Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes

Zhang, Zhongyang; Sun, Zeguo; Fu, Jia; Lin, Qisheng; Banu, Khadija; Chauhan, Kinsuk; Planoutene, Marina; Wei, Chengguo; Salem, Fadi; Yi, Zhengzi; Liu, Ruijie; Cravedi, Paolo; Cheng, Haoxiang; Hao, Ke; O’Connell, Philip J.; Ishibe, Shuta; Zhang, Weijia; Coca, Steven G.; Gibson, Ian W.; Colvin, Robert B.; He, John Cijiang; Heeger, Peter S.; Murphy, Barbara; Menon, Madhav C.

doi:10.1172/jci146643

Cited by 38 publications

(57 citation statements)

References 71 publications

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“…Studies in the past few years have demonstrated that kidney transplant recipients with APOL1 high-risk genotype donor kidneys have lower eGFR at follow-up and poorer allograft survival 15 , 59 – 61 . However, whether the presence of two APOL1 risk alleles in the transplant recipient affects the outcome of the transplanted kidney is unclear, with studies showing conflicting results 62 , 63 . Furthermore, kidney donors with two APOL1 risk alleles have an increased risk of reduced kidney function following kidney donation, which has the potential to progress to kidney failure, suggesting that counselling should be considered to inform potential kidney donors with APOL1 risk variants about the associated risks 61 .…”

Section: Apol1 and Kidney Diseasementioning

confidence: 99%

“…Several groups have assessed the implications of circulating APOL1 and showed that levels do not correlate with kidney disease risk, underscoring the essential role of kidney-expressed APOL1 in kidney disease 71 , 76 , 77 . A more recent study proposed that the circulating APOL1 variants have an immunomodulatory role, associated with T cell-mediated rejection and death-censored allograft loss 63 . Further studies are required to establish the role of circulatory APOL1 levels.…”

Section: Apol1 and Kidney Diseasementioning

confidence: 99%

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The evolving story of apolipoprotein L1 nephropathy: the end of the beginning

et al. 2022

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Genetic coding variants in APOL1 , which encodes apolipoprotein L1 (APOL1), were identified in 2010 and are relatively common among individuals of sub-Saharan African ancestry. Approximately 13% of African Americans carry two APOL1 risk alleles. These variants, termed G1 and G2, are a frequent cause of kidney disease — termed APOL1 nephropathy — that typically manifests as focal segmental glomerulosclerosis and the clinical syndrome of hypertension and arterionephrosclerosis. Cell culture studies suggest that APOL1 variants cause cell dysfunction through several processes, including alterations in cation channel activity, inflammasome activation, increased endoplasmic reticulum stress, activation of protein kinase R, mitochondrial dysfunction and disruption of APOL1 ubiquitinylation. Risk of APOL1 nephropathy is mostly confined to individuals with two APOL1 risk variants. However, only a minority of individuals with two APOL1 risk alleles develop kidney disease, suggesting the need for a ‘second hit’. The best recognized factor responsible for this ‘second hit’ is a chronic viral infection, particularly HIV-1, resulting in interferon-mediated activation of the APOL1 promoter, although most individuals with APOL1 nephropathy do not have an obvious cofactor. Current therapies for APOL1 nephropathies are not adequate to halt progression of chronic kidney disease, and new targeted molecular therapies are in clinical trials.

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Section: Apol1 and Kidney Diseasementioning

confidence: 99%

Section: Apol1 and Kidney Diseasementioning

confidence: 99%

The evolving story of apolipoprotein L1 nephropathy: the end of the beginning

et al. 2022

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“…This finding is consistent with prior reports 13,18 . This number of glomerular profiles was present in the majority of clinical biopsies from a recent dataset from the NEPTUNE consortium 15 .…”

Section: Discussionmentioning

confidence: 88%

“…The FSGS lesions in these mice models were confirmed and characterized by a renal pathologist [representative images in Supplementary Figure ]. FSGS developed in hypertrophic 1/6 th remnant BALBc/J kidneys (after sequential 2/3 rd and contralateral nephrectomy) by 6 weeks 15 . In the ageing model (mice > 12 months age), doxycycline feeding for 6 weeks, induced Shroom3 knockdown, diffuse podocyte foot process effacement and podocyte loss with the development of FSGS 10,17 .…”

Section: Animalsmentioning

confidence: 99%

“…A typical paraffin-embedded renal biopsy archived for retrospective studies includes limited numbers of glomeruli, from which further smaller sections are divided for plastic embedding. In recent data 15 we reported that a subset of paraffin-embedded biopsy tissue from the NEPTUNE consortium 16 had a mean 14+/-10 (median 12) glomerular profiles. Prior data suggests that using Vglom-Cav from >10 glomeruli was not associated with significant improvements in the Coefficient of variation while calculating MGV 11 .…”

Section: Introductionmentioning

confidence: 98%

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Comparative evaluation of glomerular morphometric techniques reveals differential technical artefacts between FSGS and normal glomeruli

Basgen

Reghuvaran

Lin

et al. 2022

Preprint

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Morphometric estimates of mean glomerular volume (MGV) have clinical implications, over and above histologic data. However, MGV estimation is time-consuming, could waste tissue sections and requires expertise limiting its utility in retrospective clinical studies. Methods: We evaluated MGV using both plastic and paraffin-embedded tissue from control and FSGS mice (n=10 each) using the gold-standard Disector/Cavalieri technique (Vglom-Cav) and other reported techniques [2- or 3-profile technique, Weibel-Gomez method (W-G)]. Within Vglom-Cav we examined the precision of MGV estimation while using MGVs obtained from 5- or 10- individual glomeruli measurements vs the true mean (20 glomeruli). Results: In both FSGS and controls, we identified an acceptable precision of 10-glomerular sampling vs true MGV within Vglom-Cav technique [88 (79-94) % of MGV obtained were within 10% of the true MGV]. The 5-glomerular sampling was less precise [70 (56, 81) % of MGV obtained were within 10% of true MGV]. In plastic based techniques, 2- or 3-profile MGVs showed greater concordance with Vglom-Cav, than W-G MGV. The new 3-profile technique offered incremental benefit to the existing 2-profile method (improved Lins concordance in control and FSGS animals). We observed a consistent reduction of Vglom values within control animals (52+/-0.06%) in paraffin-embedded tissue (vs corresponding methods in plastic) demonstrating a clear shrinkage artefact due to tissue processing. FSGS glomeruli showed significantly less and more variable shrinkage artefact likely due to glomerular fibrosis. Conclusion: We report the precision of 5- or 10-glomerular sampling for MGV estimation using controls and FSGS animals. We demonstrate and quantify the shrinkage bias in MGV during tissue processing for paraffin-embedding that also differentiated control animals and FSGS. Our findings have implications for experimental studies using glomerular morphometry.

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