Bromadiolone may cause severe acute kidney injury through severe disorder of coagulation: a case report

Abstract

Background

Bromadiolone is a wide-use long-acting anticoagulant rodenticide known to cause severe coagulation dysfunction. At present, there have been no detailed reports of acute kidney injury (AKI) resulting from bromadiolone poisoning.

Case presentation

A 27-year-old woman was admitted to the hospital due to severe coagulopathy and severe AKI. Coagulation test revealed a prothrombin time exceeding 120 s and an international normalized ratio (INR) greater than 10. Further examination for coagulation factors showed significantly reduced level of factors II, VII, IX and X, indicating a vitamin K deficiency. The AKI was non-oliguric and characterized by gross dysmorphic hematuria. Following the onset of the disease, the patient’s serum creatinine rose from 0.86 to 6.96 mg/dL. Suspecting anticoagulant rodenticide poisoning, plasma bromadiolone was identified at a concentration of 117 ng/mL via gas chromatography/mass spectrometry. All other potential causes of AKI were excluded, except for the presence of a horseshoe kidney. The patient’s kidney function fully recovered after the coagulopathy was corrected with high doses of vitamin K and plasma transfusion. At a follow-up 160 days post-discharge, the coagulation function had normalized, and the serum creatinine had returned to 0.51 mg/dL.

Conclusion

Bromadiolone can induce AKI through a severe and prolonged coagulation disorder. Kidney function can be restored within days following treatment with high-dose vitamin K1.

Background

Poison control centers across the United States receive about 2.3 million reports of human poisonings annually, of which rodenticides account for about 0.5% [1]. Rodenticides include long-acting “superwarfarin” anticoagulants, warfarin, and phosphide, with anticoagulant rodenticides being the most common. Bromadiolone, a second-generation biscoumarin rodenticide and a member of the “superwarfarin” class, is known for its high fat solubility, long half-life in vivo, and significantly stronger anticoagulant effect compared to warfarin [2]. Due to its chemical structure’s similarity to vitamin Kl, bromadiolone will competitively inhibit vitamin K1 when it enters the body, inhibit vitamin K1 epoxide reductase [2], affecting the synthesis of coagulation factors II, VII, IX and X in the liver. This disruption, in turn, impairs the production of thrombin and fibrin, leading to coagulation dysfunction and a prolonged coagulation time. Additionally, bromadiolone causes sustained damage to capillaries, increasing the permeability of blood vessel walls and heightening the risk of bleeding [3].

Clinically, the primary manifestations of bromadiolone-related poisoning are mainly bleeding complications in various organs and tissues related to coagulation dysfunction, such as gastrointestinal tract, urogenital tract and intracranial hemorrhage, with symptoms often beginning 24 to 48 h post-exposure [4]. Some patients may be complicated with rare symptoms such as acute toxic encephalopathy [5], spontaneous abortion [6], pericardial and mediastinal hemorrhages [7], hematoperitoneum [8]. Notably, 16% transient acute kidney injury (AKI) was record in 42 hospitalization due to brodifacoum (another superwarfarin) poisoning [9], but here have been no detailed information of AKI related to superwarfarin poisoning in humans. In this report, we present a case of severe AKI caused by bromadiolone poisoning and highlight the potential pathogenesis and rapid recovery of renal function following the correction of severe coagulation dysfunction.

Case presentation

A 27-year-old female patient was admitted with complaints of hematuria and black stools for over 11 days. Eleven days before admission, the patient reported multiple blood blisters in the right buccal mucos after eating out and subsequently developed gross hematuria with foamy urine later that evening. After seven days of persistent hematuria, she sought medical attention at a local hospital. Initial laboratory results indicated normal hemoglobin (126 g/L), an elevated platelet count (420 × 10⁹/L), impaired renal function (creatinine: 0.86 mg/dL), hematuria (urine erythrocyte 3+) and proteinuria (urine protein 3+), and abnormal coagulation function, including a prothrombin time (PT) > 180.0 s, activated partial thromboplastin time (APTT) > 180 s,, international normalized ratio (INR) > 10 and hyperfibrinogenemia (7.65 g/L). Despite the administration of antibiotics and plasma transfusions, her condition deteriorated, evidenced by a notable reduction in hemoglobin levels (90 g/L) and exacerbated kidney dysfunction (serum creatinine 4.71 mg/dL). She was then transferred to our hospital. Further lab tests showed a decline in hemoglobin (51 g/L), elevated urea (25.55 mmol/L) and creatinine (6.95 mg/dL) levels, along with gross hematuria (urine red blood cells 3298/µl), leukocyturia, and abnormal coagulation parameters (Table 1). A chest and abdominal CT scan ruled out thoracic and abdominal hemorrhage. In the emergency room, the patient was treated with anti-infection measures (levofloxacin 0.4 g per day), acid suppression, hemostasis and blood transfusion before being transferred. to our department.

