Acute kidney injury (AKI) following anticoagulant application has received growing attention as a significant emerging complication of anticoagulation. Nevertheless, there remains a lack of ...real-world studies to compare the incidence, clinical features, and prognosis of AKI across different anticoagulant regimens.
Disproportionality analysis and Bayesian analysis were used to identify suspected AKI cases after different anticoagulant use within the Food and Drug Administration's Adverse Event Reporting System from January 2004 to March 2023. The time to onset, fatality, and hospitalization rates of anticoagulant-associated AKI were also investigated.
We identified 9313 anticoagulant-associated AKIs, which appeared to influence mostly patients over 65 years old (65.37%). Lepirudin displayed a stronger AKI association than others, based on the highest reporting odds ratio (ROR = 6.66, 95% CI = 3.97-11.18), proportional reporting ratio (PRR = 6.08, χ2 = 69.12), and empirical Bayes geometric mean (EBGM = 6.08, the lower 90% one-sided CI = 3.95). Warfarin showed the slightest association with AKI in oral anticoagulants, lower than any direct oral anticoagulants excluding apixaban. Edoxaban exhibited the highest potential renal risk among direct oral anticoagulants, with an ROR of 3.32 (95% CI = 2.95-3.72). The median time to AKI onset was 36 (IQR 7-205) days following the initiation of anticoagulation therapy, and most AKI cases occurred within the first month.
Particular attention should be directed toward monitoring renal function in individuals receiving anticoagulants, including warfarin and direct oral anticoagulants, as well as other anticoagulant agents. This diligence is particularly imperative within the first month after anticoagulant administration for individuals with a tendency for AKI.
Acute kidney injury (AKI) during warfarin therapy usually is hemodynamic secondary to massive blood loss. Here, we report pathological findings in kidney biopsy specimens from 9 patients with ...warfarin overdose, hematuria, and AKI. Kidney biopsy specimens from patients on warfarin therapy with AKI were identified in our database within a 5-year period. Each kidney biopsy specimen was evaluated by using semiquantitative morphometric techniques, and medical history was reviewed for conditions explaining AKI. Biopsy specimens with morphological findings of active glomerulonephritis and active inflammatory lesions were excluded from the study. Biopsy specimens from 9 patients were selected. At presentation with AKI, each patient had an abnormal international normalized ratio (mean 4.4 ± 0.7 IU) and increased serum creatinine level (mean, 4.3 ± 0.8 mg/dL). Morphologically, each biopsy specimen showed evidence of acute tubular injury and glomerular hemorrhage: red blood cells (RBCs) in Bowman space and numerous occlusive RBC casts in tubules. Each biopsy specimen showed chronic kidney injury. Six of 9 patients did not recover from AKI. These data suggest that warfarin therapy can result in AKI by causing glomerular hemorrhage and renal tubular obstruction by RBC casts. Our experience suggests that this may be a potentially serious complication of warfarin therapy, especially in older patients with underlying chronic kidney injury.
Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since ...a renal biopsy is not performed in most cases, the diagnosis is often presumptive.
Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database).
In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function.
Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.
Glomerular capillary hemorrhage can be induced by ultrasonic cavitation during contrast-enhanced diagnostic ultrasound (US) exposure, an important nonthermal US bioeffect. Recent studies of pulmonary ...US exposure have shown that thresholds for another nonthermal bioeffect of US, pulmonary capillary hemorrhage, is strongly influenced by whether xylazine is included in the specific anesthetic technique. The objective of this study was to determine the influence of xylazine on contrast-enhanced diagnostic US-induced glomerular capillary hemorrhage.
In this study, anesthesia with ketamine only was compared to ketamine plus xylazine for induction of glomerular capillary hemorrhage in rats by 1.6-MHz intermittent diagnostic US with a microsphere contrast agent (similar to Definity; Lantheus Medical Imaging, Inc, North Billerica, MA). Glomerular capillary hemorrhage was measured as a percentage of glomeruli with hemorrhage found in histologic sections for groups of rats scanned at different peak rarefactional pressure amplitudes.
There was a significant difference between the magnitude of the glomerular capillary hemorrhage between the anesthetics at 2.3 MPa, with 45.6% hemorrhage for ketamine only, increasing to 63.2% hemorrhage for ketamine plus xylazine (P < .001). However, the thresholds for the two anesthetic methods were virtually identical at 1.0 MPa, based on linear regression of the exposure response data.
Thresholds for contrast-enhanced diagnostic US-induced injury of the microvasculature appear to be minimally affected by anesthetic methods.
