Novel Treatment Paradigms: Focal Segmental Glomerulosclerosis

Abstract

Focal segmental glomerulosclerosis (FSGS) is a histologic pattern of injury defined by the presence of sclerosis in some (segmental) of certain glomeruli (focal). On electron microscopy, it is characterized by a variable degree of podocyte foot process effacement and gaps in the coverage of the glomerular basement membrane. The pattern of injury occurs when podocytes, highly differentiated cells with limited regenerative capacity, are reduced in number. The heterogeneity in underlying causes of podocyte loss results in equally variable clinical phenotypes. Recent work acknowledging advances in defining the genetic and immunologic basis of disease has redefined the classification of FSGS. Unprecedented clinical trial activity and efficacy of repurposed agents presents hope for improved therapeutic options. This minireview summarizes recent advances with a focus on novel treatment paradigms in FSGS. Focal segmental glomerulosclerosis (FSGS) is a histologic pattern of injury defined by the presence of sclerosis in some (segmental) of certain glomeruli (focal). On electron microscopy, it is characterized by a variable degree of podocyte foot process effacement and gaps in the coverage of the glomerular basement membrane. The pattern of injury occurs when podocytes, highly differentiated cells with limited regenerative capacity, are reduced in number. The heterogeneity in underlying causes of podocyte loss results in equally variable clinical phenotypes. Recent work acknowledging advances in defining the genetic and immunologic basis of disease has redefined the classification of FSGS. Unprecedented clinical trial activity and efficacy of repurposed agents presents hope for improved therapeutic options. This minireview summarizes recent advances with a focus on novel treatment paradigms in FSGS. As a pattern of injury and not a disease, the histologic finding of FSGS in a kidney biopsy is considered the beginning of a process to identify a specific and hopefully treatable underlying cause. Appropriate treatment decisions are based on sound clinical entity characterization. Contemporary classification relies on integrating the clinical history, laboratory results, kidney biopsy, and genetic testing results, among other data sources. FSGS cases can be divided into 4 categories: (i) those resulting from an immunologic cause, thought to be a circulating glomerular permeability factor (defined as primary); (ii) those that occur secondary to a systemic process known to cause FSGS (including maladaptive FSGS, viral or drug-induced FSGS); (iii) those caused by a genetic mutation in a podocyte or glomerular basement membrane protein; and (iv) those that occur in the absence of an identifiable cause but seem to be unrelated to a circulating permeability factor (or FSGS of undetermined cause).1Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work GroupKDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases.Kidney Int. 2021; 100: S1-S276https://doi.org/10.1016/j.kint.2021.05.021Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar Stratification of patients into these groups is sometimes challenging because different causes and risk factors can overlap to reach the threshold of podocyte injury that leads to FSGS. In addition, patients designated as having FSGS–undetermined cause may have as yet unidentified secondary or genetic underpinnings. No light microscopic changes distinguish the subtypes, but some unique clinical and pathologic features have been identified. Patients with primary FSGS typically have abrupt-onset marked proteinuria and overt nephrotic syndrome with diffuse podocyte foot process effacement on electron microscopy.2De Vriese A.S. Sethi S. Nath K.A. et al.Differentiating primary, genetic, and secondary FSGS in adults: a clinicopathologic approach.J Am Soc Nephrol. 2018; 29: 759-774https://doi.org/10.1681/ASN.2017090958Crossref PubMed Scopus (140) Google Scholar Glomerulomegaly is very common in FSGS secondary to obesity, reflux nephropathy, and individuals with low birth weight, but it can also be seen in primary disease.3Kambham N. Markowitz G.S. Valeri A.M. et al.Obesity-related glomerulopathy: an emerging epidemic.Kidney Int. 2001; 59: 1498-1509https://doi.org/10.1046/j.1523-1755.2001.0590041498.xAbstract Full Text Full Text PDF PubMed Scopus (1031) Google Scholar Genetic FSGS can have variable clinicopathologic features but is more common in patients with a family history of glomerular disease and in those resistant to glucocorticoids. The recently updated Kidney Disease: Improving Global Outcomes practice guidelines for the treatment of FSGS recommend supportive treatment for all patients with persistent proteinuria with the use of renin angiotensin aldosterone system (RAAS) blockade, optimal blood pressure control, and dietary salt restriction.1Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work GroupKDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases.Kidney Int. 2021; 100: S1-S276https://doi.org/10.1016/j.kint.2021.05.021Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar Although RAAS blockade reduces proteinuria in patients with FSGS,4Campbell K.N. Pennese N. Zaffalon A. et al.Efficacy and safety of ACE inhibitor and angiotensin receptor blocker therapies in primary focal segmental glomerulosclerosis treatment: a systematic review and meta-analysis.Kidney Med. 2022; 4: 100457https://doi.org/10.1016/j.xkme.2022.100457Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar additional agents are typically required to achieve a sustained clinical remission. The use of sodium glucose cotransporter 2 inhibitor therapy has emerged as an attractive supportive agent class used in conjunction with RAAS inhibitors for across the spectrum of proteinuric kidney disease. Prespecific analyses of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease study have shown protective benefits of dapagliflozin from estimated glomerular filtration rate decline in IgA nephropathy and FSGS, although the effect was not statistically significant in the FSGS substudy.5Wheeler D.C. Toto R.D. Stefansson B.V. et al.A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy.Kidney Int. 2021; 100: 215-224https://doi.org/10.1016/j.kint.2021.03.033Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar,6Wheeler D.C. Jongs N. Stefansson B.V. et al.Safety and efficacy of dapagliflozin in patients with focal segmental glomerulosclerosis: a prespecified analysis of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial.Nephrol Dial Transplant. 2022; 37: 1647-1656https://doi.org/10.1093/ndt/gfab335Crossref PubMed Scopus (20) Google Scholar Future studies will be needed to further define the benefit of sodium glucose cotransporter 2 inhibitor in FSGS. An additional drug class likely to be considered for supportive therapy is nonsteroidal mineralocorticoid receptor antagonists. These agents have anti-inflammatory and antifibrotic properties with finerenone, a nonsteroidal mineralocorticoid receptor antagonist now approved by the US Food and Drug Administration for diabetic kidney disease.7Agarwal R. Kolkhof P. Bakris G. et al.Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine.Eur Heart J. 2021; 42: 152-161https://doi.org/10.1093/eurheartj/ehaa736Crossref PubMed Scopus (168) Google Scholar Kidney Disease: Improving Global Outcomes guidelines recommend that patients with clinical and histologic features of primary FSGS, including the presence of nephrotic syndrome, be treated with high-dose immunosuppression (initially with high-dose glucocorticoids) as first-line therapy. Patients who fail to respond to glucocorticoids or those with a contraindication to their use are treated with calcineurin inhibitors.1Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work GroupKDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases.Kidney Int. 2021; 100: S1-S276https://doi.org/10.1016/j.kint.2021.05.021Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar Alternative therapies such as mycophenolate mofetil, adrenocorticotropic hormone, or rituximab, have been used over time with different degrees of success, but their efficacy is still debatable and have therefore not been included in the current guidelines. Extracorporeal therapies such as plasma exchange, immunoadsorption, and low-density lipoprotein apheresis may have a role as adjunctive therapy for patients who fail to respond to steroids and other immunosuppressive agents.8Raina R. Wang J. Sharma A. Chakraborty R. Extracorporeal therapies in the treatment of focal segmental glomerulosclerosis.Blood Purif. 2020; 49: 513-523https://doi.org/10.1159/000506277Crossref PubMed Scopus (14) Google Scholar In the absence of robust randomized clinical trial data, patient selection criteria, the optimal apheresis approach, and concomitant immunosuppressive regimens remain unclear. For those patients with secondary FSGS, treatment is focused on the underlying condition.1Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work GroupKDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases.Kidney Int. 2021; 100: S1-S276https://doi.org/10.1016/j.kint.2021.05.021Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar A summary of Kidney Disease: Improving Global Outcomes guidelines treatment recommendations based on FSGS etiology can be found in Figure 1. Despite translational research advances and increased knowledge regarding the pathogenesis of FSGS, targeted therapies are still lacking, and treatment strategies have not changed significantly over the past several decades. Nevertheless, there has recently been a notable increase in emerging therapies targeting defined pathogenic signaling cascades. A summary of recent and ongoing clinical trials for FSGS is provided in Table 1. A brief, and not comprehensive, discussion