Current and emerging treatments for idiopathic focal and segmental glomerulosclerosis in adults

Abstract

Idiopathic focal and segmental glomerular sclerosis is a frequent cause of nephrotic syndrome and end-stage renal disease. The pathogenesis is still unknown, although the body of evidence suggests that focal and segmental glomerular sclerosis is caused by a not clearly identified circulating factor that alters the permselectivity of the glomerular barrier. Proteinuria is followed by podocyte injury. Glucocorticoids, calcineurin inhibitors, cytotoxic agents and mycophenolate mofetil, either given alone or in combination, may obtain complete or partial remission of proteinuria in 50–60% of patients and protect them from end-stage renal disease, but the remaining patients are resistant to the available drugs. A number of new drugs, including rituximab, galactose and antifibrotic agents, are under investigation.

Keywords::

• calcineurin inhibitors
• focal glomerulosclerosis
• glomerulonephritis
• glucocorticoids
• mycophenolate
• nephrotic syndrome
• rituximab

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Release date: 28 February 2013; Expiration date: 28 February 2014

Learning objectives

Upon completion of this activity, participants will be able to:

• • Assess the clinical presentation and prognosis of iFSGS

• • Distinguish the first-line therapy for iFSGS

• • Analyze other treatments for iFSGS

• • Evaluate practical therapeutics for iFSGS

Financial & competing interests disclosure

EDITOR

Eliza Manzotti

Publisher, Future Science Group, London, UK.

Disclosure: Eliza Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD

Health Sciences Clinical Professor and Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA.

Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Claudio Ponticelli

Division of Nephrology, IRCCS Humanitas Hospital, via Manzoni 56, 20089 Rozzano, Milano, Italy.

Disclosure: Claudio Ponticelli has disclosed the following relevant financial relationships: consultant for Novartis, Italy until 31 December 2011.

Giorgio Graziani

Division of Nephrology, IRCCS Humanitas Hospital, via Manzoni 56, 20089 Rozzano, Milano, Italy.

Disclosure: Giorgio Graziani has disclosed no relevant financial relationships.

Focal and segmental glomerular sclerosis (FSGS) is a glomerular lesion caused by podocyte injury. FSGS is associated with proteinuria, usually in the nephrotic range (>3.5 g/day in an adult), accompanied by the typical constellation of signs and symptoms of the nephrotic syndrome (NS) and arterial hypertension. Some congenital forms of FSGS are caused by mutations of genes encoding proteins that have a critical role in maintaining the permselectivity of the glomerular barrier. However, in most cases, the congenital forms of FSGS associated with NS occur in children. In other cases, glomerular sclerotic lesions may be associated with other renal or systemic diseases, infections or may develop after assumption of drugs (Box 1). In many cases of secondary focal sclerosis, particularly those associated with glomerulomegaly, the lesions are caused by podocyte stress [1]. In contradistinction to idiopathic FSGS, the secondary forms are associated with lower frequency of hypoalbuminemia, particularly when the disease is caused by glomerular hyperfiltration. Edema is infrequent in secondary FSGS, perhaps because the foot effacement is more segmental than diffuse. The progression to renal failure is also much less frequent and usually slower in forms caused by glomerular hyperfiltration than in idiopathic FSGS [2]. However, the most frequent forms of FSGS have an unknown etiopathogenesis and are called idiopathic or primary FSGS.

Idiopathic FSGS can affect both children and adults, and is usually associated with NS and arterial hypertension. Most untreated adults with NS tend to progress to end-stage renal disease (ESRD), but an appropriate treatment may obtain complete or partial remission of proteinuria and preservation of kidney function in 50–60%. At optic microscopy, the lesions of FSGS initially affect only a few glomeruli and are characterized by sclerosis (collapse and solidification) limited to a portion of the glomerulus. According to the location of the initial sclerotic lesion, five different histological variants of FSGS have been classified – these are as follows: classic or no otherwise specified FSGS, characterized by a small area of capillary collapse or sclerosis at the periphery of an otherwise normal tuft; perhilar variant, in which perihilar sclerosis is adjacent to the vascular pole; tip variant, characterized by collapsed or sclerotic capillaries adherent to the epithelial cells of the tubular pole of the glomerulus; cellular variant, with segmental endocapillary hypercellularity and variable glomerular epithelial cell hyperplasia; and collapsing FSGS, a variant with global collapse of glomerular capillaries of at least 20% of glomeruli [3]. In this variant, podocyte dysregulation leads to glomerular epithelial cell proliferation and de-differentiation of podocytes to a more primitive state, transdifferentiation and epithelial–mesechymal transition.

