Original Research 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 Q1 Q13 Anticoagulant-Related Nephropathy in Kidney Biopsy: A Single-Center Report of 41 Cases Sergey V. Brodsky, Anjali Satoskar, Jessica Hemminger, Brad Rovin, Lee Hebert, Margaret (Maggie) S. Ryan, and Tibor Nadasdy Rationale & Objective: In 2009, the first case of acute kidney injury and occlusive red blood cell (RBC) tubular casts associated with a high international normalized ratio in a patient receiving warfarin was identified. This entity, named warfarin-related nephropathy, was later renamed anticoagulantrelated nephropathy (ARN) after similar cases with other anticoagulants were described. We provide our 10-year experience with ARN based on a single-center kidney biopsy laboratory. Study Design: The kidney pathology database at the Ohio State University Wexner Medical Center (OSUWMC) was searched for native kidney biopsy cases consistent with ARN. Clinical data were obtained from patient medical records. Q2 Setting & Participants: Native kidney biopsies performed between January 1, 2009, and December 31, 2017, at OSUWMC. Results: Among 8,636 native kidney biopsies reviewed at the OSUWMC, there were 41 (0.5%) patients for whom deterioration in kidney function could not be explained by kidney biopsy findings alone if anticoagulation was not considered. There were 63% men and 95% were white; average age I was 62 ± 14 years. Most were on warfarin therapy (N = 28), although cases were also attributed to direct-acting anticoagulants (N = 2), antiplatelet medications (N = 1), heparin or enoxaparin (N = 4), and disseminated intravascular coagulopathy (N = 6). Morphologically, there was acute tubular necrosis and RBC casts. The majority of biopsies had an underlying glomerular disease and many patients had positive serologic test results. In all these cases, the severity of kidney failure, RBC casts, and hematuria were disproportionate to glomerular morphologic changes. Limitations: Selection bias in the decision to perform a kidney biopsy. Conclusions: ARN is an uncommon diagnosis in kidney pathology practice, but it should be considered when the number of RBC casts is disproportionate to the severity of glomerular changes in a kidney biopsy in patients either receiving anticoagulation therapy or who presented with acute coagulopathy. Our data suggest that anticoagulation aggravates underlying glomerular diseases rather than directly affecting the glomerular filtration barrier. n 2009, we described the first patient we had identified who presented with acute kidney injury (AKI) while being treated with warfarin. The patient had a supratherapeutic international normalized ratio (INR) before the AKI. Kidney biopsy showed acute tubular necrosis (ATN) with occlusive red blood cell (RBC) tubular casts.1 The glomerular changes alone could not explain this severe glomerular hematuria. After searching our renal pathology database, 8 other patients with similar clinical presentation were identified. These patients also were receiving warfarin therapy with high INRs (>3.0) and had ATN and glomerular hematuria (defined by RBCs in Bowman space and RBC tubular casts and acanthocytes in urine sediment) that were unexplained by other morphology findings.1 This AKI associated with a high INR initially was named warfarin-related nephropathy. Two subsequent retrospective studies by our group described warfarin-related nephropathy in patients both with and without chronic kidney disease.2,3 Warfarin-related nephropathy was demonstrated in animal models, including a 5/6 nephrectomy rat chronic kidney disease model and in these experiments, in the setting of anticoagulation with vitamin K antagonists, animals showed morphologic futures Complete author and article information provided before references. Correspondence to S.V. Brodsky (sergey. brodsky@hotmail.com) Kidney Med. XX(XX):1-6. Published online Month X, XXXX. doi: 10.1016/ j.xkme.2019.03.002 © 2019 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is an open access article under the CC BYNC-ND license (http:// creativecommons.org/ licenses/by-nc-nd/4.0/). of