ARTICLE IN PRESS The Association Between Autism and Errors in EarlyEmbryogenesis: What Is the Causal Mechanism?Annemie Ploeger, Maartje E.J. Raijmakers, Han L.J. van der Maas, and Frietson Galis The association between embryonic errors and the development of autism has been recognized in the literature, but the mechanismunderlying this association remains unknown. We propose that pleiotropic effects during a very early and specific stage of embryonicdevelopment— early organogenesis— can explain this association. In humans early organogenesis is an embryonic stage, spanning Day 20to Day 40 after fertilization, which is characterized by intense interactivity among body parts of the embryo. This implies that a singlemutation or environmental disturbance affecting development at this stage can have several phenotypic effects (i.e., pleiotropic effects).Disturbances during early organogenesis can lead to many different anomalies, including limb deformities, craniofacial malformations,brain pathology, and anomalies in other organs. We reviewed the literature and found ample evidence for the association between autismand different kinds of physical anomalies, which agrees with the hypothesis that pleiotropic effects are involved in the development ofautism. The proposed mechanism integrates findings from a variety of studies on autism, including neurobiological studies and studies onphysical anomalies and prenatal influences on neurodevelopmental outcomes. The implication is that the origin of autism can be muchearlier in embryologic development than has been frequently reported.
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The treatment of idiopathic focal segmental glomerulosclerosis in adultsThe Treatment of Idiopathic Focal Segmental Glomerulosclerosis in AdultsJonathan Hogan and Jai Radhakrishnan Focal segmental glomerulosclerosis (FSGS) is the histologic end point of many disease processes that affect the kidney.
Clinically, adults with FSGS present with proteinuria that may be accompanied by the nephrotic syndrome. Once identifiable(secondary) causes are excluded, the diagnosis of idiopathic FSGS, a challenging glomerular disease to understand andmanage, is made. On the basis of mostly retrospective data, first-line treatment for idiopathic FSGS patients with nephrotic-range proteinuria is a prolonged course of corticosteroids. However, steroid resistance is common and portends an increasedrisk of long-term decline in kidney function and end-stage kidney disease in these patients compared with responders. Multipleother immunosuppression regimens have been used in steroid-resistant FSGS, some of which have been studied in randomizedcontrolled trials. Here, we review the data on the treatment for idiopathic FSGS in adults.
Q 2014 by the National Kidney Foundation, Inc. All rights reserved.
Key Word: Focal segmental glomerulosclerosis Epidemiology and Clinical Presentation Focal segmental glomerulosclerosis (FSGS) is one of the FSGS may comprise up to 35% of biopsies for adults with most challenging glomerular diseases to understand and idiopathic nephrotic syndrome and 19% of native kidney treat for nephrologists and patients alike. Histologically, biopsies overaBiopsies may reveal FSGS in more FSGS is diagnosed with a kidney biopsy that contains at than half of black patients with idiopathic nephrotic least 1 glomerulus exhibiting segmental increase in matrix syndrome,and multiple studies have demonstrated an that obliterates the capillary lumina, immunoﬂuorescence increasing incidence of FSGS over time in the Unit- microscopy with segmental granular deposition of immu- ed States.Adults with FSGS often present with the noglobulin M and C3, and wrinkling and retraction of the nephrotic syndrome, which is present in 54% to 72% glomerular basement membrane with podocyte foot pro- of cases at the time of diagnosis.The largest pro- cess effacement on electron microscopyThe FSGS lesion spective cohort of adult idiopathic FSGS (n ¼ 281) found is a common end point for multiple disease processes that that 78% of patients had nephrotic-range proteinuria at can be divided into those which result in primary podo- some point during the follow-up period.Hypertension cyte alteration and those that have resulted from reduced (36%-63%), microscopic hematuria (29%-94%), and kidney nephron mass, glomerular adaptations, or other glomer- insufﬁciency (48%-59% of adults presenting with a serum ular diseases ().
