Volume 53, Issue 2 , Pages 346-350, February 2009
Thrombotic Microangiopathy and Renal Failure Exacerbated by ε-Aminocaproic Acid
Article Outline
Index Words: Thrombotic microangiopathy, hemolytic anemia, antiphospholipid syndrome, antiphospholipid antibodies, antiphospholipid syndrome nephropathy, systemic lupus erythematosus, ϵ-aminocaproic acid, Amicar, renal failure
ε-Aminocaproic acid (EACA) is used to treat bleeding associated with systemic fibrinolysis, as well as hematuria resulting from urinary tract procedures or tumors. EACA inhibits urokinase and other activators of plasminogen, decreasing the formation of plasmin and inhibiting the breakdown of fibrin.1, 2 EACA-associated renal failure may be caused by obstruction of the upper urinary system by blood clots, hypotension with acute tubular necrosis, renal infarction, and myoglobinuria.2 This is the first report of EACA causing renal failure by accelerating a preexisting thrombotic microangiopathic process.
Case Report
Clinical History
A 51-year-old woman with systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and a bleeding disorder presented with microscopic hematuria and an increasing creatinine level. She reported weight loss, Raynaud phenomenon, dyspnea on exertion, hair loss, and an urticarial rash. Serum creatinine level increased from 0.9 to 1.3 mg/dL (80 to 115 μmol/L) over 2 years. SLE was diagnosed based on a history of sun sensitivity, hair loss, joint pain and swelling, episodes of colitis and iritis, anemia, and positive antinuclear antibody with anti-Smith antibodies. She had been treated with prednisone in the past. Urological evaluation of recurrent microscopic hematuria was unrevealing.
The patient had a history of heavy postoperative bleeding and menorrhagia requiring hysterectomy. Evaluation of her bleeding diathesis was consistent with a disorder of fibrinolysis. A diagnosis of plasminogen activator inhibitor 1 (PAI-1) deficiency was made based on an abnormal euglobulin lysis time (clot lysis at 2 hours) and very low PAI-1 activity of less than 6 IU/mL (normal, <31.1 IU/mL), although PAI-1 antigen level was normal. Antiplasmin and von Willebrand cofactor levels were normal.
The patient also was noted to have a prolonged partial thromboplastin time and a positive lupus anticoagulant. Lactate dehydrogenase level was mildly increased, but there were no schistocytes on peripheral blood smear. Platelet count and haptoglobin level were normal, and urine hemosiderin was negative. A renal infarction was identified by computed tomography after an episode of gross hematuria. APS was diagnosed based on her history of renal infarction and a positive lupus anticoagulant. Treatment with aspirin 81 mg/d was started. Warfarin was not prescribed because of the PAI-1 deficiency and history of severe bleeding.
Physical examination was unremarkable. Laboratory studies were notable for urea nitrogen level of 40 mg/dL (14.3 mmol/L), creatinine level of 1.3 mg/dL (115 μmol/L), hematocrit of 30.1%, platelet count of 195,000/μL, C3 level of 72 mg/dL (0.07 g/L; range, 90 to 180 mg/dL), normal C4 level, and antinuclear antibody titer of 1:640 (speckled pattern). Urinalysis showed large blood, 1+ protein, and 20 red blood cells/high-power field, with many acanthocytes and occasional mixed cellular casts. Urine protein-creatinine ratio was 0.5.
A renal biopsy was performed. Because of the disorder of fibrinolysis, the patient received intravenous EACA (Amicar; Immunex, Seattle, WA) at a 75-mg/kg loading dose and 1 g every 2 hours on the day of biopsy, as well as oral EACA, 2 g, every 4 hours for 10 days after the procedure.