warfarin-related nephropathy similar to human disease, including ATN and glomerular hemorrhage.4,5 Later it was demonstrated that morphologic features similar to warfarin-related nephropathy may also be seen in 5/6 nephrectomy rats treated with the direct thrombin inhibitor dabigatran.6 This observation and clinical data suggested that such AKI may be associated not only with vitamin K antagonists, but other agents that predispose to bleeding. Accordingly, the term “anticoagulant-related nephropathy” (ARN) is preferred. Since the seminal report of pathologic features of warfarin-related nephropathy,1 several investigators published case reports and retrospective studies showing AKI in association with different anticoagulants, including multiple case reports and case series that describe warfarin-related nephropathy,7-12 several reports of dabigatran-associated AKI,13-17 a case report of AKI in a patient with thrombocytopenia,18 and a case of biopsy-proven ARN in a patient receiving antiplatelet medications.19 Given the existing data for this newly described entity and the presence of multiple causes for anticoagulation, we explored our database of existing kidney biopsies since our initial description of ARN to describe ARN in Kidney Med Vol XX | Iss XX | Month 2019 FLA 5.5.0 DTD XKME12_proof 14 March 2019 4:58 pm ce 1 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 Original Research 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 greater detail, including agents that may predispose to this unusual cause of AKI. METHODS This study was deemed exempt from the need for informed consent.20 We reviewed The Ohio State University Wexner Medical Center Renal and Transplant Pathology Laboratory Database between January 1, 2009, and December 31, 2017, for the following key words: “nephropathy,” “warfarin,” or “anticoagulant,t” or “coagulation.” Kidney biopsy pathology reports were deidentified and reviewed along with the clinical history and list of medications. Criteria for warfarin-related nephropathy (ARN) included history of anticoagulation and/ or coagulopathy, clinical presentation with AKI, and RBC casts in the kidney biopsy. Slides stained with hematoxylin and eosin were blindly reviewed by a renal pathologist (S.V.B.) and the percentage of RBC tubular casts was evaluated for each individual case. Interstitial fibrosis and tubular atrophy were estimated using a semiquantitative scale of 0 to 3 on slides stained with double periodic acid–Schiff/trichrome stain.21 Statistical analysis was performed using GraphPad Prizm 5.0 software (GraphPad Software). Data are presented as mean ± standard deviation, unless specified otherwise. RESULTS There were 8,636 native kidney biopsy cases in the Renal Pathology database between January 1, 2009, and December 31, 2017. We identified 57 kidney biopsy reports that contained the keywords “nephropathy,” “warfarin,” or “anticoagulant,” or “coagulation.” After reviewing kidney biopsy pathology reports, clinical history, and medications, 48 (0.6%) patients for whom deterioration in kidney function could not be explained by kidney biopsy findings alone if anticoagulation was not considered were included in the study. Among those, 7 patients had AKI and increased hematuria that were associated with anticoagulation, but kidney biopsies from those patients did not contain RBC tubular casts, making the diagnosis of glomerular bleeding uncertain. Because of the lack of RBC tubular casts in the kidney biopsy specimens, these 7 patients were excluded from further analyses, resulting in a final study population of 41 (0.5%) patients. Warfarin-related nephropathy (or ARN) was suggested in >6.3% of native kidney biopsies per year in the first 4 years of this study (2009-2012), whereas since 2014, such diagnosis was suggested in w4.3% of the native kidney biopsies, decreasing w33%. Demographic characteristics and clinical data for these patients are shown in Table 1 stratified by the cause of coagulopathy. There were 26 (63%) men, and most patients (95%) were white. Average age of the cohort was 62 ± 14 years. Mean body weight was 103.7 ± 29.3 kg, mean systolic