Editing Glomerulation

'''Glomerulation''' refers to [[Urinary bladder|bladder]] [[hemorrhage]]s which are thought to be associated with some types of [[interstitial cystitis]] (IC).

The presence of glomerulations, also known as [[petechia]]l [[hemorrhage]]s, in the [[Urinary bladder|bladder]] suggests that the bladder wall has been damaged, irritated, and/or inflamed. Petechial hemorrhages originate from punctuate hemorrhages.<ref>{{Citation|title=Glomerulations|date=2007|url=https://doi.org/10.1007/978-3-540-29805-2_1641|encyclopedia=Encyclopedia of Pain|pages=828|editor-last=Schmidt|editor-first=Robert F.|place=Berlin, Heidelberg|publisher=Springer|language=en|doi=10.1007/978-3-540-29805-2_1641|isbn=978-3-540-29805-2|access-date=2021-07-30|editor2-last=Willis|editor2-first=William D. |url-access=subscription}}</ref> The [[National Institute of Diabetes and Digestive and Kidney Diseases]] (NIDDK) Diagnostic Criteria for IC, developed in 1987, required the presence of glomerulations or [[Hunner's Ulcers]] for diagnosis of IC and is still used today, to determine eligibility for some clinical trials.<ref name=":0">{{Cite journal|last1=Gillenwater Jay Y.|last2=Wein Alan J.|date=1988|title=Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis, National Institutes of Health, Bethesda, Maryland, August 28-29, 1987|url=https://www.auajournals.org/doi/10.1016/S0022-5347%2817%2941529-1|journal=Journal of Urology|volume=140|issue=1|pages=203–206|doi=10.1016/S0022-5347(17)41529-1|pmid=3379688|url-access=subscription}}</ref> However other research has theorized that the hydrodistention procedure used for the diagnosis of IC itself may have created these tiny broken [[blood vessel]]s.<ref name=":10">{{Cite journal|last1=Ueda|first1=Tomohiro|last2=Hanno|first2=Philip M.|last3=Saito|first3=Ryoichi|last4=Meijlink|first4=Jane M.|last5=Yoshimura|first5=Naoki|date=2021|title=Current Understanding and Future Perspectives of Interstitial Cystitis/Bladder Pain Syndrome|journal=International Neurourology Journal|volume=25|issue=2|pages=99–110|doi=10.5213/inj.2142084.042|issn=2093-4777|pmc=8255826|pmid=34218637}}</ref> Studies have found glomerulations in asymptomatic populations, suggesting that they are not applicable as a marker for IC.<ref name=":4" />  Thus, a diagnosis of IC is now based upon other, less invasive methods, such as the PUF Scale (Pelvic Pain and Urgency/Frequency Patient Symptom Scale).  Glomerulation has been observed to be one of the feature for [[prostate cancer]].<ref>{{Cite journal|last=Epstein|first=Jonathan I.|date=2004|title=Diagnosis and reporting of limited adenocarcinoma of the prostate on needle biopsy|journal=Modern Pathology |volume=17|issue=3|pages=307–315|doi=10.1038/modpathol.3800050|issn=0893-3952|pmid=14739905|doi-access=free}}</ref> However, efforts to determine whether this is association or causation have concluded that while glomerulations may be a common finding in individuals with prostate cancer, they are not a significant predictor.<ref name=":6">{{Cite journal|last1=Furuya|first1=Ryoji|last2=Masumori|first2=Naoya|last3=Furuya|first3=Seiji|last4=Oda|first4=Toshiro|last5=Takahashi|first5=Satoshi|last6=Takeuchi|first6=Masaya|date=2007|title=Glomerulation Observed During Transurethral Resection of the Prostate for Patients With Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia is a Common Finding But No Predictor of Clinical Outcome|url=https://www.sciencedirect.com/science/article/abs/pii/S009042950702105X|journal=Urology|language=en|volume=70|issue=5|pages=922–926|doi=10.1016/j.urology.2007.06.1153|issn=0090-4295|pmid=18068448|url-access=subscription}}</ref>

