Visual Abstract
Keywords: glomerulopathy, membranous nephropathy, Apolipoprotein L1, Disease Progression, Genotype
Abstract
Background
Disparity in CKD progression among Black individuals persists in glomerular diseases. Genetic variants in the apolipoprotein L1 (APOL1) gene in the Black population contribute to kidney disease, but the influence in membranous nephropathy remains unknown.
Methods
Longitudinally followed participants enrolled in the Glomerular Disease Collaborative Network or Cure Glomerulonephropathy Network were included if they had DNA or genotyping available for APOL1 (Black participants with membranous nephropathy) or had membranous nephropathy but were not Black. eGFR slopes were estimated using linear mixed-effects models with random effects and adjusting for covariates and interaction terms of covariates. Fisher exact test, Kruskal–Wallis test, and Kaplan–Meier curves with log-rank tests were used to compare groups.
Results
Among 118 Black membranous nephropathy participants, 16 (14%) had high-risk APOL1 genotype (two risk alleles) and 102 (86%) had low-risk APOL1 genotype (zero or one risk alleles, n=53 and n=49, respectively). High-risk APOL1 membranous nephropathy participants were notably younger at disease onset than low-risk APOL1 and membranous nephropathy participants that were not Black (n=572). eGFR at disease onset was not different between groups, although eGFR decline (slope) was steeper in participants with high-risk APOL1 genotype (−16±2 [±SE] ml/min per 1.73 m2 per year) compared with low-risk APOL1 genotype (−4±0.8 ml/min per 1.73 m2 per year) or membranous nephropathy participants that did not identify themselves as Black (−2.0±0.4 ml/min per 1.73 m2 per year) (P<0.0001). Time to kidney failure was faster in the high-risk APOL1 genotype than low-risk APOL1 genotype or membranous nephropathy participants that were not Black.
Conclusions
The prevalence of high-risk APOL1 variant among Black membranous nephropathy participants is comparable with the general Black population (10%–15%), yet the high-risk genotype was associated with worse eGFR decline and faster time to kidney failure compared with low-risk genotype and participants that were not Black.
Introduction
Black Americans have a higher propensity for progression of CKD to kidney failure, and this disparity persists in glomerular diseases. In a study on glomerular disease epidemiology in Southeastern United States, up to 40% of participants with glomerular diseases identified as Black.1 Membranous nephropathy is a common glomerular disease causing idiopathic nephrotic syndrome in nondiabetic adults.2 Despite the fact that membranous nephropathy remains one of the most prevalent causes of nephrotic syndrome, no large studies have been conducted that examine outcomes in Black participants with membranous nephropathy. In SLE, ANCA-associated vasculitis, and FSGS, there is evidence that Black American patients have different clinical presentations and treatment outcomes.3–5 One small observational study of membranous nephropathy with 24 Black participants showed an higher risk of kidney failure among Black participants compared with White, Asian, and other participants.6 If there is a worse prognosis on the basis of race or genetic factors in membranous nephropathy, it will be clinically valuable for closer monitoring, aggressive therapy, and additional counseling.
There are two variants in the apolipoprotein L1 (APOL1) gene in the Black population that have been associated with higher risk for developing CKD when two alleles of either of the variants are inherited together (termed high-risk). The variants are associated with higher resistance to trypanosomiasis individually.7,8 In lupus nephritis, FSGS, and HIV-associated nephropathy, individuals with high-risk APOL1 alleles have more rapid decline in eGFR and more severe damage on kidney biopsy.9,10 A case series of biopsies of Black participants with membranous nephropathy noted a higher risk for development of collapsing glomerulopathy and more tubule-interstitial disease in patients with high-risk APOL1 genotype.11 The clinical impact of high-risk APOL1 genotype in membranous nephropathy remains unknown.