blood pressure was 130 ± 17 mm Hg, and mean diastolic blood pressure was 75 ± 11 mm Hg. Twenty-eight (68%) were receiving warfarin (INR before AKI was 5.6 ± 6.0), 1 (3%) was receiving combined clopidogrel/aspirin, 4 (10%) were receiving heparin (2, unfractionated heparin; and 2, enoxaparin), and 2 (5%) were receiving the factor Xa inhibitor apixaban. Six (15%) patients did not have records of anticoagulation therapy, but they had acute coagulopathy (such as disseminated intravascular coagulation syndrome) at the time of deterioration of kidney function and their biopsy findings were consistent with ARN. Table 1. Clinical and Demographic Data in Patients With ARN Based on the Anticoagulation Used Anticoagulation Demographic and Clinical Data Age, y Sex (male/female) Race (W/AA) Weight, kgb Reason for anticoagulation (AF/DVT/APLS)b Common comorbid conditionsc Diabetes mellitus Hypertension Positive ANCA SLE Baseline Scr, mg/dL Peak Scr at AKI diagnosis, mg/dL Warfarin/DOAC (n = 30) 61.2 ± 15.6 18/12 (60%/40%) 25/2 (93%/7%)b 99.4 ± 22.5 19/6/2 Othera (n = 11) 65.5 ± 10.8 8/3 (73%/37%) 10/0b 114.6 ± 42.6 1/2/0 4 (13%) 7 (23%) 7 (23%) 1 (3%) 1.29 ± 0.4 4.16 ± 2.0 2 (18%) 2 (18%) 3 (27%) 2 (18%) 1.17 ± 0.4 4.82 ± 2.4 Note: Values expressed as mean ± standard deviation or number (percent). Abbreviations: AA, African American; AF, atrial fibrillation; AKI, acute kidney injury; ANCA, antineutrophil cytoplasmic antibodies; APLS, antiphospholipid antibody syndrome; ARN, anticoagulant-related nephropathy; DOAC, direct-acting oral anticoagulant; DVT, deep vein thrombosis; Scr, serum creatinine; SLE, systemic lupus erythematous; W, white. a Other anticoagulation/coagulopathy included 1 patient using antiplatelet medications, 4 using heparin/enoxaparin, and 6 patients with disseminated intravascular coagulopathy. b Data are not available for some patients. c Some patients have more than 1 comorbid condition. 2 Kidney Med Vol XX | Iss XX | Month 2019 FLA 5.5.0 DTD XKME12_proof 14 March 2019 4:58 pm ce 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 Original Research Table 2. Histologic Findings in Kidney Biopsies With Diagnosis Suggestive of ARN Q3 Q9 281 Anticoagulation Q11 282 Histologic Findings Warfarin/DOAC (n = 30) Othera (n = 11) Q10 283 Glomerular lesions 284 1 (6%) IgA-predominant immune complexes in 13 (43%) 285 glomeruli (nonmembranous) 286 2 (12%) IgG-predominant immune complexes in 3 (10%) 287 glomeruli (nonmembranous) 288 4 (24%) Pauci-immune crescentic glomerulonephritis 4 (13%) 1 (6%) Focal segmental glomerulosclerosis 3 (10%) 289 1 (6%) Lupus nephritis ISN/RPS class I or II 2 (7%) 290 1 (6%) Diabetic glomerulosclerosis 1 (3%) 291 1 (6%) Other 4 (13%) 292 No. of glomeruli in biopsy specimen 293 Total 27.9 ± 18.2 37.1 ± 28.7 294 Globally sclerotic 3.3 ± 3.3 3.7 ± 4.1 295 0.27 ± 0.6 (1%)b Cellular crescents 1.47 ± 3.0 (4%)b 296 IFTAc 1.8 ± 0.5 1.8 ± 0.6 297 Tubules with red blood cell casts 20.0 ± 16.6 12.7 ± 9.6 298 Abbreviation: ARN, anticoagulant-related nephropathy; DOAC, direct-acting oral anticoagulant; IFTA, interstitial fibrosis and tubular atrophy; IgA, immunoglobulin A; 299 ISN/RPS, International Society of Nephrology/Renal Pathology Society. a Other anticoagulation/coagulopathy included 1 patient using antiplatelet medications, 4 using heparin/enoxaparin. and 6 with disseminated intravascular coagul300 opathy. 301 b Percentage of glomeruli with open capillary loops. c On a semiquantitative scale of 0 to 3: 0 = no IFTA, 1 = 0% to 24% IFTA, 2 = 25% to 49% IFTA, and 3 = 50% to 100% IFTA. 302 303 Among the common comorbid conditions, the most glomerular findings, including one with membranous 304 frequent was positive antineutrophil cytoplasmic antibody glomerulonephritis, 1 with fibrillary glomerulone- 305 (ANCA; in 11 (27%) patients, including 7 with peri- phritis, 1 with mild C3-containing deposits, and 2 bi- 306 nuclear ANCA, 2 with cytoplasmic ANCA, 1 with both opsies with no specific glomerular lesions but 307 perinuclear and cytoplasmic ANCA, and 1 with atypical moderately to prominently enlarged glomeruli. All bi- 308 ANCA). Nine (22%) patients had a clinical