Table 1.

Laboratory examination

	Reference Range, This Hospital	4 days before this admission	2 days before this admission	Emergency room/ on this admission	1 day after admission	3 days after admission (discharge)
Prothrombin time (s)	8–14	—	> 180.0	17.1	44.7	29.9
International normalized ratio	0.9–1.1	—	> 10	1.50	4.05	2.68
Activated partial thromboplastin time (s)	25.0–31.3	—	> 180	31.8	42.3	39.6
Thrombin time (s)	15–21	—	14.9	14.7	15.3	15.6
Fibrinogen (g/L)	2.0–4.0	—	7.65	6.04	6.61	4.09
Antithrombin (%)	80–120	—	—	—	100	—
Hemoglobin(g/L)	115–150	126	90	51→66	80	90
Platelet count(*10^9/L)	125–350	420	516	245	298	366
Leukocyte(*10^9/L)	3.5–9.5	16.03	24.43	12.87	NA	10.8
Neutrophilspercentage	40–75	81	85	82	93	72
Lymphocytes percentage	20–50	11	7	10	5	0.18
Urea (mmol/L)	2.6–7.5	—	—	26	14	10
Creatinine (mg/dL)	0.56–0.83	0.85	4.70	6.96	1.59	1.05
Corrected calcium (mmol/L)	2.10–2.54		1.75	1.98	2.33	2.32
Urine color	Clear to yellow	red	red	red	yellow	yellow
Urine erythrocyte (/ul)	0–17	1860	—	3298	—	40
Urinary white blood cell (/ul)	0–28	20/HP	—	1006	—	33
Urine volume (ml)	800–2500	—	—	4130	1700	2750
Urinary protein	negative	1+	2+	+-	–	+-
Urine albumin (mg/L)	< 30	—	—	76.7	—	—
Urine protein (mg/L)	< 100	—	—	1867	—	—
Urinary albumin to creatinine ratio (mg/g)	0–30	—	—	241	—	—
Urinary protein to creatinine ratio (mg/g)	0–150	—	—	5866	—	—
Urinary N-acetyl-beta-D-glucosaminidase (U/L)	0–10.6	—	—	4.7	—	—
Urine α-1 microglobulin (mg/L)	0–14	—	—	5.5	—	—
Urine sediment		—	—	Gross dysmorphic RBC	—	Microscopic dysmorphic RBC

RBC: red blood cell

Upon admission, the physical examination revealed normal body temperature, an elevated pulse rate, and normal blood pressure. The patient displayed ecchymosis on various body parts, including the chest wall, left elbow, left groin, right middle thigh, and left ankle. Obvious moist rales were heard in both lower lungs, while the heart and abdominal examination were normal. There was no lower limb edema. The patient’s medical history did not indicate any pre-existing hematological or coagulation disorders. Random urinary chemistry showed the fractional excretion of sodium of 5.8% (suggesting little possibility of pre-renal AKI), normal urinary N-acetyl-beta-D-glucosaminidase and urinary α-1 microglobulin concentration, and an obvious discrepancy between urinary protein to creatinine ratio (5866 mg/g) and urinary albumin to creatinine ratio (241 mg/g). Random urine sediment indicated gross dysmorphic red blood cells (Table 1). The kidney ultrasound indicated a horseshoe kidney without kidney stones or hydronephrosis.

Further examination of coagulation factors revealed vitamin K deficiency, with significantly reduced levels of factors II (26.9↓%), VII (16.9↓%), IX (28.2↓%), and X (26.2↓%). The levels of factor V (76.1%), factor XI (94.8%) were normal and factor VII (208.9↑%) was elevated. Given this patient’s severe coagulopathy, characterized by low activity of vitamin K1-dependent clotting factor, prolonged PT and INR, and normal liver function, we considered the possibility of exposure to a coumarin-based anticoagulant rodenticide. Therefore, a toxicological examination was performed on the first day of admission, which revealed a plasma bromadiolone concentration of 117 ng/ml by gas chromatography/mass spectrometry.

The patient received treatment, including vitamin K1 injections (two 10 mg dose intramuscularly before the confirmation of bromadiolone intoxication, and 20 mg twice daily intramuscularly after the confirmation), 1.5 units of red blood cell transfusion to correct anemia, and other symptomatic therapies. On the first day after admission, renal function tests indicated the improved levels of urea (14 mmol/L) and creatinine (1.59 mg/dL). Coagulation function remained abnormal, with prolonged PT and APTT, while the fibrinogen and platelet counts were within or above the normal range (Table 1). After three days of treatment, creatinine levels decreased further to 1.05 mg/dL (Fig. 1), INR dropped to 2.68, and urine color returned to normal. Due to bromadiolone’s long half-life, repeat measurement of its levels was not performed.

