Applications of Biobanking in Neuro-Urology

Applications of Biobanking in Neuro-Urology: History

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Subjects: Biology | Urology & Nephrology | Neurosciences

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Understanding the molecular mechanisms underlying neuro-urological disorders is crucial for the development of targeted therapeutic interventions. Through the establishment of comprehensive biobanks, researchers can collect and store various biological specimens, including urine, blood, tissue, and DNA samples, to study these mechanisms. In the context of neuro-urology, biobanking facilitates the identification of genetic variations, epigenetic modifications, and gene expression patterns associated with neurogenic lower urinary tract dysfunction. These conditions often present as symptoms of neurological diseases such as Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, spinal cord injury, and many others. Biobanking of tissue specimens from such patients is essential to understand why these diseases cause the respective symptoms and what can be done to alleviate them.

neuro-urology
neurogenic lower urinary tract dysfunction
lower urinary tract symptoms
biobank
biomarker

1. Introduction

1.1. Overview of Neuro-Urology and Its Importance in Healthcare

Neurogenic lower urinary tract dysfunction is highly prevalent, affects the life of millions of people worldwide, and causes considerable economic burden [1,2]. Neuro-urology, a highly specialized field at the intersection of neurology and urology, plays a crucial role in understanding and managing neurogenic lower urinary tract dysfunction (NLUTD) [3]. The coordination between the central and peripheral nervous system across parasympathetic, sympathetic, and somatic pathways is vital for maintaining normal urinary function. Disruptions in this delicate balance leads to a wide range of NLUTD, necessitating specialized evaluation and management.

One of the key aspects of neuro-urology is the comprehensive assessment of patients with NLUTD. This involves a thorough medical history, physical examination, and diagnostic testing to identify the underlying cause of urinary tract dysfunction. The evaluation may include urodynamic studies, which assess bladder function and the coordination between the bladder and the urethra during the filling and emptying phases [4,5]. Neuroimaging techniques, such as magnetic resonance imaging (MRI) [6] or computed tomography (CT) [7], may also be utilized to visualize the structures or the control of the urinary tract and identify anatomical or neurological abnormalities.

The findings from these assessments guide the development of tailored treatment plans for patients with neuro-urological conditions. The management strategies employed in neuro-urology aim to preserve upper urinary tract function, to improve quality of life, to control urinary tract infections, and to maintain a low-pressure reservoir that is both continent and capable of emptying completely [1,2,3].

Neuro-urology’s importance in healthcare extends beyond the realm of diagnosis and treatment. It also plays a crucial role in advancing our understanding of the mechanisms underlying urinary tract disorders. By studying the complex interactions governing bladder filling and emptying, involving the nervous system, urinary tract anatomy, and musculature in the lower urinary tract, researchers can gain valuable insights into the pathophysiology of these conditions, leading to the development of novel diagnostic techniques [8] and innovative therapies [9,10,11]. In recent years, large efforts have been made by the International Continence Society (ICS) to standardize treatment guidelines of NLUTD [12,13]. However, current treatment strategies differ between centers [14] and many guidance gaps fail to address key issues in NLUTD care, including possibilities for cathether reuse in low-resourced countries, comorbid conditions frequently associated with NLUTD, such as sexual and bowel dysfunction, care transitions from pediatric to adult urological clinics, and surveillance protocols for NLUTD patients, leaving many without appropriate monitoring in real-world settings [15].

1.2. Introduction to Biobanking and Its Relevance to Neuro-Urological Research

Biobanking involves systematically and reproducibly collecting, processing, storing, and managing biological samples, such as tissues, blood, urine, and DNA, along with associated clinical and demographic data. These samples and data are preserved in biorepositories, known as biobanks, for use in medical research. Biobanks provide access to well-characterized and consented samples representing NLUTD and various diseases with neuro-urological complications, including Alzheimer’s disease, multiple sclerosis, and spinal cord injury. Tissue banks play a crucial role in advancing scientific knowledge in these areas, as they form the key to discovering biomarkers, which may help to better understand disease mechanisms, to develop into new diagnostic approaches, or to evaluate the effectiveness of different interventions [16,17].

With respect to neuro-urology research, implementing biobanking as part of a research study offers numerous advantages. Firstly, the establishment of large-scale, longitudinal collections of biological specimens from patients with different types and stages of urinary disorders allows further disease discrimination and an understanding of temporal differences in affected tissues such as the bladder wall. In addition, through cross-sectional comparisons of samples from affected individuals and healthy controls, researchers can highlight which differences may be associated with disease susceptibility and disease prognosis. Finally, the tracking of these differences in clinical trials testing new treatment intervention schemes allows to see the effect of treatment at the molecular level and can ultimately assist in the development of novel therapeutic strategies.

