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Nephrol Dial Transplant (2015) 30: 375–384 doi: 10.1093/ndt/gfu035 Advance Access publication 2 March 2014

Focal segmental glomerulosclerosis: towards a better understanding for the practicing nephrologist

Sanjeev Sethi1, Richard J. Glassock2 and Fernando C. Fervenza3

1Division of Anatomic Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA, 2Geffen School of Medicine School at UCLA, Laguna Niguel, CA, USA and 3Division of and Hypertension, Mayo Clinic College of Medicine, Rochester, MN, USA

Correspondence and offprint requests to: Fernando C. Fervenza, E-mail: [email protected]

nephron mass reduction, a scar from a healing vasculitic ABSTRACT lesion, direct drug toxicity or viral infection among other sec- ondary causes. Thus, the presence of an FSGS lesion in a renal Focal and segmental glomerulosclerosis (FSGS) is a common biopsy does not confer a disease diagnosis, but rather repre- histopathological lesion that can represent a primary podocy- sents the beginning of an exploratory process, hopefully topathy, or occur as an adaptive phenomenon consequent to leading ultimately to identification of a specific etiology and its

© The Author 2014. Published by Oxford University Press 375 on behalf of ERA-EDTA. All rights reserved. appropriate treatment. We define primary FSGS as a ‘primary’ cannot exclude FSGS with any degree of confidence. This is podocytopathy characterized clinically by the presence of further complicated by the well-known fact that the inner nephrotic syndrome in a patient with an FSGS lesion on light (deep) juxta-medullary glomeruli are preferentially affected in microscopy and widespread foot process effacement on elec- the early phases of primary FSGS [4]. A biopsy specimen con- tron microscopy (EM). Secondary FSGS is commonly charac- taining only cortical glomeruli may underestimate the fre- terized by the absence of nephrotic syndrome and the quency of FSGS lesion in the whole kidney. In order to presence of segmental foot process effacement on EM. Failure maximize accuracy, the diagnostic set should be comprised of to accurately differentiate between the primary and secondary consecutive sections selected from 12 to 15 routinely cut serial forms of FSGS has resulted in many patients undergoing un- sections [5, 6] and should contain a minimum of eight glom- necessary immunosuppressive treatment. Here, we review eruli [3]. Another point frequently overlooked (see below) is some key points that may assist the practicing nephrologist to that the electron microscopy (EM) changes are the initial distinguish between primary and secondary FSGS. phase of the pathological process; only with time will the char- acteristic sclerotic lesion develop. This can explain the absence Keywords: glomerulosclerosis, nephrotic syndrome, primary, of FSGS lesions in an initial biopsy when a second biopsy, per- secondary Downloaded from formed months or even years later, clearly demonstrates lesions of FSGS [7]. The bottom line is that the lesion of FSGS by light microscopy (which is how FSGS is defined) is not FOCAL AND SEGMENTAL really segmental and is only rarely truly focal in its distribu- GLOMERULOSCLEROSIS: A tion. It should be also recognized that focal global glomerulo- http://ndt.oxfordjournals.org/ MISLEADING NAME sclerosis (FGGS) is not synonymous with FSGS and is most frequently a manifestation of aging per se, vascular injury from Focal and segmental glomerulosclerosis (FSGS; often incor- prolonged poorly managed hypertension or a . rectly abbreviated as focal sclerosis) is a morphologic pattern Also, experimental studies have suggested that FGGS can arise of glomerular injury primarily directed at the glomerular vis- from targeted tubular injury [8]. While FSGS is not a very ceral epithelial cell (the ) and defined by the presence common cause of nephrotic syndrome in the elderly [9], some of sclerosis in parts (segmental) of some (focal) glomeruli, by such patients may present with nephrotic syndrome and with

light microscopy of a renal biopsy specimen. However, the an FSGS (not simply FGGS) as the only apparent lesion on at Universidad Nacional Autonoma de Mexico on February 20, 2016 name in itself is misleading. In experimental models of FSGS, optical microscopy. As will be discussed below, EM evaluation lesions in often involve the entire glomerular popu- of nonsclerosed glomeruli will be helpful in identifying a lation, but light microscopic examination shows that only a primary podocytopathy [e.g. primary FSGS or minimal limited number of glomeruli have segmental sclerotic lesions. change disease (MCD) superimposed on age-related changes, The use of serial sections with three-dimensional morphomet- such as FGGS] and in the setting of widespread foot process

