Direct oral anticoagulants (DOACs) are among the most commonly prescribed medications, and DOAC-associated kidney dysfunction may be a problem that is underrecognized by clinicians. We report on the case of an 82-year-old patient who, two weeks after the prescription of rivaroxaban for atrial fibrillation, was hospitalized for a drug-induced hypersensitivity syndrome whose main clinical manifestations were low-grade fever with a petechial rash in the legs and acute renal failure (ARF). Within one week after rivaroxaban withdrawal, the patient’s clinical condition improved and the renal function normalized. In a review of the literature, we only found five case reports of rivaroxaban-related ARF: two patients had tubulo-interstitial nephritis (TIN), two had anticoagulant-related nephropathy (ARN), and the last one had IgA nephropathy. As some recent publications suggest that kidney injury due to anticoagulation drugs may be largely underdiagnosed, we also analyzed the data from the VigiAccess database, the World Health Organization pharmacovigilance program that collects drug-related adverse events from 134 national registries worldwide. Among all the rivaroxaban-associated adverse events reported in VigiAccess since 2006, 4,323 (3.5%) were renal side effects, of which 2,351 (54.3%) were due to unspecified ARF, 363 (8.4%) were due to renal hemorrhage (characteristically associated with ARN), and 24 (0.6%) were due to TIN. We also compared these results with those reported in VigiAccess for other DOACs and vitamin K antagonists. This analysis suggests that the frequency of renal adverse events associated with rivaroxaban and other DOACs may be appreciably higher than what one might currently consider based only on the small number of fully published cases.
Since the introduction of direct oral anticoagulants (DOACs) into the market at the beginning of the century, they have rapidly risen to become one of the most commonly prescribed medications by clinicians [
However, since the introduction of DOACs in clinical practice, some authors have highlighted the risk of renal dysfunction associated with the use of DOACs [
So, the aim of the present work is to present the case of a patient who developed rivaroxaban-induced hypersensitivity syndrome with reversible acute renal failure (ARF), to review the cases associating rivaroxaban with renal dysfunction that have already been reported in the literature and to search the pharmacovigilance data to establish if there is, indeed, an increased risk of renal injury associated with rivaroxaban and other DOACs, when compared to antivitamin K.
An 82-year-old Caucasian woman with a known history of metabolic syndrome (hypertension, dyslipidemia, type II diabetes, and hyperuricemia) developed atrial fibrillation 15 days before admission to our hospital and received 20 mg of rivaroxaban once a day, in addition to the usual treatment that she had regularly been undergoing for a long time and that remained unchanged, namely, moxonidine 0.2 mg/day, metoprolol 200 mg/day, losartan 100 mg/day, spironolactone 50 mg/day, furosemide 20 mg/day, simvastatin 40 mg/day, ezetimibe 10 mg/day, allopurinol 100 mg/day, 500 mg of calcium, and 400 UI of cholecalciferol/day.
Three days before admission, she noticed petechial lesions in the legs and developed progressive bilateral pitting edema in the lower limbs, associated with a weight gain of 4–5 kg, which made her fall twice at home. At admission, the clinical examination was remarkable for a petechial rash of the legs and the massively swollen lower limbs with pitting edema. The patient had low-grade fever with a temperature of 38.0°C. The blood pressure was 132/70 mmHg, heart rate was regular at 92/min, and oxygen saturation was 94%. The remainder of the exam was unremarkable. Diuresis was conserved at a rate of 0.55–0.60 ml/kg/hour. Table
Laboratory results of the patient at admission and at discharge from our hospital.
