Case Presentation: A 65-year-old man with hypertension presented to his primary care doctor with six months of lower extremity swelling. He also reported dyspnea on exertion, fatigue, unintentional weight loss, maculopapular rash, and foamy urine. Labs revealed hypoalbuminemia, elevated inflammatory markers, and protein-to-creatinine ratio of 3882, raising concern for nephrotic syndrome.He was referred to nephrology and scheduled for a renal biopsy, but then presented to the emergency department with worsening lower extremity edema and dyspnea on exertion, as well as right upper quadrant abdominal pain. Admission labs showed normal creatinine, worsening hypoalbuminemia, normal LFTs and bilirubin, and elevated alkaline phosphatase. Abdominal ultrasound showed a distended, thickened gallbladder with gallstones and biliary sludge, concerning for acute cholecystitis. Patient underwent cholecystectomy; while pathology was pending, planning resumed for inpatient renal biopsy given high suspicion for primary nephrotic disease. Workup revealed negative ANA, ANCA, RF, PLA2R, HIV, HBV, and HCV. Cholecystectomy pathology ultimately showed poorly differentiated gallbladder carcinoma, and renal biopsy was aborted due to the patient’s ongoing dyspnea and high suspicion for secondary membranous nephropathy due to malignancy.
Discussion: Glomerular disease is the third leading cause of ESKD in the U.S., behind hypertension and diabetes. Glomerular disorders present as two patterns – nephrotic and nephritic. “Nephrotic syndrome” is characterized by elevated urine protein (>3g/24h), hypoalbuminemia (< 3.5), peripheral edema, hyperlipidemia, and a hypercoagulable state. Nephrotic syndrome is associated with primary and secondary etiologies, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and amyloidosis. Workup includes CBC, renal function testing, inflammatory markers, lipid panel, and urine testing to quantify proteinuria and evaluate for hematuria. Anti-phospholipase A2 receptor (PLA2R) antibodies can be measured to evaluate for primary membranous nephropathy. Renal biopsy is required for definitive diagnosis; treatment depends on etiology. This patient had many symptoms concerning for nephrotic syndrome: edema, dyspnea on exertion, fatigue, foamy urine, and maculopapular rash. A primary etiology was initially suspected as he did not have known history to suggest a secondary cause (diabetes, autoimmune disease, amyloidosis). However, once a previously undiagnosed malignancy was found, secondary membranous nephropathy became highest on the differential. In retrospect, the patient reported unintentional weight loss and fatigue both outpatient and on admission, which could have prompted a malignancy workup. This case highlights the importance of considering malignancy on the differential for patients presenting with nephrotic syndrome of unknown etiology, particularly for patients reporting constitutional symptoms.
Conclusions: Glomerular disease is a major cause of ESKD in the U.S., and should be considered in patients with unexplained peripheral edema, shortness of breath, or urinary changes. Nephrotic syndrome is characterized by elevated urine protein, hypoalbuminemia, peripheral edema, hyperlipidemia, and a hypercoagulable state. In patients with nephrotic syndrome of unknown etiology, it is important to consider malignancy on the differential, especially in those reporting constitutional symptoms.