APOL1 Variants Research Articles

APOL1 Bi- and Monoallelic Variants and Chronic Kidney Disease in West Africans.

Apolipoprotein L1 gene (APOL1) variants are risk factors for chronic kidney disease (CKD) among Black Americans. Data are sparse on the genetic epidemiology of CKD and the clinical association of APOL1 variants with CKD in West Africans, a major group in the Black population. We conducted a case-control study involving participants from Ghana and Nigeria who had CKD stages 2 through 5, biopsy-proven glomerular disease, or no kidney disease. We analyzed the association of CKD with APOL1 variants among participants with high-risk genotypes (two APOL1 risk alleles) and those with low-risk genotypes (fewer than two APOL1 risk alleles) by fitting logistic-regression models that controlled for covariates, including clinical site, age, and sex. Among 8355 participants (4712 with CKD stages 2 through 5, 866 with glomerular diseases, and 2777 with no kidney disease), the prevalence of monoallelic APOL1 variants was 43.0% and that of biallelic APOL1 variants was 29.7%. Participants with two APOL1 risk alleles had higher odds of having CKD than those with one risk allele or no risk alleles (adjusted odds ratio, 1.25; 95% confidence interval [CI], 1.11 to 1.40), as well as higher odds of focal segmental glomerulosclerosis (adjusted odds ratio, 1.84; 95% CI, 1.30 to 2.61). Participants with one APOL1 risk allele had higher odds of having CKD than those with no risk alleles (adjusted odds ratio, 1.18; 95% CI, 1.04 to 1.33), as well as higher odds of focal segmental glomerulosclerosis (adjusted odds ratio, 1.61; 95% CI, 1.04 to 2.48). The inclusion of covariates did not modify the association of monoallelic and biallelic APOL1 variants with CKD or focal segmental glomerulosclerosis. In this study, monoallelic APOL1 variants were associated with 18% higher odds of CKD and 61% higher odds of focal segmental glomerulosclerosis; biallelic APOL1 variants were associated with 25% higher odds of CKD and 84% higher odds of focal segmental glomerulosclerosis. (Funded by the National Human Genome Research Institute and others.).

Apolipoprotein-L1 (APOL1): From Sleeping Sickness to Kidney Disease.

Apolipoprotein-L1 (APOL1) is a membrane-interacting protein induced by inflammation, which confers human resistance to infection by African trypanosomes. APOL1 kills Trypanosoma brucei through induction of apoptotic-like parasite death, but two T. brucei clones acquired resistance to APOL1, allowing them to cause sleeping sickness. An APOL1 C-terminal sequence alteration, such as occurs in natural West African variants G1 and G2, restored human resistance to these clones. However, APOL1 unfolding induced by G1 or G2 mutations enhances protein hydrophobicity, resulting in kidney podocyte dysfunctions affecting renal filtration. The mechanism involved in these dysfunctions is debated. The ability of APOL1 to generate ion pores in trypanosome intracellular membranes or in synthetic membranes was provided as an explanation. However, transmembrane insertion of APOL1 strictly depends on acidic conditions, and podocyte cytopathology mainly results from secreted APOL1 activity on the plasma membrane, which occurs under non-acidic conditions. In this review, I argue that besides inactivation of APOL3 functions in membrane dynamics (fission and fusion), APOL1 variants induce inflammation-linked podocyte toxicity not through pore formation, but through plasma membrane disturbance resulting from increased interaction with cholesterol, which enhances cation channels activity. A natural mutation in the membrane-interacting domain (N264K) abrogates variant APOL1 toxicity at the expense of slightly increased sensitivity to trypanosomes, further illustrating the continuous mutual adaptation between host and parasite.

Association between APOL 1 Risk Genotypes and Left Ventricular Hypertrophy among Sub-Saharan Africans in Trypanosoma Brucei Gambiense Endemic Rural Area