== Presentation ==
Glomerulations appear as checkerboard/lattice patterns, splotches, or pinpoint-sized red marks on the [[Urinary bladder|bladder]].<ref>{{Cite web|date=2018|title=How is a finding of glomerulations characterized in interstitial cystitis/bladder pain syndrome (IC/BPS)?|url=https://www.medscape.com/answers/2055505-61988/how-is-a-finding-of-glomerulations-characterized-in-interstitial-cystitisbladder-pain-syndrome-icbps|access-date=2020-07-28|website=www.medscape.com}}</ref><ref>{{Cite web|date=2015|title=Cystoscopy with Hydrodistention|url=https://www.ichelp.org/diagnosis-treatment/diagnosis-of-ic/cystoscopy-with-hydrodistention/|access-date=2020-07-28|website=Interstitial Cystitis Association|language=en-US}}</ref> Glomerulations are classified into five grades that take into consideration the type and location of injury: Grade 0 (normal [[Mucous membrane|mucosa]]), Grade I ([[petechia]]e in at least two quadrants), Grade II (large [[submucosa]]l bleeding), Grade III (diffuse global submucosal bleeding), and Grade IV (mucosal disruption, with or without bleeding).<ref name=":22" /><ref>{{Cite journal|last1=Nordling|first1=J|last2=Anjum|first2=F.H|last3=Bade|first3=J.J|last4=Bouchelouche|first4=K|last5=Bouchelouche|first5=P|last6=Cervigni|first6=M|last7=Elneil|first7=S|last8=Fall|first8=M|last9=Hald|first9=T|last10=Hanus|first10=T|last11=Hedlund|first11=H|date=2004|title=Primary Evaluation of Patients Suspected of Having Interstitial Cystitis (IC)|url=https://linkinghub.elsevier.com/retrieve/pii/S0302283803006262|journal=European Urology|language=en|volume=45|issue=5|pages=662–669|doi=10.1016/j.eururo.2003.11.021|pmid=15082211|url-access=subscription}}</ref>

According to [[National Institute of Diabetes and Digestive and Kidney Diseases|NIDDK]] criteria for inclusion in IC studies, examination for glomerulations is performed following hydrodistention of the bladder. In this procedure, water is instilled into the bladder to a pressure of 80–100&nbsp;cm for 1–2 minutes. When water is drained from the bladder, glomerulations may appear. To be considered as IC, these [[submucosa]]l [[Bleeding|hemorrhages]] must be present in at least 3 quadrants of the bladder with over 10 glomerulations per quadrant. Glomerulations should not be along the path of [[Cystoscopy|cystoscope]] which may suggest trauma instead.<ref>{{Cite journal|last=Meijlink|first=Jane M.|date=2014|title=Interstitial cystitis and the painful bladder: A brief history of nomenclature, definitions and criteria|journal=International Journal of Urology|language=en|volume=21|issue=S1|pages=4–12|doi=10.1111/iju.12307|pmid=24807485|issn=1442-2042|doi-access=free}}</ref>

== Pathophysiology ==
The pathophysiologic mechanism of glomerulations is unknown and debated.<ref name=":4" /> Some researchers suggest it may be the bladder's response to prolonged periods of underfilling.<ref name=":7">{{Cite journal|last1=Hassan|first1=Ayman A.|last2=Elgamal|first2=Samir A.|last3=Sabaa|first3=Magdy A.|last4=Salem|first4=Khalid|date=2007|title=Evaluation of intravesical potassium sensitivity test and bladder biopsy in patients with chronic prostatitis/chronic pelvic pain syndrome|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1442-2042.2007.01821.x|journal=International Journal of Urology|language=en|volume=14|issue=8|pages=738–742|doi=10.1111/j.1442-2042.2007.01821.x|pmid=17681066|s2cid=22816619|issn=1442-2042|url-access=subscription}}</ref> Another possible mechanism of glomerulation is over expression of [[angiogenic]] growth factors in the bladder.<ref>{{Cite journal|last1=Tamaki|first1=Masahiro|last2=Saito|first2=Ryoichi|last3=Ogawa|first3=Osamu|last4=Yoshimura|first4=Naoki|last5=Ueda|first5=Tomohiro|date=2004|title=Possible mechanisms inducing glomerulations in interstitial cystitis: relationship between endoscopic findings and expression of angiogenic growth factors|url=https://pubmed.ncbi.nlm.nih.gov/15311005/|journal=The Journal of Urology|volume=172|issue=3|pages=945–948|doi=10.1097/01.ju.0000135009.55905.cb|issn=0022-5347|pmid=15311005}}</ref>

