Warfarin-Related Nephropathy: Unveiling the Hidden Dangers of Anticoagulation

Warfarin-Related Nephropathy: Unveiling the Hidden Dangers of Anticoagulation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Warfarin-Related Nephropathy: Unveiling the Hidden Dangers of Anticoagulation 徐丰博 xufengbo, Guoqin Wang, Lijun Sun, Hong Cheng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4179190/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Warfarin-related nephropathy (WRN) is defined as acute kidney injury (AKI) subsequent to excessive anticoagulation with warfarin. Patients with mechanical prosthetic valves required long-term anticoagulant therapy, and warfarin remains the sole available option for anticoagulant therapy. Consequently, patients with mechanical prosthetic valves constitute a special group among the entire anticoagulant population. The present study recorded two cases in which patients who had undergone mechanical prosthetic valve surgery and were receiving warfarin therapy presented to the hospital with gross hematuria and progressive creatinine levels. Notably, the international normalized ratio (INR) did not exceed 3 in these two patients. Subsequent renal biopsies confirmed the presence of WRN with IgA nephropathy. The two patients continued to receive anticoagulation with warfarin and were prescribed oral corticosteroids and cyclophosphamide, which resulted in improved renal function during the follow period. Based on a review of all relevant literature and the present study, we also pose a new challenge, whether elevated INR levels must be as one of the criteria for clinical diagnosis of WRN? Perhaps it can get some inspiration from the present article. warfarin-related nephropathy acute kidney injury international normalized ratio IgA nephropathy Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Warfarin-related nephropathy (WRN) is an increasingly recognized disease, mainly associated with warfarin excessive anticoagulation. The preliminary description of WRN indicated that patients receiving warfarin therapy experienced significant glomerular hemorrhage during renal biopsy [ 1 ]. WRN was defined as the manifestation of acute kidney injury (AKI) occurring within a week subsequent to the elevation of the international normalized ratio (INR) above 3 [ 2 ]. Despite the development of direct oral anticoagulants (DOACs), research findings on the efficacy of DOACs in preventing valve thrombosis in patients with artificial valves have been inconsistent [ 3 – 5 ]. As a result, warfarin remains the only available option for anticoagulant in this population. Patients who undergo mechanical artificial valve surgery are usually younger and have fewer comorbidities compared to those with atrial fibrillation, and necessitating long-term anticoagulant therapy [ 6 ]. Consequently, patients with mechanical prosthetic valve constitute a special subgroup in the whole population of patients with anticoagulation. The present study reported two cases of patients with mechanical prosthetic valves who experienced gross hematuria and AKI, ultimately establishing their diagnosis as WRN through renal biopsy. However, INR > 3 was not be observed. Case presentation Case 1 A 56-year-old female patient, who had previously undergone mechanical aortic valve replacement surgery nine months ago and was prescribed warfarin as post-surgery treatment, was admitted to the hospital due to the occurrence of gross hematuria six days before hospitalization. Additionally, her creatinine levels exhibited a rapid increase from 120.5umol/L to 207.5μmol/L within three days. Upon admission, the patient's vital signs were recorded as follows: blood pressure of 132/74 mmHg, heart rate of 83 beats per minute, and temperature of 36.3°C. Subsequent laboratory analysis revealed the following findings: creatinine level of 167.8μmol/L, eGFR of 30.5ml/min.1.73m 2 , blood urea nitrogen/creatinine ratio of 17.9, albumin level of 39.6g/L, hemoglobin level of 10.4 g/dl, white blood cell count of 6.6×10 9 /L, platelet count of 238×10 9 /L, and an INR value of 2.08. The urinary test results indicated the presence of urinary protein(+) and urinary occult blood(3+).Microscopic examination of the urine sediment revealed the presence of 20-40 red blood cells per high-power field, with a deformation rate of 70%. The quantification of urinary protein over a 24-hour period was measured at 0.69g. Additionally, the C-reactive protein level was found to be 8.49mg/L (normal range 0-5mg/L). Other tests including serum immunoglobulins (IgA, IgG, and IgM), Antinuclear antibody, acute hepatitis panel, double-stranded deoxyribonucleic acid, rheumatoid factor, complement levels (C3 and C4), and antineutrophil cytoplasmic antibody profile all yielded negative results. Serum protein electrophoresis and serum immunofixation yielded negative results. Renal ultrasound examination indicated a right kidney size of 9.4 cm and a left kidney size of 9.9 cm, both exhibiting normal cortical thickness. A renal biopsy was performed on the 7th day after admission. Immunofluorescence analysis demonstrated a 3+ intensity of IgA and a 2+ intensity of C3, primarily displaying a coarse-grained pattern within the mesangial region.Upon light microscopy examination, it was observed that the renal tissue contained a total of 21 glomeruli. Among these, one glomeruli exhibited ischemic sclerosis, accounting for approximately 4.8% of the total, while two glomeruli displayed ischemic shrinkage, representing approximately 9.5%. The remaining glomeruli showed mild mesangial cell proliferation and an increased mesangial matrix. Furthermore, the renal capsule displayed one large cell crescent, one small fiber crescent. Renal interstitial fibrosis, which accounts for approximately 35%, and renal tubular atrophy were observed. Tubular cross sections displayed a notable presence of red cell casts.Perl’s Prussian Blue stain diaplayed hemosiderin deposits in the tubular epithelial cells. Immunohistochemical stain for cytokeratin AE1/AE3 highlights distal tubules with occlusive RBC casts. Additionally, a mild thickening of the renal arteriole wall was observed. Electron microscopy (EM) demonstrated a mild increase in the proliferation of glomerular mesangial cells and matrix, accompanied by the accumulation of clustered electron-dense substances within the mesangial region and fusion of a majority of epithelial foot processes. (Figure 1) Consequently, the patient was diagnosed as WRN with focal proliferative IgA nephropathy.The patient continued to receive warfarin anticoagulant, and were prescribed a supplementary treatment regimen comprising oral sodium bicarbonate, prednisolone at a daily dosage of 20mg, and cyclophosphamide at a dosage of 50mg every other day. Before being discharged, the patient's creatinine level was assessed and found to be 156.6μmol/L. During a subsequent follow-up after a two-month period, the patient's creatinine level had decreased to 109.2μmol/L, and the urine protein quantification was recorded as 119.7 mg/24 hours. (Figure 2) Case 2 A 63-year-old male patient, who has been diagnosed with hypertension for the twenty years, underwent a partial nephrectomy for left renal clear cell carcinoma five years ago. Additionally, five and a half years ago, the patient underwent Bentall+Sun's surgery, which involved aortic root replacement, total aortic arch replacement, and stent elephant nose surgery, for managing type A aortic dissection. Following the surgery, the patient was prescribed warfarin due to the replacement of a mechanical valve. The patient was admitted to the hospital due to persistent gross hematuria for a duration of forty days and an increase in creatinine levels for one month. Upon admission, the patient's vital signs were recorded as follows: blood pressure of 192/124 mmHg, heart rate of 76 beats per minute, and temperature of 36.3°C. Subsequent laboratory analysis revealed a creatinine level of 169.9μmol/L (which was within the normal range one year ago), eGFR of 37.2ml/min.1.73m 2 , a blood urea nitrogen/creatinine ratio of 14.1, albumin level of 39.5g/L, hemoglobin level of 13.3 g/dl, white blood cell count of 6.27×10 9 /L, platelet count of 204×10 9 /L, and an INR of 2.69. The urinary test indicated the presence of urinary protein (2+) and urinary occult blood (3+). The microscopic analysis of urine sediment reveals full of red blood cells in high-power field, exhibiting an 80% deformation rate. Urinary protein quantification was 3.06g/24hours. The serum IgA level was measured at 4.55g/L, falling within the normal range of 1.0-4.2g/L. Conversely, IgG and IgM levels were found to be within the normal limits. Results for antinuclear antibody, acute hepatitis panel, double-stranded deoxyribonucleic acid, rheumatoid factor, complement levels (C3 and C4), and antineutrophil cytoplasmic antibody profile were all normal. Negative results were obtained from serum protein electrophoresis and serum immunofixation. Renal ultrasound revealed a right kidney size of 11.8 cm and a left kidney size of 11.5 cm, both demonstrating normal cortical thickness. During the patient's hospitalization, his creatinine levels reached a maximum of 231.4μmol/L. A renal biopsy was performed on the fourteenth day after admission. The subsequent immunofluorescence analysis demonstrated a 2+ intensity of IgA and C3, accompanied by segmental mesangial granular deposition. Under the observation using light microscopy, it was found that among the total of 21 glomeruli, approximately 33.2% (7 glomeruli) exhibited ischemic sclerosis, while approximately 14.3% (3 glomeruli) displayed ischemic shrinkage. The remaining glomeruli demonstrated mild mesangial cell proliferation and an increase in mesangial matrix, accompanied by segmental exacerbation and occasional endothelial cell proliferation. One glomerulus exhibited segmental sclerosis. Renal interstitial multifocal fibrosis, accounting for approximately 60%, was accompanied by a significant infiltration of mononuclear cells, occasional eosinophils, and plasma cells. Furthermore, the presence of granular and vacuolar degeneration in the renal tubular epithelial cells, as well as multifocal renal tubular atrophy, was