There is are associations between the high-risk variant alleles of apolipoprotein L1 (APOL1), G1, and G2 and rapid progression of hypertensive chronic kidney disease (CKD). However, according to Jamrose Durrani, MD, and colleagues, additional genetic or environmental “second hits” are required to promote the onset of kidney disease.
The researchers provided a case report of a patient with early onset treatment resistant-hypertensive CKD who was found to have homozygous APOL1 G2 variants as well as an unexpected concomitant genetic variant. The case study was reported during a virtual poster session at the NKF Spring Clinical Meetings 2021 in a poster titled Homozygous G2 APOL1 Allele and a Heterozygous Complement 5 Variant in Hypertensive Chronic Kidney Disease.
The patient was a 28-year-old African American male who was evaluated for maintenance hemodialysis due to CKD stage 5, secondary to uncontrolled hypertension. The patient’s medical history included sickle cell trait, congestive heart failure, and long-standing hypertension (diagnosed at age 19 years). The progressive clinical course was related to medication non-adherence. HIV infection and secondary causes of hypertension, such as hyperaldosteronism or pheochromocytoma, were ruled out.
Results of genetic testing with Renasight, a 382 panel of genes associated with CKD, yielded homozygous APOL1 variants c.1164_1169del (p.Asn388_Tyr389del) (G2 allele); a heterozygous C5 variant c.55C>T (p.Gln19*); and a heterozygous HBB variant c.20A>T (p.Glu7Val).
In cohorts of African American patients, there is an association between homozygous inheritance of high-risk APOL1 variants and early onset progressive CKD. For patients who are homozygous for G1 variants, the age of onset of nephropathy is earlier than for their G2 counterparts. The patient in question had early loss of renal function with G2 homozygosity and an apparently unrelated C5 variant.
The C5 c.55C>T (p.Gln19*) variant introduces a premature stop codon and is expected to result in the loss of function of the C5 protein that is part of the complement system. There is an association between inheritance of this variant and C5 deficiency. Dysregulation of the complement system is implicated in glomerular disease; however, the role of C5 variants is unclear.
In conclusion, the researchers said, “Identification of a concomitant C5 variant, through testing with a broad renal-focused genetic panel, may reveal a potential second hit mechanism in rapidly progressing CKD that is associated with high-risk APOL1 variants.”
Source: Durrani J, Kerner P, Langan L, Clark D, Tabriziani H, Yap E. Homozygous G2 APOL1 Allele and a Heterozygous Complement 5 Variant in Hypertensive Chronic Kidney Disease. Abstract of a poster presented at the National Kidney Foundation virtual Spring Clinical Meetings 2021 (Abstract #161), April 9, 2021.