Treatment Horizon Expanding for Focal Segmental Glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS), a rare and aggressive kidney disease characterized by scarring of the glomeruli, has no known cure but treatment options are expanding.

The progressive disease, which is estimated to affect more than 40,000 people in the U.S., causes chronic proteinuria and irreversible damage, frequently leading to kidney failure.

“This is a difficult diagnosis to treat and one that is both frustrating for patient and nephrologists,” Kristin Meliambro, MD, of the Icahn School of Medicine at Mount Sinai in New York City, told MedPage Today.

One of the primary goals of treatment is to lower proteinuria, said Abbal Koirala, MD, of the Johns Hopkins School of Medicine in Baltimore. “Ongoing persistent proteinuria is a risk factor for chronic kidney disease progression and progression to end-stage renal disease,” he told MedPage Today.

Current Treatments

Margaret De Oliveira, MD, of NYU Langone Health in New York City, divides FSGS treatments into two categories: immunosuppressive and non-immunosuppressive.

Non-immunosuppressive agents include SGLT2 inhibitors and renin-angiotensin-aldosterone system (RAAS) blockade via angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and aldosterone antagonists. These drugs help reduce proteinuria and lower hydrostatic pressure inside the glomeruli.

Immunosuppressant treatments, including high-dose oral glucocorticoids and calcineurin inhibitors, are recommended as first-line therapies for primary FSGS, according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. However, guidelines advise against using immunosuppression in patients with secondary or undetermined causes of FSGS.

The response rate to steroids in FSGS is not very high, Meliambro noted. A 2016 review found that response rates for first-line treatment with daily oral prednisolone, for example, ranged from 50% to 68.8%.

The non-immunosuppressive agent sparsentan (Filspari) may offer a more targeted alternative, De Oliveira suggested. Approved this year for FSGS, sparsentan is indicated to reduce proteinuria in patients ages 8 years and older who do not have nephrotic syndrome (proteinuria over 3.5 g/day). It features a dual mechanism of action, targeting both endothelin A and angiotensin II receptors.

“I am shifting my first-line management strategy to include sparsentan, given the benefit in proteinuria reduction,” De Oliveira said. Appropriate patient selection mostly boils down to whether or not the patient clinically has nephrotic syndrome versus non-nephrotic range proteinuria, she noted.

New Drugs in Development

“There are so many new medications in the pipeline and available now to help slow down the progression of chronic kidney disease from many different etiologies,” De Oliveira said. “I really think this is a renaissance period for our specialty and am excited to see what happens in the next few years.”

Meliambro agreed that the outlook was positive, given the frustrations and complexities associated with treating FSGS. “As a field, nephrology is moving in the right direction towards the development and investigation of therapeutics that target specific pathogenic mechanisms, particularly within the subfield of glomerular diseases,” she observed.

“APOL1 inhibitors and CCR2 pathway inhibitors are great examples of this active movement and have the potential to really expand the treatment arsenal for FSGS patients and meaningfully alter their disease course,” she pointed out. “These investigational drugs are both being studied in conjunction with first-line RAAS blockade, so they would presumably be used in a combination or multi-targeted manner in the future.”

Among the drugs being studied is the investigational agent inaxaplin, a small molecule that inhibits APOL1 function to target APOL1-mediated kidney disease. A small phase II trial yielded positive findings for the drug in patients with biopsy-proven FSGS and two APOL1 mutations.

The investigational oral drug DMX-200 also is undergoing phase III testing. The treatment, which is administered on top of standard ARB therapy, blocks the CCR2 receptor to reduce inflammation and demonstrated proteinuria reduction during a 16-week phase II trial.

“There is mounting evidence that the future will be brighter for our FSGS patients,” Meliambro said. “A future that offers more, better, and personalized treatments that can truly alter disease course.”

Dietary Modifications May Help

Besides pharmacologic agents, lifestyle and dietary interventions may help protect glomeruli. Every FSGS patient should follow a low-salt diet, Koirala said. “It’s not just to control hypertension or edema: the salt itself increases pressure in the glomeruli and causes a transient rise in proteinuria,” he explained.

KDIGO guidelines state that daily salt intake should be limited to under 2 grams. FSGS patients also should limit excess protein intake, which Koirala said should be capped at 0.6 to 0.8 g/kg per day.

“There is also some supportive data on the role of plant-protein based diets with respect to proteinuria reduction and reduction of eGFR decline,” Meliambro noted.

FSGS patients should ensure their diabetes is well-controlled, follow a low-cholesterol diet, and stop smoking, Koirala advised. Maintaining a healthy weight is key, he added: “Obesity increases blood flow to the glomeruli and increases progression of kidney disease, independent of diabetes.”