Nephrotic syndrome in the first year of life, characterized by renal dysfunction and proteinuria, is associated with a heterogeneous group of disorders. These disorders are often related to genetic mutations, but the syndrome can also be caused by a variety of other diseases. We report an infant with nephrotic syndrome associated with a neuroblastoma. A 6-month-old girl was admitted with a 10% weight loss over 10 days and nephrotic-range proteinuria. She was ill-looking, and her blood pressure was higher than normal for her age. Her cystatin-C glomerular filtration rate was decreased, and levels of plasma renin, aldosterone, and catecholamines were elevated. Renal ultrasonography and abdominal computed tomography showed a retroperitoneal prevertebral mass encasing both renal arteries and the left renal vein. The mass was partially resected laparoscopically, and the pathologic diagnosis was neuroblastoma. Findings on a simultaneous renal biopsy were unremarkable. The patient was treated with chemotherapy and several anti-hypertensive drugs, including an alpha blocker. Two months later, the mass had decreased in size and the proteinuria and hypertension were gradually improving. In an infant with abnormal renin-angiotensin system activation, severe hypertension, and nephrotic-range proteinuria, neuroblastoma can be considered in the differential diagnosis.
Congenital nephrotic syndrome presents at birth or during the first 3 months of life, whereas infantile nephrotic syndrome is diagnosed during the first year [
A 6-month-old girl was admitted with nephrotic-range proteinuria after a febrile illness. Over the preceding 10 days, her oral intake had decreased by half and her weight had dropped from 9 to 8.1 kg (a 10% decrease). She had been healthy at birth at a gestational age of 37 weeks and with a birth weight of 2,770 g. However, she had required neonatal intensive care unit for 10 days after birth due to a febrile illness. Prenatal ultrasonography had shown no remarkable findings, and there was no family history of renal disease. Her blood pressure on admission was high on repeated measurements (163/106 mmHg, above the 95th percentile for age). Her temperature was 36.9℃, heart rate 156 beats/min, and respiratory rate 40 breaths/min. She appeared acutely ill. There was no lymphadenopathy, her breath sounds were clear, and there was no cardiac murmur, hepatosplenomegaly, or generalized edema.
On complete blood count, the leukocyte count was 14,800/mm3, hemoglobin 10.8 g/dL, and platelets 278,000/mm3. Arterial blood gas analysis reported a pH of 7.49, pCO2 38.0 mmHg, and bicarbonate 29 mEq/L. Blood urea nitrogen was 9 mg/dL, creatinine 0.2 mg/dL, and the cystatin-C glomerular filtration rate (GFR) 69 mL/min/1.73m2. The cholesterol was 390 mg/dL, total plasma protein 4.5 g/dL, and albumin 1.7 mg/dL. The aspartate aminotransferase was 36 IU/L, alanine aminotransferase 40 IU/l, total bilirubin 0.2 mg/dL, sodium 131 mmol/L, potassium 3.5 mmol/L, and chloride 94 mmol/L. The C-reactive protein was 1.06 mg/dL (normal range 0–0.6 mg/dL) and B-type natriuretic peptide 272 pg/mL (normal range 0–100 pg/mL). Immunoglobulin and complement levels were all within the normal ranges. The plasma renin activity was 40.0 ng/mL/h (normal range 0–1.16 ng/mL/h), aldosterone 242 ng/dL (normal range 5–90 ng/dL), cortisol 8.4 ug/dL (normal range 5-25 ug/dL), parathyroid hormone 22.1 pg/mL (normal range <0.90 pg/mL), epinephrine 148.8 pg/mL (normal range <50 pg/mL), norepinephrine 3,375.2 pg/mL (normal range 110–410 pg/mL), and plasma normetanephrine 12.33 nmol/L (normal range <0.90 nmol/L), while the metanephrine level was normal at 0.46 nmol/L (normal range <0.50 nmol/L). These laboratory results are summarized in
Urinalysis revealed a spot urine albumin-to-creatinine ratio of 19,792 mg/g and a spot urine protein-to-creatinine ratio of 19,098.4 mg/g. The pH was 7.0 and specific gravity 1.015. A urine culture was sterile.