Membranous nephropathy is a pathological term to characterize a pattern of disease with thickened glomerular basement membranes with deposition of IgG and complement. It is recognized as a clinical disease in which the treatment response and eventual kidney outcome can be difficult to predict. Identification of antibodies to the M-type phospholipase A2 receptor (anti-PLA2R) have shed light on disease pathogenesis, and levels are routinely used as a disease biomarker.12 Among all membranous nephropathy patients, a significant percentage will have poor response to immunosuppressive therapies and up to 40% will have recurrence in transplanted kidney.13,14 Among participants with membranous nephropathy, FSGS, and minimal change disease in the Nephrotic Syndrome Study Network study, those with APOL1 high-risk variants had advanced disease across histopathological classes and lower complete remission rates and eGFR.15
The primary objective of this study was to report kidney outcome in Black participants with membranous nephropathy and elucidate the effect of APOL1-related risk in this population. We describe the frequency of variant APOL1 alleles in Black participants with membranous nephropathy and clinical outcomes. In addition to long-term end points such as kidney failure, eGFR change is an important and clinically useful outcome and increasingly used in clinical trials because it has high probability of predicting CKD progression.16 We sought to examine the association of high-risk APOL1 variants with eGFR slope and progression to kidney failure after diagnosis.
Methods
Patient Cohort
The Glomerular Disease Collaborative Network (GDCN) patient registry is an ethnically and racially diverse registry of clinical data and biospecimens from participants diagnosed with glomerular disease and followed longitudinally. The GDCN registry serves as a biorepository for numerous research studies that were approved by the University of North Carolina (UNC) Chapel Hill Institutional Review Board (IRB) and in accordance with the ethical principles of the Declaration of Helsinki. Consented participants were eligible for this study if they had a biopsy-proven diagnosis of membranous nephropathy and had available DNA for genotyping. This study was approved under UNC IRB# 97-0523. Data abstraction occurs from regular chart review performed by a dedicated study coordinator and clinician. The Cure Glomerulonephropathy Network (CureGN) comprises 72 participating clinical sites in the United States, Canada, Italy, and Poland. It is a prospective multicenter cohort study of participants with biopsy-proven minimal change disease, FSGS, membranous nephropathy, or IgA nephropathy/vasculitis. Inclusion criteria for CureGN enrollment include an initial diagnostic kidney biopsy within 5 years before enrollment. Those with kidney failure including a kidney transplant, diabetes mellitus, lupus erythematosus, HIV, active malignancy, or hepatitis B or C at the time of first kidney biopsy were excluded. The study protocol was approved by the IRB at each participating center, and all participants provided written informed consent or assent if appropriate at enrollment. Detailed methods for the CureGN study have been previously published.17 Race was self-identified by the patients and as recorded in their medical records. Black participants without available DNA or APOL1 genotyping were excluded. Kidney biopsy analysis has been completed by CureGN, and the scores were used for histology; additional available biopsies from GDCN cohort were scored by VM.
Genotyping
Genomic DNA obtained from the GDCN registry was extracted from peripheral blood specimens and quantified using a NanoDrop 2000 spectrophotometer. CureGN provided either previously extracted DNA or whole blood specimens for genomic DNA extraction to be completed by the UNC study team. Using available isolated genomic DNA or whole blood, participants were genotyped by PCR amplification of a single 380 base pair amplicon containing the G1 and G2 risk variants (forward primer 5′-AGACGAGCCAGAGCCAATC-3′, reverse primer 5′-CTGCCAGGCATATCTCTCCT-3′). PCR was performed using the HOTStarTaq Master Mix Kit (QIAGEN, Valencia, CA) with the following reagents: 100 ng DNA, 12.5 µl of Master Mix (HotStarTaq Master Mix), 10 pmol of each primer (Integrated DNA Technologies), and Nuclease free water. The amplification conditions were as follows: 95°C heat activation for 5 minutes; 27 cycles of 94°C for 30 seconds, 55°C for 30 seconds, and 72°C for 1 minute; and a final extension of 72°C for 10 minutes. Sanger sequencing was completed by Eton Biosciences (Research Triangle Park, NC), and resulting chromatograms were analyzed by our study team using FinchTV for variant identification.
