Biology and Time Course of Obstruction-Induced Detrusor Underactivity Causing Postvoid Residual Urine

Article information

Int Neurourol J. 2026;30(2):86-94

Publication date (electronic) : 2026 June 30

doi : https://doi.org/10.5213/inj.2652010.005

Karl-Erik Andersson ¹^,²

, Karl Swärd ³^,⁴

, Bengt Uvelius^,³^,⁴^,⁵

¹Department of Laboratory Medicine, Lund University, Lund, Sweden

²Wake Forest Institute for Regenerative Medicine, Winston Salem, NC, USA

³Cellular Biomechanics, Department of Experimental Medical Science, Lund University, Lund, Sweden

⁴Department of Urology, Skåne University Hospital, Lund, Sweden

⁵Department of Clinical Sciences, Lund University, Lund, Sweden

Corresponding author: Bengt Uvelius Department of Clinical Sciences, Lund University, Spolegatan 16A, Lund, Sweden Email: bengt.uvelius@med.lu.se

Received 2026 January 7; Accepted 2026 April 26.

Abstract

To review the time course of muscle mechanics, etiological factors, and molecular mechanisms contributing to the development of postvoid residual urine (PVR), with an emphasis on transcriptomic changes in detrusor underactivity secondary to bladder outlet obstruction (BOO). PVR, the volume of urine remaining in the bladder after micturition, is a key marker of lower urinary tract dysfunction. While often overlooked in routine assessment, it may signal underlying BOO or detrusor underactivity and is associated with serious complications. PVR, bladder physiology and mechanics, and BOO-associated molecular changes were integrated with mRNA expression data from patients with bladder outlet obstruction, as well as from short- and long-term obstructed rat bladders from our own laboratory. Efficient voiding depends on tightly coordinated neural and muscular activity; disruption by elevated outlet resistance, impaired detrusor contractility, or failed coordination can produce residual urine. Chronic BOO and detrusor underactivity are interlinked, with chronic obstruction initiating time-dependent compensatory mechanisms, but ultimately the bladder decompensates. Transcriptomic studies in humans reveal fibroblast-macrophage-epithelial crosstalk driving extracellular matrix remodeling, inflammation, and tissue repair, with conserved molecular pathways across species, including transforming growth factor beta, nuclear factor-kappa B, and phosphoinositide 3-kinase/protein kinase B signaling. Rat models highlight Cthrc1 as a regulator of smooth muscle proliferation after denervation and implicate hypoxia-responsive transcription factors. PVR arises from a multifactorial interplay of timedependent mechanical, myogenic, and neurogenic factors, underpinned by conserved molecular pathways. Molecular diagnostics integrating messenger RNA/microRNA signatures hold promise for early detection of detrusor decompensation, enabling targeted interventions to preserve bladder function and prevent complications.

Keywords: Urinary bladder; Urinary retention; Bladder outlet obstruction; Transcriptome

INTRODUCTION

Postvoid residual urine (PVR), the volume of urine remaining in the bladder following micturition, serves as a clinically significant marker of lower urinary tract dysfunction [1, 2]. Although frequently underappreciated in routine assessments, its presence may reflect a range of underlying pathologies, including bladder outlet obstruction (BOO) and neurogenic bladder syndromes as causes of detrusor underactivity [1-4]. Crucially, residual urine is not merely a passive finding but may act as a precursor to serious complications such as recurrent urinary tract infections, bladder overdistension, and progressive renal impairment.

In the aging population, the prevalence of conditions such as benign prostatic hyperplasia (BPH) [5] and diabetes-related autonomic neuropathy [6] continues to rise. In parallel, incomplete bladder emptying is emerging as an increasingly important concern. This essay explores some of the etiological factors contributing to residual urine, with a focus on the time course of bladder mechanics and changes in cellular and molecular pathways involved in detrusor underactivity caused by outflow obstruction. Based on our messenger RNA (mRNA) expression arrays in obstructed rat bladders, we aim to provide an understanding of this condition and to identify potential therapeutic target areas for mitigating the progression of the condition.

