Focal Segmental Glomerulosclerosis

D’Agati, Vivette D.; Kaskel, Frederick J.; Falk, Ronald J.

doi:10.1056/nejmra1106556

Cited by 682 publications

(731 citation statements)

References 101 publications

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“…Critical is the elimination of other systemic diseases or primary renal diseases that may result in a similar presentation. Many reviews cover various aspects of FSGS and include comprehensive reviews (1)(2)(3)(4), disease mechanisms (5)(6)(7)(8), pediatric disease (9), immunologic aspects (10), treatment in children (11), and treatment in adults (12)(13)(14). We focus here on a practical approach to FSGS assessment on clinical and histopathologic grounds in the context of our current understanding of disease mechanisms and genetics.…”

Section: Introductionmentioning

confidence: 99%

Focal Segmental Glomerulosclerosis

Rosenberg

Kopp

2017

CJASN

414

366

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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.

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Section: Introductionmentioning

confidence: 99%

Focal Segmental Glomerulosclerosis

Rosenberg

Kopp

2017

CJASN

414

366

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“…These variants include the common generic NOS type, the aggressive collapsing type, the abruptly presenting tip type, the early-stage cellular type, and the perihilar type common in secondary adaptive FSGS (13)(14)(15)(16)(17). Several retrospective series have suggested that FSGS histologic subtypes vary in incidence and correlate with remission status and outcome.…”

Section: Discussionmentioning

confidence: 99%

Association of Histologic Variants in FSGS Clinical Trial with Presenting Features and Outcomes

D’Agati

Alster

Jennette

et al. 2013

Clinical Journal of the American Society of Nephrology

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140

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SummaryBackground and objectives FSGS histologic variants have correlated with outcomes in retrospective studies. The FSGS Clinical Trial provided a unique opportunity to study the clinical impact of histologic variants in a well defined prospective cohort with steroid-resistant primary FSGS.Design, setting, participants, & measurements Renal biopsies of 138 FSGS Clinical Trial participants aged 2-38 years enrolled from 2004 to 2008 were analyzed using the Columbia classification by core pathologists. This study assessed the distribution of histologic variants and examined their clinical and biopsy characteristics and relationships to patient outcomes.Results The distribution of histologic variants was 68% (n=94) FSGS not otherwise specified, 12% (n=16) collapsing, 10% (n=14) tip, 7% (n=10) perihilar, and 3% (n=4) cellular. Individuals with not otherwise specified FSGS were more likely to have subnephrotic proteinuria (P=0.01); 33% of teenagers and adults had tip or collapsing variants compared with 10% of children, and subjects with these variants had greater proteinuria and hypoalbuminemia than not otherwise specified patients. Tip variant had the strongest association with white race (86%) and the lowest pathologic injury scores, baseline creatinine, and rate of progression. Collapsing variant had the strongest association with black race (63%, P=0.03) and the highest pathologic injury scores (P=0.003), baseline serum creatinine (P=0.003), and rate of progression. At 3 years, 47% of collapsing, 20% of not otherwise specified, and 7% of tip variant patients reached ESRD (P=0.005).Conclusions This is the first prospective study with protocol-defined immunomodulating therapies confirming poor renal survival in collapsing variant and showing better renal survival in tip variant among steroid-resistant patients.

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“…Here we use kidney disease as a proof of concept application, focusing on the podocytes, the highly differentiated glomerular epithelial cells responsible for most hereditary and acquired glomerular disease (Gerstein 2001;Kim et al 2003;Roselli et al 2004;Groop et al 2009;D'Agati et al 2011;Niewold 2011). As with most other differentiated cell lineages in solid tissues, discovering human podocyte-specific genes on a whole-genome scale has remained infeasible due to the challenge of obtaining pure ex vivo populations of sufficient size for highthroughput evaluation, making this important cell lineage an ideal proof of concept application for nanodissection.…”

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confidence: 99%

Defining cell-type specificity at the transcriptional level in human disease

et al. 2013

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Cell-lineage–specific transcripts are essential for differentiated tissue function, implicated in hereditary organ failure, and mediate acquired chronic diseases. However, experimental identification of cell-lineage–specific genes in a genome-scale manner is infeasible for most solid human tissues. We developed the first genome-scale method to identify genes with cell-lineage–specific expression, even in lineages not separable by experimental microdissection. Our machine-learning–based approach leverages high-throughput data from tissue homogenates in a novel iterative statistical framework. We applied this method to chronic kidney disease and identified transcripts specific to podocytes, key cells in the glomerular filter responsible for hereditary and most acquired glomerular kidney disease. In a systematic evaluation of our predictions by immunohistochemistry, our in silico approach was significantly more accurate (65% accuracy in human) than predictions based on direct measurement of in vivo fluorescence-tagged murine podocytes (23%). Our method identified genes implicated as causal in hereditary glomerular disease and involved in molecular pathways of acquired and chronic renal diseases. Furthermore, based on expression analysis of human kidney disease biopsies, we demonstrated that expression of the podocyte genes identified by our approach is significantly related to the degree of renal impairment in patients. Our approach is broadly applicable to define lineage specificity in both cell physiology and human disease contexts. We provide a user-friendly website that enables researchers to apply this method to any cell-lineage or tissue of interest. Identified cell-lineage–specific transcripts are expected to play essential tissue-specific roles in organogenesis and disease and can provide starting points for the development of organ-specific diagnostics and therapies.

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Focal Segmental Glomerulosclerosis

Cited by 682 publications

References 101 publications

Focal Segmental Glomerulosclerosis

Focal Segmental Glomerulosclerosis

Association of Histologic Variants in FSGS Clinical Trial with Presenting Features and Outcomes

Defining cell-type specificity at the transcriptional level in human disease

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