Primary or Secondary? A Diagnostic Dilemma in Tip Lesion FSGS

Introduction: The nomenclature of FSGS has evolved from the 2004 Columbia classification, which focused on histopathologic variants, to the 2021 KDIGO guidelines, which categorize FSGS into primary, secondary, genetic, and undetermined types. Although diagnostic algorithms have been proposed, ambiguity remains, increasing the risk of misclassification and potentially affecting treatment decisions. We present a case highlighting these overlapping features between primary and secondary FSGS. Case Description: A 55-year-old woman with no prior kidney disease developed progressive dyspnea, periorbital and lower extremity edema, and a 30-pound weight gain over two weeks. She noted taking 150mg of oral diclofenac daily over the past year for a labral tear. Initial evaluation revealed hypoalbuminemia (2.7 g/dL), nephrotic-range proteinuria (spot UPCR 6.68 g/g), and preserved renal function (serum creatinine 0.82 mg/dL). Kidney biopsy consisting of four glomeruli demonstrated FSGS with a tip lesion pattern and 100% podocyte foot process effacement on electron microscopy. Diclofenac tablets were discontinued, and she was managed conservatively with telmisartan, bumetanide, and dietary sodium restriction. Immunosuppression was deferred due to the suspected NSAID-related secondary etiology. At two-week follow-up, she had complete resolution of edema, blood pressure normalization, and weight loss of 30 pounds. Laboratory results showed improved albumin (3.6 g/dL), reduced proteinuria (spot UPCR 0.29 g/g), and stable creatinine (0.76 mg/dL). She was able to discontinue all supportive therapies, and as of two months after the inciting event, she has had no recurrence. Discussion: This case highlights the rapid remission in secondary FSGS with tip lesion morphology and the importance of identifying reversible triggers to guide management. It also illustrates the diagnostic uncertainty in FSGS, as no clinical or histopathologic findings are pathognomonic for a specific subtype. Although the biopsy showed features typical of primary FSGS (tip lesion and diffuse podocyte effacement), the clinical context pointed to a secondary NSAID-induced cause. Moving forward, a more precise classification system is needed to better distinguish subtypes as this is crucial in guiding appropriate management.