<i>APOL1</i>nephropathy: from gene to mechanisms of kidney injury

Kruzel-Davila, Etty; Wasser, Walter G.; Aviram, Sharon; Skorecki, Karl

doi:10.1093/ndt/gfu391

Cited by 97 publications

(81 citation statements)

References 67 publications

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“…5,21 The G1 and G2 variants are mutations that appear to prevent neutralization of apolipoprotein 1, a defense mechanism which has evolved in Trypansoma brucei rhodesiense. 22 Whether G1-/G2-encoded apolipoprotein 1 has additional nephrotoxic action is not known. There is some evidence that active infection or inflammation may modify APOL1-related risk: in one study of HIV-infected individuals, eGFR trajectory differed by APOL1 high-risk status only among those with unsuppressed viremia.…”

Section: Discussionmentioning

confidence: 99%

Race, APOL1 Risk, and eGFR Decline in the General Population

Grams

Rebholz²,

Chen³

et al. 2016

JASN

127

123

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The APOL1 high-risk genotype, present in approximately 13% of blacks in the United States, is a risk factor for kidney function decline in populations with CKD. It is unknown whether genetic screening is indicated in the general population. We evaluated the prognosis of APOL1 high-risk status in participants in the population-based Atherosclerosis Risk in Communities (ARIC) study, including associations with eGFR decline, variability in eGFR decline, and related adverse health events (AKI, ESRD, hypertension, diabetes, cardiovascular disease, pre-ESRD and total hospitalization rate, and mortality). Among 15,140 ARIC participants followed from 1987-1989 (baseline) to 2011-2013, 75.3% were white, 21.5% were black/APOL1 low-risk, and 3.2% were black/APOL1 high-risk. In a demographic-adjusted analysis, blacks had a higher risk for all assessed adverse health events; however, in analyses adjusted for comorbid conditions and socioeconomic status, blacks had a higher risk for hypertension, diabetes, and ESRD only. Among blacks, the APOL1 high-risk genotype associated only with higher risk of ESRD in a fully adjusted analysis. Black race and APOL1 high-risk status were associated with faster eGFR decline (P,0.001 for each). However, we detected substantial overlap among the groups: median (10th-90th percentile) unadjusted eGFR decline was 1.5 (1.0-2.2) ml/min per 1.73 m 2 per year for whites, 2.1 (1.4-3.1) ml/min per 1.73 m 2 per year for blacks with APOL1 low-risk status, and 2.3 (1.5-3.5) ml/min per 1.73 m 2 per year for blacks with APOL1 high-risk status. The high variability in eGFR decline among blacks with and without the APOL1 high-risk genotype suggests that population-based screening is not yet justified.

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Section: Discussionmentioning

confidence: 99%

Race, APOL1 Risk, and eGFR Decline in the General Population

Grams

Rebholz²,

Chen³

et al. 2016

JASN

127

123

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“…78 APOL1 is expressed not only in the kidney but also in other organs, including the liver, lung, and placenta, and is the only member of the apolipoprotein family that produces a soluble form. 79 This has led to questions over whether APOL1 variants contribute to transplant outcome by causing increased APOL1 in the kidneys leading to nephrotoxicity or through the soluble form of APOL1 causing altered binding/reabsorption of high-density lipoprotein (as reviewed in Kruzel-Davila et al 79 ). Differences in APOL1 expression in normal kidneys compared to those from people with human immunodeficiency virus-associated nephropathy and focal segmental glomerulosclerosis have been found.…”

Section: Recipient Only Analysismentioning

confidence: 99%

Using Genetic Variation to Predict and Extend Long-term Kidney Transplant Function

Simmonds

2015

Transplantation

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Renal transplantation has transformed the life of patients with end-stage renal disease and other chronic kidney disorders by returning endogenous kidney function and enabling patients to cease dialysis. Several clinical indicators of graft outcome and long-term function have been established. Although rising creatinine levels and graft biopsy can be used to determine graft loss, identifying early predictors of graft function will not only improve our ability to predict long-term graft outcome but importantly provide a window of opportunity to therapeutically intervene to preserve graft function before graft failure has occurred. Since understanding the importance of matching genetic variation at the HLA region between donors and recipients and translating this into clinical practise to improve transplant outcome, much focus has been placed on trying to identify additional genetic predictors of transplant outcome/function. This review will focus on how candidate gene studies have identified variants within immunosuppression, immune response, fibrotic pathways, and specific ethnic groups, which correlate with graft outcome. We will also discuss the challenges faced by candidate gene studies, such as differences in donor and recipient selection criteria and use of small data sets, which have led to many genes failing to be consistently associated with transplant outcome. This review will also look at how recent advances in our understanding of and ability to screen the genome are starting to provide new insights into the mechanisms behind long-term graft loss and with it the opportunity to target these pathways therapeutically to ultimately increase graft lifespan and the associated benefits to patients.

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“…APOL1 risk alleles are present at high frequency in sub-Saharan Africa, owing to evolutionary adaptive pressures that led to the restoration of APOL1 trypanolytic activity against Trypanosoma brucei rhodesiense (1) and potentially other pathogens (1,3). Most studies have reported that significant association requires two parental risk alleles (4). However, notwithstanding the high frequency of the risk genotypes among African Americans, lifetime kidney disease risk estimates range from 4% for FSGS to .50% for untreated HIV-associated nephropathy (5), consistent with the modulating effect of other allelic variants in the genomic region and nongenetic modifiers.…”

mentioning

confidence: 99%

“…and (2) What precipitating "second hits" transform APOL1 risk into progressive kidney disease? The knowledge that APOL1 is absent from the genomes of most mammals and at least one individual from India without a deleterious effect on kidney function leads to the conclusion that APOL1 is dispensable for kidney integrity and suggests a dose-dependent "gain of injury" effect (4). Several in vitro and in vivo studies have supported this theory (3,4,6).…”

mentioning

confidence: 99%