Case 1: The case of the irritable nephrotic

A 22-month-old previously healthy boy presented to a tertiary care emergency department with a one-week history of periorbital and bilateral leg swelling. He had no fever, no recent illnesses and no blood in his urine or stool. He was known to have chronic constipation and had a poor diet consisting mainly of cow’s milk. On physical examination, he had no hypertension, was in no apparent distress and displayed normal vital signs. He had marked periorbital edema and pitting edema of his lower limbs. His abdomen was distended and he had mild ascites. The rest of his examination was normal.

A urine dipstick showed a high protein level (20 g/L) and a large amount of blood. He had low serum albumin of 18 g/L (normal 32 g/L to 56 g/L), high serum triglycerides of 2.17 g/L (normal 0.31 g/L to 1.41 g/L) and high serum cholesterol of 8.82 mmol/L (normal 3.2 mmol/L to 4.4 mmol/L). His electrolytes and renal function were normal. A complete blood count revealed a low hemoglobin of 79 g/L (normal 110 g/L to 140 g/L) with a low mean corpuscular volume of 53 fL (normal 80 fL to 94 fL). His platelet count was elevated at 934×10⁹/L (normal 150×10⁹/L to 400×10⁹/L). A blood film showed marked hypochromasia and microcytosis. His iron and ferritin levels were both low.

He was diagnosed with nephrotic syndrome, as well as iron deficiency anemia (secondary to his poor diet), and was admitted to the hospital. He was initially treated with intravenous methylprednisone because he could not tolerate oral prednisone. He was also started on iron supplementation for his iron deficiency. In addition, the nephrology department recommended starting him on dipyridamole, an antiplatelet agent, because his thrombocytosis and nephrotic syndrome put him at an increased risk for thrombosis. Two days after admission, he was found to be hypertensive and more edematous. He was then treated with two doses of intravenous albumin and furosemide. The next day, his edema had significantly improved. He was switched to oral prednisone and seemed to be doing much better.

However, the next day he began vomiting his medications, and was unhappy and irritable. It was thought that he had gastritis from the prednisone and was started on ranitidine. His parents thought he may be constipated and he was also started on lactulose. He had a normal neurological examination. Two days later, he was able to tolerate his medications, and was discharged home despite his irritability. Close outpatient follow-up was arranged. Two days after his discharge, he was seen in the nephrology clinic and was found to be extremely irritable and inconsolable. He had a normal examination, and his edema was markedly improved. He was readmitted to the hospital, and further investigations revealed the etiology of his symptoms.

CASE 1 DIAGNOSIS: NEPHROTIC SYNDROME WITH CEREBRAL SINOVENOUS THROMBOSIS

An eye examination performed by the ophthalmology consultant showed bilateral papilledema. A computed tomography scan revealed an extensive sinovenous thrombosis of his superior sagittal and transverse sinuses. There were no infarcts or hemorrhages. He was diagnosed with cerebral sinovenous thrombosis (CSVT) secondary to nephrotic syndrome. He was initially started on unfractionated heparin, and then switched to low-molecular-weight heparin (enoxaparin). He clinically improved in hospital and was discharged home one week later. He remained on enoxaparin for six months. He finished the initial course of prednisone for his nephrotic syndrome, and has not had any relapses to date.

Nephrotic syndrome is a common renal disorder in childhood characterized by proteinuria, hypoalbuminemia and edema. The majority of cases are attributable to minimal change glomerulopathy, and referred to as idiopathic nephrotic syndrome. The peak age of onset occurs at two to three years (1).

The mainstay of treatment for nephrotic syndrome is steroids. Prednisone is the drug of choice, and is usually administered at a dose of 60 mg/m² for six weeks, and then tapered off over the next 10 weeks. In some patients with severe edema, albumin infusions with furosemide are given to help mobilize fluids.

The major complications of nephrotic syndrome that contribute to morbidity and mortality include infections (peritonitis, cellulitis and sepsis) and thromboembolism (1).

Nephrotic children are prone to develop thromboembolic complications secondary to an acquired hypercoagulable state (1). There are several potential mechanisms for the hypercoagulable state including urinary loss of proteins that inhibit coagulation (antithrombin III), a raised fibrinogen concentration, destabilization of platelets by hyperlipidemia and intravascular volume depletion (which can worsen with aggressive diuresis). To date, no predictors for thrombosis have been established in children with nephrotic syndrome, and prophylactic anticoagulation remains controversial. In our patient, the platelet count was elevated, which was an additional risk factor for thromboembolism, and dipyridamole was started. However, there is little evidence that this is a beneficial treatment.

The most common site of thrombosis in nephrotic syndrome is renal vein thrombosis. CSVT is not common in nephrotic children, but nevertheless can carry an increased morbidity compared with clots in other locations.

A recent review of cases of CSVT in nephrotic syndrome in Canada (2) revealed four cases documented in Toronto, Ontario, between 1992 and 2004. Fluss et al (2) also reviewed all cases documented in the literature, and included an additional 17 cases in their analysis. They found that the majority of cases of thrombosis presented with the first episode or within the first six months of diagnosis of nephrotic syndrome. Clinical manifestations were nonspecific, and consisted of seizures in eight cases and signs of increased intracranial pressure (headache, vomiting, lethargy and irritability) in 16 cases. Focal neurological deficits were seen in seven children (cranial nerve palsy or hemiparesis). All patients were anticoagulated with either unfractionated heparin or low-molecular-weight heparin, and the outcome was good in the majority of patients. One patient was left with cognitive impairment, and another died from a pulmonary embolus.

In conclusion, CSVT is a known complication of nephrotic syndrome. As in the present case, the signs and symptoms can be nonspecific, and patients do not necessarily present with seizures or neurological deficits. A high index of suspicion is needed, and head imaging should be ordered when CSVT is suspected because prompt initiation of therapy can decrease morbidity.

CLINICAL PEARLS

• Patients with nephrotic syndrome are prone to develop thromboembolic complications.

• CSVT is a rare, but a well-described complication of nephrotic syndrome.

• Symptoms of CSVT can be nonspecific and careful attention should be paid to any neurological symptoms, including irritability in patients with nephrotic syndrome.

• Treatment of CSVT with anticoagulants can lead to good outcomes.