APOL1-Mediated Kidney Disease

Ancestry and Chronic Kidney Disease

Racial disparities in the incidence rates of chronic kidney disease (CKD) are widely appreciated. Compared to Americans of European descent, Americans of African descent face approximately a 4-fold higher risk for developing end-stage kidney disease (ESKD) with an estimated lifetime risk for ESKD approaching 8% (versus 2%–3% in European Americans). Although lower socioeconomic status and poorer access to healthcare contribute to this disparity, epidemiologic studies demonstrating familial aggregation of disparate causes of ESKD in families of African descent suggested an inherited basis.

Genetic association between two coding “kidney-risk variants” (KRVs) in the apolipoprotein L1 gene ( APOL1 ) on chromosome 22q12 with nondiabetic ESKD ultimately proved this concept. The ancestral allele, designated G0, does not increase the risk of nephropathy. The derived KRVs include G1 (encoding S342G and I384M substitutions) and G2 (encoding N388 and Y389 amino acid deletions). The two variants constituting G1 are in near perfect linkage disequilibrium; however, G342 is causative because it confers the same risk as possessing both variants. It is rare for the G1 and G2 KRVs to occur on a single chromosome. Allele frequencies of APOL1 KRVs are extremely high; approximately 38% of Americans of African descent possess one KRV and 13% have two KRVs comprising APOL1 high-risk genotypes with increased risk for CKD (e.g., G1G1, G2G2, or G1G2). Based on these frequencies, it is estimated that more than 70 million people worldwide, including approximately 6 million Americans of African descent, have APOL1 high-risk genotypes.

APOL1 KRVs are among the most powerful common variants causing complex disease. G1 and G2 arose in sub-Saharan Africa less than 10,000 years ago, and a selective sweep likely led to today’s high frequencies. Their current frequencies stem from an evolutionary advantage that confers protection from Trypanosoma brucei rhodesiense , a parasite causing African sleeping sickness. Enhanced survival was seen in those with one or two KRVs, at the expense of increased risk for CKD later in life among those with two KRVs.

Clinical Implications of APOL1

In Americans of African descent, APOL1 underlies approximately 70% of cases of idiopathic focal segmental glomerulosclerosis (FSGS) and HIV-associated nephropathy (HIVAN); the population-attributable risk approximates 70%. In essence, the risk for nondiabetic ESKD in Americans of African vs European descent would approach unity if G1 and G2 KRVs did not occur.

The most common reported cause of nondiabetic ESKD in Americans of African descent is “hypertension-attributed” nephropathy. This term is applied to nondiabetic patients with CKD, low-level (or absent) proteinuria, and hypertension. However, discovery of APOL1 made it clear that many such patients had secondary hypertension related to CKD and not hypertensive nephropathy. In most cases, APOL1 -associated solidified glomerulosclerosis is present. Significant proteinuria does not develop due to the lack of patent capillaries (reduced perfusion) in solidified glomerular tufts. Compared to arteriolar nephrosclerosis, solidified glomeruli lack collagen deposition in the urinary space, ischemic collapse of capillaries, or thickening of Bowman’s capsule. APOL1 -associated nephropathy reveals that the primary glomerular disease “solidified glomerulosclerosis” typically presents without heavy proteinuria and forces us to reconsider the interpretation of likely sites of kidney injury based on the urinalysis.

Results from the National Institutes of Health (NIH)-sponsored “African American Study of Kidney Disease and Hypertension” (AASK) trial revealed that aggressively lowering blood pressure with high-dose angiotensin-converting enzyme (ACE) inhibitors in nondiabetic Americans of African descent felt to have essential hypertension as the cause of kidney disease does not slow progression of nephropathy. AASK recruitment criteria include hypertensive and nondiabetic Americans of African descent between the ages of 18–70 years, with an estimated glomerular filtration rate (eGFR) of 20–65 mL/min/1.73 m ² , proteinuria <2.5 g/day, and no other known cause of CKD. After almost 10 years of follow-up, nearly 70% of AASK participants developed ESKD, doubling of serum creatinine concentration, or death. Antihypertensive medication class and blood pressure target failed to predict the risk of CKD progression. APOL1 genotypes were the strongest predictor of kidney outcomes, an effect independent from the blood pressure treatment arm. The AASK and “Systolic Blood Pressure Intervention Trial” (SPRINT) provide evidence that intensive blood pressure control in patients felt to have “hypertension-attributed” CKD does not delay progression of CKD. Results support that mild-moderate hypertension is an infrequent initiator of CKD.

