Focal Segmental Glomerulosclerosis

GENERAL PRINCIPLES

• FSGS is not a single disease but rather a pattern of glomerular injury with various mechanisms. It typically presents with nephrotic syndrome, hypertension, and sometimes renal insufficiency.

• FSGS can be classified into primary (idiopathic) and secondary forms.¹⁸ Secondary forms of FSGS are associated with obesity, vesicoureteral reflux, sickle cell disease, medications (pamidronate, α- interferon, tyrosine kinase inhibitors), and infections (HIV, parvovirus, CMV, EBV).

DIAGNOSIS

The kidney biopsy reveals segmental sclerosis of some glomeruli under light microscopy. The degree of interstitial fibrosis and tubular atrophy (rather than glomerular scarring) correlates with prognosis. Immunofluorescence shows deposition of IgM and C3 in areas of sclerosis, representing areas of trapped immune deposits. Electron microscopy shows effacement of the podocyte foot processes similar to that seen in MCD. Lesions can be classified into distinct histomorphologic variants, though their clinical significance is uncertain. The tip variant tends to have the most favorable prognosis while the collapsing variant is associated with the poorest outcomes.

TREATMENT

Management is similar to MCD. For patients with nephrotic range proteinuria, a trial of high-dose oral prednisone at 1 mg/kg daily (not exceeding 80 mg daily) or 2 mg/kg on alternate days (not exceeding 120 mg, every other day) may induce remission and then be tapered off over a 6-month period. Patients who relapse after a period of apparent responsiveness may benefit from a repeat course of steroids. Nonresponders and relapsers may respond to treatment with cyclosporine 5 mg/kg/d. Cyclophosphamide and mycophenolate mofetil can also be used. Induction of a complete remission (that may progress to ESRD.

DIAGNOSIS

Diagnostic Testing

Kidney biopsy is not usually performed in patients who present with classic DN unless the rate of renal decline is more rapid than would be anticipated, or to rule out other causes of nephrotic syndrome.

TREATMENT

Tight glycemic control was associated with better outcomes in patients with type 1 diabetes mellitus; the benefit was not as profound in patients with type 2 diabetes mellitus.²³ Specific hyperglycemic therapy is discussed further in Chapter 23, Diabetes Mellitus and Related Disorders. An ACE inhibitor or ARB is considered the first-line agent in the treatment of hypertension in diabetic patients and can improve proteinuria. Studies combining ACE inhibitors with an ARB or the direct renin inhibitor aliskiren have shown worse renal and cardiovascular outcomes.²⁴ Metformin should not be started in patients with a GFR infection) or decreased clearance (hepatic cirrhosis) may predispose to development of this disease.

• This disease process is typically idiopathic, characterized by a nephritic picture with microscopic (and less commonly, macroscopic) hematuria and nonnephrotic range proteinuria.

• Presentation is usually in the second or third decade of life, often following a slowly progressive course. Multiple forms of pathology exist, from mild lesions and mesangial proliferation to global sclerosis resulting in progression to ESRD.

• Henoch-Schonlein purpura is a related disorder that may represent a systemic form of the disease, with vasculitis of the skin (palpable purpura of the lower trunk and extremities), gastrointestinal tract, and joints.

DIAGNOSIS

Diagnostic Testing

Kidney biopsy shows increased mesangial cellularity on light microscopy, with predominant IgA and C3 deposition on immunofluorescence. On electron microscopy, there are electron dense deposits in the mesangium.

TREATMENT

• Aggressiveness of therapy depends on the severity of disease. For patients with a benign course, conservative management with ACE inhibitors or ARBs is recommended. The benefit of omega-3 fatty acid fish oil remains controversial.

• For patients with persistent proteinuria of >1 g/d despite maximally tolerated RAAS blockade, corticosteroids have been shown to provide benefit with reduction of proteinuria and slowed decline in GFR.³⁰ Long-term sustained benefit with immunosuppression is less well-established.³¹ The incidence of adverse events was higher in subjects receiving immunosuppression rather than conservative therapy alone, thus treatment decisions need to be individualized.