Dealing With Uncertainty

Apolipoprotein L1 (APOL1) may explain much of the excess rate of end-stage renal disease (ESRD) in Blacks compared to Whites. Kidney grafts from deceased donors with two APOL1 risk alleles have worse graft survival, but outcomes appear unaffected by recipient APOL1 status. Unknown is whether unilateral nephrectomy increases the risk of ESRD in living donors with two APOL1 risk alleles and whether their donated kidneys have worse graft survival compared with other living donor grafts. This chapter addresses the decision-making processes of the donor and candidate with their respective separate transplant teams when incomplete data about long-term safety and outcome have implications for both patients. The chapter argues that voluntary APOL1 testing should be offered to prospective Black living donors but the results should only be shared with potential recipients with the living donor’s consent. Living donors are patients who have a right to privacy about their genetic makeup.

Stakeholder Perspectives on Returning Nonactionable Apolipoprotein L1 (APOL1) Genetic Results to African American Research Participants

The ethics of returning nonactionable genetic research results to individuals are unclear. Apolipoprotein L1 ( APOL1) genetic variants are nonactionable, predominantly found in people of West African ancestry, and contribute to kidney disease disparities. To inform ethical research practice, we interviewed researchers, clinicians, and African American community members ( n = 76) about the potential risks and benefits of returning APOL1 research results. Stakeholders strongly supported returning APOL1 results. Benefits include reciprocity for participants, community education and rebuilding trust in research, and expectation of future actionability. Risks include analytic validity, misunderstanding, psychological burdens, stigma and discrimination, and questionable resource tradeoffs. Conclusions: APOL1 results should be offered to participants. Responsibly fulfilling this offer requires careful identification of best communication practices, broader education about the topic, and ongoing community engagement.

Structures of the ApoL1 and ApoL2 N-terminal domains reveal a non-classical four-helix bundle motif

Apolipoprotein L1 (ApoL1) is a circulating innate immunity protein protecting against trypanosome infection. However, two ApoL1 coding variants are associated with a highly increased risk of chronic kidney disease. Here we present X-ray and NMR structures of the N-terminal domain (NTD) of ApoL1 and of its closest relative ApoL2. In both proteins, four of the five NTD helices form a four-helix core structure which is different from the classical four-helix bundle and from the pore-forming domain of colicin A. The reactivity with a conformation-specific antibody and structural models predict that this four-helix motif is also present in the NTDs of ApoL3 and ApoL4, suggesting related functions within the small ApoL family. The long helix 5 of ApoL1 is conformationally flexible and contains the BH3-like region. This BH3-like α-helix resembles true BH3 domains only in sequence and structure but not in function, since it does not bind to the pro-survival members of the Bcl-2 family, suggesting a Bcl-2-independent role in cytotoxicity. These findings should expedite a more comprehensive structural and functional understanding of the ApoL immune protein family.

Apolipoprotein L1 risk genotypes in Ghanaian patients with systemic lupus erythematosus: a prospective cohort study

ObjectiveTwo apolipoprotein L1 (APOL1) risk variants (RV) are enriched in sub-Saharan African populations due to conferred resistance to Trypanosoma brucei. These variants associate with adverse renal outcomes by multiple causes including SLE. Despite emerging reports that SLE is common in Ghana, where APOL1 variant allelic frequencies are high, the regional contribution to SLE outcomes has not been described. Accordingly, this prospective longitudinal cohort study tested the associations between APOL1 high-risk genotypes and kidney outcomes, organ damage accrual and death in 100 Ghanaian patients with SLE.MethodsThis was a prospective cohort study of 100 SLE outpatients who sought care at Korle bu Teaching Hospital in Accra, Ghana. Adult patients who met 4 American College of Rheumatology criteria for SLE were genotyped for APOL1 and followed longitudinally for SLE activity as measured by the Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) hybrid and organ injury as measured by the Systemic Lupus International Collaborating Clinics Damage Index (SDI) at baseline and every 6 months for 1 year. Outcomes of interest were kidney function, SDI and case fatality.ResultsAssuming a recessive inheritance, the APOL1 high-risk genotype (2RV) associated with end-stage renal disease (ESRD) at an OR of 14 (p=0.008). These patients accrued more SDI points particularly in renal and neurological domains. The SDI was 81.3% higher in 2RV patients compared with 0RV or 1RV patients despite no difference in SLE activity (p=0.01). After a 12-month period of observation, 3/12 (25%) of the 2RV patients died compared with 2/88 (2.3%) of the 0RV or 1RV carriers (OR=13.6, p=0.01). Deaths were due to end-stage kidney disease and heart failure.ConclusionAPOL1 RVs were heritable risk factors for morbidity and mortality in this Ghanaian SLE cohort. Despite no appreciable differences in SLE activity, APOL1 high-risk patients exhibited progressive renal disease, organ damage accrual and a 13-fold higher case fatality.

Kidney disease-associated variants of Apolipoprotein L1 show gain-of-function in cation channel activity

Variants in Apolipoprotein L1 (ApoL1) are known to be responsible for increased risk of some progressive kidney diseases among people of African ancestry. ApoL1 is an amphitropic protein that can insert into phospholipid membranes and confer anion- or cation-selective permeability to phospholipid membranes depending on pH. Whether these activities differ among the variants or whether they contribute to disease pathogenesis is unknown. We used assays of voltage-driven ion flux from phospholipid vesicles and of stable membrane association to assess differences among ApoL1 isoforms. There is a significant (approximately two-fold) increase in the cation-selective ion permease activity of the two kidney-disease-associated variants compared to the reference protein. In contrast, we find no difference in the anion-selective permease activity at low pH among the isoforms. Compared with the reference sequence, the two disease-associated variants show increased stable association with phospholipid vesicles under conditions that support the cation permease activity, suggesting that the increased activity may be due to more efficient membrane association and insertion. There is no difference in membrane association among isoforms under optimal conditions for the anion permease activity. These data support a model in which enhanced cation permeability may contribute to the progressive kidney diseases associated with high-risk ApoL1 alleles.