Chapter 25. Focal Segmental Glomerulosclerosis

• Focal segmental glomerulosclerosis (FSGS) can be primary or secondary.
• Diagnosis requires the presence of the characteristic histopathologic lesion.
• Genetic abnormalities in podocyte proteins may account for 25% of primary FSGS.
• The presenting complaint is usually proteinuria or nephrotic syndrome.
• Nearly 50% of cases progress to end-stage renal disease (ESRD) over 5–10 years and disease recurs in 30% of those who receive a kidney transplant.
• Failure to respond to corticosteroid treatment is a poor prognostic sign and there is no proven therapy in these patients.

Epidemiology

FSGS is an important glomerulopathy because it has a high risk of progression to ESRD. It is not a distinct disease but rather represents a pattern of response to injury that probably originates in the podocyte. FSGS occurs in all ethnic groups, both genders, and all geographic locales. Recent data indicate that the incidence of FSGS is rising, especially in black patients. This has been confirmed in reviews of renal biopsy findings in the United States and Canada that demonstrate a 2- to 3-fold increase in the incidence of FSGS over the period from 1984 to 2002. In addition, according to the North American Pediatric Renal Transplant Collaborative Study, FSGS is the most frequent form of acquired renal disease necessitating renal replacement therapy in pediatric patients. Similarly, it is the most common cause of idiopathic nephrotic syndrome in adults and is a major cause of ESRD.

Presenting Complaints

FSGS usually presents with asymptomatic proteinuria or overt nephrotic syndrome. In those patients who are diagnosed with isolated proteinuria, the abnormality is usually detected on a routine urinalysis. The clinical picture in those who present with nephrotic syndrome is almost indistinguishable from those with minimal change nephrotic syndrome (MCNS). Hematuria, evidence of tubular dysfunction such as glycosuria, hypertension, and mild azotemia, may be present in 15–30% of patients with new-onset nephrotic syndrome and these features may increase the clinical suspicion that a patient has FSGS. However, the key feature that prompts further investigation to establish the diagnosis of FSGS is failure to respond to a standard course of corticosteroids. It is this clinical finding that triggers the performance of a diagnostic renal biopsy; however, the utilization and timing of this procedure may differ among those who care for children or adults. Although the prognosis may be better in patients who present with subnephrotic-range proteinuria versus nephrotic syndrome, this difference has not been confirmed in patients of all ages.

Pathologic Findings

The diagnosis of FSGS requires histopathologic evidence of segmental glomerular sclerosis and hyalinosis. The lesion often manifests in juxtamedullary nephrons during the early stages of disease and it can be associated with periglomerular scarring, tubular atrophy, and interstitial fibrosis in the vicinity of the affected glomerulus (Figure 25–1). Generally, immunofluorescence studies are unrevealing. Electron microscopy demonstrates foot process effacement, the absence of immune deposits, and mesangial sclerosis.