The APOL1 Genotype of African American Kidney Transplant Recipients Does Not Impact 5-Year Allograft Survival

Lee, B. T; Kumar, Vineeta; Williams, Timothy; Abdi, Reza; Bernhardy, Andrea J.; Dyer, Charissa A.; Conte, S; Genovese, Giulio; Ross, Michael D.; Friedman, David J.; Gaston, Robert S.; Milford, Edgar L.; Pollak, Martin R.; Chandraker, Anil

doi:10.1111/j.1600-6143.2012.04033.x

Cited by 167 publications

(147 citation statements)

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“…On the other hand, the clear pathogenicity associated with the G1 and G2 disease alleles suggests that while wild-type APOL1 may promote cell survival, consistent with the long half-life of podocytes, these disease variants may have acquired a deleterious gain of function, which becomes manifest in combination with other genetic and/or environmental inputs. On the basis of kidney transplant studies, in which donor but not recipient APOL1 genotypes affected graft survival, 21,22 some would conclude that circulating APOL1 protein is less likely than intrinsic renal gene expression to be involved in the pathogenesis of APOL1-associated nephropathy. However, we caution against applying the transplant model to the pathogenesis of native kidney disease, in part because APOL1-associated kidney disease is a decades-long process whereas transplant failure is a short-term outcome confounded by many issues, including cold ischemia and use of nephrotoxic immunosuppressive medications.…”

Section: Discussionmentioning

confidence: 99%

Localization of APOL1 Protein and mRNA in the Human Kidney

Ma¹,

Shelness²,

Snipes³

et al. 2015

Journal of the American Society of Nephrology

117

115

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Although APOL1 gene variants are associated with nephropathy in African Americans, little is known about APOL1 protein synthesis, uptake, and localization in kidney cells. To address these questions, we examined APOL1 protein and mRNA localization in human kidney and human kidney-derived cell lines. Indirect immunofluorescence microscopy performed on nondiseased nephrectomy cryosections from persons with normal kidney function revealed that APOL1 protein was markedly enriched in podocytes (colocalized with synaptopodin and Wilms' tumor suppressor) and present in lower abundance in renal tubule cells. Fluorescence in situ hybridization detected APOL1 mRNA in glomeruli (podocytes and endothelial cells) and tubules, consistent with endogenous synthesis in these cell types. When these analyses were extended to renal-derived cell lines, quantitative RT-PCR did not detect APOL1 mRNA in human mesangial cells; however, abundant levels of APOL1 mRNA were observed in proximal tubule cells and glomerular endothelial cells, with lower expression in podocytes. Western blot analysis revealed corresponding levels of APOL1 protein in these cell lines. To explain the apparent discrepancy between the marked abundance of APOL1 protein in kidney podocytes observed in cryosections versus the lesser abundance in podocyte cell lines, we explored APOL1 cellular uptake. APOL1 protein was taken up readily by human podocytes in vitro but was not taken up efficiently by mesangial cells, glomerular endothelial cells, or proximal tubule cells. We hypothesize that the higher levels of APOL1 protein in human cryosectioned podocytes may reflect both endogenous protein synthesis and APOL1 uptake from the circulation or glomerular filtrate.

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Section: Discussionmentioning

confidence: 99%

Localization of APOL1 Protein and mRNA in the Human Kidney

Ma¹,

Shelness²,

Snipes³

et al. 2015

Journal of the American Society of Nephrology

117

115

View full text Add to dashboard Cite

show abstract

“…Due to the abundance of APOL1 in human serum and uptake of free APOL1 into podocytes in vitro ( 5 ), it was initially hypothesized that circulating APOL1 protein might contribute to APOL1 -associated nephropathy. Subsequent kidney transplantation studies failed to support this hypothesis (18)(19)(20); however, potential roles for circulating APOL1 protein in CVD and HDLcholesterol metabolism remain plausible ( 7 ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of circulating APOL1 protein complexes in African Americans

