Syncope in a patient with minimal change disease without nephrotic-range proteinuria

Introduction

Nephrotic syndrome is a hypercoagulation state that carries an increased risk of thromboembolic events. Alterations in the plasma levels of proteins involved in coagulation and fibrinolysis, increased platelet aggregation, low plasma albumin level, hyperviscosity, hyperlipidemia, and the use of some drugs all contribute to its pathogenesis. ¹ Deep vein thrombosis, renal vein thrombosis, and pulmonary embolism (PE) are the most common venous thromboembolic complications, whereas arterial thromboembolism occurs less frequently. Among these complications, PE is a critical complication that can lead to lethal morbidity and death.

The clinical presentation of PE varies widely and ranges from clinically silent disease to the classical triad of dyspnea, chest pain, and hemoptysis. Syncope is an uncommon presentation of PE and has been reported rarely in nephrotic patients. ² The development of PE in nephrotic patients is usually accompanied by severe hypoalbuminemia and heavy proteinuria. Here, we describe a case involving a 35-year-old man with relapsed minimal change disease who was taking diuretics and steroids. He presented to our department after syncope caused by PE, despite the absence of severe hypoalbuminemia and heavy proteinuria.

Case presentation

A 35-year-old man presented to the emergency department after syncope. He had a 10-year history of minimal change disease with two episodes of relapse. Two weeks earlier, he had developed disease relapse (urinary protein-to-creatinine ratio 3800 mg/g) and was given oral prednisolone 60 mg and furosemide 40 mg daily. Prophylactic anticoagulant therapy was not used because there was no thromboembolic event during the prior episodes of relapse. He had no history of other medical diseases, such as previous thromboembolism, chronic heart and lung disease, or malignancy. He did not smoke, consume alcohol, or use other medications. He had no history of recent long distance flight, immobility, or surgical procedures. He denied precipitating events such as postural changes, stress, or severe pain, or that a prodrome had preceded the syncopal event. There was no witnessed seizure activity. His family history was non-revealing.

On examination, his height was 174 cm, weight 72 kg, blood pressure 81/49 mmHg, pulse rate 94 beats/minute and regular, respiratory rate 18 breaths/minute, temperature 36.9℃, and oxygen saturations 99% while breathing ambient air. There were distended neck veins and mild edema around both ankles. The remainder of the physical examination was unremarkable. Relevant laboratory data included blood urea nitrogen 6.1 mmol/L, creatinine 99 µmol/L, albumin 28 g/L, and total cholesterol 7.5 mmol/L. Electrocardiography (ECG) revealed an S wave in lead I, and a Q wave and inverted T wave in lead III. Chest radiography revealed distal abrupt tapering of the right pulmonary artery, consistent with the knuckle sign (Figure 1(a)). The causes of syncope in patients with nephrotic syndrome include neurocardiogenic and cardiovascular disorders, as in the general population, episodes of hypovolemia after diuretic treatment, and amyloidosis with involvement of the heart and sympathetic nervous system. The patient’s history of minimal change disease and hypervolemia on physical examination made the last two causes unlikely. The typical ECG and chest radiography findings raised suspicion of PE. A plasma D-dimer test was ordered and revealed a level of 724 ng/mL. Transthoracic echocardiography showed a dilated right ventricle with impaired systolic function, suggestive of right-sided heart strain. He received emergency computed tomography (CT) of the chest, which showed thrombi in the bilateral main pulmonary arteries with occlusion of the right segmental arteries, which confirmed the diagnosis of acute massive PE (Figure 1(b)). OPEN IN VIEWER

The patient decided against thrombolytic therapy because of the fear of severe bleeding complications. He was given anticoagulation therapy with intravenous heparin (loading 4000 U followed by maintenance 1000 U/h). Four hours later, his compromised hemodynamics resolved. The urinary protein-to-creatinine ratio was 300 mg/g. Autoimmune and coagulation studies, including measurement of antiphospholipid antibodies, homocysteine, fibrinogen, antithrombin III, and protein C and S, gave negative results. Ultrasonography of the deep venous system revealed normal findings. He was concomitantly treated with warfarin, and heparin was withdrawn five days later. Six months after the initial presentation, he remained asymptomatic. The warfarin was discontinued because he remained in remission from his nephrotic syndrome and several minor bleeding events. There was no recurrence of PE at the one-year outpatient visit.

