Novel Therapies for FSGS: Preclinical and Clinical Studies Laura Malaga-Dieguez, Diana Bouhassira, Debbie Gipson, and Howard Trachtman Focal segmental glomerulosclerosis (FSGS) is a rare but important cause of end-stage kidney disease in children and adults. Current therapy, consisting of corticosteroids and calcineurin inhibitors, fails to achieve a sustained remission in most patients. Therefore, there is a pressing need to develop new treatments for this glomerulopathy. Traditional approaches have focused on agents that modulate the immune system. In this review, we summarize preclinical and clinical data with newer agents that may ameliorate FSGS. We focus on drugs that inhibit immune injury or inflammation, such as abatacept, rituximab, adalimumab, and stem cells. The potential of agents that block the glomerular action of circulating permeability factors such as soluble urokinase receptor is reviewed. Finally, because fibrosis represents the final common pathway of glomerular damage in FSGS, the experience with a wide range of antifibrotic agents is presented. Despite extensive research on the podocyte dysfunction in the pathogenesis of FSGS, there are few agents that directly target podocyte structure or viability. We conclude that FSGS is a heterogeneous disorder and that intensified translational research is vital to improve our understanding of distinct subtypes that have a defined prognosis and predictable response to targeted therapeutic interventions. Q 2015 by the National Kidney Foundation, Inc. All rights reserved. Key Words: FSGS, Inflammation, Immune modulators, Fibrosis, Circulating factors

Introduction Focal segmental glomerulosclerosis (FSGS) is one of the most common forms of glomerular disease. The entity is defined based on the finding of segmental glomerular sclerosis and hyalinosis.1 Various histopathologic variants including tip lesion and a collapsing form have been identified, and they may shed light on response to therapy and prognosis.2 Disturbances in podocyte structure, number, and function are considered pivotal to the development of all forms of FSGS, and this glomerular disease is now classified as a podocytopathy.3 FSGS accounts for nearly 5% to 10% of pediatric and adult patients who progress to end-stage kidney disease (ESKD). Among those patients who require kidney replacement therapy, 15% to 30% will develop recurrent disease in a transplanted kidney.1 The etiology of FSGS is divided into 3 categories—primary or idiopathic, genetic, and secondary disease associated with various medications (eg, pamidronate), infections (eg, HIV, parvovirus 19), medical conditions (obesity, reflux nephropathy), or critical reduction in kidney mass (eg, subtotal nephrectomy for Wilms’ tumor).1,4 The goal of treatment in patients with FSGS is normalization of urinary protein excretion and preservation of kidney function. However, even partial reduction in proteinuria is beneficial. Studies in children and adults have demonstrated a direct relationship between the degree of lowering of proteinuria and prolongation of kidney survival. The standard of care for patients with primary FSGS includes initial treatment with a course of corticosteroids. Up to 25% of patients will respond to this therapy, and their prognosis is more favorable.1 For those who are steroid resistant, the next option is a calcineurin inhibitor with an expected complete or partial remission rate in 40% to 50% of patients.5 If these drugs are ineffective, then there is no proven therapy that can consistently achieve a significant and sustained reduction in proteinuria. The current treatment of FSGS has recently been reviewed in this journal.6

There are a number of possible disease mechanisms that can be targeted by novel therapies for FSGS. These include modulation of immunologic pathways, inflammation, podocyte cell growth and survival, actin cytoskeleton, circulating factors, and fibrosis. In the following sections, we will review preclinical and clinical data that support the potential use of novel therapies that are directed at each of these pathophysiological abnormalities.