FULL REVIEW ric analysis in rats treated with Adriamycin (a model of neph- effacement supports the use of immunosuppressive therapy rotic syndrome) showed that up to 94% of the glomeruli were (see below). affected by sclerotic lesions [1]. On the other hand, conven- tional counting of glomeruli affected by sclerosis in single sec- tions highly underestimated the percentage of sclerotic glomeruli (23–39%). Similarly, three-dimensional glomerular MODELS OF ‘ PRIMARY’ (TOXIC) VERSUS morphologic analysis in patients with subtotal nephrectomy ‘ SECONDARY’ (POSTADAPTIVE) FSGS showed that among 65 glomeruli examined, only 8% were normal, 42% revealed segmental sclerosis and 51% global Studying the sequence of podocyte alteration, using the puro- sclerosis [2]. Morphometric analysis on complete glomeruli mycin nephropathy model, Inokuchi et al. [10] showed that, from renal biopsies obtained from patients with FSGS shows following exposure to the toxin, the foot processes lose their that the volume of the sclerotic lesions averages just 12.5% of interdigitated appearance and become gradually effaced. Sub- the entire glomerular volume [3]. These results confirmed that sequently, Reiser et al. [11], using a lipopolysaccharide (LPS) evaluation of renal biopsies by single sections overestimates the endotoxin model to induce , showed that mice number of normal glomeruli and greatly underestimates the exposed to the toxin develop widespread foot process efface- number of glomeruli classified as abnormal. This is easy to ment and proteinuria mimicking human MCD. On the other understand considering that a is a sphere with a hand, in the postadaptive FSGS model of nephron mass reduc- diameter of ∼200 µm, and that sections are usually cut at a tion (subtotal nephrectomy), there is glomerular tuft hyper- thickness of ∼2 µm; therefore, a segmental lesion in a single trophy, but podocyte cell numbers do not increase [12]. glomerulus can be easily missed. Consequently, adequate Podocytes are then forced to stretch to cover a larger surface quantification of the percentage of glomeruli affected by scler- area with resulting podocyte attenuation, but the foot pro- osis can only be made by three-dimensional morphologic ana- cesses are largely preserved [13, 14]. In this model, areas of po- lysis of the entire glomerulus and by examination of sufficient docyte detachment and attachment to Bowman’s capsule glomeruli in a specimen to assure that the specimen is reason- (synechiae) are the initiating event in the development of a ably representative of the population of glomeruli in the segmental area of sclerosis [12], resembling the typical perihi- kidney as a whole. Renal biopsies with few glomeruli (e.g. <15) lar lesion seen in human postadaptive FSGS [6].

