There has been an explosion of data demonstrating an increased risk for non–diabetic kidney disease among relatives of patients with end-stage renal disease (ESRD); please refer to eAJKD interview with Dr. Barry Freedman [1-4]. The increased risk in African Americans has been centered on mutations within the APOL1 gene (G1 and G2 variants), which are present in more than 30% of African American chromosomes [3-6]. This exciting discovery leads to more questions, such as should African Americans relatives of patients with ESRD be screened for APOL1 gene polymorphisms and should such patients be excluded from donation?
We recently created a poll in eAJKD so readers could share their thoughts. It turns out that the most common answer to the poll was to perform genetic testing on African American donors and exclude any donors with APOL1 gene polymorphisms (54% of responders). The second highest answer was to accept healthy African Americans donors with informed consent (29% of responders). This was followed by excluding all African Americans with a first degree relative with ESRD, and allowing African Americans to donate only if they were above age 40 (7% of responders each). Four percent of responders were comfortable clearing any healthy African American donor.
This provocative poll raises several important points of discussion. First, as African Americans have a lower rate of living donation , is it right to exclude the limited number of donors based on such recent discoveries in the absence of validation in potential donors? In a recent study featured in AJKD and an interview with the lead author posted on eAJKD , there was no effect of family history in predicting ESRD when excluding patients with low glomerular filtration rate (GFR) and albuminuria . As potential donors are almost universally screened out for low GFR (less than 80) and proteinuria, it is unclear if the remaining individuals are at a higher risk for chronic kidney disease even if they have APOL1 at risk alleles.
Age may also play a part in the decision process to clear a donor. In can be expected that younger patients have a higher “lifetime risk” to develop chronic kidney disease. More data is needed to understand at what age kidney disease manifests in patients with APOL1 risk alleles, and if at any age they “bypass” the risk. This is supported by recent analysis of the ArMORR study which revealed the mean age of initiating dialysis in patients with two G1 APOL1 risk alleles to be 49 years, suggesting that impaired kidney function may be detectable at an earlier age .
In addition, the effect of donor nephrectomy on individuals with a normal GFR that have APOL1 risk alleles is unclear. Although it stands to reason that decreased nephron mass in such individuals would place them at a higher risk for chronic kidney disease, this association is unproven. Although limited, published studies of African American donors have shown an increase in the risk of hypertension and ESRD as compared to white donors, but not higher than the general African American population . This may suggest that potential donors predisposed to kidney disease are often excluded on a clinical basis and the remaining donors may not have an accelerated path to ESRD as compared to their counterparts who have not donated.
In conclusion, if and when APOL1 genetic testing becomes commercially available, we must question where it fits in the scheme of risk assessment for potential living donors. Future studies will need to clarify the role of genetic testing in this vulnerable population. Understanding the characteristics and mechanism of APOL1-associated kidney disease, whether resulting in inevitable kidney failure or requiring an avoidable triggering mechanism, will be of utmost importance. This will be paramount not only in attaining medical clearance, but also in education and informed consent. Until then, we must rely on existing published data to make the best decisions, not only protect potential donors, but also to improve transplantation rates in African Americans.
Dr. Vinay Nair
Assistant Professor of Medicine
Mount Sinai School of Medicine
eAJKD Advisory Board member
1. Kao, W.H., et al.: MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 2008; 40: 1185-92
2. Kopp, J.B., et al.: MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 2008; 40: 1175-84
3. Genovese, G., et al.: Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 2010; 329: 841-5
4. Bostrom, M.A., et al.: Genetic association and gene-gene interaction analyses in African American dialysis patients with nondiabetic nephropathy. Am J Kidney Dis 2012; 59: 210-21
5. Tzur, S., et al.: Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. Hum Genet 2010; 128: 345-50
6. Friedman, D.J., et al.: Population-based risk assessment of APOL1 on renal disease. J Am Soc Nephrol 2011; 22: 2098-105
7. Gore, J.L., et al.: Disparities in the utilization of live donor renal transplantation. Am J Transplant 2009; 9: 1124-33
8. McClellan, W.M., et al.: Association of Family History of ESRD, Prevalent Albuminuria, and Reduced GFR With Incident ESRD. Am J Kidney Dis 2012; 59: 25-31
9. Kanji, Z., et al.: Genetic variation in APOL1 associates with younger age at hemodialysis initiation. J Am Soc Nephrol 2011; 22: 2091-7
10. Lentine, K.L., et al.: Racial variation in medical outcomes among living kidney donors. N Engl J Med 2010; 363: 724-32