Study Design and Statistical Methods
Continuous measures are described as mean and SD or median and interquartile range, and categorical data are reported as frequencies and percentages. Per established protocols, participants with zero or one variant APOL1 alleles were categorized as low risk and those with two risk alleles were termed high risk. Kidney failure was defined as dialysis, kidney transplantation, or eGFR<15 ml/min per 1.73 m2. Group comparisons were performed using Fisher exact tests for categorical measures and Kruskal–Wallis tests for continuous measures. Kidney failure survival analysis was performed using Kaplan–Meier estimators. The probability of kidney failure (survival curves) was compared using a log-rank test. Proportional hazards models of time to relapse were used to assess relapse hazard rates between groups, with hazards ratios, P values, and 95% confidence intervals (CI) reported. eGFR at disease onset was based on available creatinine (Cr) at the time of diagnosis or biopsy. eGFR calculation was performed using the non–race-based Chronic Kidney Disease Epidemiology Collaboration equation for adults older than 26 years and Schwartz bedside equation for children younger than 18 years. For ages 18–26 years, new Chronic Kidney Disease Epidemiology Collaboration and Schwartz were combined as previously reported.18 For the use of the Schwartz equation, height was available through clinical chart review or extrapolated on the basis of growth curve. Available Cr values over follow-up were used to calculate eGFR slope. Participants with less than two Cr values were excluded. eGFR over follow-up was estimated and risk groups compared using linear mixed-effects models with intercept and slope as random effects, assuming an unstructured covariance and adjusting by risk groups, eGFR at disease onset, and interaction between visit years and groups. All analyses and figures were conducted with SAS (v.9.4, Cary, NC).
Results
APOL1 Risk Alleles in Patient Cohort
There were 690 participants with membranous nephropathy included in this study. There were 118 Black participants: 16 participants (14% of Black participants) with high-risk APOL1 genotype (two risk alleles) and 102 participants (86% of Black participants) with low-risk APOL1 genotype (zero or one risk alleles, n=53 and 49, respectively), and these groups were compared with 572 participants with membranous nephropathy that were not Black (Table 1). We tested 120 individuals that were not Black, for the presence of APOL1 risk variants and did not find any risk alleles; therefore, remainder of population that did not identify themselves as Black was not genotyped.
Table 1.
Participants with membranous nephropathy in the Glomerular Disease Collaborative Network and Cure Glomerulonephropathy Network
| Cohort Characteristics | Black Participants with Membranous Nephropathy (n=118) | Participants with Membranous Nephropathy that Were Not Black | |
|---|---|---|---|
| Two APOL1 Risk Alleles | Zero/One APOL1 Risk Alleles | ||
| n=16 | n=102 | n=572 | |
| CureGN participants (n) | 9 | 59 | 457 |
| GDCN participants (n) | 7 | 43 | 115 |
| Age at disease onset, median (IQR) | 41 (34–51) | 50 (35–57) | 50 (37–62) |
| Sex, female, n (%) | 9 (56) | 58 (57) | 211 (37) |
| eGFR at disease onset (ml/min per 1.73 m2), median (IQR)a | 83 (59–100) | 80 (57–105) | 85 (59–104) |
| Hypertension during study periodb, n (%) | 14 (93) | 79 (80) | 383 (71) |
| Peak UPCRc, median (IQR) | 18.6 (4.8–21.6) | 5.6 (1.5–11.4) | 4.8 (1.8–9.2) |
APOL1, apolipoprotein L1; CureGN,Cure Glomerulonephropathy Network; GDCN, Glomerular Disease Collaborative Network; IQR, interquartile range; UPCR, urine protein-creatinine ratio.
Missing data: Two APOL1 risk alleles n=3, zero/one APOL1 risk alleles n=3, not Black n=122.
Missing data: Two APOL1 risk alleles n=1, zero/one APOL1 risk alleles n=3, not Black n=30.
Missing data: Two APOL1 risk alleles n=5, zero/one APOL1 risk alleles n=31, not Black n=117.
