Medications mostly associated with hematuria: assessment of the EudraVigilance and Food and Drug Administration pharmacovigilance databases entries.

BACKGROUND: Drugs may have a direct causative role in triggering hematuria. The range of medications which may be responsible for hematuria is wide, but little is known on those which are most frequently involved. The aim of our study was to identify and compare drugs mostly related with hematuria. METHODS: The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database and the EudraVigilance (EV) database were queried to identify the drugs which were associated the most with hematuria individual reports till 30 September 2021. Rivaroxaban, aspirin, warfarin sodium, clopidogrel bisulfate, dabigatran etexilate mesylate, apixaban, warfarin, cyclophosphamide, lansoprazole, enoxaparin sodium, and ibuprofen were analyzed. Analysis per gender, age and severity was performed. Disproportional analysis was performed to compare drugs. RESULTS: Overall, 15,687 reports of hematuria were recorded in the FDA database and 15 007 in the EV database. Rivaroxaban and Warfarin appear to be the most dangerous medications in terms of hematuria when compared to the other medications (PRR>1, P<0.05) while apixaban is the safest one (PRR<1, P<0.05) when compared to the other medications. In terms of severity only 162/15 007 (1.08%) were fatal. Between the drugs analyzed cyclophosphamide 7.2%, enoxaparin (3%) and dabigatran (2.5%) presented a higher number of fatal hematuria episodes when compared to the other drugs (<1%). CONCLUSIONS: Anticoagulants and antiplatelets are more frequently related to hematuria episodes however some differences exist between them. Particularly warfarin and rivaroxaban should be prescribed with caution in patients at increased risk of hematuria. Prescribers should inform those treated with these medications about the risk of hematuria and its sequelae.

Identifying patients with prostate cancer at increased risk for haematuria during anticoagulation for venous thromboembolism.

BACKGROUND: Haematuria is a common complication in prostate cancer patients receiving anticoagulation for venous thromboembolism (VTE). Early identification of at-risk patients might help to reduce its incidence and severity. METHODS: We used data from the RIETE registry to develop a prognostic score for haematuria during the first year of anticoagulation for VTE. The prognostic score was built using regression coefficients. RESULTS: From March 2001 through March 2021, 1934 patients with prostate cancer and acute VTE were enrolled. Of these, 1034 (53 %) initially presented as pulmonary embolism and 900 (47 %) as isolated deep vein thrombosis (DVT). During anticoagulation (median 181 days; inter-quartile range: 97-354), 99 patients (5.1 %) developed haematuria (fatal 1, major 27, non-major 72). The incidence rate was: 8 events per 100 patient-years (95%CI 6.5-9.7). Median time to haematuria was 53 days (IQR 4-134). On multivariable analysis, recent haematuria, initial presentation as DVT, comorbidity, metastases, haemoglobin levels <11 g/dL, creatinine >1.2 mg/dL, and radiotherapy independently predicted the risk for haematuria. C-statistics was 0.71 (95%CI: 0.65-0.77). A cut-off of ≥1.5 points classified 312 patients (20 %) at high-risk and had the highest sensitivity (51 %; 95%CI: 39-62) and specificity (82 %; 95%CI: 79-83). Our score improved the performance and non-event net reclassification index (NRI) of the RIETE score (c-statistics: 0.61; 95%CI: 0.54-0.68; NRI: 0.09) or VTE-BLEED score (c-statistics: 0.64; 95%CI: 0.58-0.71; NRI: 0.76). CONCLUSIONS: A prognostic score for haematuria during anticoagulation for VTE performed well in patients with prostate cancer, and improved identification compared to other validated scores.

N-acetylcysteine ameliorates hematuria-associated tubulointerstitial injury in 5/6 nephrectomy mice.

