APOL1-Mediated Kidney Disease

Figure 1. Frequencies of APOL1-mediated risk variants. Figure created with Biorender.com.

​

The two genetic risk alleles of APOL1 are strongly associated with an increased risk of kidney diseases such as focal segmental glomerulosclerosis (FSGS; up to 20-fold increased risk), HIV-associated nephropathy (HIVAN, up to 90-fold increased risk), hypertension-attributed kidney disease (up to 10-fold increased risk), and End-stage kidney disease (ESKD) (up to 40-fold increased risk). Approximately 40% of African Americans who develop kidney disease are estimated to carry two APOL1 risk variants.

Historically, many patients with APOL1-mediated kidney disease were diagnosed as having "FSGS.” However, more recently, we understand that FSGS is not a diagnosis but merely a histological pattern of kidney injury characterized by scarring and damage to the glomeruli (hence the term focal segmental glomerulosclerosis). FSGS can be due to numerous etiologies, including autoimmune, genetics, drug exposures, environmental, or infections. Therefore, it is critical to recognize APOL1-mediated kidney disease as the cause of the patient's presentation, for which genetic testing and clinical trials are available. 

The prognosis for patients with APOL1-mediated kidney disease is generally poor, with the APOL1 risk variants associated with faster progression to ESKD. The histological pattern of kidney injury is characterized by scarring and damage to the glomeruli. Clinically, it presents as proteinuria, which can be mild or severe and may or may not be associated with nephrotic syndrome and progressive loss of kidney function. 

Although the exact pathogenic mechanisms are unclear, several hypotheses have been proposed. One theory posits that APOL1 risk variants disrupt intracellular processes within podocytes and endothelial cells, leading to a loss of regular kidney function. An influx of calcium ions, autophagic dysfunction, and endoplasmic reticulum stress have all been implicated in this process. It is also important to note that second hits, such as viral infections or systemic inflammation, often trigger the manifestation of kidney disease in patients with high-risk APOL1 genotypes. 

Diagnosis of APOL1-mediated kidney disease largely depends on genetic testing to identify the high-risk alleles, coupled with clinical and histopathologic evaluation. Kidney biopsy may reveal an FSGS pattern of injury.

A recent open-label Phase 2 study investigated the efficacy of inaxaplin in treating proteinuric nephropathy in individuals with two high-risk APOL1 gene variants (G1 or G2). Participants with both APOL1 variants, biopsy-proven focal segmental glomerulosclerosis, and proteinuria received inaxaplin for 13 weeks, along with standard care, to assess changes in urinary protein-to-creatinine ratio and the safety of the treatment.

The results from this study showed a significant reduction in proteinuria among 13 adherent participants, with a mean change in the urinary protein-to-creatinine ratio of −47.6% at week 13. This reduction was also observed in almost all participants, regardless of adherence to therapy. The adverse events recorded were mild or moderate in severity, and none caused discontinuation of the study. The conclusion was that targeted inhibition of APOL1 channel function with inaxaplin significantly reduced proteinuria in participants with the specified genetic traits and condition, indicating a promising direction for developing targeted therapeutic interventions.

Building on this success, inaxaplin is further being studied in a Phase 2/​3 Adaptive study in adults and adolescents with APOL1-mediated kidney disease (AMPLITUDE Study).

​

Other ongoing early-stage clinical trials are underway, such as a Phase 2 study evaluating the efficacy and safety of baricitinib in reducing albuminuria in African American/Black patients with APOL1- associated focal segmental glomerulosclerosis (FSGS) and non-diabetic APOL1-associated chronic kidney disease due to hypertension (HTN-CKD) (JUSTICE Study).

The APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) studies the impact of APOL1 genetic variants on kidney transplant outcomes.