creatinine . 1.3 mg/dL) are also common at presentation The variety of disease processes associated with FSGS reﬂects the nonspeciﬁc nature of this lesion, and despiteresearch that has provided some insight into pathophysi- ology, the mechanisms by which many of these processes The pathophysiology of idiopathic FSGS is poorly under- lead to podocyte damage and the FSGS lesion are not stood, and it is likely that multiple different mechanisms known. Moreover, in many adults with the nephrotic syn- are involved. In a subset of patients, a circulating perme- drome and FSGS on kidney biopsy, no etiology or associ- ability factor may be associated with FSGS. Clinical expe- ated condition is discovered. This results in the diagnosis rience supports the presence of such a factor in patients of idiopathic FSGS, which is a poorly understood, who undergo kidney transplantation for FSGS and expe- difﬁcult-to-treat, and morbid condition that may lead to rience recurrence of disease in the allograft that is end-stage kidney disease (ESKD). Here, we review the ev- improved with plasma exchange therapy. Savin and col- idence for treating idiopathic FSGS in adults, with a partic- leaguesdescribed such a permeability factor from ular focus on immunosuppressive therapies.
patients with recurrent FSGS after transplant thatincreased in vitro glomerular permeability to albumin.
Candidate molecules include cardiotrophin-like cytokine1 and, recently, the soluble urokinase protein receptorHowever, permeability factors are not found universally, From Division of Nephrology, Department of Medicine, Columbia Univer- and thus, no speciﬁc biomarker exists to guide therapy sity Medical Center, New York, NY.
in FSGS. Consequently, the mechanisms by which Financial Disclosure: The authors declare that they have no relevant ﬁnan- cial interests.
Address correspondence to Jonathan Hogan, MD, Division of Nephrology, The diagnosis of "secondary" FSGS is based on different Department of Medicine, Columbia University Medical Center, 622 West histologic ﬁndings in the setting of an appropriate clinical 168th Street, PH 4-124, New York, NY 10032. E-mail: Ó 2014 by the National Kidney Foundation, Inc. All rights reserved.
history. The hope is that research will lead to FSGS clas- siﬁcation that incorporates disease mechanism. It is important to note that, with the elucidation of these Advances in Chronic Kidney Disease, Vol 21, No 5 (September), 2014: pp 434-441 Treatment of FSGS in Adults mechanisms, it is possible there will be overlap in patho- compel most physicians to recommend ACEI or ARB genesis between these histologic groups, and because all use in idiopathic FSGS with persistent proteinuria when studies in adult idiopathic FSGS have excluded secondary not contraindicated by hypotension, signiﬁcant kidney cases, such insight could lead to a re-evaluation of the pre- impairment, or hyperkalemia. The use of dual RAAS sentation, natural history, prognosis, and approach to blockade with ACEI and ARB therapy may further reduce treatment in FSGS.
proteinuria. However, this approach should be used withcaution given studies showing an increased cardiovascularrisk with combination therapy, along with the absence of Conservative Management: Blood Pressure data on improving kidney survival with dual therapy Control and Renin-Angiotensin-Aldosterone Finally, although RAAS blockade may be deferred in adults with minimal change disease who are treated with No randomized trial has been conducted speciﬁcally in immunosuppression, the lower remission rates, longer FSGS to explore kidney outcomes with different levels time-to-remission, and higher morbidity observed in adult of blood pressure control. The recommendation of FSGS compel many physicians to prescribe ACEI or ARB achieving speciﬁc pressure goals in adults and using of therapy early in the disease course if not contraindicated.
angiotensin-converting enzyme inhibitors (ACEIs) andangiotensin II receptor blockers (ARBs) in idiopathic Approach to Treatment Based on the Amount of FSGS are extrapolated from trials showing treatment- related improvement in proteinuria and long-term kidney The decision of whether to treat adult FSGS with immuno- function in other proteinuric kidney diseasesMany suppression is based on the natural history of the disease.