Chronic kidney disease (CKD) is characterized by increased interstitial fibrosis and tubular atrophy (IFTA) in the kidney. Chronic hematuria is a hallmark of several human kidney diseases and often is seen in patients on anticoagulation therapy. We had previously demonstrated that chronic hematuria associated with warfarin increases IFTA in 5/6 nephrectomy (5/6NE) rats, and such treatment increases reactive oxygen species (ROS) in the kidney. The goal of this study was to evaluate the effects of the antioxidant N-acetylcysteine (NAC) on the progression of IFTA in 5/6NE mice. 5/6NE C57BL/6 and 5/6NE 129S1/SvImJ mice were treated with warfarin alone or with warfarin and NAC for 23 weeks. Serum creatinine (SCr), hematuria, blood pressure (BP), and ROSs in the kidney were measured; kidney morphology was evaluated. Warfarin doses were titrated to achieve prothrombin time (PT) increase to the levels seen with therapeutic human doses. Warfarin treatment resulted in an increased SCr, systolic BP, hematuria, expression of TGF-ß and ROS in the kidney in both mouse strains. Tumor necrosis factor alpha (TNF-ɑ) levels in the serum were increased in 5/6NE mice treated with warfarin. IFTA was increased as compared with control 5/6NE mice, and this increase in IFTA was more prominent in 129S1/SvImJ than in C57BL/6 mice. NAC ameliorated the warfarin-associated increase in SCr and BP but not hematuria. IFTA, TGF-ß, and ROS in the kidney as well as TNF-ɑ levels in the serum were reduced in mice treated with NAC and warfarin as compared to mice treated with warfarin alone. NAC mitigates the increase in SCr and IFTA in mice with chronic hematuria by reducing oxidative stress in the kidney. This data open novel possibilities for treatments in CKD patients.

The application of gemcitabine and pirarubicin in patients with non-muscle invasive bladder cancer.

OBJECTIVE: To investigate the value of gemcitabine and pirarubicin in patients with non-muscle-invasive bladder cancer (NMIBC). METHODS: 405 patients with non-muscle invasive bladder cancer admitted to our hospital from January 2012 to December 2020 who underwent transurethral bladder tumor electronic resection were studied. 177 patients were treated with gemcitabine (Gemcitabine group) and 228 patients were treated with pirarubicin (Pirarubicin group) after surgery. The efficacy and adverse effects of the two groups were observed and the patients were followed up. RESULTS: No differences were found when comparing age, gender, smoking, bladder mass, number of masses, hypertension, diabetes, coronary artery disease, hematuria and tumor diameter between the 2 groups (P > 0.05). In the Gemcitabine group, bladder irritation signs, meatus hematuria, fever, nausea and vomiting were lower than those in the Pirarubicin group (P < 0.05). The recurrence rates were 6.21% and 12.28% at 1 year, 11.86% and 23.68% at 2 years, 15.82% and 25.88% at 3 years in the Gemcitabine and Pirarubicin groups respectively, with the Gemcitabine group having a significantly lower recurrence rate than the Pirarubicin group (P < 0.05). The tumor recurrence-free survival rate for 5 years of gemcitabine was significantly higher than that of the Pirarubicin group (P < 0.05). CONCLUSION: Gemcitabine and pirarubicin are both effective in treating patients with non-muscle invasive bladder cancer, with gemcitabine having a lower incidence of adverse reactions, a higher safety rating, a lower recurrence rate and an improved survival outcome.

Association between selective serotonin and serotonin-noradrenaline reuptake inhibitor therapy and hematuria.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs) are used as first-line treatment for many psychiatric diseases, especially major depressive disorder. However, an important side effect of these drugs is the risk of bleeding due to platelet dysfunction. The aim of this study was to determine the frequency of hematuria in patients using SSRI/SNRIs and to compare with a control group. METHODS: This study included patients who were followed up and treated with SSRI/SNRI in the psychiatric outpatient clinic of the Antalya Medical Park Hospital between 1 January 2021 and 31 March 2021 and a control group comprising patients who presented to the medical check-up outpatient clinic between the same dates. Complete urinalysis was performed for all patients and the results were compared between the groups. RESULTS: Each group included 100 patients with a female/male ratio of 1. The mean age was 41.45 ± 13.47 (16-74) years in the study group and 40.51 ± 13.75 (20-70) years in the control group (p = 0.519). Mean duration of SSRI/SNRI use in the study group was 13.35 ± 1.32 (1-64) months. The prevalence of hematuria was 17% in the SSRI/SNRI group and 6% in the control group (p = 0.015). All cases of hematuria were microscopic hematuria. CONCLUSION: Hematuria is significantly more common in patients receiving SSRI/SNRI treatment. The use of SSRI/SNRI should also be taken into account when investigating the etiology of hematuria.