Kidney Biopsy
The renal biopsy specimen contained 9 glomeruli. One was globally sclerotic. Two glomeruli had extensive double contours. Another had a fresh thrombus at the junction of the vascular pole and arteriole (Fig 1). There was mild interstitial fibrosis and tubular atrophy. Arteries showed moderate intimal fibroplasia. Arterioles showed moderate mural thickening, with occasional hyaline change. No mucoid hyperplasia was present. No vasculitis or large-vessel thrombosis was observed. Immunofluorescence findings were negative, except for C3 (1+ to 2+) in the mesangium, peripheral capillary loops, and vessels. One glomerulus showed segmental fibrin. Electron microscopy of 2 glomeruli showed focal foot-process effacement. One tuft had a segmental area of capillary collapse with an associated loss of cellular elements and coarse granular electron-dense material suggestive of hyaline. Both glomeruli showed extensive mesangial interposition (Fig 2) and areas of subendothelial electron lucency and “fluff” (Fig 3). No subepithelial or mesangial electron-dense deposits were noted, and no tubuloreticular inclusions were seen.
Figure 1.
Glomerulus with a thrombus involving the vascular pole and its arteriole (arrow). Extensive double-contour formation is also noted (arrowhead) (Jones stain; original magnification ×40).
Figure 2.
Electron microscopy. Asterick indicate well-developed mesangial interposition. No fibrin tactoids or electron-dense deposits are seen. These findings were seen in all 3 glomeruli studied (original magnification ×3,200).
Figure 3.
Electron Microscopy. Asterick indicate messangial interposition and electron lucent expansion of the subendothelial zone (arrow) (original magnification ×3,200).
Pathological Diagnosis
Biopsy findings were consistent with acute and chronic thrombotic microangiopathy (TMA). TMA refers to a group of disorders caused by vascular endothelial injury. Histopathologic expression is primarily in glomeruli and small vessels. Acute changes within glomeruli include thrombosis, mesangiolysis, and expansion of the subendothelial space (presumably by products of fibrin breakdown). Parallel vascular changes seen in the acute phase are thrombosis, fibrinoid necrosis, and a distinctive intimal change often known as “mucoid intimal hyperplasia.” Over time, fibrin and thrombosis diminish and scarring takes place. Reduplication of the glomerular basement membrane with double-contour formation develops, creating a “membranoproliferative pattern.” Immune complexes are not seen in any of these lesions. Our patient showed both acute (thrombosis) and chronic (double contours) changes specific for TMA. The clinical context suggests APS is the cause. Thrombi of varying ages or degrees of organization, although not specific, may be suggestive of APS. Interestingly, there was no evidence of immune-complex deposition in glomeruli, as would be seen in lupus nephritis.
TMA may be seen in association with commonly used drugs. Several chemotherapeutic agents may cause TMA, including mitomycin c, cisplatin, daunorubimicin, cytosine arabinoside, and gemcitabine.3, 4 Ticlodipine, clopidogrel, and quinine may rarely cause thrombotic thrombocytopenic purpura or hemolytic uremic syndrome with associated TMA.4 Perhaps the most significant offenders are calcineurin inhibitors (cyclosporine and tacrolimus), frequently used in patients with preexisting renal disease and in renal transplant recipients.5, 6, 7 In our patient, none of these drugs were present.
Identification of APS as the specific cause of TMA is clinically important because there is a high risk of recurrent thrombosis, and anticoagulation therefore must be considered. The diagnosis should be considered whenever TMA is found, particularly if the patient has experienced thrombotic events and/or pregnancy loss.
Clinical Follow-up
Ten days after the biopsy, the patient developed worsening anemia, thrombocytopenia, and an increased creatinine level. Evidence of intravascular hemolysis included increased lactate dehydrogenase level, depressed haptoglobin, and the presence of schistocytes. She experienced a rapid increase in blood pressure and developed heavy proteinuria. Oliguric renal failure and persistent severe hemolysis rapidly ensued despite treatment with oral prednisone, 60 mg/d, and plasma exchange. Unfractionated intravenous heparin was administered, followed by slow resolution of thrombotic microangiopathic hemolytic anemia (TMHA) over a period of several days. She did not have fever, mental status change, or evidence of other organ involvement. Therapy was transitioned from heparin to warfarin. Anemia improved and platelet count and lactate dehydrogenase level returned to baseline, but she progressed to end-stage renal disease.