of some of these promising emerging agents (Figure 2) and representative signaling pathways they target will now be discussed.Table 1Some recent and ongoing clinical trials in focal segmental glomerulosclerosisNCT numberDrugMechanism of actionStatusPhaseCompletionNCT01613118SparsentanDual ETA receptor/AT1 receptor antagonistActive, not recruitingPhase 2February 2026NCT03493685Phase 3NCT05003986Peds: RecruitingPhase 2June 2025NCT04573920AtrasentanDual ETA receptor/AT1 receptor antagonistRecruitingPhase 2February 2026NCT03970122GFB-887TRPC5 channel inhibitorCompletedPhase 1April 2020NCT04387448RecruitingPhase 2August 2022NCT04950114Phase 2September 2025NCT03448692PF-067301512SLIT2 antagonistRecruitingPhase 2August 2025NCT04340362VX-147APOL1 antagonistCompletedPhase 2December 2021NCT05312879RecruitingPhase 2/3June 2026NCT05267262R3R01Lipid-modifying drugNot yet recruitingPhase 2December 2023NCT05213624BI764198TRPC6 inhibitorRecruitingPhase 2August 2023NCT05183646DMX-200 (repagermanium)CCR2 inhibitorRecruitingPhase 3June 2026NCT05314231ALXN1720Anti-C5 mini-bodyNot yet recruitingPhase 1March 2023NCT05237388BaricitinibJanus kinase-STAT inhibitorNot yet recruitingPhase 2March 2026NCT00814255AdalimumabAntihuman TNF-α antibodyCompletedPhase 2February 2014NCT04009668+TR-MCD: RecruitingPhase 2July 2024NCT05441826VB119Anti-CD19 antibodyRecruitingPhase 2February 2024NCT04983888ObinutuzumabAnti-CD20 antibodyRecruitingPhase 2September 2024AT1, angiotensin II receptor type 1 ; CD, cluster of differentiation; ETA, endothelin type A; MCD, minimal change disease; TNF-α, tumor necrosis factor-α. Open table in a new tab AT1, angiotensin II receptor type 1 ; CD, cluster of differentiation; ETA, endothelin type A; MCD, minimal change disease; TNF-α, tumor necrosis factor-α. Podocytes rely on a complex cytoskeletal repertoire consisting of cortical actin and a central actin bundle anchored to the glomerular basement membrane to maintain normal morphology. Disrupted intracellular calcium homeostasis is a key event in podocyte injury. Increased intracellular podocyte calcium results in activation of the calcium-dependent phosphatase calcineurin leading to dephosphorylation of the actin-bundling protein synaptopodin, rendering it susceptible to cathepsin L–mediated cleavage. Gain-of-function disease-causing mutations in TRPC6, associated with enhanced intracellular calcium levels, were identified in 2005 in familial FSGS.9Winn M.P. Conlon P.J. Lynn K.L. et al.A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis.Science. 2005; 308: 1801-1804https://doi.org/10.1126/science.1106215Crossref PubMed Scopus (903) Google Scholar TRPC family members activate small GTPases in podocytes with TRPC6 and TRPC5 activating RhoA and Rac1, respectively. Rac1 activation further induces TRPC5 translocation to the podocyte membrane, resulting in a Rac1-TRPC5 feed-forward loop. TRPC6 inhibition is a potential therapeutic strategy for FSGS (NCT05213624), whereas GFB-887, an inhibitor of TRPC5, is in clinical trials for FSGS, minimal change disease, and diabetic nephropathy.10Walsh L. Reilly J.F. Cornwall C. et al.Safety and efficacy of GFB-887, a TRPC5 channel inhibitor, in patients with focal segmental glomerulosclerosis, treatment-resistant minimal change disease, or diabetic nephropathy: TRACTION-2 trial design.Kidney Int Rep. 2021; 6: 2575-2584https://doi.org/10.1016/j.ekir.2021.07.006Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Endothelin-1 has numerous pathogenic effects on the glomerulus, including vasoconstriction and mediation of intraglomerular hypertension and promotion of inflammation and fibrosis.11Komers R. Plotkin H. Dual inhibition of renin-angiotensin-aldosterone system and endothelin-1 in treatment of chronic kidney disease.Am J Physiol Regul Integr Comp Physiol. 2016; 310: R877-884https://doi.org/10.1152/ajpregu.00425.2015Crossref PubMed Scopus (52) Google Scholar In addition, angiotensin II and endothelin-1 can synergistically promote podocyte apoptosis and reorganization of the actin cytoskeleton. Earlier studies investigating dual blockade of endothelin-1 and RAAS in mouse models of membranous nephropathy and diabetic nephropathy demonstrated reduction of proteinuria, glomerular sclerosis, and tubulointerstitial damage compared with monotherapies.11Komers R. Plotkin H. Dual inhibition of renin-angiotensin-aldosterone system and endothelin-1 in treatment of chronic kidney disease.Am J Physiol Regul Integr Comp Physiol. 2016; 310: R877-884https://doi.org/10.1152/ajpregu.00425.2015Crossref PubMed Scopus (52) Google Scholar Sparsentan, a dual endothelin type A and angiotensin II type 1 receptor antagonist, was shown in a phase 2, randomized, double-blind, active-control study of patients with FSGS to decrease proteinuria from baseline by 45% versus 19% for patients on irbesartan control over 8 weeks (P = 0.006).12Trachtman H. Nelson P. Adler S. et al.DUET: A phase 2 study evaluating the efficacy and safety of Sparsentan in patients with FSGS.J Am Soc Nephrol. 