Pathogenesis

The pathogenesis of primary FSGS is still a matter of investigation. Proteinuria is the first clinical sign of the disease. It precedes histologic lesions, but electron microscopy usually shows that the development of proteinuria is associated with effacement of foot processes of podocytes. Today, idiopathic FSGS is categorized as a ‘podocytopathy’, the podocyte being a major player in its pathogenesis [3,4]. This highly differentiated and specialized cell type has essential roles in maintaining the integrity of glomerular architecture, resisting endocapillary hydraulic pressure and preventing leakage of proteins into the urinary space [5]. Podocytes are unable to replicate, and even the damage of a single podocyte may initiate a sequence of events that can lead to the degeneration of the whole glomerulus [6]. The question of what is the primum movens leading to podocyte injury in primary FSGS remains unanswered. A host of factors, including an early recurrence of FSGS after renal transplantation and response to plasmapheresis, would indicate that the main culprit is a circulating permeability factor inducing loss of glomerular permselectivity, podocyte foot process effacement and proteinuria [7]. Of interest, a multicenter study, including 21 cases of post-transplant recurrent FSGS from 19 patients, showed that in 81% of cases, the histologic variant found in patients with recurrence was the same seen in the native kidneys [8]. The pathogenetic role of a circulating factor seemed to be validated by the discovery that a cardiotrophin-like cytokine-1 is an active factor in FSGS [9]. Wei et al. recently showed that the permeability factor could rather be the serum soluble urokinase receptor (suPAR), a glycoprotein involved in reorganization of tissues [10]. Actually, suPAR was elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. Moreover, a higher concentration of suPAR before transplantation underlined an increased risk for recurrence of FSGS after transplantation. Finally, by using three mouse models, the authors also showed that circulating suPAR activated podocyte b-3 integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy, suggesting that the renal disease only develops when suPAR activates podocyte b-3 integrin.

Other mechanisms may concur to impair the permselectivity of the glomerular barrier. The molecule CD80, also known as B7-1, is expressed on podocytes of patients with minimal change disease, a condition that can herald the development of FSGS in steroid-resistant patients [11]. Recent experimental studies suggested that activation of Toll-like receptor 3 (TLR3) on cultured human podocytes induced increased expression of cathepsin L, decreased synaptopodin expression and reorganization of actin cytoskeleton [12]. Since TLR3 recognizes the RNA carried by some viruses, these data may suggest a possible role for virus infections (such as hepatitis B virus, hepatitis C virus, HIV, cytomegalovirus and Epstein–Barr virus) in triggering abnormal function of glomerular barrier and proteinuria. Other studies suggested that a subset of patients with FSGS may produce anti-actin, anti-ATP synthase and/or anti-nephrin autoantibodies, which would cooperate with permeability factor in altering the glomerular permselectivity [13]. To support this hypothesis, Charba et al. showed that the injection of antibodies directed against the protein tyrosine phosphatase receptor-O (a protein expressed on foot processes that regulates nephrin in the filtration barrier) increased the glomerular permeability to albumin [14].

Considering these data, it is possible that the circulating suPAR with the contribution of other factors would cause podocyte injury. Podocytes would respond by the reorganization of the actin cytoskeleton leading to foot process effacement. The continuous injury by permeability factor or a second hit would cause a critical level of cell stress with consequent death of podocytes, detachment from the glomerular basement membrane, foot process effacement and adhesion to the parietal layer of Bowmans’ space [3]. From this site, activated parietal epithelial cells invade the affected segment of the glomerular tuft and deposit extracellular matrix that eventually leads to ensuing sclerosis [15]. Glomerular sclerosis may also be aggravated by the incapacity of podocytes to respond to hypertrophic stress. Experimental studies showed that failure of podocytes to match glomerular tuft growth in response to growth signaling through the mTORC1 pathway can trigger proteinuria, glomerulosclerosis and progression to ESRD [16].

Natural course & prognosis

Primary FSGS is usually progressive. Spontaneous complete remission of proteinuria is exceptional [17,18]. Older studies reported that approximately two-thirds of patients developed ESRD within 10–15 years. In few cases, called ‘malignant’ FSGS, the disease shows a rapidly progressive course associated with severe hypertension, marked hyperlipidemia and thrombotic complications. The prognosis for FSGS is better today as most patients receive adequate symptomatic and specific treatments (see below).

