Anticoagulant-related nephropathy

INTRODUCTION — 

Anticoagulant-related nephropathy (ARN; previously referred to as warfarin-related nephropathy) is a type of acute kidney injury (AKI) that may be caused by excessive anticoagulation with warfarin or a direct oral anticoagulant (DOAC) [1,2]. ARN has been associated with irreversible kidney injury in some patients and with increased risk of mortality.

This topic reviews the epidemiology, pathogenesis, clinical features, and treatment of ARN. The differential diagnosis of AKI, glomerulonephritis, and hematuria are discussed elsewhere:

●(See "Evaluation of acute kidney injury among hospitalized adult patients".)

●(See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting".)

●(See "Glomerular disease: Evaluation and differential diagnosis in adults".)

●(See "Evaluation of hematuria in adults".)

EPIDEMIOLOGY

Incidence — The incidence of ARN is difficult to determine. This is because studies that have examined incidence have relied upon a presumptive diagnosis of ARN (defined by an elevation in the serum creatinine within several days of an abnormally elevated International Normalized Ratio [INR]) rather than a more definitive diagnosis (defined by biopsy) [3-5]. (See 'Diagnosis' below.)

Studies have suggested that an increase in serum creatinine above baseline is observed in approximately 17 percent of warfarin-treated patients who do not have underlying chronic kidney disease (CKD) and who have an elevated INR >3 [4,5].

However, it is not clear that the increase in creatinine was related to ARN in these studies [4,5]. Studies were based on review of charts or administrative data (such as diagnostic codes). Thus, other possible causes of acute kidney injury (AKI) were not rigorously excluded, and biopsies were not performed. In addition, in contrast to the landmark biopsy study cited above, in which all nine cases had hematuria [6], hematuria was absent in many patients in the large, retrospective series [4]. (See 'Pathogenesis and histology' below.)

Thus, in the absence of biopsy data, epidemiologic studies probably overestimated the incidence of ARN. Incidence was also overestimated by ascertainment bias since the detection of AKI was dependent upon having the serum creatinine measured within one week of the elevated INR; sicker patients are more likely to have creatinine measured and are also more likely to develop ARN. (See 'Risk factors' below.)

However, in practice, ARN may be underdiagnosed because of two major reasons:

●Generally, nephrologists are reluctant to perform kidney biopsy in patients who need therapeutic anticoagulation. This is because of concerns related to the risk of thrombosis/thromboembolism while systemic anticoagulation is held and to the risk of hemorrhage from the kidney biopsy site after the systemic anticoagulants are restarted.

Concerns regarding the risk of hemorrhage may be heightened in the patient whose AKI occurred in a setting of recent over-anticoagulation, which is the situation typical of ARN. In such cases, the biopsy is often delayed until the INR returns to a therapeutic range. Since, in ARN, the creatinine often improves or stabilizes when the INR returns to a therapeutic range, the clinician may conclude that a biopsy is no longer needed.

●The possibility of ARN may be overlooked because it is most common among patients who have multiple risk factors for AKI from any cause, and AKI may be attributed to other causes. For example, patients at highest risk for ARN are those with underlying CKD and heart disease. CKD and heart disease both predispose to AKI from any cause and are often treated with therapies that can cause AKI (such as angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], diuretics, and low-salt diet). (See 'Risk factors' below and "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults", section on 'Etiology'.)

In such patients, episodes of AKI are often attributed to multifactorial causes, and extensive diagnostic evaluation is not performed. (See "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults", section on 'Etiology'.)

Also, the prevalence of ARN may be low even though the incidence is high. This may add to the perception that it is an uncommon problem. Most of the described episodes of potential ARN occurred in the first eight weeks after initiating anticoagulation [3,4]. In these studies, approximately 30 percent of patients with CKD and ARN died within approximately one month after the onset of ARN, thus reducing the prevalence [4].