METHODS

Literature data on PVR, bladder physiology and mechanics, and BOO-associated molecular changes were searched on PubMed and Embase and integrated with mRNA and microRNA (miRNA) expression data from patients with BOO, as well as from short- and long-term obstructed rat bladders from our own laboratory.

RESULTS

Physiology and Pathophysiology of Bladder Emptying and Residual Urine

Normal bladder emptying is a finely tuned physiological process involving the detrusor muscle, the bladder outlet (comprising the internal and external urethral sphincters), and an intricate network of neural control [7, 8].

During the bladder filling phase, sympathetic nervous system activity, mediated through the hypogastric nerve (T11–L2), maintains detrusor relaxation and promotes contraction of the internal sphincter via α-adrenoceptor stimulation at the bladder neck and urethra. Concurrently, the external sphincter remains contracted under somatic control via the pudendal nerve (S2–S4), ensuring continence. Afferent signals from stretch receptors in the bladder wall ascend to the brainstem’s pontine storage center, reinforcing storage and inhibiting premature voiding [9]. As bladder volume approaches a critical threshold, heightened afferent input activates the pontine micturition center, initiating the voiding reflex [10-12]. This involves parasympathetic efferent activation via the pelvic nerve (S2–S4), leading to detrusor contraction, while sympathetic output is simultaneously suppressed, allowing the internal sphincter to relax. Voluntary relaxation of the external sphincter, coordinated by higher cortical centers, completes the sequence, enabling efficient and complete urine expulsion. In a healthy system, this precise coordination ensures that detrusor contraction and sphincter relaxation occur synchronously, generating intravesical pressures of approximately 30–40 cm H₂O to achieve effective voiding [7].

Disruption of this tightly regulated mechanism underlies the development of residual urine. This can result from impaired detrusor contractility, elevated outlet resistance, or a failure of coordinated activity between the bladder and sphincters. Neurological insults or degenerative disorders can disrupt afferent or efferent pathways, impairing detrusor contraction or sphincter relaxation. Conversely, mechanical obstruction, such as BPH, urethral stricture, or pelvic organ prolapse, may hinder urine outflow despite intact detrusor function [13, 14].

In many instances, these factors coexist; for example, chronic BOO may induce compensatory detrusor hypertrophy that eventually decompensates into detrusor underactivity, further aggravating incomplete bladder emptying [13].

Over time, persistent residual urine can precipitate a cascade of adverse outcomes, including urinary tract infections, bladder overdistension, upper urinary tract deterioration, and diminished quality of life. Therefore, a thorough understanding of both the physiological basis of micturition and the multifactorial pathophysiology of residual urine is essential. Effective management hinges on accurately identifying whether the dysfunction arises from impaired bladder contractility, increased outlet resistance, or defective neural integration, each of which necessitates distinct therapeutic approaches.

Clinical Manifestations of Residual Urine

Bladder outlet obstruction

Mechanical obstruction of the bladder outlet remains a leading cause of residual urine [1, 2, 4, 14]. BOO refers to any physical or functional impediment at the bladder neck or urethra. In older men, BPH with consequent BOO is the predominant etiology [14]. Whether from BPH, strictures, or pelvic prolapse, the detrusor must generate elevated pressure to overcome resistance. Over time, this can lead to detrusor hypertrophy and subsequent fatigue, resulting in residual urine.

Detrusor underactivity

Detrusor underactivity has been defined by the International Continence Society [15, 16] as “a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal time span.” It may arise from age-related changes, myogenic or neurological damage, or the use of certain medications. Patients often report a weak stream and the sensation of incomplete voiding. Urodynamic studies typically confirm reduced contractile pressure.

When the bladder habitually retains large volumes of urine, it becomes progressively overdistended. Chronic mechanical stretching can damage the detrusor muscle fibers and impair their ability to contract. Overdistension reduces bladder compliance and elasticity, eventually resulting in a hypotonic or flaccid bladder incapable of effective voiding, even if the initial cause of retention is corrected. In acute settings, such as postoperative urinary retention, excessive overfilling (often exceeding 800–1,000 mL) can cause ischemic injury to the bladder wall due to compromised perfusion, further exacerbating detrusor dysfunction.