Discussion

This adult male had episodes of relapsed minimal change disease and was treated with steroids and diuretics. Although the classical symptoms, severe hypoalbuminemia, and heavy proteinuria were absent, the laboratory and imaging findings prompted the diagnosis of acute PE. There were no other predisposing factors, indicating that a relapse of nephrotic syndrome may have caused the PE in this patient.

Patients with membranous nephropathy have a predilection for the development of thromboembolism, although it can occur in association with other histological types, especially membranoproliferative glomerulonephritis, minimal change disease, or focal segmental glomerulosclerosis. ³ In addition, thromboembolism associated with nephrotic syndrome is closely linked to severe hypoalbuminemia and heavy proteinuria. An albumin concentration of <28 g/L in a patient with membranous nephropathy and <25 g/L in a patient with another histological type, and a protein excretion rate of >10 g/day are associated with an increased thrombotic risk.^4,5 Accordingly, our patient’s risk of thromboembolism was not high because of the histological diagnosis of minimal change disease, moderate hypoalbuminemia, and mild proteinuria. We hypothesize that the relapse of nephrotic syndrome may have predisposed our patient to a higher risk of thrombogenesis. Treatment with corticosteroids can increase the production of clotting factors, and the use of diuretics can cause hemoconcentration with a resultant increase in viscosity, which may thereby exacerbate the thromboembolic disturbance and lead to acute PE. ⁶ Of note, PE in nephrotic patients is frequently associated with concurrent use of steroids and diuretics. ⁷

Syncope can occur in nephrotic patients with acute PE, but this is rarely recognized. Because syncope is an uncommon presentation of PE and PE is a rare cause of syncope, the relationship between syncope and PE is not usually identified in the setting of acute medical treatment. ² However, underlying diseases with a thromboembolic tendency and laboratory and imaging studies may provide diagnostic clues. Our patient’s history of relapsed minimal change disease when on steroid and diuretic therapy, the high plasma D-dimer level, and typical ECG and chest radiography findings led us to order the chest CT scan, which confirmed the diagnosis.

PE can be categorized as massive in the presence of arterial hypotension or cardiogenic shock. Massive PE is associated more often with the presentation of syncope. ⁸ Patients with syncope as a presentation of PE are more likely to have thromboembolism involving the main pulmonary arteries and hypotension than those without syncope. ⁹ These findings suggest that massive PE is frequently associated with acute right ventricular failure with subsequent decreased cardiac output and cerebral hypoperfusion, which may lead to syncopal events. Other mechanisms to explain the association between syncope and PE include hemodynamically unstable arrhythmia and a vasovagal effect, which frequently occur in non-massive type PE.^2,9 Our patient’s initial blood pressure was low and heart rate was rapid, and the CT scan showed thrombosis in the bilateral main pulmonary arteries, indicating that his PE was massive and that the cause of syncope was acute right ventricular dysfunction.

Anticoagulation is the mainstay therapeutic strategy for acute PE. Systemic thrombolysis remains the first-line therapy for massive PE, but the current evidence does not demonstrate survival benefits conclusively. ¹⁰ Our patient was given only anticoagulation therapy and recovered well. In patients with exacerbations of nephrotic syndrome, steroids and diuretics should be used carefully in a monitored setting. To prevent the occurrence of PE as a complication of nephrotic syndrome, anticoagulation may be effective; however, the potential benefits must be weighed carefully against the risk of bleeding events.^1,11 After experiencing PE, the thromboembolic risk is greater in our patient and prophylactic anticoagulation is indicated during the next flare of nephrotic syndrome.

Conclusion

PE should be listed as a differential diagnosis in nephrotic patients presenting after syncope even when hypoalbuminemia and proteinuria are not severe, especially in patients taking concurrent steroid and diuretic therapy. Prompt recognition of PE and immediate anticoagulation treatment can help prevent the potential complications.