Anticoagulant-related nephropathy (ARN) classically presents with hematuria followed
by acute kidney injury (AKI) during a period of overanticoagulation with supratherapeutic
international normalized ratio (INR). The corresponding renal histology is acute tubular
injury (ATI) associated with red blood cells (RBCs) within the Bowman space and obstructive
tubular RBC casts.
It has been observed that ARN is more common among patients with chronic kidney disease
(CKD), and it was shown to accelerate CKD progression and increase mortality.2, 3,
4 Therapeutic options other than withholding the anticoagulant and reversing its effect
are limited. N-acetyl cysteine and steroids have shown some benefit in experimental
settings, with anecdotal evidence of success in patients.
Anticoagulant-related nephropathy was first described by Atb et al. in a patient taking
warfarin with thin basement membrane disease.
Subsequently, 2 cases of ARN with underlying IgA nephropathy
and systemic lupus erythematosus
were reported. Brodsky et al. coined the term “warfarin-related nephropathy” in a
clinicopathological study of 9 patients.
Since its original description in patients taking warfarin, this entity has been reported
in patients taking all classes of vitamin K antagonists (warfarin, acenocoumarol,
thrombin inhibitors (dabigatran),S1 factor Xa inhibitors (apixaban, rivaroxaban),S2
and dual antiplatelet therapy, and in coagulopathies unrelated to medication.S3
Anticoagulant-related nephropathy, which is well described in native biopsy results,
has not yet been reported in the published literature in a transplant kidney, except
in abstract form.S4 We provide a detailed case report of a patient developing biopsy-proven
ARN in the kidney allograft, and discuss possible pathogenetic mechanisms.
A 61-year-old man, 8 years post−renal transplantation, presented with a 1-day history
of dysuria and graft pain. On examination, he was febrile with a blood pressure of
153/79 mm Hg. Blood investigations showed neutrophil leucocytosis (white cell count
21.9 × 109/l) and raised C-reactive protein (135 mg/l). Serum creatinine (sCr) was
224 μmol/l (baseline 210−230 μmol/l) and INR was 2.5. Urinalysis showed 3+ protein,
3+ blood, 1+ leukocytes, and positive nitrites. Transplant kidney ultrasound showed
a globally well-perfused, unobstructed kidney. Intravenous fluids and empirical treatment
with temocillin and vancomycin were commenced for urosepsis, which was confirmed by
positive urine culture for Escherichia coli.
The patient had been on warfarin for 20 years following metallic mitral valve replacement.
Although he had a history of gout and a ureteric calculus, the cause for end-stage
renal failure was uncertain. He had undergone renal transplantation 8 years prior,
from a deceased donor following cardiac death. He had received alemtuzumab induction
followed by tacrolimus monotherapy maintenance immunosuppression.
The patient had undergone 3 allograft biopsies from the time of the transplantation
until the current admission. Initially, the immediate post-transplantation period
was complicated by a postoperative bleed and suboptimal graft function. An allograft
biopsy on day 20 post-transplantation showed acute tubular injury with <5% scarring,
with mild arterial intimal thickening. An increase in sCr prompted a second biopsy
2 years post-transplantation, which showed 15% cortical scarring with nodular arteriolar
hyaline and mild arterial intimal thickening without evidence of rejection. The patient’s
sCr continued to rise during the third year post-transplantation, and a renal biopsy
showed acute T-cell−mediated rejection (Banff 1b). He was treated with alemtuzumab
and steroids. His renal function remained stable (sCr 210−230 μmol/l) under regular
clinic follow-up for the next 5 years. Posttransplantation, he had been investigated
for intermittent hematuria for which no urological cause had been found.
During the current admission, following initiation of antibiotics, from day 2 onward
he developed acute kidney injury on chronic kidney disease. His sCr rose to 570 μmol/l.
His INR was above therapeutic range at 3.5 (Figure 1). Warfarin was suspended, and
he was commenced on heparin i.v. infusion in preparation for an allograft biopsy.
