New Onset of Nephrotic Syndrome in a 17-year-old

A 17-year-old girl presents to the emergency department with facial swelling and 24 hours of persistent vomiting. She also reports acute onset of fatigue and weakness beginning the day of presentation. She denies fever, headaches, change in weight, chest pain, cough, abdominal pain, loss of appetite, diarrhea, rash, pruritus, bloody urine, or change in urination (frequency, color, odor, or volume). The patient is active in soccer and notes some intermittent fatigue and vomiting after practice occurring approximately 3 to 4 times during the past month. Further questioning reveals that the patient had undergone evaluation of right supraclavicular lymphadenopathy 2 months earlier with an otolaryngologist. A computed tomography (CT) scan with contrast was completed after this evaluation and confirmed the presence of an enlarged 2-cm supraclavicular lymph node and an additional 3.1-cm lymph node inferior to the thyroid gland, although with incomplete visualization on limited neck CT. After CT results, she underwent fine-needle aspiration (FNA), with results showing likely reactive lymphadenitis, for which she received a 10-day course of amoxicillin-clavulanate, which was completed 3 days before presentation. She had no improvement in the lymphadenopathy. Two days before presentation, she noted bilateral periorbital edema that persisted throughout the day, with no associated erythema, pruritus, or tearing. With concern for allergic rhinosinusitis, her primary care physician prescribed her a 5-day course of oral methylprednisolone. The patient had taken 1 dose of methylprednisolone on the day before presentation.On examination she is afebrile (temperature, 99°F [37.2°C]), hypotensive (blood pressure, 87/60 mm Hg), and tachycardic (heart rate, 101 beats/min), with a normal respiratory rate (12 breaths/min). Her weight is 121.3 lb (55 kg) (48th percentile), which her parents believe is her baseline weight. She has a delayed capillary refill time and mottling of her extremities, which improves with 2 L of fluid resuscitation. Blood pressure and heart rate also improve to 101/62 mm Hg and 86 beats/min, respectively. She is now alert and tired but nontoxic appearing. She is normocephalic, with pupils equal and reactive to light, and extraocular movements are intact. She does, however, have notable bilateral periorbital edema. Mucous membranes are moist, without pharyngeal erythema or exudates. Cardiac examination reveals a normal regular rate and rhythm with a normal S1/S2 and no murmurs. Capillary refill time is now 2 seconds, with strong radial and distal pulses bilaterally. Her lungs are clear to auscultation, with equal chest rise, normal work of breathing, and good air entry bilaterally. Her abdomen is soft, nontender, and nondistended. Her skin is without rash. She has 2+ pitting edema of her bilateral lower extremities. A 3-cm firm lymph node is palpable above the right clavicle, without additional palpable lymphadenopathy in the cervical, left supraclavicular, axillary, or inguinal nodal basins. She is neurologically intact and fully oriented, with full and equal extremity movement and full sensation. Laboratory evaluation includes a complete blood cell count with a white blood cell count of 18,200/µL (18.2 × 109/L) (83% neutrophils, 15% lymphocytes, no bands), a hemoglobin level of 19.7 g/dL (197 g/L), and a platelet count of 565 × 103/µL (565 × 109/L). Uric acid level is 3 mg/dL (0.18 mmol/L) (reference range, <7.5 mg/dL [<0.45 mmol/L]), and lactate dehydrogenase level is 226 U/L (3.77 µkat/L) (reference range, <3.4 µkat/L. A comprehensive metabolic panel shows normal electrolyte levels, including a creatinine level of 0.67 mg/dL (59.23 µmol/L) but a nearly undetectable albumin level (<1.0 g/dL [<10 g/L]). Urinalysis findings are normal except for 3+ protein with a urine protein-to-creatinine ratio of 11.4 mg/mg (reference range, <0.2 mg/mg). Total cholesterol level is 279 mg/dL (7.23 mmol/L) (reference range, <170 mg/dL [<4.40 mmol/L]). With these results, she is transferred to the nephrology service for further evaluation.The patient's clinical and laboratory features are consistent with nephrotic syndrome. Nephrotic syndrome is a condition caused by increased permeability of the glomerular filtration barrier to protein, resulting in heavy proteinuria with subsequent development of hypoalbuminemia, hyperlipidemia, and edema. Nephrotic-range proteinuria is typically defined as a urine