observed. Additionally, the detachment of brush-like edges of renal tubular epithelial cells, flattened epithelial cells, and the presence of a small amount of protein tubular type, a large amount of red blood cell tubular type, and a small amount of exfoliated cells in the lumen were noted. Moreover, evidence of epithelial cell regeneration was observed, along with the disappearance of normal structures in numerous renal tubules. Perl’s Prussian Blue stain diaplayed hemosiderin deposits in the tubular epithelial cells Immunohistochemical stain for cytokeratin AE1/AE3 highlights distal tubules with occlusive RBC casts. EM demonstrated mild mesangial cell proliferation and an augmentation of mesangial matrix within the glomerulus. Moreover, the deposition of blocky electronic dense substances can be observed in the mesangial and paramesangial regions, along with the fusion of segments of foot processes. Additionally, an increase in lysosomes within renal tubular epithelial cells and partial detachment of microvilli have been noted. Lastly, renal interstitial edema is present. (Figure 3) The patient was diagnosed as ARN with focal proliferative IgA nephropathy. The patient’s anticoagulation therapy with warfarin was continued, along with a daily dosage of 20mg of prednisolone and an oral dosage of 50mg of cyclophosphamide every other day. Before being discharged, the patient's creatinine level was assessed at 213.5μmol/L. During a subsequent follow-up after four months, the patient's creatinine level had decreased to 125μmol/L, and the quantification of urine protein was recorded at 600mg/24hours.(Figure 4) Literature review In previous literature, a total of ten cases of WRN confirmed by renal biopsy in patients with prosthetic valves were summarized [7-13]. The age range of the cases was between 50 and 76 years, with a time interval of 11 months to 26 years from the initiation of oral warfarin administration to the onset of WRN. Six of them had elevated baseline creatinine levels. The INR values varied from 1.36 to 6.08, and two patients had an INR<3 upon admission. All the cases exhibited progressive elevation in creatinine levels and presence of hematuria. Among these cases, eight presented with gross hematuria, while the remaining two cases showed microscopic hematuria. Nine cases showed renal function progression. Furthermore, six cases were complicated by the presence of IgAnephropathy. Steroids were administered in five cases, and four cases initiated dialysis treatment upon the onset of the WRN. Ultimately, among these four cases, three remained on dialysis, while one case experienced improved renal function and no longer dependent on dialysis. Whereas it is noteworthy that the three cases who failed to recover renal function had elevated baseline creatinine levels, ranging from 180-430μmol/L. The remaining six cases showed varying degrees of improvement in renal function. (Table 1) Discussion WRN is described as AKI that occurs due to excessive warfarinization, without the evidence of clinically relevant hemorrhage [ 2 ]. The main mechanism behind AKI in WRN is the occurrence of glomerular hemorrhage and tubular obstruction caused by red blood cell casts [ 1 ]. Patients who had undergone mechanical artificial valve surgery require long-term anticoagulation treatment with warfarin. The pharmacokinetics of warfarin are subject to influenced by various drugs and foods, and there exists a potential risk for excessive warfarinization during long-term use. And the patients with mechanical artificial valve have a high risk of "valve blockage" if discontinuing warfarin, which in turn limits the number of patients who can undergo renal biopsy when WRN is suspected in clinical practice. Additionally, previous literature indicates that warfarin can be substituted with DOACs once WRN occurs, but guidelines do not recommend DOACs for patients with mechanical prosthetic valves [ 14 ]. Consequently, there are currently no alternative oral anticoagulants that can be use as a substitute for warfarin. We reported two cases of gross hematuria and creatinine progression after long-term warfarin anticoagulant therapy in patients with mechanical valves. The renal biopsy reveal the presence of renal tubular red blood cell castsin both cases, WRN was diagnosed through typical clinical and pathological evidence. In terms of clinical characteristics, similar to the cases of WRN patients documented in the literature review [ 7 – 13 ], the two patients in the present study also exhibited gross hematuria and creatinine progression. WRN was initially characterized as AKI that occurs following excessive anticoagulation, with INR > 3 commonly regarded as indicative of excessive anticoagulation. However, the two patients in the present study did not detect an INR > 3. In our literature review, out of ten cases who developed WRN after valve replacement surgery, two cases also had an INR < 3. Furthermore, previous research has also reported that the patients with INR<3 have been confirmed to WRN through renal biopsy [ 1 , 15 – 16 ]. Considering the lack of available INR levels before the AKI episode in these two patients, it is highly probable that the highest value of INR was not been detected. Consequently, when patients on long-term warfarin treatment exhibit both hematuria and AKI in clinical practice, the possibility of WRN must be considered regardless of whether the INR<3. Both patients in the present study all have the potential glomerular diseases, which was IgA nephropathy. It is consistent with the previous literature. A study in Spain involving 26 patients diagnosed with WRN demonstrated that 73% of the patients presented with IgA nephropathy [ 16 ]. A study of 41 cases of WRN in the United States revealed that 43% of patients exhibited IgA deposition [ 17 ]. In a retrospective study comprising 13 cases of WRN in Slovenia, it was observed that 84.6% of the patients presented with IgA nephropathy. 7 According to the evidence previously mentioned, it can be inferred that IgA nephropathy might be the predominant glomerular disease in patients with WRN. In the clinical practice, IgA nephropathyis also characterized by hematuria and AKI, thus emphasizing the significance of renal biopsy as the definitive diagnostic tool for WRN. According to the findings in previous literature, with the exception of IgA nephropathy, WRN frequently coexists with diabetes nephropathy, lupus nephritis, thin basement membrane nephropathy and other glomerular diseases [ 1 , 18 , 19 ]. It is widely recognized that warfarin can decrease thrombin levels through the inhibition of prothrombin synthesis. Thrombin, in turn, has the capacity to bind and activate a family of proteinase activated receptors (PARs) that are expressed in numerous cells, including glomerular endothelial cells [ 20 ]. It is hypothesized that the activation of PARs provides trophic support to maintain endothelial integrity. Consequently, the decrease in thrombin levels induced by warfarin leads to the breakdown of the endothelial barrier, thereby facilitating glomerular hemorrhage [ 21 ]. Chronic kidney disease (CKD) patients caused by multiple etiologies frequently have a pathological foundation of glomerular endothelial injury, thereby significantly elevating the probability of WRN occurrence. Meanwhile, studies had revealed that the transcription and concentration of cytochrome P450 enzymes are lower in CKD animal models, which lead to reduce the drug metabolism and increase the risk of overdose [ 22 ]. This may also contribute to the heightened susceptibility of CKD patients to WRN. Currently, there is a lack of established guidelines for the treatment of WRN. The predominant strategies seem to involve addressing coagulopathy and offering comprehensive supportive care.Most literature reports recommended to modify the anticoagulant therapy from warfarin to NOACs [ 14 ]. For patients with mechanical prosthetic valves, NOAC was not recommended by the guidelines. In the present study, both patients continued to receive anticoagulation with warfarin and strengthened monitoring to ensure their INR within the range of 3.Early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [ 22 – 25 ]. There are also studies indicating that the etiopathogenesis of tubular injury associated with RBC casts has been ascribed to the detrimental local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, resulting in damage of the lipoprotein components of tubular cell membranes and ultimately leading to apoptosis/necrosis of the tubular cells [ 26 , 27 ]. Studies have demonstrated that corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Theoretically, glucocorticoids may be a viable option for WRN therapy. Certain scholars also highlighted that glucocorticoids are commonly used in ARN patients with potential IgA nephropathy, as well as in patients with more prominent crescent lesion or tubulointerstitial inflammation. The objective of such treatment is to alleviate inflammatory responses and promote renal recovery [ 28 ]. Out of the ten cases reviewed in the literature, five received glucocorticoids treatment, with four of them presenting immune nephritis and the remaining patient displaying acute interstitial tubular lesions. According to the pathological findings in the present article, both patients exhibited typical red blood cell tubular and acute renal tubular injury in ARN, along with IgA nephropathy. The first patient displayed crescentic lesions, while the second patient had proteinuria measuring 3.1g/24 hours. So we administered an oral corticosteroid combined with low-dose oral cyclophosphamide. In the subsequent follow-up, the renal function of both patients exhibited varying degrees of recovered. Among the ten patients in our literature review, three required maintenance dialysis. Notably, the baseline creatinine levels of these three patients were higher than those of other patients.