2. Applications of Biobanking in Neuro-Urology

2.1. Specimen Types Collected and Recommended Collection Procedures

Neuro-urology biobanks gather a diverse array of specimens to conduct comprehensive studies on urinary disorders. These specimens include urine, blood, and tissue samples, such as bladder biopsies. Of these, urine specimens offer non-invasive access to biomarkers, metabolites, and cellular components that reflect the physiological and pathological status of the urinary system [22,23]. Blood plasma or serum, derived by centrifugation from whole blood samples, provide valuable information about systemic factors and circulating biomarkers relevant to neuro-urological conditions. By isolating specific blood cells, the patients’ immunological system can be studied. Tissue samples, obtained through surgical procedures or biopsies, allow for detailed histopathological and molecular analyses. Genetic material, including DNA and RNA isolated from both blood and tissue samples aids in identifying genetic predispositions and studying gene expression profiles. Collectively, these specimens provide a comprehensive resource for researchers to explore the underlying mechanisms of urinary disorders.

2.1.1. Neurofilaments

Neurofilaments are proteins found in nerve cells and their levels can be measured in cerebrospinal fluid (CSF) or blood. Elevated levels of neurofilaments have been associated with neuronal damage or degeneration in various neurological conditions, including those affecting the urogenital system [30]. Monitoring neurofilament levels can provide insights into the extent of neurological damage and give insight into renal functioning in these disease cohorts [31].

2.1.2. Cytokines and Inflammatory Markers

Inflammatory markers, such as cytokines, can be measured in blood or urine samples. Inflammatory processes often accompany neurological conditions and urogenital disorders. Monitoring the levels of specific cytokines or markers of inflammation can help assess the presence and severity of inflammation and guide treatment strategies [35]. Cytokines and inflammatory markers can be measured in blood or urine samples (e.g., [36]). Urine samples for cytokine and inflammatory marker analysis are typically collected using clean catch midstream urine collection methods to minimize contamination. Specialized urine collection containers or tubes may be used.

2.1.3. Specific Urinary Tract Biomarkers

Whilst the previously mentioned biomarkers are often found elevated as part of systemic (inflammatory) or central (Alzheimer) diseases leading in addition to urinary tract problems, several specific urinary tract biomarkers produced within the urinary tract itself can provide insights into disease progression. For example, elevated levels of the protein Neural Growth Factor (NGF), produced by the bladder urothelium and bladder smooth muscle cells, may indicate renal dysfunction or bladder pathology [37]. Other examples include urinary markers related to smooth muscle stretch, such as urinary ATP, or specific metabolites, such as the purine derivative hypoxantin [38].

2.2. Applications in Multicenter Clinical Trials

Multicenter studies in neuro-urological research offer valuable opportunities to study larger patient populations, increase statistical power, and enhance the generalizability of research findings. Our center is currently involved in several multicenter clinical trials in which tissue samples are being banked. These studies are aimed at preventing neurogenic detrusor overactivity and detrusor sphincter dyssynergia emergence and consequent damage to the upper urinary tract in spinal cord injury patients through stimulation of the tibial nerve (TASCI, (https://clinicaltrials.gov/, accessed on 10 August 2023) NCT03965299 [24,40]), as well as several initiatives to overcome urinary tract infections using non-antibiotic treatment strategies (CAUTIphage, ImmunoPhage, mTORUS: [41,42,43,44,45]. These multicenter studies pose significant challenges, described in more detail below, in several aspects pertaining to collection, storage, and distribution of collected tissue samples.

2.2.1. Heterogeneity within Patient Populations

Patients may be biologically heterogeneous in terms of symptoms, or by having different etiologies leading to similar phenotypes that are then diagnosed as belonging to the same disease, but clinical heterogeneity is also an important factor, as non-standardized clinical input and outcome measures create technical variation that obscures disease progression of treatment response, making tracking of these processes difficult. For instance, with respect to urinary tract infections (UTI), there has been a lack of standardization in the definition of UTIs in neuro-urological patients [46]. This lack of standardization is also found in other patient cohorts [47,48]. This heterogeneity makes it difficult to standardize patient populations across multiple research centers, leading to variability in data collection and introducing confounding factors, all potentially affecting the validity and generalizability of study findings. Achieving protocol standardization in neuro-urological research is challenging due to variations in clinical practices, diagnostic criteria, and treatment approaches among different centers.