Purpose. The relationship between APOL1 variants and cardiovascular disease remains controversial, thus, this study assessed the association between APOL1 high-risk genotypes and left ventricular hypertrophy (LVH) among sub-Saharan African in T.b. gambiense endemic area. Methodology. We enrolled 238 subjects living in the region of Masimanimba, an endemic area of T.b.gambiense HAT. We evaluated the association between LVH on echocardiography and the status of APOL1 genes in participants with or without HAT. APOL1 high-risk genotype (HRG) was defined as the presence of two risk variants (G1/G1, G2/G2, or G1/G2), and a low-risk genotype (LRG) with the presence of 0 or 1 single variant. Student’s and Pearson's Chi2 tests or Fisher’s exact test were used to compare means and proportions. The Wilcoxon/Mann–Whitney test was used to compare medians. A multivariate logistic regression model was used to identify independent determinants of LVH. Odds ratios were provided with their 95% confidence intervals (Cis). Statistical significance was set at p < 0.05, based on 2-tailed test. Findings. The prevalence of LVH (31.5%) increased with age and was similar in HAT-infected and non-infected subjects (29.8% vs. 32.6%; p=0.376). The trend of a greater left ventricular mass in participants with LVH carrying APOL1 HRG compared to those with LRG was not statistically significant (141g/m2 vs. 125 g/m2; p = 0.253). The frequency of HRG among participants with LVH was similar between HAT-infected and non-infected (15.8% vs. 9.1%; p = 0.806). Age ≥ 38 years [OR 2.5 (95% CI: 1.4-4.5), p = 0.001], hypertension [OR 2.4 (95% CI: 1.1-5.3), p = 0.034], WHR > 0.5 [OR 2.0 (95% CI: 1.0-3.6), p = 0.018] and CKD [OR 1.7 (95% CI: 1.0-3.0), p = 0.049] were associated with LVH. In multivariable logistic regression analysis age ≥ 38 years was the only independent determinant of LVH [ORa 2.0 (95% CI: 1.1-3.8), p = 0.020]. Unique contribution to theory, practice and policy. An assessment of cardiovascular risk is essential for individuals with LVH carrying APOL1 HRG in order to benefit from early and appropriate medical intervention. Further larger prospective follow-up survey is required to assess the incidence of LVH in individuals with APOL1 HRG variants.

#228 APOL1 variants and chronic kidney disease in Morocco: case control study

Abstract Background and Aims APOL1 genetic variants account for much of the excess risk of chronic and end stage kidney disease, which results in a significant global health disparity for persons of African ancestry. We estimate the lifetime risk of kidney disease in APOL1 dual-risk allele individuals to be at least 15%. These genetic variants were never tested in north African patients and this is the first study aimed to search the existence of this variants in general Moroccan people and patients with chronic kidney disease. Method This is a case control multi center study including Moroccan adult with GFR less than 60 ml per min secondary to unknown etiology or nephroangiosclerosis. Patients with known nephropathy or diabetes were excluded. Between July 2014 and June 2017, patients and 100 controls were enrolled for testing APOL1 variants. ADN extraction was done by isolate II Blood DNA kit and nucleic acid concentration by spectrophotometry. The allele frequency was calculated by PCR TaqMan. Results During the inclusion period 117 patients with chronic kidney disease from unknown etiology and 8 patients with nephroangiosclerosis were included from all the twelve Moroccan regions. There mean age was 49 years and more than 60% were males. The age of end stage renal disease was 42 years. Testing APOL1 variants did not find G1 or G2 classic mutations but we find a G2 deletion and a new mutation GAT to AAT in two patients. We find also a silent mutation AGA to AGG that we are exploring in a family investigation. Conclusion APOL1 genetic variants as described in the literature are not significantly present in Moroccan patient with chronic kidney disease and cannot be yet used as a risk factor in our context. However we find a new mutation needing a wide exploration in a bigger cohort

African ancestry-derived APOL1 risk genotypes show proximal epigenetic associations

Apolipoprotein L1 (APOL1) coding variants, termed G1 and G2, are established genetic risk factors for a growing spectrum of diseases, including kidney disease, in individuals of African ancestry. Evidence suggests that the risk variants, which show a recessive mode of inheritance, lead to toxic gain-of-function changes of the APOL1 protein. Disease occurrence and presentation vary, likely due to modifiers or second hits. To understand the role of the epigenetic landscape in relation to APOL1 risk variants, we performed methylation quantitative trait locus (meQTL) analysis to identify differentially methylated CpGs influenced by APOL1 risk variants in 611 African American individuals. We identified five CpGs that were significantly associated with APOL1 risk alleles in discovery and replication studies, and one CpG-APOL1 association was independent of other genomic variants. Our study highlights proximal DNA methylation alterations that may help explain the variable disease risk and clinical manifestation of APOL1 variants.