A number of factors are associated with the outcome of FSGS (Box 2). Among them, the most important are the entity of proteinuria and the response to therapy. Several papers showed that most patients with non-nephrotic proteinuria are free from dialysis in the long term, while more than 50% of patients with NS enter ESRD within 10 years from clinical onset [19–21]. Other series reported that more than 90% of patients who entered complete remission of proteinuria (<0.2–0.3 g/day) were still alive with kidney functioning after 10 years [22,23]. Patients with partial remission (<2 g/day) also have a better long-term outcome in comparison with untreated or nonresponder patients [23].

Current treatments

Patients with FSGS and NS should receive a symptomatic treatment based on renin–angiotensin system inhibitors, statins, vitamin D, low-salt diet and diuretics, when needed. Reducing body weight may also reduce glomerular growth and may represent a useful adjunctive therapy to slow or prevent progression to ESRD.

A ‘specific’ treatment should have the following three main goals: to reverse, halt or delay the progression to ESRD; to obtain a complete or partial remission of proteinuria, also to prevent the complications related to the NS; and to prevent the undesirable side effects of therapy.

Glucocorticoids

The first therapeutic attempts in FSGS have been done with glucocorticoids. In 1988, a review of the studies in adults showed that only 16% of 151 patients with FSGS treated with glucocorticoids obtained a complete remission [24]. However, most patients reported in those studies received prednisone for only 2–3 months. The results would be better if one takes into account the few series in which patients were given prednisone for a longer period of time. Considering the data of four studies in which patients received prednisone for 6 months [17,25–27] 69 out of 196 patients (35%) achieved complete remission (Table 1). Moreover, another 20–30% of patients obtained partial remission. As expected, those patients maintained kidney function in the long term. Glucocorticoids interfere with the inflammatory and the immune responses; but, at least in experimental models, they could also increase the expression of nephrin, stabilize the actin cytoskeleton, abolish the expression of the proliferation marker (CDKI) P21 and preserve the glomerular permselectivity [28,29].

The guidelines of Kidney Disease Improving Global Outcomes (KDIGO) for treatment of FSGS suggested starting with prednisone at a daily single dose of 1 mg/kg (maximum 80 mg) or alternate-day dose of 2 mg/kg (maximum 120 mg). The initial high dose should be given for a minimum of 4 weeks and continued up to a maximum of 16 weeks, as tolerated, or until complete remission has been achieved. Prednisone should be tapered slowly over a period of 6 months after achieving complete remission. The same initial doses of glucocorticoids may be used in case of relapses [30]. However, it should be noted that a prolonged treatment with steroids is of little, if any, benefit in African–American adults [31].

The use of large doses of glucocorticoids may be followed by a number of complications that are usually dose- and time-dependent. To reduce the risk of these adverse events, the following precautions can be taken: the full daily dose should be administered early in the morning (between 6 and 8 AM, or even earlier if possible) in order to mimic the circadian rhythm of cortisol secretion; a low-calorie, low-salt diet should be followed to prevent obesity, diabetes, hyperlipemia, hypertension and edema; physical activity should be encouraged to reduce the risk of hypertension, obesity, myopathy, osteopenia and cardiovascular disease; to prevent osteoporosis, postmenopausal women and men aged >50 years treated with glucocorticoids should receive biphosphonates according to the risk of fractures and the doses of glucocorticoids (Table 2) [32] and, of great importance, the steroid dose should be tailored according to the tolerance of the patient, which is extremely variable.

Calcineurin inhibitors

In steroid-resistant patients, frequent relapsers, and/or in patients with contraindications or intolerance to glucocorticoids, cyclosporine or tacrolimus are usually prescribed as a second option. The main mechanism of action of calcineurin inhibitor (CNI) rests on the inhibition of calcineurin, a system of phosphatases that, by dephosphorylating the nuclear-factor of activated T cells, allows its entrance into the nucleus, where these cells encode IL-2, a cytokine necessary for activating T cells. Apart from this immunomodulating activity, cyclosporine can also stabilize the podocyte actin cytoskeleton by blocking the calcineurin-mediated dephosphorylation of synaptopodin, a protein critical for actin filament reformation [33]. Therefore, it is possible that the main benefit with CNI in FSGS and in other glomerular diseases is mainly due to its antiproteinuric effect.

