Apolipoprotein L1 Risk Variants

Plasma or serum

0.3 mL

0.2 mL (Note: This volume does not allow for repeat testing).

Lavender-top (EDTA) tube or gel-barrier tube

The higher risk of end stage renal disease (ESRD) in the African American (AA) population has created a barrier for donor selection for kidney transplant programs. Due to this risk association, The Organ Procurement and Transplantation Network (OPTN) maintains an algorithm that assigns a risk coefficient for prospective donors of AA ethnicity that is higher than coefficients assigned for donors with hypertension and diabetes.^1,2 As of July 2018 there are more than 102,000 patients waiting for a kidney in the US. Even a small increase in the available donor pool can be helpful for the waiting recipients. The generic higher risk factor currently used for kidney allocation from prospective AA donors reduces the donor pool especially in an underserved high risk population.

Most laboratories perform APOL1 variant analysis using DNA sequencing that identifies the nucleotide polymorphisms that code for the different phenotypes. However, the LabCorp method employs LC-MS/MS to determine the APOL1 phenotype by detecting expressed mature proteins. It is possible that for some patients, the LabCorp LC-MS/MS results might be different than those determined by DNA sequence, due to an absence of expression of proteins caused by patient specific transcription/translation factors.

This test was developed and its performance characteristics determined by Labcorp. It has not been cleared or approved by the Food and Drug Administration.

Three genetic variants of Apolipoprotein L1 (ApoL1) — wild- type (WT), G1, and G2 — are determined by identifying the corresponding mutations in the protein sequence of ApoL1 circulating in whole blood. This is accomplished by first denaturing serum or plasma, followed by trypsin digestion to produce proteolytic surrogate peptides specific to the three variant forms of ApoL1. The digested plasma is then directly analyzed by liquid chromatography (LC) coupled with tandem mass spectrometry (MS/MS) to determine the presence or absence of the respective surrogate peptides to infer the presence or absence of the associated ApoL1 variant. Based on the pattern of surrogate peptides detected, the genotype of ApoL1 in the specimen/individual can be determined.

Recently, the association of apolipoprotein L1 (APOL1) variants has been reported as a possible mechanism for the increased presence of ESRD in the AA population. Two APOL1 variants G1 (Ser342Gly/Ile384Met) and G2 (deletion 388-389 Asn-Tyr) have been shown to be associated with the increased incidence of renal disease in African Americans.^3,4,6 The highest risk for ESRD are individuals that carry two of the variants (i.e. G1:G1, G1:G2, G2:G2).^3,4 These APOL1 variants convey resistance to trypanosome infection that is endemic in sub-Saharan Africa, especially West Africa. This evolutionary pressure caused these variants to be prominent in this population and subsequent descendents of the population worldwide.⁵

Identification of prospective donors of AA heritage that have only a single copy or do not carry either APOL1 variant could increase the number of available donors for patients that are waiting for a kidney. In a single center study, Reeves-Daniel reported that kidneys from donors that had two APOL1 variants had a lower percentage of graft survival (less than 50% by 3.5 years) as compared to donors with a single or no risk variants (75% survival by 3 years).⁷ The presence of two variants had a greater hazard ratio (HR-3.84) vs. a single variant copy or no variants. The presence of both APOL1 variants had a greater HR than both HLA mismatch (HR- 1.52) and cold ischemia time (HR-1.06).⁷

In a multi-center study, Freedman et al reports a similar pattern of HR of allograft failure in patients that received kidneys from donors with two APOL1 variants (HR-2.26 from full data set).⁸ The presence of two variants exceeded all other HRs including maximum PRA, HLA mismatch, and cold ischemia time. Although the overall survival of high risk variant donors (73% at 5 years) was higher than the single center study by Reeves-Daniel, it was still significantly lower than the single or no variant population (81% at 5 years). In both studies^7,8 when APOL1 variants were excluded, African ancestry was not associated with decreased graft survival.

The high risk of ESRD in the AA population has caused a reduction in available kidney donors from this ethnic group. The identification of two APOL1 variants that are frequent in the AA population and strongly associated with renal disease has provided a screening tool that can provide better evidence for kidney survival from AA donors. Assigning a risk coefficient to all AA donors unfairly reduces available donors in this population. Deceased AA donors that can be screened for APOL1 can provide a better assessment of risk of graft survival based on the individual rather than being generalized with a group risk factor. In addition, living donors can be identified in AA families. Assessing if a prospective living donor contains two risk variants is important for both the recipient and the risk for the donor of ESRD.⁹