Apolipoprotein L1 Risk Variants Associate with Systemic Lupus Erythematosus-Associated Collapsing Glomerulopathy

Larsen, Christopher P.; Beggs, Marjorie L.; Saeed, Mohammad; Walker, Patrick D.

doi:10.1681/asn.2012121180

Cited by 184 publications

(147 citation statements)

References 21 publications

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“…One setting in which the adaptive processes drive APOL1 FSGS is perhaps the report that APOL1 variants are associated with proteinuric sickle cell nephropathy (97), although a systematic study of kidney histology in APOL1-associated sickle nephropathy is still lacking. APOL1 high-risk alleles are strongly associated with collapsing glomerulopathy in several settings: (1) HIVAN, in which 72% have two APOL1 high-risk alleles (83), and (2) the use of exogenous IFN (98) and in lupus (99).…”

Section: Emerging Pathologic Mechanisms: Apol1-associated Fsgsmentioning

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: Emerging Pathologic Mechanisms: Apol1-associated Fsgsmentioning

confidence: 99%

Focal Segmental Glomerulosclerosis

Rosenberg

Kopp

2017

CJASN

414

366

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“…This scenario is proposed for renal disease associated with sickle cell disease, with collapsing nephropathy associated with lupus or HIV and with compromised graft survival after transplantation. [4][5][6][7][8][9] APOL1 risk variants are associated with earlier age of onset and progression to renal failure of subjects with FSGS, and prospective studies in the African American Study of Kidney Disease and Chronic Renal Insufficiency cohorts show that carriage of two APOL1 risk variants is associated with more rapid progression to clinical endpoints in persons with renal insufficiency at study entry. 2,3,5,7,8 Moreover, African-American participants without renal disease on enrolment in the ARIC study were more likely to develop CKD and to progress to renal failure if they had two APOL1 risk alleles, compared with those with no alleles or one allele.…”

Section: The Similarity Of Thementioning

confidence: 99%

APOL1 Risk Alleles Are Associated with Exaggerated Age-Related Changes in Glomerular Number and Volume in African-American Adults

Hoy

Hughson

Kopp

et al. 2015

Journal of the American Society of Nephrology

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APOL1 genetic variants contribute to kidney disease in African Americans. We assessed correlations between APOL1 profiles and renal histological features in subjects without renal disease. Glomerular number (N glom ) and mean glomerular volume (V glom ) were measured by the dissector/fractionator method in kidneys of African-American and non-African-American adults without renal disease, undergoing autopsies in Jackson, Mississippi. APOL1 risk alleles were genotyped and the kidney findings were evaluated in the context of those profiles. The proportions of African Americans with none, one, and two APOL1 risk alleles were 38%, 43%, and 19%, respectively; 38% of African Americans had G1 allele variants and 31% of African Americans had G2 allele variants. Only APOL1-positive African Americans had significant reductions in N glom and increases in V glom with increasing age. Regression analysis predicted an annual average loss of 8834 (P=0.03, sex adjusted) glomeruli per single kidney over the first 38 years of adult life in African Americans with two risk alleles. Body mass index above the group medians, but below the obesity definition of $30 kg/m 2 , enhanced the expression of age-related changes in N glom in African Americans with either one or two APOL1 risk alleles. These findings indicate that APOL1 risk alleles are associated with exaggerated age-related nephron loss, probably decaying from a larger pool of smaller glomeruli in early adult life, along with enlargement of the remaining glomeruli. These phenomena might mark mechanisms of accentuated susceptibility to kidney disease in APOL1-positive African Americans.

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“…4 The G1 S342G (rs73885319) and G2 insertion/ deletion (rs71785313) were typed to assess kidney disease risk. Genome-wide ancestry informative markers were not genotyped as they have not significantly altered association results beyond G1 and G2 in prior reports.…”

Section: Genotypingmentioning

confidence: 99%

“…1 Two coding risk variants in the apolipoprotein L1 gene (APOL1), termed G1 and G2, are responsible for much of the increased incidence of progressive, nondiabetic kidney disease in African Americans relative to European Americans (EAs). 2,3 The spectrum of APOL1-associated kidney disease includes focal segmental glomerulosclerosis, nondiabetic end-stage kidney disease often attributed to systemic hypertension, collapsing glomerulopathy in the settings of systemic lupus erythematosus 4,5 and HIV, 6 and sickle cell nephropathy. 7 The pathogenic mechanisms by which these risk variants produce disease are unknown.…”

mentioning

confidence: 99%

Histopathologic findings associated with APOL1 risk variants in chronic kidney disease

et al. 2015

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The effects of nephropathy risk variants in the apolipoprotein L1 gene (APOL1) on renal histopathology in African Americans with arterionephrosclerosis or putative 'hypertension-associated' nephropathy are unknown. APOL1 genotype-phenotype correlations were performed in a blinded manner from renal biopsies in 196 self-reported African Americans with arterionephrosclerosis on kidney biopsy at a large national nephropathology practice. Subjects had chronic kidney disease without nephrotic syndrome. A discovery analysis compared histopathologic changes in the glomerular and tubulointerstitial compartments in 58 subjects with 2 versus 56 subjects with 0 APOL1 risk variants. Validation was performed in biopsies from 82 additional subjects with 0, 1, and 2 risk variants. Two risk variant versus zero risk variant group genotype associations and subphenotypes were assessed by v 2 analyses. ANOVA compared means of continuous variables. In discovery analyses, significantly less obsolescent glomerulosclerosis, more (solidified and disappearing) glomerulosclerosis, more thyroidization-type tubular atrophy, and more microcystic tubular dilatation were seen in patients with two versus zero APOL1 risk alleles. Greater degrees of arteriosclerosis were present in those with zero risk alleles. Segmental glomerulosclerosis did not differ significantly between groups. Presence of two of the following discriminatory histopathologic findings from discovery, that is, o50% obsolescent glomerulosclerosis, thyroidization-type tubular atrophy, and microcystic tubular dilatation, was specific for the presence of two APOL1 risk alleles in the validation phase. African Americans with arterionephrosclerosis who possess two APOL1 risk variants more often lack obsolescent glomerulosclerosis and have greater degrees of (solidified and disappearing) glomerulosclerosis, thyroidization-type tubular atrophy, and microcystic tubular dilation than patients with fewer than two risk variants. These findings support involvement of multiple cell types in subnephrotic forms of APOL1-associated nephropathy, particularly renal tubule cells with resultant tubulointerstitial disease.

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Apolipoprotein L1 Risk Variants Associate with Systemic Lupus Erythematosus-Associated Collapsing Glomerulopathy

Cited by 184 publications

References 21 publications

Focal Segmental Glomerulosclerosis

Focal Segmental Glomerulosclerosis

APOL1 Risk Alleles Are Associated with Exaggerated Age-Related Changes in Glomerular Number and Volume in African-American Adults

Histopathologic findings associated with APOL1 risk variants in chronic kidney disease

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