protein-to-creatinine ratio of 2 mg/mg or greater or a 24-hour urine level of 1,000 mg/m2 per day or greater, corresponding to 3+ or 4+ by urine dipstick. (1) Nephrotic syndrome has many etiologies and is traditionally classified as primary (idiopathic) or secondary causes. A third subset is classified based on age at presentation and includes congenital and infantile nephrotic syndrome. Idiopathic nephrotic syndrome encompasses different histologic patterns of primary kidney diseases obtained through percutaneous kidney biopsy, including minimal change disease (MCD), focal segmental glomerulosclerosis, and membranous nephropathy. (2) Secondary nephrotic syndrome results from systemic diseases, including autoimmune conditions (systemic lupus erythematosus and vasculitis), infection (hepatitis B, hepatitis C, human immunodeficiency virus, syphilis, toxoplasmosis), medication toxicity (lithium, nonsteroidal anti-inflammatory drugs), and malignancy. (3) In childhood, nephrotic syndrome most commonly presents in school-age children, and in this age group MCD is the most common underlying histology. (3) Older age at onset is associated with a higher likelihood of corticosteroid-resistant nephrotic syndrome and should lead one to suspect disease other than MCD.Based on the patient's history and older age at presentation, a wide differential diagnosis including secondary causes of nephrotic syndrome was considered. Erythrocyte sedimentation rate was elevated (22 mm/hr [reference range, <20 mm/hr]), but C-reactive protein, serum C3 and C4, and antinuclear antibody levels were normal. Studies for infection, including hepatitis B, hepatitis C, and human immunodeficiency virus testing, were negative. Kidney ultrasonography revealed slightly enlarged kidneys for age. She subsequently underwent a kidney biopsy, with pathology diagnostic of MCD. Given her examination findings of supraclavicular lymphadenopathy, oncology was consulted and further cross-sectional imaging of neck, chest, abdomen, and pelvis were recommended, as well as excisional lymph node biopsy. A contrast-enhanced CT of the neck, chest, and abdomen again demonstrated right supraclavicular and prevascular lymphadenopathy, unchanged in size compared with her previous CT scan. Excisional lymph node biopsy showed abnormal lymphoid tissue in a nodular pattern with aggregates of large atypical cells (Reed-Sternberg cells and mononuclear Hodgkin variants) diagnostic of classical Hodgkin lymphoma (cHL), nodular sclerosing subtype. Staging evaluation revealed normocellular trilineage hematopoietic bone marrow on biopsy and no metastasis on positron emission tomography scan. Her final Hodgkin lymphoma staging was 2A without bulk and stratified as low risk.Persistent cervical lymphadenopathy in children may represent primary or metastatic malignancy. The most common malignancies before age 6 years are rhabdomyosarcoma and non-Hodgkin lymphoma. After age 6 years, cHL is the most common malignancy diagnosed in persistent cervical lymphadenopathy. Red flag physical examination characteristics that should raise suspicion for malignancy include unilateral, firm, indurated, "matted down" masses that are nontender to palpation. Patients with persistent symptoms for more than 4 to 6 weeks despite appropriate therapies (such as a course of corticosteroids or antibiotics) may require tissue diagnosis, with the gold standard for diagnosis being excisional biopsy. This patient initially had an FNA that showed reactive lymphadenitis, with the stated caveat that malignancy could not be ruled out. FNA has certain limitations. It has sensitivity of 86% and specificity of 96%, but 20% of FNA biopsy results are nondiagnostic and require further investigation. (4) Furthermore, an excisional biopsy should be considered for 1) suspicion of malignancy, 2) lack of resolution of lymphadenopathy in 4 to 6 weeks, 3) lymphadenopathy that steadily increases in size over 2 to 3 weeks, 4) lymphadenopathy greater than 2 cm, or 5) multiple lymph nodes that have concerning features on ultrasonography or CT. (4)Nephrotic syndrome can be paraneoplastic in origin. In 2 large studies of 1,700 adult patients with cHL, there were 2 main glomerulopathies significantly associated with the disease, including amyloidosis and MCD, noted in 0.1% and 0.4% of patients, respectively. (5) Data in pediatrics are lacking. Although the pathogenesis of MCD in cHL is unclear, research suggests that it may result from immune cell dysfunction and a