Transfemoral thrombolysis with thrombosuction: an aid to renal biopsy in a case of acute Budd Chiari syndrome complicating nephrotic syndrome

Abstract

Renal biopsy is usually a prerequisite in the diagnosis of adult patients with nephrotic syndrome. Acute Budd Chiari syndrome is a known complication of certain aetiologies of nephrotic syndrome like membranous glomerulopathy and minimal change disease. This complication requires emergent anticoagulation, which would preclude the performance of a renal biopsy. We report the case of a 47-year-old woman who presented with acute Budd Chiari syndrome as the initial presentation of nephrotic syndrome. The difficult situation in which we had to give anticoagulation and also perform a renal biopsy led us to devise a novel way to treat the patient, namely, the initial use of transfemoral thrombolysis and thrombosuction followed by a renal biopsy, which confirmed the diagnosis of primary membranous nephropathy. Anticoagulation was safely instituted 48 hours later with documented clinical and radiological improvement.

Background

Thrombotic complications in nephrotic syndrome usually occur after the diagnosis, during the course of the disease. Adult nephrotic syndrome presenting with thrombotic complications as the initial complaint is a relatively rare occurrence. Furthermore, acute Budd Chiari syndrome as the initial presentation of nephrotic syndrome is a rarity. Our patient’s initial presentation of nephrotic syndrome was as an acute Budd Chiari syndrome, which brought up the therapeutic dilemma of a diagnostic renal biopsy versus emergent therapeutic anticoagulation. This made us adopt the novel approach that we describe below successfully.

Case presentation

A 47-year-old female presented to the emergency department with sudden onset abdominal pain since 2 days, which was epigastric in location, dull aching in nature without any radiation and was not associated with fever, nausea, vomiting or loose stools. The patient had generalised abdominal tenderness, guarding and rigidity, with massive ascites.

The laboratory parameters in the emergency room (ER) are given in table 1 (day 1). She had a raised serum creatinine level, leucocytosis and severe hypoalbuminaemia. Urine routine examination showed the presence of 3+ proteinuria, 10–12 Red Blood Cells and 1–2 pus cells per high power field. An emergency ultrasound was done in the ER and confirmed the presence of massive ascites. It also showed normal sized kidneys with maintained corticomedullary differentiation. On detailed questioning, the patient gave history of periorbital puffiness, pedal oedema and intermittent oliguria since the past 3 months for which no medical help was sought.

Table 1.

Serial laboratory values of the case

Time	Day 1	Day 2	Day 5	Day 7	Day 12	Day 20
Haemoglobin (g/L)	126	116	117	118	116	114
Platelets (×109/L)	425	455	421	344	315	246
Erythrocyte sediment rate (mm/hour)	33
BUN (g/dl)	22	31	22	11	11	11
Creatinine (mg/dl)	2.2	2.1	1.7	1.1	1.2	1.1
Total bilirubin (mg/dl)	0.6		0.6		0.6	0.6
Direct bilirubin (mg/dl)	0.1		0.1		0.1	0.2
AST (IU/L)	21		23		11	22
ALT (IU/L)	22		25		12	11
Total protein (g/dl)	5.2		5.7		5.7	6
Albumin (g/dl)	1.4		1.8		2.0	2.6
ALP (IU/L)	78		56		67	66
Serum sodium (mEq/L)	133		132		133	140
Serum potassium (mEq/L)	3.6		3.1		3.5	4.2
Serum chloride (mEq/L)	111		108		109	109
TG (mg/dl)	315
Cholesterol (mg/dl)	266

ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; BUN, blood urea nitrogen; TG, triglycerides.

Her 24-hour urine protein was 23 g/day. International normalised ratio (INR) was 1.1. Serum C3 was 122 IU/L (normal range: 80–160 IU/L) and serum C4 was 44 IU/L (normal range: 16–48 IU/L). HIV, hepatitis B surface antigen and hepatitis C virus ELISA were negative. Antinuclear antibody, anti-proteinase 3, anti-myeloperoxidase and antimitochondrial antibody were negative. Serum antibody to phospholipase A2 receptor (PLA2R) was negative. Markers of Antiphospholipid Antibody Syndrome were negative—that is, lupus anticoagulant, anticardiolipin antibodies and antibodies to beta-2 glycoprotein I. The patient denied history of blunt abdominal trauma, past usage of oral contraceptive pills, previous history/treatment of thromboembolic episodes. Also, physical and imaging examination did not reveal the presence of malignancy.

Persistent abdominal pain warranted an upper gastrointestinal endoscopy, which was normal, and an abdominal contrast-enhanced CT scan, which showed the presence of a large thrombus (7×3×2 cm) in the inferior vena cava extending into both the renal veins, suggesting an acute Budd Chiari syndrome complicating the nephrotic syndrome (figure 1A and B).