Progressive change in serum creatinine and international normalized ratio (INR) following
The renal biopsy (Figure 2) showed severe acute tubular injury and widespread RBC
casts occluding the tubules with hemosiderin within tubular epithelial cells. Moderate
interstitial inflammation was present, with foci of lymphocytic tubulitis and a few
neutrophil casts. Cortical scarring was estimated at 30%. Moderate arteriolar hyalinosis
and mild intimal thickening were present. C4d and SV40 immunostains were negative.
Immunofluorescence for IgG, IgA, IgM, C3, C1q, kappa, and lambda light chains were
negative on protease-digested paraffin-embedded tissue. Electron microscopy showed
dysmorphic RBCs in tubules (Figure 3). The findings were in keeping with ARN, with
evidence of resolving urinary tract infection and features of acute T-cell−mediated
rejection (Banff 1b).
Representative post-transplantation kidney biopsy findings. Representative post-transplantation
kidney biopsy findings. (a) Widespread occlusive red blood cell casts and acute tubular
injury (hematoxylin and eosin [H&E], original magnification ×100). (b) Severe interstitial
edema, hemorrhage, and inflammation (H&E, original magnification ×200). (c) Neutrophil
casts within tubules (H&E, original magnification ×200). (d) A glomerulus showing
mild segmental mesangial expansion. There is lymphocytic tubulitis (arrow). The arterioles
show moderate hyaline arteriolosclerosis (arrowhead) (H&E, original magnification ×200).
Hemosiderin deposition within tubular epithelial cell cytoplasm and dysmorphic red
blood cells within damaged tubules on ultrastructural examination. (a) Hemosiderin
deposition within tubular epithelial cell cytoplasm; a biomarker of local release
of catalytic iron which results in cell injury. (Perl stain, original magnification ×400).
(b) Dysmorphic red blood cells within damaged tubules on ultrastructural examination
(electron microscopy, original magnification ×2500).
The patient was treated with 2 weeks of i.v. antibiotics. His immunosuppression was
not augmented in view of the concomitant infection, the burden of immunosuppression,
and on the basis of frailty. He was started on acenocoumarol, aiming for an INR of
2 to 3. His renal function returned to baseline (Figure 1), and inflammatory markers
normalized. Four months after discharge from the hospital, his renal function remains
A sequence of events has been proposed in the pathophysiology of ARN. In susceptible
individuals, glomerular RBC leakage into the Bowman space and tubules during periods
of over-anticoagulation causes tubular RBC cast formation and tubular epithelial cell
injury resulting in AKI.
It appears that an underlying glomerular permeability alteration is essential for
RBC leak to occur during periods of over-anticoagulation. This susceptibility to glomerular
RBC leak can be related to a range of underlying kidney pathologies, including IgA
nephropathy and other glomerulonephritides, thin glomerular basement membranes, and
nephrosclerosis. A summary of the clinicopathological characteristics of all published
ARN reports to date is provided in Table 1. Animal studies suggest that thrombin inhibition
can contribute to susceptibility of glomerular hemorrhage through inhibition of protease-activated
receptor 1, which plays a role in maintaining the endothelial barrier intact.S5 Interestingly
inhibition of thrombin is common to all drugs implicated in ARN.
Summary of clinical characteristics, management, and outcomes of previously published
biopsy-proven cases of anticoagulation-related nephropathy
Underlying kidney disease
First author (year) reference
Gross hematuria, flank pain
Thin basement membrane disease
sCr 1.3 mg/dl at 6 mo
Gross hematuria, edema, dyspnea
Phen-procoumon stopped, HD, steroids
1 - 0.6
Vitamin K, prednisolone, azathioprin
Recovery (sCr 0.75 mg/dl at 2.5 yr); no recurrence.
