Hemorrhagic cystitis

　　The causes of hemorrhagic cystitis are complex and are closely related to the drugs used in conditioning, post-transplant viral infection, and the occurrence of GVHD.

　　1. Drug

　　1. Cyclophosphamide (Cy): Since Coggins reported the first case of Cy-induced aseptic hemorrhagic cystitis in 1995, the association between Cy and hemorrhagic cystitis has attracted people's attention. Clinical findings show that both long-term low-dose or short-term high-dose application of Cy can cause hemorrhagic cystitis. As the conditioning regimen for hematopoietic stem cell transplantation often involves Cy, it is considered a major risk factor for early hemorrhagic cystitis in hematopoietic stem cell transplantation. Cy is inactive in vitro and is metabolized in the liver to form a highly alkylating phosphoramide mustard, while also producing a side metabolite crodein. Crodein binds to the bladder mucosal epithelium, causing mucosal damage. Histological changes in bladder epithelial cells occur within 4 hours after administration, with the injury lasting up to 36 hours. Cystoscopy may reveal mucosal congestion, edema, followed by mucosal hemorrhage, epithelial necrosis, and ulcer formation. If the ulcer area is large, it can lead to massive hemorrhage in the bladder.

　　2. Myleran (Busulfan, Bu): Long-term use of Myleran can cause hemorrhagic cystitis. The incidence of hemorrhagic cystitis is high in patients who have used Myleran before hematopoietic stem cell transplantation, or who have applied Myleran to the pretreatment before transplantation. The incidence of hemorrhagic cystitis in patients who use Myleran plus Cy as a pretreatment regimen is higher than that in patients who do not use Myleran.

　　After discontinuing Cy for 48-72 hours, the delayed hematuria that occurs is due to the patient's propene oxide being basically cleared, and it cannot be explained by the side effects of CY, so other triggering factors outside of Cy should be considered. It is generally believed that viral infection after transplantation is one of the important pathogenic factors for delayed hemorrhagic cystitis. Anskar reported that the urine BK virus level in patients with hemorrhagic cystitis is 105 times higher than that in patients without hemorrhagic cystitis, and the urine BK virus level in patients without hemorrhagic cystitis is similar to that of normal people. Patients with persistent positive urine BK virus have a 50% chance of developing hemorrhagic cystitis, while patients with negative urine BK virus do not develop hemorrhagic cystitis. Other viruses associated with hemorrhagic cystitis include adenovirus type 2 (AdV), cytomegalovirus (CMV), type A influenza virus, and herpes simplex virus (HSV). The pathogenesis may be that after the initial infection with the virus, due to normal immune function of the body, the virus潜伏 in the bladder mucosal epithelial cells. During the period of hematopoietic stem cell transplantation, due to strong immunosuppressive therapy, the latent virus is activated, replicates to a certain level, leading to damage to the bladder mucosal epithelial cells, and the appearance of viraluria or hematuria. As the patient's immune function gradually recovers and the immune response strengthens, the damage to the bladder mucosal epithelial cells worsens, leukocyte infiltration occurs, the mucosa sloughs off, and ulcers appear. Viruses in urine are commonly detected by: ①Urine cytology: Under the microscope, a

　　Three, radiation injury

　　Pelvic local irradiation can cause severe hemorrhagic cystitis, with an incidence of 15%-20%, and can reach 34% when combined with Cv. The pathological changes are primarily inflammation of the bladder mucosa, followed by capillary dilation, submucosal hemorrhage, interstitial fibrosis, progressive arteritis, and ultimately leading to ischemic contraction of the bladder wall, erosion, ulceration, or hemorrhagic necrosis of the mucosa.

　　Four, other factors

      In addition to its clinical manifestations, hemorrhagic cystitis can also cause other diseases. If hemorrhagic cystitis occurs in large quantities, it may lead to secondary anemia. Some patients may also experience ascending infection, leading to urethritis and nephritis.

　　Clinical characteristics of hemorrhagic cystitis:

　　1. Hematuria: It is the typical manifestation of the patient, but the degree of onset varies, from mild to severe. The mild form may only show microscopic hematuria, while the severe form may show gross hematuria, with clots of blood may be excreted from the urine, sudden massive hematuria may cause anemia, and it can also manifest as refractory recurrent hematuria. In severe cases, blood clots may block the urethra, causing difficulty in urination, urinary retention, renal pelvis hydronephrosis, increased blood urea nitrogen, lumbar pain, and lower abdominal pain.