[ 7 – 13 ] In Brodsky's study including nine WRN patients, three patients who experienced complete renal function recovery had a normal baseline creatinine, while four patients requiring maintain dialysis all had basal renal insufficiency, with two patients having a baseline eGFR below 30ml/min.1.73m 2 . Due to the limited availability of clinical studies with large sample sizes on WRN, it has only been reported in some few samples study and cases individual cases reports between renal prognosis and the severity of tubulointerstitial lesions, as well as the impact of early administration of glucocorticoid therapy [ 7 , 29 ]. The above suggests that for the treatment of ARN patients after valve replacement surgery, in addition to adjusting the dosage of warfarin and strengthening monitoring to control INR standards as much as possible, it is also possible to consider the rational use of low-dose corticosteroid and immunosuppressants based on the results of renal biopsy. Of course, it is still requires confirmation from larger sample size studies. In conclusion, given the widespread utilization of warfarin across various medical conditions, it is imperative for clinicians to promptly identify and diagnose WRN. Clinicians should maintain a state of increased alertness with regards to the potential occurrence of WRN who exhibit hematuria and elevated creatinine levels while on warfarin therapy, even if their INR remains within the normal range. Considering most WRN have an underlying glomerular disease (mostly IgA nephropathy), the use of corticosteroid and immunosuppressive drugs may appear to be an attractive option, particularly in patients who are unable to replace warfarin with NOACs. Declarations Ethics approval The study was approved by the Ethics Committee of Beijing Anzhen Hospital, Capital Medical University (protocol code 2023224X). Consent for publication Written informed consent for publication was obtained from all participants. Availability of data and materials The data are available from the corresponding author upon reasonable request Competing interests The authors declare that they have no competing financial interests. Acknowlegements The authors acknowledge the support in making renal pathological specimens from Lingqiang Kong. Funding Capital’s Fund for Health Improvement and Research (2022-2-2066)；Beijing Municipal Hospital Research and Cultivation Program Project（PX2022024） Author contributions HC and GQW designed the study; FBX wrote the manuscript. LJS provide renal pathological support. All authors reviewed and edited the manuscript. All authors read and approved the final manuscript. All authors have read and agreed to the published version of the manuscript. References Brodsky SV, Satoskar A, Chen J, et al. Acute kidney injury during warfarin therapy associated with obstructive tubular red blood cell casts: a report of 9 cases. Am J Kidney Dis. 2009;54(6):1121–1126. Brodsky SV, Nadasdy T, Rovin BH, et al. Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate. Kidney Int. 2011;80(2):181–189. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. 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Table Table 1 Clinical and demographic data of WRN patients with prosthetic valves Patient No. Country of author Age (y) Sex Symptoms Time to ARN onset Surgery INR (IU) Baseline Scr (μmol/L) Scr at Biopsy (μmol/L) Renal biopsy pathology Medications Outcome 1 [9] Slovenia 51 M gross hematuria 15 years aortic valvereplacement 5.0 170-200 249 IgAN, ATI Temporarystop warfarin steroids Incomplete recovery 2 [9] Slovenia 76 M gross hematuria 10 years aortic valvereplacement 4.4 430 487 global glomerular sclerosis, ATI dialysis; better control of INR dialysis 3 [9] Slovenia 56 F microscopic hematuria 11 months aortic valvereplacement 2.42 72 81 IgAN better control of INR stable kidney function 4 [9] Slovenia 66 M gross hematuria 26years , aortic valvereplacement 1.36 149 669 IgAN transiently converted to heparin kidney function slightly improved 5 [10] Singapore 56 F microscopic hematuria 6 years valve replacement 4.95 72 317 IgAN prednisolone; acetylcysteine; Incomplete recovery 6 [11] India 50 F gross hematuria 2 years mitral valve replacement 4.70 80 415 acute tubulointerstitial nephritis steroids; temporarystop warfarin complete recovery 7 [12] USA 57 F gross hematuria 26 years aortic valve replacement 3.71 274 518 Diffusemesangial proliferative glomerulonephritis ATI steroids, dialysis dialysis 8 [13] Japan 55 M gross hematuria 13 years aortic valvereplacement 3.75 67 796 IgAN supportive care Incomplete recovery 9 [14] Tailand 56 M gross hematuria 2 years aortic valve replacement 6.08 124 1017 ATI Temporarystop warfarin oral vitamin K; hemodialysis Incomplete recovery 10 [15] USA 61 M gross hematuria available mitral valve replacement 3.52 180 601 IgAN steroids, dialysis dialysis. 11* China 56 F gross hematuria 9 months aortic valve replacement 2.08 121 215 IgAN, ATI steroids, cyclophosphamide Incomplete recovery 12* China 63 F gross hematuria 5.5 years aortic valve replacement 2.69 170 219 IgAN, ATI steroids, cyclophosphamide Incomplete recovery *the present study Abbreviations: SCr, serum creatinine; INR, international normalized ratio; RBC, red blood cell; IgAN, IgA nephropathy; LMWH, low molecular weight heparin.ATI, acute tubular injury Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 02 May, 2024 Reviews received at journal 11 Apr, 2024 Reviewers agreed at journal 07 Apr, 2024 Reviewers agreed at journal 02 Apr, 2024 Reviewers invited by journal 01 Apr, 2024 Editor assigned by journal 31 Mar, 2024 Submission checks completed at journal 31 Mar, 2024 First submitted to journal 27 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4179190","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":286543027,"identity":"b163072c-c318-44b1-95d3-d09f9dcc0b89","order_by":0,"name":"徐丰博 xufengbo","email":"","orcid":"","institution":"Beijing Anzhen Hospital","correspondingAuthor":false,"prefix":"","firstName":"徐丰博","middleName":"","lastName":"xufengbo","suffix":""},{"id":286543028,"identity":"24573618-8ede-496c-8061-6c6a87b31c62","order_by":1,"name":"Guoqin Wang","email":"","orcid":"","institution":"Beijing Anzhen Hospital","correspondingAuthor":false,"prefix":"","firstName":"Guoqin","middleName":"","lastName":"Wang","suffix":""},{"id":286543029,"identity":"95fc358f-ca0c-4abe-92f7-987041cd5152","order_by":2,"name":"Lijun Sun","email":"","orcid":"","institution":"Beijing Anzhen Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lijun","middleName":"","lastName":"Sun","suffix":""},{"id":286543030,"identity":"0f962873-f473-4e56-9e7a-bf5c06b4919d","order_by":3,"name":"Hong Cheng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuUlEQVRIiWNgGAWjYDCCAwxsICqBn5n58APStEi2s6UZkKbF4DyPggRROvhuH3724OOO2jzjwzwMBgw1NtEEtUieSzM3nHnmeLHZYd4DDxiOpeU2ENJicIaHTZq37VjitsN8CQaMDYeJ1PIXqGVzM4+BBPFaGNtqEjcwE6tF8gybmWRv24HEGYeBgZxAjF/4zjA/k/jZVpfY33/48IMPNTaEtUDBYQiVQKRyEKgjQe0oGAWjYBSMOAAAt3RBV6EK3yQAAAAASUVORK5CYII=","orcid":"","institution":"Beijing Anzhen Hospital","correspondingAuthor":true,"prefix":"","firstName":"Hong","middleName":"","lastName":"Cheng","suffix":""}],"badges":[],"createdAt":"2024-03-28 03:29:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4179190/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4179190/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54043708,"identity":"99da69c6-33f9-4e31-b1ab-fcedf70e0f4b","added_by":"auto","created_at":"2024-04-03 18:30:35","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1553877,"visible":true,"origin":"","legend":"\u003cp\u003e(A)Immunoglobulin A (IgA) deposition on the nephron(×200).(B)Mild mesangial cell proliferation and increased mesangial matrix in the glomeruli(PAS×400).(C)Signs of one large cell crescent(PASM+Mas×200).(D) Signs of red blood cell casts in the tubules (PASM+Mas×200).(E)Signs of hemosiderin deposits in the tubular epithelial cells (Perl’s Prussian Blue stain×400). (F) Immunohistochemical stain for cytokeratin AE1/AE3 highlights distal tubules with occlusive RBC casts. (HE×200)\u003c/p\u003e","description":"","filename":"floatimage1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4179190/v1/2a7644c1d8d810e55d56acc7.jpg"},{"id":54043710,"identity":"5939d3fb-17b3-498f-a70c-2bbba0fd27c8","added_by":"auto","created_at":"2024-04-03 18:30:35","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":390234,"visible":true,"origin":"","legend":"\u003cp\u003eClinical course in case 1\u003c/p\u003e","description":"","filename":"floatimage2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4179190/v1/2bccfff023bf58181a2bfc8d.jpg"},{"id":54044176,"identity":"d36eec74-f4a7-4cf5-9145-a5546431b498","added_by":"auto","created_at":"2024-04-03 18:38:35","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1467418,"visible":true,"origin":"","legend":"\u003cp\u003e(A)Immunoglobulin A (IgA) deposition on the nephron(×200). (B)Mild mesangial cell proliferation and increased measngial matrix in the glomeruli(PASM+M×400). (C)Signs of red blood cell casts in the tubules(HE×200). (D)Multiple infiltration of mononuclear cells and occasional eosinophils and plasma cells in the renal interstitium(HE×400). (E)Signs of hemosiderin deposits in the tubular epithelial cells (Perl’s Prussian Blue stain×400).(F) Immunohistochemical stain for cytokeratin AE1/AE3 highlights distal tubules with occlusive RBC casts. (HE×200.)\u003c/p\u003e","description":"","filename":"floatimage3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4179190/v1/0f3c2e7127302d5a379dfda3.jpg"},{"id":54044177,"identity":"d6f818ad-4545-4168-b022-04e6b2bdf0fa","added_by":"auto","created_at":"2024-04-03 18:38:35","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":287886,"visible":true,"origin":"","legend":"\u003cp\u003eClinical course in case 2\u003c/p\u003e","description":"","filename":"floatimage4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4179190/v1/87f8cb9883932016d4e92c92.jpg"},{"id":54044573,"identity":"ad654624-176b-4c05-9e7a-24bbedb80efc","added_by":"auto","created_at":"2024-04-03 18:46:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":698970,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4179190/v1/534115ea-4867-4fcc-890f-b2aa4d589897.