Unveiling APOL1 haplotypes in a predominantly African-American cohort of kidney transplant patients: a novel classification using probe-independent quantitative real-time PCR.

Apolipoprotein-L1 (APOL1) is a primate-specific protein component of high-density lipoprotein (HDL). Two variants of APOL1 (G1 and G2), provide resistance to parasitic infections in African Americans but are also implicated in kidney-related diseases and transplant outcomes in recipients. This study aims to identify these risk variants using a novel probe-independent quantitative real-time PCR method in a high African American recipient cohort. Additionally, it aims to develop a new stratification approach based on a haplotype-centric model. Genomic DNA was extracted from recipient PBMCs using SDS lysis buffer and proteinase K. A quantitative PCR assay with modified forward primers and a common reverse primer enabled us to quantitatively identify single nucleotide polymorphisms (SNPs) and the 6-bp deletion. Additionally, we used Sanger sequencing to verify our QPCR findings. Our novel probe-independent qPCR effectively distinguished homozygous wild-type, heterozygous SNPs/deletions, and homozygous SNPs/deletions, with at least 4-fold differences. A high prevalence of APOL1 variants was observed (18% two-risk alleles, 34% one-risk allele) in our recipient cohort. Intriguingly, no significant impact of recipient APOL1 variants on transplant outcomes was observed up to 12-month of follow-ups. Ongoing research will encompass more time points and a larger patient cohort, allowing for a comprehensive evaluation of G1/G2 variant subgroups categorized by new haplotype scores, enriching our understanding. Our cost-effective and rapid qPCR technique facilitates APOL1 genotyping within hours. Prospective and retrospective studies will enable comparisons with long-term allograft rejection, potentially predicting early/late-stage transplant outcomes based on haplotype evaluation in this diverse group of kidney transplant recipients.

Safety and Tolerability of the APOL1 Inhibitor, Inaxaplin, following Single- and Multiple-Ascending Doses in Healthy Adults

Introduction: Toxic gain-of-function Apolipoprotein L1 (APOL1) variants contribute to the development of proteinuric nephropathies collectively referred to as APOL1-mediated kidney disease (AMKD). Despite standard-of-care treatments, patients with AMKD experience accelerated progression to end-stage kidney disease. The identification of two APOL1 variants as the genetic cause of AMKD inspired development of inaxaplin, an inhibitor of APOL1 channel activity that reduces proteinuria in patients with AMKD. Methods: We conducted two phase 1 studies evaluating the safety, tolerability, and pharmacokinetics of single-ascending doses (SAD) and multiple-ascending doses (MAD) of inaxaplin in healthy participants. In the SAD cohorts, participants were randomized to receive inaxaplin as a single dose (range, 7.5 mg to 165 mg) or placebo. In the MAD cohorts, participants were randomized to receive multiple doses of inaxaplin (range, 15 to 120 mg daily) or placebo for 14 days. We assessed safety and tolerability based on adverse events (AEs), clinical laboratory values, electrocardiograms (ECGs), and vital signs. Results: A total of 178 participants were randomized in the SAD/MAD cohorts of both studies (mean age: 36.7 years; 94.9% male). The proportion of participants with any AEs was similar in the inaxaplin (24.6%) and placebo (22.7%) groups. All AEs were mild or moderate in severity; there were no serious AEs. Headache was the most common AE: 10.4% and 2.3% in the inaxaplin and placebo groups, respectively. There were no drug-related treatment discontinuations and no clinically relevant trends in laboratory values, ECGs, or vital signs. Discussion/Conclusion: Inaxaplin is safe and well tolerated at single doses up to 165 mg and multiple doses up to 120 mg daily for 14 days. These results are consistent with the favorable safety profile of inaxaplin in a completed phase 2a proof-of-concept study. Together, these findings support continued evaluation of inaxaplin in an ongoing phase 2/3 pivotal trial as a potential precision medicine for patients with AMKD.

