APOL1 kidney disease is a genetic condition that disproportionately impacts certain populations. It represents a collection of kidney conditions linked to specific genetic variations. Understanding this disease is important for addressing health disparities and improving outcomes.
The APOL1 Gene and Its Variants
The APOL1 gene, located on chromosome 22, produces a protein vital for the immune system. This protein, a component of high-density lipoprotein, protects humans from trypanosomal parasites like Trypanosoma brucei brucei, which causes African sleeping sickness.
However, specific high-risk variants of the APOL1 gene, G1 and G2, increase the risk of kidney disease. The G1 variant involves two protein sequence changes, while G2 is a deletion of two amino acids. These variants are found almost exclusively in individuals of recent African ancestry.
These variants are highly prevalent in Western and Central African populations, with frequencies up to 49% for G1 and 17% for G2 in regions like Nigeria. In the U.S., about 13% of African Americans carry two copies of these APOL1 risk alleles, reflecting their West African ancestry. These variants are believed to have arisen through natural selection over the past 3,000 to 10,000 years, as they provided protection against more virulent forms of Trypanosoma brucei. While carrying one copy of a risk variant offers protection against these parasites, inheriting two copies significantly increases the risk of kidney disease.
How APOL1 Variants Lead to Kidney Damage
APOL1 risk variants cause kidney injury through a “gain-of-function” mechanism, making the altered protein toxic to kidney cells. These variants damage podocytes, specialized cells in the kidney’s filtering units (glomeruli). Podocytes are essential for preventing protein leakage into the urine.
The altered APOL1 variants form active ion channels within kidney cell membranes, particularly in podocytes. This disrupts the cell’s internal balance, leading to swelling and cell death. These variants can localize to various cellular membrane environments, where they may form toxic oligomers.
APOL1 risk variants also increase endoplasmic reticulum (ER) stress in podocytes. The ER, involved in protein folding, can cause cell injury when stressed. This ER stress damages podocytes and inhibits the translation of important proteins for their function. These disruptions can lead to conditions like focal segmental glomerulosclerosis (FSGS), a kidney disease with scarring of kidney filters, or other forms of kidney failure. APOL1 variants uniquely target the kidney, despite gene expression in other tissues.
Recognizing and Diagnosing APOL1 Kidney Disease
Recognizing APOL1 kidney disease is challenging due to similar symptoms as other kidney conditions. Many individuals show no noticeable symptoms until advanced stages. Common symptoms include swelling in the legs, ankles, or around the eyes (edema), weight gain from fluid retention, and foamy urine, indicating excess protein.
Other signs include difficult-to-control high blood pressure, fatigue, loss of appetite, and changes in urine output. A detailed medical history, including family history, and a physical examination are initial steps. Since APOL1 kidney disease often progresses rapidly, early identification is beneficial.
Diagnosis often begins with general kidney function tests, such as blood tests for estimated glomerular filtration rate (eGFR) and urine tests for protein (uACR). An eGFR below 60 mL/min/1.73m² or a uACR over 30 mg/g for three months or more can indicate kidney disease. A definitive diagnosis requires genetic testing for two APOL1 risk variants (G1, G2), typically using a blood or saliva sample. A kidney biopsy may also confirm the type and extent of damage, often revealing focal segmental glomerulosclerosis (FSGS).
Treatment and Management Strategies
Current treatments for APOL1 kidney disease focus on managing symptoms and slowing progression, as no approved therapies target the underlying genetic cause. Approaches include controlling blood pressure to reduce kidney strain. Reducing proteinuria (excess protein in urine) is another goal, often achieved with medications that relax blood vessels and decrease pressure within kidney filters.
Despite these efforts, APOL1-mediated kidney disease often progresses more rapidly to kidney failure than other forms. If kidney function deteriorates to end-stage, renal replacement therapies become necessary. These include dialysis (filtering blood with a machine) or kidney transplantation. Both require ongoing medical management, carry risks, and need lifelong follow-up.
Ongoing research explores targeted therapies for APOL1-mediated kidney disease. One promising area involves small molecule inhibitors designed to block the toxic APOL1 protein. For instance, inaxaplin (VX-147) has shown promising early-phase clinical trial results, significantly reducing proteinuria in patients with APOL1-associated FSGS. Other research explores therapies to reduce APOL1 synthesis or address cellular stress pathways like ER stress or inflammation, implicated in kidney injury. These advancements aim for more precise and effective interventions.