The APOL1–HIV Interaction Extends to Monoallelic Carriers with Increased Odds of Advanced CKD in a South African Cohort

Background: Apolipoprotein L1 (APOL1) G1 and G2 kidney risk variants (APOL1 KRV) are strongly associated with chronic kidney disease (CKD) in populations of African ancestry, yet evidence from sub-Saharan Africa remains limited, particularly regarding infectious modifiers of APOL1-associated risk. We investigated APOL1 KRV prevalence and whether HIV modifies risk associated with monoallelic and biallelic carriage in a South African CKD cohort. 

Methods: We conducted a cross-sectional study of 493 adults with CKD in Gqeberha, South Africa. APOL1 G1, G2, and p.N264K modifier 1 (M1) variants were identified using Sanger sequencing. Multivariable logistic regression evaluated associations with advanced CKD, including an HIV × APOL1 interaction term. 

Findings: At least one APOL1 risk allele was present in 32.5% of participants while 7.1% carried two risk alleles. HIV was present in 16.6% and prior tuberculosis (TB) in 22.1%. Neither APOL1 carriage nor HIV infection alone was associated with advanced CKD. However, participants with both HIV and ≥1 APOL1 risk allele had substantially higher odds of advanced CKD (adjusted odds ratio 4.7, 95% CI 1.07-20.64). This association persisted in analyses restricted to monoallelic carriers and in ancestry-restricted sensitivity analyses.

Interpretation: APOL1 KRV are common in this South African CKD cohort and interact with HIV infection to substantially increase the risk of advanced CKD, even among monoallelic carriers. These findings support an exposure-dependent model of APOL1 kidney disease and highlight the importance of integrating genetic and infectious risk factors in African CKD populations.