The age at disease onset was notably younger among the high-risk APOL1 participants (41 years) compared with low-risk APOL1 participants (50 years) and participants that were not Black (50 years old), although not statistically significant (P = 0.09). There were no differences within the Black patient populations in terms of percentage of female patients versus male patients; however, there were fewer female patients that did not identify themselves as Black (approximately 56% in low-risk APOL1 and high-risk APOL1 Black participants compared with 37% in participants that were not Black, P<0.001). eGFR at the time of diagnosis was not different across groups (83 ml/min per 1.73 m2 in high-risk group versus 80 and 85 ml/min per 1.73 m2 in low-risk and participants that were not Black, respectively, P = 0.85). The groups were also compared by separating out zero and one risk allele carriers, and the baseline differences remained the same (Supplemental Table 1). Comparisons among the Black participants only (zero, one, two risk alleles) revealed no significant differences between groups (Supplemental Table 1). Most participants had elevated BP during the study period: 93% in the high-risk APOL1 group compared with 80% in the low-risk and 71% in participants that were not Black. Proteinuria is also a hallmark of membranous nephropathy, and we evaluated peak urine protein-creatinine ratio and found that high-risk participants had peak urine protein-creatinine ratio of 18.6 compared with low-risk (5.6) and participants that were not Black (4.8) (Table 1).
We evaluated histology from available biopsies from Black participants. We found that high-risk participants (two APOL1 risk alleles) had higher prevalence of global sclerosis and segmental sclerosis (Supplemental Table 2) when compared with low-risk participants (zero or one APOL1 risk alleles). There were more participants with FSGS lesions in the high-risk participants (71%) compared with low-risk participants (zero and one APOL1 risk alleles), 31% and 48%, respectively. The high-risk group all had interstitial fibrosis and tubular atrophy present with higher mean score. The high-risk group also had higher prevalence of arteriosclerosis and arteriolar hyalinosis.
Kidney Outcomes: eGFR Slope and Kidney Failure
There was a median follow-up of 52 months (interquartile range, 32–79), which was not different across groups, and all groups had similar numbers of available serum creatinine for eGFR calculation (Table 2). Among the high-risk group, 31% (n=5) reached kidney failure during follow-up, compared with 11% (n=11) of low-risk Black participants and 5% (n=31) of participants that were not Black. Time to kidney failure was faster in the high-risk APOL1 group compared with low-risk APOL1 group and participants that were not Black (log-rank P = 0.006, Figure 1; log-rank P = 0.02, Supplemental Figure 1).
Table 2.
Follow-up and outcomes
| Follow-up and Outcomes | Black Participants with Membranous Nephropathy (n=118) | Participants with Membranous Nephropathy that Were Not Black | |
|---|---|---|---|
| Two APOL1 Risk Alleles | Zero/One APOL1 Risk Alleles | ||
| (n=16) | (n=102) | (n=572) | |
| Follow-up months, median (IQR) | 42 (27–121) | 51 (29–79) | 52 (32–79) |
| eGFR measurements per person, median (IQR)a | 10 (6–21) | 10 (5–22) | 9 (5–15) |
| Kidney failure, n (%) | 5 (31) | 11 (11) | 31 (5) |
APOL1, apolipoprotein L1; IQR, interquartile range.
Missing data: Two APOL1 risk alleles n=1, zero/one APOL1 risk alleles n=1, not Black n=125.
Figure 1.
Longitudinal eGFR after disease onset (using linear mixed-effects models) and confidence intervals are shown in participants with membranous nephropathy. Low-risk group includes Black participants with zero or one APOL1 risk alleles. APOL1, apolipoprotein L1.