Blood analysis (reference ranges) | At admission | At discharge |
---|---|---|
Hemoglobin (120–160 g/l) | 105 g/l | 109 g/l |
Leucocytes (4.0–10.0 G/l) | 7.2 G/l | 5.8 G/l |
Eosinophils (0–0.7 G/l) | 0.36 G/l | — |
Lymphocytes (1.0–4.0 G/l) | 0.11 G/l | — |
Platelets (150–300 G/l) | 156 G/l | 317 G/l |
Urea (2.8–7.0 mmol/) | 23.2 mmol/l | 9.7 mmol/l |
Creatinine (50–95 | 215 | 86 |
Sodium (136–146 mmol/l) | 133 mmol/l | 139 mmol/l |
Potassium (3.7–5.0 mmol/l) | 4.1 mmol/l | 4.2 mmol/l |
Albumin (37–51 g/l) | 30.2 g/l | — |
Aspartate transaminase (<44 U/l) | 77 U/l | 48 U/l |
Alanine aminotransferase (<44 U/l) | 70 U/l | 58 U/l |
Alkaline phosphatase (35–105 U/l) | 107 U/l | 75 U/l |
Gamma-glutamyl transferase (<40 U/l) | 54 U/l | 40 U/l |
Total bilirubin (3.1–18.8 | 25.7 | 14.3 |
Direct bilirubin (<3.4 | 19.6 | 9.7 |
Prothrombin time % (75–100%) | 34% | 69% |
Partial thromboplastin time (26–36 sec) | 58 sec | — |
Factor VII (70–120%) | 66% | — |
Creatinine kinase (<170 U/l) | 210 U/l | — |
C-reactive protein (<5 mg/l) | 129 mg/l | 24 mg/l |
At admission, rivaroxaban was immediately stopped. In the first 48 hours of the hospitalization, the diuretics were stopped, and the patient received cautious intravenous hydration with vitamin K supplementation. Over the following days, we observed a rapid clinical and biological improvement. The petechial lesions in the lower limbs improved, while the edema affecting the legs rapidly diminished under low-dose diuretics (5 mg/day of torasemide), with a weight loss of 4.3 kg in five days. At the same time, the blood analysis showed a rapid and spontaneous improvement in the renal and hepatic dysfunction, as well as in the inflammatory syndrome (see Table
Time course of creatinine after stopping rivaroxaban from admission up to day 9, the day of discharge from our hospital.
The patient we report presented with features of a drug-induced hypersensitivity syndrome fulfilling the RegiSCAR diagnostic criteria for DRESS [
Over the recent years, some publications have pointed out that there may be an increased risk of renal dysfunction in patients receiving DOACs. However, we found only five fully published case reports reporting an association between rivaroxaban and ARF in our review of the literature [
Clinical characteristics of the full-published case reports of rivaroxaban-associated acute renal failure.
Country | Age (y) | Sex | Comorbidities | Nephrological signs | Time to appearance | Renal biopsy | Treatment | Evolution |
---|---|---|---|---|---|---|---|---|
France (2017) [ | 87 | M | Hypertension | ARF with conserved diuresis | 2 days | TIN | Steroids (0.5 mg/kg for 1 month followed by a taper schedule) | Partial recovery |
Dyslipidemia | Proteinuria 1 g/l | |||||||
Heart failure | Microscopic hematuria | |||||||
Atrial fibrillation | Leucocyturia | |||||||
Stroke in the past | ||||||||
Carotid artery stenosis | ||||||||
Arteriopathy of the lower limbs | ||||||||
Netherlands (2017) [ | 82 | M | Hypertension | ARF with decreased diuresis | 3 weeks | TIN | Steroids (40 mg prednisone for 2 weeks followed by a taper schedule of 5 mg/week) | Full recovery |
Pacemaker for a third-degree atrioventricular block | Proteinuria 0.3 g/24 h | |||||||
Atrial fibrillation | Microscopic hematuria | |||||||
CKD (eGFR 39 ml/min/1.73 m2) | Leucocyturia but concomitant urinary infection | |||||||
Portugal (2017) [ | 82 | F | CKD (eGFR 52.4 ml/min/1.73 m2) | ARF with conserved diuresis | 2 months | Anticoagulant-related nephropathy | N-Acetylcystein 600 mg/day | Chronic hemodialysis |
Australia (2018) [ | 45 | M | Asthma | ARF with conserved diuresis | 7 days | IgA nephropathy | Ramipril | CKD |
Nephrotic range proteinuria | ||||||||
Microscopic hematuria | ||||||||
RBC casts | ||||||||
Japan (2019) [ | 75 | M | Hypertension | ARF | 3 years | Anticoagulant-related nephropathy | No specific treatment was initiated | Chronic hemodialysis |
Diabetes mellitus | Nephrotic range proteinuria | |||||||
Atrial fibrillation | Macroscopic hematuria | |||||||
Stroke in the past | RBC and granular casts | |||||||
IgA vasculitis |
F, female; M, male; ARF, acute renal failure; CKD, chronic kidney disease; TIN, tubulointerstitial nephritis; RBC, red blood cells.