Retrospective reviews showed that cyclosporine could maintain 73% of patients who responded to glucocorticoids in complete remission [34], but among adults who did not respond to prednisone, only 17% of those treated with cyclosporine entered complete remission, and another 20% had a partial response (Table 3) [35–40]. Of note, Meyrier et al. pointed out that the probabilities of response to cyclosporine doubled if patients were added small doses of prednisone [41]. Two small, randomized controlled trials compared the effects of cyclosporine in comparison with controls receiving symptomatic treatment. In one of these trials, 45 patients were randomly assigned to receive symptomatic treatment or the old formulation of cyclosporine at a dose of 5 mg/kg/day for 6 months, then progressively tapered off at the end of the twelfth month. At completion of the treatment, 40% of patients were in complete remission and another 20% were in partial remission. However, many patients had a relapse of NS after cyclosporine withdrawal [42]. In the other trial, 49 adults with FSGS were assigned to receive 6 months of cyclosporine plus low-dose prednisone or placebo plus prednisone. All patients were followed for an average of 200 weeks. At the end of 6 months of treatment, 50% of patients attained complete remission and another 20% attained a partial remission. Only 30% of patients were still in complete remission and less than 10% were in partial remission after 18 months. However, only a fourth of treated patients versus half of untreated patients had a decline of creatinine clearance >50% in comparison with baseline [43]. These data suggest that the beneficial effect of cyclosporine on proteinuria would compensate for its nephrotoxicity. Few observational studies in adults with FSGS reported similar results with tacrolimus [44–47]. Out of 45 adults treated with tacrolimus, 29% obtained a complete remission and 31% a partial remission, but NS often relapsed after withdrawal of the drug. Many of these patients had been treated with steroids, but no details were given about the doses and the duration of steroid treatment (Table 4).

The KDIGO guidelines suggest the use of CNI as a second option therapy for patients with FSGS who are resistant or intolerant to glucocorticoids. If cyclosporine is chosen, the drug should be initiated at doses of 3–5 mg/kg/day. In case of remission, treatment should be continued for 1 year, then the dose should be reduced by 25% every 2 months. If no remission occurs within 6 months, cyclosporine should be discontinued. Prednisone at 0.15 mg/kg/day should be added for 4–6 months, then tapered off over 4–8 weeks. If tacrolimus is chosen, the initial dose should range between 0.1 and 0.2 mg/kg/day; in cases of remission, the same advice for cyclosporine should be followed. Prednisone should also be added with the same modalities suggested for cyclosporine. No precise guidelines for relapses are given, but it is reasonable to assume that patients may be given the same initial dosage of CNI that allowed them to obtain remission [30].

The main problems with the use of CNI are the frequent relapse of NS and the interruption of therapy and nephrotoxicity. Thus treatment should be prolonged in many patients. In a retrospective study evaluating the impact of cyclosporine on FSGS, the risk of irreversible renal lesions was increased when cyclosporine was given to patients with abnormal levels of serum creatinine, when there was a high number of sclerotic glomeruli at initial renal biopsy and when the initial doses of cyclosporine were elevated, that is, higher than 5.5 mg/kg/day [48]. The same risk factors should also be taken into account when using tacrolimus. Careful monitoring of renal function and blood pressure, lowering the maintenance dose and utilizing repeat renal biopsy in patients receiving long-term therapy can minimize this risk of nephrotoxicity [49]. With such as strategy, CNI may be given for years in patients achieving remission.

Alkylating agents

Cytotoxic agents can attain good remission rates in steroid-responsive patients with idiopathic FSGS (iFSGS), but a complete remission may be obtained in only 10% of steroid-resistant patients [50]. Present available data do not support the general use of alkylating substances for the treatment of FSGS in adults [51]. These drugs can cause disquieting side effects, such as bone marrow toxicity, gonadal toxicity and oncogenic risk. A cumulative dose of cyclophosphamide >250 mg/kg may cause sterility [52], and malignancy may occur when the cumulative dose of cyclophosphamide exceeds 360 mg/kg [53]. The KDIGO guidelines pointed out that there is insufficient evidence to support the use of alkylating agents in patients with steroid-resistant FSGS [30].