Discussion
APS is defined as the presence of antiphospholipid antibodies (aPLs) associated with thrombosis or repeated spontaneous abortions.8, 9 Our patient had both a history of vascular thrombosis (renal infarction) and a positive lupus anticoagulant. APS is primary when it occurs in isolation and secondary when associated with another condition (usually SLE). The standard treatment of patients with APS is anticoagulation with warfarin to prevent recurrent thrombosis.10, 11 However, our patient also had an increased risk of bleeding given her PAI-1 deficiency and therefore initially was started on treatment with aspirin only. Aspirin may protect against thrombosis in patients with aPLs without a history of thrombosis, but is of unclear value in patients with known thrombosis.10, 11, 12 Her kidney function continued to decline while on aspirin therapy. No studies having shown that aspirin or warfarin slow the progression of renal disease associated with APS.
TMHA is associated with SLE and may contribute to decreased kidney function, although it is not clear if aPLs are necessary or sufficient to cause disease.13, 14 In a recent review, aPLs were present in 5 of 8 patients with SLE-associated TMHA.15 However, a causal link is difficult to establish because aPLs are present in up to 50% of SLE patients without a history of thrombosis or TMHA.14 Interestingly, autoantibodies directed against components of the fibrinolysis cascade may contribute to the thrombotic tendency in patients with APS.16
The term antiphospholipid syndrome nephropathy (APSN) has been suggested to refer to non–immune complex–mediated renal injury seen in patients with SLE, APS, or both.17, 18, 19, 20 APSN is a new and evolving category of renal injury, but generally is defined as the presence of occlusive lesions of intrarenal vessels associated with acute thrombosis and chronic arterial and arteriolar lesions leading to zones of cortical ischemic atrophy.19 Tektonidou et al18 recently performed a retrospective review of 151 patients with SLE who underwent renal biopsy to evaluate the prevalence, clinical associations, and outcome of APSN in SLE patients with and without aPLs. In their study, APSN was defined as the presence of any of the following on renal biopsy: (1) TMA, characterized by fibrin thrombi in arterioles and/or glomeruli; (2) myofibroblastic intimal cellular proliferation leading to intimal thickening of interlobular arteries; (3) organized thrombi with or without recanalization; (4) fibrous arterial and arteriolar occlusion; or (5) focal cortical atrophy in the subcapsular zone.18 Using these criteria, APSN was identified in 39.5% of SLE patients with aPLs, but only 4.3% of SLE patients without aPLs, suggesting that aPLs may have an important role in the pathogenesis. APSN was found in a majority of patients with APS. However, one third of patients with APSN on renal biopsy did not meet clinical criteria for APS. Therefore, the clinical diagnosis of APS is not necessary to meet APSN biopsy criteria. Only the presence of aPLs is necessary. Importantly, the finding of APSN on biopsy predicted worse outcomes because patients were more likely to develop hypertension, increased creatinine levels, and progressive histological lesions over time.18 Another group recently found that APSN is an independent risk factor for hypertension, increased serum creatinine levels, and interstitial fibrosis.19
In conclusion, the biopsy findings of acute and chronic TMA in this patient with APS are consistent with APSN. Patients with SLE and/or APS and APSN on biopsy may have a worse renal prognosis then those who do not have findings characteristic for APSN. In addition, aPLs are an independent risk factor for loss of kidney function in patients with lupus nephritis.21 However, the change from a relatively indolent clinical course to an aggressive one immediately after the biopsy, resulting in TMHA and end-stage renal disease, is atypical.
We hypothesize that the administration of EACA dramatically shifted the balance of prothrombotic and antithrombotic forces in favor of microvascular thrombosis, resulting in an aggressive acceleration of the underlying APS with TMA. Moreover, we speculate that the patient's initial clinical manifestations of APS may have been relatively mild because of her coincidental disorder of thrombolysis (PAI-1 deficiency), which would potentially accelerate degradation of microthrombi.
Acknowledgements
Support: None.
Financial Disclosure: None.
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Originally published online as doi:10.1053/j.ajkd.2008.07.023 on September 22, 2008.
PII: S0272-6386(08)01195-5
doi:10.1053/j.ajkd.2008.07.023
© 2009 National Kidney Foundation, Inc. Published by Elsevier Inc All rights reserved.
Volume 53, Issue 2 , Pages 346-350, February 2009
