Update on Focal Segmental Glomerulosclerosis Lori-Ann Fisher Division of Nephrology and Hypertension University of the West Indies

Background Describes a renal histologic lesion with diverse causes and pathogenicities that are linked by podocyte injury and depletion. The lesion of FSGS represents a segmental increase in glomerular matrix with obliteration of the capillary lumina in at least one glomerulus in the entire kidney biopsy Over last few years, we have gained significant insight in the understanding of the pathogenesis of disease J Am Soc Nephrol 2018 Jan 10

Objectives Epidemiology Classification of Disease Mechanisms of Disease Treatment

Epidemiology Worldwide incidence 0.2/100 000/year to 1.1/100 000/year Higher incidence in Australia A population-based study in the southwestern United States examined 2501 adult kidney biopsies performed between the years 2000 and 2011 Over the 12 years studied, FSGS was the most common diagnosis (39% of biopsies), with an increasing incidence rate (from 1.6 to 5.3 patients per million). Incidence rates are generally higher in men Nephrol Dial Transplant. 2011 Feb;26(2):414-30. doi: 10.1093/ndt/gfq665 Nephrol Dial Transplant 16: 1367, 2001 Am J Kidney Dis 68: 533-544, 2016

FSGS and ESRD Most common cause of GN-related ESRD. FSGS 2.3%, 0.4% for membranous GN and 0.3% for IgA nephropathy Kitiyakara et al. using data from USRDS noted a two-decade-long trend of increasing ESRD attributed to FSGS in the United States. Nigeria The leading cause of nephrotic syndrome has shifted from quartan malaria (ca. 1960s) to membranoproliferative GN (ca. 1980s) to FSGS (present) Am J Kidney Dis 44: 815-825 BMC Nephrol 16: 213, 2915

Why more FSGS? Improved recognition ? Increased Adaptive FSGS compounded by obesity and chronic inflammation?

Classification of FSGS Primary Increased Circulating Podocyte toxic Factor Secondary 1.Maladaptive 2. Infectious 3. Medications Genetic Renal limited Syndromic APOL 1 related Am J Kidney Dis 43: 368-382, 2004 CJASN Vol 12 no 3 502-517

Histopathology of minimal change disease and focal segmental glomerulosclerosis. Histopathology of minimal change disease and focal segmental glomerulosclerosis. Minimal change disease shows patent glomeruli in the absence of tubulointersitial scarring (silver stain, ×40). The tip lesion represents a focal adhesion of the glomerular tuft to Bowman’s capsule near the proximal tubule takeoff (silver stain, ×400). The most common forms of FSGS seen in adaptive FSGS and across all etiologies of FSGS are the perihilar variant (periodic acid–Schiff stain, ×40) and not otherwise specified pattern (silver stain, ×400). The most distinctive variant is the collapsing variant (collapsing glomerulopathy; silver stain, ×40). A specific instance of collapsing variant can be appreciated in the setting of endothelial tubuloreticular inclusions seen on ultrastructural analysis. These may be observed in high IFN states, including viral infection and exogenous IFN. The red arrowhead indicates the relative response to therapy and propensity of progression of these various forms, with minimal change disease and tip lesion being most responsive and least progressive and collapsing glomerulopathy being most therapy resistant and rapidly progressing. Avi Z. Rosenberg, and Jeffrey B. Kopp CJASN 2017;12:502-517 ©2017 by American Society of Nephrology

Mechanisms of Disease Podocyte detachment Podocyte effacement Podocyte injury Podocyte effacement Podocyte detachment Increased ECM

Maladaptive Glomerular Glomerular Capacity Load Podocyte Mechanical Stress Mechanical Podocyte Hypertrophy

Primary FSGS FSGS likely involves a circulating factor, possibly a cytokine that makes particular subjects susceptible. Crosses the GBM barrier causes generalized podocyte dysfunction, ensuing in sudden and widespread Foot process effacement (FPE) Recurrent FSGS immediately (on a scale of hours to several weeks) after kidney transplant. J Am Soc Nephrol 2018 Jan 10

Primary FSGS It is probably the most common form in adolescents and young adults Commonly associated with nephrotic-range proteinuria (sometimes massive), reduced plasma albumin levels, and hyperlipidemia. Histologically, it may manifest as the tip variant, collapsing variant, or NOS variant. A foot process width >1500 nm adequately differentiated primary from secondary FSGS

APOL 1 Associated FSGS Apolipoprotein L1 (APOL1) 2 common variants (G1 and G2) in the last exon of APOL1 that confer resistance to lethal Trypanosoma brucei infections. The G1 and G2 variants are common in populations of recent African descent but are very rare or absent in most other populations.

