ApoL related FSGS

1. APOL related FSGS
SEN

2. APOL 1 gene & its function
• APOL1 gene encodes for a protein : Apolipoprotein L1
• Gene : only found in humans, African green monkeys, and gorillas
• 14,522 base pairs long, on the human chromosome 22 q 13.1
• Close to the MYH9 gene
• APOL1 and MYH9 are independent nephropathy susceptibility loci

3. Function of Apolipoprotein L1 (APOL1)
• Minor apoprotein component of HDL 3
• Synthesized in the liver & also in many other tissues-pancreas, kidney,
brain
• APOL1 - found in vascular endothelium, liver, heart, lung, placenta,
podocytes, proximal tubules, and arterial cells
• APOL 1 - member of bcl2 genes which are involved in Apoptosis
• An overabundance of APOL1 within a cell results in autophagy
• APOL1 has a role in innate immunity :
• Protection against Trypanosoma brucei infection, transmitted by the tsetse fly
• Trypanosomes endocytose the secreted form of APOL1
• APOL1 forms pores on the lysosomal membranes of the trypanosomes which
causes in influx of chloride, swelling of the lysosome and lysis of the trypanosome

4. APOL 1 allelic variants
• Two coding sequence variants in APOL1- G1 or G2 variant
• People who have :
at least one copy of either the G1 or G2 variant are resistant to infection by trypanosomes
two copies of either variant are at an increased risk of developing a non-diabetic kidney
disease
• Risk alleles underwent positive selection as a defense mechanism for Trypanosomiasis.
• T. b. rhodesiense carries a serum resistance-associated (SRA) protein that binds and
inactivates the wild type ApoL1 protein.

5. Pathogenesis Unknown?
• HDL3 protects LDL particles from oxidation
• Whether apolipoproteinL1 has a role in this antioxidant function is unknown.
• It remains to be determined whether circulating apoL1, kidney-expressed
apoL1, or both contribute to kidney injury
• Both the G1 and G2 risk variants display increased toxicity compared to G0 in
HEK-293 cells and human podocytes in vitro
• lysosomal membrane permeabilization ?

6. Prevalence of APOL 1 risk allele
• In the Yoruba people of Nigeria (West Africa) the prevalence of G1 and G2 risk
alleles are 40% and 8% respectively
• Many African Americans are descendants of people of West African nations
• High prevalence of APOL1 risk alleles as well as APOL1 associated kidney
diseases.
• Frequency of the risk alleles in African Americans is more than 30%

7. Diseases Associated with APOL 1 Allele
• Focal Segmental Glomerulosclerosis (FSGS)—2 to 4 fold increased risk
• Hypertension Attributed-End Stage Kidney Disease—4 fold increased risk
• HIV-Associated Nephropathy(HIVAN) –18 to 50 fold increased risk
• Others:
• Sickle-cell nephropathy
• collapsing glomerulopathy in lupus nephritis
• Microalbuminuria
• Interferon related collapsing glomerulopathy
• greater decline in glomerular number and greater increase in glomerular volume over lifespan
• Early age of dialysis initiation: Two risk alleles begin dialysis approximately 10 years
earlier than ESKD patients without the risk variants
• Early allograft failure : Kidneys from donors containing two APOL1 variants
experience allograft failure more rapidly than donors with 0 or 1 variants

8. APOL1 related FSGS
• APOL1 genotypes were compared among
• 271 African-American cases of FSGS,
• 168 European-American cases of FSGS, and
• 939 control subjects.
• 17-fold higher odds (95% CI 11-26) for FSGS &
• 29-fold higher odds (95% CI 13-68) for HIVAN.
• Individuals with two APOL1 risk alleles
• an earlier age of onset
• had a lower eGFR
• a higher frequency of severe lesions (collapsing FSGS, cortical atrophy/fibrosis, arteriosclerosis)
• similar sensitivity to glucocorticoids compared with other subjects.
• remission rates to the cyclosporine and mycophenolate-based regimens were not significantly
different
• faster progression to ESRD
• HIVAN—Collapsing FSGS

9. APOL1 risk alleles
Onset Age
(years)
0 or 1 APOL1 Risk
Alleles (n = 64)
2 APOL1 Risk
Alleles (n = 118)
<15 9% 5%
15–39 42% 70%
≥ 40 48% 25%
Onset age for primary FSGS in African Americans stratified by G1 or G2 APOL1 risk alleles
APOL1 variants and kidney survival
0 or 1 APOL1 Risk
Alleles (n = 64)
2 APOL1 Risk
Alleles (n = 118)
Steroid Sensitivity
(8 w) (P>0.5)
33% 29%
Steroid sensitivity

10. Concludes APOL1-FSGS
• 12 to 13% of African Americans carry two APOL1 risk alleles
• An estimated 4% lifetime risk for FSGS
• Comparable responsiveness to treatment
• Tend to progress to ESKD rapidly