Clinical Research

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

Wendy E. Hoy, Michael D. Hughson, Jeffrey B. Kopp, Susan A. Mott, John F. Bertram and Cheryl A. Winkler
JASN December 2015, 26 (12) 3179-3189; DOI: https://doi.org/10.1681/ASN.2014080768

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 (Nglom) and mean glomerular volume (Vglom) 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 Nglom and increases in Vglom 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/m2, enhanced the expression of age-related changes in Nglom 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.

Recent studies have shown that the accentuated risk of African Americans for renal disease is associated strongly with APOL1 risk alleles,1 with odds ratios of 7 for ESRD attributed to hypertension,2 17 for FSGS and 29 for HIV-associated nephropathy.3 Conditions also associated with APOL1 risk alleles include sickle nephropathy,4 collapsing HIV glomerulopathy,5,6 and collapsing nephropathy and ESRD associated with lupus nephritis,7,8 as well as increased allograft loss in deceased donor kidney transplants.9 Further, the progression of CKD is more rapid in patients with two APOL1 risk alleles, despite remittive therapy for FSGS and control of blood pressure for hypertension-attributed CKD,2,3 with earlier institution of dialysis.10,11 Furthermore, African Americans without renal disease on enrollment in the community-based Atherosclerosis Risk in Community (ARIC) study were more likely to develop CKD and progress to ESRD on follow-up if they had two APOL1 risk alleles, compared with those with no alleles or one allele.5 Hence, APOL1 risk alleles increase the risk for progressive CKD when various injurious stimuli are present, and also predispose to the de novo development of CKD.

The accentuated susceptibility of African Americans for kidney disease has been the focus of various hypotheses. Brenner et al. proposed that reduced glomerular number present at birth, predisposes to hypertension and CKD in adult life, and suggested that the increased susceptibility of African Americans for diabetic nephropathy might also be related to this phenomenon.12 However, in previous studies from the Mississippi autopsy cohort, using an unbiased dissector/fractionator stereological technique to count glomeruli, we did not find significantly lower total glomerular number (Nglom) in African Americans than in European Americans.13 In that study we also found that, although mean glomerular volume (Vglom) in African Americans was only marginally (and nonsignificantly) larger than in non–African Americans, the value was significantly larger in African Americans with hypertension than in those without.13–15 Moreover, our studies on individual glomerular volumes showed more size heterogeneity and net enlargement in African Americans than in non–African Americans.16–18

The intent of the autopsy series in which this study is nested was to examine microanatomy in normal kidneys. Here we describe histomorphometric phenotype in adult African-American subjects in that series according to their APOL1 risk allele profiles.

Results

DNA was successfully extracted from formalin-fixed, paraffin-embedded tissue for 98% of African Americans and 99% of non–African Americans and genotyped for the two APOL1 renal risk missense variants comprising the G1 allele and the G2 insertion/deletion allele. Of subjects, ≥18 years, who were successfully genotyped (159 African Americans and 135 non–African Americans), 19% (30) of African Americans had two risk alleles, 43% (68) had one risk allele and 38% (61) had no risk alleles. More African-American women than men tended to have two risk alleles than zero or one (P>0.02). Among non–African Americans, three people (2%) had a single APOL1 risk allele.

As shown in Table 1, APOL1 genotype distributions and allele frequencies in African Americans were similar to those in a community-based sample of middle-aged African Americans, initially without renal disease, who were enrolled in the ARIC study.5 As in the ARIC study, the genotypes in African Americans were in Hardy–Weinberg equilibrium; although women had a slightly higher proportion of risk allele genotypes than expected, this was not significant.

View this table:
Table 1.

African-American APOL1 genotype and risk allele frequencies, in the ARIC and current studies

Table 2 shows some characteristics of subjects by race and number of APOL1 risk alleles. African-American women with APOL1 risk alleles tended to be younger at time of death. Women and men with two risk alleles tended toward lower weight, body mass index (BMI), and levels of obesity than other African Americans. However, only the younger ages at death for the dominant and additive models in women, and the lower levels of obesity for women for the additive model were individually significant, and none of the associations were significant with Bonferroni adjustments for multiple tests.

View this table:
Table 2.

Characteristics of subjects at autopsy age 18–67 years, by race, sex and number of APOL1 risk alleles

Figure 1 shows more detail on some of these associations, with adjustment for age. The data similarly suggest an additive model for lower BMI with increasing numbers of APOL1 risk alleles in women, whereas men with two alleles (only ten subjects) had the lower levels of obesity. The frequency of hypertension did not differ by number of APOL1 alleles in women, whereas among men, it was apparently highest in those with a single APOL1 risk allele, although this was not significant (P>0.10). The data also hint at an additive model for cardiovascular deaths in men, although it was not significant (P<0.14), and the converse for deaths form misadventure.