Bladder cancer with pioglitazone: A case-control study.

BACKGROUND: Varied reports suggest a contentious relationship of bladder malignancy with pioglitazone in patients with type 2 diabetes. AIM: To study an association (prevalence and predictors) of bladder malignancy with pioglitazone therapy in Asian-Indian type 2 diabetes patients. METHOD: In this observational multicenter study, type 2 diabetic patients attending out-patient diabetes-clinic were evaluated. A detailed history of anti-diabetic medication, dose, duration, pioglitazone usage, time since initiation of pioglitazone, physical examination, biochemical tests and details pertaining to prevalent neuropathy, retinopathy and nephropathy were recorded. Details of bladder cancer or any malignancy (if present), time since diagnosis, risk factors for bladder cancer and histopathology records were noted. The study cohort was divided into two groups-pioglitazone ever users (Group A) and never users (Group B). RESULTS: A total of 8000 patients were screened out of which 1560 were excluded. Among 6440 included patients, 1056 (16.3%) patients were in group A and 5384 (83.6%) group B. Patients on pioglitazone were older (59.1 vs 57.7 years, p < 0.001), had longer duration of diabetes (12.7 vs 10.6 years, p < 0.001) with poor glycemic control (HbA1c 8.5 vs 8.3%, p < 0.01). A total of 74 patients had prevalent bladder cancer [16 (1.5%) in Group A and 58 in Group B (1.0%)]. Prevalent bladder cancer was not significantly greater in ever-users (odds ratio OR = 1.29, 95% confidence interval CI, 0.83-2.00) compared to never-users (odds ratio OR = 0.94, 95% confidence interval CI, 0.834-1.061) of pioglitazone (p = 0.207). However, history of hematuria in pioglitazone-users; while older age (>58 year), history of smoking and hematuria in the whole cohort were significant associated with bladder cancer. In the entire study cohort, 254 patients; 3.5% of males (128 out of 3575) and 4.6% of females (126 out of 2713) developed any malignancy. Age was significantly associated with prevalent malignancy in people with diabetes (odds ratio OR 1.036, 95% confidence interval CI: 1.022-1.051, p = 0.00) on multivariate forward regression. CONCLUSION: Pioglitazone use in Asian-Indians is not associated with an increased bladder cancer risk. However, pioglitazone should be restricted in individuals with history of hematuria. Age more than 58 years is a significant risk factor for development of any malignancy, particularly bladder cancer.

Role of protease-activated receptor-1 (PAR-1) in the glomerular filtration barrier integrity.

Protease-activated receptors (PAR) play an important role in the regulation of cellular function by the coagulation system, and they are activated by thrombin. PAR-1 is expressed in both endothelial cells and podocytes in the kidney. The role of PAR1 in the maintenance of the glomerular filtration barrier is not clear. Anticoagulant-related nephropathy (ARN) is a kidney disease with glomerular hematuria and red blood cell tubular casts. We validated 5/6 nephrectomy (5/6NE) in rats as a model of ARN and had demonstrated that direct thrombin inhibitor (dabigatran) induces ARN. The aim of this study was to investigate the role of PAR-1 in the ARN pathogenesis. 5/6NE rats were treated with dabigatran (150 mg/kg/day), PAR-1 inhibitor SCH79797 (1 and 3 mg/kg/day) and PAR-1 agonist TFLLR-NH2 (0.25 and 0.50 µmol/kg/day) for 7 days. Serum creatinine and hematuria were assessed daily. Kidney morphology was evaluated at the end of the study. In 5/6NE rats treated with either dabigatran or combination with a PAR-1 modulator, there was an elevation in serum creatinine, glomerular hematuria, red blood casts in the tubules, and acute tubular epithelial cell injury. Interestingly, both PAR-1 modulators in a dose-depended manner had similar effects on the serum creatinine levels and hematuria as those of dabigatran. Dabigatran-induced increase in the systolic blood pressure was not affected by PAR-1 modulators. In conclusion, the normal function of PAR-1 is crucial to maintain the glomerular filtration barrier integrity. Either activation or blockage of PAR-1 leads to glomerular hematuria and subsequent acute tubular epithelial cell injury.

