Glomerulation
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Glomerulation refers to
bladder The urinary bladder, or simply bladder, is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. In humans the bladder is a distensible organ that sits on the pelvic floor. Urine enters ...
hemorrhage Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...
s which are thought to be associated with some types of
interstitial cystitis Interstitial cystitis (IC), a type of bladder pain syndrome (BPS), is chronic pain in the bladder and pelvic floor of unknown cause. It is the urologic chronic pelvic pain syndrome of women. Symptoms include feeling the need to urinate right awa ...
(IC). The presence of glomerulations, also known as
petechia A petechia () is a small red or purple spot (≤4 mm in diameter) that can appear on the skin, conjunctiva, retina, and Mucous membrane, mucous membranes which is caused by haemorrhage of capillaries. The word is derived from Italian , 'freckle,' ...
l
hemorrhage Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...
s, in the
bladder The urinary bladder, or simply bladder, is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. In humans the bladder is a distensible organ that sits on the pelvic floor. Urine enters ...
suggests that the bladder wall has been damaged, irritated, and/or inflamed. Petechial hemorrhages originate from punctuate hemorrhages. The
National Institute of Diabetes and Digestive and Kidney Diseases The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is part of the United States National Institutes of Health, which in turn is part of the Department of Health and Human Services. NIDDK is approximately the fifth-largest ...
(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. However other research has theorized that the hydrodistention procedure used for the diagnosis of IC itself may have created these tiny broken
blood vessel The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away ...
s. Studies have found glomerulations in asymptomatic populations, suggesting that they are not applicable as a marker for IC. 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 Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...
. 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.


Presentation

Glomerulations appear as checkerboard/lattice patterns, splotches, or pinpoint-sized red marks on the
bladder The urinary bladder, or simply bladder, is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. In humans the bladder is a distensible organ that sits on the pelvic floor. Urine enters ...
. Glomerulations are classified into five grades that take into consideration the type and location of injury: Grade 0 (normal
mucosa A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is ...
), Grade I (
petechia A petechia () is a small red or purple spot (≤4 mm in diameter) that can appear on the skin, conjunctiva, retina, and Mucous membrane, mucous membranes which is caused by haemorrhage of capillaries. The word is derived from Italian , 'freckle,' ...
e in at least two quadrants), Grade II (large
submucosa The submucosa (or tela submucosa) is a thin layer of tissue (biology), tissue in various organ (anatomy), organs of the gastrointestinal tract, gastrointestinal, respiratory tract, respiratory, and genitourinary system, genitourinary tracts. It i ...
l bleeding), Grade III (diffuse global submucosal bleeding), and Grade IV (mucosal disruption, with or without bleeding). According to
NIDDK The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is part of the United States National Institutes of Health, which in turn is part of the Department of Health and Human Services. NIDDK is approximately the fifth-largest ...
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 cm for 1–2 minutes. When water is drained from the bladder, glomerulations may appear. To be considered as IC, these
submucosa The submucosa (or tela submucosa) is a thin layer of tissue (biology), tissue in various organ (anatomy), organs of the gastrointestinal tract, gastrointestinal, respiratory tract, respiratory, and genitourinary system, genitourinary tracts. It i ...
l
hemorrhages Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, ...
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
cystoscope Cystoscopy is endoscopy of the urinary bladder via the urethra. It is carried out with a cystoscope. The urethra is the tube that carries urine from the bladder to the outside of the body. The cystoscope has lenses like a telescope or microscope ...
which may suggest trauma instead.