Figure 1.
Figure 1.

Proportions of obesity, hypertension, cardiovascular deaths and deaths by misadventure in African Americans aged 18–67 years at autopsy, by sex and number of APOL1 risk alleles, adjusted for age. p1, P value of F-test for linear trend (Additive model) from age-adjusted logistic regression. p2, P value for the Dominant model from age-adjusted logistic regression.

Table 3 shows the kidney features of subjects aged 18–67 years. In women and men kidney weight was lowest in people with two APOL1 risk alleles. As expected,13,19 women had fewer nephrons than men, by about 15% for non–African Americans and 10% for African Americans. In African-American women there was no difference in Nglom according to APOL1 risk alleles, whereas Nglom tended to be higher in men with APOL1 risk alleles. Aggregate Vglom in women tended to be smaller than in men, but the lowest Vglom value in both sexes was in those with two risk alleles. However, none of these associations was significant, individually, or with Bonferroni correction. Furthermore, proportions of sclerosed glomeruli, degree of cortical fibrosis and intimal thickening in remote resistance vessels and in capacitance vessels did not differ significantly by APOL1 risk allele profile.

View this table:
Table 3.

Kidney features in subjects at autopsy age 18–67 years, by race, sex, and number of APOL1 risk alleles

Although Nglom and Vglom were not significantly correlated with APOL1 profiles when all ages were considered together, there were apparent differences in the relationships of each to age. Table 4 shows these data for women and men. The data suggest higher baseline values of Nglom in young “APOL1-positive” (one or two risk alleles as a group) African-American subjects, and a ranked order of glomerular “loss” with increasing age by number of APOL1 risk alleles in African Americans. The decrease is significant in women with two APOL1 risk alleles, and but not in men with two risk alleles, because of the small sample size (n=10). A gradient is also suggested in APOL1-positive African-American women and men. Vglom increased with age in all female African-American risk allele groups, without substantial differences between them. However, in men with two risk alleles, Vglom rose sharply from an apparently lower value in young adult life to higher values in middle age, compared with those with no risk alleles, whereas the pattern in those with one risk allele was arguably intermediate.

View this table:
Table 4.

Regression characteristics of predictions of average annual changes in Nglom and Vglom versus age, around specified age ranges, by race, sex, and number of APOL1 risk alleles

Figures 2A and B illustrate these phenomena over a more uniform age range. Table 5 shows changes expressed in absolute values, as well as in fractional changes. These approaches give internally consistent results. The age-related reductions in Nglom were significant in African-American subjects with two risk alleles, with one or two alleles, and in those with two G2 risk alleles (although there are only five subjects in this group). Age-related increases in Vglom were significant in those with one risk allele, two risk alleles, and with one or two risk alleles, and marginally in those with G1/wild-type and G2/G2 profiles.

Figure 2.
Figure 2.

Age-related change in Nglom and Vglom. Nglom (A) and Vglom (B) at autopsy age 20–57 years, by race, number of APOL1 risk allele profiles and sex, adjusted for age. Nglom, estimated total number of glomeruli per kidney; Vglom, estimated mean glomerular volume (µm3×106).

View this table:
Table 5.

Predicted annual and fractional changes in Nglom and Vglom versus age at autopsy age 20–57 years, by race and APOL1 risk allele profiles, adjusted for age and sex

The data in Table 5 suggest an inverse correlation between changes in Nglom and Vglom. The relationship between the fractional change is significant by nonparametric (Kendall τ) testing when the G2/G2 group (five subjects only) is included (coefficient –0.73, P<0.02), but not when that group is excluded (coefficient –0.33, P=0.215).

However, the predicted age-related changes in Nglom and Vglom were BMI dependent. Figure 3 shows data for each African-American APOL1 risk profile group of 20 or more subjects, divided around their group-specific BMI medians. These median BMIs were all below the threshold for obesity (≥30 kg/m2). Age-related decrements in Nglom were only significant in African-American risk allele–positive subjects with BMIs greater than their group medians. The significance of age-related Vglom increments associated with one or two APOL1 risk alleles was enhanced by higher BMIs. BMI was not a significant independent predictor of Nglom in African American women and men, regardless of APOL1 profiles, but addition of an age and BMI interaction term modestly improved the explained variance of Nglom in women with two risk alleles. BMI was an additional independent risk factor for Vglom in African-American women with one risk allele (P<0.04), and BMI age interaction term modestly improved the explained variance of Vglom in females with one and two risk alleles.