Vitamin K antagonist-associated microscopic hematuria.

BACKGROUND: Vitamin K antagonists (VKA) are the most widely used anticoagulants for the prevention of thrombotic events. Several renal adverse effects have been associated with the use of VKA. The main aim of our study was to explore the association between international normalized ratio (INR) levels and microscopic hematuria in patients with VKA. METHODS: We performed a cross-sectional study of patients treated with VKA that attended the outpatient clinic for routine INR control. A simple urinalysis was performed on the day of the INR control and the precise number of red cells in the urine sediment was quantified. Demographic data, kidney function tests, comorbidities, anticoagulant dose and concomitant treatment were registered. RESULTS: A total of 337 patients were included with median INR levels of 2.6 (IQR 2.1-3.3). 11.9% of the patients presented microscopic hematuria (≥14 RBCs/µl). There was a significant correlation between INR levels and the number of red blood cells in the urine sediment (r = 0.201, p = 0.024). In the univariate analysis, microscopic hematuria was associated with having an INR >3.5 (19% vs. 10.2%, p = 0.046), bacteriuria (15.2% vs. 3.6%, p = 0.015), leukocyturia (14.8% vs. 6.6%, p =  0.026), hypertension (16.2% vs. 9.5%, p = 0.053), and the use of renin-angiotensin system (RAS) blockers (6.9% vs. 17.2%, p = 0.004). Multivariate logistic regression showed an association between microscopic hematuria and RAS blockade (OR 0.38, CI 95% 0.163-0.886, p = 0.025), independent from INR levels, hypertension, leukocyturia or bacteriuria. CONCLUSIONS: INR overdose was significantly associated with the presence of microscopic hematuria. RAS blockade is an independent protective factor for the presence of microscopic hematuria in anticoagulated patients.

Association of Rosuvastatin Use with Risk of Hematuria and Proteinuria.

BACKGROUND: Despite reports of hematuria and proteinuria with rosuvastatin use at the time of its approval by the US Food and Drug Association (FDA), little postmarketing surveillance exists to assess real-world risk. Current labeling suggests dose reduction (maximum daily dose of 10 mg) for patients with severe CKD. METHODS: Using deidentified electronic health record data, we analyzed 152,101 and 795,799 new users of rosuvastatin and atorvastatin, respectively, from 2011 to 2019. We estimated inverse probability of treatment-weighted hazard ratios (HRs) of hematuria, proteinuria, and kidney failure with replacement therapy (KFRT) associated with rosuvastatin. We reported the initial rosuvastatin dose across eGFR categories and evaluated for a dose effect on hematuria and proteinuria. RESULTS: Overall, we identified 2.9% of patients with hematuria and 1.0% with proteinuria during a median follow-up of 3.1 years. Compared with atorvastatin, rosuvastatin was associated with increased risk of hematuria (HR, 1.08; 95% confidence interval [95% CI], 1.04 to 1.11), proteinuria (HR, 1.17; 95% CI, 1.10 to 1.25), and KFRT (HR, 1.15; 95% CI, 1.02 to 1.30). A substantial share (44%) of patients with eGFR <30 ml/min per 1.73 m2 was prescribed high-dose rosuvastatin (20 or 40 mg daily). Risk was higher with higher rosuvastatin dose. CONCLUSIONS: Compared with atorvastatin, rosuvastatin was associated with increased risk of hematuria, proteinuria, and KFRT. Among patients with eGFR <30 ml/min per 1.73 m2, 44% were prescribed a rosuvastatin daily dose exceeding the FDA's recommended 10 mg daily dose. Our findings suggest the need for greater care in prescribing and monitoring rosuvastatin, particularly in patients who receive high doses or who have severe CKD.