Salt of mycophenolic acid

Observational studies in adults with FSGS treated with mycophenolate mofetil (MMF), either given alone or in combination with steroids or cyclosporine, reported that only 11% of patients entered a complete remission and 22% a partial remission. Some patients failed to respond to previous treatments, but little information is available about type and duration of those treatments (Table 5) [54–58]. In a randomized controlled trial, 138 children and adults with FSGS and urine protein:creatinine ratio higher than 1: 1g were assigned to receive dexamethasone pulses and oral MMF or cyclosporine for 1 year. At the end of the study, there was no difference in complete remission (3 vs 5.6%) or in partial remission (4.2 vs 26.4%). Serious adverse events tended to be more frequent with dexamethasone/MMF treatment [59]. The available data do not show any advantage of MMF over other available treatments, although the small size of the studies and the short-term follow-up may have prevented the detection of potential advantages of a long-term administration. The KDIGO guidelines concluded that there is insufficient evidence to support the use of these immunosuppressive drugs in patients with steroid-resistant FSGS [30].

Inhibitors of the mTOR

In spite of some benefit reported by anecdotal case reports [60], the use of sirolimus in patients with FSGS should be discouraged. This drug can impair the pathways essential for podocyte integrity, and therefore, predisposes patients to glomerular injury [61]. In a small study, sirolimus had to be stopped prematurely in five out of six patients with iFSGS, because of precipitous decrease in renal function, increase in proteinuria and/or severe hypertriglyceridemia [62]. Other investigators found that sirolimus can even cause a de novo FSGS [63].

Combined treatments with apheresis

Plasmapheresis and immunoabsorption with protein A have been shown to be useful in reducing proteinuria in patients with posttransplant recurrence of FSGS, most likely by removing circulating permeability factor [53,64]. Mitwalli treated 11 adults with biopsy-proven primary FSGS and NS resistant to steroids and cytotoxic drugs with plasmapheresis, oral prednisolone and intravenous cyclophosphamide [65]. On average, each patient had undergone 17 sessions. A month after the last plasmapheresis session, eight patients were in clinical remission of NS. After a mean follow-up of 27 months, six of the eight responders remained in sustained complete or partial remission of proteinuria with stable renal function. Their mean proteinuria at the latest examination was 0.9 g per day. Instead, patients who did not respond had a gradual decline in renal function. Other single-case reports also obtained good results with plasmapheresis or immunoadsorption associated with glucocorticoids, cytotoxic drugs and/or rituximab. NS recurred in a number patients, but it is impossible to quantify the risk of relapse as the follow-ups were short in many cases. Due to the uncontrolled designs and small patient cohorts, the level of evidence of the available studies cannot allow one to draw any firm conclusion from the available data.

Emerging treatments

Rituximab

This monoclonal antibody might interfere with the antigen presentation from B cells to T cells, or with antibody-dependent cell-mediated cytotoxicity, or may increase the production of T regulators [66]. Rituximab can also prevent the actin cytoskeleton disruption by binding SMPDL-3b protein and regulating acid sphingomyelinase activity [67].

In adults with FSGS, there are only scanty reports. By reviewing the clinical experience in Spain, Fernandez-Fresnedo et al. reported one case of complete remission and two cases of partial remission out of eight adults with FSGS who received rituximab treatment [68]. In other anecdotal reports, patients with FSGS who were sensitive to steroids also responded to rituximab, while steroid-resistant patients did not respond [69] or entered only partial remission after rituximab therapy [70]. A trial investigating the role of rituximab in patients, 5–60 years of age, with recurrent or resistant FSGS has been completed but not published yet [101]. According to KDIGO guidelines, there is insufficient evidence to support the use of rituximab in iFSGS [30].

Galactose

Savin et al. postulated that the permeability factor involved in the pathogenesis of FSGS may consist of anionic low-molecular weight protein(s) that may interact with sugars of the glycocalyx [71]. They tested the affinity of permeability factor for sugars using column chromatography and discovered a high affinity for galactose; plasma permeability activity was absent from unbound material and present in eluate after dialysis to remove galactose. In parallel studies, activity of serum was lost after adding galactose. To determine whether galactose could also abolish plasma permeability activity in vivo, galactose was infused intravenously to a patient with post-transplant FSGS. Permeability activity reduced from 0.88 before infusion to undetectable levels postinfusion and at 48 h. Following this report, oral galactose at a dose of 0.2 g/kg twice a day was given to a patient with FSGS refractory to previous treatments. A long-term remission of NS was obtained [72]. Another group used galactose in a patient with FSGS resistant to steroids, cyclophosphamide and tacrolimus. Oral galactose was added to tacrolimus for 1 month, after which proteinuria decreased by 50%. Seven months later, galactose was again added for 6 months, after which proteinuria remained <2 g/24 h and the plasma albumin and cholesterol concentrations normalized [73]. It is impossible to evaluate the efficacy of galactose by these anecdotal studies. A pilot study to determine if oral galactose can lower the FSGS permeability factor has been terminated [102]. Another trial evaluating the effects of galactose in children with steroid-resistant NS on treatment with CNI, MMF and steroids is still recruiting patients [103].