Phenome-wide analysis reveals epistatic associations between APOL1 variants and chronic kidney disease and multiple other disorders

APOL1 variants G1 and G2 are common in populations with recent African ancestry. They are associated with protection from African sleeping sickness, however homozygosity or compound heterozygosity for these variants is associated with chronic kidney disease (CKD) and related conditions. What is not clear is the extent of associations with non-kidney-related disorders, and whether there are clusters of diseases associated with individual APOL1 genotypes. Using a cohort of 7462 UK Biobank participants with recent African ancestry, we conducted a phenome-wide association study investigating associations between individual APOL1 genotypes and conditions identified by the International Classification of Disease phenotypes. We identified 27 potential associations between individual APOL1 genotypes and a diverse range of conditions. G1/G2 compound heterozygotes were specifically associated with 26 of these conditions (all deleteriously), with an over-representation of infectious diseases (including hospitalisation and death resulting from COVID-19). The analysis also exposed complexities in the relationship between APOL1 and CKD that are not evident when risk variants are grouped together: G1 homozygosity, G2 homozygosity, and G1/G2 compound heterozygosity were each shown to be associated with distinct CKD phenotypes. The multi-locus nature of the G1/G2 genotype means that its associations would go undetected in a standard genome-wide association study. Our findings have implications for understanding health risks and better-targeted detection, intervention, and therapeutic strategies, particularly in populations where APOL1 G1 and G2 are common such as in sub-Saharan Africa and its diaspora. This study was funded by the Wellcome Trust (209511/Z/17/Z) and H3Africa (H3A/18/004).

Evaluating ApoL1 Genetic Testing Policy Options for Transplant Centers: A Delphi Consensus Panel Project with Stakeholders.

Apolipoprotein L1 (ApoL1) variants G1 and G2 are associated with a higher risk of kidney disease. ApoL1 risk variants are predominantly seen in individuals with sub-Saharan African ancestry. In most transplant centers, potential organ donors are being selectively genetically tested for ApoL1 risk variants. Transplant programs have highly variable ApoL1 testing practices and need guidance on essential ApoL1 clinical policy questions. We conducted a Delphi consensus panel focused on ApoL1 clinical policy questions, including who gets tested, who decides whether testing occurs, how test results are shared, who receives test results, and how test results are used. A total of 27 panelists across seven stakeholder groups participated: living kidney donors ( n =4), deceased donor family members ( n =3), recipients of a deceased donor kidney ( n =4), recipients of a living donor kidney ( n =4), nephrologists ( n =4), transplant surgeons ( n =4), and genetic counselors ( n =4). Nineteen panelists (70%) identified as Black. The Delphi panel process involved two rounds of educational webinars and three rounds of surveys administered to panelists, who were asked to indicate whether they support, could live with, or oppose each policy option. The panel reached consensus on one or more acceptable policy options for each clinical policy question; panelists supported 18 policy options and opposed 15. Key elements of consensus include the following: ask potential donors about African ancestry rather than race; make testing decisions only after discussion with donors; encourage disclosure of test results to blood relatives and organ recipients but do not require it; use test results to inform decision making, but never for unilateral decisions by transplant programs. The panel generally supported policy options involving discussion and shared decision making among patients, donors, and family stakeholders. There was general opposition to unilateral decision making and prohibiting donation altogether.

APOL1 Risk Variants Associate With the Prevalence of Stroke in African American Current and Past Smokers.

African American smokers have 2.5 times higher risk for stroke compared with nonsmokers (higher than other races). About 50% of the African American population carry 1 or 2 genetic variants (G1 and G2; rare in other races) of the apolipoprotein L1 gene (APOL1). Studies showed these variants may be associated with stroke. However, the role of the APOL1 risk variants in tobacco-related stroke is unknown. In a cross-sectional study, we examined whether APOL1 risk variants modified the relationship between tobacco smoking and stroke prevalence in 513 African American adults recruited at University of California, San Francisco. Using DNA, plasma, and questionnaires we determined APOL1 variants, smoking status, and stroke prevalence. Using logistic regression models, we examined the association between smoking (ever versus never smokers) and stroke overall, and among carriers of APOL1 risk variants (1 or 2 risk alleles), and noncarriers, separately. Among participants, 41% were ever (current and past) smokers, 54% were carriers of the APOL1 risk variants, and 41 had a history of stroke. The association between smoking and stroke differed by APOL1 genotype (Pinteraction term=0.014). Among carriers, ever versus never smokers had odds ratio (OR) 2.46 (95% CI, 1.08-5.59) for stroke (P=0.034); OR 2.00 (95% CI, 0.81-4.96) among carriers of 1 risk allele, and OR 4.72 (95% CI, 0.62-36.02) for 2 risk alleles. Among noncarriers, smoking was not associated with a stroke. Current and past smokers who carry APOL1 G1 and/or G2 risk variants may be more susceptible to stroke among the African American population.

