Update on Focal Segmental Glomerulosclerosis LoriAnn Fisher Division

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/gfq 665 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 Ig. A nephropathy Kitiyakara et al. using data from USRDS noted a twodecade-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. 1960 s) to membranoproliferative GN (ca. 1980 s) 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 Secondary Genetic APOL 1 related Renal limited 1. Maladaptive Increased Circulating Podocyte toxic Factor Syndromic 2. Infectious 3. Medications Am J Kidney Dis 43: 368 -382, 2004 CJASN Vol 12 no 3 502 -517

Histopathology of minimal change disease and focal segmental glomerulosclerosis. Avi Z. Rosenberg, and Jeffrey B. Kopp CJASN 2017; 12: 502517 © 2017 by American Society of Nephrology

Mechanisms of Disease Podocyte injury Podocyte effacement Podocyte detachment Increased ECM

Maladaptive Glomerular Load Glomerular Capacity Podocyte Glomerular Hypertrophy Mechanical Stress

Primary 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 nephroticrange 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 L 1 (APOL 1) 2 common variants (G 1 and G 2) in the last exon of APOL 1 that confer resistance to lethal Trypanosoma brucei infections. The G 1 and G 2 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 G 1 has a significant association with HIVAN 40% of ESRD attributed to FSGS occurs in blacks, and of this, 72% is associated with APOL 1 genetic variants

APOL 1 high-risk alleles are strongly associated with collapsing glomerulopathy in several settings: (1) HIVAN, in which 72% have two APOL 1 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 APOL 1 risk alleles, with an odds ratio of 29 in the United States Most individuals with HIV-associated nephropathy (HIVAN) have one or two APOL 1 risk alleles. 2 hit hypothesis Parvovirus B 19, CMV Plasmodium malaria

Genetic Renal Limited 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 2 38 genes have been identified Syndromic MYH 9 Eptein Fechtner INF 2 Charocot Marie Tooth

Unclear Role for Genetic Testing 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. Note that viral- and drugassociated 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 NR 3 C 1 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 m. Ab Pirfenidone, an antifibrotic agent that suppresses TGF-β signaling Fresolimumab, an anti–TGF-β m. Ab Pulse steroids plus cyclophosphamide Saquinivir Achtar gel

Treatment Irbesartan-like molecule that also antagonizes endothelin receptor, Abatacept CD 80 antagonist Targeted therapies Response to treatment Complete remission (CR) is defined as u. PCR<0. 2 g/g, and partial remission (PR) is defined as having 50% reduction from baseline proteinuria and u. PCR<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