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Warfarin-Related Nephropathy: Unveiling the Hidden Dangers of Anticoagulation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eWarfarin-related nephropathy (WRN) is an increasingly recognized disease, mainly associated with warfarin excessive anticoagulation. The preliminary description of WRN indicated that patients receiving warfarin therapy experienced significant glomerular hemorrhage during renal biopsy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. WRN was defined as the manifestation of acute kidney injury (AKI) occurring within a week subsequent to the elevation of the international normalized ratio (INR) above 3 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite the development of direct oral anticoagulants (DOACs), research findings on the efficacy of DOACs in preventing valve thrombosis in patients with artificial valves have been inconsistent [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. As a result, warfarin remains the only available option for anticoagulant in this population. Patients who undergo mechanical artificial valve surgery are usually younger and have fewer comorbidities compared to those with atrial fibrillation, and necessitating long-term anticoagulant therapy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Consequently, patients with mechanical prosthetic valve constitute a special subgroup in the whole population of patients with anticoagulation.\u003c/p\u003e \u003cp\u003eThe present study reported two cases of patients with mechanical prosthetic valves who experienced gross hematuria and AKI, ultimately establishing their diagnosis as WRN through renal biopsy. However, INR\u0026thinsp;\u0026gt;\u0026thinsp;3 was not be observed.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003e\u003cstrong\u003eCase 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 56-year-old female patient, who had previously undergone mechanical aortic valve replacement surgery nine months ago and was prescribed warfarin as post-surgery treatment, was admitted to the hospital due to the occurrence of gross hematuria six days before hospitalization. Additionally, her creatinine levels exhibited a rapid increase from 120.5umol/L to 207.5\u0026mu;mol/L within three days. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUpon admission, the patient\u0026apos;s vital signs were recorded as follows:\u0026nbsp;blood pressure of 132/74 mmHg, heart rate of 83 beats per minute, and temperature of 36.3\u0026deg;C. Subsequent laboratory analysis revealed the following findings: creatinine level of 167.8\u0026mu;mol/L, eGFR of 30.5ml/min.1.73m\u003csup\u003e2\u003c/sup\u003e, blood urea nitrogen/creatinine ratio of 17.9, albumin level of 39.6g/L, hemoglobin level of 10.4 g/dl, white blood cell count of 6.6\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, platelet count of 238\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, and an INR value of 2.08. The urinary test results indicated the presence of urinary protein(+) and urinary occult blood(3+).Microscopic examination of the urine sediment revealed the presence of 20-40 red blood cells per high-power field, with a deformation rate of 70%. The quantification of urinary protein over a 24-hour period was measured at 0.69g. Additionally, the C-reactive protein level was found to be 8.49mg/L (normal range 0-5mg/L). Other tests including serum immunoglobulins (IgA, IgG, and IgM), Antinuclear antibody, acute hepatitis panel, double-stranded deoxyribonucleic acid, rheumatoid factor, complement levels (C3 and C4), and antineutrophil cytoplasmic antibody profile all yielded negative results. Serum protein electrophoresis and serum immunofixation yielded negative results. Renal ultrasound examination indicated a right kidney size of 9.4 cm and a left kidney size of 9.9 cm, both exhibiting normal cortical thickness.\u003c/p\u003e\n\u003cp\u003eA renal biopsy was performed on the 7th day after admission. Immunofluorescence analysis demonstrated a 3+ intensity of IgA and a 2+ intensity of C3, primarily displaying a coarse-grained pattern within the mesangial region.Upon light microscopy examination, it was observed that the renal tissue contained a total of 21 glomeruli. Among these, one glomeruli exhibited ischemic sclerosis, accounting for approximately 4.8% of the total, while two glomeruli displayed ischemic shrinkage, representing approximately 9.5%. The remaining glomeruli showed mild mesangial cell proliferation and an increased mesangial matrix. Furthermore, the renal capsule displayed one large cell crescent, one small fiber crescent. Renal interstitial fibrosis, which accounts for approximately 35%, and renal tubular atrophy were observed. Tubular cross sections displayed a notable presence of red cell casts.Perl\u0026rsquo;s Prussian Blue stain diaplayed hemosiderin deposits in the tubular epithelial cells. Immunohistochemical stain for cytokeratin AE1/AE3 highlights distal tubules with occlusive RBC casts. Additionally, a mild thickening of the renal arteriole wall was observed. Electron microscopy (EM) demonstrated a mild increase in the proliferation of glomerular mesangial cells and matrix, accompanied by the accumulation of clustered electron-dense substances within the mesangial region and fusion of a majority of epithelial foot processes. (Figure 1) Consequently, the patient was diagnosed as WRN with focal proliferative IgA nephropathy.The patient continued to receive warfarin anticoagulant, and were prescribed a supplementary treatment regimen comprising oral sodium bicarbonate, prednisolone at a daily dosage of 20mg, and cyclophosphamide at a dosage of 50mg every other day. Before being discharged, the patient\u0026apos;s creatinine level was assessed and found to be 156.6\u0026mu;mol/L. During a subsequent follow-up after a two-month period, the patient\u0026apos;s creatinine level had decreased to 109.2\u0026mu;mol/L, and the urine protein quantification was recorded as 119.7 mg/24 hours. (Figure 2)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 63-year-old male patient, who has been diagnosed with hypertension for the twenty years, underwent a partial nephrectomy for left renal clear cell carcinoma five years ago. Additionally, five and a half years ago, the patient underwent Bentall+Sun\u0026apos;s surgery, which involved aortic root replacement, total aortic arch replacement, and stent elephant nose surgery, for managing type A aortic dissection. Following the surgery, the patient was prescribed warfarin due to the replacement of a mechanical valve. The patient was admitted to the hospital due to persistent gross hematuria for a duration of forty days and an increase in creatinine levels for one month.\u003c/p\u003e\n\u003cp\u003eUpon admission, the patient\u0026apos;s vital signs were recorded as follows: blood pressure of 192/124 mmHg, heart rate of 76 beats per minute, and temperature of 36.3\u0026deg;C. Subsequent laboratory analysis revealed a creatinine level of 169.9\u0026mu;mol/L (which was within the normal range one year ago), eGFR of 37.2ml/min.1.73m\u003csup\u003e2\u003c/sup\u003e, a blood urea nitrogen/creatinine ratio of 14.1, albumin level of 39.5g/L, hemoglobin level of 13.3 g/dl, white blood cell count of 6.27\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, platelet count of 204\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, and an INR of 2.69. The urinary test indicated the presence of urinary protein (2+) and urinary occult blood (3+). The microscopic analysis of urine sediment reveals full of red blood cells in high-power field, exhibiting an 80% deformation rate. Urinary protein quantification was 3.06g/24hours.\u0026nbsp;The serum IgA level was measured at 4.55g/L, falling within the normal range of 1.0-4.2g/L. Conversely, IgG and IgM levels were found to be within the normal limits. Results for antinuclear antibody, acute hepatitis panel, double-stranded deoxyribonucleic acid, rheumatoid factor, complement levels (C3 and C4), and antineutrophil cytoplasmic antibody profile were all normal. Negative results were obtained from serum protein electrophoresis and serum immunofixation. Renal ultrasound revealed a right kidney size of 11.8 cm and a left kidney size of 11.5 cm, both demonstrating normal cortical thickness.\u003c/p\u003e\n\u003cp\u003eDuring the patient\u0026apos;s hospitalization, his creatinine levels reached a maximum of 231.4\u0026mu;mol/L. A renal biopsy was performed on the fourteenth day after admission. The subsequent immunofluorescence analysis demonstrated a 2+ intensity of IgA and C3, accompanied by segmental mesangial granular deposition. Under the observation using light microscopy, it was found that among the total of 21 glomeruli, approximately 33.2% (7 glomeruli) exhibited ischemic sclerosis, while approximately 14.3% (3 glomeruli) displayed ischemic shrinkage. The remaining glomeruli demonstrated mild mesangial cell proliferation and an increase in mesangial matrix, accompanied by segmental exacerbation and occasional endothelial cell proliferation. One glomerulus exhibited segmental sclerosis. Renal interstitial multifocal fibrosis, accounting for approximately 60%, was accompanied by a significant infiltration of mononuclear cells, occasional eosinophils, and plasma cells. Furthermore, the presence of granular and vacuolar degeneration in the renal tubular epithelial cells, as well as multifocal renal tubular atrophy, was observed. Additionally, the detachment of brush-like edges of renal tubular epithelial cells, flattened epithelial cells, and the presence of a small amount of protein tubular type, a large amount of red blood cell tubular type, and a small amount of exfoliated cells in the lumen were noted. Moreover, evidence of epithelial cell regeneration was observed, along with the disappearance of normal structures in numerous renal tubules. Perl\u0026rsquo;s Prussian Blue stain diaplayed hemosiderin deposits in the tubular epithelial cells Immunohistochemical stain for cytokeratin AE1/AE3 highlights distal tubules with occlusive RBC casts. EM demonstrated mild mesangial cell proliferation and an augmentation of mesangial matrix within the glomerulus. Moreover, the deposition of blocky electronic dense substances can be observed in the mesangial and paramesangial regions, along with the fusion of segments of foot processes. Additionally, an increase in lysosomes within renal tubular epithelial cells and partial detachment of microvilli have been noted. Lastly, renal interstitial edema is present. (Figure 3) The patient was diagnosed as ARN with focal proliferative IgA nephropathy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u0026nbsp;\u003c/strong\u003eThe patient\u0026rsquo;s anticoagulation therapy with warfarin was continued, along with a daily dosage of 20mg of prednisolone and an oral dosage of 50mg of cyclophosphamide every other day. Before being discharged, the patient\u0026apos;s creatinine level was assessed at 213.5\u0026mu;mol/L. During a subsequent follow-up after four months, the patient\u0026apos;s creatinine level had decreased to 125\u0026mu;mol/L, and the quantification of urine protein was recorded at 600mg/24hours.