Rat Bladder Data

Muscle mechanics behind the early development of overstretch and residual urine in the obstructed bladder

The length-active tension relation of the bladder wall [17], and its smooth muscle cells (SMCs) is, in principle, shown in Fig. 1. When the bladder is filled, and its wall is distended, the SMCs can, when activated, produce more and more active force on the upward part of the length-active tension relation, until a plateau is reached. Further stretch results in a decreasing active tension. The muscle cells are now on the downward slope of the length-active tension relation [18].

Fig. 1.

Control bladder. Relation between length (radius) and active tension in rabbit bladder. On the upward slope of the length-active tension curve isometric and isotonic radius-tension relations are similar (radius a and b). If the detrusor is stretched beyond this, the muscle cannot shorten isotonically to the length where the corresponding isometric tension was developed. A shortening defect has developed [17].

According to the Frank-Starling law of the heart, an increased diastolic filling of a ventricle results in an increased systolic pressure. A corresponding relationship is found for the relation between bladder filling and active pressure during micturition. Fig. 1 shows that the upward part of the length-active tension relation can be reached either isometrically or by isotonic shortening, independent of the initial length (see starting lengths a and b, where b illustrates an increased filling).

Early overstretch of the wall of the obstructed bladder

Upon further stretch of the detrusor muscle cells, a shortening defect develops [17], i.e., the muscle cells cannot shorten to the same length as before (Fig. 1, starting length c). This shortening defect might be essential for the early development of residual urine. Bladder emptying is increasingly compromised (see below), and the downward part of the length-active tension curve is reached, resulting in further increases in residual urine.

Control rats emptied their bladders completely [19]. Rats with partial outlet obstruction developed a residual volume that increased linearly with the time of obstruction and did not reach a plateau value [19, 20]. After 6 weeks the residual urine amounted to 6 mL, and only 10% of the prevoid volume was emptied during a micturition.

A rightward shift of the radius-pressure and radius-force curves in the obstructed bladder

There is a rightward shift (Fig. 2) of the relation between bladder filling and active pressure in the obstructed bladder [21]. If this relation between volume and pressure is transformed to radius and force, using the law of Laplace, it can be seen (Figs. 2 and 3 in [21]) that the active force holding the bladder hemispheres together is also shifted to the right (i.e., to higher radius values). We can see no advantage for the bladder with this shift. On the contrary, it results in a decreased emptying and could contribute to the development of residual urine. The mecha-nism behind this shift is not known with certainty but might be related to the phenomenon in skeletal muscle [22, 23] that if a skeletal muscle is fixed in a stretched length, the number of sarcomeres in series are increased, leading to a corresponding rightward shift of the length-active tension curve.

Fig. 2.

Schematic drawing showing that the opening pressure for the hypertrophic rat bladder (OPH, red line) is higher than for the control (OPC, black line) opening pressure, and is reached at a higher prevoid volume. After voiding the hypertrophic bladder has, unlike the control, a postvoid residual volume (based mainly on [21]).

Fig. 3.

Early and late events following the development of a partial infravesical obstruction. The bladder wall is first stretched to overcome the increased outlet resistance (“Frank-Starling law of the bladder”). Then compensatory mechanisms set in. Finally, the bladder becomes underactive due to molecular events presented in this article.

Zeng et al. [20] found that bladders with BOO had mechanoreceptors with higher threshold volumes and lower tension sensitivity. Such changes would result in a weaker afferent drive of micturition and may contribute to the development of residual urine and retention in patients with BOO. It is, however, difficult to assess if the lowered sensitivity is causing the residual urine, or is caused by the distension, in the same manner as the rightward shift of the volume-pressure relation described above.

Compensatory attempts of the obstructed rat bladders

In order to compensate for the increased outlet resistance the detrusor muscle hypertrophies. The weight gain is remarkable. The female rat bladder can increase [24, 25] from a control weight of about 80 mg to 600 mg. The rabbit bladder increases from about 2.5 g to 10 g [26], and the guinea pig from 0.4 to 1.2–1.7 g [27, 28]. The weight gain is rapid initially, but levels off at about 6 weeks [29]. The amount of contractile proteins per bladder increases [30] to overcome the outlet obstruction. The concentration of desmin [30] increases in the detrusor cells, indicating an increased number of intermediate filaments, enforcing the cytoskeleton of the detrusor muscle cells.

