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 to underlying type 4 collagen mutations; (2) polymorphisms in the APOL1 gene in those of African descent; or (3) increased levels of a circulating permeability factor. Secondary causes include renal overwork injury, obesity, hypertension, chronic urinary reflux, HIV infection, or analgesic or bisphosphonate exposure. Genetic testing in primary cases is becoming more common, especially in the pediatric population.
Proteinuria is present in patients with FSGS. In FSGS caused by a primary renal disease, 80% of children and 50% of adults have overt nephrotic syndrome; however, when it develops due to a secondary cause, frank 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.
Focal segmental glomerulosclerosis. (Used, with permission, from Jean Olson, MD.)
Treatment for all forms of FSGS includes diuretics for edema, ACE inhibitors or ARBs to control proteinuria and hypertension, and statins or niacin for hyperlipidemia. 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 nonhereditary 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 inciting cause.
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et al. Rituximab therapy ...