　　2. Urinary tract irritation symptoms: Most patients may also experience symptoms such as urgency, frequency, and dysuria at the same time as hematuria.

　　3. Infection: If there is a bacterial infection at the same time as hematuria, it may exacerbate the symptoms of hematuria or increase systemic infection.

　　4. Cystoscopy: The bladder mucosa is congested and edematous, with dilated vessels and diffuse pinpoint hemorrhages, and may form mucosal ulcers.

　　5. Other: For patients with refractory hematuria, symptoms such as mucosal erosion, ulceration, necrosis, and vesicovaginal fistula may also occur.

　　Preventive measures for hemorrhagic cystitis:

　　One: Hydration and forced diuresis

　　Currently, the preventive measures for hemorrhagic cystitis are mainly aimed at drug-induced hemorrhagic cystitis. Since hemorrhagic cystitis is mainly caused by the direct toxicity of propenal, a metabolite of Cy, to the bladder epithelial cells, the administration of large amounts of fluid to dilute and induce diuresis can prevent hemorrhagic cystitis. Generally, fluid administration starts 4 hours before medication and continues until 24 hours after Cy is discontinued, with a daily fluid intake of 2500 to 3500mL, administered intravenously at a uniform rate throughout the day, and encouraging patients to urinate once every hour to maintain urine output at 150 to 200mL per hour.

　　Two: Application of Mesna (Sodium-2-mercaptoethanesulfonate)

　　In recent years, sulfhydryl-based compounds such as Mesna have been widely used to prevent hemorrhagic cystitis. Its mechanism of action is that Mesna is rapidly excreted from the kidneys into the bladder, where it can specifically bind to propenal to form a non-toxic thioether complex. At the same time, Mesna can reduce the degradation rate of 4-hydroxycyclophosphamide, reducing the toxicity of Cy. Mesna has no tissue penetrability, rapid excretion, a half-life of 1.5h, low toxicity, no tissue damage, no effect on the antitumor action of Cy, and is unrelated to disease recurrence after transplantation and GVHD, making it a good preventive agent for hemorrhagic cystitis. It is generally believed that the effect of Mesna is better within 24 hours of Cy infusion. The method of use is to give Mesna simultaneously with CY, and repeat it once every 3h, 6h, and 9h, with a total dose of 120% to 160% of Cy. Some people suggest that the combined use of Mesna and hyperbaric oxygen (HBO) can achieve complete bladder protection and more effectively prevent hemorrhagic cystitis.

　　3. Prevention of viral infection

　　So far, there is no sensitive and effective antiviral drug for BK virus and adenovirus. That is, it is not possible to completely clear the virus through medication, but it can inhibit the replication of the virus, such as intravenous injection of arabinoside 10mg/(kg?d) (intravenous maintenance for 12h) for 5 days is effective for BK virus.

　　4. Other

　　Recent studies have shown that certain fruits and vegetables have the effect of protecting the bladder from the toxic effects of Cy. Assreuy et al. used a high dose (10mg/kg) of glucose, mannose, combined with plant agglutinin (glucose-mannose-binding plant lectins) to prevent mice from Cy chemotherapy-induced hemorrhagic cystitis, achieving a preventive effect similar to Mesna. The mechanism is that plant agglutinin competes to bind to sialic acid glycoprotein ligands on the surface of leukocytes or endothelial cells, blocking the binding of selectin to its ligand, thereby preventing the interaction between leukocytes and endothelial cells and inhibiting leukocyte infiltration and tissue damage. This animal experiment lays the foundation for the clinical application of plant agglutinin to prevent hemorrhagic cystitis. Okamura et al. also confirmed that intravesical instillation of chitosan 1 hour after Cy application can reduce the incidence of hemorrhagic cystitis.

　　For those with a history of contact with alkylating agents, busulfan, aniline, toluene derivative, insecticides, and when clinical blood urine occurs to varying degrees, consider the possibility of this disease, combined with cystoscopy and ultrasound examination, a diagnosis can usually be made.

　　Laboratory examination: Urinalysis may show microscopic or gross hematuria; when anemia occurs, blood routine examination shows decreased hemoglobin.

　　Other auxiliary examinations: Ultrasound, cystoscopy: exclude space-occupying lesions, visible mucosal congestion and edema, with ulcerative necrotic foci.