history of hy- opsies had features of ATN and RBC casts in the tubules 309 pertension, 6 (15%) had diabetes mellitus type 2, and 3 (Fig 1). On average, 18.0% ± 15.0% of tubules had RBC Q4310 (8%) had systemic lupus erythematous. No comorbid casts. Interstitial fibrosis and tubular atrophy were on 311 condition data were available for 2 patients. Serum creat- average moderate (1.8 ± 0.7 on the scale of 0-3). Focal 312 inine levels had increased from 1.25 ± CC mg/dL at mild to moderate active-appearing interstitial 313 baseline to 4.33 ± 1.99 mg/dL at the time of kidney bi314 opsy (Table 1). Before the presentation with AKI, all pa315 tients developed either de novo hematuria (from moderate 316 [2+ on dipstick] to gross) or had a significant increase in 317 pre-existing hematuria. 318 Histologic findings from kidney biopsies are pre319 sented in Table 2. In general, biopsies contained 320 33.4 ± 20.6 glomeruli, with 7.0 ± 3.5 (14%) of those 321 globally sclerosed. Active cellular crescents were seen in 322 1.1 ± 2.7 glomeruli (5% of glomeruli with open capil323 lary loops). All patients with a presumed diagnosis of 324 ARN had some glomerular injury. The most common 325 finding was mild immune complex deposition in 326 glomeruli, which was seen in 22 (53%) patients 327 (including 14 [34%] with immunoglobulin A [IgA]328 predominant, 5 (12%) with IgG-predominant de329 posits, and 3 (7%) with nonproliferative (International 330 Society of Nephrology/Renal Pathology Society classes I 331 and II) lupus nephritis. Pauci-immune crescentic Figure 1. Common light microscopy findings in patients with 332 necrotizing glomerulonephritis was diagnosed in 8 anticoagulant-related nephropathy (ARN). In a patient with 333 (20%) patients. Four (10%) patients had focal segmental ARN, red blood cell tubular casts and acute tubular injury are 334 glomerulosclerosis (FSGS), and 2 (5%) had diabetic the common light microscopy morphologic findings. Glomeruli 335 glomerulosclerosis. Five (12%) patients had other usually do not show significant morphologic changes. 336 web 4C=FPO 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 Kidney Med Vol XX | Iss XX | Month 2019 FLA 5.5.0 DTD XKME12_proof 14 March 2019 4:58 pm ce 3 Original Research 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 inflammatory cell infiltrates were noted in 22 (54%) kidney biopsies. Histologic findings stratified by the type of anticoagulation used (warfarin and direct-acting oral anticoagulants vs others) are presented in Table 2. Q5 DISCUSSION Our 10-year study from a single-center pathology laboratory suggests that ARN is an uncommon diagnosis in kidney pathology practice, but that ARN should be considered when the number of RBC casts and/or hematuria is disproportionate to the severity of glomerular changes in a kidney biopsy specimen in patients either receiving anticoagulation therapy or who presented with acute coagulopathy. Our data further suggest that ARN develops in individuals with underlying glomerular diseases rather than directly affecting the glomerular filtration barrier, while reinforcing that any agent or condition resulting in coagulopathy may predispose individuals to ARN. Our study shows that the prevalence of ARN in kidney biopsies was low, at w0.5%. Several possibilities may influence the low prevalence of ARN described here. First, we do not know how many of the native kidney biopsies that we received in our renal pathology laboratory are from patients previously receiving anticoagulation. Therefore, the percentage of patients on anticoagulation therapy who developed ARN cannot be evaluated based on the total number of kidney biopsies. Second, nephrologists (and radiologists) are reluctant to perform a kidney biopsy in a patient on anticoagulation therapy; therefore, the true incidence rate of ARN cannot be determined based on the kidney biopsy database. Third, with the recognition of warfarin-related nephropathy (and ARN), the number of kidney biopsies from patients with AKI on anticoagulation therapy is decreasing because nephrologists now associate AKI with anticoagulation and may be less likely to