Clinical Kidney Journal, 2018, vol. 11, no. 2, 179–190 doi: 10.1093/ckj/sfx143 Advance Access Publication Date: 9 January 2018 CKJ Review CKJ REVIEW Clinical and pathological phenotype of genetic causes of focal segmental glomerulosclerosis in adults Nicola Lepori1,2, Ladan Zand1, Sanjeev Sethi3, Gema Fernandez-Juarez1,4 and Fernando C. Fervenza1 1Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA, 2Division of Nephrology and Dialysis, Azienda Ospedaliera G. Brotzu, Cagliari, Italy, 3Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA and 4Nephrology Division, Hospital Universitario Fundacion Alcorcon, Madrid, Spain Correspondence and offprint requests to: Fernando C. Fervenza; E-mail: [email protected] Abstract Focal segmental glomerulosclerosis (FSGS) is a histologic lesion resulting from a variety of pathogenic processes that cause injury to the podocytes. Recently, mutations in more than 50 genes expressed in podocyte or glomerular basement membrane were identified as causing genetic forms of FSGS, the majority of which are characterized by onset in childhood. The prevalence of adult-onset genetic FSGS is likely to be underestimated and its clinical and histological features have not been clearly described. A small number of studies of adult-onset genetic FSGS showed that there is heterogeneity in clinical and histological findings, with a presentation ranging from sub-nephrotic proteinuria to full nephrotic syndrome. A careful evaluation of adult-onset FSGS that do not have typical features of primary or secondary FSGS (familial cases, resistance to immunosuppression and absence of evident cause of secondary FSGS) should include a genetic evaluation. Indeed, recognizing genetic forms of adult-onset FSGS is of the utmost importance, given that this diagnosis will have major implications on treatment strategies, selecting of living-related kidney donor and renal transplantation success. Key words: genetic FSGS, nephrotic syndrome, podocin, podocytopathies, steroid-resistant nephrotic syndrome Introduction exerts a toxic effect on the podocytes. Widespread foot process Focal segmental glomerulosclerosis (FSGS) is a histologic lesion effacement on EM is the morphologic expression of the podo- defined by the presence of sclerosis in part of some glomeruli cyte injury in primary FSGS, clinically manifested by the devel- seen on light microscopy (LM), immunofluorescence (IF) or elec- opment of severe proteinuria and nephrotic syndrome (NS) [3]. tron microscopy (EM) examination on a kidney biopsy sample Primary FSGS typically responds to immunosuppressive treat- [1]. This histologic pattern is the result of a variety of pathogenic ment. On the other hand, secondary FSGS occurs as a result of processes, which share as a common mechanism injury to glomerular hyperfiltration (e.g. reduction in renal mass) or due podocytes that in turn leads to loss of selectivity of glomerular to drug toxicity, or as a result of a viral infection. filtration barrier and proteinuria [2]. Primary FSGS is a podocyt- Morphologically, podocyte damage secondary to glomerular opathy due to a not yet identified circulating factor(s) that hyperfiltration is characterized by segmental foot process Received: October 15, 2017. Editorial decision: November 17, 2017 VC The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] 179 180 | N. Lepori et al. effacement on EM and clinical manifestation of proteinuria in bundles surrounded by a branched subcortical actin network [13]. the absence of NS [4]. Treatment of secondary FSGS is focused Loss of this characteristic structure has been shown in animal on eliminating the offending agent, lowering hemodynamic experimental models of FSGS. The mutations causing FSGS due stress on glomeruli (e.g. weight loss) and maximizing antipro- compromise of the cytoskeleton can involve either structural teinuric strategies. (ACTN4, Myo1E, MYH9) or regulatory [IFN2, ARHGAP24, ARHGDIA, The term ‘genetic FSGS’ has been coined based on the dis- anilin (ANLN)] cytoskeleton proteins (Table 1)[14]. covery of genes that if mutated can cause monogenic forms of Podocytes must adhere tightly to the GBM to maintain the FSGS in humans [5]. All the encoded proteins are either glomerular filtration barrier and mutations in adhesion proteins expressed on the podocytes or the glomerular basement mem- have been found in different syndromic forms of SRNS (laminin brane (GBM) and as a result, if mutated, result in damage to the b2, integrin a3 and integrin b4), often in association with skin glomerular filtration barrier