376 S. Sethi et al. transplanted kidneys with recurrent FSGS are reimplanted in CAN MOLECULAR MARKERS HELP patients with end-stage renal disease secondary to diseases TO DIFFERENTIATE PRIMARY VERSUS other than FSGS [30, 31]. However, despite extensive research, SECONDARY FSGS? the putative permeability factor(s) has (have) not been precise- ly identified and biochemically characterized. In fact, it is pos- It has been suggested that podocyte expression of B7-1 sible that the phenotype of primary FSGS could be due to (CD80) may help to differentiate between primary and sec- multiple pathogenetic mechanisms and a variety of permeabil- ondary FSGS. CD80 is a T-cell co-stimulatory molecule that is ity factors of different biochemical nature. associated with an increased glomerular permselectivity in More recently, the soluble form of the urokinase-plasmino- animal models. Injection of LPS in mice results in proteinuria gen activator receptor (suPAR) has been proposed as the and enhanced podocyte expression of CD80, but no - missing permeability factor. The uPAR has important functions uria develops if LPS is injected into CD80 knockout mice [11]. in cell migration and in the maintenance of the slit diaphragm Although results vary, CD80 is not commonly expressed in through its ability to form signaling complexes with other trans- normal human podocytes, and has been found to be upregu- membrane , including αvβ3 integrin. It can be released lated in some patients with certain glomerular diseases includ- Downloaded from from the plasma membrane of many cells including leukocytes ing MCD [15] and to a lesser extent in primary FSGS [11]. Of and podocytes in the form of suPAR and has also been found to great interest, Yu et al.[16] have observed strong podocyte be up-regulated in FSGS [32]. Further cleavage results in mo- CD80 staining in glomeruli in biopsy specimens from two of lecular isoforms with largely unknown functions ranging from three patients with primary FSGS, but it was absent in four of 20 to 50 kDa in mass, depending on the degree of glycosylation five patients with secondary FSGS despite extensive podocyte http://ndt.oxfordjournals.org/ and proteolytic cleavage [33, 34]. This molecular size is close to damage. Furthermore, positive CD80 staining of podocytes the putative permeability circulating permeability factor discussed was observed in the allograft specimen from a patient with above, which has a predicted size in the range of 30–50 kDa recurrent FSGS, whereas the allograft specimens from all the [35]. Activation of podocyte β3-integrin by high levels of suPAR other patients were negative. On the other hand, Garin et al. leads to podocyte effacement, proteinuria, glomerular damage [17, 18] found a significant increase in urinary CD80 only in and loss of renal function [36]. patients with MCD in relapse, but not in those MCD patients Patients with FSGS have elevated levels of suPAR with

in remission or patients with FSGS. In addition, no CD80 REVIEW FULL

high levels seen in patients with post-transplant recurrent at Universidad Nacional Autonoma de Mexico on February 20, 2016 staining was present in the glomeruli of two patients with disease [36, 37]. Exposure to sera from patients with recurrent FSGS and one patient with MCD in remission [18]. A recent FSGS resulted in increased activation of β3-integrin in podo- study found that urinary CD80 mRNA could not differentiate cytes, but activation was reduced when the sera came from pa- between MCD and FSGS in adults [19]. At the present time, it tients with FSGS who were in remission following is unclear whether quantification of urinary CD80 or immu- plasmapheresis or the use of antibodies against uPAR [36]. In- nohistochemistry for CD80 on kidney biopsies will be useful creased activation of β3-integrin has been reported in the to differentiate between MCD and FSGS or to distinguish native glomeruli of patients with primary FSGS as well as in between the primary and secondary forms of FSGS. the transplanted kidney, compared with controls with MCD or membranous nephropathy. A decrease of serum suPAR and β3-integrin activation after plasmapheresis has been associated WHAT HAS RECURRENT PRIMARY FSGS with remission of proteinuria. Although the results from POST-TRANSPLANT TAUGHT US? in vitro and animal studies are highly suggestive of a role for suPAR in the pathogenesis of FSGS, a number of recent In recurrences of primary FSGS post-kidney transplant, diffuse studies have added skepticism to the specific pathogenic role foot process effacement can be observed within minutes after of suPAR in ‘primary’ FSGS (reviewed in [38]). Briefly, the reperfusion [20]. Diffuse foot process effacement is followed data need to be reconciled with the fact that: (i) suPAR levels (at by massive proteinuria developing within hours to days after least the isoforms measured by conventional assays) are very the kidney transplant [21]. With time, the characteristic FSGS much determined by the prevailing glomerular filtration rate lesion develops. Thus, foot process effacement is the earliest (GFR) level [39]; (ii) the exact source of the suPAR found in the structural change and key initial event in the development plasma of some subjects with primary FSGS is unknown; (iii) of FSGS. A putative circulating permeability factor has elevated suPAR levels (even higher than patients with biopsy- been proposed to play a role in the pathogenesis of primary proven FSGS) have been reported in other glomerular diseases FSGS [22] and is supported by clinical and experimental evi- [40, 41] as well as a number of diseases in the absence of pro- dence, including (i) the rapid appearance of proteinuria fol- teinuria [42–46]; (iv) pretransplant suPAR levels do not lowing kidney transplant [20, 23, 24]; (ii) the efficacy of predict the recurrence of FSGS following transplantation [47, plasmapheresis (and immunoabsorption) in reducing protein- 48]; (v) serum suPAR levels are higher in FSGS secondary to uria following recurrence [25, 26]; (iii) administration of genetic mutations compared with primary FSGS [48]; (vi) a serum from patients with FSGS into rat causes proteinuria [27, significant number of patients with FSGS have normal suPAR 28]; (iv) transplacental transmission of permeability factors levels; (vii) the speci ficity of elevated serum suPAR levels for from mother to child causing neonatal proteinuria [29]; (v) primary versus secondary forms of FSGS and other primary resolution of proteinuria and histological changes when glomerular diseases is debated [38, 39]. At the present time, it