Animal Models of FSGS Much of our knowledge on the pathophysiology and potential therapeutic targets for FSGS has come from different kinds of animal models that have been developed to mimic the clinical and pathological features of human FSGS. These models induce damage to podocytes. These animal models include the reduction of kidney mass by resecting five-sixth of the kidney tissue (unilateral nephrectomy and removal of two-thirds of the contralateral kidney), injury to the kidney parenchyma because of drug-induced FSGS using adriamycin (ADR), puromycin aminonucleoside (PAN), or streptozocin, virus-induced FSGS, genetically-induced FSGS, such as via Mpv-17 inactivation and a-actinin 4, and podocin knockouts using Cre/ lox P recombination.7,8 Unfortunately, almost all of these animal models are based on the induction of secondary forms of FSGS and are consequently limited in the ability to mimic primary idiopathic human FSGS. From Division of Nephrology, Department of Pediatrics, CS Mott Children’s Hospital; and NYU Langone Medical Center, New York, NY. Support: This work was supported in part by a grant from the NIDDK (DK70341). This article was originally slated to appear in ACKD March 2014, Treatment of Glomerular Disease: Newer Therapies and a New Look at Older Therapies (Guest Editors: Jai Radhakrishnan and Andrew S. Bomback). Address correspondence to Howard Trachtman, MD, NYU Langone Medical Center, CTSI, Room 3110, 227 East 30th Street, New York, NY 10016. E-mail: [email protected] Ó 2015 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2014.10.001

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Modulation of Immunological Pathways and Inflammation Rituximab Rituximab, a monoclonal antibody against CD20 on B cells, was first demonstrated to induce remission of proteinuria in a single patient with a transplant-related lymphoma and recurrent FSGS after kidney transplantation.9 Subsequent reports have evaluated the effect of rituximab in case series of patients with primary FSGS. Overall, the response has been low, in the range of 20% to 30%, suggesting that this therapy may have a role in selected patients with primary FSGS.10 There is evidence that rituximab may have off-target effects on lipid metabolism in podocytes by binding to sphingomyelin phosphodiesterase acid-like 3b protein and regulating acid sphingomyelinase activity. This action may contribute to the efficacy of rituximab in posttransplant FSGS.11 Further research is required to place rituximab into a rational framework for the treatment of FSGS.

had B7-1 immunostaining of podocytes. The authors selected 5 patients with FSGS and B7-1 staining of podocytes in kidney biopsy for management with abatacept. Four of these patients had rituximab-resistant recurrent FSGS after transplantation and 1 patient had glucocorticoid-resistant primary FSGS. Clinical remission, more specifically, nephrotic-range proteinuria, resolved in all the patients over a period of weeks to months.18 If validated, abatacept may be a new therapeutic tool for the subgroup of patients with FSGS who exhibit B7-1 immunostaining in the kidney biopsy specimens. This drug may stabilize b1-integrin activation in podocytes and reduce proteinuria in patients with B7-1-positive glomerular disease.