Hematuria (n = 9), proteinuria (n = 6),eosinophilurea (n = 1)
4.3 ± 2.3
IgAN (n = 2),IgAN/DN (n = 1) ICGN (SLE) (n = 1), ICGN (IgG) (n = 1), FSGS (n = 1),
HTNS (n = 2)
Recovery (n = 4), HD (n = 3), death (n = 1), CKD (n = 1), recurrence (n = 1), no recurrence
(n = 8)
Switched to enoxaparin steroids
sCr remained increased (1.3 mg/dl); recurrence (1)
Switched to warfarin
CKD (sCr 1.8 mg/dl at 3 mo); no recurrence
Vitamin K, continued warfarin
NaHCO3 (no response), followed by steroids
CKD (4.4 mg/dl at 3 mo)
Di Maso (2014)S15
Gross hematuria, AKI
Warfarin withheld, vitamin K
Oliguria, nausea, and vomiting
Dabigatran stopped, HD/i.v. fluids
CKD (sCr 1.9 mg/dl at 2 wk)
Warfarin stopped, vitamin K, HD
CKD (sCr 4.95 mg/dl at 1 yr)
Warfarin switched to LMWH and restarted after 5 days of prednisolone
CKD (sCr 3 mg/dl)
Recovered kidney function
Acenocoumarol stopped; bridged with enoxaparin
CKD (sCr 1.7 mg/dl at 7 mo)
Urothelial carcinoma of renal pelvis
CKD (sCr 1.66 mg/dl at 3 mo)
Recovery (1.1 mg at 1 yr)
Fluindione (n = 7), aceno-coumarol (n = 2),warfarin (4)
5.7 ± 3
HD (n = 6), 492.7±1 91.2μmol/l
eGFR 77.8±25 ml/min
IgAN (n = 5),IgAN + DN (n = 1), HSP (n = 1), PIGN (n = 1), ICGN (IgG κ) (n = 1), HTNS
(n = 3), not identified (n = 1)
Fluindione switched to warfarin (n = 6), fluindione continued (n = 1),aceno-coumarol
stopped (1),acenocoumarol continued (1), warfarin continued (1),warfarin stopped (2)
Recovery (n = 1), partial improvement eGFR at 1 yr28−59 ml/min (n = 9), HD dependent
at 1 yr (n = 1), died (n = 2), recurrences (n = 2), no recurrences (n = 9), not known
(n = 1)
HTNS, chronic TIN
Rivaroxaban stopped and bridged with enoxaparin
HD dependent; no recurrences.
Oliguria, microscopic hematuria, AKI
Focal and segmental necrotizing and crescentic GN (active)
Apixaban stopped, LMW heparin, steroids
Warfarin stopped, heparin
CKD (sCr 1.43 mg/dl at 18 mo)
Gross hematuria, vomiting
Switched to warfarin steroids
Gross hematuria, AKI
GN (monoclonal IgG3 kappa), renal tumor,lymphoma
Antiplatelet therapy discontinued, HD, chemo
ICGN (resolving PIGN) (inactive)
Dabigatran stopped, HD
Dabigatran stopped, vitamin K, HD
CKD (sCr 2.5 mg/dl)
Focal and segmental necrotizing and crescentic GN (active)
Gross hematuria, AKI
Recovery; no recurrence
Warfarin withheld, LMWH, steroids,
CKD (sCr 1.3 at 3 mo)
62 ± 14 n=41
Warfarin (n = 28), heparin (n = 4),apixaban (n = 2),clopidogrel,and aspirin (n = 1),coagulopathy
(n = 6)
AF 20, DVT 8, APLS 2
5.6 ± 6
4.33 ± 1.99
1.25 ± 0.40
IgAN (n = 14), ICGN−IgG (n = 5), ICGN−SLE (n = 3), ICGN−MGN (n = 1), PICGN (n = 8),
FSGS (n = 4), DN (n = 2), FGN (n = 1),C3 GM (n = 1), glomerulomegaly (n = 2)
AF, atrial fibrillation; AKI, acute kidney injury; APLS, antiphospholipid syndrome;
chemo, chemotherapy; CKD, chronic kidney disease; CVR, cardiac valve replacement;
DN, diabetic nephropathy; DVT, deep venous thrombosis; eGFR, estimated glomerular
filtration rate; F, female; FGN, DVT, deep venous thrombosis; FSGS, focal segmental
glomerulosclerosis; GN, glomerulonephritis; HD, hemodialysis; ICGN, immune-complex
glomerulonephritis; IgAN, IgA nephropathy; IHD, intermittent hemodialysis; LMWH, low-molecular-weight
heparin; M, male; MGN, membranous glomerulonephritis; PIGN, post-infectious glomerulonephritis;
PICGN, pauci-immune crescentic glomerulonephritis; PM, pacemaker; PTE, pulmonary thromboembolism;
PVT, portal vein thrombosis; sCr, serum creatinine; SLE, systemic lupus erythematosus;
TIN, tubulointerstitial nephritis; TIPS, transjugular intrahepatic portosystemic shunt.