Fig. 1.

Relationship between INR and serum creatinine in this patient

During a telephone follow-up three days after discharge, the patient exhibited normal renal function (serum creatinine of 0.71 mg/dL), with coagulation function and blood routine returning to normal. Vitamin K treatment was discontinued under the recommendation of the local physician 11 days after discharge. Six months later, the patient was re-examined in the local hospital, where routine blood and coagulation function were within normal ranges, and renal function was stable (serum creatinine of 0.51 mg/dL). Urine test showed 1 + urine glucose, 1 + urine occult blood, 2 + urine leukocyte esterase. The patient is advised to continue close monitoring kidney function, urine examination, and kidney ultrasound during follow-ups. Consent for publication of this case was obtained and provided to the journal in accordance with BMC policy.

Discussion

Severe coagulation disorders can potentially result in the development of AKI. Anticoagulant-related nephropathy (ARN) is characterized by AKI when other causes are excluded and an INR above 3.0 following anticoagulant therapy. ARN typically presents with a distinct pattern of glomerular hemorrhage on kidney biopsy, most commonly associated with anticoagulants like warfarin and other vitamin K antagonists (such as fluindione and acenocoumarol), and direct oral anticoagulants. ARN is more likely to occur in individuals with preexisting glomerular disease, with renal biopsies often revealing IgA nephropathy as the most common type [10]. Overanticoagulation can lead to the disruption of the glomerular filtration barrier and diffuse glomerular hemorrhage, which manifests on renal biopsy as numerous renal tubules and Bowman space are filled with red cells and red cell casts, causing obstruction, ischemia, and eventual obliteration [11, 12]. In most ARN cases, the severity of renal failure, red cell tubular casting, and hematuria is disproportionately severe when compared to the observed changes in glomerular morphology [10]. Prior research suggests that anticoagulation may exacerbate glomerular disease rather than directly affecting the glomerular filtration barrier [10].

We consider that there exists a causal relationship between coagulation dysfunction due to bromadiolone intoxication and AKI in this patient. The supporting evidence is as follows: Firstly, previous reports on ARN indicate that any agent or condition causing severe coagulopathy may lead to ARN [10], thus laying a theoretical foundation for our hypothesis. Secondly, the patient’s serum creatinine level increased over several days following an abnormal rise in INR and rapidly improved after correcting coagulation dysfunction, suggesting that AKI was induced by coagulation dysfunction. Thirdly, we have ruled out other potential causes of AKI, encompassing hypotension, obstructive nephropathy, intrinsic renal factors, lupus nephropathy, ANCA-associated vasculitis, anti-GBM nephropathy, and so on. Fourthly, the patient’s urine examination results indicated pleomorphic gross hematuria, suggesting the leakage of red blood cells through the glomerular basement membrane, which aligns with the pathological characteristics of anticoagulant-related nephropathy.

In this case, the recovery of kidney function surpassed what has been reported in cases of ARN. Previously documented cases of classic ARN have often demonstrated limited or negligible recovery of kidney function (Table 2). This discrepancy in outcomes might be attributed to the following two factors: First, a significant number of patients may have had pre-existing kidney diseases or decreased glomerular filtration rate (GFR) prior to the onset of ARN. These underlying renal disorders may render the kidney more susceptible to ARN and restrict the kidney’s inherent capacity for self-repair. The cornerstone of treatment for ARN is ensuring an adequate urine flow to expel the obstructive elements, such as red blood cells and damaged tubules. Most patients with ARN may have no enough urine flow from decreased GFR or additional fluid limited by heart function, which potentially contributing to the unfavorable prognosis. In contrast, this patient had adequate urine output and received unlimited fluid therapy that contributing rapid recovery of kidney function. Secondly, many patients requiring long-term anticoagulant therapy often have cardiovascular conditions such as atrial fibrillation, necessitating the use of medications like warfarin to prevent thrombosis. These drugs demand regular monitoring of clotting function to ensure that the INR falls within the therapeutic range. For example, the utilization of warfarin for anticoagulation in patients with atrial fibrillation mandates precise control of INR within the range of 2.0 to 3.0. Maintaining INR within this range may not completely arrest kidney bleeding and can consequently impede the recovery of renal function. In contrast, the rapid decrease of INR from above 10 to the normal range may effectively correct coagulation disorder and halter renal bleeding in this case.