It has been shown that glomerulations are also presented under hydrodistension procedures.<ref name=":22">{{Cite journal|last1=Ens|first1=Gisela|last2=Garrido|first2=Gustavo L.|date=2015|title=Role of cystoscopy and hydrodistention in the diagnosis of interstitial cystitis/bladder pain syndrome|journal=Translational Andrology and Urology|volume=4|issue=6|pages=624–628|doi=10.3978/j.issn.2223-4683.2015.09.04|issn=2223-4691|pmc=4708540|pmid=26816863}}</ref>  During the filling portion of hydrodistension, one can see white fibrous bundles as the bladder is stretched. When stretched, blood flow is interrupted in these fibrous bundles. After this stretching phase, the emptying phase allows blood flow to resume. This is where one can see bleeding from capillaries.<ref name=":22" />

In relation to interstitial cystitis, when noxious stimuli are present, it causes injury to the bladder [[Mucous membrane|mucosa]] resulting in recruitment of [[Inflammation|inflammatory]] cells.<ref name=":10" /> Disruption of [[glycosaminoglycan]] (GAG) layer<ref>{{Cite journal|last1=Daniels|first1=Amanda M.|last2=Schulte|first2=Adam R.|last3=Herndon|first3=Christopher M.|date=2018|title=Interstitial Cystitis: An Update on the Disease Process and Treatment|url=https://doi.org/10.1080/15360288.2018.1476433|journal=Journal of Pain & Palliative Care Pharmacotherapy|volume=32|issue=1|pages=49–58|doi=10.1080/15360288.2018.1476433|issn=1536-0288|pmid=30212267|s2cid=52274813|url-access=subscription}}</ref> along with the increased presence of [[mast cell]]s, [[T cell]]s, and [[B cell]]s causes the bladder [[epithelium]] to become more permeable. Injury to the GAG layer may lead to increased release of adhesion factors that bind to angiogenic molecules, which generally have little presence under normal conditions, to promote [[wound healing]]. Ultimately, increased adhesion factors and overproduction of angiogenic factors from [[mast cell]]s and disruption of the GAG layer results in tissue [[fibrosis]].<ref name=":10"/> As mentioned above, the technique of hydrodistention is one method used to diagnose [[interstitial cystitis]], in which the [[Atrophy|atrophic]] bladder is filled and emptied and thus, the stretch of the bladder wall is one possible mechanism of glomerulations.<ref name=":22"/>

== Risk factors ==
Diagnosis of chronic [[pelvic pain]] or discomfort, accompanied with urinary symptoms, seems to be the most likely risk factor for glomerulation.<ref name=":22" /> Research has shown that up to 7.5% of the adult female population is associated with [[Chronic prostatitis/chronic pelvic pain syndrome|chronic pelvic pain]] (CPP), in which irritative voiding is commonly seen.  Bladder tissue damage is a component that could lead to CPP.  These symptoms are also seen in IC which may have led to the pathogenesis of glomerulation through hydrodistention.<ref>{{Cite journal|last=Forrest|first=John B.|date=2006|title=Epidemiology and quality of life|url=https://pubmed.ncbi.nlm.nih.gov/16676917/|journal=The Journal of Reproductive Medicine|volume=51|issue=3 Suppl|pages=227–233|issn=0024-7758|pmid=16676917}}</ref><ref name=":10"/>

It is speculated that chronic underfilling of the bladder contributes to glomerulations. For example, glomerulations can be seen after [[radiation therapy]], in individuals undergoing [[Kidney dialysis|dialysis]], and after [[urinary diversion]].<ref name=":7" />

