ase) is an enzyme produced by the liver that breaks down HA.^60,63 Its sensitivity is low for low-grade bladder tumors but is more sensitive in the detection of high-grade bladder tumors than HA.⁶⁴ HA-ase levels increase in bladder tumor associated with tumor grade.⁶⁴ Therefore, when two markers are used in combination (the combined HA–HA-ase assay), sensitivity ranges from 83% to 94%. In general, specificity ranges from 77% to 93.4%.^60,65–67

Overactive bladder (OAB) is characterized by the sudden urge to urinate (urgency), frequent urination (more than 8 times per day), urination more than once at night, and a feeling of urgency or urinary incontinence in the absence of urinary tract infection (UTI) or other pathologies.⁶⁸ OAB is considered to be a disorder resulting from the loss of inhibition or an increase in excitation mechanisms in the detrusor muscle during filling or emptying of the bladder.

The glycosaminoglycan layer has been hypothesized to be damaged in OAB.⁶⁸ OAB may benefit from GAG replacement therapy with HA and CS by increasing the integrity of the urothelial GAG layer, thereby reducing the frequency of urination.^69,70

However, the study results for urinary GAGs as non-invasive OAB biomarkers are not consistent. Siracusano et al.⁷¹ demonstrated that patients with OAB had a lower GAG concentration than the healthy controls. Meanwhile Alkis et al.⁷⁰ showed that GAG/Cre levels were high in OAB patients. It is clear that more controlled studies are needed in OAB patients.

Nocturnal enuresis (NE) is defined as the involuntary wetting at night during sleep in children 5 years and older in the absence of a congenital or acquired defect. The treatment of incontinence caused by sphincter insufficiency in children and adolescents with dextranomer/HA copolymer reported an improvement during a 24-month follow-up in day and night dryness.⁷² GAG excretion in patients with NE was significantly higher than that in normal children, suggesting that the measurement of urinary GAG excretion could be useful in assessing the physiopathological conditions of the bladder wall.^73,74

Recently, Salvaggio et al.⁷⁵ suggested that urinary GAG excretion could be a valuable marker indicating the onset of bladder damage.

Interstitial cystitis is a chronic inflammatory disease of the bladder of unknown etiology. Damage to the urothelium caused by infection, primary neurogenic inflammation, oncology drugs or radiation, bladder trauma, or autoimmune response is considered to be central to all bladder pathologies.^76,77

Loss of the GAG layer at the interface between urine and bladder due to ureteral damage is indicative of the disruption of the bladder defense mechanism.⁷⁸

Regardless of the actual cause of the damage, the inflammatory process develops in a similar manner in each case after it has begun. The urothelium loses its barrier function, and then drugs and toxins come in contact with the subepithelial layers, triggering a deeper inflammation.⁴

The sequence of events following the leakage of urinary components from the damaged urothelium into the interstitium of the bladder wall leads to mast cell activation and histamine release.⁷⁹ After injury, the urothelium typically heals with self-preservation, but untreated inflammation blocks the spontaneous healing of the urothelium’s GAG layer by secreting an antiproliferative factor through the epithelial cells.⁸⁰

Urine GAG levels have been studied in interstitial cystitis, but the results are not uniform. Studies have shown a decreased urinary excretion of GAG in patients with interstitial cystitis.^81,82

Meanwhile, Lokeshwar et al.⁸³ showed that the level of urinate, which is an essential component of urothelial glycosaminoglycans, increased in the urine samples of patients with severe interstitial cystitis. In their study, uronate content and HA levels were correlated with the severity of interstitial cystitis. Erickson et al.⁸⁴ found that the urinary HA levels were higher in the interstitial cystitis patients than in the healthy controls. Wei et al.⁸⁵ demonstrated that the ratio of total GAGs to sulfated GAGs was increased and that the marginally high HA levels in urine indicated that the GAG layer changed in patients with interstitial cystitis.

A urinary tract infection (UTI) is the term for infections that involve any part of the urinary tract, namely, the kidneys, ureters, bladder, and urethra.

GAGs have been proposed to provide a natural defense mechanism against UTIs. Cengiz et al. measured the urinary GAG levels of patients at the beginning of an acute infection and after a 10-day antibiotic treatment. The mean urinary GAG level at the onset of an acute infection was significantly higher in the patient group than in the control group. In the patient group, the mean urinary GAG level decreased after the antimicrobial treatment compared with the pretreatment level. The results of the study suggest that the measurement of urine GAGs may be a valuable non-invasive method to evaluate UTIs in this patient group.⁸⁶

Urinary GAGS in prostate diseases

Prostate cancer is one of the common malignancies in urologic oncology but is treatable in the early stages. Although prostate specific antigen (PSA) is the best biomarker for prostate cancer diagnosis, it has its limitations because of its low specificity.^87,88 The need for new biomarkers to improve the effectiveness of PSA is urgent. Skarmoutsos et al. studied the possible use of HA and HA-ase as new urine markers for the detection of prostate cancer; both showed significant predictive ability for prostate cancer diagnosis.⁸⁹

Limitations

The lack of commercial assays for the standardized assessment of GAG subgroups is a problem.

Implications for future research are not provided.

Conclusion

GAGs have minimal invasive biomarker potential. The potential value of urinary GAGs as predictive biomarkers can be limited by generalizability concerns.

Footnotes

Author contributions

Y.U.: design and implementation of the research, reviewed the data from all eligible studies, analysis of the manuscripts, manuscript writing. K.H.: design and implementation of the research, reviewed the data from all eligible studies, analysis of the manuscripts, manuscript writing. M.G.: design and implementation of the research, analysis of the manuscripts, resolve the disagreements on inclusion, manuscript writing. C.G.: design and implementation of the research, analysis of the manuscripts, manuscript writing. A.Y.: design and implementation of the research, analysis of the manuscripts, manuscript writing.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Yasemin Ustundağ

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