Risk factors — Risk factors for ARN are as follows:

●Coagulopathy – The major risk factor for ARN is moderate or severe coagulopathy induced by warfarin or other anticoagulants, including direct thrombin inhibitors (dabigatran) or factor Xa inhibitors (eg, apixaban) [1,7-10]. The severity of the coagulopathy required to cause ARN is not known. Most commonly, the INR in patients with warfarin-mediated ARN is in the 4s [3-5]. Some patients with warfarin-mediated ARN may present with INR levels in the therapeutic range [11]; however, we consider it likely that such patients had undetected, higher INR values that preceded the development of AKI.

●Chronic kidney disease – The risk of ARN may be higher among patients with underlying CKD [3-5,12-16]. In one study cited above, presumed ARN occurred in 34 percent of patients who had CKD at baseline [4]. In another retrospective analysis of 49 warfarin-treated CKD patients who had at least one episode of INR >3, 37 percent developed an increase in serum creatinine ≥0.3 mg/dL within one week of their first INR >3 [3]. This reported incidence is higher than the reported incidence of 17 percent among warfarin-treated patients who do not have underlying CKD [4,5]. (See 'Epidemiology' above.)

In one case series of 26 patients with ARN, IgA nephropathy was the most common cause of underlying CKD, observed in 19 (73 percent) of patients [17].

Other proposed risk factors include older age (ie, >80 years), male sex, diabetes mellitus, heart failure, hypertension, and glomerulonephritis, particularly with nephrotic syndrome [3-5,16].

PATHOGENESIS AND HISTOLOGY — 

The predominant lesion of ARN is tubular injury and obstruction with red blood cells (RBCs) and RBC casts [6].

●Pathogenesis – Our understanding of pathogenesis is based upon histologic analysis of kidney tissue obtained by biopsy and on experiments in animal models [6,18,19]. The pathogenesis of ARN is likely multifactorial and includes:

•Glomerular hemorrhage

•Obstruction of renal tubules by RBC casts

•Tubular epithelial cell injury

The initiating event appears to be glomerular hemorrhage, caused by excessive anticoagulation due to warfarin or other anticoagulants [1,7]. Structurally abnormal glomerular barriers, such as are present in thin basement membrane disease or thick basement membrane disease, are especially vulnerable to hemorrhage [20,21].

Glomerular hemorrhage results in the formation of obstructing RBC casts within renal tubules. Obstructing intraluminal RBC casts are the most conspicuous histologic feature of ARN in tissue obtained from patients who have undergone biopsy [6] and in animal models [18,19].

However, the number of obstructed tubules observed on microscopy does not appear sufficient to explain the decrease in the glomerular filtration rate (GFR). In both patients and animals with ARN, only a small percentage of tubules in any given histologic section show complete obstruction with RBC casts [20-22].

One explanation for this is that analysis by microscopy underestimates the total number of obstructed tubules since only a very small cross section of any given tubule can be viewed on a slide. Tubules that do not appear obstructed in one histologic section could be completely obstructed at a section of the tubule that is either proximal or distal to the section being examined.

Another explanation is that, in addition to obstruction, glomerular hemorrhage resulting from anticoagulation causes pervasive tubular injury. This hypothesis is supported by evidence that glomerular hemorrhage and/or hemoglobinuria are associated with tubular epithelial cell injury in patients with immunoglobulin A (IgA) nephropathy [23-25] or paroxysmal nocturnal hemoglobinuria [26,27]. Tubular injury may be caused, at least in part, by oxidative activity of heme and iron [28-31] and elevated intra-renal levels of reactive oxygen species mediated by plasminogen activated inhibitor-1 (PAI-1) [32]. Alternatively, anticoagulants may be directly toxic to renal tubules [22].

●Histologic features – The major histologic feature of ARN is obstruction of renal tubules (mainly distal) by RBC casts (picture 1) [6]. The glomeruli show little or no abnormalities by light, immunofluorescence, or electron microscopy other than the feature of an underlying condition if present [6].

CLINICAL PRESENTATION — 

ARN is usually characterized by the following features:

●Acute kidney injury (AKI) occurring shortly after initiation of anticoagulation therapy (ie, <8 weeks) [3-5,8,33]. Based on clinical observations [4] and animal models, only a few days of coagulopathy are needed to cause ARN [4,18].