Antifibrotic agents

From a theoretical point of view, antifibrotic agents may slow or halt the progression of FSGS in resistant cases. Pirfenidone is an orally available antifibrotic agent that has been shown to be beneficial in animal models of pulmonary and renal fibrosis, and in clinical trials of pulmonary fibrosis, multiple sclerosis and hepatic cirrhosis. An open-label trial was performed to evaluate the safety and efficacy of pirfenidone in patients with idiopathic and postadaptive FSGS [74]. Eighteen patients received angiotensin antagonist therapy and completed a median of 13 months of pirfenidone treatment. The monthly change in glomerular filtration rate (GFR) improved from a median of -0.61 ml/min per 1.73 m² during the baseline period to -0.45 ml/min per 1.73 m² with pirfenidone therapy, a median improvement of 25% in the rate of decline. Pirfenidone had no effect on blood pressure or proteinuria. Adverse events included dyspepsia, sedation and photosensitive dermatitis. A pilot Phase II trial to evaluate the ability of pirfenidone to reduce the proteinuria and slow the rate of progression of renal insufficiency in patients with FSGS has been completed [104].

In a Phase II clinical trial, ten patients with a GFR >40 ml/min and an urine protein:creatinine ratio >1:1g were assigned to receive adalimumab (a TNF inhibitor with antifibrotic properties) at a dose of 24 mg/m² every 14 days. In the same study, 11 patients with similar values of GFR and proteinuria received rosiglitazone (an antidiabetic drug with antifibrotic properties) at a dose of 3 mg/m² for 16 weeks. After completion of the treatment, 71% in the rosiglitazone cohort and 56% in adalimumab cohort had a reduced negative slope of the line plotting GFR versus time [75].

A number of studies evaluated the potential of endothelin antagonists for proteinuric renal disease. Although several drugs were found to reduce proteinuria in some patients, most clinical trials were stopped before termination [76,77].

Deoxyspergualin derivates

The Buff/Mna rats spontaneously develop FSGS and show recurrence of disease after transplantation. The administration of the deoxyspergualin derivative LF15-0195 to these rats normalized proteinuria and led to the regression of renal lesions during both the initial disease and post-transplantation recurrence. Remission was associated with a significant increase of CD4⁺CD25⁺FoxP3⁺ T lymphocytes. These data would suggest that regulatory T cells are able to induce regression of rat nephropathy. However, it still remains to be elucidated whether and how this regulation leads to the reorganization of the podocyte cytoskeleton [78].

Expert commentary

We still have much uncertainty about the pathogenesis of iFSGS, and this represents a major limit for organizing an effective therapeutic approach. Moreover, it is difficult to obtain firm conclusions from the available therapeutic trials, as most studies were noncontrolled, the number of patients was small and follow-ups were short. Moreover, the definitions of complete or partial response were different in different studies. Finally, too many patients were considered refractory to treatment even if they received therapy for too a short period of time.

The current treatments can obtain complete or partial remission, as a first event, in 50–60% of patients. Although a number of responders can show relapse of NS, their long-term prognosis is better in comparison with those who do not respond to any treatment. The sad truth, however, is that the treatments we are using today cannot prevent the progression to ESRD or the deleterious complications of NS in a consistent subset of patients who do not respond to glucocorticoids. Moreover, the preliminary results with new drugs and treatments are not particularly encouraging.

From a clinical point of view, patients with iFSGS may be subdivided into those who respond to a correct treatment with glucocorticoids and those who do not respond. For patients who respond, relapses may be treated with the same initial therapy. However, in frequent relapsers, repeated administrations of high-dose steroids may cause a number of serious adverse events. Some of them may benefit from a prolonged treatment with CNI, but even these agents may cause side effects. In responders with serious adverse events, rituximab, mycophenolate or short-term cyclophosphamide may also obtain a response. If no response is seen, it is better to maximize the symptomatic therapy with renin–angiotensin system inhibitors, statins and diet. During this interval without steroids and CNI, a relief of untoward effects caused by previous treatments may be achieved. In this case, patients may receive further courses of the initial treatment.