Compared with adult mini- severely nephrotic (.10 g/ mal change disease, in d of proteinuria) patients which most patients may treated with immunosup- Idiopathic FSGS is a poorly understood glomerular disease pression. However, observa- that frequently presents as nephrotic syndrome and may have multiple different pathogeneses leading to the FSGS FSGS is rare.Multiple worsened kidney outcomes lesion on kidney biopsy.
studies have demonstrated that the kidney prognosis FSGSand other proteinu- Patients who experience a remission in proteinuria have better long-term kidney outcomes than patients who do of FSGS is associated with ric kidney diseases have led not undergo remission.
the amount of proteinuria to a recommended goal and the degree of kidney blood of 130/80 mm Hg, Based mostly on uncontrolled data, a prolonged course of insufﬁciency, with better with a lower goal of 125/ high-dose corticosteroids is considered first-line therapy long-term kidney survival for nephrotic idiopathic FSGS patients.
in those with subnephrotic with more than 1 g of Relapsing, steroid-dependent, and steroid-resistant FSGS are proteinuria vs nephrotic common and often require additional immunosuppression, patients.The largest se- The experience with ACEI with treatment decisions guided by a few randomized and ARB use speciﬁcally for controlled trials and extensive uncontrolled experience.
idiopathic FSGS is limited to 250 patients with FSGS, case series data. Crenshaw two-thirds of whom had and associatesretrospec- nephrotic syndrome at the time of biopsy.Nephrotic tively reviewed 40 cases of idiopathic FSGS in African patients had a signiﬁcantly lower 10-year kidney survival Americans, 24 of whom had taken ACEIs (and some of rate (56%) compared with non-nephrotic patients (94%), whom had also taken steroids) and found that ACEI use although subgroup analysis was not performed with prolonged time to ESKD, but this effect was not signiﬁcant respect to treatment. This association has been conﬁrmed when adjusted on multivariate analysis. Troyanov and col- in multiple other case series, with some demonstrating leagfound that the use of ACEI or ARB therapy was worsened outcomes with "severe" or "massive" protein- associated with a slower progression of kidney disease uria (10-14 g/The importance of stratifying treat- and improved kidney survival in a prospective cohort of ment by level of proteinuria is reﬂected in the Kidney 281 adults with FSGS, 54% whom were on ACEI or ARB Disease: Improving Global Outcomes (KDIGO) recom- therapy, on univariate analysis, but this beneﬁt was mendation for conservative management (ie, without not observed in multivariate linear or time-dependent immunosuppression) in FSGS patients with subnephrotic Cox regression analyses. Indeed, renin-angiotensin- proteinuria and immunosuppressive treatment for ne- aldosterone system (RAAS) blockade may be the most phrotic patients.
warranted in cases of secondary FSGS with normal serumalbumin levels and features suggestive of hyperﬁltrationcompared with idiopathic FSGS with low serum albumin Remission of Proteinuria: A Clinically Important Despite these data, the beneﬁts demonstrated with ACEI The deﬁnition of a "remission in proteinuria" is not stan- and ARB use in trials of other proteinuric kidney diseases dardized across the FSGS literature. Many recent studies Hogan and Radhakrishnan Table 1. Causes of the FSGS Processes Leading to Primary Alterations of the Podocyte 1. Idiopathic (primary) FSGS 2. Viral diseases (HIV, parvovirus B19, and hepatitis C) 3. Drugs (anabolic steroids, intravenous bisphosphonates, lithium, interferon a, and heroin) 4. Genetic mutations Attributed to adaptive/structural changes in the glomerulus 1. Reflux nephropathy 2. Low nephron mass 3. Unilateral kidney agenesis/surgical kidney ablation 4. Kidney dysplasia 5. Chronic allograft nephropathy 6. Chronic damage with other glomerular diseases (proliferative glomerulonephritis, hereditary nephritis, thrombotic micro-angiopathy, and other primary glomerular diseases) 10. Sickle cell disease (and also the KDIGO guidelines) deﬁne a complete remission as a decease in proteinuria to 500 mg/d and a partial remission as a 50% decrease in proteinuria to a ﬁnal amount between 500 and 3500 mg/d (with pre- served or improved kidney function in both cases).
However, this proteinuria threshold has varied between studies, with 200 or 300 mg/d used for complete remis- sion and 2000, 2500, or 3000 mg/d chosen for a partial Troyanov and colleagueused the Toronto Glomerulo- nephritis Registry to conduct the largest prospective observational cohort of 281 nephrotic adults with FSGS.