Two possible mechanisms have been proposed to explain the AKI: tubular obstruction
by RBC casts, and heme toxicity.
A study of kidneys with glomerular diseases that had macrohematuria-associated renal
damage failed to show retrodiffusion of Tamm Horsfall protein into the Bowman space.
This argues against tubular occlusion as the cause of renal impairment.S6 Hemoglobin
released from intratubular degradation of RBCs is reabsorbed by the proximal tubular
epithelium and further degraded within the tubular lumina. Free hemoglobin within
tubules promotes lipid peroxidation. Intracellular hemoglobin, heme, and/or iron generate
reactive oxygen species, resulting in activation of caspases, which in turn trigger
apoptosis and mitochondrial damage and upregulate vascular adhesion molecules and
proinflammatory/profibrotic cytokines.S7 An experimental model has shown that treatment
with antioxidants (N-acetylcysteines) can prevent AKI in rats with 5/6 nephrectomy
and warfarin-induced over-anticoagulation without a change in glomerular hematuria
or RBC cast formation,S8 supporting further the role of heme-induced oxidative damage
as the cause of AKI.
It is likely that ARN in an allograft is mechanistically similar to ARN in a native
kidney. Overall risk factors for the development of ARN in a native kidney include
older age, chronic kidney disease, diabetes, hypertension, cardiovascular disease,
heart failure, drugs (aspirin, angiotensin-converting enzyme inhibitors, calcium channel
blockers), thin and thick basement membranes, low serum basal albumin, high serum
aspartate aminotransferase (AST), hematuria, urinary infection, hypotension, hypovolemia,
coagulopathy, rapid normalization of INR, and gene polymorphisms affecting warfarin
S9 Many of these risk factors are common in transplant patients, as discussed below.
Reduced Nephron Mass/Chronic Kidney Disease
In experimental studies, ARN occurred in rats with 5/6 nephrectomy but not in controls,S10
suggesting that underlying reduction in nephron mass plays a role in its pathogenesis.
In the current case, the kidney biopsy showed 30% tubulointerstitial scarring, causing
reduced nephron mass.
In our case, there was moderate arteriolar hyaline and mild intimal thickening. Many
transplanted kidneys, especially from deceased donors, have significant vascular pathology,
which may increase susceptibility to ARN. The presence of arteriovenous fistulas in
allografts could cause regional hemodynamic changes in the kidney, which could, in
theory, add to this susceptibility.
Antibiotics are a common group of drugs that interact with vitamin K antagonists.
Temocillin could have potentiated the anticoagulant effect of warfarin in our patient.
In this patient, the presence of focal tubulitis with moderate inflammation amounted
to acute T-cell−mediated rejection (Banff 1b). The presence of concomitant tubulointerstitial
nephritis contributes to tubular injury and exacerbates hypoxia-induced tubular injury.
The differential diagnoses include drug-induced and infectious acute tubulointerstitial
nephritis, which cannot be excluded.
The presence of occasional neutrophil casts in our case is likely due to the resolving
urosepsis, which is a risk factor for ARN.
Performing a renal biopsy in anticoagulated patients can be a challenge for the nephrologist
because of the increased risk of bleeding and/or the risk of thrombosis when anticoagulation
is withheld. Studies in the native kidney setting have suggested that an increase
in sCr closely following an increase in INR >3 is adequate for the diagnosis of ARN
in the absence of any other etiology, even without histological confirmation.S11 However,
this case illustrates that renal biopsy gives additional information and is at times
essential for diagnosis in clinical practice. This is especially pertinent in the
case of a transplant, for which causes of AKI and their therapeutic implications are
It is interesting to note that this patient has had several episodes of macroscopic
hematuria during the post-transplantation period, for which a urological cause had
been excluded. It has not been possible to ascertain retrospectively whether any of
these episodes were associated with an increase in INR or an impairment in renal function.
However, the possibility that macroscopic hematuria can be precipitated by episodes
of over-anticoagulation, which can result in subclinical renal damage, must be considered.