The arteries to the bladder enlarge to accommodate for an increased total blood flow [31]. Increased glucose transport over the cell membrane [32], and increased lactate dehydrogenase activity [32] and isoforms that are unaffected by product inhibition [33] makes the detrusor less sensitive to anoxia.

The cross-bridge turnover rate is decreased [34] so less adenosine triphosphate will be consumed for force development [35]. The glucose transporter 1 and lactate dehydrogenase increases are hypoxia-inducible factor (HIF) mediated [32], so the cells must encounter hypoxia/ischemia, most probably during the prolonged micturition phase [36, 37] with intravesical pressures higher than the systolic blood pressure.

These compensatory mechanisms might delay and decrease the development of residual urine but in many obstructed bladders a vicious circle develops (Fig. 3).

Transcriptomic Changes in Bladder Underactivity Caused by Outflow Obstruction

Rat bladder data

In a rat model, pelvic ganglia were cryo-ablated and subsequent bladder transcriptomes were analyzed using microarrays [38]. Ten days postdenervation, bladder weight increased 5.6-fold, and 2,890 mRNAs along with 135 miRNAs were differentially expressed. Comparison with data from obstructed bladders [39] revealed that approximately 10% of mRNAs were significantly altered in the same direction in both conditions. Shared signatures included Cthrc1, Prc1, Plod2, and Dkk3, as well as miR-212 and miR-29. Discordantly regulated transcripts were rare, representing only 0.07% of all changes, and localized to the urothelium in normal bladders, suggesting potential diagnostic utility for detecting sensory denervation. Western blot analysis confirmed consistent protein-level changes, including increased expression of Cthrc1, Prc1, Plod2, and Dkk3. Cthrc1 was selected for further study and found to be induced in the SMC layer following denervation. Additional experiments demonstrated that transforming growth factor beta 1 (TGF-β1) stimulation and miR-30d-5p inhibition elevated Cthrc1 in bladder SMCs, while Cthrc1 knockdown and overexpression decreased and increased SMC proliferation, respectively. These findings define common and distinct transcriptional features of bladder denervation and BOO and suggest a role for Cthrc1 in bladder growth following denervation.

Ito et al. [40] stratified BOO model rats into 2 groups based on the degree of bladder smooth muscle hypertrophy. The strong hypertrophy group, characterized by a higher proportion of bladder smooth muscle and elevated HIF1α mRNA levels compared with controls, was considered a model of hypertrophy termination, whereas the mild hypertrophy group represented hypertrophy initiation. Several genes associated with urinary function showed distinct expression patterns between the groups. Notably, D-box binding PAR bZIP transcription factor (DBP), involved in circadian gene expression [41], was upregulated exclusively in the mildly hypertrophic group. DBP expression increased in bladder SMCs under hypoxic stress and was shown to bind enhancer and promoter regions of the NOS3 gene, thereby upregulating NOS3 expression in hypoxic conditions. These results indicate that regulatory mechanisms of gene expression are altered during tissue remodeling following BOO and suggest that circadian clock components may contribute to the regulation of urinary function through transcriptional responses to hypoxia.

In a recent article [39], we presented array data showing an increased expression of genes promoting fibrosis in both shortand long-term obstruction in rats. There were no genes upregulated in the long-term obstructed bladders that were not upregulated in the short-term obstructed bladders. There was no sign of a shift of gene expression from hypertrophic to fibrotic that has been reported for the underactive human bladder ([42], see below). A muscle marker, acta1 had increased 6.94 times in the 10 days bladders, and 5.93 times in the 6 weeks bladders. Ctgf, a marker of fibrosis [39], had increased 8.02 times in the 10 days bladders, and 5.93 times in the 6 weeks obstructed bladders. Thus, both muscle and fibrosis transcripts were upregulated in both short-term and long-term obstructed rat bladders.