(Figure 4)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLiterature review\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn previous literature, a total of ten cases of WRN confirmed by renal biopsy in patients with prosthetic valves were summarized [7-13]. The age range of the cases was between 50 and 76 years, with a time interval of 11 months to 26 years from the initiation of oral warfarin administration to the onset of WRN. Six of them had elevated baseline creatinine levels. The INR values varied from 1.36 to 6.08, and two patients had an INR\u0026lt;3 upon admission. All the cases exhibited progressive elevation in creatinine levels and presence of hematuria. Among these cases, eight presented with gross hematuria, while the remaining two cases showed microscopic hematuria. Nine cases showed renal function progression. Furthermore, six cases were complicated by the presence of IgAnephropathy. Steroids were administered in five cases, and four cases initiated dialysis treatment upon the onset of the WRN. Ultimately, among these four cases, three remained on dialysis, while one case experienced improved renal function and no longer dependent on dialysis. Whereas it is noteworthy that the three cases who failed to recover renal function had elevated baseline creatinine levels, ranging from 180-430\u0026mu;mol/L. The remaining six cases showed varying degrees of improvement in renal function. (Table 1)\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWRN is described as AKI that occurs due to excessive warfarinization, without the evidence of clinically relevant hemorrhage [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The main mechanism behind AKI in WRN is the occurrence of glomerular hemorrhage and tubular obstruction caused by red blood cell casts [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Patients who had undergone mechanical artificial valve surgery require long-term anticoagulation treatment with warfarin. The pharmacokinetics of warfarin are subject to influenced by various drugs and foods, and there exists a potential risk for excessive warfarinization during long-term use. And the patients with mechanical artificial valve have a high risk of \"valve blockage\" if discontinuing warfarin, which in turn limits the number of patients who can undergo renal biopsy when WRN is suspected in clinical practice. Additionally, previous literature indicates that warfarin can be substituted with DOACs once WRN occurs, but guidelines do not recommend DOACs for patients with mechanical prosthetic valves [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Consequently, there are currently no alternative oral anticoagulants that can be use as a substitute for warfarin.\u003c/p\u003e \u003cp\u003eWe reported two cases of gross hematuria and creatinine progression after long-term warfarin anticoagulant therapy in patients with mechanical valves. The renal biopsy reveal the presence of renal tubular red blood cell castsin both cases, WRN was diagnosed through typical clinical and pathological evidence. In terms of clinical characteristics, similar to the cases of WRN patients documented in the literature review [\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11 CR12\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], the two patients in the present study also exhibited gross hematuria and creatinine progression. WRN was initially characterized as AKI that occurs following excessive anticoagulation, with INR\u0026thinsp;\u0026gt;\u0026thinsp;3 commonly regarded as indicative of excessive anticoagulation. However, the two patients in the present study did not detect an INR\u0026thinsp;\u0026gt;\u0026thinsp;3. In our literature review, out of ten cases who developed WRN after valve replacement surgery, two cases also had an INR\u0026thinsp;\u0026lt;\u0026thinsp;3. Furthermore, previous research has also reported that the patients with INR\u0026lt;3 have been confirmed to WRN through renal biopsy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Considering the lack of available INR levels before the AKI episode in these two patients, it is highly probable that the highest value of INR was not been detected. Consequently, when patients on long-term warfarin treatment exhibit both hematuria and AKI in clinical practice, the possibility of WRN must be considered regardless of whether the INR\u0026lt;3.\u003c/p\u003e \u003cp\u003eBoth patients in the present study all have the potential glomerular diseases, which was IgA nephropathy. It is consistent with the previous literature. A study in Spain involving 26 patients diagnosed with WRN demonstrated that 73% of the patients presented with IgA nephropathy [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. A study of 41 cases of WRN in the United States revealed that 43% of patients exhibited IgA deposition [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In a retrospective study comprising 13 cases of WRN in Slovenia, it was observed that 84.6% of the patients presented with IgA nephropathy.\u003csup\u003e7\u003c/sup\u003e According to the evidence previously mentioned, it can be inferred that IgA nephropathy might be the predominant glomerular disease in patients with WRN. In the clinical practice, IgA nephropathyis also characterized by hematuria and AKI, thus emphasizing the significance of renal biopsy as the definitive diagnostic tool for WRN. According to the findings in previous literature, with the exception of IgA nephropathy, WRN frequently coexists with diabetes nephropathy, lupus nephritis, thin basement membrane nephropathy and other glomerular diseases [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. It is widely recognized that warfarin can decrease thrombin levels through the inhibition of prothrombin synthesis. Thrombin, in turn, has the capacity to bind and activate a family of proteinase activated receptors (PARs) that are expressed in numerous cells, including glomerular endothelial cells [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. It is hypothesized that the activation of PARs provides trophic support to maintain endothelial integrity. Consequently, the decrease in thrombin levels induced by warfarin leads to the breakdown of the endothelial barrier, thereby facilitating glomerular hemorrhage [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Chronic kidney disease (CKD) patients caused by multiple etiologies frequently have a pathological foundation of glomerular endothelial injury, thereby significantly elevating the probability of WRN occurrence. Meanwhile, studies had revealed that the transcription and concentration of cytochrome P450 enzymes are lower in CKD animal models, which lead to reduce the drug metabolism and increase the risk of overdose [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. This may also contribute to the heightened susceptibility of CKD patients to WRN.\u003c/p\u003e \u003cp\u003eCurrently, there is a lack of established guidelines for the treatment of WRN. The predominant strategies seem to involve addressing coagulopathy and offering comprehensive supportive care.Most literature reports recommended to modify the anticoagulant therapy from warfarin to NOACs [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. For patients with mechanical prosthetic valves, NOAC was not recommended by the guidelines. In the present study, both patients continued to receive anticoagulation with warfarin and strengthened monitoring to ensure their INR within the range of 3.Early administration of steroids has been reported to accelerate recovery from the more classic inflammation observed in drug (anticoagulants)-induced nephritis [\u003cspan additionalcitationids=\"CR23 CR24\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. There are also studies indicating that the etiopathogenesis of tubular injury associated with RBC casts has been ascribed to the detrimental local effects of catalytic iron released from decaying erythrocytes. The latter is thought to stimulate excessive production of hydroxyl radicals, resulting in damage of the lipoprotein components of tubular cell membranes and ultimately leading to apoptosis/necrosis of the tubular cells [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Studies have demonstrated that corticosteroids have been shown to ameliorate the associated tubulointerstitial injury and prevent the progression to irreversible fibrosis. Theoretically, glucocorticoids may be a viable option for WRN therapy. Certain scholars also highlighted that glucocorticoids are commonly used in ARN patients with potential IgA nephropathy, as well as in patients with more prominent crescent lesion or tubulointerstitial inflammation. The objective of such treatment is to alleviate inflammatory responses and promote renal recovery [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Out of the ten cases reviewed in the literature, five received glucocorticoids treatment, with four of them presenting immune nephritis and the remaining patient displaying acute interstitial tubular lesions. According to the pathological findings in the present article, both patients exhibited typical red blood cell tubular and acute renal tubular injury in ARN, along with IgA nephropathy. The first patient displayed crescentic lesions, while the second patient had proteinuria measuring 3.1g/24 hours. So we administered an oral corticosteroid combined with low-dose oral cyclophosphamide.