Approach Considerations
Treatment of focal segmental glomerulosclerosis (FSGS) can be divided into nonspecific and specific treatment.
In patients with primary or secondary FSGS (non-nephrotic or nephrotic) and proteinuria, the initial approach consists of optimal blood pressure (BP) control and the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). For patients who remain non-nephrotic or become non-nephrotic after 6 months of therapy, this remains the primary therapeutic approach. [41]
In patients with secondary FSGS and nephrotic-range proteinuria, the mainstay of therapy remains BP control and ACEIs and ARBs, along with disease-specific treatment if available (eg, antiretroviral therapy in HIV-associated nephropathy). Patients who are persistently nephrotic after a course of conservative therapy or who present with complications from nephrotic syndrome require more aggressive treatment with prednisone or immunosuppressive agents. [41]
Nonspecific Treatment
Nonspecific treatment goals in patients with nephrotic syndrome include maintenance of adequate nutrition, minimization or elimination of proteinuria, and prevention of complications resulting from edema. Control of hypertension is one of the most important aspects of overall management. Lowering of lipid levels is necessary to reduce cardiovascular risk and to possibly delay the progression of renal disease.
The mainstay of treatment is reduction in daily salt intake to 2 g of sodium (6 g of salt) and the use of diuretics in varying doses and combinations. Because a high level of protein intake may further aggravate proteinuria, adversely affecting renal function, current recommendations call for an intake of 1-1.3 g of high biologic value protein per kilogram of body weight. A reduction of dietary fat intake may help with dyslipidemia.
In most patients, loop diuretics (eg, furosemide) are needed to promote diuresis. Patients with massive edema with impaired oral absorption may require intravenous administration. In patients with refractory conditions, addition of other diuretics (eg, metolazone) and potassium-sparing agents (eg, spironolactone, triamterene) facilitates diuresis and prevents hypokalemia.
Rarely, some patients (especially children) with intractable edema may need intravenous albumin and mannitol in a hospital setting to initiate diuresis. Protracted use of intravenous albumin should be discouraged; the regimen is expensive and ineffective, because most of the infused albumin is lost in the urine.
ACEIs and ARBs are nonspecific agents that reduce proteinuria because of their antihypertensive and intrarenal hemodynamic effects of reducing glomerular capillary pressure and resistance. ACEIs and ARBs are effective in reducing protein loss even in normotensive patients. These agents do not eliminate proteinuria completely or reverse the primary glomerular disease process.
Since most patients with idiopathic FSGS develop hypertension, which further contributes to renal functional deterioration, meticulous attention must be paid to maintain BP in the reference range. In addition to lowering BP, all classes of antihypertensive agents have a beneficial effect in reducing proteinuria. In many patients, combination antihypertensive therapy may be needed to maintain normal blood pressure.
Another nonspecific therapy is the use of lipid-lowering agents to control hyperlipidemia. Statins are better tolerated than some of the older agents.
Specific Treatment
Idiopathic FSGS is a difficult disease to treat because of its highly variable clinical course. Because of a lack of prospective controlled trials, the specific treatment approach is still empirical, and no consensus has evolved. Spontaneous remissions are very rare, probably occurring in less than 5% of patients.
In patients with non-nephritic proteinuria, many physicians use only the nonspecific measures outlined above, and the general consensus is that aggressive approaches should be used in persistently nephritic patients. Ultimately, prognosis in nephritic FSGS patients is determined by their response to prednisone and other immunosuppressive agents.
Steroid therapy
Current evidence, mostly derived from retrospective analyses, favors prolonged corticosteroid therapy (6 mo or longer) to induce remission in patients with idiopathic FSGS.
Since long-term steroid therapy may lead to serious toxicity, patient counseling and close monitoring for adverse effects are essential before embarking on such a protracted regimen. The current approach calls for initiating therapy with prednisone in a dose of 1 mg/kg (60-80 mg/d) for 2-6 months or longer, depending on patient response as assessed by the following:
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Presence or absence of edema
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24-hour urine protein excretion
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Creatinine clearance
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Serum creatinine, albumin, and lipid levels
Studies indicate that 30-60% of patients may undergo complete or partial remission with such a regimen, and relapses are frequent when steroids are discontinued. Complete remission is protein excretion of less than 200-300 mg/d, and partial response is excretion of 200-3500 mg/d, or a greater than 50% reduction in baseline proteinuria. In children, results from several studies show a remission of proteinuria in 11% of patients, persistence of nephrotic syndrome with preservation of renal function in 31%, decline in the glomerular filtration rate in 23%, and development of end-stage renal disease (ESRD) in 21%. In adults, 10-year renal survival in nephrotic patients ranges from 25-55%, compared with 85-90% in patients with mild proteinuria.