Focal segmental glomerulosclerosis 377 seems doubtful that measurement of plasma suPAR levels of the commonly adaptive origin of the lesion in many forms (with available assays) will be able to accurately distinguish of secondary FSGS (such as in the obesity-related glomerulo- primary from secondary forms of FSGS [40], but additional pathy or vesico-ureteric nephropathy), these patients are more work in this area may ultimately yield a biochemical marker likely to have mild foot process effacement and present with that is unique to primary FSGS. subnephrotic-range proteinuria, while patients with primary (or idiopathic) FSGS are more likely to resemble MCD on EM examination as evidenced by the presence of widespread foot PRIMARY VERSUS SECONDARY FSGS: process effacement and nephrotic syndrome (Figure 1). Toxic WHATISTHEROLEOFEMEXAMINATION? drug or viral-induced forms of secondary FSGS may show extensive foot process effacement. Thus, the degree of foot An important consideration in the evaluation of a renal biopsy process effacement by EM is a crucial clue to a primary versus showing a lesion of FSGS, in any of its light microscopic var- secondary form of FSGS, with some exceptions, such as cases iants, is the degree of foot process effacement on EM examin- of ‘collapsing’ FSGS, secondary to HIV [56], interferon [57]or ation. Although in early studies the degree of foot process pamidronate [58] therapy that are characterized by widespread Downloaded from effacement correlated with the amount of proteinuria [49, 50], foot process effacement on EM. In addition, some patients can more recent studies showed that the degree of foot process ef- exhibit widespread foot process effacement while presenting facement is determined primarily by the nature of the patho- with subnephrotic-range proteinuria. Typically, these latter genic process affecting the podocyte [51]. In biopsies showing patients have primary forms of FSGS (see below). It is critically a lesion of FSGS, the mean percentage of the glomerular important to select relatively intact and not segmentally scler- http://ndt.oxfordjournals.org/ surface area affected by foot process effacement has been osed glomeruli for ultrastructural studies. Segmentally scler- reported to be less in secondary versus primary FSGS [52, 53]. osed or scarred glomeruli in the setting of either primary or Deegens et al. [54] analyzed the differences in foot process secondary FSGS may show extensive foot process effacement. width between patients with primary versus secondary FSGS On the other hand, nonsclerosed glomeruli in primary FSGS and found the effacement to be most severe in cases of show widespread foot process effacement, while there is only primary FSGS, with foot process relatively preserved in sec- segmental effacement in secondary FSGS (Figure 1). ondary cases, with little overlap between the two. Variants of Rarely, however, a patient may present with widespread foot ‘ ’ ‘ ’ ‘ ’

primary FSGS such as tip , cellular and collapsing lesions process effacement without nephrotic syndrome (Figure 2). As at Universidad Nacional Autonoma de Mexico on February 20, 2016 usually have widespread foot process effacement. On the other stated above, it is crucial that a nonsclerotic glomerulus is se- hand, in the ‘not otherwise specified’ variant, foot process ef- lected for EM. If a nonsclerotic glomerulus is selected and the facement is variable, and in the ‘perihilar’ variant, foot process patient is non-nephrotic, we would recommend conservative effacement may be relatively mild and segmental [55]. Because treatment only, with a close follow-up (because it may represent FULL REVIEW

