Approach

The treatment of focal segmental glomerulosclerosis (FSGS) depends on whether the patient has primary or secondary disease and should be initiated by a nephrologist. Patients without nephrotic syndrome are more likely to remit spontaneously or have more slowly progressive disease, and therefore do not require immunosuppressive therapy. Patients with nephrotic-range proteinuria (3 g or more/24 hours) or edema should be given immunosuppressive therapy as the risk of progression to end-stage renal failure is high in this population. Management of the underlying cause is the mainstay of treatment in secondary disease. Additional therapies to reduce proteinuria, treat hypertension and edema, delay disease progression, and prevent cardiovascular complications may also be required.

Primary FSGS

Recommendations for the initial treatment of primary FSGS are primarily based on retrospective studies as there are few randomized controlled trials.[4][24] Patients without nephrotic syndrome (proteinuria <3 g/24 hours) are more likely to remit spontaneously or have more slowly progressive disease. Thus, immunosuppressive treatment is generally not recommended in these patients. Patients with nephrotic-range proteinuria (3 g or more/24 hours) or nephrotic syndrome should be given immunosuppressive therapy, as the risk of progression to end-stage renal failure is high in this population.

Initial therapy with corticosteroids

  • According to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, high-dose corticosteroids are the immunosuppressant of choice. Therapy should be initiated with oral prednisone, which should be given for a minimum of 4 weeks and continued until complete remission is achieved (or up to a maximum of 16 weeks, whichever is earlier). After achieving complete remission, the dose should be tapered slowly over a 6-month period.[25]

  • Remission is complete (reduction in proteinuria to <300 mg/day) in 20% to 50% of patients. Others experience partial remission (reduction in proteinuria by 50% or more).[26][27][28][29]

Corticosteroid-dependent FSGS

  • Most patients will be corticosteroid-dependent and will require repeated or long-term low-dose corticosteroid therapy to maintain remission. Relapse in these patients occurs during, or within 2 weeks of completing, corticosteroid therapy.

  • Only a few patients with corticosteroid-sensitive nephrotic FSGS do not require any long-term therapy and achieve stable remission after corticosteroids are tapered to a stop.[30]

  • If long-term toxicity is a concern, a calcineurin inhibitor (cyclosporine or tacrolimus) can be added as a corticosteroid-sparing agent to maintain remission in combination with low-dose prednisone.

  • The cytotoxic alkylating agents cyclophosphamide and chlorambucil may have a limited role in managing corticosteroid-dependent and multirelapsing FSGS if calcineurin inhibitors are contraindicated or poorly tolerated. The remission attained by these agents has been shown to be long lasting. These agents are not appropriate for the treatment of corticosteroid-resistant disease, which is highly predictive of resistance to these alkylating agents.[30]

Corticosteroid-resistant FSGS

  • If remission is not achieved after 4 months of corticosteroid treatment, the disease is defined as being corticosteroid resistant.[30]

  • According to the KDIGO guidelines, these patients should be treated with a calcineurin inhibitor (cyclosporine or tacrolimus) for at least 4 to 6 months. If there is partial or complete remission, treatment should be continued for at least 12 months, followed by a slow taper over 6 to 12 months as tolerated.[25]

  • Several studies have shown that cyclosporine can induce remission and preserve renal function, although 60% of patients relapse when cyclosporine alone is used.[31][32]​ 

  • Cyclosporine plus low-dose prednisone in corticosteroid-resistant patients may be more effective than cyclosporine alone.[30][31][33][34]​ 

  • There is a lack of randomized controlled trials evaluating tacrolimus in the treatment of FSGS; however, several uncontrolled trials have demonstrated its suitability as an alternative to cyclosporine.[35][36]​ One randomized controlled trial comparing tacrolimus to cyclosporine in corticosteroid-resistant and corticosteroid-dependent FSGS found they showed similar rates of efficacy.[37]

  • Prolonged use of calcineurin inhibitors is associated with a significant increase in risk of tubulointerstitial fibrosis.[38]

  • If calcineurin inhibitors are contraindicated because of creatinine clearance, or they are poorly tolerated, agents such as mycophenolate can be considered. However, adequate randomized studies supporting this approach are lacking.[39] If mycophenolate is being considered, calcineurin inhibitors should be discontinued.