Figure 1.

(A) Contrast-enhanced CT of the abdomen showing a filling defect in the inferior vena cava suggestive of thrombus. The arrow points to the thrombus in the inferior vena cava. (B) shows extension of the thrombus into the right renal vein. The arrow points to the extension of the thrombus into the right renal vein.

Treatment

She needed urgent anticoagulation to dissolve the thrombus, although at a risk of bleeding during a subsequent renal biopsy. Faced with this diagnostic conundrum, we decided to perform a catheter-guided thrombolysis and thrombosuction for the inferior vena cava (IVC) thrombus.

The catheter was inserted in the femoral vein and advanced up to the inferior vena cava where the thrombus could clearly be seen (figure 2A, B). Urokinase (750 000 IU) was infused via the catheter followed by mechanical thrombosuction which removed all traces of the thrombus (figure 3A, B). In this case, a continuous infusion of urokinase was not given (which is the normal protocol for such a procedure) because the patient had to undergo a renal biopsy. After 48 hours, we performed a renal biopsy, which showed the characteristic changes of membranous nephropathy (figure 4). The biopsy showed uniform diffuse capillary wall thickening without hypercellularity, without mesangial sclerosis and without inflammatory cells. Immunofluorescence showed positive staining for PLA2R. Serial ultrasound examinations were done to confirm the absence of a perirenal, intracapsular or retroperitoneal haematoma.

Figure 2.

Conventional angiogram during the interventional radiology procedure. The blue arrows in (A) point to the large thrombus in the inferior vena cava. The orange arrow in (B) shows thrombus in the renal vein.

Figure 3.

Post-thrombolysis and thrombosuction images (A) show good resolution of the thrombus in the inferior vena cava. The orange arrow points to a small residual thrombus in the Inferior vena cava (IVC). (B) shows resolution of renal vein thrombus. There is minimal residual thrombus as shown by the orange arrow.

Figure 4.

Renal biopsy showing characteristic changes of membranous nephropathy–uniform thickening of the basement membrane with expansion of the mesangium. There is mesangial and cellular proliferation without sclerosis. No evidence of crescents, tuft necrosis, interstitial fibrosis or tubular atrophy (H&E stain).

On the third day after biopsy, we started anticoagulation with unfractionated heparin 5000 U four times per day. This was overlapped with warfarin 5 mg/day. Heparin was stopped after 7 days. Warfarin was continued to a target INR of 2.5. The patient was also given human albumin infusion along with intravenous furosemide 20 mg three times per day for 3 days to induce diuresis and resolve the oedema.

Outcome and follow-up

The patient was started on the modified Ponticelli regimen¹ for membranous glomerulopathy (MGN), which consists of cyclic therapy with alternate months of steroids and cyclophosphamide for 6 months. Her laboratory parameters on discharge are mentioned in table 1 under day 20. The serum creatinine dropped to 1.1 mg/dL and the serum albumin rose to 2.6 mg/dL. Proteinuria had decreased to 4 g/day. Figure 5 shows a normal inferior vena cava on a CT scan done 1 month later. The patient continues to maintain follow-up and her proteinuria has decreased to 2.3 g/day at 12 weeks after discharge.

Figure 5.

Contrast-enhanced CT done 1 month later shows resolution of the inferior vena cava thrombus along with patent renal veins. The blue arrows point to the patent renal vein.

Discussion

The aetiology of nephrotic syndrome in adults is varied with considerable demographic variation (immunoglobulin A nephropathy and lupus nephritis is common in Asia, focal segmental glomerulosclerosis (FSGS) in Europe, etc).² Paediatric nephrotic syndrome has a 95% likelihood of responding to empirical steroid use as it is most commonly minimal change disease. In contrast adult nephrotic syndrome due to its more diverse aetiology, including FSGS, membranous nephropathy, C3-related glomerulopathy, etc does not show universal steroid responsiveness. Therefore, it warrants an early kidney biopsy to appropriately categorise the disease and direct the subsequent management, including specific therapy. Also, the resultant thromboembolic complication due to imbalance between the prothrombotic and antithrombotic factors as well as impaired thrombolytic activity is a well-known complication of nephrotic syndrome if undiagnosed or improperly treated.² The published literature regarding treatment in adult-onset nephrotic syndrome without histopathological diagnosis is scarce, thus making the renal biopsy the diagnostic gold standard in adult nephrotic syndrome.^{3 4}