FIGURE 1: FSGS. Each panel represents one separate case. Top panel showing primary FSGS: (A) light microscopy showing segmental sclerosis in the perihilar location. (B) Ultrastructural studies showing diffuse and widespread foot process effacement. Bottom panel showing secondary FSGS: (C) light microscopy showing segmental sclerosis in the perihilar location. Note the thickened walls of adjacent arteriole. (D) Ultrastructural studies showing segmental foot process effacement. [Black arrows point to segmental sclerosis, red arrows point to diffuse foot process effacement and blue arrows point to preserved foot processes. (A and C) Periodic acid Schiff ×40, (B) ×3100 and (D) ×4730.]

378 S. Sethi et al. Downloaded from http://ndt.oxfordjournals.org/ ULREVIEW FULL at Universidad Nacional Autonoma de Mexico on February 20, 2016 FIGURE 2: (A) Light microscopy showing segmental sclerosis in a patient without nephrotic syndrome. Periodic acid Schiff ×40. (B)EM showing extensive foot process effacement of the podocytes in the same patient. Also, note microvillous degeneration of the podocytes. Arrow points to foot process effacement (×4200). (C) Proteinuria over time in the same patient treated conservatively.

early phase primary FSGS) and only consider immunosuppres- likely to present with nephrotic syndrome and marked edema sive therapy if there is progression to full nephrotic syndrome and hyperlipidemia. On the other hand, patients with second- (see section on treatment below). An even rarer scenario is a ary FSGS are less likely to have edema or hyperlipidemia [52, patient with a full nephrotic syndrome with segmental foot 59]. Patients with obesity-related FSGS, reflux nephropathy or process effacement on EM of a nonsclerosed glomerulus. In this renal mass reduction do not develop complete nephrotic case, it is important to rule out the use of immunosuppressive syndrome even in the presence of massive proteinuria (>10– therapy prior to or concomitantly at the time of the renal 15 g/day) [59]. The reason why patients with secondary FSGS biopsy, because the EM findings may represent a resolving do not develop hypoalbuminemia is unknown. Praga et al. process. If true segmental foot process effacement is present on [59] suggest that the very slow appearance of proteinuria ob- EM as well as nephrotic syndrome, we would recommend maxi- served in secondary FSGS may allow for compensatory me- mizing conservative therapy and, if the nephrotic syndrome chanisms to counterbalance the loss of protein, while in persists, then commence on a trial of corticosteroid therapy. patients with primary FSGS the onset is sudden. The sudden onset of severe proteinuria and edema is another clue that the physician is dealing with a patient with primary FSGS, which THE IMPORTANCE OF DISTINGUISHING is in contrast to secondary FSGS where edema is usually NEPHROTIC-RANGE PROTEINURIA absent or develops gradually. Interestingly, a significant FROM NEPHROTIC SYNDROME number of patients with collapsing FSGS do not present with edema despite massive proteinuria perhaps due to the rapid It should also be recognized that nephrotic-range proteinuria loss in GFR [56, 60, 61]. It has been often stated that nephrotic (>3.5 g/24 h) and nephrotic syndrome (>3.5 g/24 h and serum syndrome occurs in only 50–60% of patients with FSGS, but in albumin <3.5 g/dL) are not necessarily synonymous. This is an our opinion this is due to failure of past studies to recognize important clinical distinction particularly in patients with the differences between primary and secondary FSGS [62]. nephrotic-range proteinuria in which a kidney biopsy shows The inclusion of such patients, as well as African-Americans FSGS, but who do not have full-blown nephrotic syndrome labeled as FSGS (see below) in previous studies has given the [52]. These patients are more likely to have FSGS due to a sec- impression that nephrotic syndrome is less common in FSGS ondary process while patients with primary FSGS are more than in MCD.