Immunosuppression was used in 66% of patients, and ACEI or ARB therapy was used in 54% of patients. Pa- tients achieving complete (proteinuria , 300 mg/d) or partial (proteinuria 300-3500 mg/d) remissions had improved 5- and 10-year kidney survivals vs nonremitters ), even when relapse occurred. Moreover, no improved kidney outcomes were observed in patients who achieved a 50% reduction in proteinuria without achieving less than 3.5 g/d of proteinuria or in the partial remission group when they were stratiﬁed by those achieving greater or less than 2 g/d of proteinuria.
Multiple other retrospective case series support the importance of achieving a remission in nephrotic adults and children with These data, combined with the rarity of spontaneous remission in nephrotic adults with FSGS, have prompted in the recommendation to treat nephrotic patients to achieve
Treatment of FSGS in Adults Figure 1. Renal survival for adults with FSGS at 5and 10 years from diagnosis, stratified by remissionstatus. Abbreviation: FSGS, focal segmental glomer-ulosclerosis. Adapted with permission from Troya-nov et al.
Treatment of the Initial Episode of Nephrotic are derived from these case series data. Of note, 1 retro- spective study did not show a difference in remission rates, The bulk of the data supporting the use of oral corticos- decrease in proteinuria, or rate of progression to ESKD in teroids as ﬁrst-line therapy in nephrotic patients is based nephrotic patients with FSGS treated with steroids 1 ACEI on nonrandomized, mostly retrospective case series with (n ¼ 12) vs ACEI alone (n ¼ 10).
signiﬁcant heterogeneity in patient population, corticoste- Alternate-day steroid regimens (2 mg/kg every other roid dose and duration, additional immunosuppression day) are used in nephrotic FSGS patients in an attempt used, and duration of follow-up. Senthil Nayagam and as- to decrease the adverse events associated with daily sociatesconducted the only prospective, randomized corticosteroid use. The data to support alternate-day pre- (open label) trial of steroids in FSGS, treating 33 adults scriptions in FSGS are limited to retrospective, uncon- in India with prednisolone (1 mg/kg/d for 3-6 months trolled case series, the largest of which found a 44% followed by taper, n ¼ 16) or mycophenolate mofetil complete remission rate in 17 elderly (.60 years), mostly (MMF) 1 low-dose prednisolone (n ¼ 17). Cumulative Caucasian patients.No studies have compared remis- (complete or partial) remission was observed in 69% of sion rates, long-term kidney outcomes, or adverse event patients treated with prednisolone vs 71% in MMF 1 pred- proﬁles of daily vs alternate-day regimens in adult nisolone group.
The largest description of remission rates with steroid monotherapy in nephrotic adults with FSGS is a retrospec- Alternatives to Corticosteroids for the Initial tive series that comprised 53 patients, 30 of whom received oral steroids (1 mg/kg/d 3 8 weeks, then taper by Avoiding steroids may be preferred for the initial 5-10 mg/d ever 1-2 weeks) and 23 of whom received nephrotic episode in FSGS in patients for whom high- pulse methylprednisolone followed by oral prednisone dose prednisone therapy is concerning or contraindicated, (.5 mg/kg/d 3 8 weeks, followed by taper)The median such as in patients with poorly controlled diabetes, obesity, treatment duration was 16 weeks in both steroid-treated psychosis, or prior prolonged steroid use for other indica- groups. Cumulative remission was observed in 59% of pa- tions. However, the data on the use of these agents are tients (40% complete remission and 19% partial remission).
