Renal · Glomerular Diseases
The facts most likely to be tested
Focal Segmental Glomerulosclerosis is the most common cause of nephrotic syndrome in African American and Hispanic adults.
The primary histologic finding is sclerosis of some, but not all, glomeruli (focal) and involving only segments of the affected glomeruli (segmental).
Electron microscopy reveals effacement of podocyte foot processes, which is the hallmark of all nephrotic syndromes.
Secondary FSGS is strongly associated with HIV infection, heroin abuse, sickle cell disease, and morbid obesity.
Patients typically present with nephrotic-range proteinuria, edema, and hypoalbuminemia, often accompanied by hypertension and renal insufficiency.
Immunofluorescence microscopy is typically negative for immune complex deposits, distinguishing it from other glomerulonephritides.
First-line treatment for primary FSGS involves corticosteroids or calcineurin inhibitors to induce remission and preserve renal function.
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A 34-year-old African American male presents to the clinic with a two-week history of progressive lower extremity edema and frothy urine. His medical history is significant for obesity (BMI 36) and untreated HIV infection. Physical examination reveals 3+ pitting edema to the knees and a blood pressure of 148/92 mmHg. Laboratory studies demonstrate a serum albumin of 2.4 g/dL, a total cholesterol of 310 mg/dL, and a urine protein-to-creatinine ratio of 4.2 g/g. Renal biopsy shows segmental sclerosis in a subset of glomeruli with effacement of podocyte foot processes on electron microscopy.
What is the most likely diagnosis?
Focal Segmental Glomerulosclerosis (FSGS)
The patient's presentation of nephrotic syndrome in the setting of HIV and obesity, combined with the classic biopsy findings of segmental sclerosis and podocyte effacement, is diagnostic for FSGS.
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Etiology / Epidemiology
Most common cause of nephrotic syndrome in African American adults; associated with HIV, heroin use, and sickle cell disease.
Clinical Manifestations
Presents with nephrotic syndrome: heavy proteinuria, edema, and hypoalbuminemia; often with hypertension.
Diagnosis
Renal biopsy is the gold standard showing segmental sclerosis on light microscopy and effacement of foot processes on EM.
Treatment
ACE inhibitors or ARBs for proteinuria; corticosteroids are the first-line immunosuppressive therapy.
Prognosis
High risk of progression to end-stage renal disease (ESRD); recurrence is common in renal transplant.
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Epidemiology & Etiology
FSGS is the leading cause of primary glomerular disease in adults, particularly in African Americans. Secondary causes include HIV-associated nephropathy, obesity, heroin abuse, and reflux nephropathy. It is characterized by damage to the podocytes leading to protein leakage.
Pertinent Anatomy
The disease targets the glomerular capillary tuft. Damage is restricted to a subset of glomeruli (focal) and only portions of the individual glomerulus (segmental).
Pathophysiology
Primary injury involves podocyte depletion or dysfunction, leading to the collapse of capillary loops. This results in hyalinosis and sclerosis of the glomerular segments. The loss of the slit diaphragm integrity causes massive proteinuria.
Clinical Manifestations
Patients present with classic nephrotic syndrome: peripheral edema, frothy urine, and hyperlipidemia. Unlike minimal change disease, hypertension and hematuria are frequently present. Acute kidney injury may occur in rapid-onset cases.
Diagnosis
Renal biopsy is required for definitive diagnosis. Light microscopy reveals segmental sclerosis and hyalinosis. Electron microscopy shows diffuse effacement of foot processes. Immunofluorescence is typically negative, distinguishing it from IgA nephropathy.
Treatment
Initial management focuses on ACE inhibitors or ARBs to reduce intraglomerular pressure. Corticosteroids are the first-line immunosuppressive agent for primary FSGS. Cyclosporine or tacrolimus are used for steroid-resistant cases. Avoid nephrotoxic agents in patients with declining GFR.
Prognosis
FSGS has a poor prognosis with a high rate of progression to ESRD. Patients require long-term monitoring of serum creatinine and urine protein-to-creatinine ratio. Recurrence in renal transplant is a significant clinical challenge.
Differential Diagnosis
Minimal Change Disease: usually pediatric, normal light microscopy
Membranous Nephropathy: associated with malignancy/SLE, 'spike and dome' on EM
IgA Nephropathy: hematuria following URI, IgA deposits on IF
Diabetic Nephropathy: Kimmelstiel-Wilson nodules, history of DM
Amyloidosis: Congo red stain positive, apple-green birefringence