Figure 3.
Figure 3.

Comparison of fractional annual age changes at autopsy age 20–57 years in Nglom and Vglom, in those with BMI ≥ and < their group median, by race and APOL1 risk allele profiles, adjusted by age and sex. The group median BMI for African Americans with no risk alleles was 28.8 kg/m2 and for African Americans in groups with risk alleles it ranged from 25.6 to 27.6 kg/m2. Nglom, estimated total number of glomeruli per kidney; Vglom, estimated mean glomerular volume (µm3×106). AA, African American.

The age-related decrease in Nglom in APOL1-positive people could not be readily attributed to hypertension or cardiovascular disease. Figure 4A and B show similar trends in APOL1-positive subjects without hypertension and without a cardiovascular cause of death.

Figure 4.
Figure 4.

Age-related change in Nglom in African Americans with one or two APOL1 risk alleles at autopsy age 18–67 years. Age-related change in Nglom in African Americans without hypertension (A) and without a cardiovascular cause of death (B), adjusted for age and sex. Nglom, estimated total number of glomeruli per kidney; N, number of subjects; P, P value of modeled age.

Discussion

This is the largest study of microanatomy in kidneys of African Americans without renal disease at autopsy, and it is the only one in which associations with APOL1 risk alleles have been evaluated.

The similarity of the APOL1 risk allele frequencies to those of ARIC enrollees suggests that there is little segregation of particular APOL1 genotypes among the African Americans undergoing autopsy in our series. However, the higher proportions of APOL1 risk allele–negative African-American men with deaths of misadventure, and the trend toward lower ages at death of APOL1-positive women hints at some contribution of APOL1 risk alleles to risk of natural death.

Our data suggest that certain characteristics are associated with APOL1 risk alleles in African Americans. Women with two risk alleles tended toward lower weight, BMI and levels of obesity than other African-American women, and both women and men with two risk alleles had lower kidney weight than other African Americans. Furthermore, starting from an apparently higher baseline level of Nglom in early adult life, African Americans with two APOL1 risk alleles had an apparent loss of nephrons with increasing age over the next four decades. APOL1 risk alleles were also associated with smaller average Vglom in early adult life as well as with more pronounced increases in Vglom with age. These phenomena were dependent on, or were enhanced by, higher BMIs. The trends to smaller body size, kidney size, and glomerular volume in APOL1 homozygotes are compatible with our observations in autopsy subjects from Senegal in western Africa,20 a region with a high prevalence of APOL1 variants.21

Our data do not suggest that coexisting hypertension was the major driver of age-related changes in Nglom in subjects with two APOL1 risk alleles. APOL1-positive women did not have more hypertension than those without APOL1 risk alleles, whereas the apparently higher levels in men were not significant. Furthermore, APOL1-positive African Americans without hypertension or cardiovascular deaths also tended toward reductions in Nglom with age. However, it is likely that age-related reductions in Nglom can predispose to hypertension and cardiovascular risk, as well as renal disease, as discussed below.

Although the age-related trends in Nglom and Vglom are derived from a cross-sectional study, they probably reflect changes as an individual ages. Non–African Americans and APOL1 risk allele–negative African Americans appeared to have minimal loss of glomeruli with age up through their mid-50s, whereas some risk allele–positive African Americans had lower Nglom in the first 38 years of adult life. Those with two APOL1 risk alleles “lost” a predicted average of about 350,000 nephrons per single kidney over that interval, and those with one or two alleles lost about 300,000 per single kidney. These are significant decrements in view of the mean single kidney nephron count of about 900,000.13 The data suggest far more serious age-related decrements of Nglom in G2/G2 subjects, but the numbers are very small. We could not detect, but cannot exclude, an association of these age-related changes with accelerated processes of glomerulosclerosis, cortical scarring, or vascular change. Although extrapolations to kidney disease are hazardous, these findings are compatible with those of Larsen et al. who found, in renal biopsies in African Americans with arteriolar nephrosclerosis, that a relative lack of obsolescent glomeruli, greater degrees of solidified and disappearing glomerulosclerosis, as well as less arteriolar change, distinguished those with two APOL1 risk alleles from those with no risk alleles.22

Age-related reductions in Nglom and exacerbated increases in Vglom in APOL1 risk allele–positive subjects appear to be linked. This mimics the strong inverse correlation between Nglom and Vglom seen in all groups in this autopsy series.13,19 These changes could reflect compensatory hypertrophy of remaining glomeruli in the setting of progressive nephron deficiency, or glomerular loss due to intrinsic glomerular volume expansion placing glomeruli at extra risk for glomerulosclerosis.15 In either scenario the initially smaller glomeruli in APOL1-positive people might be at accentuated risk for damage from excessive hypertrophy. Furthermore, a recent study describes the influence of APOL1 risk variants on enhanced podocyte necrosis through compromised lysosomal membrane permeability.23 Much remains to be explored in this area, including, the full degree of heterogeneous individual glomerular enlargement that the estimate of average Vglom disguises,17,24 and indices of podocyte number and density in the younger and older at-risk subjects25 in the various APOL1 subgroups.

