22-18: Focal Segmental Glomerulosclerosis

GENERAL CONSIDERATIONS

This relatively common renal pattern of injury results from damage to podocytes; such damage may be a primary/renal-limited disorder or may be secondary to another underlying disease state. Primary causes fall into three categories: (1) heritable abnormalities in any one of several podocyte proteins, or underlying type 4 collagen mutations; (2) polymorphisms in the APOL1 gene in those of sub-Saharan African ancestry; or (3) increased levels of a circulating permeability factor. Secondary causes include renal overwork injury, obesity, hypertension, chronic urinary reflux, HIV or SARS-CoV-2 infection, or analgesic or bisphosphonate exposure. Genetic testing in primary cases is becoming more common, especially in the pediatric population.

CLINICAL FINDINGS

In FSGS caused by a primary kidney disease, 80% of children and 50% of adults have overt nephrotic syndrome; however, when it develops due to a secondary cause, nephrotic syndrome is uncommon. Decreased GFR is present in 25–50% of those with FSGS at time of diagnosis.

Diagnosis requires kidney biopsy; there is no helpful serologic test. Light microscopy shows sclerosis of segments of some, but not all, glomeruli (eFigure 22–14). On immunofluorescence, IgM and C3 are seen in the sclerotic lesions, although it is presumed that these immune components are simply trapped in the sclerotic glomeruli and not pathogenetic. As in minimal change disease, electron microscopy shows fusion of epithelial foot processes.

TREATMENT

Treatment for all forms of FSGS includes diuretics for edema, ACE inhibitors and ARBs to control proteinuria and hypertension, and statins for hyperlipidemia; SGLT2-inhibitors may be considered for those not receiving immunosuppression. Immunosuppression therapy (oral prednisone, 1 mg/kg/day for 4–16 weeks followed by a slow taper) is reserved for nephrotic primary FSGS cases presumed to be due to a circulating permeability factor; in those with steroid-resistance or intolerance, calcineurin inhibitors and mycophenolate mofetil can be considered. Kidney transplantation in this subgroup of FSGS patients is complicated by a relatively high relapse rate and risk of graft loss. Plasma exchange therapy, and possibly rituximab, just prior to the transplant surgery and with early signs of relapse, appear to be beneficial. Those with APOL1-associated and hereditary primary renal disease may not benefit from immunosuppression, although robust clinical trials are lacking. Patients with secondary FSGS do not benefit from immunosuppressive therapy; treatment should be directed at the underlying cause.