The new era of APOL1 -associated glomerulosclerosis

The association between apolipoprotein L1 gene (APOL1)variants and non-diabetic chronic kidney disease (CKD)has dramatically altered the landscape in nephrology [1,2]. The pathogenesis of glomerulosclerosis is now betterunderstood, providing the possibility of novel treatmentsand hope for millions with, and at risk of, CKD worldwide[3, 4]. The article by Tzur et al. [5] in the current issue ofNephrology Dialysis Transplantation provides importantnew information in this fast moving ﬁeld. To put this paperin perspective, it is appropriate to review how APOL1has revolutionized our understanding of non-diabeticglomerulosclerosis.Relative to European Americans (EAs), nephrologistshave observed ‘different renal responses’ to systemic hyper-tension and Type 2 diabetes mellitus in African Americans(AAs) [6]. This vague phenomenon was widely applied toexplain the higher incidence rates of common forms ofend-stage renal disease (ESRD) in AAs compared to EAs.The hypothesis that mild–moderate essential hypertensionwas the proximate cause of ‘hypertensive kidney disease’or arteriolar nephrosclerosis in non-diabetic AAs with low-level proteinuria was deeply ingrained in the literature,despite strong evidence to the contrary [3, 7, 8]. Higher ratesof non-diabetic nephropathy in AAs, relative to EAs, werealso ascribed to differences in socioeconomic status andenvironment between population groups.Three important developments led to identiﬁcation ofAPOL1 and variants in the adjacent non-muscle myosinheavy chain 9 gene (MYH9), as initiating factors for mostcases of ‘hypertension-attributed’ nephropathy in those withAfrican ancestry, as well as a spectrum of related kidneydiseases in AAs, Hispanic Americans (HAs), Europeansand EAs. The ﬁrst development was recognition of markedfamilial aggregation of kidney disease. In AA families, clus-tering of disparate forms of ESRD was often present. Thisobservation suggested the presence of an overarching kidneyfailure susceptibility gene inherited independently from sys-temic disorders, such as hypertension, HIV infection, diabe-tes and systemic lupus erythematosus [9–13]. The seconddevelopment was a series of molecular genetic advances,particularly admixture mapping (also called mapping by ad-mixture linkage disequilibrium; MALD) [14]. MALD is apowerful genome-wide method useful to detect associatedgenes in admixed populations, where ancestral populationshave markedly different disease frequencies. AAs are anadmixed population with ~80% African and 20% Europeanancestry, while kidney disease is far more common inAfricans than Europeans. MALD detected linkage betweengenetic markers on Chromosome 22q containing the MYH9and APOL1 genes with focal segmental glomerulosclerosis(FSGS) and HIV-associated collapsing glomerulopathy inAAs [15, 16]. The third development was broad geneticscreening for MYH9 and APOL1 polymorphisms, whosevariants were strongly associated with the clearly deﬁnedFSGS phenotype, in large numbers of AAs and HAs withcommon complex forms of ESRD [1, 2, 17]. These sequen-tial developments led to the realization that FSGS,HIV-associated nephropathy, arteriolar nephrosclerosis andhypertension-attributed ESRD were members of a single dis-ease spectrum [18]. This spectrum has expanded to includesickle cell nephropathy [19] and C1q-associated collapsingglomerulopathy [20].It is now apparent that many patients with African an-cestry and ESRD attributed to diabetes or lupus had beenmisdiagnosed, they actually have APOL1-associated FSGS(with coexisting diabetes or lupus) [21, 22]. APOL1 geno-typing has been used to ‘genetically dissect’ cases withdiabetes and ESRD, enriching for those with diabeticnephropathy by removing those with two APOL1 risk var-iants likely with FSGS. This allowed for detection of dia-betic nephropathy genes [23, 24]. Variation in APOL1 isstrongly associated with the kidney disease that has histor-ically been labeled ‘hypertensive’ or arteriolar nephroscle-rosis, as in the African American Study of Kidney Diseaseand Hypertension (AASK) [25]. The strongest APOL1 as-sociation was present in AASK participants with higherbaseline proteinuria and progressive nephropathy [26].Aggressive hypertension control and universal use ofangiotensin-converting enzyme inhibitors failed to reliablyhalt nephropathy progression in AASK, strongly supportingnephropathy initiation from mechanisms other than hyper-tension. It appears that AASK patients predominantly hadfocal global glomerulosclerosis (FGGS) with interstitial and