Our patient was a 47-year-old woman who presented as an acute Budd Chiari syndrome with severe abdominal pain and intractable ascites on the background of adult nephrotic syndrome. She had ignored symptoms of periorbital puffiness and pedal oedema for months. Her workup revealed massive nephrotic range proteinuria of 23 g/day associated with severe hypoalbuminaemia (1.4 g/dL). In adult nephrotic syndrome, if serum anti-PLA2R antibody is positive and the patient has thromboembolic complications, empirical treatment presuming the aetiology to be primary membranous nephropathy can be initiated.⁵ In our patient, the immunological markers, including serum anti-PLA2R antibody, were negative, thus making renal biopsy an absolute necessity to confirm the aetiology of the adult nephrotic syndrome before starting immunosuppression. Interestingly, the immunofluorescence revealed positive staining for anti-PLA2R antibody, thus clinching the diagnosis of primary membranous nephropathy on renal biopsy. The presence of acute Budd Chiari syndrome with thrombus extending into both the renal veins necessitated emergency anticoagulation.

The dilemma of simultaneous needs of diagnostic renal biopsy and emergent therapeutic anticoagulation made us seek the help of interventional radiology. Thompson et al⁶ describe a case in which a 34-year-old man with MGN presented with extensive thrombosis of the inferior vena cava, renal veins and iliac veins. This patient had to be treated with intravenous alteplase, heparin injections as well as the placement of multiple endovascular stents. Endovascular stenting in general has excellent long-term patency rates and is associated with minimal complications when performed by a centre with expertise in the area.^{7 8}

The use of catheter-directed thrombolysis (CDT) for deep venous thrombosis of leg veins and also for the IVC has been a relatively recent development in the field of interventional radiology. A number of clinical trials unequivocally show that CDT is far superior to anticoagulation alone for the treatment of IVC thrombosis.⁹

Thrombosuction when combined with CDT improves the long-term recanalisation rates even further and is associated with reduction in hospital stay, costs and also bleeding complications.⁹ Our patient was an adult-onset nephrotic syndrome complicated with an acute inferior vena cava thrombus extending into bilateral renal veins, which required urgent anticoagulation. The procedure of targeted thrombolysis with thrombosuction made the subsequent renal biopsy much safer as compared with giving systemic anticoagulation prior to the biopsy. Complications, including haematuria, intracapsular renal haematoma and retroperitoneal haematoma, are described if the patient has received systemic anticoagulation prior to the renal biopsy.^{10 11}

Our patient underwent successful CDT with urokinase followed by thrombosuction for the IVC and renal vein thrombosis. She safely underwent the performance of a diagnostic renal biopsy 48 hours later, which showed the presence of primary MGN.

MGN is a common cause of nephrotic syndrome with the greatest propensity to cause thromboembolic events.¹² These are attributed to loss of anticoagulants like protein C, protein S, antithrombin III, diuretic use, dehydration, increased recumbence, corticosteroids, coagulation protein abnormalities, impaired fibrinolysis, increased platelet aggregation and activation and increased fibrinogen levels, among other factors.¹³ In fact, Gambaro et al describe a case in which membranous nephropathy and Budd Chiari syndrome occurred together, and the cause was activated protein C resistance.¹² Our patient was Anti Phospholipid Antibody (APLA) negative.

In spite of the known association between nephrotic syndrome and thrombosis, it is advisable that a full coagulation profile and a detailed history regarding abdominal trauma and the other modifiable risk factors including incriminating drugs, should nevertheless be sought in such cases.^{14 15} Economic constraints did not allow us to study the levels of protein C, protein S and antithrombin III. Her interventional radiology procedure (thrombolysis with thrombosuction) was done entirely free by the interventional radiology department.

There is a paucity of literature on the simultaneous occurrence of membranous nephropathy and Budd Chiari syndrome. Reported cases describe the occurrence of Budd Chiari syndrome in established cases of membranous nephropathy, when the patient was already taking treatment. Hence, in these cases, it was easy to start anticoagulation or increase the dose of anticoagulants, sometimes with complete resolution of the thrombus.¹³

Nephrotic syndrome is associated with increased risk of thrombosis. Our patient presented with acute Budd Chiari syndrome and turned out to have membranous nephropathy. Instead of avoiding renal biopsy and starting empirical immunosuppression, one can use the novel method that we adopted, taking the help of interventional radiology to solve the problem of anticoagulation. To the best of our knowledge, this is the first case in which this stratagem was adopted—the use of transfemoral thrombolysis with thrombosuction of inferior vena cava thrombus in a difficult clinical situation warranting a subsequent renal biopsy.

Learning points.

• Nephrotic syndrome by itself, irrespective of the aetiology, is a risk factor for thrombotic episodes.

• Emergent anticoagulation to treat the thrombotic episode may preclude a renal biopsy that is necessary for the diagnosis of the aetiology of nephrotic syndrome.

• Use of interventional radiology with catheter-directed thrombolysis and thrombosuction, if possible, helps in buying time before starting systemic anticoagulation during which the renal biopsy may be performed.