Studies have identified a gene on chromosome 22 encoding for apolipoprotein L1 (APOL1) that has been associated with a variety of nephropathies. Two variants of the gene, G1 and G2, are considered risk alleles and are associated with increased risk of CKD; these variants are common in people of African ancestry but have not been found in people with European ancestry. It is hypothesized that the gene follows the recessive model, meaning that two copies of the high-risk variant are needed for phenotypic expression. Genotyping of the APOL1 gene in multiple studies suggest about 11%-13% of African Americans have the high-risk 2 APOL1 risk alleles.
The effect of APOL1 on CKD progression was examined in self-identified black participants with chronic kidney disease attributed to hypertension from the African American Study of Kidney Disease and Hypertension (AASK) Study. Patients were genotyped for the APOL1 risk alleles and over a median follow-up of 9 years, measured for serum creatinine levels every 6 months. The primary outcome is a composite renal outcome of doubling of serum creatinine or end-stage renal disease (ESRD). A recessive genetic model is used to compare patients with 0 or 1 copies of the risk variant (low-risk group) with patients with 2 copies of the risk variant (high-risk group). The composite outcome occurred in 37% of the low-risk group and was significantly higher (p-value <0.001) in the high-risk group, occurring in 58% of the high-risk patients.
Chart Explanation: The high risk group (patients with 2 copies of APOL1 risk variant) was significantly more likely to progress to ESRD (HR 2.16 p-value <0.001) and to reach the composite of ESRD progression or doubling of serum creatinine (HR 1.88 p-value <0.001). However, APOL1 risk status was not associated with death before ESRD (HR 1.25 p-value 0.43).
The African American Study of Kidney Disease and Hypertension (AASK) is a randomized, double-blind, controlled study in nondiabetic African Americans with hypertensive renal disease. Participants assigned to two levels of target blood pressure and also randomized to receive one of three antihypertensive drugs. The study aim was to determine the effects of blood pressure control level and specific antihypertensive drugs with the primary outcome of progression of hypertensive kidney disease as measured by change in GFR. The trial phase of the study was from 1995-2001 with a cohort follow-up phase from 2002-2007. Participants who provided written consent for DNA collection during the trial were genotyped for data including apolipoprotein L1 (APOL1) markers.
Analyses for this measure were performed in 693 AASK Study patients with usable genotype data. The three measured outcomes included incident end-stage renal disease, a doubling of serum-creatinine levels, and a composite of either of these outcomes. Death before ESRD was also analyzed to identify the possibility of death as a competing risk event in outcome progression. The genetic model presented on this website is a recessive genetic model. The association between APOL1 and the aforementioned outcomes was analyzed with adjusted Cox proportional-hazards models.
| Field | Data |
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| Description of Measure | Risk of ESRD or Doubling of Serum Creatinine Among Patients in the AASK Study |
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| Data Source | AASK Multi-center prospective longitudinal cohort study |
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| Type of Data Source | Public |
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| Data Set | AASK summarized data |
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| Health Care System Data | No |
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| Regional or National? | National |
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| Demographic Group | Self-identified African Americans with hypertension, no diabetes, and aged between 18 to 70 years with a GFR of 20 -65 mL/min per 1.73 m2 enrolled in the AASK study |
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| Numerator | Composite outcome of ESRD or doubling of serum creatinine |
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| Denominator | AASK participants with genotyped APOL1 data |
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| Definition of CKD | GFR of 20 - 65 mL/min per 1.73 m2 (for entry into study) |
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| Glomerular filtration rate | Estimated, MDRD Study equation |
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| Primary Data Source Indicator | Serum creatinine level, incident ESRD, or death |
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| Primary Indicator Method of Measurement | Serum creatinine via blood test; ESRD as indicated by dialysis or transplant, medical record review |
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| Secondary (1) Variable | APOL1 risk variant |
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| Secondary (1) Indicator Method of Measurement | APOL1 genotype |
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| Frequency of Measurement (Primary) | Baseline and every 6 months of the study |
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| U.S. Region Covered by Primary Variable | 11 clinical centers throughout the United States (Cleveland, Ohio; Nashville, Tennessee; Dallas, Texas; Baltimore, Maryland; Washington, D.C.; Atlanta, Georgia; Los Angeles, California) |
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| Period Currently Available | 2007 |
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| Pending Data | None |
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| Additional Data Items of Interest | Adjusted variables (age, gender, European ancestry percentage, baseline GFR) |
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| Limitations of Indicator | CKD-cause not identified |
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| Analytical Considerations | As with all cohort studies, selection bias and possible confounding |
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