2.2.2. Site Selection and Recruitment

Identifying and selecting appropriate research centers that have the necessary expertise and resources to participate in the study can be challenging. When undertaking biobanking efforts, each study center must in addition have certain infrastructure considerations that need to align with the study’s objectives; for instance, regular maintenance of devices such as centrifuges and freezers must take place, and backup strategies in case of power failure must be in place. Prior to commencing multicenter studies involving biobanking, it is highly recommendable to organize site visits to create an overview of local infrastructure and to gain insight in local logistic processes, such as the distance and time needed between taking samples from a patient in the operating theatre and/or hospital ward and freezer. It is equally important to make sure that all sample processing is performed according to a centralized Standard Operating Procedure (SOP) and that processing efforts of the different sites are harmonized prior to the trial commencing, e.g., by organizing parallel sample processing or sample analysis with a single parental bio-sample as the source [51]. Finally, it is recommended to utilize a centralized data entry system capable of receiving (patient-sensitive) encrypted sample data from all locations, such as REDCap (Research Electronic Data Capture) [52].

2.2.3. Regulatory and Ethical Considerations

Research protocols, informed consent processes, and data protection procedures may vary between different regions or countries. Ensuring compliance with regulatory requirements and ethical standards across multiple centers and jurisdictions is a time-consuming challenge, and is unsurprisingly associated with increased costs [53]. This issue is not only related to the neuro-urological research field and several initiatives aimed at streamlining this process have been proposed within other research areas [54,55,56,57].

2.2.4. Logistics

If the study involves the collection of biological samples or specimens, logistics related to their collection, storage, transportation, and analysis can be complex, and the potential effects of logistics on sample quality are often underestimated. For instance, the distance between the operating theatre or nursing facilities and the laboratory may influence sample processing times (timepoint sample taken from patient until timepoint storage of sample in a −80 °C freezer) and hence, sample quality may differ between centers depending on the biomarker of interest. To optimize logistics processes, effective communication among all stakeholders is vital.

2.3. Translation into Clinical Applications

Findings from neuro-urology biobanking studies can have a significant impact on clinical practice and contribute to the development of personalized treatment strategies and targeted interventions. There are several ways in which these findings may be translated into clinical applications:

Understanding molecular mechanisms: Biobanking has played a pivotal role in elucidating the molecular mechanisms underlying urinary disorders. By analyzing the collected specimens, researchers can investigate genetic variations, gene expression patterns, epigenetic modifications, and protein profiles associated with specific neuro-urological conditions, such as in Alzheimer’s disease or bladder pain syndrome [31,58,59,60]. These investigations contribute to a deeper understanding of disease pathophysiology and potential therapeutic targets.
Biomarker-guided diagnosis and prognosis: Neuro-urology biobanking studies can identify biomarkers associated with specific neuro-urological conditions analogous to other urological conditions, e.g., acute kidney injury [61]. These biomarkers can aid in the early diagnosis, classification, and prognosis of patients [62,63]. Clinicians can then utilize these biomarkers to improve diagnostic accuracy, predict disease progression, and adjust treatment plans accordingly.
Identification of drug targets and development of novel therapies: By studying human and animal tissue samples, researchers can identify novel drug targets, validate existing targets, and develop new therapies that specifically address the underlying mechanisms of neuro-urological conditions such as overactive bladder syndrome [64,65,66].
Personalized treatment and treatment tailoring approaches: Neuro-urology biobanking studies contribute to the development of personalized medicine approaches [17]. By analyzing the genetic, molecular, and clinical data from biobanked samples, researchers can identify patient subgroups with distinct characteristics or treatment needs. This knowledge can guide the selection of appropriate therapies and dosage adjustments or the use of combination therapies tailored to individual patients whilst minimizing adverse effects.

3. Challenges and Considerations in Neuro-Urology Biobanking

3.1. Privacy and Data Protection

Biobanking raises important ethical and legal considerations regarding informed consent, privacy, and data protection [67]. It is crucial to ensure that appropriate ethical guidelines are followed and that consent is obtained from patients prior to sample collection and usage. As biobanking involves the storage and utilization of personal health information, strict protocols must be implemented to protect patient privacy and ensure compliance with data protection regulations. Anonymization and encryption techniques should be employed to safeguard sensitive information and prevent unauthorized access [68]. This is important as participants are more likely to join a study if biobanks can ensure that participants’ identities and sensitive information remain confidential and protected [69]. Challenges include obtaining a valid signed informed consent [70], implementing robust security measures to safeguard data from unauthorized access or breaches [71], and navigating legal and ethical regulations governing data privacy. At our institution, the latter aspect is managed by a specialized team of study coordinators. Their role involves facilitating communication among researchers, physicians, and the local ethical board.

