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Focal Segmental Glomerulosclerosis
Focal segmental glomerulosclerosis is scattered (segmental) mesangial sclerosis that begins in some but not all (focal) glomeruli and eventually involves all glomeruli. It is most often idiopathic but may be secondary to use of heroin or other drugs, HIV infection, obesity, sickle cell disease, atheroembolic disease, or nephron loss (eg, in reflux nephropathy, subtotal nephrectomy, or renal dysgenesis). It manifests mainly in adolescents but also in young and middle-aged adults. Patients have insidious onset of proteinuria, mild hematuria, hypertension, and azotemia. Diagnosis is confirmed by renal biopsy. Treatment is with angiotensin inhibition and, for idiopathic disease, corticosteroids and sometimes cytotoxic drugs.
Focal segmental glomerulosclerosis (FSGS) is now the most common cause of idiopathic (or primary) nephrotic syndrome among adults in the US. It is especially common in black men. Though usually idiopathic, FSGS can occur in association with other factors (secondary FSGS), including drugs (eg, heroin, lithium, interferon alfa, pamidronate, cyclosporine, or NSAIDs [causing analgesic nephropathy]), atheroembolic disease affecting the kidneys, obesity, HIV infection (see HIV-Associated Nephropathy), and disorders causing nephron loss (eg, reflux nephropathy, subtotal nephrectomy, renal dysgenesis [eg oligomeganephronia: renal hypoplasia with a decreased number of nephrons]). Familial cases exist.
In FSGS, because charge as well as size ultrafiltration barriers are defective, proteinuria is typically nonselective, affecting high molecular-weight proteins (eg, Igs) as well as albumin. Kidneys tend to be small.
FSGS is suspected in patients with nephrotic syndrome, proteinuria, or renal dysfunction with no obvious cause, particularly patients who have disorders or use drugs associated with FSGS.
Urinalysis is done and BUN, serum creatinine, and 24-h urinary protein excretion are measured.
Diagnosis is confirmed by renal biopsy, which shows focal and segmental hyalinization of the glomeruli, often with immunostaining showing IgM and complement (C3) deposits in a nodular and coarse granular pattern. Electron microscopy reveals diffuse effacement of podocyte foot processes in idiopathic cases but may show patchy effacement in secondary cases. Global sclerosis may be visible, along with secondary atrophic glomeruli. Biopsy may be falsely negative if areas of focal abnormalities are not sampled.
Prognosis is poor. Spontaneous remissions occur in < 10% of patients. Renal failure occurs in > 50% of patients within 10 yr; in 20%, end-stage renal disease occurs within 2 yr despite treatment and is more likely if patients have significant tubulointerstitial fibrosis. The disorder is more rapidly progressive in adults than in children.
The presence of segmental sclerosis consistently at the glomerular pole where the tubule originates (tip lesion) may portend a more favorable response to corticosteroid therapy. Another variant, in which the capillary walls are wrinkled or collapsed (collapsing FSGS, which is typical in association with IV drug abuse or HIV infection), suggests more severe disease and rapid progression to renal failure. Pregnancy may exacerbate FSGS.
FSGS may recur after kidney transplantation; proteinuria sometimes returns within hours of transplantation. Of patients whose transplant was for end-stage renal disease caused by FSGS, about 8 to 30% lose their graft due to recurrent FSGS; risk is highest in young children, patients who are not black, patients who develop renal failure < 3 yr after disease onset, patients with mesangial proliferation, and patients with repeat transplants when the diagnosis before the first transplant was primary FSGS. Familial forms of FSGS rarely recur after transplantation.
Heroin addicts with nephrotic syndrome due to FSGS can experience complete remission if they cease taking heroin early in the disease.
Treatment often is not effective. Patients with FSGS should be treated with angiotensin inhibition (with an ACE inhibitor or an angiotensin II receptor blocker) unless contraindicated by angioedema or hyperkalemia. Patients with nephrotic syndrome should be treated with a statin.
In idiopathic FSGS, a trial of immunosuppressive therapy is indicated if proteinuria reaches the nephrotic range or if renal function worsens, especially if kidney biopsy reveals a tip lesion. In contrast, patients with secondary FSGS, collapsing FSGS, or advanced tubulointerstitial fibrosis on renal biopsy are generally not treated with immunosuppression because they tend to not respond; instead, the primary disorder is treated.
Corticosteroids (eg, prednisone 1 mg/kg po once/day or 2 mg/kg every other day) are recommended for at least 2 mo, although some experts recommend use for up to 9 mo. Response rates of 30 to 50% have been reported with prolonged therapy and vary by the histologic classification of FSGS. After a 2-wk remission of proteinuria, the corticosteroid is slowly tapered over ≥ 2 mo. Secondary and familial cases, collapsing FSGS, and advanced tubulointerstitial fibrosis are more likely to be corticosteroid-resistant.
If only slight improvement or relapse occurs with corticosteroid therapy, remission may be induced with cyclosporine 1.5 to 2 mg/kg po bid for 6 mo or, alternatively, mycophenolate mofetil 750 to 1000 mg po bid for 6 mo in patients > 1.25 m2 BSA or 600 mg/ m2 BSA bid up to 1000 mg bid.
In patients with contraindications to high-dose corticosteroids (eg, diabetes, osteoporosis), cyclosporine can be given along with a lower dose of corticosteroids (eg, prednisone 0.15 mg/kg po once/day).
An alternative is plasma exchange with tacrolimus immunosuppression.
Suspect FSGS if patients have nephrotic syndrome, proteinuria, or renal dysfunction with no obvious cause, particularly patients who have disorders or use drugs associated with FSGS.
When possible, confirm FSGS by renal biopsy with immunostaining and electron microscopy.
Consider treatment with corticosteroids and possibly cyclosporine or mycophenolate mofetil if FSGS is idiopathic and proteinuria reaches the nephrotic range or renal function worsens.
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