limited. One retrospective study described (as a secondary Of the 27 patients treated with steroids for less than end point) the remission rates of 20 nephrotic FSGS pa- 16 weeks, only 15% achieved complete remission, tients treated with prolonged courses of prednisolone compared with 61% complete remission and 11% partial (n ¼ 8, 62.5% remission), prednisolone 1 azathioprine remission for those treated for more than 16 weeks. Other (n ¼ 5, 80% remission), or prednisolone 1 cyclosporine case series have described cumulative remission rates (n ¼ 7, 87.5% remission) as ﬁrst-line therapyDuncan with steroid therapy in the 40% to 60% range, but and colleaguesprospectively followed 6 adults with many of these results are confounded by the use of idiopathic FSGS treated with tacrolimus (mean trough 5.5 ng/mL) for mean duration of 12.8 months, with all 6 pa- standard steroid treatment dose (prednisone 1 mg/kg/d), tients achieving partial remission (mean time-to-remission duration (up to 16 weeks of full-dose steroid therapy fol- 6.5 months). The estimated glomerular ﬁltration rate lowed by taper), and deﬁnition of steroid-resistant FSGS (calculated by the Modiﬁcation of Diet in Renal Disease Hogan and Radhakrishnan Table 3. Definitions of Steroid-Resistant and Steroid-Dependent mended in patients with steroid-dependent FSGS and preserved kidney function. The published experience Steroid-resistant FSGS Failed to achieve remission with treating steroid-dependent FSGS with cyclosporine is 16 weeks of daily (1 mg/kg/d) limited and often confounded by the inclusion of children or alternate-day (2 mg/kg and patients with minimal change disease, but may lead to every other day) steroids remission in up to 80% of patients with steroid-responsive Steroid-dependent FSGS 2 relapses during steroid taper FSGSThe use of tacrolimus with prednisone has been or within 2 weeks of described in 2 small, prospective studies in steroid- discontinuing steroid therapy dependent and steroid-resistant FSGS patients.The Abbreviation: FSGS, focal segmental glomerulosclerosis.
largest trial compared tacrolimus 1 prednisone withintravenous cyclophosphamide 1 prednisone in 33Chinese adults with steroid-dependent or steroid-resistant FSGS,with 6- and 12-month cumulative remis- formula) decreased from 72 to 56 mL/min per 1.73 m2 sion rates of 67% and 73% in the tacrolimus 1 prednisone (P ¼ nonsigniﬁcant [NS]) with tacrolimus therapy. No group compared with 56% and 67% in the cyclophospha- relapses were observed, but all patients remained on tacro- mide group (P ¼ NS). However, the remission rate specif- limus for the duration of the study.
ically for steroid-dependent patients was not presented.
As noted earlier, MMF (2 g/d 3 6 months) 1 prednisolone The use of cyclosporine and tacrolimus requires close (0.5 mg/kg/d 3 2-3 months) was compared with conven- monitoring of trough levels and kidney function, particu- tional therapy (prednisone 1 mg/kg/d for 3-6 months larly with prolonged administration.
followed by taper) for the initial FSGS episode in 33 Alkylating agents, such as cyclophosphamide, as noted Indian adults, with no difference in cumulative remission earlier, have also been used in relapsing nephrotic between groups (MMF group 71% vs conventional group syndrome. Similar to the experience with calcineurin 69%).Relapse rates and infectious complications were inhibitors, the published data on oral cyclophosphamide similar between the 2 groups. These results are encour- (usually at doses of 2.0-2.5 mg/kg/d) often include adults aging, but controlled trials with longer follow-up are war- and children with other etiologies of the nephrotic syn- ranted to further determine the efﬁcacy and durability of drome in addition to FSGS.Compared with calcineurin these agents in adult idiopathic FSGS.
inhibitors, alkylating agents are associated with higherremission rates and slower time-to-remission and higher Treatment of Relapse relapse rates. These clinical observations support evi- Relapse after remission in FSGS is common. In the largest dence that the antiproteinuric effects of calcineurin inhib- prospective cohort of adult FSGS, 52% of patients who itors may be via stabilization of the podocyte actin experienced a partial remission and 36% of patients who skeleton rather than immunomodulatory effects on experienced a complete remission had a relapse during the follow-up period (cumulative relapse rate Time Other therapies, such as MMF, may be used in steroid- from remission-to-relapse was shorter in the partial dependent FSGS, but no studies have been conducted to remission group (7 vs 20 months), and relapse in partial help guide its use. A recent case series demonstrated lower remitters was associated with male gender and having a relapse rates and deceased doses of other immuno- higher nadir protein during remission. Spontaneous suppression in adults with steroid-dependent minimal remission occurred more commonly in these relapsers change disease treated with rituximab,but further study than in other descriptions of the natural history of is needed to determine the usefulness of rituximab in FSGS, and this and other studies describe remission rates of more than 50% to 70% in relapsed adults andchildren with FSGS with repeat treatment courses.
No controlled trials exist evaluating treatment for relapse Treatment of Steroid-Resistant FSGS after steroid treatment in adults with idiopathic FSGS.