●Supratherapeutic International Normalized Ratio (INR) among patients treated with warfarin. In various studies, the average INR among patients with warfarin-mediated ARN was in the mid to upper 4s [3-6]. Patients taking direct oral anticoagulants (DOACs), such as dabigatran, may have INR levels in the normal range [1,9].

●Hematuria, especially with evidence of a glomerular source (ie, dysmorphic red blood cells (RBCs) or RBC casts on analysis of the urinary sediment) [6,20,34]. Microscopic hematuria is more common than gross hematuria [3,4,6].

●Proteinuria of varying severity. Studies of ARN that have examined proteinuria included only patients with underlying chronic kidney disease (CKD) [6,20,34]. Thus, it is not clear whether ARN in the absence of underlying CKD causes significant abnormal proteinuria.

Other presenting features depend on the severity of AKI. Patients with severe AKI (ie, marked reduction in the glomerular filtration rate [GFR]) may present with hypertension, signs of volume overload, and reduced urine output [20,21]. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting", section on 'Clinical manifestations'.)

DIAGNOSIS

When to suspect anticoagulant-related nephropathy — The diagnosis of ARN should be suspected among patients who present with acute kidney injury (AKI) in the setting of excessive anticoagulation, especially if no other cause of AKI is readily apparent.

Diagnostic evaluation — Because AKI in patients taking anticoagulants is often not due to ARN, patients should be evaluated thoroughly for other causes of AKI using a similar approach as that for patients not taking anticoagulants. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting" and "Evaluation of acute kidney injury among hospitalized adult patients".)

In patients with suspected ARN and hematuria, laboratory testing should be performed to evaluate potential causes of glomerulonephritis (see 'Differential diagnosis' below). These specific tests are discussed elsewhere. (See "Glomerular disease: Evaluation and differential diagnosis in adults", section on 'Evaluation of glomerulonephritis'.)

Establishing the diagnosis — A definitive diagnosis of ARN is made by kidney biopsy (see 'Pathogenesis and histology' above). However, biopsies are usually not performed, at least initially, among patients who are anticoagulated, because the risk of bleeding is high. Criteria for a presumptive diagnosis of ARN and the role of kidney biopsy are discussed below.

●Presumptive diagnosis – We make a presumptive diagnosis of ARN in patients who meet both of the following criteria:

•Alternative causes of AKI have been excluded by clinical features and serologic tests. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting", section on 'Overview'.)

•Clinical or laboratory evidence of a severe coagulopathy:

-In patients taking warfarin, a supratherapeutic International Normalized Ratio (INR) or evidence of abnormal bleeding outside the urinary tract. Although the severity of the coagulopathy required to cause ARN is not known, the INR is usually >4 [3-6]. However, in some patients, the coagulopathy may have already been corrected by the time AKI comes to attention.

-In patients taking direct oral anticoagulants (DOACs), who may have a normal INR, evidence of abnormal bleeding outside the urinary tract. In the case reports describing ARN associated with dabigatran, patients had obvious hemorrhage from multiple sites [1,7,9].

We do not believe the absence of hematuria excludes a possible diagnosis of ARN. Hematuria has not been universally described in all patients with presumed ARN [3,4], and the absence of hematuria has been observed in animal models [18,19]. It is possible that hematuria is transient and not detected in all patients at the time of presentation with AKI. This may be due to the fact that nephrons with hemorrhaging glomeruli are shut down by red blood cell (RBC) tubular casts or acute tubular injury by the time patients came to clinical attention.

●Role of kidney biopsy – A presumptive diagnosis of ARN precludes, at least initially, the need for a biopsy. However, a kidney biopsy is warranted if any of the following conditions apply:

•The serum creatinine continues to increase or remains stably elevated above the patient's baseline, even though the coagulopathy has been restored to a therapeutic range. Among most patients with ARN, the serum creatinine will improve slightly within the first few weeks after restoration of a therapeutic INR. Continued increase of the creatinine restoration of a therapeutic INR suggests that another cause of AKI is present.