\u003c/p\u003e \u003cp\u003eIn the subsequent follow-up, the renal function of both patients exhibited varying degrees of recovered. Among the ten patients in our literature review, three required maintenance dialysis. Notably, the baseline creatinine levels of these three patients were higher than those of other patients.[\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11 CR12\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] In Brodsky's study including nine WRN patients, three patients who experienced complete renal function recovery had a normal baseline creatinine, while four patients requiring maintain dialysis all had basal renal insufficiency, with two patients having a baseline eGFR below 30ml/min.1.73m\u003csup\u003e2\u003c/sup\u003e. Due to the limited availability of clinical studies with large sample sizes on WRN, it has only been reported in some few samples study and cases individual cases reports between renal prognosis and the severity of tubulointerstitial lesions, as well as the impact of early administration of glucocorticoid therapy [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The above suggests that for the treatment of ARN patients after valve replacement surgery, in addition to adjusting the dosage of warfarin and strengthening monitoring to control INR standards as much as possible, it is also possible to consider the rational use of low-dose corticosteroid and immunosuppressants based on the results of renal biopsy. Of course, it is still requires confirmation from larger sample size studies.\u003c/p\u003e \u003cp\u003eIn conclusion, given the widespread utilization of warfarin across various medical conditions, it is imperative for clinicians to promptly identify and diagnose WRN. Clinicians should maintain a state of increased alertness with regards to the potential occurrence of WRN who exhibit hematuria and elevated creatinine levels while on warfarin therapy, even if their INR remains within the normal range. Considering most WRN have an underlying glomerular disease (mostly IgA nephropathy), the use of corticosteroid and immunosuppressive drugs may appear to be an attractive option, particularly in patients who are unable to replace warfarin with NOACs.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval\u0026nbsp;\u003c/strong\u003eThe study was approved by the Ethics Committee of Beijing Anzhen Hospital, Capital Medical University (protocol code 2023224X).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003eWritten informed consent for publication was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003eThe data are available from the corresponding author upon reasonable request\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing financial interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowlegements\u0026nbsp;\u003c/strong\u003eThe authors acknowledge the support in making renal pathological specimens from Lingqiang Kong.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003eCapital’s Fund for Health Improvement and Research (2022-2-2066)；Beijing Municipal Hospital Research and Cultivation Program Project（PX2022024）\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003eHC and GQW designed the study; FBX wrote the manuscript. LJS provide renal pathological support. All authors reviewed and edited the manuscript. All authors read and approved the final manuscript. All authors have read and agreed to the published version of the manuscript.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBrodsky SV, Satoskar A, Chen J, et al. Acute kidney injury during warfarin therapy associated with obstructive tubular red blood cell casts: a report of 9 cases. Am J Kidney Dis. 2009;54(6):1121\u0026ndash;1126.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrodsky SV, Nadasdy T, Rovin BH, et al. Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate. Kidney Int. 2011;80(2):181\u0026ndash;189.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206\u0026ndash;1214.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCardoso R, Ternes CMP, Justino GB, et al. Non-Vitamin K Antagonists Versus Warfarin in Patients with Atrial Fibrillation and Bioprosthetic Valves: A Systematic Review and Meta-Analysis. Am J Med. 2022;135(2):228\u0026ndash;234.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLester PA, Coleman DM, Diaz JA, et al. Apixaban Versus Warfarin for Mechanical Heart Valve Thromboprophylaxis in a Swine Aortic Heterotopic Valve Model. Arterioscler Thromb Vasc Biol. 2017;37(5):942\u0026ndash;948.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, et al. ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2017;38(36):2739\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBelčičMikič T, Kojc N, Frelih M, Aleš-Rigler A, Večerić-Haler Ž. Management of Anticoagulant-Related Nephropathy: A Single Center Experience. J Clin Med. 2021;10(4):796.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGolla A, Goli R, Nagalla VK, Kiran BV, Raju DSB, Uppin MS. Warfarin-related Nephropathy. Indian J Nephrol. 2018;28(5):378\u0026ndash;381.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNg CY, Tan CS, Chin CT, et al. Warfarin related nephropathy: a case report and review of the literature. BMC Nephrol. 2016;17:15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAcquah F, Ganta N, Alnabwani D, Alaan C, Anantharaman P, Cheriyath P. Warfarin-Related Nephropathy Manifested as Diffuse Mesangial Proliferative Glomerulonephritis. Cureus. 2022;14(2):e22284.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIshii H, Hirai K, Yanai K, et al. Warfarin-related nephropathy with acute kidney injury in a patient with immunoglobulin A nephropathy. CEN Case Rep. 2018;7(2):198\u0026ndash;203.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLarpparisuth N, Cheunsuchon B, Chawanasuntorapoj R, Vasuvattakul S, Vareesangthip K. Warfarin related nephropathy: the first case report in Thailand. J Med Assoc Thai. 2015(2);98:212\u0026ndash;216.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRawala MS, Ahmed AS, Khan MY, Riaz MN, Eltoukhy A. Supratherapeutic International Normalized Ratio causing Nephropathy: A Rare Adverse Effect of Warfarin. Cureus. 2019;11(7):e5201.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrodsky S, Eikelboom J, Hebert LA. Anticoagulant-Related Nephropathy. J Am Soc Nephrol. 2018;29(12):2787\u0026ndash;2793.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNagasako Y, Fujii A, Furuse S, Saito K, Mise N. Warfarin-related nephropathy in a patient with renal pelvic cancer. Clin Nephrol Case Stud. 2017;5:5\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTrujillo H, Sandino J, Cavero T, et al. IgA Nephropathy Is the Most Common Underlying Disease in Patients With Anticoagulant-Related Nephropathy. Kidney Int Rep. 2022;7(4):831\u0026ndash;840.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrodsky SV, Satoskar A, Hemminger J, et al. Anticoagulant-Related Nephropathy in Kidney Biopsy: A Single-Center Report of 41 Cases. Kidney Med. 2019;1(2):51\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbt AB, Carroll LE, Mohler JH. Thin basement membrane disease and acute renal failure secondary to gross hematuria and tubular necrosis. Am J Kidney Dis. 2000;35(3):533\u0026ndash;536.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKabir A, Nadasdy T, Nadasdy G, Hebert LA. An unusual cause of gross hematuria and transient ARF in an SLE patient with warfarin coagulopathy. Am J Kidney Dis. 2004;43(4):757\u0026ndash;760.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCoughlin SR. Thrombin signalling and protease-activated receptors. Nature. 2000;407(6801):258\u0026ndash;264.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWheeler DS, Giugliano RP, Rangaswami J. Anticoagulation-related nephropathy. J ThrombHaemost. 2016;14(3):461\u0026ndash;467.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatel S, Hossain MA, Ajam F, et al. Dabigatran-Induced Acute Interstitial Nephritis: An Important Complication of Newer Oral Anticoagulation Agents. J Clin Med Res. 2018;10(10):791\u0026ndash;794.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbdulhadi B, Mulki R, Goyal A, Rangaswami J. Novel oral anticoagulant and kidney injury: apixaban-related acute interstitial nephritis. BMJ Case Rep. 2017;2017:bcr2017221641.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMonahan RC, Suttorp MM, Gabre\u0026euml;ls BATF. A case of rivaroxaban-associated acute tubulointerstitial nephritis. Neth J Med. 2017;75(4):169\u0026ndash;171.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKapoor KG, Bekaii-Saab T. Warfarin-induced allergic interstitial nephritis and leucocytoclastic vasculitis. Intern Med J. 2008;38(4):281\u0026ndash;283.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eL\u0026rsquo;Imperio, V.; Guarnieri, A.; Pieruzzi, F.; Sinico, R.A.; Pagni, F. Anticoagulant-related nephropathy: A pathological note. J. Thromb. Thrombolysis 2018, 46(2), 260\u0026ndash;263.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGlassock, R.J. Anticoagulant-Related Nephropathy: It\u0026rsquo;s the Real McCoy. Clin. J. Am. Soc. Nephrol. 2019, 14(6), 935\u0026ndash;937.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen S, Liao D, Yang M, Wang S. Anticoagulant-related nephropathy induced by direct-acting oral anticoagulants: Clinical characteristics, treatments and outcomes. Thromb Res. 2023;222:20\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYadav P, Yadav S, Pathak S. Warfarin: A double-edged sword. J Family Med Prim Care. 2019;8(9):3045\u0026ndash;3047.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e Clinical and demographic data of WRN patients with prosthetic valves\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"983\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003ePatient\u003c/p\u003e\n \u003cp\u003eNo.