　　Hemorrhagic cystitis is mainly caused by infection, but daily living habits are also a factor in the formation of hemorrhagic cystitis, and it is very important, for example: long-term use of aluminum cooking pots, addictive consumption of coffee, carbonated drinks, chocolate, alcohol, and other foods harmful to the bladder can lead to bladder inflammation.

　　Patients should note that during the period of taking medication for hemorrhagic cystitis, it is strictly forbidden to drink alcohol, chili, chicken, fish, beef, shrimp, seafood pickles; spices can only be salt, vinegar, monosodium glutamate (other seasonings should not be used). If the patient's diet control is not good, it will extend the treatment time.

　　Pay attention to the following points in diet during daily life:

　　1. Eat more diuretic foods, such as watermelons, grapes, pineapples, celery, pears, and so on.

　　2. Snails, corn, mung beans, and white scallions can help alleviate symptoms such as frequent urination, urgency, and pain during urination.

　　3. Drink plenty of water to maintain at least 1500 milliliters of urine output per day.

　　4. Avoid spicy and acidic foods, such as strong alcohol, chili, original vinegar, sour fruits, and the like.

　　5. Avoid eating oranges, as oranges can cause alkaline urine, which is conducive to bacterial growth.

　　6. Caffeine can cause the neck of the bladder to contract and produce spasmodic pain, so it is recommended to drink less coffee.

　　The clinical manifestations of hemorrhagic cystitis basically conform to the category of 'Blood dripping' in traditional Chinese medicine. Dribbling syndrome refers to a category of diseases with frequent urination, dripping urine, urethral pain, lower abdominal contraction, and pain extending to the waist and abdomen as the main clinical manifestations, caused by the dysfunction of kidney and bladder Qi, and the obstruction of waterways. Among them, if there are symptoms of hematuria and pain, it belongs to the syndrome of blood dripping. The treatment method can refer to the following methods for treatment.

　　Body Acupuncture

　　1. Treatment method: For实证, clear heat and relieve dripping, cool blood and stop bleeding; for虚证, nourish Yin and clear heat, replenish deficiency and produce blood. The main acupoints are those on the Ren meridian and the Foot Taiyin spleen meridian.

　　2. Prescription.

　　(1) Main points: Bladder Shu, Zhongji, Xuehai, Sanyinjiao.

　　(2) Auxiliary points: For实证 patients, add Shaofu and Laogong; for虚证 patients, add Fuliu and Taixi, or add Zusanli and Qihai.

　　3. Operation method

　　(1) Main points: After routine sterilization, select filiform needles with a diameter of 0.30-0.35mm, puncture Xuehai 0.9±0.1 cun perpendicularly, puncture Bladder Shu 0.9±0.1 cun perpendicularly, puncture Sanyinjiao 0.8±0.2 cun perpendicularly, puncture Zhongji 0.8±0.2 cun perpendicularly (needling should be performed after urination, pregnant women are prohibited from needling).

　　(2) Auxiliary points: After routine sterilization, puncture Shaofu 0.2-0.3 cun perpendicularly, puncture Laogong 0.4±0.1 cun perpendicularly; puncture Fuliu 0.9±0.1 cun perpendicularly, puncture Taixi 0.6±0.2 cun perpendicularly; puncture Zusanli 1.0±0.4 cun perpendicularly, puncture Qihai 1.0±0.2 cun perpendicularly.

　　Treat once a day, retain the needle for 20-30 minutes each time, and perform needling 2-3 times during retention. The main acupoints use twisting flat supplementation and elimination method, with a twisting range of 2-3 turns, a twisting frequency of 2-4 times per second, and each needling for 5-10 seconds. Other auxiliary acupoints should be purgative for实证 and tonifying for虚证.

　　4. Theory of the prescription: Dribbling syndrome is mainly due to the dysfunction of bladder Qi, so Bladder Shu and Zhongji are selected to smooth the bladder Qi. Sanyinjiao and Xuehai can clear heat and dampness, cool blood and stop bleeding.

　　Auricular Acupuncture

　　1. Prescription: Bladder, Kidney, Sympathetic, Occiput, Adrenal gland.

　　2. Operation method: Strong stimulation, each time select 2-4 acupoints, retain the needle for 20-30 minutes, once a day.

　　Traditional Chinese medicine can be given Da Chi San, Ba Zheng San and other prescriptions.