Human data

By using single-cell RNA sequencing, Chen et al. [43] sequenced 69,973 cells from 5 controls and 9 patients with obstruction-induced detrusor underactivity. Twelve distinct cell types were identified. They showed high cellular and functional heterogeneity within each group. Among them, fibroblasts, macrophages, and epithelial cells exhibited the most extensive intercellular communication. Their aberrant gene expressions and altered intercellular interactions were mainly involved in extracellular matrix organization, inflammation/immune regulation, and cellular injury. Further re-cluster analysis revealed an accumulation of the RBFOX1+ fibroblasts and RIPOR2+ macrophages in the dysfunctional bladder wall, which mediated bladder remodeling through dysfunctional extracellular matrix organization and inflammation/immune reaction. Besides, the urothelial cells showed signs of inflammation, damage, and repair during bladder remodeling.

Gheinani et al. [42] reported mRNA and miRNA transcriptome sequencing of bladder samples from human patients with different urodynamically defined states of BOO. Patients’ miRNA and mRNA expression profiles correlated with urodynamic findings. Validation of RNA sequencing results in an independent patient cohort identified combinations of 3 mRNAs (NRXN3, BMP7, UPK1A) and 3 miRNAs (miR-103a-3p, miR-10a-5p, miR-199a-3p) sufficient to discriminate between bladder functional states. All BOO patients shared cytokine and immune response pathways, TGF-β and nitric oxide signaling pathways, and hypertrophic phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathways. Activator protein-1 and NF-κB were dominant transcription factors, and TNF-α was the top upstream regulator. Integrated miRNA-mRNA expression analysis identified pathways and molecules targeted by differentially expressed miRNAs. Prefibrotic transcripts and miRNAs were increased, and smooth muscle specific mRNAs and miRNAs were decreased in underactive bladders. The results of Gheinani et al. [42] further suggested an increasing involvement of miRNAs in the control of bladder function from the overactive to underactive/acontractile states.

Mild outlet obstruction mirrors transcriptomic shifts linked to circadian rhythms, including activation of the transcription factor DBP (see above). Circadian timing arises from cell-autonomous transcription-translation loops in which CLOCK and BMAL1 drive expression of PER and CRY genes, whose proteins later repress their own transcription. Auxiliary loops fine-tune this ~24-hour cycle, influencing nearly 40% of genes [44] and aligning it with cues such as light. Although circadian control has been studied in mouse bladder [45-47], data from humans remain scarce due to underreported collection times. Tools for time-stamping RNA-seq [48] and RNA-seq-based atlases of cycling transcripts [49] have yet to include the bladder. Pending such analyses, correlating PER1 with all other genes [50, 51] in the human bladder offers a first glimpse, revealing transcripts with positive and negative associations (Fig. 4). These findings suggest circadian modulation of transcriptional (MRTFB), sensory (TRPV2), inflammatory (IRF1), and fibrotic pathways. Notably, MRTFB, in complex with serum response factor, regulates smooth muscle development. Thus, micturition volume and postvoid residual volume may undergo daily variations. This would constitute a hypothesis for future study on the early phase of the development of residual urine and bladder underactivity.

Fig. 4.

For identification of cycling transcripts in the human urinary bladder we used GTEx RNA-sequencing data. The core circadian gene period 1 (PER1) was correlated versus all transcripts. Positive (A–C) and negative (D–F) extremes were inspected. Among positively correlating transcripts were HIF3A, MRTFB, and TGFBR3. Among the anticorrelating transcripts were IRF1, TRPV2, and CCL2. These molecular findings suggest that profibrotic transcripts cycle in antiphase with inflammatory and nociceptive transcripts. This is of possible relevance for circadian variation of fibrosis, sensory function, and inflammation.

DISCUSSION

The present findings by us and others contribute to a growing body of evidence that PVR is not simply a passive marker of lower urinary tract dysfunction, but a measurable endpoint of complex and multifactorial pathophysiological processes. Both clinical and experimental data converge on the conclusion that BOO and detrusor underactivity are interdependent drivers of residual urine accumulation, with the transition from early compensated to the later decompensated detrusor function being central to disease progression (Fig. 3).