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003eCountry\u003c/p\u003e\n \u003cp\u003eof author\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.8657171922685656%\" valign=\"top\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003cp\u003e(y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6622583926754833%\" valign=\"top\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.138351983723297%\" valign=\"top\"\u003e\n \u003cp\u003eSymptoms\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.408952187182096%\" valign=\"top\"\u003e\n \u003cp\u003eTime to ARN onset\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.614445574771109%\" valign=\"top\"\u003e\n \u003cp\u003eSurgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003eINR\u003c/p\u003e\n \u003cp\u003e(IU)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.714140386571719%\" valign=\"top\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003cp\u003eScr\u003c/p\u003e\n \u003cp\u003e(\u0026mu;mol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003eScr\u003c/p\u003e\n \u003cp\u003eat Biopsy\u003c/p\u003e\n \u003cp\u003e(\u0026mu;mol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.44557477110885%\" valign=\"top\"\u003e\n \u003cp\u003eRenal biopsy pathology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.428280773143438%\" valign=\"top\"\u003e\n \u003cp\u003eMedications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.562563580874873%\" valign=\"top\"\u003e\n \u003cp\u003eOutcome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003csup\u003e[9]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003eSlovenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.8657171922685656%\" valign=\"top\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6622583926754833%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.138351983723297%\" valign=\"top\"\u003e\n \u003cp\u003egross hematuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.408952187182096%\" valign=\"top\"\u003e\n \u003cp\u003e15 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.614445574771109%\" valign=\"top\"\u003e\n \u003cp\u003eaortic valvereplacement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e5.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.714140386571719%\" valign=\"top\"\u003e\n \u003cp\u003e170-200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003e249\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.44557477110885%\" valign=\"top\"\u003e\n \u003cp\u003eIgAN,\u003c/p\u003e\n \u003cp\u003eATI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.428280773143438%\" valign=\"top\"\u003e\n \u003cp\u003eTemporarystop warfarin\u0026nbsp;\u003c/p\u003e\n \u003cp\u003esteroids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.562563580874873%\" valign=\"top\"\u003e\n \u003cp\u003eIncomplete recovery\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003csup\u003e[9]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003eSlovenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.8657171922685656%\" valign=\"top\"\u003e\n \u003cp\u003e76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6622583926754833%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.138351983723297%\" valign=\"top\"\u003e\n \u003cp\u003egross hematuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.408952187182096%\" valign=\"top\"\u003e\n \u003cp\u003e10 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.614445574771109%\" valign=\"top\"\u003e\n \u003cp\u003eaortic valvereplacement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.714140386571719%\" valign=\"top\"\u003e\n \u003cp\u003e430\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003e487\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.44557477110885%\" valign=\"top\"\u003e\n \u003cp\u003eglobal glomerular sclerosis,\u003c/p\u003e\n \u003cp\u003eATI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.428280773143438%\" valign=\"top\"\u003e\n \u003cp\u003edialysis;\u003c/p\u003e\n \u003cp\u003ebetter control of INR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.562563580874873%\" valign=\"top\"\u003e\n \u003cp\u003edialysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003csup\u003e[9]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003eSlovenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.8657171922685656%\" valign=\"top\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6622583926754833%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.138351983723297%\" valign=\"top\"\u003e\n \u003cp\u003emicroscopic\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ehematuria\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.408952187182096%\" valign=\"top\"\u003e\n \u003cp\u003e11 months\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.614445574771109%\" valign=\"top\"\u003e\n \u003cp\u003eaortic valvereplacement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e2.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.714140386571719%\" valign=\"top\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003e81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.44557477110885%\" valign=\"top\"\u003e\n \u003cp\u003eIgAN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.428280773143438%\" valign=\"top\"\u003e\n \u003cp\u003ebetter control of\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eINR \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.562563580874873%\" valign=\"top\"\u003e\n \u003cp\u003estable kidney\u0026nbsp;\u003c/p\u003e\n \u003cp\u003efunction\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003csup\u003e[9]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003eSlovenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.8657171922685656%\" valign=\"top\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6622583926754833%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.138351983723297%\" valign=\"top\"\u003e\n \u003cp\u003egross hematuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.408952187182096%\" valign=\"top\"\u003e\n \u003cp\u003e26years ,\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.614445574771109%\" valign=\"top\"\u003e\n \u003cp\u003eaortic valvereplacement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e1.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.714140386571719%\" valign=\"top\"\u003e\n \u003cp\u003e149\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003e669\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.44557477110885%\" valign=\"top\"\u003e\n \u003cp\u003eIgAN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.428280773143438%\" valign=\"top\"\u003e\n \u003cp\u003etransiently converted to heparin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.562563580874873%\" valign=\"top\"\u003e\n \u003cp\u003ekidney function\u003c/p\u003e\n \u003cp\u003eslightly improved\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003csup\u003e[10]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003eSingapore\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.8657171922685656%\" valign=\"top\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6622583926754833%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.138351983723297%\" valign=\"top\"\u003e\n \u003cp\u003emicroscopic hematuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.408952187182096%\" valign=\"top\"\u003e\n \u003cp\u003e6 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.614445574771109%\" valign=\"top\"\u003e\n \u003cp\u003evalve replacement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e4.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.714140386571719%\" valign=\"top\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003e317\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.44557477110885%\" valign=\"top\"\u003e\n \u003cp\u003eIgAN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.428280773143438%\" valign=\"top\"\u003e\n \u003cp\u003eprednisolone;\u003c/p\u003e\n \u003cp\u003eacetylcysteine;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.562563580874873%\" valign=\"top\"\u003e\n \u003cp\u003eIncomplete recovery\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003csup\u003e[11]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003eIndia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.8657171922685656%\" valign=\"top\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6622583926754833%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.138351983723297%\" valign=\"top\"\u003e\n \u003cp\u003egross hematuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.408952187182096%\" valign=\"top\"\u003e\n \u003cp\u003e2 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.614445574771109%\" valign=\"top\"\u003e\n \u003cp\u003emitral valve replacement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e4.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.714140386571719%\" valign=\"top\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003e415\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.44557477110885%\" valign=\"top\"\u003e\n \u003cp\u003eacute tubulointerstitial nephritis\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.428280773143438%\" valign=\"top\"\u003e\n \u003cp\u003esteroids;\u003c/p\u003e\n \u003cp\u003etemporarystop warfarin\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.562563580874873%\" valign=\"top\"\u003e\n \u003cp\u003ecomplete recovery\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003csup\u003e[12]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.8657171922685656%\" valign=\"top\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6622583926754833%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.138351983723297%\" valign=\"top\"\u003e\n \u003cp\u003egross hematuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.408952187182096%\" valign=\"top\"\u003e\n \u003cp\u003e26 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.614445574771109%\" valign=\"top\"\u003e\n \u003cp\u003eaortic valve replacement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e3.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.714140386571719%\" valign=\"top\"\u003e\n \u003cp\u003e274\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003e518\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.44557477110885%\" valign=\"top\"\u003e\n \u003cp\u003eDiffusemesangial proliferative glomerulonephritis\u003c/p\u003e\n \u003cp\u003eATI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.428280773143438%\" valign=\"top\"\u003e\n \u003cp\u003esteroids,\u003c/p\u003e\n \u003cp\u003edialysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.562563580874873%\" valign=\"top\"\u003e\n \u003cp\u003edialysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003csup\u003e[13]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003eJapan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.8657171922685656%\" valign=\"top\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6622583926754833%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.138351983723297%\" valign=\"top\"\u003e\n \u003cp\u003egross hematuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.408952187182096%\" valign=\"top\"\u003e\n \u003cp\u003e13 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.614445574771109%\" valign=\"top\"\u003e\n \u003cp\u003eaortic valvereplacement\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e3.