perform kidney biopsies in such patients. In addition, we recognized 7 patients on anticoagulation therapy who had AKI and significantly increased hematuria, but the kidney biopsy did not show RBC casts. Because the kidney biopsy in these patients did not show RBC casts, although these patients had increased hematuria, we do not have morphologic evidence of glomerular hemorrhage; therefore, the diagnosis of ARN cannot be made with certainty. A sampling error could occur, but this is less likely because in patients with ARN, there is an increased number of RBC casts or tubular RBCs that is disproportional to the glomerular injury or changes (such as mild immune complex deposition or very focal crescentic glomerulonephritis). Therefore, AKI in these patients is probably secondary to other causes. Therefore, Kidney biopsy findings of numerous tubular RBC and/or RBC casts and ATN Diffuse active glomerular disease: - Active crescentic GN with cellular crescents - Immune-complex mediated GN Focal or inactive glomerular disease: - Focal crescentic GN with fibrocellular crescents - Mild immune-complex mediated GN - Thin GBM - LN Class I or II - FSGS NOT ARN Yes Clinical history of: - Anticoagulation with warfarin, INR>3.0 - Recently started anticoagulation with DOAC or other anticoagulants - DIC or other coagulopathy Suspect ARN No - Possible sampling error - Unrecognized coagulopathy - Other conditions Figure 2. Proposed diagnostic algorithm in patients with suspected anticoagulant-related nephropathy (ARN). If a kidney biopsy shows numerous red blood cells (RBCs) in tubules or RBC casts without appropriate glomerular injury, clinical history and laboratory data should be reviewed to exclude excessive anticoagulation with warfarin (international normalized ratio [INR] > 3.0), new onset of anticoagulation therapy, or coagulopathy (although the current terminology is ARN, our data suggest that patients with underlying coagulopathy such as disseminated intravascular coagulopathy [DIC] may experience glomerular hemorrhage and ARN-like findings in the kidney biopsy). Abbreviations: ATN, acute tubular necrosis; DOAC, direct-acting oral anticoagulant; FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; GN, glomerulonephritis; LN, lupus nephritis. 4 Kidney Med Vol XX | Iss XX | Month 2019 FLA 5.5.0 DTD XKME12_proof 14 March 2019 4:58 pm ce 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 Original Research 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 at this moment, the diagnosis of ARN is reserved only for cases in which an excessive number of RBC casts is present in a kidney biopsy. Our data reinforce prior findings that ARN develops in patients with underlying glomerular diseases. We identified multiple different pathologic changes in glomeruli. The spectrum of these changes is broad, from cellular crescents to glomerular enlargement. The most common pathologic finding, seen in more than half the biopsies, was mild immune complex deposition in glomeruli. These glomeruli had mild segmental immune complex deposits (most commonly IgA, but including some patients with class I or II lupus nephritis) and did not show significant proliferative lesions by light microscopy. Therefore, the presence of numerous RBC tubular casts could not be explained just by these glomerular findings. The second most common finding was focal crescentic glomerulonephritis (usually pauci-immune). Although RBC tubular casts are a hallmark of crescentic glomerulonephritis, the number of RBC tubular casts in these patients was significantly higher than the number of glomeruli with crescents, suggesting that anticoagulation played a role in the formation of this excessive number of RBC tubular casts. Other glomerular diseases included FSGS, diabetic glomerulosclerosis, and others such as membranous glomerulonephritis and C3 deposits. In all these cases, AKI was associated either with excessive anticoagulation (INR > 3.0) or the initiation of anticoagulation therapy (such as in patients with heparinor apixaban-associated AKI). Therefore, we propose that rather than directly affecting the glomerular filtration