== Relation to interstitial cystitis ==
The identification of glomerulations as diagnostic criteria for interstitial cystitis/ bladder pain syndrome is unclear.<ref name=":4" /> Interstitial cystitis (IC)/ bladder pain syndrome (BPS) is associated with chronic pelvic pain, pressure and discomfort within the urinary system.<ref name=":1" /> In 1987, the [[National Institute of Diabetes and Digestive and Kidney Diseases|National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)]] developed diagnostic criteria for IC which included the presence of glomerulations or petechial hemorrhages.<ref name=":0" /> The purpose of the NIDDK diagnostic criteria was to facilitate comparable groups for research.<ref>{{Cite journal|last=Hanno|first=Philip M|date=2002|title=Interstitial Cystitis—Epidemiology, Diagnostic Criteria, Clinical Markers|journal=Reviews in Urology|volume=4|issue=Suppl 1|pages=S3–S8|issn=1523-6161|pmc=1476008|pmid=16986032}}</ref> It was not intended to set strict criteria for the diagnosis of IC.

Interstitial cystitis may also induce angiogenic factors including [[Vascular endothelial growth factor|VEGF (vascular endothelial growth factor)]] and [[Platelet-derived growth factor|PD-ECGF (platelet-derived endothelial cell growth factor)]] resulting in [[neovascularization]].<ref name=":10"/> Angiogenic Factors are crucial in vessel development as high values may lead to vessels without enough [[pericyte]] coverage.<ref>{{Cite journal|last1=Kiuchi|first1=Hiroshi|last2=Tsujimura|first2=Akira|last3=Takao|first3=Tetsuya|last4=Yamamoto|first4=Keisuke|last5=Nakayama|first5=Jiro|last6=Miyagawa|first6=Yasushi|last7=Nonomura|first7=Norio|last8=Takeyama|first8=Masami|last9=Okuyama|first9=Akihiko|date=2009|title=Increased vascular endothelial growth factor expression in patients with bladder pain syndrome/interstitial cystitis: its association with pain severity and glomerulations|journal=BJU International|volume=104|issue=6|pages=826–831; discussion 831|doi=10.1111/j.1464-410X.2009.08467.x|issn=1464-410X|pmid=19298410|doi-access=free}}</ref> Formation of these newer and weaker vessels in the [[submucosa]] associated specifically with IC or BPS, may rupture during hydrodistention causing glomerulation.<ref name=":10"/>

In addition to hydrodistension related glomerulations, a study by Rosamilia et al. has shown that biopsied bladders from women with interstitial cystitis have decreased vessel density in the subepithelium. With this, data collected by Irwin et al. also showed that blood perfusion in interstitial cystitis bladders is reduced. Thus, decreased blood perfusion may further increase the expression of angiogenic factors [[VEGF]] and [[Platelet-derived growth factor|PD-ECGF]].<ref name=":22" /> Alongside with VEGF there is an increase in [[Hypoxia-inducible factor|Hypoxia-inducible factor-1]] (HIF-1), for HIF-1 binds to VEGF when oxygen is limited in availability.<ref>{{Cite journal|last1=Lee|first1=Jane-Dar|last2=Lee|first2=Ming-Huei|date=2011|title=Increased expression of hypoxia-inducible factor-1α and vascular endothelial growth factor associated with glomerulation formation in patients with interstitial cystitis|url=https://pubmed.ncbi.nlm.nih.gov/21813166/|journal=Urology|volume=78|issue=4|pages=971.e11–15|doi=10.1016/j.urology.2011.05.050|issn=1527-9995|pmid=21813166}}</ref>