Focal segmental glomerulosclerosis 379 Finally, it is important to verify the identity of the protein- have the APOL1 risk variants, the diagnosis should be uria: is it due mainly to albumin? Or is it due to other pro- ‘APOL1-associated nephropathy’ (the term nephropathy to teins? In this regard, it is important to rule out proteinuria due reflectthefactthatitismorethanpureglomerulosclerosis). to low-molecular-weight (LMW) proteins (retinol-binding We do recognize that inheriting the two APOL1 risk var- protein, beta-2-microglobulin and alpha-1-microglobulin) or iants does not equal the development of , al- light chain proteins in patients presenting with a focal glom- though carrying the two risk alleles increases the risk of erular lesion (FSGS or FGGS). The importance can be illu- developing FGGS by ∼20-fold [70]. However, only ∼25% strated by a recent report of a patient with FGGS on a renal of African-Americans with hypertension-associated chronic biopsy and nephrotic-range proteinuria who had been treated kidney disease, as defined by the AASK study, carry the G1 as primary FSGS while ultimately quantification of urinary and G2 risk alleles. Conversely, 75% of such patients do not LMW proteins allowed to the correct diagnosis of Dent disease have the risk genotype. Thus, APOL1 variants alone cannot [63]. As previously discussed, it seems clear that tubulopathies account for the marked predisposition to chronic kidney can give rise to focal glomerular lesions, predominantly of the disease seen in Africa-Americans [74]. Thus, a ‘second hit’, FGGS category [8]. A simple approach is to compare a urinary either environmental (e.g. obesity, hyperlipidemia and Downloaded from protein/creatinine ratio to a urinary albumin/creatinine ratio. smoking) or genetic nature (e.g. mutation), has been If <40–50% of total proteinuria are due to albumin, then the proposed [75]. Why inheriting the two APOL1 risk variants is possibility of tubular proteinuria or the presence of light associated with arterionephrosclerosis in African-Americans chains should be considered. A similar clue that proteins other and faster progression of renal disease is unknown. Apolipo- than albumin account for the proteinuria is the finding of a protein L1 is a lipid-binding protein and a component of http://ndt.oxfordjournals.org/ dipstick proteinuria of trace/1+ in a patient with a quantified high-density lipoprotein class 3, which is involved in protect- urinary protein >1 g/24 h. ing low-density lipoprotein particles from oxidation. Abnor- malities in APOL1 expression in the arterial beds may alter cellular physiology as to promote vascular sclerosis [76]. The GLOMERULOSCLEROSIS IN distribution of the APOL1 gene along the nephron (podocytes AFRICAN-AMERICANS: IT IS and tubules) still needs to be defined, but immunohistochem- NOT PRIMARY FSGS istry studies in normal kidney tissue demonstrate APOL1

protein in the podocyte and arteriolar endothelial cells, while at Universidad Nacional Autonoma de Mexico on February 20, 2016 The confusion between primary and secondary FSGS also in FSGS and HIV-associated nephropathy positive the staining applies to the diagnosis of FSGS in African-Americans, which is also seen within glomerular arterioles and interlobular we think is an altogether different disease from primary FSGS arteries [77]. In vitro expression of APOL1 protein sensitizes seen in Caucasians. To start with, in the majority of renal cell death pathways and shortens cell survival [78, 79]. Thus, it biopsy cases in hypertensive African-Americans do not show is possible that APOL1 overexpression results in an increase