•Hematuria persists or emerges after restoration of a therapeutic INR. Hematuria that persists despite this suggests that the patient may have an underlying glomerulonephritis [3,35,36] or abnormally thin [21] or thick glomerular basement membrane [20].

Such patients should undergo a kidney biopsy for diagnosis. The coagulopathy must be reversed prior to biopsy in order to minimize the risk of bleeding.

Differential diagnosis — The differential diagnosis of AKI in patients with excessive anticoagulation is broad and depends on findings on the urinalysis:

●Patients with hematuria – Patients with hematuria, particularly those with urinary sediment findings of dysmorphic RBCs or RBC casts, may have glomerulonephritis. Although there are a number of reasonably sensitive and specific tests for the glomerulonephritides, a kidney biopsy may be necessary to distinguish among ARN, glomerulonephritis, and other kidney diseases. (See 'Establishing the diagnosis' above and "Glomerular disease: Evaluation and differential diagnosis in adults".)

●Patients without hematuria – As noted above, some patients may present without hematuria. Among such patients, one should consider prerenal and urinary tract obstruction.

•Prerenal AKI – Prerenal disease caused by volume depletion may be excluded by history (absence of vomiting, diarrhea, decreased oral intake) and occasionally by a trial of volume repletion. (See "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults", section on 'Evaluation and diagnosis'.)

•Urinary tract obstruction – Urinary tract obstruction may be excluded with a kidney ultrasound. (See "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis".)

Other causes of AKI with a benign urine sediment include hypercalcemia, acute phosphate nephropathy, acute high-dose use of nonsteroidal antiinflammatory drugs (NSAIDS) or acetaminophen, crystal-induced nephropathy (eg, urate from acute overproduction or oxalate from acute high intake), and myeloma cast nephropathy. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting", section on 'Overview'.)

TREATMENT — 

There are no prospective studies to specifically inform the management of the patient who develops unexplained acute kidney injury (AKI) while receiving oral anticoagulant therapy. In addition to the supportive care provided for all patients with AKI (see "Overview of the management of acute kidney injury (AKI) in adults"), treatment consists of the following:

●Correcting excess anticoagulation – For patients with a presumptive diagnosis of ARN, we correct excess anticoagulation. Our strategy depends on whether presumptive ARN occurs in the setting of warfarin or direct oral anticoagulant (DOAC) therapy:

•Patients on warfarin – The optimal method for correcting excess anticoagulation after the use of warfarin (eg, returning an increased International Normalized Ratio [INR] to the therapeutic range) generally depends upon the degree of INR elevation, the indication for anticoagulation, and whether clinically significant nonglomerular bleeding is present. This approach is detailed elsewhere. (See "Management of warfarin-associated bleeding or supratherapeutic INR" and "Anticoagulation for prosthetic heart valves: Management of bleeding and invasive procedures".)

•Patients on a DOAC – The reversal of coagulopathy induced by DOACs depends on the severity of nonglomerular bleeding, and is discussed elsewhere (see "Management of bleeding in patients receiving direct oral anticoagulants"). In two case reports of patients taking dabigatran, administration of the reversal agent idarucizumab was associated with resolution of ARN [37,38].

●Modifying anticoagulant therapy when feasible – For patients with presumptive or biopsy confirmed ARN in whom modifying long-term anticoagulant therapy is clinically feasible (eg, a patient with atrial fibrillation), we take the following approach [39]:

•If the patient is taking warfarin, we switch to a DOAC.

•If the patient is taking a DOAC, we lower the dose.

The use of glucocorticoids in the treatment of ARN has been suggested but is unproven [40].

OUTCOME — 

In most patients with ARN, the serum creatinine stabilizes or improves slightly within the first few weeks after correction of the warfarin coagulopathy. However, many patients may have little or no recovery of kidney function [6,41]. In case series of biopsy proven ARN, the proportion of patients who had a full recovery from AKI ranged between 24 and 44 percent [6,17,41].