barrier, excessive anticoagulation aggravates an underlying glomerular disease and increases glomerular hematuria, which leads to the formation of RBC casts and ATN. Several patients with pauci-immune crescentic glomerulonephritis did not have clinical symptoms of this disease until they initiated anticoagulation therapy, but kidney biopsy specimens from these patients showed fibrocellular and fibrous crescents, indicating chronic disease. In some patients, RBC casts do not form (or may be not seen in the kidney biopsy due to sampling issues), but those patients have increased hematuria, which results in ATN, possibly through increased oxidative stress.22 Demographically, patients with ARN in our study population were obese, suggesting that glomerular hyperfiltration/hyperperfusion plays a significant role in the pathogenesis of ARN. We modeled ARN in a warfarintreated 5/6 nephrectomy rat model that is characterized by glomerular hyperfiltration/hyperperfusion.4-6 These animals developed ARN within 3 weeks after the ablative surgery, much earlier than changes of FSGS could be seen histologically.4,6 The major limitation of the current study is selection bias in the decision to perform biopsy on patients with AKI who are on anticoagulation therapy. Nephrologists are reluctant to perform biopsy on such patients, and sometimes only other laboratory data (such as positive ANCA results) may prompt the biopsy decision. However, the number of biopsies with ARN decreased as the nephrology and pathology community became more aware that AKI may be associated with anticoagulation therapy, potentially resulting in an empiric clinical diagnosis without a kidney biopsy, particularly in individuals with high INRs. Clinical features of ARN and a suggested algorithm for the evaluation of patients receiving anticoagulation who present with AKI were recently described by our group.23 In conclusion, ARN is an uncommon diagnosis in renal pathology practice, but it should be considered when there is a disproportion between the severity of glomerular changes and number of RBC casts and/or hematuria in a kidney biopsy in patients on anticoagulant therapy or who presented with acute coagulopathy (Fig 2). The glomerular changes in patients with suspected ARN are insufficient to explain the occurrence of substantial blood and RBC casts in tubules, but the high prevalence of underlying glomerular diseases and obesity suggests that ARN may be most likely to occur in individuals with pre-existing glomerular damage increasing their susceptibility to glomerular bleeding in the setting of systemic anticoagulation or other coagulopathy. ARTICLE INFORMATION Authors’ Full Names and Academic Degrees: Sergey V. Brodsky, MD, PhD, Anjali Satoskar, MD, Jessica Hemminger, MD, Brad Rovin, MD, Lee Hebert, MD, Margaret (Maggie) S. Ryan, MD, and Tibor Nadasdy, MD, PhD. Authors’ Affiliations: Departments of Pathology (SVB, AS, JH, TN) and Medicine (BR, LH), Ohio State University, Columbus, OH; and Department of Pathology, Mayo Clinic, Scottsdale, AZ (MSR). Address for Correspondence: Sergey V. Brodsky, MD, PhD, Department of Pathology, The Ohio State University, 333 W 10th Ave, Graves Hall, B078, Columbus, OH 43210. E-mail: sergey. brodsky@hotmail.com Authors’ Contributions: Research idea and study design: SVB, LH, TN; data acquisition: SVB, AS, JH, MR; data analysis/interpretation: SVB, BR, LH, TN; statistical analysis: SVB; MR, JH; supervision or mentorship: BR, LH, TN. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. Support: This study partially was supported by National Institutes of Health grant DK117102 to Dr Brodsky. The funder had no role in study design; data collection, analysis, or reporting; or the decision to submit for publication. Financial Disclosure: The authors declare that they have no relevant financial interests. Peer Review: Received December 5, 2018. Evaluated by 2 external peer reviewers, with direct editorial input from the Editor-in-Chief. Accepted in revised form March 4, 2019. REFERENCES 1. 