Table 2.

Main results of renal recovery in patients with classic anticoagulant-related nephropathy

Year	Author	Age/Sex	Anticoagulant	Baseline SCr (mg/dL)	Peak SCr (mg/dL)	Peak INR	SCr at discharge/Follow-up (mg/dL)	Follow up time
2017	Góis [13]	84/M	acenocoumarol	1.0	4.68	6.96	3.45/1.7	11 m
2018	Golla [14]	50/F	acenocoumarol	0.9	7.6	4.70	1.1/NA	2 w
2020	Chamberlain [15]	85/F	warfarin	2.26	5.20	3.0	NA/3.39	1 m
2020	Tennekoon [16]	61/M	warfarin	2.38	6.45	3.5	3.39/NA	4 m
2021	Nonaka [17]	73/M	warfarin	1.1	9.0	3.9	NA/1.6	1 y
2022	Bhandari [18]	64/M	warfarin	NA	8.6	6.36	NA/5.49	3 m
2023	Brittanee [19]	78/M	warfarin	0.96	12.88	6.9	0.9/NA	NA
2023	This study	27/F	bromadiolone	0.51	6.95	> 10	0.9/0.51	160d

Note: the literatures without serum creatinine value at discharge or during follow-up were deleted; NA: not available

In cases of bromadiolone or other superwarfarin poisoning, the primary treatment strategy involves administering high doses of vitamin K1 and transfusion [4]. The recommended initial dose of vitamin K1 typically ranges from 10 to 50 mg, administered intravenously, depending on the severity of the coagulopathy. In some cases, higher doses, up to 100 mg, may be required [4, 20]. Treatment often needs to be continued for an extended period, with twice-daily dosing, due to the short half-life of vitamin K1. Pervious research showed elimination of bromadiolone followed a two-compartment model, with an estimated half-life of 3.5 day from ingestion to day 8, and estimated half-life of 24 days from day 8 to day 107 [21]. Therefore, this patient may require a high-dose of vitamin K1 for 14 days and could discontinue therapy thereafter. Regular monitoring of coagulation parameters, such as PT and INR, is essential to adjust the dosage and duration of vitamin K1 therapy.

To our acknowledge, there have been no detailed reports of AKI in adult patients caused by bromadiolone poisoning at present. This case firstly presents a rare instance of bromadiolone-induced AKI accompanied by pleomorphic gross hematuria. The kidney function could restore within several days after treatment with large dose of vitamin K1. This clinical case could extend clinicians’ current knowledge of AKI caused by ingestion of bromadiolone. Our findings suggest that AKI can be caused by severe coagulopathy, and that correcting severe coagulopathy may help treat AKI. However, further research is needed to confirm this relationship.

There are several limitations of this case report. Firstly, a kidney biopsy was not conducted to confirm ARN in the patient due to the coagulation disorder and the presence of a horseshoe kidney [22]. Typically, renal biopsy is not initially recommended in patients receiving anticoagulant therapy due to the heightened risk of bleeding. Secondly, our observations lacked similar cases for comparative analysis, emphasizing the necessity for further validation of our findings.

Conclusion

This case suggested that bromadiolone can cause AKI due to a prolonged and severe coagulation disorder. Unlike other cases of anticoagulant-related nephropathy, kidney function may recover within days after treatment with a large dose of vitamin K1. The findings are crucial for clinicians managing coagulopathy in critical care, as recognizing the potential link between severe coagulopathy and AKI could lead to earlier identification, monitoring, and intervention, thereby improving patient outcomes. Routine renal function monitoring in cases of severe coagulopathy, along with early correction of coagulation abnormalities, should be integral in managing patients at risk for AKI.

Abbreviations

AKI

Acute kidney injury

INR

International normalized ratio

PT

Prothrombin time

APTT

Activated partial thromboplastin time

NA

Not Available

ARN

Anticoagulant-related nephropathy

GFR

Glomerular filtration rate

Author contributions

Material preparation, data collection, and literature search were performed by WH. WB analyzed and interpreted the patient’s data. The first draft of the manuscript was written by WH and all authors commented on previous versions of the manuscript. WB provided diagnoses and treatments for the patient in this case. XC and MH supervised the manuscript drafting. All authors read and approved the final manuscript.

Funding

This report was supported by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions (CN), General Project of the National Natural Science Foundation of China (81970639, 82151320), Jiangsu Provincial Medical Key Discipline (Laboratory) Cultivation Unit (JSDW202206). The funders had no role in the design of the study or in the collection analysis or interpretation of the data.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University. The ethic committee waived the need for informed consent for this case report and the data were analyzed anonymously.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report.

Competing interests

The authors declare no competing interests.