Adalimumab

Monoclonal antibodies are increasingly being used in the treatment of steroid-resistant and steroid-dependent FSGS. Adalimumab is a human monoclonal antibody directed against tumor necrosis factor-a (TNF-a). Because TNF-a is upregulated in both human and experimental models of FSGS, attempts to lower proteinuria by inhibiting TNF-a ACTH have been made. In the phase Injections with adrenocorti1 trial conducted by the CLINICAL SUMMARY cotropic hormone (ACTH), “Novel Therapies for Resisa pituitary neuroimmunoentant FSGS” (FONT) study  Current therapy of focal segmental glomerulosclerosis is docrine polypeptide, were group in children and adults, generally ineffective and cannot prevent progression to one of the first therapies adalimumab was well tolerend-stage kidney disease in most patients. used for childhood nephrotic ated, and after 16 months of syndrome.12,13 Broad clinical  Novel therapies are under development that target follow-up, 4 patients of the immune-mediated inflammation and glomerular damage, and experimental evidences adalimumab-treated group inhibit the action of circulating permeability factors, or prehad long suggested that (n ¼ 10) showed stabilization vent glomerular fibrosis. ACTH has antiproteinuric, of kidney function and lipid-lowering, and renopro None of the novel therapies have been successfully applied reduced proteinuria.19,20 This 14 tective properties, and the to the treatment of patients with focal segmental observation suggests that drug was reintroduced as a glomerulosclerosis. Intensified translational research is adalimumab may have a role vital to develop targeted therapeutic interventions for treatment alternative for in slowing the progression of patients with this serious glomerulopathy. nephrotic syndrome, initially FSGS in a selected subgroup in Europe with a synthetic of patients, but further studies ACTH depot and then in are needed to confirm this. the United States with natural ACTH gel. Hogan and col15 leagues treated 24 adult patients with steroid-resistant or steroid-dependent FSGS with ACTH and achieved Circulating Factors remission in 7 (29%), indicating that this drug may repreThe rapid recurrence of FSGS after kidney transplantasent an alternative in patients who do not respond to stetion, the ability of plasma from patients with FSGS to roids and other common second-line agents. It is induce proteinuria after infusion into animals, and the suggested that ACTH may have actions beyond those remission of post-transplant FSGS achieved by plasmaattributable to corticosteroids, possibly acting via antipheresis have fostered the notion that proteinuria in inflammatory mechanisms or directly on podocytes via FSGS is caused by excessive levels of circulating factors the melanocortin 1 receptor.16 that cause dysfunction of the glomerular filtration barrier in some patients.21 Over the years, a number of molAbatacept ecules have been proposed as circulating permeability Abatacept (CTLA-4-Ig) is a costimulatory inhibitor that factors including hemopexin and vascular endothelial growth factor. Savin and colleagues have searched for targets B7-1 and is currently approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. these molecules by using a volumetric assay of changes Reiser and others17 have shown that induction of the in glomerular size after imposition of an oncotic gradient. They have linked high levels of a circulating T-cell costimulatory molecule B7-1 in podocytes is associated with nephrotic syndrome. Yu and colleagues FSGS permeability factor with recurrence of disease afrandomly selected biopsy specimens of native human ter transplant and investigated the effect of various therapeutic interventions on the glomerular permeability to kidneys and identified a subpopulation of patients albumin.21 with minimal change disease or primary FSGS who

Novel Therapies for FSGS

Galactose

22

Savin and colleagues have conducted extensive studies on permeability factors in patients with FSGS. They have demonstrated that the molecules have a high affinity for galactose. This has led to the use of oral galactose supplementation in single patients or small case series. There have been several published case reports showing some success with oral galactose in reducing the plasma activity of the FSGS-soluble factor,23-25 but these results were difficult to attribute only to galactose because the patients received concomitant treatments including plasmapheresis. Galactose was included as a test treatment in the FONT study, and results of this trial are pending. Recent evidence suggests that cardiotrophinlike cytokine factor 1 may be another candidate for the unidentified permeability factor in FSGS that mediates podocyte injury.21,26

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supplementation with coenzyme Q10,33 yet this appears to be a key target for a very rare subset of the Mendelian causes of nephrotic syndrome.1 Glomerulosclerosis is the only feature that is shared by all forms of FSGS, primary or secondary, and prevention of glomerular fibrosis has been successfully applied in animal models of FSGS and demonstrated to slow the rate of progression of kidney disease. Fibrosis represents the final common pathway of tissue damage in other organs, such as hepatic cirrhosis and cardiac fibrosis. Thus, this strategy should benefit from utilization of basic science findings in a wide range of specialties. It is hoped that ongoing prospective studies of patients with primary glomerular disease that include genomics and proteomics will yield more meaningful pathophysiological mechanisms of disease that can be targeted by rational drug design.

Transforming Growth Factor-b Receptor I Inhibitors

A recently identified circulating factor that may contribute to podocyte injury and proteinuria in FSGS is soluble urokinase receptor (suPAR). It is detected in the serum of patients with primary FSGS and activates b3 integrin in podocytes leading to foot process effacement and proteinuria.27 Subsequent studies confirmed that suPAR was elevated in 55% to 85% of patients with primary steroidresistant FSGS in 2 large clinical cohorts.28 In patients with recurrent FSGS post-transplant, the degree of podocyte effacement correlates with the suPAR concentration and successful therapy is associated with reduction in suPAR levels and restoration of podocyte integrity.29 Recent reports have disputed these findings and questioned whether elevated suPAR levels are indicative of higher likelihood of having primary FSGS.30,31 Studies to clarify the role of suPAR in the pathogenesis of primary FSGS in the native kidney and allograft will be key to justifying efforts to develop novel therapies with suPAR as a target.