  • The KDIGO guidelines suggest that patients with corticosteroid-resistant FSGS who do not respond to, or tolerate, calcineurin inhibitors, should be considered for other agents, for example, a combination of mycophenolate plus high-dose dexamethasone).[25] Treatment with rituximab has also been reported; however, these guidelines acknowledge the lack of quality evidence for such alternate agents. Patients should also be considered for clinical trial enrollment and referral to specialized centers for potential rebiopsy.[25]

Corticosteroid toxicity

  • Patients who develop significant corticosteroid toxicities should have corticosteroid therapy rapidly tapered as tolerated.[25]

  • Treatment with a calcineurin inhibitor should be considered for this group.

Management of secondary FSGS

The mainstay of secondary FSGS management is treating the underlying cause. Most patients with secondary FSGS have obesity, HIV, or drug-induced FSGS. Weight loss can induce a significant decrease of proteinuria in obese patients.[40] Antiretroviral therapy has been shown to improve renal survival in patients with HIV-associated FSGS.[41][42]​ Drug-induced FSGS should resolve when the causative agent is discontinued. Patients with heroin addiction require detoxification followed by maintenance therapy with opioid agonists and psychosocial interventions; heroin-induced FSGS will only start to resolve when detoxification is successful.

Immunosuppressants may be required as part of the primary management for some underlying causes. These include: FSGS arising in a transplanted kidney; cases of drug-induced FSGS that do not resolve with discontinuation of the causative agent; and cases that are due to a maladaptive response to reduced renal mass. Corticosteroid therapy can also be used in patients with advanced HIV-induced FSGS to improve renal function and reduce or delay the need for dialysis. As these patients are already immunosuppressed, the risks and benefits of corticosteroid therapy need to be carefully weighed.

Additional therapy

Renin-angiotensin-aldosterone system blockade

  • All patients require drugs that block the renin-angiotensin-aldosterone system. They reduce proteinuria and glomerular capillary hydraulic pressure and, in turn, slow progression of chronic kidney disease associated with FSGS. They are also the preferred antihypertensive agents. However, they do not reverse the underlying disease process.

  • ACE inhibitors are the preferred initial agents. Proteinuria should be reduced to <0.5 g/24 hours. Angiotensin-II receptor antagonists can be used if the response to ACE inhibitors is suboptimal.

  • BP should be reduced to 125/75 mmHg or less in all patients. In the Modification of Diet in Renal Disease (MDRD) study, patients with proteinuria >1 g/24 hours had a significantly better outcome when their BP was reduced to 125/75 mmHg or less.

Statins

  • High serum cholesterol and LDL produced by nephrotic syndrome contribute to the high vascular risk associated with proteinuria. Normalization of lipid levels is therefore required in any patient with lipid abnormalities. Any lipid-lowering treatment can be given, but statins are the preferred agents.

  • In addition to controlling hyperlipidemia, statins may have a small, synergistic, antiproteinuric effect when combined with ACE inhibitors. However, this effect is predominantly seen in patients with subnephrotic proteinuria (proteinuria <3 g/24 hours).

  • Concomitant use of a statin with cyclosporine may cause an increased risk of adverse effects, including myopathy and rhabdomyolysis, and is therefore contraindicated.

Diuretics

  • Symptomatic patients require management of edema with dietary sodium restriction and diuretic therapy. Furosemide is the preferred agent. If the response to furosemide is inadequate, combination therapy with a thiazide diuretic can be given.

Dietary modifications

  • Patients should be instructed to follow a low-salt diet because a high intake can significantly impair the beneficial effects of angiotensin II blockade. It is also indicated in patients with significant edema.

  • A low-fat diet and exercise should also be encouraged to control the hypercholesterolemia and hypertriglyceridemia.

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