Initial ultrasonography was unremarkable. However, because the serum renin and aldosterone were increased, we repeated the ultrasonography to search for a cause of renal hypertension. The repeat renal imaging revealed a heterogeneous, echogenic, 3.9×1.9 cm mass with internal calcifications in the midline of the upper abdomen. There was swelling of the left kidney with increased parenchymal echogenicity and a poorly differentiated corticomedullary junction. Abdominal computed tomography (CT) demonstrated that the mass was located prevertebrally, surrounding the anterior margin of the abdominal aorta and encasing the celiac axis, both renal arteries, and the inferior vena cava at the insertion site of the left renal vein (
The patient underwent laparoscopic excisional biopsy of the mass and a right kidney biopsy. The frozen section of the mass revealed a neuroblastoma. The serum neuron specific enolase was elevated at 32.4 ng/mL. Histopathology of the mass showed a poorly differentiated, N-myc-negative neuroblastoma with favorable histology. Evaluation of the renal tissue specimen revealed glomeruli of normal size and distribution, with no evidence of crescent formation or sclerosis. The mesangium, interstitium, tubules, and blood vessels were all unremarkable. On transmission electron microscopy, there were no electron-dense deposits or focal effacement of foot processes (
To address the nephrotic syndrome and hypertension, the patient was treated with deflazacort, 2.25 mg/kg/day, and anti-hypertensive drugs, including an alpha blocker. An angiotensin converting enzyme (ACE) inhibitor was added before chemotherapy was started. The latter consisted of 4 cycles of carboplatin, etoposide, cyclophosphamide, and doxorubicin. Her blood pressure and proteinuria gradually improved during chemotherapy, eventually reaching levels normal for her age. Most of the drugs therefore could be discontinued except for the ACE inhibitor. After chemotherapy, the spot urine protein-to-creatinine ratio decreased to 381.2 mg/g. Follow-up abdominal CT showed that the neuroblastoma had decreased in size to 1.4×1.1×2.4 cm over 2 months. After chemotherapy was completed, the neuroblastoma was even smaller and subsequently remained stable and she underwent excision operation of residual neuroblastoma. Serum albumin levels increased, and the serum renin activity and aldosterone level decreased to 25.1 ng/mL/h (normal range 0–1.16 ng/mL/h) and 16.9 ng/dL (normal range 5–90 ng/dL).
In adults, nephrotic syndrome is known in some cases to be associated with cancer and a worse cancer prognosis [
However, the coexistence of nephrotic syndrome and a neoplasm is rarely found in children [
In the present case, because the neuroblastoma encased both renal arteries and the left renal vein, there was partial compression of the renal vessels by the tumor mass, with disruption of the renal blood supply. Compression of the renal vein is not only a common cause of treatable hypertension, but it also increases intraglomerular pressure and renin activity [
As an embryonal malignancy of the sympathetic nervous system, neuroblastoma can also be associated with elevated plasma catecholamine levels, which may, along with renal artery compression, contribute to severe hypertension [
On admission, our patient’s cystatin-C GFR was below normal at 69 mL/min/1.73m2. This presumably indicated impaired renal function due to bilateral compression of the renal arteries. Renal-artery stenosis may occur in combination with renal insufficiency. In patients with renal-artery stenosis and renal failure, renal revascularization may improve or stabilize renal function [
As noted above, there are few reported cases of infantile nephrotic syndrome associated with a neuroblastoma. The initial presentation of neuroblastoma may vary considerably from case to case depending on where it arises in the widespread sympathetic nerve system [
This study was approved by the institutional review board (IRB), and the consent was waived due to the nature of the retrospective study [IRB number S2018-1230-0001].
No potential conflict of interest relevant to this article was reported.
Abdominal computed tomography in a 6-month-old girl ; Serial abdominal computed tomography (CT) views show a neuroblastoma that gradually decreased in size with treatment. (A) and (B): Initial CT shows a lobulated, low attenuating, 3.9×2.2×4 cm mass in the midline of the retroperitoneum (white arrow). (C) and (D): Interval decrease and stabilization in size of the neuroblastoma after chemotherapy.
Excisional biopsy specimen of the neuroblastoma; (A) Tissue from an excisional biopsy of the retroperitoneal mass (H&E, 400), demonstrating a poorly differentiated neuroblastoma with favorable histology. (B) The tissue is negative for a change in the N-myc gene copy number on fluorescent in situ hybridization. (C) Right kidney tissue (H&E, 200) showing no obvious histologic lesion. None of the glomeruli have crescent formation or sclerosis, and the mesangium is unremarkable. (D ) Right kidney tissue electron microscopy (3,000) showng no electron-dense deposits or focal foot process effacement.
Details in Initial and Final Laboratory Tests
Laboratory test (normal range) | Initial | Final |
---|---|---|
Spot urine protein to Cr ratio | 19,098.4 mg/g | 381.2 mg/g |
BUN/Cr | 9 mg/dL / 0.2 mg/dL | 8 mg/dL / 0.25 mg/dL |
Cystatin-C GFR | 69 mL/min/1.73m2 | 105 mL/min/1.73 m2 |
Total plasma protein | 4.5 g/dL | 7.0 g/dL |
albumin | 1.7 mg/dL | 4.0 mg/dL |
Renin (0–1.16 ng/mL/h) | 40.0 | 25.1 |
Aldosterone (5–90 ng/dL) | 242 | 16.9 |
Epinephrine (<50 pg/mL) | 148.8 | 56.0 |
Norepinephrine (110–410 pg/mL) | 3,375.2 | 851.5 |
Normetanephrine (<0.90 nmol/L) | 12.33 | 2.27 |
Metanephrine (<0.50 nmol/L) | 0.46 | 0.14 |
Neuroblastoma size | 3.9× 2.2×4 cm | 1.4×1.1×2.4 cm |
Neuroblastoma size before excision operation.
Final laboratory tests underwent after 4 cycles of chemotherapy.
Abbreviations: BUN, blood urea nitrogen; Cr, creatinine; GFR, glomerular filtration rate.