The differences in eGFR trajectories started after the first year of diagnosis, and those with two APOL1 risk alleles (high-risk) had significantly worsening eGFR (Supplemental Table 3). Participants with high-risk APOL1 genotype had eGFR slope of −16±2 ml/min per 1.73 m2 annually that was significantly worse compared with those with one APOL1 risk allele (−3.0±1 ml/min per 1.73 m2, P<0.001), zero APOL1 risk alleles (−4±1 ml/min per 1.73 m2, P<0.001), or participants that were not Black (−2.0±0.44 ml/min per 1.73 m2, P<0.001). The slopes remained largely unchanged even when we adjusted for age, sex, or baseline eGFR (Supplemental Table 4). No statistical differences were observed between zero and one risk allele (low-risk) individuals for eGFR changes over follow-up years (Supplemental Table 2), therefore, the zero and one risk allele groups were combined into zero/one risk allele (low-risk) risk group (Figure 2). Separated curves for zero versus one risk alleles are shown in Supplemental Figure 2.
Figure 2.
Kidney survival in participants with membranous nephropathy. Low-risk group includes Black participants with zero or one APOL1 risk alleles. Number at risk is shown for each group below the survival curve.
The observed rapid decline in eGFR among the high-risk APOL1 group translated to higher risk of kidney failure. The hazard ratio for risk of kidney failure was higher in the high-risk group compared with all others and increased after adjustment for age, sex, and eGFR (Supplemental Table 5), although only reached significance when compared with participants that were not Black, adjusted hazard ratio (HR) 8.06 (95% confidence interval [CI], 2.34 to 27.78). High-risk Black participants had higher risk of kidney failure compared with both groups of low-risk Black participants, adjusted HR 3.39 (95% CI, 0.79 to 14.60) for two risk alleles compared with zero risk alleles and adjusted HR 3.46 (95% CI, 0.81 to 14.86) when comparing participants with two risk alleles to one risk allele.
Discussion
While studies are ongoing to understand the underlying mechanisms causing kidney disease in those carrying high-risk APOL1 variants, it is becoming increasingly relevant to understand the role of this genotype in Black patients with existing kidney disease, especially glomerular diseases. This is the first study to report the kidney-related outcomes of membranous nephropathy in the Black population and describe the role of APOL1 in membranous nephropathy. We used data from a local glomerular disease registry (GDCN) and an international study (CureGN); the clinical characteristics were comparable in the two groups (Supplemental Table 6). In a total cohort of 118 Black participants, 14% of the population had high-risk APOL1 genotype (two risk alleles), which is comparable with the rate in the general Black population. We show that high-risk APOL1 genotype is associated with worse eGFR decline and faster time to kidney failure in participants with membranous nephropathy. Among Black participants with low-risk APOL1 genotype (zero or one risk alleles), the risk of eGFR decline and kidney failure was similar to that in participants that identify themselves as Black. Despite nonsignificant differences in eGFR trajectory, the low-risk Black participants had higher risk of kidney failure when compared with participants that were not Black. This is an interesting finding, and additional studies examining social determinants of health, therapies, access to care, and follow-up would be needed to understand this difference.
The mechanisms contributing to APOL1-related kidney disease are not yet fully understood. APOL1 is localized to podocytes and endothelial cells within normal glomeruli,19 and data from animal and in vitro models suggest cytotoxicity resulting from mechanisms including dysregulation of autophagy and inflammasome activation.20–24 It should be noted that not all individuals with high-risk APOL1 genotypes develop associated kidney disease. However, there are data to suggest that podocytes are affected even before clinical disease.25 While the exact mechanism remains unknown, it is plausible that in high-risk individuals, a second “hit” leads to irrecoverable podocyte drop-out and kidney failure. In the case of membranous nephropathy, the second hit may be immunological. One can postulate that a high inflammatory state and complement activation could contribute to irreparable cell damage in susceptible podocytes, leading to glomerulosclerosis and eGFR decline. An important question not addressed by this study is the effect of social determinants of health as a second hit contributing to disease, which should be evaluated in future, larger studies.
Discovery of PLA2R fundamentally changed the understanding of membranous nephropathy and more recently has become a routine part of the workup of this disease; however, these data were not available for all participants in our cohort, and a larger study would need to be performed to understand the role of both APOL1 and PLA2R antibodies together. We anticipate that there will be increased APOL1 genotyping of participants with membranous nephropathy, and the interaction with PLA2R can be parsed out in future studies.
