Spontaneous remission rarely occurs in patients with primary FSGS. Patients with primary FSGS and massive proteinuria are also unlikely to respond to angiotensin II blockade with reduction of proteinuria or preservation of renal function.46
Patients with primary FSGS (excluding collapsing FSGS) can respond to corticosteroids although at a lower rate than MCD and require a more prolonged course of therapy.47,48 Prednisone at a dose of 1 mg/kg/day orally (not to exceed 80 mg/day) for at least 4 months is recommended as the initial therapy, although is not based on data from randomized controlled trials.49
Patients who fail to respond after 4 months of high-dose prednisone are considered steroid-resistant. Proteinuria response should be observed early, i.e., some reduction every month. A patient whose proteinuria does not decrease by >20% after 2 months of high-dose prednisone suggest non-responsiveness and early steroid-taper and discontinuation should be considered.
The use of high-dose corticosteroid doses (> 20 mg of prednisone for a period of 8 weeks or more) was associated with a significant risk of Pneumocystis carinii pneumonia (PCP) in patients who did not have AIDS.50 The UK National Comprehensive Cancer Network recommends PCP prophylaxis in patients receiving >20 mg/day of prednisolone for over 4 weeks (http://www. nccn.org).
A Cochrane meta-analysis of 12 randomized trials of PCP prophylaxis in 1,245 immunocompromised transplant recipients concluded that PCP prophylaxis is warranted for adults when the risk for PCP is above 3.1%.51 In addition, the American Thoracic Society recommends that immunosuppressed patients without HIV should take PCP prophylaxis if their prednisolone dose exceeds 20 mg/day for >1 month.52
Monotherapy with a calcineurin inhibitor (CNI)— either cyclosporine (CSA) or tacrolimus (TAC)—can be considered for patients who are steroid-resistant or have relapsing disease,53,54 or as initial therapy in patients who have contraindications to high-dose prednisone or would like to avoid steroids all together (e.g., obesity, diabetes). Failure to reduce proteinuria after 6 months of calcineurin inhibitor treatment at therapeutic targets equals resistance to therapy and medication should be discontinued.
Resistance to CSA does not equal resistance to TAC. Both CSA and TAC should not be regarded as “curative” agents for FSGS, as relapses occur frequently when they are discontinued, even after prolonged usage. These agents may act primarily by reducing glomerular permeability to protein and stabilization of the cytoskeleton but may not dramatically alter the underlying immune mechanism or pathogenesis process responsible for initiating the glomerular injury in primary FSGS.55
Long-duration (e.g., >1 year), with low-dose CNI therapy may be considered in patients with CNI dependency but the risk of cumulative nephrotoxicity requires careful followup. Mycophenolate mofetil,56 adrenocorticotropic hormone (native ACTH),57 and rituximab,58 have all been tried with various degrees of success but patients who are resistant to corticosteroids are not likely to respond to rituximab.
Similarly, patients who are steroid-dependent or are frequent relapsers can respond to cyclophosphamide, but patients with steroidresistant FSGS are unlikely to respond to this medication.49,59 Despite one encouraging report on the use of sirolimus in patients with FSGS,60 we recommend against this medication in patients with a marked proteinuria because of the risk of precipitating acute renal failure in these patients.61,62
A recent study reported on the benefit the cytotoxic T-lymphocyteassociated antigen 4-immunoglobulin fusion protein abatacept, a co-stimulatory inhibitor that targets CD80 (also own as B7-1), in 5 patients with recurrent GS after transplantation and in 1 patient with primary FSGS with all patients showing positive podocyte CD80 staining on renal biopsy.63
Patients his study were also treated with plasmapheresis, uximab, daclizumab, and antithymocyte globulin. Further research is needed to confirm these observations and to evaluate if abatacept benefits the majority of patients with FSGS who are not CD80 positive.64,65
Patients with secondary FSGS should be treated conservatively, with the goal of maximizing blood pressure control with the use of angiotensin II blockade (as opposed to primary FSGS, hypertension is more common in patients with secondary FSGS), low salt diet (<4 g/d), low protein diet (0.8-1 g/kg/d), lipid control with the use of a statin, smoking cessation, weight control, and avoidance of nephrotoxic medications.
The position to recommend conservative therapy in patients with secondary FSGS is based on the fact that angiotensin II blockade is usually able to reduce proteinuria to sub-nephrotic levels in these patients. In patients with FSGS, proteinuria <3.5 g/24 h is associated with good longterm renal prognosis (<15% progress to ESRD over a course of 10 years), making it difficult to justify high-dose corticosteroids in these patients.66,67
Recent Kidney Disease Improving Global Outcomes (KDIGO) guidelines state that: “There is no evidence to suggest corticosteroid or immunosuppressive therapy in secondary FSGS.”68 Similarly, a study by Crook et al showed no benefit of corticosteroid therapy in African-Americans with FSGS reinforcing our views that majority of African-Americans do not have primary FSGS.69
Familial cases of MCD70 as well as rare cases of familial diffuse mesangial sclerosis71 can respond to corticosteroids and other immunosuppressive agents but genetic forms of FSGS are considered corticosteroidresistant.72–74 Poor response to cyclosporine has also been reported in children with genetic forms of FSGS,75–78 but we are unaware of any benefit in genetic forms of FSGS presenting in adults.