Weckerle

Snipes

Cheng

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org G1 and G2 renal-risk variants on chromosome 22q13.1 ( 1-3 ). Although APOL1 mRNA and APOL1 protein are present in human kidney ( 4, 5 ), the major APOL1 reservoir appears to be circulating protein ( 5, 6 ). APOL1 was initially discovered as a minor apolipoprotein of plasma HDLs ( 6 ); however, its distribution among HDL subfractions has not been well-defi ned. APOL1 nephropathy variants associate with HDL subfraction concentrations ( 7 ) and CVD risk, although controversial results have been reported with CVD ( 8-11 ). Trypanosome lytic factors (TLF1 and TLF2) contain APOL1 protein ( 12 ) and are minor HDL subfractions in humans that contribute to innate immunity via protection from infection, including from African trypanosomes ( 13 ).Association was not observed between plasma APOL1 concentrations and APOL1 genotype in African Americans with treated HIV infection; plasma APOL1 levels also did not associate with the risk of HIV-associated nephropathy or chronic kidney disease ( 14 ). Whether serum APOL1 protein levels and their distribution among HDL particles are associated with APOL1 genotypes in healthy individuals is unknown. Because free APOL1 protein may be taken up by podocytes in vitro ( 5 ), it remains critical to determine whether serum APOL1 concentrations or the structure/composition of variant APOL1 proteins and their associated complexes are specifi c to the G1 and G2 renalrisk variants, relative to nonrisk G0.To address these issues, serum APOL1 protein levels and size distribution were examined in age-and gender-matched African Americans without kidney disease based on APOL1 genotype using fast protein LC (FPLC) and immunoblot analysis. Proteomics analysis was performed to compare the composition of APOL1 protein-containing complexes. These Abstract APOL1 gene renal-risk variants are associated with nephropathy and CVD in African Americans; however, little is known about the circulating APOL1 variant proteins which reportedly bind to HDL. We examined whether APOL1 G1 and G2 renal-risk variant serum concentrations or lipoprotein distributions differed from nonrisk G0 APOL1 in African Americans without nephropathy. Serum APOL1 protein concentrations were similar regardless of APOL1 genotype. In addition, serum APOL1 protein was bound to protein complexes in two nonoverlapping peaks, herein referred to as APOL1 complex A (12.2 nm diameter) and complex B (20.0 nm diameter). Neither of these protein complexes associated with HDL or LDL. Proteomic analysis revealed that complex A was composed of APOA1, haptoglobin-related protein (HPR), and complement C3, whereas complex B contained APOA1, HPR, IgM, and fibronectin. Serum HPR was less abundant on complex B in individuals with G1 and G2 renal-risk variant genotypes, relative to G0 ( P = 0.0002-0.037). These circulating complexes may play roles in HDL metabolism and susceptibility to CVD. A major breakthrough in human molecular genetics was identifi cation of the powerful contribution of APOL1 gene ...

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“…In a small study involving 119 African American kidney transplant recipients, Lee et al found no difference in graft survival in highrisk APOL1 (two alleles) compared to low-risk (zero or one allele) recipients (HR 0.96; 95% CI 0.61-1.49; p ¼ 0.84) (3). In a single center study from North Carolina, Reeves-Daniel et al examined outcomes from 106 African American deceased donors, of whom 22 (21%) had two APOL1 copies, and found that two APOL1 variants in a deceased donor was independently associated with a greater risk of graft failure (HR 3.84; p ¼ 0.0.84) (4).…”

mentioning

confidence: 98%

APOL1 Genotyping of African American Deceased Organ Donors: Not Just Yet

Knoll

2015

American Journal of Transplantation

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The APOL1 Genotype of African American Kidney Transplant Recipients Does Not Impact 5-Year Allograft Survival

Cited by 167 publications

References 15 publications

Localization of APOL1 Protein and mRNA in the Human Kidney

Localization of APOL1 Protein and mRNA in the Human Kidney

Characterization of circulating APOL1 protein complexes in African Americans

APOL1 Genotyping of African American Deceased Organ Donors: Not Just Yet

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