subsequent release of a glomerular permeability factor, leading to the loss of large amounts of protein in the urine. (6) A 2006 case review of 21 adult patients with cHL and MCD showed that nephrotic syndrome appeared before the diagnosis of lymphoma in 38% of patients. Nephrotic syndrome was described as corticosteroid-resistant (50%) or corticosteroid-dependent (12.5%) in most of these patients. (5) However, remission of nephrotic syndrome was consistently achieved with remission of the underlying lymphoma. (5)In children 2 to 10 years of age at initial presentation, the most likely etiology of nephrotic syndrome is idiopathic MCD, and a kidney biopsy is typically not needed in this group. In the absence of clinical features or laboratory findings suggestive of alternative diagnoses, treatment consists of a course of oral corticosteroids with a recommended maximum daily dose of 60 mg/m2 or 2 mg/kg with a maximum of 60 mg/kg for 4 to 6 weeks. In uncomplicated cases, proteinuria resolves within a few weeks as patients enter remission. However, in patients older than 10 years, there is higher risk of histology other than MCD associated with nephrotic syndrome, underscoring the need to obtain a biopsy for histologic diagnosis. Other indications for kidney biopsy include poor or no response to initial therapy after 4 to 6 weeks of standard treatment (defined as corticosteroid-resistant disease) or other atypical features, such as concurrent hematuria, worsening kidney function, age younger than 1 year at presentation, hypocomplementemia, or significant hypertension at presentation. (7)Aside from initiation of corticosteroids, acute therapy of nephrotic syndrome is largely supportive and dependent on the patient's clinical status. Treatment is aimed at returning fluid to the intravascular space with intravenous albumin (usually 1 g/kg of a 25% solution) and encouraging diuresis with a loop diuretic such as furosemide to avoid fluid overload. Adjuvant therapies include dietary salt and fluid restrictions. (7) Although the literature for the treatment of paraneoplastic MCD is sparse and limited to case studies in adults, effective treatment of cHL is associated with simultaneous remission of nephrotic syndrome regardless of chemotherapy regimen used. It should be noted that these regimens often contain corticosteroids. This would suggest that MCD remission is conditioned by the response of the lymphoma to appropriate cancer-directed systemic therapy rather than by the specific agents used for the treatment of cHL. (5) Of the 21 patients in the study, most (72.2%) went into remission with corticosteroid therapy. Five patients (23.8%) developed MCD 12 months to 10 years after their first episode of nephrotic syndrome, and none of the patients had progressed to end-stage kidney disease by the end of the mean 6.3-year follow-up. (5)The patient received 25% albumin replacement on admission, with improvement in the edema. Corticosteroids were not started given the concern for possible malignancy. Corticosteroid pretreatment would have risked obscuring accurate lymphoma diagnosis and staging, as well as potential therapeutic trial eligibility, given the known highly cytolytic action of corticosteroids on lymphocytes. (8) Chemotherapy was started shortly after diagnosis of cHL with vincristine, etoposide, prednisone, and doxorubicin. She was also started on prophylactic enoxaparin therapy given her need for a central line, with an increased risk of thrombosis associated with both nephrotic syndrome and malignancy. The patient entered remission from her nephrotic syndrome, with resolution of proteinuria within her first week of chemotherapy.New onset of nephrotic syndrome in a child older than 10 years should prompt further evaluation for secondary causes, including autoimmune disease, infection, and malignancy.For persistent lymphadenopathy with red flag features on examination (unilateral, firm, indurated masses that are not tender to palpation), excisional biopsy should be pursued as the gold standard of evaluation; fine-needle aspiration should be avoided given the risk of equivocal or false-negative results.In a clinically stable patient with an unusual presentation of nephrotic syndrome and clinical concern for malignancy, it is important to defer corticosteroid treatment until definitive evaluation for malignancy can be performed given the lympholytic properties of corticosteroids to avoid obscuring accurate histologic diagnosis and disease staging.