It is widely accepted that transforming growth factor (TGF)-b and its downstream Smad cascade is a key mediator in the pathogenesis of kidney fibrosis both in experimental models and in human kidney diseases. Upregulation of TGF-b is a universal finding in CKD in humans and animal models. TGF-b mediates progressive kidney fibrosis by stimulating ECM production while inhibiting its degradation. Expression of TGF-b is increased in patients with primary FSGS, particularly in podocytes of sclerotic segments,34 and intrarenal transcription of TGF-b is increased in children with FSGS compared with those with minimal change disease,35 suggesting that TGF-b gene transcription is indicative of progressive kidney damage typical of FSGS. Therefore, tremendous efforts have been made to develop strategies to reduce the expression or antagonize the effects of TFG-b action in an attempt to hamper the progression of kidney fibrosis in FSGS.

Antifibrotic Agents

Li and colleagues36 reported that a combined therapy using the p38 MAPK pathway inhibitor (SB203580) and a TGF-b receptor I inhibitor (ALK5I) can attenuate kidney injury and reduce the progression of ADR-induced nephropathy in vivo. In a similar study, low dose of glycoside of tripterygium Wilfordii Hook. f., a natural medicinal plant from Chinese traditional medicine, was used to ameliorate the glomerulosclerosis in the same model of ADR-induced FSGS through TGF-b receptor I inhibition.37 Resveratrol. Resveratrol, a polyphenol with welldocumented antifibrotic and anti-inflammatory properties, attenuated the expression of ECM proteins in both the five-sixth remnant kidney model in rats and cultured mesangial cells exposed to TGF-b1. This effect was at least partially associated with Sirt1, an antifibrotic factor that inhibits TGF-b1 signaling by deacetylating Smad3.38

Kidney fibrosis, characterized by glomerulosclerosis and tubulointerstitial fibrosis, is the final common manifestation leading to ESKD of a wide variety of CKD including FSGS. Characterized by an excessive deposition and net accumulation of extracellular matrix (ECM) components, kidney fibrosis represents a complex process involving various intricate intracellular signaling pathways. These include fibroblast and mesangial activation, tubular epithelial to mesenchymal transition, and infiltration by inflammatory cells and apoptosis.32 Antagonizing the fibrogenic action of these different signaling pathways could, therefore, be a potential therapeutic strategy in FSGS. It is important to provide a justification for such a heavy focus on antifibrotic strategies in a review of novel therapies for FSGS. Despite intensive research and advances in the role of the podocyte in this disease, none of the findings have identified a target that is shared by a large percentage of patients with FSGS and proteinuria. Some of the rare genetic mutations in podocyte proteins have pointed toward a specific intervention such as dietary

Direct TGF-b1 Inhibitors

Tranilast (n-[3,4-Dimethoxycinnamoyl] anthranilic acid).

Several preclinical studies have reported beneficial effects of tranilast, an antiallergic compound used in Japan for the treatment of hypertrophic scars, as an inhibitor of TGF-b1induced fibrosis in a range of diseases.39 No studies of this agent in human FSGS have been published to date.

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Decorin. Proteoglycans represent a major component of the ECM. Decorin, also known as PGII or PG-40, plays an important role in collagen fibrillogenesis and fibrocyte differentiation. Decorin can bind TGF-b and neutralize its biological activity and is considered a natural regulator of TGF-b1. Because the discovery that administration of decorin inhibited the increased production of ECM and attenuated the manifestations of kidney fibrosis,40 similar studies have been performed in animal models of FSGS. However, this therapeutic approach to target the adverse effects of TGF-b has not been successfully applied in patients.