This series is not a resource for the study of kidney disease, because such subjects were deliberately excluded. However, our findings might flag mechanisms of APOL1-mediated susceptibility to renal disease. Accentuated loss of Nglom with age in African Americans might contribute to earlier expression and more rapid progression of renal disease with protracted ageing and/or with additional nephropathic insults, in a two-strike or multi-determinant disease model. This scenario is proposed for renal disease associated with sickle cell disease, with collapsing nephropathy associated with lupus or HIV and with compromised graft survival after transplantation.4–9 APOL1 risk variants are associated with earlier age of onset and progression to renal failure of subjects with FSGS, and prospective studies in the African American Study of Kidney Disease and Chronic Renal Insufficiency cohorts show that carriage of two APOL1 risk variants is associated with more rapid progression to clinical endpoints in persons with renal insufficiency at study entry.2,3,5,7,8 Moreover, African-American participants without renal disease on enrolment in the ARIC study were more likely to develop CKD and to progress to renal failure if they had two APOL1 risk alleles, compared with those with no alleles or one allele.5

We could find no reports of exacerbation of APOL1-associated kidney disease by higher BMIs. If confirmed, this constitutes additional arguments for intensified surveillance of APOL1-positive African Americans, and incentives for them to remain relatively lean. It is noteworthy that the levels of BMI associated with significant age-related changes in Nglom and Vglom in this study were well below those defining “obesity” (≥30 kg/m2).

Our data hint that hypertension and cardiovascular deaths might be higher in male African Americans with APOL1 risk alleles. Ito et al. reported association of two APOL1 risk alleles (odds ratio approximately 2) with atherosclerotic events in the Jackson Heart Study, with replication in the Women’s Health Initiative study,26 although this was not replicated in the large Systolic Blood Pressure Intervention Trial.27 Numerous genome-wide association studies and admixture linkage mapping studies have not identified chromosome 22 as a locus for systolic blood pressure or hypertension, suggesting that APOL1 variants probably do not contribute to primary hypertension.

Retrospective genetic testing of additional stored autopsy samples from African Americans with clear medical histories relating to hypertension, renal disease and cause of death could confirm or refute our results.

Strengths of this report are the unique study sample and approach. The duration of the sample collection (>10 years), the ethical considerations, and the tedious nature of the measurements, all weigh against its being repeated in this fashion.

There are several limitations in this study. The subjects constitute a convenience sample, selected for autopsy on medical and legal grounds, with a broad set of indications and underlying and coexisting conditions, ranging from deaths from misadventure to deaths with hypertension and cardiovascular disease. In addition, numbers of subjects with G1/G2, G1/G1 and G2/G2 profiles, and of men with any combination of two risk alleles are small. These factors, plus the dominance of women among those with two risk alleles, all pose analytic problems. Furthermore, the use of Vglom, which is an average value of glomerular volumes for a given kidney, provides no indication the variability in volumes of individual glomeruli within a given subject.13,16–18,24 An additional caution is the inference that data on different people at different ages on a cross-sectional study necessarily represent probable changes in an individual followed over a lifetime.

Despite these important limitations, this autopsy cohort has provided a unique histologic resource. Findings of nephron loss in a setting of certain APOL1 risk profiles and compensatory or causal nephron hypertrophy should provoke and direct further investigations. Development of noninvasive techniques to assess glomerular number and glomerular volume in living human will greatly advance progress in this important field.

Concise Methods

Autopsy Cohort

The right kidney was collected from 191 African Americans and 146 non–African Americans, without known renal disease, during autopsies conducted to investigate sudden or unexpected death, between 1998 and 2005, at the University of Mississippi Medical Center, Jackson, Mississippi. Subject selection and specimen collection have been previously described.15 Race was ascertained from medical records, next-of-kin or the investigating pathologist. Subjects with known renal disease, with kidneys of significantly unequal size, and with scarred or contracted kidneys were specifically excluded, as were two subjects with unsuspected FSGS subsequently identified on histopathologic examination. Causes of death were documented and medical records were reviewed for a history of hypertension. Clinical and demographic characteristics were obtained from University of Mississippi Medical Centre records. Approval was obtained from the Institutional Review Board of the University of Mississippi Medical Center and the Human Research Ethics Committee of Monash University, Victoria, Australia, and consent was provided by next of kin.