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. Kidney Med Vol XX | Iss XX | Month 2019 FLA 5.5.0 DTD XKME12_proof 14 March 2019 4:58 pm ce 5 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 Q6 546 Q12 547 548 549 550 551 552 553 554 555 556 557 558 559 560 Original Research 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 2. Brodsky SV, Collins M, Park E, et al. Warfarin therapy that results in an international normalization ratio above the therapeutic range is associated with accelerated progression of chronic kidney disease. Nephron Clin Pract. 2010;115(2): c142-c146. 3. 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. 4. Ozcan A, Ware K, Calomeni E, et al. 5/6 nephrectomy as a validated rat model mimicking human warfarin-related nephropathy. Am J Nephrol. 2012;35(4):356-364. 5. Ware K, Brodsky P, Satoskar AA, et al. Warfarin-related nephropathy modeled by nephron reduction and excessive anticoagulation. J Am Soc Nephrol. 2011;22(10):1856-1862. 6. Ryan M, Ware K, Qamri Z, et al. Warfarin-related nephropathy is the tip of the iceberg: direct thrombin inhibitor dabigatran induces glomerular hemorrhage with acute kidney injury in rats. Nephrol Dial Transplant. 2014;29(12):2228-2234. 7. Larpparisuth N, Cheunsuchon B, Chawanasuntorapoj R, et al. Warfarin related nephropathy: the first case report in Thailand. J Med Assoc Thailand. 2015;98(2):212-216. 8. Zerah L, Brocheriou I, Galichon P, et al. [Warfarin-related nephropathy: a case report]. Rev Med Intern. 2015;36(1):51-54. 9. An JN, Ahn SY, Yoon CH, et al. The occurrence of warfarinrelated nephropathy and effects on renal and patient outcomes in Korean patients. PloS One. 2013;8(4):e57661. 10. Mendonca S, Gupta D, Valsan A, et al. Warfarin related acute kidney injury: a case report. Indian J Nephrol. 2017;27(1):78-80. 11. Mendonca S, Valsan AK. Warfarin induced glomerulonephropathy. J Assoc Physicians India. 2016;64(1):125. Q7 12. Piran S, Traquair H, Chan N, et al. Incidence and risk factors for acute kidney injury in patients with excessive anticoagulation on warfarin: a retrospective study. J Thromb Thrombolysis. 2018;45(4):557-561. 6 13. Sharfuddin N, Nourbakhsh M, Box A, et al. Anticoagulant related nephropathy induced by dabigatran. Case Rep Neph617 rol. 2018;2018:7381505. 618 14. Kadiyala D, Brewster UC, Moeckel GW. Dabigatran induced 619 acute kidney injury. Paper presented at: American Society of 620 Nephrology Annual Meeting; November 1-4, 2012; San Diego, 621 CA. FR-PO1122. 15. Moeckel GW, Luciano RL, Brewster UC. Warfarin-related ne622 phropathy in a patient with mild IgA nephropathy on dabigatran 623 and aspirin. Clin Kidney J. 2013;6(5):507-509. 624 16. Shafi ST, Negrete H, Roy P, et al. A case of dabigatran625 associated acute renal failure. WMJ. 2013;112(4):173-175. 626 quiz 176. 17. Li X, Cheung CY. Dabigatran causing severe acute kidney injury Q8 627 628 in a patient with liver cirrhosis. CEN Case Rep. 2019. 18. Medani CR, Pearl PL, Hall-Craggs M. Acute renal failure, he629 molytic anemia, and thrombocytopenia in poststreptococcal 630 glomerulonephritis. South Med J. 1987;80(3):370-373. 631 19. Kratka K, Havrda M, Honsova E, et al. Bioptically proven 632 "anticoagulation-related nephropathy" induced by dual anti633 platelet therapy. Case Rep Nephrol Dial. 2018;8(3):216-222. 634 20. US Department of Health and Human Services. Protection of 635 human subjects. Code of Federal regulations 45: Public welfare 1995; Title 45(Sections 46-101 to 46-409): Revised 636 January 15, 2009. 637 21. Brodsky SV, Albawardi A, Satoskar AA, et al. When one plus 638 one equals more than two–a novel stain for renal biopsies is a 639 combination of two classical stains. Histol Histopathol. 640 2010;25(11):1379-1383. 641 22. Ware K, Qamri Z, Ozcan A, et al. N-Acetylcysteine ameliorates 642 acute kidney injury but not glomerular hemorrhage in an animal model of warfarin-related nephropathy. Am J Physiol Renal 643 Physiol. 2013;304(12):F1421-F1427. 644 23. Brodsky S, Eikelboom J, Hebert LA. Anticoagulant-related ne645 phropathy. J Am Soc Nephrol. 2018;29(12):2787-2793. Kidney Med Vol XX | Iss XX | Month 2019 FLA 5.5.0 DTD XKME12_proof 14 March 2019 4:58 pm ce 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672