Many guidelines do not use glomerulations as a diagnostic criteria for BPS/IC. In a 2014 review of systematic literature searches on PubMed, there were no consistent correlation between the grade or severity of glomerulation and BPS/IC.<ref name=":4">{{Cite journal|last1=Wennevik|first1=Gjertrud E.|last2=Meijlink|first2=Jane M.|last3=Hanno|first3=Philip|last4=Nordling|first4=Jørgen|date=2016|title=The Role of Glomerulations in Bladder Pain Syndrome: A Review|url=https://pubmed.ncbi.nlm.nih.gov/26318984/|journal=The Journal of Urology|volume=195|issue=1|pages=19–25|doi=10.1016/j.juro.2015.06.112|issn=1527-3792|pmid=26318984}}</ref> In the ESSIC guideline, glomerulations are only used to further differentiate bladder pain syndrome (BPS) without [[Hunner's ulcer]]s into different categories: BPS Type 1 (without glomerulations) and BPS Type 2 (with glomerulations).<ref>{{Cite journal|last1=van de Merwe|first1=Joop P.|last2=Nordling|first2=Jørgen|last3=Bouchelouche|first3=Pierre|last4=Bouchelouche|first4=Kirsten|last5=Cervigni|first5=Mauro|last6=Daha|first6=L. Kurosch|last7=Elneil|first7=Suzy|last8=Fall|first8=Magnus|last9=Hohlbrugger|first9=Gero|last10=Irwin|first10=Paul|last11=Mortensen|first11=Svend|date=2008|title=Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal|url=https://pubmed.ncbi.nlm.nih.gov/17900797/|journal=European Urology|volume=53|issue=1|pages=60–67|doi=10.1016/j.eururo.2007.09.019|issn=0302-2838|pmid=17900797}}</ref><ref name=":1">{{Cite journal|last=Homma|first=Yukio|date=2019|title=Interstitial cystitis, bladder pain syndrome, hypersensitive bladder, and interstitial cystitis/bladder pain syndrome – clarification of definitions and relationships|journal=International Journal of Urology|language=en|volume=26|issue=S1|pages=20–24|doi=10.1111/iju.13970|pmid=31144731|issn=1442-2042|doi-access=free}}</ref> The [[American Urological Association]] guideline mentions that glomerulations may be detected on cystoscopy, but that it is not specific for BPS/IC.<ref>{{Cite journal|last1=Hanno|first1=Philip M.|last2=Burks|first2=David Allen|last3=Clemens|first3=J. Quentin|last4=Dmochowski|first4=Roger R.|last5=Erickson|first5=Deborah|last6=Fitzgerald|first6=Mary Pat|last7=Forrest|first7=John B.|last8=Gordon|first8=Barbara|last9=Gray|first9=Mikel|last10=Mayer|first10=Robert Dale|last11=Newman|first11=Diane|date=2011|title=AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome|journal=The Journal of Urology|volume=185|issue=6|pages=2162–2170|doi=10.1016/j.juro.2011.03.064|issn=1527-3792|pmid=21497847|pmc=9341322 }}</ref>  High rates of glomerulations have been observed in other urological conditions such as [[benign prostatic hyperplasia]], upper urinary tract stones, [[prostatitis]], ''etc.'' which challenges its use as a diagnostic marker.<ref name=":4" />

In fact, signs of interstitial cystitis can expand from glomerulations to Hunner's ulcers and [[fibrosis]]. Though one should note that many times, the diagnosis of IC in an individual may not be accurate to the time in which the individual already has IC. Therefore, whether glomerulations are observed during the time of a hydrodistension procedure cannot conclude that it is associated with interstitial cystitis.

== Prognosis ==
Glomerulation can be life-threatening when the rate of blood loss is faster than rate of blood transfusion.  Severe bleeding can arise due to IC and [[Bladder cancer|bladder carcinoma]].<ref name=":2">{{Cite journal|last1=Loffroy|first1=R.|last2=Pottecher|first2=P.|last3=Cherblanc|first3=V.|last4=Favelier|first4=S.|last5=Estivalet|first5=L.|last6=Koutlidis|first6=N.|last7=Moulin|first7=M.|last8=Cercueil|first8=J. P.|last9=Cormier|first9=L.|last10=Krausé|first10=D.|date=2014|title=Current role of transcatheter arterial embolization for bladder and prostate hemorrhage|journal=Diagnostic and Interventional Imaging|volume=95|issue=11|pages=1027–1034|doi=10.1016/j.diii.2014.03.008|issn=2211-5684|pmid=24746761|doi-access=free}}</ref> In severe bladder hemorrhages, prolonged hospitalization may occur.<ref name=":3">{{Cite web|date=2012|title=Bladder Bleeding - an overview {{!}} ScienceDirect Topics|url=https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/bladder-bleeding|access-date=|website=www.sciencedirect.com}}</ref>  However, glomerulations can occur in both symptomatic Bladder Pain Syndrome and non-symptomatic Bladder Pain Syndrome.<ref>{{Cite journal|last1=Chrysanthopoulou|first1=Eleftheria L.|last2=Doumouchtsis|first2=Stergios K.|date=2014|title=Challenges and current evidence on the management of bladder pain syndrome|url=https://pubmed.ncbi.nlm.nih.gov/23946107/|journal=Neurourology and Urodynamics|volume=33|issue=8|pages=1193–1201|doi=10.1002/nau.22475|issn=1520-6777|pmid=23946107|s2cid=13138610}}</ref>