In general, patients with tip lesions on histology are more responsive to corticosteroids, with excellent renal preservation compared with those with other forms of FSGS. Blacks and patients with collapsing FSGS are generally refractory to treatment and progress to renal failure. [42]
In responding patients, the goal is to titrate prednisone to the lowest dose that will stop or reduce proteinuria and prevent relapses. Use of steroids on alternate days can also reduce toxicity. Some have used a combination of prednisone and a cytotoxic agent such as cyclophosphamide as initial therapy to reduce the dose and duration of corticosteroids.
The optimal treatment duration is uncertain. Some authorities recommend continuing steroids indefinitely.
Other therapies
In patients whose FSGS is refractory to 2-3 months of prednisone therapy, the recommendation is to reduce the steroid dose and to add cyclophosphamide (2.5 mg/kg [150-200 mg/d]). Monitor patients for bone marrow suppression, and encourage them to drink adequate fluids to prevent hemorrhagic cystitis. Prolonged use of cyclophosphamide may lead to gonadal toxicity. Therefore, persisting with cyclophosphamide beyond 3 months in patients who do not respond is unwise.
Guidelines from Kidney Disease/Improving Global Outcomes (KDIGO) suggest considering calcineurin inhibitors (cyclosporine or tacrolimus) as first-line therapy for patients with relative contraindications or intolerance to high-dose corticosteroids (eg, uncontrolled diabetes, psychiatric conditions, severe osteoporosis). [43]
Randomized controlled trials and uncontrolled studies indicate that cyclosporine in a dose of 5-10 mg/kg/d may be beneficial in patients unresponsive to prednisone and cyclophosphamide. Few limited studies have employed tacrolimus. Since both of these calcineurin inhibitors can cause nephrotoxicity, the recommendation is to avoid them in patients with renal insufficiency.
Because of favorable results in other glomerular diseases, mycophenolate mofetil (MMF) has also been evaluated in FSGS. Although the experience is limited, the suggested dose is 750-1000 mg twice daily in patients who are refractory to corticosteroids and in whom calcineurin inhibitors may not be appropriate.
To assess whether treatment with MMF and oral pulses of dexamethasone was more effective than treatment with cyclosporine alone for steroid-resistant FSGS, a National Institutes of Health–sponsored multicenter randomized controlled trial, the largest study to date, was conducted in 138 patients aged 2-40 years. At the end of the 52-week treatment period, the incidence of complete and partial remissions was 33% in the MMF and dexamethasone group compared with 46% in the cyclosporine group, which was not significantly different. A critical analysis of this study highlights the limitations of current practices in the treatment of the individual patient with FSGS. [36]
Isolated reports have suggested that in patients with FSGS refractory to steroids and cyclophosphamide, treatment with other immunosuppressive agents, such as tacrolimus and sirolimus, may be beneficial in inducing remissions. In a prospective study of 44 patients with steroid-resistant nephrotic syndrome due to FSGS, 48 weeks of treatment with oral tacrolimus given in combination with prednisolone resulted in complete remission in 17 patients (38.6%) and partial remission in 6 patients (13.6%). Resistance to tacrolimus was observed in 21 patients (47.7%). Mean time to remission was 15.2 ± 6 weeks. [44]
Among the patients who achieved complete remission, relapse occurred in five (21.7%) after the tacrolimus dose was tapered and in 7 (30.4%) after tacrolimus was stopped. Reversible and irreversible nephrotoxicity occurred in 7 (15.9%) and 4 patients (9%), respectively. Tacrolimus-related diarrhea was observed in 10 patients (22.7%), infections in 19 patients (43.1%), and impaired fasting glucose and diabetes mellitus in 10 patients (22.7%). [44]
In an analysis of 485 patients with biopsy-proven primary FSGS who were enrolled in Glomerular Disease Collaborative Network (GDCN), use of immunosuppressive therapy with calcineurin inhibitors and/or glucocorticoids as part of early regimen was associated with improved renal outcome, but there was no superiority of calcineurin inhibitors over glucocorticoids alone. [45, 46]
Rituximab has proved effective for maintenance of remission in frequently relapsing FSGS and for treatment of remission, including in kidney transplant recipients. [47, 48] Kronbichler and colleagues, in a systematic review of 14 studies involving 86 adult patients with either steroid-dependent or frequently relapsing minimal change disease or FSGS, found that rituximab treatment significantly reduced the number of relapses per year from a mean of 1.3 before treatment to none after treatment. Rituximab treatment decreased proteinuria from 2.43 g/day to 0 g/day (P< 0.001), increased serum albumin from 2.9 to 4.0 g/dL, and decreased the need for immunosuppression. [49]
