Patient case: 32-year-old female with inflammatory myofibroblastic tumor; genetic feature: RANBP2-ALK fusion

Clinical trial: Urinary Cytokines in Patients With Overactive Bladder (OAB)

Summary: Overactive bladder (OAB) is a widespread condition characterized by urgency, urge incontinence, nocturia and excessive urinary frequency, affecting millions of people worldwide.(1) In two epidemiological studies, OAB was found in about 17% of American and European populations.(2)(3). This accounts for an estimated 33 million patients suffering from OAB in the USA. The disorder constitutes a psychological stress that impacts the patient's social life.

Detailed description: Overactive bladder (OAB) is a widespread condition characterized by urgency, urge incontinence, nocturia and excessive urinary frequency, affecting millions of people worldwide.(1) In two epidemiological studies, OAB was found in about 17% of American and European populations.(2)(3). This accounts for an estimated 33 million patients suffering from OAB in the USA. The disorder constitutes a psychological stress that impacts the patient's social life.
  The luminal surface of the bladder is covered by the urothelium, which functions as a highly efficient barrier to the movement of water and ionized substances across the bladder wall.(4) Urothelial cells also have specialized sensory and signaling properties that allow them to respond to their chemical and physical environment, and engage in reciprocal chemical communication with neighboring nerves in the bladder wall. These properties are 1) nicotinic, muscarinic, tachykinin, adrenergic and capsaicin (TRPV1) receptor expression, 2) sensitivity to transmitters released from afferent and efferent nerves, 3) mechanosensitivity, 4) close physical association with afferent nerves and 5) the ability to release chemical mediators such as ATP and NO, which can regulate the activity of adjacent nerves and, thereby, trigger local vascular changes and/or reflex bladder contractions.(5)
  Transmitter release from urothelial cells appears to be mediated by a calcium dependent exocytotic mechanism that is similar to the mechanism involved in transmitter release from nerve terminals. Transmitters released from urothelial cells can act in an autocrine/paracrine manner in the urothelium, or on subepithelial myofibroblasts, nerves or blood vessels to influence various functions, including the urothelial barrier, local blood flow and sensory mechanisms.(6)
  Urine cytokine assays have been studied in various bladder and kidney disorders with the hope of understanding the pathophysiology and developing a noninvasive, reliable predictor of disease progression and evaluate the response to treatment.
  Interstitial cystitis (IC) is a severely debilitating syndrome of unknown etiology affecting the urinary bladder that is mainly associated with urgency, frequency and pain. Pro-inflammatory molecules and neuroinflammation are suggested in the patho-mechanism of IC. Abdel Mageed and Ghoniem found out the activation of the nuclear factor kappa B (NF-k B) in the bladder biopsy of IC patients. NF-k B is a transcription factor found in some inflammatory diseases like rheumatoid arthritis, bronchial asthma, and inflammatory bowel diseases. NF-k B has a role in induction of pro inflammatory cytokines IL-6, IL-2, IL-1β and TNF-α. Activation of NF-k B was associated with 27, 8, 10 and 7 fold increase in TNF-α, IL-10, IL-6 and IL-8 transcripts respectively.(7,8) Keay et al determined that the urine of IC patients specifically contains a factor that inhibit primary bladder epithelial proliferation, anti proliferative factor (APF) and it has significantly decreased heparin binding epidermal growth factor like factor (HBEGF) and increased epidermal growth factor (EGF) levels compared to urine from normal subjects.(9) Chai et al compared urine levels of APF and HB-EGF before and after bladder distention and neurostimulation.(10,11) Both of urine markers changed toward normal levels after hydrodistention or neuromodulation treatment of IC.
  Urinary cytokines have also been studied in patients undergoing intravesical bacillus Calmette Guerin (BCG) therapy for superficial bladder cancer.(12) BCG is thought to cause local immunostimulation, resulting in infiltration of T-lymphocytes in the bladder wall. After treatment, IL-1, IL-2, IL-6, and TNF are significantly elevated in the urine. It is thought that BCG induced cytokines may generate bladder tumor killing cells, and an elevation of urine cytokines may correlate clinical response to BCG therapy.
  Recently, there have been studies that have attempted to identify specific measurable urinary factors that lead to the progression of chronic renal disease. Cytokines are involved in the recruitment of inflammatory cells, leading to infiltration in the diseased kidney, ultimately resulting in renal scarring. Elevated levels of urinary IL-6 and TNF receptor-1 are identified in children with vesicoureteral reflux associated with reflux nephropathy and renal scarring.(13)
  Acute renal allograft rejection is a result of the recipient's immune response to the donor kidney, and 35% of these patients experience an episode of acute rejection the first year after surgery. Elevated urinary cytokines have been measured in patients who have biopsy proven renal allograft acute rejection.(14)
  Urinary cytokines and markers have been identified in different urological disorders. They are used to understand the pathophysiology, diagnosis and evaluation of the treatment of these disorders. We hypothesize that there is urothelial abnormality in cases of overactive bladder that leads to elaboration of certain kinds of urinary cytokines. To our knowledge, no study has been published evaluating urinary markers in patients with OAB.

Eligibility: Inclusion Criteria:
  -  Group I (OAB patients)
  1. Women with OAB, ≥18 years and premenopausal non-menstruating, not on any anticholinergic for at least two weeks before enrollment in the study.
  2. Significant urgency,i.e., having moderate or severe urgency score.
  3. Having a score > 8 on the OAB-V8 questionnaire.
  4. Urinary frequency of more than 8/day, with urgency of urination, with or without urge incontinence.
  5. Negative screening urinalysis one month after documented UTI.
  -  Group II (Control)
  1. Age-matched normal volunteers (≥18 years and premenopausal non-menstruating)
  2. No Urgency.
  3. OAB-8 score < 8.
  4. No UTI.
  -  Group III (UTl)
  1. Age-matched
  2. ≥18 years and premenopausal non-menstruating women with culture proven UTI.
  Exclusion Criteria:
  1. Treatable genitourinary conditions that could cause incontinence
  2. Hematuria
  3. Obstructive uropathy
  4. Patients diagnosed with vaginitis
  5. History of urothelial carcinoma
  6. Urinary tract infection (except group III)
  7. Pelvic radiation.
  8. Neurogenic bladder.
  9. Renal pathology.
  10. Stress urinary incontinence.
  11. Medications.
  12. Recent history of Botox injection in the bladder (Within the last year).

Relevance to patient case: not relevant