followed by proteinuria. Clinical lesions such as epidermolysis bullosa [15–17]. Thus, mutations presentation of genetic FSGS is extremely variable, with differ- in structural components of GBM like type IV collagenic genes ences in age of onset, gene penetrance, presence or absence of (COL4A3, COL4A4, COL4A5) and laminin alpha 5 (LAMA5) can NS and time of progression to end-stage renal disease (ESRD). also present with a FSGS [18, 19]. Although genetic FSGS most commonly involves the pediatric Genes encoding the proteins involved in nuclear function population it can affect adults (age of onset after 18 years of age) are also involved in genetic forms of syndromic or isolated as well. In fact, a causal mutation has been described in 43% of FSGS/SRNS. Mutations in nuclear transcription factors, such as familial and 10% of sporadic adult cases who present with Wilms Tumor 1 (WT1) [20], SMARCA-like protein (SMARCAL1) steroid-resistant nephrotic syndrome (SRNS) [6]. This highlights [21] and LIM homeobox transcription factor 1b (LMX1b)[22], are the importance of a better understanding of monogenic forms related to different syndromic forms of SRNS (Nail-Patella syn- of FSGS in adults, in particular, given that this diagnosis will drome, Denys-Drash syndrome, Frasier syndrome, Schimke have major implications on treatment strategies and future immuno-osseous dysplasia). Furthermore, mutations in genes renal transplantation success (lower risk of recurrence com- coding the nuclear pore complex proteins, such as nucleoporin pared with primary FSGS). However, little is known regarding 93 kDa (NUP93), nucleoporin 107 kDa (NUP 107), nucleoporin the clinical presentation and histological characteristics of 205 kDa (NUP 205) and exportin 5 (XPO5), have been identified recently in some cases of isolated and syndromic familial adults with genetic forms of FSGS. In this review, we summarize childhood-onset FSGS [23, 24]. genetic, clinical and histological features of genetic FSGS in Finally, mutation in genes encoding proteins that belong to adults and propose a screening strategy in this population. several cellular metabolic pathways can involve not only podo- cytes but also other cell types resulting in familial syndromic Podocyte gene mutations and mode of FSGS. Coenzyme Q10 (ubiquinone) is a component of cell mem- inheritance in genetic FSGS brane essential for normal function of the mitochondrial respi- ratory chain. Mutations in genes related to coenzyme Q10 are More than 50 genes have been described as potential sites of associated with childhood-onset FSGS and encephalomyop- mutation responsible for monogenic forms of FSGS or SRNS [7] athy. There is data to suggest that early coenzyme Q10 supple- (Table 1). The encoded proteins belong to distinct structural pro- mentation can have beneficial effects in these patients [25]. tein complexes and signaling pathways, which are essential for Several susceptibility genes for FSGS have been described; glomerular filtration barrier integrity and function. likely an environmental factor (the so-called ‘second hit’) is nec- Podocytes, GBM and endothelium compose the so-called glo- essary to develop the disease [26]. Apolipoprotein L1 (APOL1) merular filtration barrier, the structural element responsible for gene is the best-known susceptibility gene: expression of G1 the selective permeability of renal filtration process. Podocytes and G2 polymorphisms (which show the highest prevalence are highly differentiated cells, with an arborized shape charac- in the African American population) is associated with an terized by multiple projections, subdivided into larger major increased risk of adult-onset FSGS, hypertensive nephropathy processes and finer pedicels called foot processes. Glomerular and HIV-associated nephropathy [27, 28]. capillaries are wrapped by podocyte bodies and foot processes, Mutations described in genetic FSGS/SRNS involve both reces- which form an interdigitating pattern characterized by a unique sive and dominant genes. This distinction is important as it can type of inter-cellular junctions, called slit diaphragms. Nephrin have phenotypic correlation mainly related to the age of onset of (NHPS1) is an essential component of the glomerular slit dia- the disease. Autosomal recessive mutations typically manifest phragm; mutations in this gene account for 40–60% of the con- during early childhood, with wide variability: NHPS1, LAMB2 and genital nephrotic syndrome (CNS) cases, developing in the first PLCE1 mutations are related to CNS, while mutations in NPHS2