Focal (segmental) glomerulosclerosis - Glomerular disease

Focal (segmental) glomerulosclerosis

Definition

Focal segmental glomerulosclerosis (FSGS) is one of the two most common primary causes of nephrotic syndrome in adults and the second most common cause in children.

Incidence/prevalence

Causes âˆ¼20% of cases of nephrotic syndrome in adults and children.

Aetiology

There are several classifications of FSGS, for example by the likely cause:

·        Primary FSGS: This is the idiopathic form, which tends to present with overt nephrotic syndrome in children and young adults.

·        Secondary FSGS: This tends to present with proteinuria and renal insufficiency, without nephrotic syndrome, usually in older adults. It is thought to be part of a physiological response to glomerular hyperfiltration/hypertrophy (e.g. in unilateral renal agenesis, reflux nephropathy, diabetes, preeclampsia) or previous focal damage to the glomerulus and then healing by scarring such as following vasculitis or lupus nephritis.

·        Specific causes such as drugs, toxins, HIV, heroin and familial forms.

Pathophysiology

The GBM is more permeable to proteins but the cause of this is unclear.

·        Podocyte damage: The initial problem may be damage to the epithelial cells (podocytes), attached to the GBM, possibly due to a circulating factor.

·        Glomerulosclerosis: Denudement of the basement membrane may lead to adhesion to the Bowman’s capsule. Alternatively large plasma proteins may leak through the capillary wall, accumulate in the subendothelial space and compress the capillary lumen.

·        Over time, the sclerosis affects more segments of the glomerulus, leading to global sclerosis and permanent loss of the function of that nephron.

Clinical features

In children and young adults with rapid onset of nephrotic syndrome, FSGS is suggested by atypical features such as non-selective proteinuria, haematuria, hypertension or renal impairment at the onset of nephrotic syndrome. These may develop later in the course of the illness. Steroid non-responsiveness in a patient with apparent minimal change disease also suggests FSGS.

Macroscopy/microscopy

Increase in the mesangial matrix in glomeruli in a focal segmental pattern, with collapse of the adjacent capillary loop. There may be tubular atrophy and interstitial fibrosis. Immunofluorescence usually shows a lack of immune deposits, apart from some non-specific binding of granular IgM and C3in the sclerosed areas of mesangium.

Investigations

Definitive diagnosis can only be made on renal biopsy. Because of the focal nature of the disease and the tendency for the juxtamedullary glomeruli to be affected first, the disease may be missed on renal biopsy (and hence a diagnosis of minimal change disease made).

Management

Almost all patients are treated with ACE inhibitors and cholesterollowering agents. ACE-inhibitors lower intra-glomerular pressure and so reduce proteinuria (with a probable slowing of deterioration of renal function).

In primary FSGS, approximately 50% may respond to steroids, although relapse is common and longer courses are generally required. Steroid resistant cases may respond to ciclosporin, and steroiddependent cases may benefit from the addition of ciclosporin or cyclophosphamide.

Secondary FSGS has no specific treatment. The FSGS may respond to withdrawal of any causative agent or treatment of any underlying cause.

Prognosis

Patients with marked proteinuria, tubular atrophy, interstitial fibrosis have a worse prognosis.