Glomerular capillary hemorrhage (GCH) induced by ultrasonic cavitation during diagnostic imaging represents a unique contrast agent-related nephron injury. Consequences of GCH during 1.5-MHz ...diagnostic ultrasound with contrast agent were examined by histologic methods in rats. Definity was infused at 10 microl/kg/min for 5 min at the start of 8 min of intermittent image-exposure, with 2.3 MPa in situ peak rarefactional pressure amplitude. Kidney samples were taken for histology at 5 min, 30 min, 4 h, 2 d, 1 week and 4 weeks post exposure. In addition, samples were taken at 4 h from groups treated with heparin or aminocaproic acid. GCH was found in 61% of glomeruli in the center of the scan plane 5 min after exposure, which declined (p < 0.05) to 36.3% after 4 h. The width of Bowman's space was significantly increased for glomeruli with GCH relative to glomeruli without GCH (p < 0.05), consistent with tubular obstruction. Antibody staining revealed fibrin clotting in Bowman's space in 4-h samples and this persisted in the 2-d samples. Heparin reduced and aminocaproic acid increased the GCH seen in 4-h samples. Tubular dilation was evident with injury to the epithelium after 2 d. After one week, areas of inflammatory cell infiltration were present. After four weeks, areas of interstitial fibrosis were revealed by Masson's trichrome stain. The consequences of GCH induced by diagnostic ultrasound with contrast agents include rupture of glomerular capillaries, procoagulant activity resulting in intratubular obstruction, and the potential for progression of the resulting tubular injury toward interstitial fibrosis.
The right kidney of anesthetized rats was imaged with intermittent diagnostic ultrasound (1.5 MHz; 1-s trigger interval) under exposure conditions simulating those encountered in human perfusion ...imaging. The rats were infused intravenously with 10 microL/kg/min Definity (Bristol-Myers Squibb Medical Imaging, Inc., N. Billerica, MA, USA) while being exposed to mechanical index (MI) values of up to 1.5 for 1 min. Suprathreshold MI values ruptured glomerular capillaries, resulting in blood filling Bowman's space and proximal convoluted tubules of many nephrons. The re-establishment of a pressure gradient after hemostasis caused the uninjured portions of the glomerular capillaries to resume the production of urinary filtrate, which washed some or all of the erythrocytes out of Bowman's space and cleared blood cells from some nephrons into urine within six hours. However, many of the injured nephrons remained plugged with tightly packed red cell casts 24 h after imaging and also showed degeneration of tubular epithelium, indicative of acute tubular necrosis. The additional damage caused by the extravasated blood amplified that caused by the original cavitating gas body. Human nephrons are virtually identical to those of the rat and so it is probable that similar glomerular capillary rupture followed by transient blockage and/or epithelial degeneration will occur after clinical exposures using similar high MI intermittent imaging with gas body contrast agents. The detection of blood in postimaging urine samples using standard hematuria tests would confirm whether or not clinical protocols need to be developed to avoid this potential for iatrogenic injury.
Glomerular capillary hemorrhage (GCH) has been reported and confirmed as a consequence of contrast-enhanced diagnostic ultrasound (CEDUS) imaging of rat kidney. This study assessed renal tissue ...injury in the larger porcine model.
The right kidneys of anesthetized pigs were imaged in 8 groups of 4 pigs. A Vingmed System Five ultrasound machine (General Electric Co, Cincinnati, OH) was used at 1.5 MHz in the B-mode to intermittently scan the kidney at 4-second intervals. An Acuson Sequoia 512 machine (Siemens Medical Solutions, Mountain View, CA) was used in the 1.5-MHz Cadence contrast pulse sequencing mode with intermittent agent clearance bursts at 4-second intervals. Kidneys were scanned transabdominally or after laparotomy through a saline standoff. The second machine's probe was placed in contact with the kidney for 1 group. A perflutren lipid microsphere contrast agent (Definity; Lantheus Medical Imaging, Inc, North Billerica, MA) was infused at 4 μL/kg/min (diluted 33:1 in saline) for 4 minutes during scanning.
Blood-filled urinary tubules were evident on the kidney surface for all groups except the group with the probe in contact with the kidney. Glomerular capillary hemorrhage was found by histologic processing in 31.7% ± 9.8% (mean ± SD) of glomeruli in the center of the scan plane for 1.7-MPa transabdominal scanning and 1.5% ± 2.9% of glomeruli in sham samples (P < .05). In addition, hematuria was detected after scanning, and tubular obstruction occurred in some nephrons.
Renal tissue damage was induced by CEDUS in the porcine model. This result, together with previous studies in rats, support a hypothesis that GCH would occur in humans from similar CEDUS exposure.
One kidney of anesthetized rats was imaged by diagnostic ultrasound with contrast agent under conditions simulating both the geometry and the attenuation encountered during human perfusion imaging. ...Contrary to earlier predictions, glomerular capillary rupture with blood loss into Bowman's space and proximal tubules occurred in our clinically relevant model system. Quantitative analysis of histologic sections showed that 37 +/- 5% of the glomeruli at the center of the scan plane had blood cells in Bowman's space after imaging for 1 min with 1.8 MPa (mechanical index equivalent, MIe = 1.5) with a 1 s image trigger interval during IV injection of 10 microl/kg/min of Definity contrast agent (as recommended by the manufacturer). This percentage decreased rapidly with decreasing peak rarefactional pressure amplitude to an apparent threshold of 0.73 MPa (MIe = 0.6). The percentage of glomeruli with hemorrhage decreased in proportion to dose when reduced below the recommended value, but leveled-off at doses above it. The percentage of glomerular hemorrhage increased with increasing numbers of image exposures, with an initial rate of 1.1% per image. The glomerular hemorrhage also depended on the frame trigger interval with no hemorrhage evident for continuous imaging but a maximal effect for trigger intervals greater than about 1 s. These results indicated that there is a potential for clinical diagnostic ultrasound with contrast agent to induce glomerular hemorrhage.
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