Black British people with HIV and APOL1 gene variants are more likely to develop kidney failure

Over 50% of Black people with end-stage kidney disease had high-risk variants of a gene called APOL1 in a recent UK study. These genes are most commonly found in people of West African and Caribbean descent, which may partly explain why people of Black ethnicity are three times more likely to develop end-stage kidney disease than White people. While these high-risk genes do not definitely mean that people who have them will develop end-stage kidney disease, it suggests that carriers of these genes need careful monitoring of their kidney function and good control of their HIV to reduce their risks of kidney damage.

All people have two APOL1 genes (one from each parent): for example G0 and G1, or G0 and G0. The G1 and G2 gene variants confer some protection from Trypanosoma brucei parasites, which may be why these genes are commonly found in parts of Africa, where these parasites can cause sleeping sickness. However, it appears that these genes increase the risk of end-stage kidney disease, HIV associated nephropathy (HIVAN) and the protein albumin in the urine, which suggests the kidneys are not filtering properly.

End-stage kidney disease is significant because at this point the kidneys are unable to function, so dialysis or a transplant is required to survive. Other risk factors for end-stage kidney disease include diabetes and hypertension, which are very common in Black communities, as well as immunosuppression and low CD4 counts. As we cannot yet change a person’s genetics, it is even more important to control the modifiable risk factors like hypertension, diabetes and uncontrolled HIV to prevent end-stage kidney disease.

Dr Rachel Hung and colleagues at the GEN-AFRICA study group wanted to determine the risks of kidney dysfunction in people living with HIV and APOL1 gene variations. The study was conducted in the UK, where treatment is freely available, to see how the high-risk APOL1 genes may affect the kidneys in people living with mostly well-controlled HIV.

Participants were recruited from HIV clinics and dialysis centres. A blood creatinine sample was used to estimate the glomerular filtration rate (eGFR) using the CKD Epidemiology Collaboration Equation, to which the correction factor for Black ethnicity was applied. Using this equation an eGFR <15 signifies end-stage kidney disease, an eGFR <60 indicates some renal impairment and an eGFR >90 is completely normal.

Between May 2018 and February 2020, 2864 people of Black ethnicity living with HIV in the UK were enrolled and provided a DNA sample. People’s regions of descent were based on their parents’ countries of birth and were predominantly East African (19%), South African (27%) and West African (30%), with a further 12% of Caribbean ancestry. Any participant with at least one G0 APOL1 gene was classified as low risk while those with G1/G1, G2/G2 or G1/G2 genes were classified as high risk.

“While these high-risk genes do not definitely mean that people who have them will develop end-stage kidney disease, careful monitoring is needed.”

Overall 49% had G0/G0 genes, 39% had G0/G1 or G0/G2 genes, and 12% had high-risk genes. The G1 and G2 APOL1 variants were found most frequently in people of West African or Caribbean descent (around 60%), compared to 40% of those of South and Central African descent and 20% of those of East African descent – excluding Eritrea and Ethiopia where these genes were not found at all.

In this study, 3.5% participants already had end-stage kidney disease. Of these 55% had high-risk APOL1 genes and 66% had West African and Caribbean ancestry. In comparison, only 9% of those with completely normal kidney function had high-risk APOL1 gene variants. Those with end-stage kidney disease also had lower nadir CD4 counts, were more likely to be male and to have had an AIDS-defining illness. Hypertension was present in 95% of the participants with end-stage kidney disease. Interestingly, when the APOL1 high-risk genes were accounted for, West African ancestry itself did not increase the risk of end-stage kidney disease.

High-risk APOL1 genes were found in 78% of those with HIVAN. Similarly, in 57% of participants with focal segmental glomerulosclerosis (FSGS), a disease where scar tissue is found in the kidney and often leads to kidney failure, the high-risk APOL1 genes were found.

It is however important to note that of those with these high-risk genes, 70% had reasonable kidney function with eGFR >60, so these genes do not guarantee the development of end-stage kidney disease. Furthermore, those who had one of the gene variants G1 or G2 plus the gene G0 were not at higher risk than those with two G0 genes.

The researchers concluded that this study “shows that APOL1 high-risk genotypes were strong predictors of end-stage kidney disease in people of African ancestry with HIV, even within a healthcare setting with universal access to antiretroviral therapy and in a population with mostly well-controlled HIV.” The importance of early diagnosis and treatment of people living with HIV in these populations cannot be underestimated, to try to reduce the risk of end-stage kidney disease as much as possible.