There is no consistent evidence that glomerulations are correlated to severity of urinary symptoms, quality of life, bladder inflammation, or bladder capacity.<ref name=":4" /> One study suggests that the severity of glomerulations may change over time as seen in a few individuals who have either worsened or diminished glomerulations in their subsequent evaluations.<ref name=":4" />

==Treatment==
Though there is limited research on the treatment of glomerulation, some researchers found that it is safe to implement transcatheter arterial embolization of the [[Prostatic artery embolization|prostatic]] or [[Vesical arteries|vesical]] arteries to sustainably control bladder hemorrhage.  It is a minimally invasive procedure with a 90% success rate and is well-tolerated in most cases. It is proven to improve [[Quality of life (healthcare)|quality of life]].<ref name=":2" />

Since there are not many established treatment available, the best treatment for glomerulation is prevention, ex. ensure adequate hydration to flush out infection, beware of drug-induced bleeding and continuous bladder irrigation.<ref>{{Cite journal|date=2021|title=Hemorrhagic Cystitis Treatment & Management: Approach Considerations, Clot Evacuation, Bladder Irrigation Agents|url=https://emedicine.medscape.com/article/2056130-treatment#:~:text=The%20best%20treatment%20of%20hemorrhagic,mesna%20are%20important%20preventive%20measures.|journal=Medscape}}</ref><ref name=":3" />

In people with interstitial cystitis, guidelines such as the American Urological Association (AUC) and Canada Urological Association (CUA) do not differentiate treatment strategies between those with and without glomerulations. While [[Radiofrequency ablation|fulguration]] is listed as a third-line treatment option for [[interstitial cystitis]] with [[Hunner's ulcer|Hunner's Lesions]], guidelines do not recommend it to treat glomerulations.<ref name=":9" /> Instead, guidelines have set symptom control and [[Quality of life (healthcare)|quality of life]] as some of the main goals of treatment for IC.<ref name=":8">{{Cite journal|last1=Cox|first1=Ashley|last2=Golda|first2=Nicole|last3=Nadeau|first3=Genevieve|last4=Curtis Nickel|first4=J.|last5=Carr|first5=Lesley|last6=Corcos|first6=Jacques|last7=Teichman|first7=Joel|date=2016|title=CUA guideline: Diagnosis and treatment of interstitial cystitis/bladder pain syndrome|journal=Canadian Urological Association Journal|volume=10|issue=5–6|pages=E136–E155|doi=10.5489/cuaj.3786|issn=1911-6470|pmc=5065402|pmid=27790294}}</ref><ref name=":9">{{Cite web|title=Intertitial Cystitis (IC/BPS) Guideline - American Urological Association|url=https://www.auanet.org/guidelines/guidelines/interstitial-cystitis-(ic/bps)-guideline|access-date=2021-07-29|website=www.auanet.org|language=en}}</ref> However, there is a lack of consistent evidence that the presence of glomerulations affects treatment outcomes.

In addition to traditional IC therapies, diet modification remains a core [[self care]] strategy as foods that are irritating to the bladder dramatically worsen the symptoms that people may experience. Foods high in acid and/or [[caffeine]] (such as all [[coffee]]s, regular [[tea]]s, green teas, [[Soft drink|sodas]], [[diet sodas]], [[artificial sweeteners]] and most [[fruit juices]]) should be avoided.<ref>{{Cite book|last=Waldman|first=Steven D.|url=https://books.google.com/books?id=_61SDwAAQBAJ&pg=PA369|title=Atlas of Common Pain Syndromes E-Book|date=2018|publisher=Elsevier Health Sciences|isbn=978-0-323-54732-1|language=en}}</ref> The daily goal should be to soothe rather than irritate the bladder wall.<ref name=":8" />

==References==
{{Reflist}}

[[Category:Urinary bladder disorders]]