Steroid-resistant FSGS is deﬁned as the persistence of A repeat course of steroids is recommended if the initial nephrotic-range proteinuria despite prednisone 1 mg/ therapy was well toCalcineurin inhibitors or kg/d (or 2 mg/kg every other day) for more than 4 MMF may be considered if the corticosteroids were poorly monthsBased on the remission rates with corti- tolerated or if the patient has developed a contraindication costeroid therapy, steroid-resistant FSGS occurs in 40% to their use.
to 60% of patients and is associated with signiﬁcantlong-term kidney morbidity. The experience of treating Treatment of Steroid-Dependent FSGS steroid-resistant FSGS is comprised of a few randomized FSGS patients are considered steroid dependent if trials and many observational case series and case reports they experience 2 relapses during taper or within 2 weeks evaluating various immunosuppressive agents. The inter- of completing steroid therapy ). In these patients, pretation of this literature is often confounded by the the goal is to attain or maintain remission while discontin- heterogenous concomitant use of corticosteroids, patient uing or decreasing steroid dose in the hope of avoiding the inclusion, and exclusion criteria and the grouping of adverse events of long-term, high-dose therapy. No nephrotic patients with other kidney histologies, such as controlled trials exist for the treatment of steroid- minimal change disease and membranoproliferative dependent FSGS. A calcineurin inhibitor may be recom- glomerulonephritis, in many reports.
Treatment of FSGS in Adults Calcineurin Inhibitors, Alkylating Agents, and controlled trial in China found 6- and 12-month cumula- Mycophenolate Mofetil tive remission rates of 67% and 73%, respectively, in 15 The North America Nephrotic Syndrome Study Group patients with steroid-dependent or steroid-resistant published the ﬁrst randomized trial establishing the FSGS treated with tacrolimus 1 prednisone.Other un- importance of treating steroid-resistant FSGS with controlled studies report remission rates of 48% to 100% immunosuppressioThis trial randomized 49 adults with tacrolimus use in FSGS patients who are resistant with steroid-resistant FSGS, nephrotic-range proteinuria, to, or dependent on, other immunosuppression.
and a creatinine clearance of more than 42 mL/min per Although these data are subject to publication bias, 1.73 m2 to cyclosporine 1 low-dose prednisone or they support the use of tacrolimus 1 steroids in placebo 1 prednisone for 26 weeks. Remission rates were resistant FSGS.
clinically and statistically signiﬁcant between groups, withcumulative remission occurring in 69% of the cyclosporine Additional Therapies for Steroid-Resistant FSGS group vs 4% in the placebo group (P , .001). Five remitters As described earlier, intravenous cyclophosphamide 1 experienced relapse during the 1-year follow-up period af- corticosteroids resulted in a 12-month remission rate of ter treatment. Although analyzed as a secondary end point, 67% in 18 steroid-resistant or steroid-dependent patients the percentage of patients experiencing a 50% reduction in in China, but the remission rate speciﬁcally in steroid- creatinine clearance also favored the cyclosporine group resistant patients was not reported.Other published (25% vs 52%). A large body of observational data also sup- experience with alkylating agents in steroid-resistant port the usefulness of cyclosporine 1 prednisone in treating FSGS has been uncontrolled and observational. The use of rituximab, a monoclonal anti-CD20 antibody, in The largest randomized trial for treating steroid-resistant steroid-resistant FSGS has been documented in case FSGS is the National Institutes of Health (NIH) Focal reports and small, uncontrolled case series, both in native Segmental Glomerulosclerosis Clinical Trial, which ran- FSGS and recurrence of FSGS after kidney transplant in domized 138 children and young adults with steroid- adults and children.Results have been inconsistent, and resistant FSGS to prednisone (up to 15 mg/d) plus cyclo- no predictors of response to rituximab have been identi- sporine or MMF/dexamethasone pulses for 12 months.
ﬁed. Controlled trials are needed to evaluate the effective- No signiﬁcant difference in rates of cumulative remission ness of rituximab in steroid-resistant FSGS.