What to do in patients who have a true resistance to prolonged glucocorticoid treatment is still unknown. Aggressive treatment with high-dose steroids, CNI and plasmapheresis with or without rituximab might obtain some transient benefit. However, there is a high risk of severe complications. In most cases of steroid- and CNI-resistance, it is better not to insist with useless and potentially dangerous treatments.

Five-year view

Few questions should be solved in the next years. Apart from the identified congenital forms of FSGS, is there a genetic predisposition to the disease for patients also with idiopathic FSGS? What is the role and the nature of second hits? Is the loss of glomerular permselectivity due to a unique circulating permeability factor or to different factors? What is the specific target of the permeability factor(s)? What is the role of the immune system? Is the loss of permselectivity caused by cytokines released by an abnormal clone of T cells or by autoantibodies directed against some regulators of actin cytoskeleton? Only solid answers to these questions can allow planning of a correct therapeutic strategy.

Waiting for these answers, if the pathogenetic role of suPAR would be confirmed, the disease might be abrogated by lowering plasma suPAR concentrations with monoclonal antibodies directed against epitopes of suPAR, or by interfering with the suPAR-b-3 integrin interaction through antibodies or small molecules targeting either suPAR or b-3 integrin [10]. Drugs that are able to induce the production of T-regulatory cells or to reduce the expression of CD80 on podocytes [12] may also be developed and tested in FSGS. Finally, further controlled trials should be conducted to better assess the role of treatments based on a combination or alternation of different drugs.

Table 1. Results of observational studies that used prolonged glucocorticoid administration in adults with focal and segmental glomerular sclerosis and nephrotic syndrome.

Study (year)	Patients (n)	Complete remission (n)	Mean duration (months)	Ref.
Pei et al. (1987)	18	7 (39%)	6	[25]
Agarwal et al. (1993)	38	12 (32%)	6	[26]
Ponticelli et al. (1999)	53	21 (40%)	6	[17]
Chun et al. (2004)	87	29 (33%)	4–6	[27]
Total	196	69 (35%)

Table 2. Prevention of glucocorticoid-induced osteoporosis in postmenopausal women and men older than 50 years.

Risk stratification of glucorticoid osteoporosis	Dosage regimen
Low risk	If prednisone <7.5 mg/day, no pharmacological treatment is needed
	If prednisone >7.5 mg/day, alendronate risedronate or zoledronic acid
Medium risk	If glucocorticoids are given for >3 months, alendronate isedronate or zoledronic acid irrespective of the doses of glucocorticoids
High risk	If glucocorticoids are given for >1 month, alendronate isedronate or zoledronic acid irrespective of the doses of glucocorticoids

Risk stratification is based on low BMI, smoking, parental history of hip fractures, higher alcoholic drinks per day, daily and cumulative glucocorticoid dose.

Adapted from recommendations of the American College of Rheumatology [32].

Table 3. Results with cyclosporine in adults with idiopathic focal and segmental glomerular sclerosis resistant to steroids.

Study (year)	Patients (n)	Complete remission (n)	Partial remission (n)	Ref.
Maher et al. (1988)	4	0	0	[35]
Zietse et al. (1992)	4	0	0	[36]
Meyrier (2004)	123	17	15	[37]
Lee et al. (1995)	5	2	2	[38]
Heering et al. (2004)	34	8	13	[39]
Alexopoulos et al. (2000)	11	3	6	[40]
Total	181	30 (17%)	36 (20%)

Table 4. Results of observational studies with tacrolimus in adults with idiopathic focal segmental glomerular sclerosis.

Study (year)	Patients (n)	Complete remission (n)	Partial remission (n)	Ref.
McCauley et al. (1993)	4		3	[44]
Segarra et al. (2002)	25	10	3	[45]
Duncan et al. (2004)	6		6	[46]
Li et al. (2009)	7	2	2	[47]
Total	42	12 (29%)	14 (33%)

Table 5. Results of observational studies with mycophenolate mofetil in adults with idiopathic focal and segmental glomerular sclerosis.

Study (year)	Patients (n)	Complete remission	Partial remission	Ref.
Choi et al. (2002)	9	1	4	[54]
Cattran et al. (2004)	18	1	7	[55]
Tang et al. (2005)	16	5	1	[56]
Senthil Nayagam et al. (2008)	34	8	13	[57]
Segarra Medrano et al. (2011)	27		4	[58]
Total	72	8 (11%)	16 (22%)

Box 1. Causes of secondary focal glomerulosclerosis.