3.2. Standardization and Quality Assurance

Maintaining high-quality standards in biobanking is essential to ensure the reliability and reproducibility of research findings. However, although biobanking efforts have become prevalent worldwide, there has been no standardization of storage practices or modes of operation. Given that the prevalence of irreproducible biomedical research is substantial [72,73], standardization, especially in multicenter studies, is a key aspect that biobanks should adhere to.

The principles of standardization and quality assurance can also be implemented within the biobanking infrastructure. Access to biobank storage facilities should ideally be restricted to relevant biobank staff. Staff members must be well trained for proper sample collection, registration, processing, and storage, and consistent evaluation of such training must be assessed and recorded. Additionally, a professional biobank information management system (BIMS) will ensure the accurate positioning, traceability, and recording of non-conformity incidents for each aliquot.

3.3. Further Challenges in Sample Collection

Besides the challenges alread discussed in previous paragraphs, collecting tissues from neuro-urological cohorts can present many other challenges. To maximize the quality and utility of the collected samples, these must be considered in the study design or in conversations with the biobank performing the biosampling.

Invasive procedures: Collecting tissue samples from neuro-urological cohorts may require invasive procedures, e.g., the collection of cerebrospinal fluid or the collection of biopsies that can only be taken through surgery. These procedures carry inherent risks and may not be feasible for all patients, especially in case such surgeries need to be organized in addition to standard clinical procedures.
Competition between patient cohorts: As the incidence of some patient cohorts in neuro-urological studies is relatively low, for instance in traumatic spinal cord injury [82], there may be competition for inclusion of the patients’ samples in several studies. In such cases, a feasibility analysis may be necessary prior to conducting the study.
Use of (co-)medication: Patients with neuro-urological conditions frequently receive a range of specific medications to manage their condition and related symptoms. These treatments might encompass antimuscarinic drugs and alpha-blockers for addressing an overactive bladder and urinary retention, as well as intracavernous injections of alprostadil, papaverine, and phentolamine in cases of erectile dysfunction [2].

3.4. Cost Coverage of Biobanking

As may have become clear from the previous paragraphs, biobanking efforts are labor- and time intensive, and hence, are associated with costs. At the same time, the tasks and costs involved in biobanking are often overlooked by researchers. For this reason, the long-term economic sustainability of biobanks requires careful consideration.

Like most technology support platforms, biobanks rely on some form of cost coverage to remain operable. The reimbursement, whether in monetary terms or in kind, should account for the labor invested in sample processing and associated overhead costs, while maintaining the principle of refraining from pursuing profits due to ethical considerations. Expenses can be associated with the biobank’s structure, including upkeep, equipment replacement, and acquisition. Additionally, there are costs tied to sample processing, such as consumables, customs import fees, and shipping charges (e.g., dry ice and courier expenses), as well as many other tasks [88]. Finally, salary costs for personnel time invested in sample processing, aliquoting, storage, and shipment also constitutes a significant cost factor [89].

3.5. Environmental Impact of Biobanking

Although these energy expenses are obviously necessary to keep a biobank operational, further streamlining of internal biobank processes may help to reduce energy costs and its impact on the environment. These may include:

-: Efficient sample retrieval strategies, such as the use of automated systems to retrieve samples, reducing the need for extended manual searches in which freezers need to be opened and closed regularly within a short time span;
-: The use of energy-efficient equipment, such as investments in energy-efficient, better-insulated freezers and refridgerators;
-: Data Center Optimization, such as a connected Laboratory Information Management Systems (LIMS) between study sites which omits the need for intermittent shipments of collected samples to a central storage facility. Instead, the connected system provides an overview of all sites and the samples only need to be collected in a central location during the analysis phase.

These strategies not only conserve energy but also enhance the overall efficiency as well as reducing the financial costs of biobank operations.

4. Conclusions

The utilization of biobanking in neuro-urology presents a unique opportunity to unravel the molecular mechanisms underlying urinary disorders. The systematic collection, storage, and analysis of biological specimens have facilitated a deeper understanding of disease pathogenesis, biomarker discovery, and personalized treatment approaches. However, ethical considerations, standardization, and data protection remain critical challenges that require careful attention. The future of neuro-urology biobanking holds immense potential, with advancements in biobanking techniques, advanced standardization efforts through accrediation or certification, and by embracing new ethical concepts empowering participants on their right to consent to their participation. Biobanking is a worthwhile endeavor for any research field. Those patients’ demographics and disease states that are represented in biobanking now will stand to benefit the most from future scientific discovery. By harnessing these advancements and fostering collaborative efforts between study centers, neuro-urology biobanking will assist to advance research and improve patient outcomes.

This entry is adapted from the peer-reviewed paper 10.3390/ijms241814281

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