As targeted therapies emerge for APOL1-related diseases, genotyping and trials specifically in patients with membranous nephropathy will be highly relevant. While previous trials of APOL1 therapies have been limited to participants with FSGS, additional studies will expand to include a broader group of glomerular disease participants. Given the effect of high-risk APOL1 on eGFR decline in membranous nephropathy, we hope some of these therapies will prove beneficial for this group.
Supplementary Material
Acknowledgments
We thank Mrs. Caroline Poulton and Ms. Lauren Blazek for their help in managing and retrieving patient demographic information. We thank Vertex pharmaceuticals for funding to develop the patient registry for APOL1 participants.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
*The list of nonauthor contributors is extensive and has been provided in Supplemental Material.
See related editorial, “Worsened Outcome in Patients with Membranous Nephropathy Carrying Apolipoprotein L1 High-Risk Genotype,” on pages 303–305.
Disclosures
J. Anguiano reports employment with PPD, Part of Thermo Fisher Scientific. D.P. Chen is part of Kidney Health Initiative APOL1 Group and reports research funding from Vertex Pharmaceuticals. R.J. Falk reports research funding from Vertex Pharmaceutical and honoraria from other universities for presentations and from ASN for presentations at Board Review Course. S.L. Hogan reports honoraria from National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (grant reviewer) and serving as a Veterans Affairs grant reviewer. All remaining authors have nothing to disclose.
Funding
D.P. Chen was supported by an NIH, National Institute of Diabetes and Digestive and Kidney Diseases Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grant (T32DK007750; PI R.J. Falk) and Vertex Pharmaceuticals. Funding for the CureGN consortium is provided by U24DK100845 (formerly UM1DK100845), U01DK100846 (formerly UM1DK100846), U01DK100876 (formerly UM1DK100876), U01DK100866 (formerly UM1DK100866), and U01DK100867 (formerly UM1DK100867) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Patient recruitment is supported by NephCure Kidney International. Dates of funding for first phase of CureGN were September 16, 2013–May 31, 2019 (see Supplemental Material for consortium details).
Author Contributions
D.P. Chen, R.J. Falk, C.D. Henderson, and S.L. Hogan conceptualized the study; C.P. Aiello, J. Anguiano, D.P. Chen, M. Collie, C.D. Henderson, and V. Moreno were responsible for data curation; S.L. Hogan and Y. Hu were responsible for formal analysis; D.P. Chen and R.J. Falk were responsible for funding acquisition; C.P. Aiello, D.P. Chen, and C.D. Henderson were responsible for investigation; C.P. Aiello, J. Anguiano, D.P. Chen, C.D. Henderson, S.L. Hogan, and Y. Hu were responsible for methodology; D.P. Chen and C.D. Henderson were responsible for project administration and wrote the original draft; D.P. Chen, R.J. Falk, and S.L. Hogan provided supervision; and C.P. Aiello, R.J. Falk, C.D. Henderson, S.L. Hogan, Y. Hu, and V. Moreno reviewed and edited the manuscript.
Data Sharing Statement
Identifiable data, including genetic data, are protected in our local registry and within CureGN database; however, these data are not available publicly. Deidentified data can be requested.
Supplemental Material
This article contains the following supplemental material online at http://links.lww.com/CJN/B575.
Supplemental Table 1. Patient characteristics and comparisons of all groups.
Supplemental Table 2. Kidney biopsy findings.
Supplemental Table 3. eGFR slope over time.
Supplemental Table 4. Unadjusted and adjusted eGFR slopes.
Supplemental Table 5. Hazard ratio for risk of kidney failure.
Supplemental Table 6. Clinical characteristics of CureGN and GDCN cohorts.
Supplemental Figure 1. eGFR slope over follow-up.
Supplemental Figure 2. Kidney survival in all groups.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Identifiable data, including genetic data, are protected in our local registry and within CureGN database; however, these data are not available publicly. Deidentified data can be requested.