(cyclosporine 46% vs MMF 33%) or relapse (cyclosporine There has been renewed interest in adrenocorticotropic 33% vs MMF 18%) was observed between treatment hormone (ACTH) treatment for various causes of the groups. However, the incorporation of these results into nephrotic syndrome. One recent case series described the practice in adult FSGS should be tempered because of experience using a natural ACTH gel in 24 (16 prospec- some limitations of this study, including it being under- tively followed, 8 retrospectively analyzed) adults with powered due to low enrollment (original target enrollment FSGS.The median prescription was 80 units injected sub- 500 patients), the inclusion of patients with subnephrotic cutaneously twice weekly, and most patients had steroid- proteinuria (inclusion criteria .1 g/d, 50% of patients dependent (n ¼ 6) or steroid-resistant (n ¼ 15) disease.
had ,4 g/d), the deﬁnition of steroid resistance (no remis- Five partial and 2 complete remissions occurred, with 2 re- sion in proteinuria after 4 weeks of steroid therapy), the lapses observed during the follow-up period (median uncommon general use of dexamethasone pulses in adult 66 months after stopping ACTH in remitters). The high FSGS, and a young patient population.In addition to the cost of treatment and frequently observed steroid-like NIH Clinical Trial, MMF use in FSGS has also been side effects warrant controlled trials for the evaluation of described in case reports and case series. Although MMF ACTH in FSGS.
may be an attractive treatment option, particularly in pa- Galactose has been reported to decrease in vitro glomer- tients with compromised kidney function, it is not known ular permeability to albumin when exposed to sera of how efﬁcacious MMF truly is in steroid-resistant FSGS.
patients with FSGSand subsequent case reports described The published experience of tacrolimus use in steroid- patients with recurrent FSGS after transplant whose resistant FSGS is more limited than that for cyclosporine.
proteinuria improved with oral galactose therapy Although many experts believe that the 2 calcineurin Most recently, a pilot study in 7 children with steroid- inhibitors have similar efﬁcacy in achieving remission, resistant nephrotic syndrome (n ¼ 4 with FSGS, n ¼ 2 with only 1 randomized controlled trial has compared these 2 recurrent FSGS after kidney transplant, and n ¼ 1 with min- medications. Choudhry and colleagurandomized 41 imal change disease) who were treated with oral galactose children with steroid-resistant nephrotic syndrome, 17 of for 16 weeks demonstrated a decrease in glomerular perme- whom had FSGS, to 6 months of treatment with tacrolimus ability in vitro but no signiﬁcant difference in proteinuria or cyclosporine, with both groups receiving concomitant Galactose is currently being evaluated as a treatment for prednisolone. Remission rates were 86% in the tacrolimus steroid-resistant FSGS as part of a randomized controlled group and 80% in the cyclosporine group (P ¼ NS), but the tacrolimus group had lower relapse rates during the Adalimumab, a human anti-tumor necrosis factor (TNF)- follow-up period (11% vs 50%, relative risk 4.5 for relapse a antibody, and fresolimumab, an anti-TGF-b antibody, are with cyclosporine vs tacrolimus, P ¼ .01). No subgroup also being evaluated in randomized controlled trials for analysis was performed to compare outcomes between steroid-resistant FSGS (NCT00814255 and NCT01665391) different glomerular diseases. As noted earlier, a based on data demonstrating elevated circulating TNF-a Hogan and Radhakrishnan levels in humans with FSGSand an animal FSGS model showing increased transcription of TNF-a,and addi- tional studies implicating the role of TGF-b signaling in the development of glomerulosclerosis.The use of plasma exchange therapy, routinely used for recurrent FSGS after kidney transplant, has been reported in case reports and case series in native FSGS with mixed results.
Idiopathic FSGS is a poorly understood and difﬁcult-to- treat disease with signiﬁcant long-term kidney morbidity.
The increased rate of ESKD in nephrotic vs non-nephrotic FSGS patients, combined with the evidence showing improved kidney outcomes in nephrotic patients who achieve a remission in proteinuria, support the recommen- dation of treating nephrotic FSGS patients with immuno- suppression. Randomized trials have attempted to deﬁne optimal therapy for steroid-resistant FSGS including cyclosporine and MMF. Additional agents are in use but require further study. We anticipate that future research will shed light on the various pathogeneses that lead to the nephrotic syndrome and the FSGS lesion with the goal of targeting underlying pathophysiology while mini- mizing side effects and maximizing improvement in kid- ney outcomes in these patients.
Treatment of FSGS in Adults
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