In the process of carrying out the abovementioned review, we were surprised by the small number of cases that could be retrieved from the literature, which is in contrast to the alarming tone of some recent articles associating anticoagulation with ARF [
Number and type of renal side effects reported for rivaroxaban (until 27 April 2019) retrieved from the VigiAccess database of the WHO Program for International Drug Monitoring (available at
Rivaroxaban | |
---|---|
First case reported | |
Total number of side effects | |
Sex, | |
Female | 54,116 (45) |
Male | 54,865 (45) |
Age, | |
<65 years | 23,295 (19) |
≥65 years | 62,105 (52) |
Renal side effects, | |
Acute renal failure | 2,351 (54.3) |
Renal hemorrhage | 363 (8.4) |
Chronic kidney disease | 84 (1.9) |
Tubulointerstitial nephritis | 24 (0.6) |
Nephritic and nephrotic syndromes | 16 (0.4) |
End-stage renal disease | 10 (0.2) |
Results are presented as number of subjects (valid percentage).
Therefore, even though we are aware of the limitations of the accuracy of the data obtained from registries, renal side effects associated with rivaroxaban and other DOACs seem to be more frequent than one might consider based only on the small number of published cases. In a recent paper, Glassock suggested that warfarin-/anticoagulation-related nephropathy were “the real McCoy” but that they are “rather uncommon but likely underdiagnosed clinicopathologic entities” [
Number and type of renal side effects for DOACs and antivitamin K retrieved (until 27th April 2019) from VigiAccess database of the WHO Program for International Drug Monitoring (available at
DOACs | AVKs | |
---|---|---|
Total number of reported side effects | ||
First case reported | 2003 | 1968 |
Renal side effects, | 7,725 (3.3) | 2,145 (1.8) |
Acute kidney injury | 3,796 (49.1) | 904 (42.1) |
Renal failure unspecified | 2,802 (36.3) | 704 (32.8) |
Renal hemorrhage | 553 (7.2) | 147 (6.9) |
Chronic kidney disease | 209 (2.7) | 75 (3.5) |
Tubulointerstitial nephritis | 55 (0.7) | 36 (1.7) |
Results are presented as number of subjects (valid percentage). DOACs, direct oral anticoagulants; AVKs, antivitamin K. All DOACs include rivaroxaban, apixaban, edoxaban, and dabigatran. Acenocoumarol, warfarin, and phenprocoumone were regrouped as AVKs.
This statement is at odds with the conclusions of some recent studies, suggesting that the risk of DOAC-associated renal dysfunction may be lower than for warfarin [
In summary, although we found only a few case reports of rivaroxaban-associated renal dysfunction reported in the literature, the data from the international pharmacovigilance register, VigiAccess, suggest that the frequency of renal adverse events associated with the prescription of rivaroxaban and other DOACs may be appreciably higher than that presently considered by clinicians. According to the reported data, the mechanism of renal injury most frequently involved in rivaroxaban-associated ARF seems to be anticoagulant-related nephropathy, rather than tubulointerstitial nephritis. From a practical point of view, it is, therefore, important that clinicians are aware of the risks of renal dysfunction in patients receiving DOACs and anticoagulant drugs in general. As already proposed by Wheeler et al. [
Acute renal failure
Chronic kidney disease
End-stage renal disease
Direct oral anticoagulants
Tubulointerstitial nephritis.
The authors report no conflicts of interest.
All authors contributed to the writing of the paper and to the interpretation and analysis of the data. GM was responsible for the literature review and for retrieving the data from VigiAccess. All authors read and approved the final manuscript.