Neutralizing TFG-b Antibodies—Fresolimumab The administration of neutralizing antibodies against TGF-b has been studied intensively and has been successful and well tolerated in several types of animal models, mostly in the setting of diabetic nephropathy.41,42 Trachtman and colleagues43 conducted a phase 1, single-dose study of fresolimumab, a polyclonal antiTGF-b antibody, for the treatment of resistant primary FSGS. In this study, 3 of 16 patients had at least a 50% reduction in proteinuria. Because of the important antiinflammatory effect of TGF-b, it may be necessary to develop molecules that can selectively inhibit the profibrotic effects of TGF-b. Pirfenidone [5-Methyl-1-phenyl-2(1H)-pyridone] Pirfenidone is an orally active small molecule known for its antifibrotic action. Pirfenidone inhibits TGF-b via multiple pathways: it reduces TGF-b promoter activity, TGF-b protein secretion, TGF-b-induced Smad2 phosphorylation, and generation of reactive oxygen species. The beneficial effect of pirfenidone has also been proved not only in vitro but also in patients with FSGS.44 However, despite the efficacy of pirfenidone in reducing proteinuria, there was no demonstrable decrease in the rate of decline in glomerular filtration rate. It is unknown whether earlier implementation of pirfenidone could achieve a lowering of proteinuria and stabilization in kidney function. microRNAs microRNAs (miRNAs), short noncoding RNAs (about 22 nucleotides), have emerged as participants in the pathogenesis of human diseases, including kidney fibrosis.45-47 miRNAs bind to the 30 -untranslated region of target genes to regulate gene expression by post-translational repression or induction of target mRNA degradation. The kidney is an attractive organ for antifibrotic miRNA therapy because of the observed accumulation of miRNA inhibitors within it after systemic administration. These inhibitors, however, must be delivered selectively to the kidney to avoid deleterious effects of modulating miRNAs in other organs. miRNAs, miR-214 and miR-21, are upregulated in models of kidney injury.48 Denby and colleagues49 recently showed that miR-214 functions by promoting fibrosis in kidney injury independent of TGF-b signaling in vivo. Genetic deletion of miR-214 in mice significantly attenuated

interstitial fibrosis induced by unilateral ureteral obstruction (UUO) and antagonism of miR-214 by treatment of wild-type mice with an anti-miR directed against miR-214 (anti-miR-214) before UUO resulted in similar antifibrotic effects. The authors also showed how TGF-b blockade combined with miR-214 deletion granted additional kidney protection. Using a similar model, Li and colleagues50 had previously identified miRNA, miR-433, overexpression as an important component of the TGF-b/Smad3-driven kidney fibrosis. Delivering a miR-433 knockdown plasmid to the kidney by ultrasound microbubble-mediated gene transfer was able to suppress the induction and progression of fibrosis in the UUO model. Sun and collaborators51 used low-dose paclitaxel to ameliorate fibrosis in the remnant kidney model by downregulating miR-192. Although paclitaxel may have some therapeutic value in ameliorating fibrosis in patients with FSGS, it has not been tested. The miR-30 family is downregulated in the podocytes of patients with FSGS.52 In cultured podocytes, treatment with TGF-b or PAN leads to cytoskeletal damage and apoptosis. In this particular study, the damage was ameliorated by exogenous miR-30 expression and aggravated by miR-30 knockdown. The authors nicely showed how the protective role of miR-30 is because of the direct inhibition of Notch1 and p53 (a pathway independent of TGF-b signaling) and how glucocorticoid treatment maintains miR-30 expression in vitro. A potential avenue for development of miRNA therapies and defining a novel mechanism underlying the therapeutic effect of glucocorticoids in the treatment of podocytopathies will be 2 areas for future research.

