Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney inter., Suppl. 2012; 2: 139–274.
Definition, Etiology, PathogenesisTop
Focal segmental glomerulosclerosis (FSGS) is a histologic pattern characterized by initial damage of the podocytes with progressive glomerulosclerosis and accompanying expansion of mesangial matrix. Sclerotic lesions are focal (some but not all glomeruli are involved) and segmental (only part of the glomerulus is involved), and multiple different histologic subtypes exist.
FSGS can be primary/idiopathic or secondary to a diverse group of causes. The cause of primary FSGS is unknown, although it is thought likely to be due to a circulating factor. Causes of secondary FSGS include hyperfiltration (reflux nephropathy, malignant hypertension, reduction of renal mass, obesity, and sickle cell anemia), drugs (heroin, pamidronate, lithium, calcineurin inhibitors, sirolimus), and viral infections (HIV, parvovirus B19, and less commonly cytomegalovirus or Epstein-Barr virus).
FSGS is more prevalent in African Americans and in males. Edema and proteinuria are the most common clinical manifestations. Nephrotic syndrome is often found and occurs in up to 80% of patients. Substantial edema and nephrotic range proteinuria are more common in primary FSGS. Microscopic hematuria, hypertension, and decreased glomerular filtration rate (GFR) are also frequently present.
Spontaneous remissions have been reported and are associated with preserved renal function, lower degrees of proteinuria at presentation, and the histologic “tip lesion.”
Diagnosis is based on histologic examination of kidney biopsy specimens. At least 20 glomeruli are required to exclude FSGS, given the focal nature of lesions.
All patients without contraindications should be treated with sodium restriction and renin-angiotensin system blockade to reduce proteinuria and control hypertension.
In addition to the renin-angiotensin system blockade, glucocorticoids are used to treat patients with primary FSGS There is some controversy over when to initiate immunosuppressive therapy but most elect only to treat those with nephrotic syndrome. Dosing and duration are based on observational data. Current recommendations are to use immunosuppression only in patients with nephrotic syndrome. Suggested doses are prednisone 1 mg/kg/d or 2 mg/kg every other day for 4 to 16 weeks until remission is achieved (daily proteinuria <300 mg/d) and then titrated over 6 months after remission. Remission is usually achieved slowly and will often take 3 to 4 months of glucocorticoid therapy. In patients who fail to respond or require alternative therapies to glucocorticoids, calcineurin inhibitors may be considered.
Secondary causes of FSGS are treated by addressing the underlying cause. There is no role for immunosuppression in secondary FSGS.
Without treatment most patients have progressive renal failure. Proteinuria is a strong predictor of progression: More than 50% of patients with proteinuria >3.5 g/d who do not respond to therapy progress to end-stage renal disease by 10 years, whereas patients with non–nephrotic range proteinuria have renal survival of 95%. Remission, even partial, is associated with significantly better renal outcomes. Other predictors of poor outcomes include African American populations, increased creatinine at presentation, and collapsing variant on histology.