Gross hematuria can be an impact of severe acute respiratory syndrome coronavirus 2 vaccination on immunoglobulin A nephropathy: a case report.

BACKGROUND: Immunoglobulin A nephropathy is typically accelerated by upper respiratory tract infections and can relapse following vaccination. There have been reports of patients who presented with immunoglobulin A nephropathy flares with or without gross hematuria following coronavirus disease 2019 vaccination. However, this relationship remains to be elucidated. CASE PRESENTATION: Herein, we present the case of a patient with newly diagnosed immunoglobulin A nephropathy who presented with gross hematuria following the second dose of coronavirus disease 2019 vaccine. A 21-year-old Japanese woman presented with fever and new-onset gross hematuria 1 day after receiving the second dose of the coronavirus disease 2019 vaccine (Pfizer). She had microhematuria without proteinuria for 2 years at the time of her medical check-up. Gross hematuria resolved 6 days after the second dose of the coronavirus disease 2019 vaccine; however, microhematuria (> 100 per high-power field) and mild proteinuria were observed. She was admitted to our hospital 4 weeks after the second vaccination because of persistent urinary abnormalities. She was well before the vaccination and did not have any pulmonary involvement on chest radiography or any symptoms suggestive of coronavirus disease 2019. Renal biopsy revealed an immunoglobulin A nephropathy. The Oxford MEST-C score was M0E0S0T0C0. Our patient's urinary abnormalities implied exacerbation of immunoglobulin A nephropathy after coronavirus disease 2019 vaccination. CONCLUSIONS: In our case, gross hematuria served as a trigger for immunoglobulin A nephropathy diagnosis, suggesting that nephrologists should pay close attention to gross hematuria and urinalysis after coronavirus disease 2019 vaccination.

Systematic review of hematuria and acute renal failure with tranexamic acid.

OBJECTIVES: To conduct a systematic review of tranexamic acid (TXA) and the risk of renal failure from urinary clots in adult patients with hematuria. METHODS: A systematic review of Medline, Embase, CENTRAL, www. CLINICALTRIALS: gov, and Google Scholar were searched. Randomized control trials (RCTs) and observational studies that assessed the risk of renal failure with use of TXA among adults with hematuria were included. The primary outcome was renal failure due to urinary tract clots with TXA compared to no TXA (or placebo) or comparator. RESULTS: We identified three RCTs (N = 466 patients) and three retrospective cohort studies (N=220 patients), and a total of 342 patients that had hematuria and received TXA. The patient population of the six studies included medical and surgical patients, with two of the three RCTs comprised patients undergoing percutaneous nephrolithotomy, and the third RCT comprised patients undergoing transurethral resection of the prostate. Documentation of renal function before and after TXA administration was documented in only two studies (N = 28 patients), and neither identified worsening renal function in those exposed to TXA. CONCLUSIONS: There are limited studies evaluating the risk of renal failure in patients with hematuria who were exposed to TXA, and the available data does not suggest an increased risk.

[A Case of Refractory Intermittent Hematuria that Occurred during Paclitaxel/Ramucirumab Combination Therapy for Metastatic Gastric Cancer].

A 76-year-old male patient developed right hydronephrosis due to peritoneal and retroperitoneal dissemination after surgery for gastric cancer. A ureteral stent was inserted, and systemic chemotherapy was introduced for metastatic gastric cancer. Disease progression was observed, and paclitaxel/ramucirumab combination therapy was started as the second-line treatment. After seven courses, severe gross hematuria appeared intermittently, and refractory epistaxis was observed concurrently. No hemorrhagic lesion was found in the imaging test and urethrocystoscopy. The patient received conservative treatment, such as blood transfusion, and further examination was planned. However, hematuria and epistaxis resolved spontaneously during the course of treatment. From the clinical course, it was thought to be a hemorrhagic adverse event due to ramucirumab, and the patient's treatment was therefore changed to another drug. The patient recovered without recurrence of gross hematuria.