FULL REVIEW FSGS but rather FGGS. Fogo et al. [64] evaluated renal biopsies in the rate of cell death from autophagy or apoptosis, which of 39 African-American patients enrolled in the African-Ameri- may be the main pathogenic mechanism leading to the devel- can study of kidney disease and hypertension (AASK) trial and opment of APOL1-associated nephropathy [69]. reported a high level of global glomerular sclerosis involving on average 43 ± 26% of glomeruli, a substantially greater percentage than expected for the age group. Arteriolosclerosis and/or ar- GENETIC CAUSES OF FSGS: DO THEY teriosclerosis were observed in 97.5% of the cases as was moder- ALL CAUSE NEPHROTIC SYNDROME? ate interstitial fibrosis. However, a segmental lesion was present in only 3% of the cases. Secondly, EM often shows only segmen- It is clear that a number of genetic mutations varying from tal foot process effacement [64]. Thirdly, the majority of patients coding for proteins of the slit diaphragm [NPHS1 do not have nephrotic syndrome, but rather subnephrotic-range (nephrin), NPHS2 (podocin) and CD2AP], podocyte mem- proteinuria [64, 65]. Fourthly, in these patients the disease is brane (β4-integrin, CD151, PTPRO, TRPC6 and laminin β2), progressive regardless of aggressive blood pressure control and cytosol (PLCE1), actin cytoskeleton (inverted formin, myosin blockade of the angiotensin II (AII) system [66, 67], which con- IIA, α-actinin-4 and MYO1E), (SCARB2/LIMP-2), trasts with the beneficial effect of AII blockade in other forms of mitochondria [COQ2, tRNA(Leu) and COQ6] and cellular proteinuric kidney diseases [68]. Finally, the condition is asso- nucleus (WT1) result in proteinuria and a FSGS lesion on ciated with two independent sequence G1 and G2 variants in renal biopsy [80]. The majority of the genetic causes of FSGS the APOL1 gene in African-Americans labeled as having kidney follow an autosomal recessive pattern of inheritance and are disease secondary to hypertension [69–71], and the variants cor- manifested in the first year of life with mutations in nephrin relate with the accelerated rate of decline in kidney function in and podocin genes (NPHS1 and NPHS2, respectively) being these patients [72]. The two APOL1 variants are present in 12– the most common. Autosomal dominant forms (e.g. mutations 13% of African-Americans, but virtually absent from European in α-actinin-4, TRPC6) more commonly present during ado- [73]. Based on the above observations, we lescence or later in adulthood [81, 82]. On the other hand, propose that, in African-American patients without nephrotic FSGS presenting in adulthood is rarely attributed to a specific syndrome, with an FGGS lesion on renal biopsy that reveals mutation (<15% of all adult cases) [82]. It is important to rec- only segmental foot process effacement on EM and who also ognize that while full nephrotic syndrome has been clearly

380 S. Sethi et al. documented among infantile and adolescent cases of FSGS relapsing disease [96, 97], and can be considered as initial caused by genetic mutations, in the majority of adults with therapy in patients that would benefit from avoidance or genetic forms of FSGS proteinuria is not massive (usually have contraindications to high-dose corticosteroid therapy <5 g/24) [83], and they do not frequently develop a full-blown (e.g. a diabetic person). In our opinion, CNI can also be used nephrotic syndrome. In fact, reviewing the literature, it is sur- as monotherapy, when concomitant use of corticosteroids is of prising that documentation regarding the full phenotype in concern. Failure to reduce proteinuria after 6 months of CNI these patients (i.e. presence of nephrotic syndrome versus treatment in adequate doses equals resistance to this therapy nephrotic-range proteinuria alone) is not reported in the great regimen and the drug should be discontinued. Resistance to majority of studies [84–89]. The understanding of these differ- CSA does not equal resistance to TAC. Both CSA and TAC ences is important, because adult patients with FSGS second- should not be regarded as ‘curative’ agents for FSGS, as re- ary to a genetic mutation should not be treated with prolonged lapses are quite common when they are discontinued, even steroid therapy and have a low propensity for a recurrence of after prolonged usage. Long-duration (e.g. >1 year), low-dose FSGS in a transplanted kidney. CNI therapy may be considered in patients with CNI-depend- ency, but the prospect of cumulative nephrotoxicity of these Downloaded from agents looms on the horizon and requires very careful atten- TREATMENT OF FSGS IN A NUTSHELL tion, and rebiopsy in some cases. The CNI agents as a class are best regarded as anti-proteinuric agents rather than immuno- Patients with primary FSGS very rarely develop spontaneous suppressive agents in the context of treating primary FSGS. remissions of the disorder. Initial therapy with an angiotensin- They have little or no effect on the putative circulating factors http://ndt.oxfordjournals.org/ converting enzyme inhibitor or an AII receptor blocker is likely responsible for primary FSGS and do not prevent its re- often recommended, but such treatments have no impact in currence in renal allografts. Mycophenolate mofetil [98], adre- the degree of foot process effacement [54] and are unlikely to nocorticotropic hormone (native ACTH) [99] and rituximab greatly reduce proteinuria or preserve renal function, unless [100] have all been tried with various degrees of success, moderate to severe hypertension is also present and is well mostly in patients refractory to corticosteroids and/or CNI controlled (<140/90 mmHg) on these medications [90]. treatment. In patients with primary FSGS who are intolerant Primary FSGS (possibly excluding advanced forms of collaps- of CNI, the use of Mycophenolate mofetil and high-dose ster- ULREVIEW FULL