The odds ratio for APOL1 association with “hypertension-attributed” ESKD, FSGS, HIVAN, progressive lupus nephritis, and collapsing glomerulopathy (on backgrounds of other glomerular diseases, interferon, and HIV or SARS-CoV-2 infection) approach those reported in Mendelian disorders; they range from 7 to 89. Accelerated failure of transplanted kidneys from African-ancestry donors with APOL1 high-risk genotypes also occurs. These disorders share common molecular mechanisms leading to progressive nephropathy and are considered the spectrum of APOL1- associated nephropathy.

Second Hits and Modifying Factors

Although the odds ratios in APOL1 -associated nephropathy are among the highest reported in common nonmonogenic disease, only a minority of individuals with the high-risk genotype develop kidney disease. The lifetime risk for FSGS in individuals with APOL1 high-risk genotypes is 4%, whereas the risk is 50% in untreated individuals with HIV infection and the high-risk genotypes. Overall, approximately 15%-20% of individuals with APOL1 high-risk genotypes develop nephropathy.

Autopsy and biopsy studies demonstrate that APOL1 high-risk genotypes associate with exaggerated age-related nephron loss, solidified glomerulosclerosis, thyroidization-type tubular atrophy, and “disappearing glomeruli,” often with enlargement of remaining glomeruli. Findings suggest that subclinical kidney disease may often be present, manifested as systemic hypertension prior to recognition of reduced eGFR or proteinuria. A likely paradigm explaining the variable lifetime risk for CKD is that a clinically silent pathology exists that can evolve to progressive CKD with exposure to a second hit.

Environmental factors and genetic background likely alter the risk for developing CKD. Environmental modifiers that transform APOL1 genetic risk into CKD include robust induction of APOL1 by administration of exogenous interferon, increased susceptibility to collapsing glomerulopathy in patients with HIV or SARS-CoV-2 infection, and systemic lupus erythematosus.

Second hits appear to increase the transcription of APOL1 mRNA and produce higher levels of toxic APOL1 KRV protein in kidney cells. The most powerful environmental influence on APOL1 -asssociated nephropathy is untreated HIV infection, with an odds ratio of 29 to 89 for developing HIVAN in individuals with APOL1 high-risk genotypes (odds ratio 2–5 reported in Africans with only one G1 allele). Interestingly, the frequency of HIVAN has decreased after the introduction of highly active antiretroviral treatment. Therefore, we consider antiretroviral treatment reno-protective in individuals who harbor APOL1 high-risk genotypes.

In contrast to infection with HIV and SARS-CoV-2 infection, JC polyomaviruria (signifying active kidney and/or urinary tract viral replication) associates with a paradoxically lower risk of APOL1 and non- APOL1 etiologies of CKD. This protective association may reflect reduced immune system activation, where kidneys fail to restrict replication of the nonpathogenic JC polyomavirus. Individuals who lack JC polyomaviruria likely cleared their childhood infections; thus, they may have a more robust immune system. Immune activation appears to promote development of APOL1 -associated (and other) kidney diseases. Additional protective environmental and inherited risk factors accounting for low rates of progressive kidney disease in individuals with APOL1 high-risk genotypes remain to be discovered. These factors could have therapeutic implications ( Fig. 36.1 ).

It is debated whether APOL1 initiates CKD or is a risk factor for its progression. We believe APOL1 KRV proteins promote more rapid progression of nephropathy to ESKD. We base this on the observations that a minority of individuals with APOL1 high-risk genotypes develop CKD, and it is more strongly associated with advanced CKD and ESKD than mildly reduced eGFR or low-level proteinuria. An early study in patients with lupus nephritis failed to detect APOL1 association, but most of the cases had mild CKD with preserved eGFR. However, robust association exists between APOL1 and lupus nephritis in patients with ESKD. Thus, available evidence more strongly supports APOL1 as a progression factor for CKD.