Hypertensive nephrosclerosis in African Americans versus Caucasians

Marcantoni, Carmelita; Ma, Lijun; Federspiel, Charles F.; Fogo, Agnes B.

doi:10.1046/j.1523-1755.2002.00420.x

Cited by 132 publications

(89 citation statements)

References 28 publications

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“…In contrast, obsolescent glomerulosclerosis and greater degrees of arteriosclerosis were present significantly more often in those without risk APOL1 variants. These results extend observations by Marcantoni et al 13 regarding the different renal histology in African Americans and EAs diagnosed with arteriosclerosis. In retrospect, population ancestry-based differences in many African-American subjects from that report are likely related to APOL1 risk variants; variants that are virtually absent in EAs.…”

Section: Discussionsupporting

confidence: 91%

“…A subsequent validation analysis was performed by four Globally sclerotic glomeruli were characterized as obsolescent, solidified, or disappearing, as previously reported. 13 Sclerotic glomeruli were considered obsolescent when the sclerotic glomerular tuft was retracted with accumulation of fibrous matrix replacing Bowman's space ( Figure 2). The solidified pattern of glomerulosclerosis reflected a solidified sclerotic tuft without retraction and without a fibrous matrix surrounding the tuft.…”

Section: Study Design and Histologic Grading Of Renal Biopsiesmentioning

confidence: 99%

“…12 Only one study has compared the morphologic findings in African Americans and EAs with putative hypertensive nephrosclerosis; this study showed an increase in the solidified pattern of glomerulosclerosis in African-American kidney biopsies. 13 However, the study failed to account for APOL1 risk alleles in the AfricanAmerican population as it was performed before discovery of APOL1-associated nephropathy in 2010. Therefore, we performed an APOL1 genotypephenotype correlation in kidney biopsies from African Americans who had hypertension-attributed CKD without the nephrotic syndrome.…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 91%

Section: Study Design and Histologic Grading Of Renal Biopsiesmentioning

confidence: 99%

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confidence: 99%

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Histopathologic findings associated with APOL1 risk variants in chronic kidney disease

et al. 2015

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“…17 Most im-portant, lowering BP to usual or low levels, even with inhibitors of angiotensin II action, does not slow progression of nephropathy in hypertensive African American, 2,18 -21 and the renal histologic changes normally associated with high BP, arterial and arteriolar wall thickening, do not correlate with systemic BP. 22,23 Renal biopsies in patients with a clinical diagnosis of hypertensive nephrosclerosis typically reveal segmental or global glomerulosclerosis with marked interstitial fibrosis and other glomerular diseases in the remainder. 22,24 It has long been proposed that a primary renal disease could explain all of these findings such that observed elevations in BP would be secondary.…”

Section: Essential Hypertension: An Uncommon Initiator Of Progressivementioning

confidence: 99%

Hypertension-Associated Kidney Disease

Freedman

Sedor

2008

Journal of the American Society of Nephrology

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“…14,15 Arterial hypertension is an important contributory factor but is not a conditio sine qua non. 13,14,16 Genetic susceptibility factors may modulate development and progression of glomerular sclerosis. Recently, genetic variants such as single nucleotide polymorphisms in the gene MYH9, which encodes nonmuscle myosin heavy chain type II isoform A, were found to be associated with nondiabetic end-stage renal disease in African Americans, probably including a considerable number with NSC.…”

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confidence: 99%

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

Neusser

Lindenmeyer

Moll

et al. 2010

The American Journal of Pathology

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In the kidney, hypoxia contributes to tubulointerstitial fibrosis, but little is known about its implications for glomerular damage and glomerulosclerosis. Chronic hypoxia was hypothesized to be involved in nephrosclerosis (NSC) or "hypertensive nephropathy." In the present study genome-wide expression data from microdissected glomeruli were studied to examine the role of hypoxia in glomerulosclerosis of human NSC. Functional annotation analysis revealed prominent regulation of hypoxia-associated biological processes in NSC, including angiogenesis, fibrosis, and inflammation. Glomerular expression levels of a majority of genes regulated by the hypoxia-inducible factors (HIFs) were significantly altered in NSC. Among these HIF targets, chemokine C-X-C motif receptor 4 (CXCR4) was prominently induced. Glomerular CXCR4 mRNA induction was confirmed by quantitative RT-PCR in an independent cohort with NSC but not in those with other glomerulopathies. By immunohistological analysis, CXCR4 showed enhanced positivity in podocytes in NSC biopsy specimens. This CXCR4 positivity was associated with nuclear localization of HIF1␣ only in podocytes of NSC, indicating transcriptional activity of HIF. As the CXCR4 ligand CXCL12/SDF-1 is constitutively expressed in podocytes, autocrine signaling may contribute to NSC. In addition, a blocking CXCR4 antibody caused significant inhibition of wound closure by podocytes in an in vitro scratch assay. These data support a role for CXCR4/CXCL12 in human NSC and indicate that hypoxia not only is involved in tubulointerstitial fibrosis but also contributes to glomerular damage in NSC. Hypoxia is considered a pivotal factor contributing to tubular atrophy and interstitial fibrosis, which are factors for the progression of renal disease. 1 The evidence in support of this hypothesis derives mostly from experimental animal studies.2-5 Most of these have focused on the tubulointerstitial space with little attention being paid to the glomerulus. The cellular response to hypoxia is largely mediated by heterodimeric transcription factors, the hypoxia-inducible factors (HIFs).2 The cellular levels of the HIF1␣ and HIF2␣ subunits (HIF␣) of HIF (gene symbols HIF1A and HIF2A) are controlled mainly by posttranslational protein modification. Under normoxia HIF␣ is degraded by the von Hippel-Lindau tumor suppressor protein. This process is regulated by oxygen-dependent hydroxylation of HIF␣ through specific prolyl hydroxylases. Under hypoxic conditions degradation of HIF␣ ceases and the stabilized protein can function as a transcription factor.2 In the renal glomerulus, a functional role of HIF1␣ 6 -8 and HIF2␣ 9 has been documented in podocytes of rodents. Recently, glomerular podocyte-specific deletion of von Hippel-Lindau tumor suppressor protein was achieved in mice, resulting in podocyte-specific overactivity of HIF with induction of HIF target genes. 6,8

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Hypertensive nephrosclerosis in African Americans versus Caucasians

Cited by 132 publications

References 28 publications

Histopathologic findings associated with APOL1 risk variants in chronic kidney disease

Histopathologic findings associated with APOL1 risk variants in chronic kidney disease

Hypertension-Associated Kidney Disease

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

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