ing FSGS or the rare primary forms of the perihilar variant of oids may be a satisfactory alternative [62]. Patients with FSGS at Universidad Nacional Autonoma de Mexico on February 20, 2016 FSGS) can respond to high-dose corticosteroids although at a secondary to a genetic mutation may respond to CNI [101]. lower rate than MCD and requires a more prolonged course of Patients with primary FSGS who are steroid and CNI resistant therapy [91, 92]. Oral prednisone or prednisolone, at a dose of are unlikely to respond to rituximab or cyclophosphamide 1 mg/kg/day orally (not to exceed 80 mg/day) for at least [102]. On the other hand, patients with primary FSGS who are 4 months, is the traditional therapeutic regimen, although steroid-sensitive and pursue a steroid-dependent or frequent re- there are very few randomized controlled studies to support its lapsing course can respond to cyclophosphamide or to rituxi- use [93]. Steroid resistance is considered for a patient who fails mab [103–106]. Plasmapheresis and rituximab are important to respond with a partial or complete remission of proteinuria therapeutic options in the prevention and/or treatment of re- after 4 months of high-dose corticosteroids. It is important to current FSGS after kidney transplantation [107–111]. There remember that if a patient is going to respond to therapy, has been one report of successful use of sirolimus in patients proteinuria will start to decrease early in the treatment course. with FSGS [112], but the use of this medication in patients A patient whose proteinuria does not decrease by >20% from with high-degree proteinuria carries the risk of acute renal baseline values after 2 months of high-dose corticosteroids is failure [113, 114]. A recent study reported on the beneficial unlikely to respond and early steroid-taper and discontinuation effect with the use of Abatacept [cytotoxic T-lymphocyte-as- should be considered, especially if steroid-related complications sociated antigen 4-immunoglobulin fusion protein (CTLA-4- are a cause for concern to the physician or burdensome to Ig)], a co-stimulatory inhibitor that targets CD80, in five pa- the patient. Patients on high-dose corticosteroids should rou- tients with recurrent FSGS after transplantation and in one tinely receive Pneumocystis jirovecii prophylaxis. The rationale patient with primary FSGS with all patients showing positive for this recommendation comes from studies where the use of podocyte CD80 staining on renal biopsy [115]. In patients corticosteroids at a dose of >20 mg of prednisone for a period with recurrent FSGS, a single dose of Abatacept induced partial of 8 weeks or more was associated with a significantly in- or complete remissions of proteinuria, suggesting that Abata- creased risk of Pneumocystis pneumonia in patients who did cept may stabilize β1-integrin activation in podocytes and not have AIDS [94]. The UK National Comprehensive Cancer reduce proteinuria in patients with CD80-positive glomerular Network recommends Pneumocystis prophylaxis in patients disease. It should be contemplated that the patients with recur- receiving >20 mg/day of prednisolone for over 4 weeks (http:// rent FSGS in the study were also treated with plasmapheresis, ri- www.nccn.org). In addition, the American Thoracic Society tuximab, daclizumab and antithymocyte globulin. Further recommends that immunosuppressed patients without HIV research is needed to confirm this observation and to evaluate if should receive Pneumocystis prophylaxis if their prednisolone Abatacept is of benefit to the majority of patients with FSGS dose exceeds 20 mg/day for >1 month [95]. A calcineurin in- who are not CD80 positive [17, 18]. Patients with secondary hibitor (CNI), either cyclosporine (CSA) or tacrolimus (TAC), FSGS should be treated conservatively aiming to maximize can be used for patients who are steroid-resistant or have blood pressure control with the use of AII blockade, low salt

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