Miscellaneous Antifibrotic Drugs Paclitaxel Paclitaxel (taxol) is an anticancer agent that acts by stabilizing polymerized microtubules, enhancing microtubule assembly, arresting the cell cycle in the G0/G1 and G2/M phases, and ultimately leading to cell death. Zhang and colleagues53 found that low-dose paclitaxel (taxol) ameliorates kidney fibrosis in animals with obstructive uropathy by inhibition of TGF-b/Smad activity. Sun and others51 used low-dose paclitaxel to ameliorate fibrosis in the remnant kidney model by downregulating miR192. Although paclitaxel may have some therapeutic value ameliorating fibrosis in patients with FSGS, it has not yet been tested in patients. Rosiglitazone Rosiglitazone and pioglitazone are oral peroxisome proliferator-activated receptor-g agonists that increase insulin sensitivity. They are used as hypoglycemic agents in patients with type 2 diabetes mellitus and have been shown to have antifibrotic effects in the kidney.54 The FONT phase 1 trial showed that rosiglitazone was well tolerated in children with drug-resistant FSGS, and after 16 months of follow-up, 71% of participants had stable glomerular filtration rate and reduced proteinuria.20,55 However, testing of the drug was halted after the warning by the Food and Drug Administration about the

Novel Therapies for FSGS

Table 1. Novel Therapies for FSGS Mechanism of Action Modulation of immune system/inflammation

Antagonism of circulating factors Antifibrotic

Stem cells

Agents Rituximab ACTH Abatacept Adalimumab Galactose Inhibitors of suPAR TGF-b inhibitors Direct: fresolimumab Indirect: microRNAs Human umbilical mesenchymal stem cells

Abbreviations: ACTH, adrenocorticotropic hormone; FSGS, focal segmental glomerulosclerosis; suPAR, soluble urokinase receptor; TGF-b, transforming growth factor-b.

potential cardiovascular side effects of rosiglitazone in older patients with type 2 diabetes. No specific serious safety concerns were identified in patients with FSGS who received rosiglitazone in the FONT trial. Future testing of peroxisome proliferator-activated receptor-g agonists may be warranted.

Stem Cell Therapies Future therapies for FSGS may rely on stem cells. These cells have an unlimited potential to differentiate into multiple distinct lineages and can potentially lead to structural remodeling and functional regeneration of kidney tissue. Studies have reported the use of stem cells in treatment of selected kidney diseases.56,57 Recently, Ma and colleagues58 investigated the role of human umbilical mesenchymal stem cells (MSCs) on the progression of FSGS using a model of ADR-induced nephropathy. Their study found that repeated infusions of human umbilical MSCs improved kidney fibrosis and modulated the inflammatory response in these animals. In a similar approach, Ruan and collaborators59 used autologous stem cell transplantation for the treatment of kidney interstitial fibrosis in rabbits with some success. Belingheri and colleagues60 recently reported that administration of 3 human allogeneic bone marrow MSC infusions in a 13-year-old patient with recurrent FSGS after kidney transplantation not responding to conventional therapy resulted in improvement of the proteinuria and stabilization of the kidney function leading to discontinuation of the plasmapheresis therapy. Table 1 summarizes the potential treatments for FSGS discussed in this review.

Conclusions FSGS continues to be an important cause of CKD and ESKD in pediatric patients. Treatments that can consistently achieve a durable remission in proteinuria and preservation of kidney function are sorely lacking. Despite decades of intensive basic science and clinical research, no therapeutic target has been identified that is applicable to all patients. This suggests that FSGS is a heterogeneous disease-like cancer and that multiple approaches will be needed to achieve a “cure” for affected patients. It is hoped that the ongoing Nephrotic Syndrome Study Network

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systems biology approach to disease mechanism discovery will identify biomarkers and mechanism-derived therapeutic targets that allow discrimination of patients into clinically relevant subcategories that can guide delineation of prognosis and formulation of a treatment plan.61 Because of the rarity of FSGS, multicenter collaborative efforts will be required to translate these experimental findings into clinical practice. This will represent the longawaited arrival of personalized, evidence-based medicine for patients with this serious glomerulopathy.

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Novel therapies for FSGS: preclinical and clinical studies.

Focal segmental glomerulosclerosis (FSGS) is a rare but important cause of end-stage kidney disease in children and adults. Current therapy, consistin...
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