APOL-1 and Sickle Cell Trait in HIV

Genetic Determinants of Kidney Disease in People of African Ancestry with HIV, updates from the GEN-AFRICA cohort

By: Rachel K.Y. Hung, MBBS

Since the start of the HIV epidemic in the 1980s, CKD occurs in up to ~50% of those with HIV, disproportionately affecting people of African ancestry. Hence, early detection of CKD to prevent or delay CKD progression, especially in people of African ancestry with HIV, is a global priority. A recent publication on Apolipoprotein L1 (APOL1) and sickle cell trait (SCT) in people of African ancestry with HIV in KI Reports brings us another step closer to understanding the roles of genetics and kidney disease in this population.

APOL1 and kidney disease

People of African ancestry are found to progress quicker to ESKD (non-diabetic CKD) and four times more likely to require dialysis as compared to whites despite adjusting for age, sex and other risk factors. An increased risk of CKD in some people of African ancestry is, in part, due to genetic factors. In the last decade, the discovery of the APOL1 gene variantsheralded a new era in understanding kidney disease in people of African ancestry. APOL1 kidney-risk genotypes are defined as carrying two of the high risk alleles (G1 and/or G2), either in a homozygous state (G1/G1 or G2/G2) or a compound heterozygous state (G1/G2). APOL1 kidney-risk genotypes are strongly associated with severe CKD while conferringprotection against Trypanosoma brucei (T.b. brucei) infections (Figure 1). This parasite is responsible for the insect-borne infection commonly referred to as the African sleeping sickness. APOL1 wild type is taken up by T.b. brucei and trafficked to the trypanosomal lysosome leading to lysosomal swelling and parasite death. Over time, T.b. brucei developed a virulence factor called serum resistance-associated (SRA) protein to neutralize APOL1. The new SRA-expressing trypanosomes evolved into T.b. rhodesiense. To protect against African sleeping sickness, APOL1 then underwent evolutionary change in humans to make it resistant to SRA (G1 and G2 variants). Another T.b. brucei subspecies, T.b. gambiense, is insensitive to APOL1 variants; however, the G1 variant is associated with asymptomatic carriage of T.b. gambiense. The highest rate of APOL1 kidney-risk genotypes have been reported in Western sub-saharan Africa (where prevalence of T.b. rhodesiense is low), with lower rates in South and East Africa and almost complete absence in those from the horn of Africa.

Figure 1: Protective effect of APOL1 variants against sleeping sickness. A: APOL1 wild type (WT) is taken up by T.b. brucei and leads to parasite death. B: The subspecies T.b. rhodesiense develops the serum resistance-associated (SRA) protein to neutralize the trypanolytic activity of APOL1 WT, leading to the African sleeping sickness. C: Humans then modified APOL1 to the G1 and G2 variants (increases the risk of kidney disease) that kills T.b. rhodesiense leading to the near elimination of T.b.rhodesiense in West Africa. It is likely that the elimination of T.b. rhodesiense led to the rise of another subspecies in West Africa,T.b. gambiense of which African sleeping sickness outcomes differ, depending on carriage of the G1 or G2 allele. (adapted from Pays et al)

The main kidney pathologies associated with APOL1 kidney-risk genotypes are:

1. Focal and segmental glomerulosclerosis (FSGS)

2. Focal global glomerulosclerosis (FGGS or solidified glomerulosclerosis)

3. Collapsing glomerulopathy

   1. HIV-associated nephropathy (HIVAN)

   2. Medications : i. e. Interferon (IFN) therapy

   3. SARS-COV-2 infection (COVID-associated nephropathy - COVAN)

The APOL1 kidney-risk genotypes increase susceptibility to kidney injury and disease but the precise mechanism is not fully understood. For background, high risk APOL1 genotype is present in approximately 75% of people of African ancestry with FSGS. Fifty percent of people of African ancestry with ESKD attributed to hypertension have high risk APOL1 genotypes. Finally, the lifetime probability of developing ESKD in high-risk APOL1 genotypes is estimated at 15%. It may be helpful to think of APOL1 kidney disease on a spectrum of disease (Figure 2), with different triggers such as environmental or exogenous influences that could play a role in the development of kidney disease pathogenesis (e.g. in the case of IFN therapy or disease states with high circulating IFN or cytokine levels).

Figure 2: APOL1 kidney-risk genotypes increases the risk of multiple types of kidney disease conditions and outcomes (adapted from Friedman et al).

HIVAN is a major cause of kidney failure in untreated or under-treated HIV infection, especially in those with APOL1 kidney-risk genotypes. In fact, prior to antiretroviral therapy, up to 50% of those with high risk APOL1 genotypes developed HIVAN. The ‘Genetic Markers of Kidney Disease Progression in People of African Ancestry with HIV in the United Kingdom’ (GEN-AFRICA) cohort was established to investigate the genetic associations between kidney dysfunction in people of African ancestry with HIV currently living in the UK. HIVAN/FSGS was found to be the predominant kidney disease etiology in those of West, Central, South African and Caribbean ancestry; whereas HIVAN/FSGS was notably uncommon among those of East African ancestry (Figure 4). Approximately half of ESKD cases in people from the GEN-AFRICA cohort were attributed to APOL1 kidney-risk genotypes.

Figure 4: Distribution of APOL1 kidney-risk genotypes and proportion of biopsy proven HIVAN/FSGS in the GEN-AFRICA cohort

Visual abstract by Carlo Trinidad MD (@hellokidneyMD)

Sickle cell trait and kidney disease

Another genetic variant associated with CKD is the sickle cell gene, which can be associated with SCT or sickle cell disease (SCD) based on the percentage of abnormal β-globin gene in a patient’s hemoglobin profile. Hemoglobin (HbS) is a variant of the β-globin gene, which provides protection against malaria. Although sickle cell disease is known to cause kidney disease, patients with sickle cell trait are often considered to be asymptomatic. There are conflicting associations between SCT and CKD. African Americans with SCT were found to have increased risk of CKD and experience quicker eGFR decline. With regards to ESKD, African Americans with SCT were found to be at an increased risk of developing ESKD but there are also studies showing no association between SCT and ESKD. Conversely, studies from sub-Saharan Africa did not find an association with SCT and CKD.

In the GEN-AFRICA cohort, SCT was found to be associated with an increased risk of kidney impairment and albuminuria although this was largely restricted to those with APOL1 low-risk genotypes. This data provides further support to the significance of SCT status to kidney disease outcomes and extends observations in African Americans to people of African ancestry with HIV living in the UK.

Visual abstract by Dhwani Patel MD (@iheartkidneys)

Summary and recommendations for the future

APOL1 kidney-risk genotypes are strong predictors of CKD in people of African ancestry with HIV while SCT is an additional risk factor. APOL1 kidney-risk genotypes are also particularly prevalent in those of West African and Caribbean ancestry. Generally, early HIV diagnosis and initiation of antiretroviral therapy is important to reduce the risk of CKD. This paper discusses some pertinent points of genetic testing in clinical settings, and there may be a role yet for APOL1 and SCT genotyping to improve risk stratification of kidney disease in people of African ancestry with HIV. Further studies are required to confirm these findings, including ethical considerations and cost effectiveness of genetic testing in this population.