Utility of Apolipoprotein-1 Gene Polymorphism Screening in Donor Evaluation for Kidney Transplantation in India

Abstract

Kidney transplantation is the treatment of choice for end-stage kidney disease patients. The living donor for kidney transplantation remains at risk of developing kidney diseases. The risk may increase when an individual has a genetic predisposition to developing kidney disease. On the other hand, inter-individual genetic diversity remains a barrier to unrestricted organ donation and transplantation. The evolution of human genome sequencing in health and diseases increases the scope of finding individuals at risk for specific kidney diseases. The question of screening the donor for genetic predisposition to kidney diseases is unanswered. The ambiguity in the association of genetic polymorphisms with the diseases and the cost of screening every individual will be a significant limitation in the current scenario.[1] In a narrative review of the current issue, Fernando et al. have advocated for testing apolipoprotein-1 (APOL-1) gene mutation in prospective kidney donors before transplantation. APOL-1 is a 14.5 kb gene located on the long arm of chromosome 22.[2] APOL-1 proteins are 398 amino acid-long peptide chains encoded by the APOL-1 gene. APOL-1 is synthesized primarily by the liver, lung, brain, and kidney, especially by podocyte and proximal convoluted tubule cells.[3] APOL-1 protein is made of 5 functional domains, namely the S-domain required for its secretion; the membrane addressing domain that senses pH and regulates cell death; the BH3 domain associated with apoptosis; the pore-forming domain; and serum resistance-associated binding domains, conferring resistance to Trypanosoma brucei, a causative organism for sleeping sickness.[2] APOL-1 plays a role in immunity and is especially protective against Trypanosoma parasites. APOL-1 reportedly regulates the immune response against infections, cell apoptosis, autophagy, ion exchange, and extracellular cholesterol transport to the liver.[3,4] Higher interferon-ɣ and tumor necrosis factor-α also induce APOL-1 secretion. A genetic mutation in the APOL-1 gene leads to cardiovascular and HIV-associated nephropathy.[5,6] The APOL-1 risk variants are G1 and G2, and G0 as wild type. Two coding variants, G1 and G2, are relevant to human phenotypes. Single-nucleotide polymorphism in G1 (having two amino acid substitutions (serine 342 glycine and isoleucine 384 methionine), and G2 (a two-amino acid deletion, del 388 asparagine, 389 tyrosine) alleles of the APOL-1 C-terminal, inhibits the binding of the Trypanosoma brucei virulence factors to the serum resistance-associated protein, resulting in lysis of parasites.[7,8] APOL-1 gene evolved in Africa over the past 10,000 years, and people moving out of these regions have taken these genetic variants with them. APOL-1 risk variant occurred in people of African ancestry, Black African, African-American, Afro-Caribbean, etc., Many African-Americans are descendants of people from West African nations and have a high prevalence of APOL1 risk alleles and APOL-1-associated kidney diseases, with risk allele frequency as high as 30%.[7] The mutant alleles are strongly associated with kidney diseases, such as focal segmental glomerulosclerosis (FSGS) in 66%, HIV-associated nephropathy in 67%, and hypertension-associated end-stage kidney diseases in 47% of patients of African-American ancestry.[6,7] The risk factor for developing FSGS in a single APOL-1 mutant allele was 0.3% and 4.25% in the presence of two APOL-1 mutant alleles. The risk of acquiring HIV-associated nephropathy in the presence of two APOL-1 mutant alleles was 50%.[6] The prevalence of the G1 risk alleles in African-Americans with FSGS is 52% compared to 18%–23% without FSGS. The prevalence of the G2 risk allele in African-Americans with FSGS is 23% and 15% in those without FSGS.[6,7] An incomplete kidney disease penetrance of the gene is not fully understood, and some environmental factors may trigger illnesses such as HIV-associated nephropathy and coronavirus disease 2019 in such a scenario. Furthermore, the kidneys from donors with 2 APOL-1 variants experienced rapid graft failure compared to wild-type or single-variant donors.[9] Fernando et al. also advocate that APOL-1 high-risk donor kidneys fail more frequently than nonrisk donor kidneys; nevertheless, the recipient’s APOL-1 genotype has not yet been proven to alter graft survival. These findings support the hypothesis that kidney APOL-1, rather than circulating APOL1 primarily produced by living organisms, is the critical component causing APOL-1 kidney disease. The major question arises whether these findings of strong association with APOL-1 with kidney diseases in African-Americans can be implied in the Indian scenario when the study findings show no APOL-1 gene mutations in the chronic kidney disease (CKD) population of India. The Indian CKD cohort study of 159 patients for APOL-1 mutation did not find any polymorphisms, and the authors concluded that there is no associated risk of developing CKD with APOL-1 in the region.[10] Furthermore, in another study from Southern India, authors found no APOL-1 mutations in 70 patients of CKD.[11] A study from the western part of India, on APOL-1 null patient and 50 related villagers by genotyping and immunoblotting, confirmed that this APOL-1 null individual does not have glomerulosclerosis, nor do his relatives who carry APOL-1 null alleles.[12] Although these studies had a small sample size, uniform results indicate the nonexistence of APOL-1 mutation in Indians. Therefore, with current evidence, donor screening for APOL-1 mutant alleles in every prospective donor cannot be recommended. A large population-based study to evaluate this important gene polymorphism is required.