Stereology

Kidney tissue was sent to Monash University for stereological estimation of Nglom and Vglom and assessment of other morphologic parameters. Nglom and Vglom were estimated using the physical dissector/fractionator combination as previously described.19,28,29 In brief, perfusion-fixed kidneys were sampled to provide an isotropic, uniform random sample of tissue blocks. These blocks were embedded in glycolmethacrylate and then exhaustively sectioned at 20 µm. Every tenth and eleventh sections (a section pair) were then stained with periodic acid–Schiff, and glomeruli in identical fields in each section pair were counted using the dissector principle.30 Stereological point counting at the same time on the same sampled fields allowed the calculation of Vglom.

Genetic Analysis

DNA was isolated from formalin-fixed, paraffin-embedded tissue as previously described.31 Genetic analysis was carried out under a protocol approved by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Institutional Review Board (94-DK-0133). APOL1 risk alleles were genotyped using TaqMan assays (Applied Biosystems, Foster City, CA). The APOL1 G1 allele was defined as the presence of the p.S342G variant (rs73885319A>G) and the G2 allele was defined as the deletion of p.N388Y389 (rs71785313 TTATAA/-). Genotyping of renal tissue was successfully performed on 188 African Americans and 144 non–African Americans of the autopsy cohort.

Statistical Analyses

Variables were summarized using mean (SD), geometric mean (95% confidence interval) or percent and presented in four groups, non–African Americans without risk alleles and African Americans with zero, one, or two risk alleles. Analyses of group data were performed in Stata Statistical Software, version 13.1 (StataCorp., College Station, TX) using linear regression, logistic regression and chi-squared tests. Various transformations were applied to certain variables to optimize the normalcy of their distributions, and when applied, are specified in the legends of the data in the relevant tables. Allele group differences were tested using recessive (two versus none or one risk alleles), dominant (one or two risk alleles versus none) and additive (2>1>0 risk alleles) models, including adjustments for sex and age. Two-sided Fisher’s exact tests were used to evaluate if genotype frequencies were in Hardy–Weinberg equilibria.

Renal and related physical characteristics and renal morphologic features were analyzed in the context of APOL1 risk alleles for subjects aged 18–67 years at the time of death. Only four African Americans in the entire series were older than this. The predicted annual changes of Nglom and Vglom in African-American groups with various combinations of APOL1 risk alleles were evaluated over ages 20–57 years, a range over which most APOL1 profile groups had a reasonable representation.

Disclosures

None.

Acknowledgments

The autopsy study has been supported by a project grant from the National Health and Medical Research Council (NHMRC) of Australia, (#194276), by an untied grant from the Colonial Foundation of Australia (Hoy, 2001-2011), an NHMRC Australia Fellowship (Hoy, 2008-2012, #511081), by the National Institutes of Health (NIH) NIDDK (RO1-DK065970-01, Hughson, 2004–2007), and a grant from the American Heart Association, South-eastern affiliate (Hughson, 2001–2003). This work was also supported in part by the Intramural Research Program of the National Cancer Institute and the NIDDK, NIH. This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract HHSN26120080001E.

Acknowledgments

We wish to acknowledge the contributions of other members of the research team in Australia, including Dr. Terence Samuel, Rebecca Douglas-Denton, Dr. Monika Zimanyi, Dr. Bridgette McNamara, Dr. Victor Puelles, and staff of the Monash Histology Platform, and the statistical assistance of Dr. George Nelson, the support of Dr. Sophie Limou and Dr. Justina Fryc, and the excellent technical assistance of Elizabeth Binns-Roemer.

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Footnotes

  • J.F.B. and C.A.W. as senior authors, contributed equally to this work.

  • Published online ahead of print. Publication date available at www.jasn.org.

  • See related editorial, “Glomerular Effects of Age and APOL1,” on pages 2901–2903.

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APOL1 Risk Alleles Are Associated with Exaggerated Age-Related Changes in Glomerular Number and Volume in African-American Adults: An Autopsy Study
Wendy E. Hoy, Michael D. Hughson, Jeffrey B. Kopp, Susan A. Mott, John F. Bertram, Cheryl A. Winkler
JASN Dec 2015, 26 (12) 3179-3189; DOI: 10.1681/ASN.2014080768
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