• • Renal diseases

  • − Vesicoureteral reflux

  • − Vasculitis

  • − Membranous GN

  • − IgA GN

  • − Chronic pyelonephritis

  • − Proliferative GN

  • − Renal transplant

  • − Alport syndrome

  • − Analgesic nephropathy

  • − Obstructive uropathy

• • Other diseases

  • − Familial dysautonomia

  • − Morbid obesity

  • − HBV, HCV, HIV

  • − CMV, EBV

  • − Diabetes mellitus

  • − Sickle-cell anemia

  • − Preeclampsia

  • − Arterial hypertension

  • − Polycytemia vera

  • − Bartter syndrome

  • − Glycogen store disease

  • − Elderly

• • Drugs

  • − Biphosphonates

  • − Cyclosporine

  • − Tacrolimus

  • − Adriamycin

  • − Puromycin

  • − Lithium

  • − IFN-α

  • − Anabolic steroids

  • − Heroin

Box 2. Factors influencing the outcome of idiopathic focal segmental glomerular sclerosis.

• • Proteinuria

• • Spontaneous remission

• • Response to therapy

• • Variant of FSGS

• • Interstitial fibrosis/tubular atrophy

• • Number of sclerotic glomeruli

• • Age

• • Sex

• • Ethnicity

• • Arterial hypertension

• • Hyperlipidaemia

• • Genetic forms of FSGS

• • Genetic polymorphism of RAS

• • Relapse on a transplanted kidney

Key issues

• • Idiopathic focal segmental glomerular sclerosis is usually associated with nephrotic syndrome and tends to progress to end-stage renal disease within 10 years in more than 50% of cases.

• • The initial treatment should rest on the administration of high-dose prednisone (1 mg/kg) for a minimum of 4 weeks and up to a maximum of 16 weeks, as tolerated, or until complete remission has been achieved. After remission, prednisone should be tapered slowly over a period of 6 months after achieving complete remission.

• • For patients who do not respond, in frequent relapsers or in patients with contraindications or intolerance to glucocorticoids, cyclosporine or tacrolimus are suggested as a second option.

• • Relapses are frequent after withdrawal of calcineurin inhibitors. Therefore, these agents should be given for long periods of time at the lowest effective dose by frequently monitoring renal function and blood pressure.

• • There is no evidence that cytotoxic drugs, mycophenolate salts or rituximab can offer better results than glucocorticoids or calcineurin inhibitors. However, these agents can offer a therapeutic alternative to patients with steroid or calcineurin inhibitor toxicity.

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Current and emerging treatments for idiopathic focal and segmental glomerulosclerosis in adults

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

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2. The material was organized clearly for learning to occur.
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4. The activity was presented objectively and free of commercial bias.

1. You are seeing a 20-year-old male patient with idiopathic focal and segmental glomerular sclerosis (iFSGS) diagnosed after he developed high blood pressure. Which of the following statements regarding the clinical presentation and prognosis of iFSGS is most accurate?

• □ A FSGS with nephrotic syndrome is usually identified during adulthood

• □ B Secondary FSGS is associated with a higher rate of hypoalbuminemia than primary FSGS

• □ C Hypertension is usually the first sign of idiopathic FSGS

• □ D Kidney function can be preserved with treatment in 50% to 60% of patients with nephrotic syndrome (NS)

2. Which of the following medications is recommended as a first-line treatment for this patient’s iFSGS?

• □ A Rituximab

• □ B Mycophenolate mofetil

• □ C Cyclophosphamide

• □ D Prednisone

3. The patient does not respond to initial treatment. What is the most recommended second-line therapy for iFSGS?

• □ A Cyclosporine

• □ B Prednisone

• □ C Cyclophosphamide

• □ D Galactose

4. What else should you consider regarding practical therapeutics for iFSGS?

• □ A High-dose prednisone should only be used for 1 to 2 weeks

• □ B Calcineurin inhibitors are associated with sustained improvement of NS after discontinuation of therapy

• □ C Rituximab has demonstrated strong response rates among steroid-resistant patients in randomized clinical trials

• □ D The use of sirolimus for the treatment of FSGS should be discouraged

Notes

GN: Glomerulonephritis.

FSGS: Focal segmental glomerulosclerosis; RAS: Renin–angiotensin system.