الفهرس 
Glomerular DiseasesOnly 14 pages are availabe for public view
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Abstract
Summary
FSGS was first described in 1957. It is characterized by the presence of a scarring lesion in a portion (segment) of some (focal), but not all glomeruli. The primary pathophsiologic process in FSGS is an injury to podocytes, with proliferation of mesangial, endothelial and epithelial cells in early stages followed by shrinkage and/or collapse of glomerular capillary and ultimately sclerosis.
FSGS is classified according to the etiology into idiopathic (primary) and secondary e.g. familial, virus associated as HIV, drugs as heroin. According to Columbia classification there are five histological variants:
Collapsing variant: defined by collapse of at least one capillary loop with obliteration of lumen with proliferation (hyperplasia) and hypertrophy of the overlying podocytes.
Tip variant: characterized by at least one glomerulus with a segmental lesion involving the tip domain of the glomerular capillary tuft.
Cellular variant: defined by the presence of at least one glomerulus with segmental endocapillary proliferation occluding lumina with or without karyorrhexis.
Perihilar variant: the segmental sclerotic lesion is located at the vascular pole and often accompanied by hyalinosis.
FSGS not otherwise specified: a term used when non of the above definitions apply. It is the most common histologic subtype.
FSGS usually occurs at age 18-48 years but it can occur at any age. The male to female ratio is 3:1, it is more common in blacks. It presents clinically with nephrotic syndrome, characterized by edema, massive proteinuria, hypoalbuminemia and hyperlipidemia.
The renal biopsy is the most definitive way to establish diagnosis. Segmental sclerosis is seen by light microscopy. Immunofluorescence shows deposits of C3 and IgM in the affected portion. Electron microscopy shows effacement of foot processes. Other investigations include: urine analysis, serum creatinine and ultrasound examination.
Poor prognosis is associated with black race, podocin mutations, serum creatinine >1.3 mg/dl, heavy proteinuria and some histological variants as collapsing variant.
Treatment of FSGS includes:
• Non specific treatment: diuretics for edema, ACEI and ARBs for proteinuria and statins for hyperlipidemia.
• Specific treatment:
- Corticosteroids remain the mainstay of treatment. A full dose (1mg/kg/day) prednisone is given for 8-12 weeks followed by a slow tapering dose.
- Cyclosporine is used in treatment of FSGS. It’s efficacy depends on the previous response to steroids. A major concern is the nephrotoxicity of cyclosporine which is associated with high doses (>5mg/kg/day).
- TAC is useful in steroid resistant cases and patients not responding to cyclophosphamide and cyclosporine.
- Sirolimus is a novel immunosuppressive agent but shows no long term nephrotoxicity. The supposed absence of nephrotoxicity, coupled with immunosuppressive effects, has made sirolimus an alternative to calcineurin inhibitors in renal transplantation.
- MMF may induce complete or partial remission in steroid and cyclosporine resistant FSGS without inducing the side effects of nephrotoxicity seen with calcineurin inhibitor therapy .
- Cyclophosphamide is used in steroid dependant cases and multi relapsing forms. It induces long lasting remission. Cyclophosphamide do not seem to benefit in FSGS steroid resistant patients
- Plasmapheresis and plasma immunadsorption are useful in treatment of steroid and cyclosporine resistant FSGS. It is also used in treatment of recurrent FSGS after transplantation.
- LDL apheres is in patients with steroid resistant primary FSGS have demonstrated some benefit in terms of reduction in proteinuria and improvement in serum albumin concentration
- Rosiglitazone. It is licensed for the treatment of diabetes mellitus. A recent phase I trial by the FONT study group showed that rosiglitazone was well tolerated in children with therapy resistant FSGS .
Newly discovered treatment:
(A) Monoclonal antibodies
- Rituximab (anti CD20 monoclonal antibody) which is useful in refractory steroid dependant nephrotic syndrome and post transplant recurrent FSGS.
- Adalimumab is a human monoclonal antibody directed against tumor necrosis factor α (TNF-α) . An ongoing phase I trial by the novel therapies for resistant FSGS (FONT) study group in children with therapy resistant FSGS showed that adalimumab was well tolerated and showed stabilization of renal function and reduced proteinuria .
- Fresolimumab is a human monoclonal antibody that inactivates all forms of transforming growth factor-beta (TGF-β), in a phase I open label, dose ranging study. Single dose fresolimumab was well tolerated in patients with primary resistant FSGS. Additional evaluation in a larger dose ranging study is necessary .
(B) Adrenocorticotropic hormone (ACTH)
- Natural ACTH gel might be effective in a variety of nephrotic diseases; most extensively in patients with idiopathic membranous nephropathy. Some patients with steroid dependent or steroid resistant FSGS may also respond to natural ACTH therapy .
(C) Abatacept
Abatacept : It produces a complete and a partial remission in a case series of patients with relapsing post transplant FSGS and steroid resistant FSGS. However, these patients received co interventions (eg, plasma exchange, immunosuppression). Further studies are required before abatacept therapy can be recommended in patients with primary FSGS .
(D) Galactose
FSGS soluble factor found in recurrent FSGS has an affinity for galactose in column chromatography experiments. Oral galactose reduces the plasma activity of the FSGS soluble factor in patients with recurrent FSGS and reduces proteinuria in adult patient with resistant FSGS . larger studies are needed to evaluate the role and side effects of this novel approach to the therapy of FSGS .
(E) FDA approves Liposorber LA-15 System for pediatric focal segmental glomerulosclerosis either before or after kidney transplantation.
Future therapy:
(1) Podocyte stem cells
(2) Deoxyspergualin: It is a potent immunosuppressive medication , induced complete remission and regression of FSGS in both native and transplanted kidneys in rats. The effect of this agent in human disease is unknown, but this observation may lead to the development of new agents for the treatment of FSGS.
• The treatment of secondary FSGS is directed towards the underlying etiology .