Presumptive ARN has been associated with an increase in mortality independent of age, sex, race, hemorrhage, atrial fibrillation, heart failure, and diabetes mellitus [4,5]. In the study of 4006 patients with an elevated International Normalized Ratio (INR) >3, patients who developed presumptive ARN had decreased five-year survival compared with those without (58 versus 73 percent, respectively). The sharpest reduction in survival occurred during the first few weeks after the INR increase in this study (figure 1).

PREVENTION — 

The most important measure to prevent ARN is proper adjustment of the anticoagulant dose. This is particularly important for patients with chronic kidney disease (CKD), who are more vulnerable to ARN. (See 'Epidemiology' above and 'Risk factors' above.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute kidney injury in adults".)

SUMMARY AND RECOMMENDATIONS

●Overview – Anticoagulant-related nephropathy (ARN) is a type of acute kidney injury (AKI) that may be caused by excessive anticoagulation with warfarin or a direct oral anticoagulant (DOAC). The risk of ARN may be higher among patients with underlying chronic kidney disease. The pathogenesis of ARN includes glomerular hemorrhage and obstruction of renal tubules by red blood cell (RBC) casts. (See 'Risk factors' above and 'Pathogenesis and histology' above.):

●Clinical presentation – ARN is usually characterized by the following features (see 'Clinical presentation' above):

•AKI occurring shortly after initiation of anticoagulation therapy (ie, <8 weeks).

•Supratherapeutic International Normalized Ratio (INR) among patients treated with warfarin. The average INR among patients with warfarin-mediated ARN is in the mid to upper 4s.

•Hematuria, especially with evidence of a glomerular source (ie, dysmorphic RBCs or RBC casts on analysis of the urinary sediment).

●Diagnosis – A definitive diagnosis is made by kidney biopsy. However, biopsies are usually not performed, at least initially, among patients who are anticoagulated, because the risk of bleeding is high. A presumptive diagnosis of ARN may be made if other causes of AKI have been excluded by clinical features and serologic tests, and if a severe coagulopathy is or has recently been present. A biopsy may be required for definitive diagnosis if creatinine continues to increase or remains significantly elevated above baseline after coagulopathy is corrected. (See 'Diagnosis' above.)

●Differential diagnosis – Among patients who present with hematuria, the differential diagnosis includes all causes of glomerulonephritis. Among those who present without hematuria, one should consider prerenal and postrenal causes, as well as acute tubular necrosis, and other, less common causes of AKI. (See 'Differential diagnosis' above.)

●Treatment – In addition to the supportive care provided for all patients with AKI (see "Overview of the management of acute kidney injury (AKI) in adults"), treatment of ARN consists of the following:

•Correcting excess anticoagulation

-The optimal method for correcting excess anticoagulation after the use of warfarin generally depends upon the degree of INR elevation, the indication for anticoagulation, and whether clinically significant nonglomerular bleeding is present. (See "Management of warfarin-associated bleeding or supratherapeutic INR" and "Anticoagulation for prosthetic heart valves: Management of bleeding and invasive procedures".)

-The reversal of coagulopathy induced by DOACs depends on the severity of nonglomerular bleeding. (See "Management of bleeding in patients receiving direct oral anticoagulants".)

•Modifying anticoagulant therapy – For patients in whom modifying long-term anticoagulant therapy is clinically feasible (eg, a patient with atrial fibrillation), our approach is as follows (see 'Treatment' above):

-For patients with ARN due to warfarin, we suggest switching to DOAC anticoagulant therapy (Grade 2C).

-For patients with ARN due to DOAC therapy, we suggest lowering the DOAC dose (Grade 2C).

●Outcome – In most patients with ARN, the serum creatinine stabilizes or improves slightly within the first few weeks after correction of the warfarin coagulopathy. However, many patients have little or no recovery of kidney function. Presumptive ARN has been associated with increased mortality risk. (See 'Outcome' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Lee A Herbert, MD, who contributed to earlier versions of this topic review.