Early muscle mechanical adaptations include the equivalent to the Frank-Starling law of the heart, and lead to a distension of the bladder wall. The shortening defect [17] leads to incomplete bladder emptying. This is followed by a rightward shift [21] of the radius-pressure and radius-force curves in the obstructed bladder, a result of a remodeling of the contractile apparatus within the detrusor SMCs. This rightward shift decreases bladder emptying and leads to an increase in residual urine. The shortening defect behaves as a viscous element in series with the contractile element. The rightward shift of the radius-force curve could be equivalent to the increased number of sarcomeres coupled in series in the chronically stretched skeletal muscle [22, 23].

Analysis of transcriptomic data from human patients with obstruction-induced detrusor underactivity [42, 43] underscores the heterogeneity of cellular responses in the obstructed bladder. The expansion of RBFOX1+ fibroblasts and RIPOR2+ macrophages, coupled with altered epithelial cell phenotypes, highlights the interplay between extracellular matrix remodeling, inflammation, and tissue repair. These findings align with the hypothesis that chronic BOO induces a maladaptive wound-healing response in the bladder wall, wherein persistent inflammatory signaling and fibrosis impair smooth muscle contractility. The convergence of human and rat data in identifying extracellular matrix and inflammatory pathways, including TGF-β, NFκB, and PI3K/AKT signaling, suggests these molecular cascades are conserved across species and may represent viable therapeutic targets.

Rat model information contributes to the interpretation of the human observations. For example, the identification of Cthrc1 as a regulator of SMC proliferation following denervation [38] points to a potential effector molecule in bladder hypertrophy and maladaptive remodeling. Similarly, the work by Ito et al. [40] implicates hypoxia-driven gene regulation in BOO-associated remodeling, with the circadian clock component DBP emerging as a transcriptional regulator of NOS3. These findings raise the intriguing possibility that time-of-day– dependent gene expression could influence bladder function and recovery potential, a dimension not yet integrated into current therapeutic strategies.

There seems to be a substantial overlap in the transcriptional signatures of BOO and sensory denervation, suggesting that distinct initiating insults can converge on shared molecular endpoints. This may explain why clinical phenotypes of detrusor underactivity often appear similar regardless of the initiating pathology. However, the subtle differences, such as the small set of discordantly regulated urothelial transcripts in denervation, could hold diagnostic value for differentiating underlying causes and guiding targeted therapy.

From a translational perspective, the miRNA-mRNA interaction networks identified in human BOO [42] are particularly promising. The discriminatory potential of combined mRNA/miRNA panels for defining bladder functional states raises the prospect of developing molecular diagnostics for early detection of decompensation, thereby enabling timely intervention before irreversible detrusor failure occurs.

There are, however, several limitations to consider. Human tissue studies are constrained by the availability and heterogeneity of clinical samples, and the cross-sectional nature of most datasets limits the ability to infer causality or temporal sequence. Animal models, while enabling mechanistic exploration, may not fully recapitulate the chronicity, comorbidities, and environmental influences present in human disease. Moreover, transcriptomic alterations do not necessarily equate to functional protein changes; integrating proteomic and metabolomic profiling could strengthen causal inferences.

CONCLUSION

Residual urine arises from a complex interplay of mechanical, myogenic, and neurogenic factors, with extracellular matrix remodeling, inflammation, and hypoxia emerging as central molecular themes. Future research should prioritize longitudinal studies that track molecular changes from the early compensatory phase of BOO to overt detrusor underactivity and explore interventions that modulate fibroblast-immune-epithelial crosstalk. A deeper understanding of these processes holds promise for developing targeted therapies to preserve bladder function and prevent the downstream complications of chronic urinary retention.

Notes

Grant/Fund Support

KS acknowledges support from King Gustaf V and Queen Victoria’s Foundation.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTION STATEMENT

· Conceptualization:BU, KEA, KS

· Data curation:BU, KEA, KS

· Formal analysis:BU, KEA, KS

· Funding acquisition:KS

· Methodology:BU, KEA, KS

· Project administration:BU, KEA, KS

· Visualization:BU, KEA, KS

· Writing - original draft:BU, KEA, KS

· Writing - review & editing:BU, KEA, KS

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