Despite all attempts, some patients continue to deteriorate and progress to ESRD. Counsel patients and their families early regarding treatment choices for ESRD. A well-informed patient can choose among maintenance hemodialysis, continuous ambulatory peritoneal dialysis, or cadaver or living donor transplantation. FSGS recurs in 30%-50% of patients who undergo kidney transplantation for the disease. However, most nephrologists do not consider this a contraindication for kidney transplantation. [50, 51] Recurrence of FSGS in the kidney allograft is much more common in patients with primary FSGS than in those with FSGS due to genetics or to hyperfiltration and other maladaptive or secondary forms of FSGS. [3]
In a study of recurrent FSGS in kidney transplant recipients whose initial treatment consisted of plasma exchanges, high doses of calcineurin inhibitors, and steroids, Garrouste et al reported that treatment with rituximab led to remission in 12 of 19 patients (nine complete remissions and three partial remissions). Four patients required a further course of rituximab for FSGS relapse, with good results. [52]
A multicenter retrospective case series on the use of long-term apheresis (with plasmapheresis, immunoadsorption, or both) in adult patients with recurrent FSGS after kidney transplantation reported that 23 of 27 patients (85%) had achieved partial or complete remission at one point after treatment. Median frequency of apheresis was twice monthly, and median time on apheresis was 23 months. In , and rituximab was administered in 78% of the cases (21 patients). Other treatments administered were rituximab, in 21 patients, and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, in 23 patients. [53]
In 2013, the FDA approved the Liposorber LA-15 System to treat children with primary FSGS before kidney transplantation or recurrent FSGS after kidney transplantation. [54] This product is an extracorporeal blood processing system that removes certain lipoproteins from the blood; it was previously approved to lower low-density lipoprotein cholesterol (LDL-C) in selected patients with familial hypercholesterolemia. [54]
Approval was based on two studies in children with FSGS. One study showed normal or near-normal renal function in most children who had had a high risk for progression to ESRD but who achieved remission of FSGS following treatment with the system. [54] The second study reported that posttransplant children who were treated with the Liposorber LA-15 System had less proteinuria relative to children not treated with the system. [54]
Small studies have found benefit with use of galactose, abatacept, and adalimumab. [55, 56]
Subcutaneously injected adrenocorticotropic hormone (ACTH) gel may have some efficacy for treatment of FSGS, especially in treatment-resistant or relapsing cases. [57] In a study of 24 patients with nephrotic syndrome from idiopathic FSGS, Hogan et al reported that treatment with ACTH gel resulted in full remission in two patients and partial remission in five patients. However, two responders relapsed during follow-up and 21 patients experienced adverse events, including one episode of new-onset diabetes, which resolved after stopping ACTH, and two episodes of acute kidney injury. [58]
Alhanad et al reported complete or partial remission with the use of ACTH gel in 10 of 20 cases of posttransplant recurrent and de novo FSGS resistant to therapy with therapeutic plasma exchange and rituximab. Urine protein-to-creatinine ratio improved from a mean of 8.6 g/g before ACTH gel to 3.3 afterward (P=0.004). [59]
A systematic review and meta-analysis of efficacy and safety of immunosuppressive therapy in primary FSGS concluded that treatment resulted in reduction of proteinuria, but its effect on kidney survival was uncertain. [60]
Secondary FSGS
Management of secondary FSGS is directed toward the etiology or associated disorder. For example, in HIV-associated FSGS, highly active antiretroviral therapy (HAART) is associated with remission of proteinuria and preservation of renal function. [28] Current guidelines call for initiation of HAART therapy in patients with HIV who have nephropathy irrespective of CD4 count and viral load. In selected patients with HIV infection and FSGS, corticosteroid therapy is associated with a significant improvement and, in some patients, discontinuation of dialysis. In heroin-associated FSGS, discontinuation of the drug may result in remission of proteinuria and improvement in kidney function.
Diet
Daily salt intake should be reduced to 2 g of sodium (5 g of salt). Potassium supplementation may be needed in patients treated with diuretics who develop hypokalemia.
As high protein intake may further aggravate proteinuria, adversely affecting renal function, current recommendations call for an intake of 1-1.3 g of high biologic value protein per kilogram of body weight. Reduction of fat intake may help with dyslipidemia.
