Blog entry by Meguid El Nahas
It is 30 years since we put forward the hypothesis that lipids were nephrotoxic and that dyslipidemia contributed to progressive CKD.
30 years on, a new era of APOL1-associated CKD suggest that a link may indeed exist between genetic mutations affecting HDL cholesterol concentrations and the pathogenesis of nephropathies as variants of ApoL1 proteins associate with circulating HDL.
The association between apoliporotein L1 (APOL1) gene mutations and CKD is becoming increasingly evident with APOL1 variants considered initiating factors for most hypertension-attributed nephropathies in African Americans (AA) as well as a spectrum of renal disease in hispanic as well as European Americans. Variations in APOL1 appears to be strongly associated with kidney disease historically labelled as hypertensive arterioslosclerosis in AA.
It is intriguing to realise that APLO1, a disease associated gene, has persisted in AA. However, it is of interest to realise that one copy of the APOL1 G1 or G2 nephropathy risk variant confers protection from the deadly African Sleeping Sickness while not necessarily being associated with a nephropathy as for the latter to develop a second hit is often necessary. HIV infection is one of many such second hits initating APOL1-associated nephropathy in susceptible individuals with one or two gene variants.
Of interest, individuals with two APLO1 gene variants develop ESRD at a younger age than those with zero or one gene variants. A single gene variant, G1 but not G2, also leads to an earlier onset of ESRD albeit later than those with G1 and G2 variants. This may be due to the fact that tghose with 2 APLO1 gene variants progress to ESRD at a faster rate.
It is likely that the MYH9-APOL1 gene region on chromosome 22q contains additional risk loci that may be difficult to detect due to the high degrees of linkage desiquilibrium.
Clearly, a new era of understanding non diabetic glomerulosclerosis with APLO1-MYH9 genetic mutations providing suceptibility and second hits/modifiers genes leading to initiation and progression of CKD.
Perhaps, after all, we were right when in 1982, we suggested that lipo- and apo- lipoprotein abnormalities may underly the initiation and progression of CKD.
Moorhead JF, , , M.
Lipid nephrotoxicity in chronic progressive glomerular and tubulo-interstitial disease.
Lancet. 1982 Dec 11;2(8311):1309-11.
Kanji et al. genetic variations of APOOL1 associated with younger age at hemodialysis initation. JASN 2011; 22:2091-97.
Tzur et al. APOL1 allelic variants are associated with lower age at dialysis initiation...
NDT 2012; 27:1498-1505.