2018; 29: 2745-2754https://doi.org/10.1681/ASN.2018010091Crossref PubMed Scopus (94) Google Scholar Sparsentan is currently being further evaluated in that study's open-label treatment period and in a randomized, multicenter, double-blind, parallel, active-control phase 3 study (NCT03493685).13Komers R. Diva U. Inrig J.K. et al.Study design of the phase 3 Sparsentan versus irbesartan (Duplex) study in patients with focal segmental glomerulosclerosis.Kidney Int Rep. 2020; 5: 494-502https://doi.org/10.1016/j.ekir.2019.12.017Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Atrasentan is an endothelin type A receptor antagonist without angiotensin II type 1 receptor inhibitory properties that is being studied in a phase 2, open-label basket study for patients with FSGS in addition to IgA nephropathy, Alport syndrome, and diabetic nephropathy (NCT04573920). Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease in the phase 3 randomized, placebo-controlled SONAR trial when used in conjunction with maximum labeled or tolerated renin-angiotensin system inhibition.14Heerspink H.J.L. Parving H.H. Andress D.L. et al.Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial.Lancet. 2019; 393: 1937-1947https://doi.org/10.1016/S0140-6736(19)30772-XAbstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar Thus, endothelin-1/endothelin type A inhibition may provide opportunities to potentially enhance podocyte protection beyond RAAS blockade. The ROBO2 colocalizes with the podocyte slit diaphragm protein nephrin and is a receptor for SLIT2. ROBO2/SLIT2 signaling has been shown to reduce podocyte focal adhesions and decrease podocyte adhesion to collagen-coated plates in vitro.15Fan X. Yang H. Kumar S. et al.SLIT2/ROBO2 signaling pathway inhibits nonmuscle myosin IIA activity and destabilizes kidney podocyte adhesion.JCI Insight. 2016; 1e86934https://doi.org/10.1172/jci.insight.86934Crossref PubMed Scopus (26) Google Scholar Podocyte ROBO2 expression is increased in mice and humans with glomerular disease, and loss of ROBO2 in vivo was protective in glomerular injury models as assessed by preservation of podocyte foot processes and reduction of proteinuria.16Pisarek-Horowitz A. Fan X. Kumar S. et al.Loss of roundabout guidance Receptor 2 (Robo2) in podocytes protects adult mice from glomerular injury by maintaining podocyte foot process structure.Am J Pathol. 2020; 190: 799-816https://doi.org/10.1016/j.ajpath.2019.12.009Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar The ROBO2 fusion protein (PF-067301512) inhibits ROBO2/SLIT2 signaling with the efficacy, safety, tolerability, and pharmacokinetics profile of PF-06730512 currently being investigated in a phase 2a, open-label, multicenter study in adult patients with FSGS (NCT03448692).17Beck Jr., L.H. Berasi S.P. Copley J.B. et al.PODO: trial design: phase 2 study of PF-06730512 in focal segmental glomerulosclerosis.Kidney Int Rep. 2021; 6: Full Text Full Text PDF PubMed Scopus Google Scholar Recent that of renal may to the and of kidney disease and that podocytes are susceptible to S. 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J. et protects from kidney disease in Alport syndrome and focal segmental glomerulosclerosis.Kidney Int. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar in have also been demonstrated in other models of glomerular disease, including diabetic nephropathy and Alport X. et has a role in kidney disease associated with diabetes and Alport Int. 2020; Full Text Full Text PDF PubMed Scopus Google Scholar These studies and have to the targeting of kidney and podocyte as a novel therapeutic strategy for glomerular is a small to decrease renal and a phase 2, multicenter, open-label study is currently to the safety, efficacy, and pharmacokinetics profile of in patients with FSGS and patients with Alport syndrome on receptor blocker therapy with proteinuria FSGS is included on the spectrum of kidney disease, chronic kidney disease in patients with 2 mutations or in the G. et of with kidney disease in PubMed Scopus Google Scholar These mutations are found in patients of and recent studies have demonstrated that the presence of 2 mutations can for to of kidney disease in these nephropathy: in a Nephrol. 2016; PubMed Scopus Google Scholar for podocyte injury are to the of as a protective by in and may to leading to podocyte J.F. have to with Nephrol. 37: Full Text Full Text PDF PubMed Scopus Google Scholar an inhibitor of was in an open-label, phase study in patients with FSGS and 2 results are with a phase double-blind, placebo-controlled study the agent among a patient with proteinuria and kidney disease Alternative have been for inhibition including the use of et treatment proteinuria in Insight. 2019; PubMed Scopus Google Scholar and inhibition with for G. 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