APOL1-mediated kidney disease is a genetic kidney illness that disproportionately impacts individuals of West and Central African descent. It arises from specific changes within the APOL1 gene, which can lead to a decline in kidney health, sometimes progressing rapidly.
The Genetic Basis of APOL1 Risk
The apolipoprotein L1 (APOL1) gene normally produces a protein involved in the immune system, offering protection against certain infections. This protein, for instance, helps defend against Trypanosoma brucei, the parasite responsible for African sleeping sickness. The typical version of this gene is known as G0.
Around 10,000 years ago, two specific variants of the APOL1 gene, called G1 and G2, emerged in West and Central Africa. These variants provided enhanced protection against newly evolved strains of Trypanosoma brucei that were resistant to the original G0 protein. Having even one copy of the G1 or G2 variant offered a significant survival advantage against African sleeping sickness, leading to their increased prevalence in these populations.
While a single copy of G1 or G2 protects against the parasite, inheriting two copies—one from each parent—significantly increases the risk of developing kidney disease. This “high-risk genotype” can be G1/G1, G2/G2, or G1/G2. Approximately 13% of African Americans carry two APOL1 risk alleles, making this genetic background a considerable factor in kidney disease disparity.
The precise mechanisms by which these variants cause kidney damage are still under investigation, but it is believed they lead to increased cellular stress and damage to specialized kidney cells called podocytes. This damage can result in scarring and impaired kidney function.
Disease Manifestation and Symptoms
Individuals with the high-risk APOL1 genotype can develop various forms of kidney disease. Common types include focal segmental glomerulosclerosis (FSGS), a condition where filtering units in the kidneys called glomeruli become scarred. Hypertension-attributed kidney disease, which often progresses faster in those with APOL1 risk variants, is also frequently observed.
Symptoms may not appear until kidney damage is advanced. When they do, common signs include swelling in the legs, ankles, or around the eyes (edema) due to fluid buildup. Foamy urine, indicating significant protein loss (proteinuria), is another common sign.
Other symptoms include fatigue, nausea, or loss of appetite. High blood pressure is also frequently associated with APOL1-mediated kidney disease, sometimes being the primary sign leading to diagnosis.
Diagnostic Process
Diagnosing kidney disease typically begins with standard blood and urine tests that assess overall kidney function. Blood tests measure creatinine levels to estimate the glomerular filtration rate (eGFR), which indicates how well the kidneys are filtering waste from the blood. Urine tests, such as the urine albumin-to-creatinine ratio (uACR), detect elevated protein levels in the urine, a clear sign of kidney damage.
These initial tests can confirm the presence of kidney damage but do not identify the underlying cause. To determine if the kidney disease is APOL1-mediated, genetic testing is the definitive step. This involves analyzing a blood or saliva sample to specifically identify the presence of two APOL1 G1 or G2 risk variants.
A kidney biopsy may also be performed, where a small tissue sample is taken from the kidney for microscopic examination. This procedure can provide detailed information about the specific type and extent of kidney damage, aiding in a comprehensive diagnosis and ruling out other causes.
Management and Current Research
Currently, there are no specific treatments that directly target the effects of the APOL1 gene variants to prevent or reverse kidney damage. Therefore, management focuses on supportive care aimed at slowing the progression of the disease. This often involves strict control of blood pressure, typically achieved with medications like ACE inhibitors or angiotensin receptor blockers (ARBs).
Managing proteinuria, the leakage of protein into the urine, is also a primary goal, as it indicates kidney injury and contributes to disease progression. Lifestyle modifications, such as adopting a low-sodium diet, can further support kidney health and help manage blood pressure. Regular monitoring of kidney function through blood and urine tests is also a standard part of care.
Despite the absence of specific treatments, APOL1-mediated kidney disease is an active area of research. Its known genetic cause makes it a target for developing new therapies. Scientists are exploring investigational drugs, such as inaxaplin (VX-147), which aim to inhibit the harmful function of the APOL1 protein variants. Clinical trials are underway to evaluate the safety and effectiveness of these targeted therapies.