This may have contributed to the progression of scarring in the patient’s post-transplantation
biopsy specimens, along with other insults such as calcineurin inhibiter toxicity
and T-cell−mediated rejection.
Currently, there are no prospective studies on the management of ARN. The approach
taken in previous case reports and case series are individualized to the patient,
with variable outcomes (Table 1). The optimal approach to remove or reduce the impact
of the inciting agent is a management dilemma. It is further compounded in patients
with mechanical heart valves such as our patient, in whom anticoagulation cannot be
Finally, we do not know the cause of renal failure in this patient or whether warfarin
had any role in the development or the aggravation of renal damage in his native kidney.
Meta-analysis of retrospective population studies on outpatients on warfarin anticoagulation
estimate the prevalence of ARN at 20.4% and suggest that it is likely underdiagnosed
in clinical practice.
The prevalence is greater among high-risk groups and the presence of CKD doubles the
risk of developing ARN.
Our literature review demonstrates that the current case is the first published report
of ARN in a renal transplant recipient. The presence of ARN in native kidney biopsy
specimens has been published in case reports and case series (Table 1). Warfarin was
the most commonly implicated anticoagulant, followed by dabigatran, apixaban, and
rivaroxaban. The most common presentation pattern was AKI or AKI on CKD with macroscopic
or microscopic hematuria. As with the current case, an underlying kidney pathology
was present in the majority of reports, with IgA nephropathy being the predominant
glomerular disease (n=34), followed by immune-complex GN (n=27) and FSGS or nephrosclerosis
(n=12). Selection bias in the decision to biopsy is clearly the major limitation in
this review of case reports and case series. In addition, it is acknowledged that
recognising ARN in the kidney biopsy could be challenging in view of the presence
of underling kidney pathologies. Renal outcomes varied; however, recovery of renal
function was only observed in 11 out of 51 cases which had available data. Of note,
only in a minority of cases excessive overanticoagulation was present, confirming
the initial observations by Brodsky et al in their landmark study, where moderate
overanticoagulation was sufficient to cause AKI.
Judging from the literature pertaining to native kidneys, one could extrapolate that
it is possible that ARN may be under-diagnosed among transplant patients. We therefore
have undertaken a retrospective study reviewing the histopathology of all allograft
biopsies from transplant recipients on long term anticoagulation (warfarin, apixaban,
rivaroxaban) in our institute for a period of 10 years (2006-2016) with a minimum
of 2 years follow up. There were 126 allograft biopsies from 40 patients; only the
index case had features of ARN. This limited data suggests that ARN has not been under-diagnosed
in the post-transplant setting. However, the indications for these biopsies vary and
we do not have data on the level of anticoagulation at the time of biopsy. Prospective
studies on large cohorts of post-transplant patients on anticoagulation need to be
carried out in order to get an accurate understanding of the incidence and prevalence
of ARN among the transplant population.
This case illustrates that the occurrence of ARN in a renal allograft can pose diagnostic
and management challenges to the transplant physician. Renal biopsy was useful in
this situation and should be considered on a case by case basis after careful consideration
of risks compared to benefits, especially if the cause of AKI is not apparent or if
supportive measures fail to improve AKI. Considering the limited therapeutic options
and the poor renal and overall prognosis of ARN in the non-transplant population,
it is imperative that post-transplant patients on anticoagulation are closely monitored
with the aim of prevention and early detection of over-anticoagulation (Table 2).
• Anticoagulant-related nephropathy (ARN) presents with acute kidney injury (AKI)
as a result of glomerular bleeding on a background of over-anticoagulation.
• Since the original description of ARN in patients taking warfarin, it has been reported
with use of all classes of vitamin K antagonists as well as novel oral anticoagulants.
• The main histopathological findings include acute tubular injury associated with
red blood cells (RBCs) within the Bowman space and obstructive tubular RBC casts.
• ARN can occur in the kidney allograft but is rare.
• An underlying glomerular disease is commonly seen in kidney biopsy specimens with
• Given the limited management options and the poor renal and overall prognosis of
ARN in native kidneys, as well as the challenges of performing a renal biopsy, renal
transplant patients on anticoagulation should be judiciously monitored with the aim
of early detection and prevention of anticoagulant-related renal damage.
All the authors declared no competing interests.