Gross hematuria and IgA nephropathy flare-up following the first dose of Moderna vaccine: A case report.

BACKGROUND: Since the mass vaccination for COVID-19, several case reports indicated the risk of autoimmune disease flare-ups after the vaccination. Among them, COVID-19 vaccine-induced glomerular diseases have drawn attention worldwide. The cases demonstrating the association between the mRNA vaccine and IgA nephropathy (IgAN) exacerbation had been noticed. Mostly mentioned, the flare-ups usually occurred after the second dose. METHODS: We present a Taiwanese female with IgAN who developed gross hematuria within only six hours after the first dose of the Moderna vaccine. RESULTS: Six hours after the first dose of Moderna vaccine on 8 June 2021, the patient developed gross hematuria and significantly decreased urine output. All symptoms resolved spontaneously on the fifth day after the vaccination without any intervention. On the fourth day after the vaccination, the patient were able to back to her original condition. CONCLUSION: This was an intriguing case of IgAN flare-up following the first dose of mRNA-based COVID-19 vaccination.

Hematuria and its repetition after initial control in patients receiving anti-coagulant: A prospective observational study.

OBJECTIVES: Although Gross hematuria in patients receiving anticoagulants is not very common, it is one of the most common reasons of consulting with urologists. It is recommended to investigate urinary tract malignancies but simultaneous approach to anticoagulation and hematuria so as the optimum balance could be attained, is not clearly defined in the literature yet. We aim to answer pitfalls of hematuria management in anticoagulant receiving patients in this manuscript. MATERIALS AND METHODS: In a prospective case control study during 2017-2019, we observed and collected the data of patients receiving anticoagulant therapy and suffered from gross hematuria with coagulation parameters in prophylactic or therapeutic range in an academic hospital affiliated to Tehran University of Medical Sciences. SPSS 24th version was used for descriptive analysis of collected data. RESULTS: Sixty-six patients encountered hematuria while receiving anticoagulant therapy. Although hematuria was more common in male patients, its recurrence was higher in female patients. It started mostly in first 72 h of therapy and was anticoagulant-dose dependent. Degree of hematuria was mostly mild or moderate by visual estimation and controlled easily by holding the anticoagulant therapy for less than 2 days. Anti-platelet therapy, urinary catheterization and patient's activity did not have any effect on re-bleeding rate. CONCLUSION: Considering the fact that ruling out the urinary tract malignancy is mandatory in these patients, moderate and severe hematuria can be controlled simply by short term holding the anticoagulant therapy while continuing antiplatelet therapy albeit there is possibility to continue them in mild cases. Removing urinary catheters and decreasing the patient's mobility are not recommended. In order to decrease the recurrence of hematuria, re-establishing anticoagulation with LMWH and non-Vitamin D dependent oral agents rather than continuing Heparin and Warfarin might be helpful.

Renal-limited ANCA-associated vasculitis during erlotinib treatment for lung carcinoma.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) had clinical success in the treatment of non-small cell lung carcinoma (NSCLC). An effect of this drug on kidney has not been clarified and the occurrence of glomerulonephritis related to EGFR-TKI has rarely been reported. We present the case of a 71-year-old man with NSCLC who developed proteinuria and microscopic hematuria with the rise in a titer of MPO-ANCA, when 2 years and 3 months passed since the initiation of erlotinib, one of oral EGFR-TKI. Two serial biopsies support that ANCA-associated vasculitis may have been modified by the persistent use of erlotinib. We initiated intravenous pulse therapy with methylprednisolone followed by oral prednisone. The proteinuria has decreased and serum CRP was normalized. However, the serum creatinine level and hematuria did not change during the treatment period. While EGFR inhibition is implicated in protective control for glomerulonephritis, it may exacerbate vasculitis. Close monitoring of the kidney function and urinary findings is required during the use of EGFR inhibitors, such as erlotinib, because it may cause renal adverse events.