Pathophysiology

The pathophysiologic mechanism of glomerulations is unknown and debated. Some researchers suggest it may be the bladder's response to prolonged periods of underfilling. Another possible mechanism of glomerulation is over expression of
angiogenic Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splittin ...
growth factors in the bladder. It has been shown that glomerulations are also presented under hydrodistension procedures. 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. In relation to interstitial cystitis, when noxious stimuli are present, it causes injury to the bladder
mucosa A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is ...
resulting in recruitment of inflammatory cells. Disruption of
glycosaminoglycan Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case ...
(GAG) layer along with the increased presence of
mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...
s,
T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s, and
B cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
s causes the bladder
epithelium Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellul ...
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 Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue. In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier again ...
. Ultimately, increased adhesion factors and overproduction of angiogenic factors from
mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...
s and disruption of the GAG layer results in tissue
fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
. As mentioned above, the technique of hydrodistention is one method used to diagnose
interstitial cystitis Interstitial cystitis (IC), a type of bladder pain syndrome (BPS), is chronic pain in the bladder and pelvic floor of unknown cause. It is the urologic chronic pelvic pain syndrome of women. Symptoms include feeling the need to urinate right awa ...
, in which the
atrophic Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply t ...
bladder is filled and emptied and thus, the stretch of the bladder wall is one possible mechanism of glomerulations.


Risk Factors

Diagnosis of chronic
pelvic pain Pelvic pain is pain in the area of the pelvis. Acute pain is more common than chronic pain. If the pain lasts for more than six months, it is deemed to be chronic pelvic pain. It can affect both the male and female pelvis. Common causes in include ...
or discomfort, accompanied with urinary symptoms, seems to be the most likely risk factor for glomerulation. Research has shown that up to 7.5% of the adult female population is associated with chronic pelvic pain (CPP), in which irritative voiding is commonly seen. Bladder tissues 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. It is speculated that chronic underfilling of the bladder contributes to glomerulations. For example, glomerulations can be seen after
radiation therapy Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Radia ...
, in individuals undergoing dialysis, and after
urinary diversion Urinary diversion is any one of several surgical procedures to reroute urine flow from its normal pathway. It may be necessary for diseased or defective ureters, bladder or urethra, either temporarily or permanently. Some diversions result in a ...
.


Relation to Interstitial Cystitis

The identification of glomerulations as diagnostic criteria for interstitial cystitis/ bladder pain syndrome is unclear. Interstitial Cystitis (IC)/ Bladder Pain Syndrome (BPS) is associated with chronic pelvic pain, pressure and discomfort within the urinary system. In 1987, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) developed diagnostic criteria for IC which included the presence of glomerulations or petechial hemorrhages. The purpose of the NIDDK diagnostic criteria was to facilitate comparable groups for research. It was not intended to set strict criteria for the diagnosis of IC. Interstitial cystitis may also induce angiogenic factors including VEGF (vascular endothelial growth factor) and PD-ECGF (platelet-derived endothelial cell growth factor) resulting in
neovascularization Neovascularization is the natural formation of new blood vessels ('' neo-'' + ''vascular'' + '' -ization''), usually in the form of functional microvascular networks, capable of perfusion by red blood cells, that form to serve as collateral circu ...
. Angiogenic Factors are crucial in vessel development as high values may lead to vessels without enough
pericyte Pericytes (previously known as Rouget cells) are multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries throughout the body. Pericytes are embedded in the basement membrane of blood ca ...
coverage. Formation of these newer and weaker vessels in the
submucosa The submucosa (or tela submucosa) is a thin layer of tissue (biology), tissue in various organ (anatomy), organs of the gastrointestinal tract, gastrointestinal, respiratory tract, respiratory, and genitourinary system, genitourinary tracts. It i ...
associated specifically with IC or BPS, may rupture during hydrodistention causing glomerulation. 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 sub epithelium. With this, data collected by Irwin et al. also showed that blood perfusion in Interstitial Cystitis bladders are reduced. Thus, decreased blood perfusion may further increase the expression of angiogenic factors
VEGF Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
and PD-ECGF. Alongside with VEGF includes an increase in Hypoxia-inducible factor-1 (HIF-1) for HIF-1 binds to VEGF when oxygen is limited in availability. 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. In the ESSIC guideline, glomerulations are only used to further differentiate bladder pain syndrome (BPS) without Hunner's Ulcers into different categories: BPS Type 1 (without glomerulations) and BPS Type 2 (with glomerulations). The
American Urological Association The American Urological Association (AUA) is a professional association in the United States for urology professionals. It has its headquarters at the William P. Didusch Center for Urologic History in Maryland. AUA works with many international o ...
guideline mentions that glomerulations may be detected on cystoscopy, but that it is not specific for BPS/IC. High rates of glomerulations have been observed in other urological conditions such as
benign prostatic hyperplasia Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, inability to urinate, or loss o ...
, upper urinary tract stones,
prostatitis Prostatitis is an umbrella term for a variety of medical conditions that incorporate bacterial and non-bacterial origin illnesses in the pelvic region. In contrast with the plain meaning of the word (which means "inflammation of the prostate"), the ...
, ''etc.'' which challenges its use as a diagnostic marker. In fact, symptoms of
Interstitial Cystitis Interstitial cystitis (IC), a type of bladder pain syndrome (BPS), is chronic pain in the bladder and pelvic floor of unknown cause. It is the urologic chronic pelvic pain syndrome of women. Symptoms include feeling the need to urinate right awa ...
can expand from glomerulations to Hunner's ulcers and
fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
. 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 carcinoma Bladder cancer is any of several types of cancer arising from the tissues of the urinary bladder. Symptoms include blood in the urine, pain with urination, and low back pain. It is caused when epithelial cells that line the bladder become mali ...
. In severe bladder hemorrhages, prolonged hospitalization may occur. However, glomerulations can occur in both symptomatic Bladder Pain Syndrome and non-symptomatic Bladder Pain Syndrome. There is no consistent evidence that glomerulations are correlated to severity of urinary symptoms, quality of life, bladder inflammation, or bladder capacity. 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.