Single copy of a risk allele G1 has a significant association with HIVAN 40% of ESRD attributed to FSGS occurs in blacks, and of this, 72% is associated with APOL1 genetic variants

APOL 1 APOL1 high-risk alleles are strongly associated with collapsing glomerulopathy in several settings: (1) HIVAN, in which 72% have two APOL1 high-risk alleles (2) the use of exogenous IFN Lupus Role in Sickle Nephropathy

Infection HIV-1 is strongly associated with FSGS, particularly the collapsing glomerulopathy variant, although other variants are also seen The mechanisms likely involve direct infection of podocytes Interestingly, the effect of HIV on podocytes is strongest in individuals with two APOL1 risk alleles, with an odds ratio of 29 in the United States Most individuals with HIV-associated nephropathy (HIVAN) have one or two APOL1 risk alleles. 2 hit hypothesis Parvovirus B19, CMV Plasmodium malaria

Genetic Renal Limited Syndromic Variance in susceptibility genes High-penetrance mutations that manifest either Mendelian inheritance (for nuclear genes) or maternal inheritance (for genes encoded by mitochondrial DNA) NPHS NPHS2 38 genes have been identified Syndromic MYH9 Eptein Fechtner INF2 Charocot Marie Tooth

Role for Genetic Testing Unclear Potential advantages Guide therapy Prognosis Diagnose Genetic test resources around the world are available at the Genetic Test Registry, National Center for Biotechnology Information, National Institutes of Health (http://www.ncbi.nlm.nih.gov/gtr).

Opinion-based approach to genetic testing in adult-onset FSGS Opinion-based approach to genetic testing in adult-onset FSGS. Note that viral- and drug-associated forms of FSGS are usually excluded by clinical and serologic evaluation. Opinion-based approach to genetic testing in adult-onset FSGS. Note that viral- and drug-associated forms of FSGS are usually excluded by clinical and serologic evaluation. An S. De Vriese et al. JASN doi:10.1681/ASN.2017090958 ©2018 by American Society of Nephrology

FSGS – Treatment Nephrotic Syndrome If due to medications/viruses treat underlying cause, stop offending medication ACEI/ ARB Corticosteriods Polymorphisms in the glucocorticoid receptor encoded by NR3C1 have been associated with both relapse and frequent relapse Cyclosporin plus low-dose prednisone. Mycophenolate combination with glucocorticoids in three trials against active comparators that were either glucocorticoids or cyclosporin None of the trials showed significant differences between groups, and although sample sizes were small, particularly for noninferiority trials, these data suggest efficacy. Kidney Int 85: 1444-1453, 2014 Kidney Int 56: 2220-2226 NDT 23: 1926-1930, 2008

Other drugs Cyclophosphamide, azathioprine, levamisole, mizorbine, and rituximab Many other agents have been tested in small trials or reported as case series, and they have been the subject of recent reviews Adalimumab, an anti-TNF mAb Pirfenidone, an antifibrotic agent that suppresses TGF-β signaling Fresolimumab, an anti–TGF-β mAb Pulse steroids plus cyclophosphamide Saquinivir Achtar gel

Treatment Irbesartan-like molecule that also antagonizes endothelin receptor, Abatacept CD80 antagonist Targeted therapies Response to treatment Complete remission (CR) is defined as uPCR<0.2 g/g, and partial remission (PR) is defined as having 50% reduction from baseline proteinuria and uPCR<2 g/g.

Treatment of Recurrent FSGS in Transplanted Kidney Plasmapharesis Rituximab Abalacept

SUMMARY FSGS is a histologic lesion with diverse causes linked by podocyte injury Clinical and histological evaluation to elucidate cause guides therapy Novel approaches to the understanding of the disease in the future will management…. STAY TUNED