Could SGLT2 Inhibitors Be the Next 'Game Changer' in Focal Segmental Glomerulosclerosis?

Anthony T.P. Chan; Sydney C.W. Tang


Nephrol Dial Transplant. 2022;37(9):1593-1594. 

Focal segmental glomerulosclerosis (FSGS) is a nephrotic condition that is commonly refractory to treatment and carries a relatively poor renal prognosis among the spectrum of nephrosis. Classification of FSGS has been evolving over the years, with the integration of clinical, histological and genetic classification into the original classification (primary and secondary causes). Clinical classification is used in secondary forms of FSGS include virus-associated, drug-induced and forms mediated by adpative structural–functional responses. Histological classification includes the tip lesion, collapsing, perihilar and not other specified (NOS) variants.[1] Genetic components, specifically APOL-1 gene and high-penetrance genetic variants either by Mendelian or mitochondrial inheritance, were commonly observed in specific populations.[2] Among glomerulonephritides, FSGS has the highest rate of progression, with 55% of patients who have persistent high-grade proteinuria reaching kidney failure within 10 years.[3] In some subtypes of FSGS, recurrence is frequent after kidney transplantation compared with other causes of nephrotic syndrome.[4]

The management and prognosis of FSGS largely depend on the underlying cause and classification. Treatment of the underlying cause, if identified, could prevent kidney damage, whereas the adpative form of FSGS may respond to adequate renin–angiotensin–aldosterone blockade. However, the management of primary FSGS remains challenging, as therapeutic options are limited and steroid resistance often requires additional immunosuppressive therapies. According to the 2021 KDIGO Clinical Practice Guideline on Glomerular Diseases, corticosteroid is the first-line treatment for primary FSGS and calcinurin inhibitors should be used for no less than 6 months in steroid-resistant cases.[5] However, steroid resistant disease is not uncommon, and other alternative agents have been proposed such as cyclophosphamide, mycophenolic acid or rituximab, that could increase the risk of infection, malignancy and other complications. The therepeutic option for the genetic form of FSGS is not well established.

Sodium-glucose co-transporter-2 inhibitor (SGLT2i) was discovered >100 years ago,[6] but its impact on diabetic kidney disease (DKD) was only demonstrated within the last decade.[7,8] Apart from glycemic control, it also triggers a tubuloglomerular feedback and natriuretic effect, which reduces glomerular hyperfiltration and proteinuria. Reduction of proteinuria also attenuates inflammation and fibrosis in the kidney parenchyma, which can retard progression to advanced chronic kidney disease.[7] In the CREDENCE study,[8] the addition of SGLT2i to a stable dose of renin–angiotensin–aldosterone system inhibitor (RAASi) reduced albuminuria and renal composite endpoints in DKD. A pre-specified analysis of the DAPA-CKD trial[5] also indicated a kidney protective effect of SGLT2i in immunoglobulin A nephropathy.[9]

SGLT2i was previously suggested as a potential treatment option for FSGS. In a pilot study to determine the effect of 8 weeks of dapagliflozin on glomerular filtration rate (GFR) in 10 human subjects and in experimental FSGS using subtotal nephrectomized rats, the SGLT2i did not modify kidney hemodynamics or attenuate proteinuria.[10] In a more recent short-term crossover, randomized controlled trial (DIAMOND) to investigate the efficacy of SGLT2i in proteinuric kidney disease without diabetes, 11 patients with FSGS who were treated with dapagliflozin for 6 weeks had a nonsignificant reduction in proteinuria by 0.9% compared with placebo.[11] The lack of long-term data and a larger study population to address the potential efficacy of SGLT2i in FSGS leaves a knowledge gap.

In this issue of Neprhology Dialysis Transplantation, Wheeler et al. reported a pre-specified analysis of DAPA-CKD[7] to assess the efficacy and safety of dapagliflozin in 104 participants with FSGS confirmed by kidney biopsy. Due to the relatively small number of patients, the primary endpoint was changed from a 50% decline in estimated GFR (eGFR) in the original DAPA-CKD study to a 40% decline in this analysis.[7,9] With this 'new' composite endpoint, the authors reported that the primary composite outcome and secondary kidney-specific composite outcomes were both in favor of the dapagliflozin arm. The risk of developing end-stage kidney disease and kidney- or cardiovascular-related death was reduced. The annual rate of eGFR decline was also slower in the dapagliflozin group (by 2 mL/min/1.73 m2 per year compared with placebo (95% CI 0.6–3.5)). Urine albumin-to-creatinine ratio (UACR) was drastically decreased in the dapagliflozin versus placebo group from week 2 (−26.1% versus −9.9% compared with baseline; intergroup difference, 19.7%). The reason for taking week 2 is believed to arise from the need to exclude the acute effect of SGLT2i on eGFR during this period. However, UACR levels were similar between the two groups at 12 months. There was also no difference in blood pressure between the treatment and placebo groups.

Despite having a longer follow-up duration in a sizeable cohort of FSGS subejcts, there are several caveats on the results from this study. First, the proposed beneficial effect of dapagliflozin is driven mainly by eGFR decline and it remains uncertain whether the same favorable effects would have been observed if the authors had not replaced the "≥50% eGFR decline" component with "≥40% eGFR decline" in the primary outcome. Second, FSGS is a pattern of kidney histologic lesion with diverse causes and pathogenesis that are characterized by podocyte injury and depletion due to a primary form, or genetic, and secondary causes.[12] It is also important to differentiate FSGS from nonspecific focal global glomerulosclerosis, and the histological subclasses or the variants of FSGS can affect the ultimate choice of therapy.[13] The fact that DAPA-CKD did not differentiate between patients with primary and secondary or genetic forms of FSGS is an inherent limitation. However, as patients were excluded if any immunosuppressive therapies were prescribed within 6 months prior to enrolment,[7] it is likely that the majority of patients had secondary FSGS. This could be good news as immunosuppression is generally not recommended for secondary FSGS,[5] and the results from this analysis could bring hope for SGLT2i to be considered in the limited treatment armamentarium for this condition. Finally, even if SGLT2i may offer kidney protection in secondary FSGS, one may wonder, of the variety of secondary causes such as maladaptive, viral and drug-induced FSGS, which one(s) may benefit from SGLT2 inhibition. Furthermore, as UACR levels were no longer different between the dapagliflozin and placebo arms by 12 months, the long-term antiproteinuric and kidney protective effect of SGLT2i in FSGS requires validation. Dedicated multicentre randomized controlled trials of the different forms of FSGS are needed to address the efficacy of SGLT2i in this heterogenous condition.