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 On either side of the urethral crest is a slightly depressed fossa, the prostatic sinus, the floor of which is perforated by numerous apertures, the orifices of the prostatic ducts from the lateral lobes of the prostate The prostate is bo ...
or 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 Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...
. 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. In regards to surgery, it has been mentioned that surgery is often the last resort. 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
fulguration Radiofrequency ablation (RFA), also called fulguration, is a medical procedure in which part of the electrical conduction system of the heart, tumor or other dysfunctional tissue is ablated using the heat generated from medium frequency alternat ...
is listed as a third-line treatment option for
interstitial cystitis Interstitial cystitis (IC), a type of bladder pain syndrome (BPS), is chronic pain in the bladder and pelvic floor of unknown cause. It is the urologic chronic pelvic pain syndrome of women. Symptoms include feeling the need to urinate right awa ...
with Hunner's Lesions, guidelines do not recommend it to treat glomerulations. Instead, guidelines have set symptom control and
quality of life Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...
as some of the main goals of treatment for IC. 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 Self-care has been defined as the process of establishing behaviors to ensure holistic well-being of oneself, to promote health, and to actively management of illness when it occurs. Individuals engage in some form of self-care daily with food ...
strategy as foods that are irritating to the bladder dramatically worsen the symptoms that people may experience. Foods high in acid and/or
caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...
(such as all
coffee Coffee is a drink prepared from roasted coffee beans. Darkly colored, bitter, and slightly acidic, coffee has a stimulant, stimulating effect on humans, primarily due to its caffeine content. It is the most popular hot drink in the world. S ...
s, regular
tea Tea is an aromatic beverage prepared by pouring hot or boiling water over cured or fresh leaves of '' Camellia sinensis'', an evergreen shrub native to East Asia which probably originated in the borderlands of southwestern China and northe ...
s, green teas, sodas, diet sodas,
artificial sweeteners A sugar substitute is a food additive that provides a sweetness like that of sugar while containing significantly less food energy than sugar-based sweeteners, making it a zero-calorie () or low-calorie sweetener. Artificial sweeteners may b ...
and most
fruit juices Juice is a drink made from the extraction or pressing of the natural liquid contained in fruit and vegetables. It can also refer to liquids that are flavored with concentrate or other biological food sources, such as meat or seafood, such as ...
) should be avoided. The daily goal should be to soothe rather than irritate the bladder wall.


References

{{Reflist Urinary bladder disorders