A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis

Yu, Haiyang; Artomov, Mykyta; Brähler, Sebastian; Ständer, M; Shamsan, Ghaidan A.; Sampson, Matthew G.; White, Janicé; Kretzler, Matthias; Miner, Jeffrey H.; Jain, Sanjay; Winkler, Cheryl A.; Mitra, Robi D.; Kopp, Jeffrey B.; Daly, Mark J.; Shaw, Andréy S.

doi:10.1172/jci82592

Cited by 49 publications

(55 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By far, the most common example of this is the newly identified association with APOL1 as discussed below. Other genetic risk loci include PDSS1 (71) and numerous others (72,73). More are likely to be discovered in the near future.…”

Section: Genetic Fsgsmentioning

confidence: 99%

Focal Segmental Glomerulosclerosis

Rosenberg

Kopp

2017

CJASN

Self Cite

392

366

View full text Add to dashboard Cite

Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies arenow recognized asdrivers of FSGS: high-penetrance geneticFSGSdue to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e.g., glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (e.g., to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.

show abstract

Section: Genetic Fsgsmentioning

confidence: 99%

Focal Segmental Glomerulosclerosis

Rosenberg

Kopp

2017

CJASN

Self Cite

392

366

View full text Add to dashboard Cite

show abstract

“…In humans, APOL1 expression does not show tissue specificity, making it difficult to identify the cell type critical for renal disease development 11 . Furthermore, the variant is seemingly associated with diverse clinical phenotypes, including hypertensive nephrosclerosis, FSGS, HIVAN and lupus nephritis 12 . Recent pathological studies indicate increased incidence of solidified-type global sclerosis in subjects with high-risk APOL1 genotypes compared to people with kidney disease who carry the reference allele 13–15 .…”

Section: Introductionmentioning

confidence: 99%

Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice

Beckerman

Bi‐Karchin

Park

et al. 2017

Nat Med

291

403

View full text Add to dashboard Cite

African-Americans have an increased risk of developing chronic and end-stage kidney disease, with much of it attributed to two common genetic variants in the APOL1 gene, termed G1 and G2. Direct evidence demonstrating that these APOL1 risk alleles are pathogenic is still lacking as the APOL1 gene is only present in some primates and humans; thus experimental proof of causality of these risk alleles for renal disease has been challenging. Here, we generated mice with podocyte-specific inducible expression of the APOL1 reference allele (termed G0) or each of the risk alleles (G1 or G2). We show that mice with podocyte-specific expression of either APOL1 risk allele, but not the G0 allele, develop functional (albuminuria, azotemia), structural (foot process effacement and glomerulosclerosis) and molecular (gene expression) changes that closely resemble the human kidney disease. Disease development was cell-type specific, and likely reversible, and the severity correlated with the level of expression of the risk allele. We further found that expression of the APOL1 risk alleles interferes with endosomal trafficking and blocks autophagic flux, leading ultimately to inflammatory-mediated podocyte death and glomerular scarring. In summary, this is the first in vivo demonstration that expression of APOL1 risk alleles are causal for altered podocyte function and glomerular disease.

show abstract

“…In many cases FPE is accompanied by the appearance of an actin mat juxtaposed to the GBM (21,22) and observed after both human and animal podocyte injuries (23). A dynamic disruption of the actin cytoskeleton leads to a profound disruption of the filtration barrier (24).…”

Section: Introductionmentioning

confidence: 99%