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.714140386571719%\" valign=\"top\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003e796\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.44557477110885%\" valign=\"top\"\u003e\n \u003cp\u003eIgAN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.428280773143438%\" valign=\"top\"\u003e\n \u003cp\u003esupportive care\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.562563580874873%\" valign=\"top\"\u003e\n \u003cp\u003eIncomplete recovery\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003csup\u003e[14]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003eTailand\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.8657171922685656%\" valign=\"top\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6622583926754833%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.138351983723297%\" valign=\"top\"\u003e\n \u003cp\u003egross hematuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.408952187182096%\" valign=\"top\"\u003e\n \u003cp\u003e2 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.614445574771109%\" valign=\"top\"\u003e\n \u003cp\u003eaortic valve replacement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e6.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.714140386571719%\" valign=\"top\"\u003e\n \u003cp\u003e124\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003e1017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.44557477110885%\" valign=\"top\"\u003e\n \u003cp\u003eATI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.428280773143438%\" valign=\"top\"\u003e\n \u003cp\u003eTemporarystop warfarin\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eoral vitamin K;\u003c/p\u003e\n \u003cp\u003ehemodialysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.562563580874873%\" valign=\"top\"\u003e\n \u003cp\u003eIncomplete recovery\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003csup\u003e[15]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.8657171922685656%\" valign=\"top\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6622583926754833%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.138351983723297%\" valign=\"top\"\u003e\n \u003cp\u003egross hematuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.408952187182096%\" valign=\"top\"\u003e\n \u003cp\u003eavailable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.614445574771109%\" valign=\"top\"\u003e\n \u003cp\u003emitral valve replacement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e3.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.714140386571719%\" valign=\"top\"\u003e\n \u003cp\u003e180\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003e601\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.44557477110885%\" valign=\"top\"\u003e\n \u003cp\u003eIgAN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.428280773143438%\" valign=\"top\"\u003e\n \u003cp\u003esteroids,\u003c/p\u003e\n \u003cp\u003edialysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.562563580874873%\" valign=\"top\"\u003e\n \u003cp\u003edialysis.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e11*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.8657171922685656%\" valign=\"top\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6622583926754833%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.138351983723297%\" valign=\"top\"\u003e\n \u003cp\u003egross hematuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.408952187182096%\" valign=\"top\"\u003e\n \u003cp\u003e9 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.614445574771109%\" valign=\"top\"\u003e\n \u003cp\u003eaortic valve replacement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e2.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.714140386571719%\" valign=\"top\"\u003e\n \u003cp\u003e121\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003e215\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.44557477110885%\" valign=\"top\"\u003e\n \u003cp\u003eIgAN,\u003c/p\u003e\n \u003cp\u003eATI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.428280773143438%\" valign=\"top\"\u003e\n \u003cp\u003esteroids,\u003c/p\u003e\n \u003cp\u003ecyclophosphamide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.562563580874873%\" valign=\"top\"\u003e\n \u003cp\u003eIncomplete recovery\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e12*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.8657171922685656%\" valign=\"top\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.6622583926754833%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.138351983723297%\" valign=\"top\"\u003e\n \u003cp\u003egross hematuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.408952187182096%\" valign=\"top\"\u003e\n \u003cp\u003e5.5 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.614445574771109%\" valign=\"top\"\u003e\n \u003cp\u003eaortic valve replacement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.781281790437436%\" valign=\"top\"\u003e\n \u003cp\u003e2.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.714140386571719%\" valign=\"top\"\u003e\n \u003cp\u003e170\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.798575788402848%\" valign=\"top\"\u003e\n \u003cp\u003e219\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.44557477110885%\" valign=\"top\"\u003e\n \u003cp\u003eIgAN,\u003c/p\u003e\n \u003cp\u003eATI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.428280773143438%\" valign=\"top\"\u003e\n \u003cp\u003esteroids,\u003c/p\u003e\n \u003cp\u003ecyclophosphamide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.562563580874873%\" valign=\"top\"\u003e\n \u003cp\u003eIncomplete recovery\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*the present study\u003c/p\u003e\n\u003cp\u003eAbbreviations: SCr, serum creatinine; INR, international normalized ratio; RBC, red blood cell; IgAN, IgA nephropathy; LMWH, low molecular weight heparin.ATI, acute tubular injury\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"clinical-and-experimental-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"clem","sideBox":"Learn more about [Clinical and Experimental Medicine](https://www.springer.com/journal/10238)","snPcode":"10238","submissionUrl":"https://submission.nature.com/new-submission/10238/3","title":"Clinical and Experimental Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"warfarin-related nephropathy, acute kidney injury, international normalized ratio, IgA nephropathy","lastPublishedDoi":"10.21203/rs.3.rs-4179190/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4179190/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWarfarin-related nephropathy (WRN) is defined as acute kidney injury (AKI) subsequent to excessive anticoagulation with warfarin. Patients with mechanical prosthetic valves required long-term anticoagulant therapy, and warfarin remains the sole available option for anticoagulant therapy. Consequently, patients with mechanical prosthetic valves constitute a special group among the entire anticoagulant population. The present study recorded two cases in which patients who had undergone mechanical prosthetic valve surgery and were receiving warfarin therapy presented to the hospital with gross hematuria and progressive creatinine levels. Notably, the international normalized ratio (INR) did not exceed 3 in these two patients. Subsequent renal biopsies confirmed the presence of WRN with IgA nephropathy. The two patients continued to receive anticoagulation with warfarin and were prescribed oral corticosteroids and cyclophosphamide, which resulted in improved renal function during the follow period. Based on a review of all relevant literature and the present study, we also pose a new challenge, whether elevated INR levels must be as one of the criteria for clinical diagnosis of WRN? Perhaps it can get some inspiration from the present article.\u003c/p\u003e","manuscriptTitle":"Warfarin-Related Nephropathy: Unveiling the Hidden Dangers of Anticoagulation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-03 18:30:30","doi":"10.21203/rs.3.rs-4179190/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-05-02T10:10:20+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-12T00:08:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"88cfb2d8-dfc7-4ae9-8903-6f97b139ab6d","date":"2024-04-07T08:12:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"37f7a1ad-d2af-456b-9847-2775347cd833","date":"2024-04-02T05:48:09+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-01T17:59:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-01T02:25:40+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-01T02:25:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Clinical and Experimental Medicine","date":"2024-03-28T03:26:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"clinical-and-experimental-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"clem","sideBox":"Learn more about [Clinical and Experimental Medicine](https://www.springer.com/journal/10238)","snPcode":"10238","submissionUrl":"https://submission.nature.com/new-submission/10238/3","title":"Clinical and Experimental Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4ba0cb76-0dad-4fc2-b07b-3ff549c96f91","owner":[],"postedDate":"April 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-06-19T09:01:14+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-03 18:30:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4179190","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4179190","identity":"rs-4179190","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}