APOL1 Risk Alleles Are Associated with Exaggerated Age-Related Changes in Glomerular Number and Volume in African-American Adults

Abstract

APOL1 genetic variants contribute to kidney disease in African Americans. We assessed correlations between APOL1 profiles and renal histological features in subjects without renal disease. Glomerular number (N glom ) and mean glomerular volume (V glom ) were measured by the dissector/fractionator method in kidneys of African-American and non-African-American adults without renal disease, undergoing autopsies in Jackson, Mississippi. APOL1 risk alleles were genotyped and the kidney findings were evaluated in the context of those profiles. The proportions of African Americans with none, one, and two APOL1 risk alleles were 38%, 43%, and 19%, respectively; 38% of African Americans had G1 allele variants and 31% of African Americans had G2 allele variants. Only APOL1-positive African Americans had significant reductions in N glom and increases in V glom with increasing age. Regression analysis predicted an annual average loss of 8834 (P=0.03, sex adjusted) glomeruli per single kidney over the first 38 years of adult life in African Americans with two risk alleles. Body mass index above the group medians, but below the obesity definition of $30 kg/m 2 , enhanced the expression of age-related changes in N glom in African Americans with either one or two APOL1 risk alleles. These findings indicate that APOL1 risk alleles are associated with exaggerated age-related nephron loss, probably decaying from a larger pool of smaller glomeruli in early adult life, along with enlargement of the remaining glomeruli. These phenomena might mark mechanisms of accentuated susceptibility to kidney disease in APOL1-positive African Americans.

Clinical and Pathology Findings Associate Consistently with Larger Glomerular Volume

“…12 Genetic variants (specifically APOL1) have been linked to larger glomeruli and nephron loss. 34 The glomerular hypertrophy pathway may dominate parenchymal injury beyond aging alone ("real CKD") as larger GSG associated with the severity of nephrosclerosis on biopsy specimen. The reason for larger GSG volumes in patients with renal tumor compared with living kidney donors is unclear, but may be related to other unmeasured comorbidities, or differences in the severity of comorbidities.…”

APOL1-G0 or APOL1-G2 Transgenic Models Develop Preeclampsia but Not Kidney Disease

“…30 Careful histomorphometric analyses of kidney microanatomy in an autopsy series of blacks without kidney diseases demonstrated that APOL1 risk alleles exaggerated agerelated increases in glomerular volume, which may predispose these individuals to kidney diseases. 32 Since the podocyte is postmitotic, this additional glomerular tuft enlargement reduces podocyte density even in the absence of podocyte loss. The Tg-G2 mice suggest blacks with risk genotypes may have inadequate podocyte numbers for their age-related increases in glomerular volume.…”

APOL1 Kidney Disease Risk Variants: An Evolving Landscape

“…The spectrum of APOL1-related nephropathies consists of HIVAN [4,84–88], FSGS [4,89,90], sickle-cell nephropathy [91], arterionephrosclerosis [92], lupus nephritis [93,94], microalbuminuria [95], CKD [96,97], and ESKD [98,99]. There is also increased deceased donor kidney transplant rejection [47], and greater decline in glomerular number and greater increase in glomerular volume over lifespan [84], as summarized in Table 1. The strongest association is with collapsing glomerulopathy in many settings that include HIVAN [86], primary collapsing glomerulopathy [4,90], and collapsing glomerulopathy seen in the setting of in systemic lupus erythematosus [94,100] and PLA2R-positive membranous glomerulopathy [101].…”