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APOL1-Mediated Kidney Disease

Apolipoprotein L1 (APOL1)-mediated kidney disease is a substantial public health issue, notably among individuals of West African origin and those of recent African descent, including African-Americans, Latin Americans, Hispanics, and people of Afro-Caribean heritage.

Emerging Therapeutics for APOL1 Mediated Kidney Disease

The APOL1 gene encodes the apolipoprotein L1 protein, a high-density lipoprotein (HDL) component that plays a crucial role in innate immunity, particularly against Trypanosoma brucei. The risk alleles (G1 and G2) arose thousands of years ago to confer protection against African sleeping sickness but predispose to kidney disease.

 

The G1 and G2 alleles are more prevalent in individuals of recent African ancestry, with the frequency of high-risk APOL1 genotypes in African Americans about 13-15%, whereas it is negligible in Europeans.

The risk alleles are referred to as G1 and G2, using the first initial of the first author (Giulio Genovese) of the study reporting on the link between APOL1 risk alleles and kidney disease in patients with African ancestry. These risk variants are thought to be a “gain of function mutation,” i.e., they have acquired the ability to damage kidney function and are not needed for healthy kidney function.

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. Several other ongoing clinical trials are examining novel treatment strategies for APOL1-mediated kidney disease. The APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) studies the impact of APOL1 genetic variants on kidney transplant outcomes. 

 

Furthermore, APOL1 inhibitors are under investigation. A phase 2 trial of the small molecule APOL1 inhibitor, ionis-APOL1Rx, demonstrated preliminary efficacy and safety in reducing proteinuria in patients with APOL1-associated FSGS. 

Another study focuses on using the anti-CD40 antibody, CFZ533 (iscalimab), to reduce proteinuria and protect the kidney in patients with high-risk APOL1 genotypes and FSGS. Preliminary results suggest a decrease in proteinuria and improved kidney function.

 Figure 2. Therapeutic targets in APOL1-mediated kidney disease. Figure created with Biorender.com. Abbreviations: APOL1, apolipoprotein L1; FSGS, focal segmental glomerulosclerosis; HIVAN, human immunodeficiency virus-associated nephropathy; HTN, hypertension; LN, lupus nephritis; siRNA, small interfering ribonucleic acid.

APOL1-mediated kidney disease poses a significant health burden among populations of recent African descent. While understanding disease mechanisms has dramatically improved, there is still a critical need for effective therapies. Current and future clinical trials offer hope for more targeted and effective treatments, potentially changing patients' prognoses. As clinicians, staying abreast of these advancements and incorporating genetic testing into clinical practice may lead to earlier detection, better management, and improved patient outcomes.

References

  1. Friedman DJ, Pollak MR. APOL1 Nephropathy: From Genetics to Clinical Applications. Clin J Am Soc Nephrol. 2021 Feb 8;16(2):294-303. doi: 10.2215/CJN.15161219. Epub 2020 Jul 2. PMID: 32616495; PMCID: PMC7863644. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863644/

  2. Freedman BI. APOL1 and kidney disease: new insights leading to novel therapies. Am J Kidney Dis. 2015 Jul;66(1):9-11. doi: 10.1053/j.ajkd.2015.05.005. PMID: 26111904. https://pubmed.ncbi.nlm.nih.gov/26111904/

  3. Nadkarni GN, Gignoux CR, Sorokin EP, Daya M, Rahman R, Barnes KC, Wassel CL, Kenny EE. Worldwide Frequencies of APOL1 Renal Risk Variants. N Engl J Med. 2018 Dec 27;379(26):2571-2572. doi: 10.1056/NEJMc1800748. PMID: 30586505; PMCID: PMC6482949. https://pubmed.ncbi.nlm.nih.gov/30586505/

  4. Kopp JB, Heymann J, Winkler CA. APOL1 Renal Risk Variants: Fertile Soil for HIV-Associated Nephropathy. Semin Nephrol. 2017 Nov;37(6):514-519. doi: 10.1016/j.semnephrol.2017.07.004. PMID: 29110758; PMCID: PMC5745063. https://pubmed.ncbi.nlm.nih.gov/29110758/

  5. Wu J, Raman A, Coffey NJ, Sheng X, Wahba J, Seasock MJ, Ma Z, Beckerman P, Laczkó D, Palmer MB, Kopp JB, Kuo JJ, Pullen SS, Boustany-Kari CM, Linkermann A, Susztak K. The key role of NLRP3 and STING in APOL1-associated podocytopathy. J Clin Invest. 2021 Oct 15;131(20):e136329. doi: 10.1172/JCI136329. PMID: 34651582; PMCID: PMC8516463. https://pubmed.ncbi.nlm.nih.gov/34651582/

  6. Freedman BI, Spainhour M, Hicks PJ, Turner J, Robertson J, Langefeld CD, Murea M, Divers J. Nephropathy Progression in African Americans With a Family History of ESKD: Implications for Clinical Trials in APOL1-Associated Nephropathy. Am J Kidney Dis. 2019 Aug;74(2):284-286. doi: 10.1053/j.ajkd.2019.03.414. Epub 2019 May 7. PMID: 31076172; PMCID: PMC9121021. https://pubmed.ncbi.nlm.nih.gov/31076172/

  7. Egbuna O, Zimmerman B, Manos G, Fortier A, Chirieac MC, Dakin LA, Friedman DJ, Bramham K, Campbell K, Knebelmann B, Barisoni L, Falk RJ, Gipson DS, Lipkowitz MS, Ojo A, Bunnage ME, Pollak MR, Altshuler D, Chertow GM; VX19-147-101 Study Group. Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants. N Engl J Med. 2023 Mar 16;388(11):969-979. doi: 10.1056/NEJMoa2202396. PMID: 36920755. https://pubmed.ncbi.nlm.nih.gov/36920755/

  8. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010 Aug 13;329(5993):841-5. doi: 10.1126/science.1193032. Epub 2010 Jul 15. PMID: 20647424; PMCID: PMC2980843. https://pubmed.ncbi.nlm.nih.gov/20647424/

Acknowledgement

This content is part of the "Emerging Therapeutics" program, which is an educational program supported through educational grants from corporate sponsors and aims to provide scientific and clinical information about therapeutics recently approved or on the horizon (under clinical investigation). GlomCon has developed all content with complete editorial independence from sponsors.

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