Development of a Genetic Risk Score for Albuminuria in Pediatric Patients with Sickle Cell Anemia

Introduction Sickle cell anemia (SCA) causes progressive, age-dependent, kidney damage. Albuminuria is an early clinical biomarker for chronic kidney disease (CKD) and is associated with progressive glomerular injury. Identifying patients at risk for albuminuria is critical for early institution of renoprotective interventions to prevent progressive kidney injury. Developing a genetic risk score (GRS) to predict albuminuria is one approach to identifying high risk patients. Our prior data demonstrates that Apolipoprotein-L1 ( APOL1 G1/G2) is associated with early development of albuminuria in children with SCA (PMID:30890594). However, this gene variant does not account for all kidney disease progression. Multiple other gene variants that modify SCA-severity have been associated with CKD in adults with SCA. We hypothesized that developing a genetic risk score (GRS) will allow for identification of pediatric patients at increased risk for development and progression of kidney disease. We aimed to develop a novel pediatric GRS that can identify pediatric SCA patients at high risk for albuminuria. Methods Gene allele variants in APOL1 G1/G2, HMOX1, BCL11A and α-thalassemia (α -3.7 allele), were identified in 324 African American patients with SCA (HbSS or HbS 0-thalassemia genotypes) enrolled in the Sickle Cell Clinical Research and Intervention Program (NCT02098863), a lifespan, longitudinal cohort study. The first urine albumin to creatinine ratio (ACR) collected after birth was analyzed as a continuous variable and dichotomized by a threshold of ACR ≥30mg/g creatinine as albuminuria. We defined a GRS 3 based on established risk alleles in three genes: APOL1 (G1/G2 ), BCL11A (rs1427407), and α -3.7(PMID:27658436). High risk was defined as patients with APOL1 (G1/G1, G2/G2 or G1/G2), without α -3.7 and with wildtype BCL11A (G/G); low-risk was defined as patients negative for APOL1 G1/G2 and with α -3.7 (either α -3.7/αα or α -3.7/α -3.7) and the BCL11A T allele (either G/T or T/T). All other combinations were defined as intermediate risk. By adding HMOX1 (rs743811), C allele (TT/TC vs CC), we further refined GRS 3 as GRS 4 using the summation of the number of high-risk alleles of kidney outcomes for four variants and created four risk categories. The generalized linear regression model was used to associate additive dose-effect models for GRS 3 and GRS 4 with continuous ACR and albuminuria, adjusted for age, sex, hydroxyurea treatment, 5 principal components, and, if significant, the age-genotype interaction. ACR was log-transformed to approximate normality. As we included variants with known associations, we used a one-sided p-value for testing associations of individual variants, GRS 3, and two-sided p-values for GRS 4. P-values <0.05 were considered significant. Results In 324 individuals with SCA, those with albuminuria (34, 10.5%) appeared to be older than those without albuminuria (290, 89.5%) (mean 9.8 years [standard deviation ±4.4 years] vs. 8.6 [± 4.0], p=0.053). There were no significant differences between these groups by sex (female 58% vs. 49%, p=0.37), proportion on hydroxyurea (62% vs. 59%, p=0.85) or fetal hemoglobin (15.6 [± 10.61] vs. 14.8% [± 10.0], p= 0.81). All four individual genetic variants were associated with the first ACR (all p ≤ 0.028) and albuminuria (all p≤ 0.03). GRS 3 was significantly associated with the first ACR (estimate=1.4, standard error [SE]=0.5, p=0.0035) and albuminuria (odds ratio [OR]=3.0, 95% CI: 1.2-7.5, p= 0.008). After adding HMOX1 to GRS 3, GRS 4 was more significantly associated with the first ACR (estimate=0.9, SE=0.3, p=0.0005) and albuminuria (OR=2.0, 95% CI: 1.2-3.4, p=0.003). Summary We developed a GRS 3 based on three genetic variants associated with albuminuria in pediatric patients with SCA and stratified patients into different risk categories. Addition of a fourth genetic variant to create GRS 4improved the model. Our findings will need to be validated in larger longitudinal studies to further examine the association between GRS 4 and development of albuminuria and chronic kidney disease. Genetic prediction strategies using GRS has the potential to identify high risk SCA patients for whom renoprotective measures could prevent the development of albuminuria.

Disease Progression in Patients with Two APOL1 Variants and Proteinuric CKD from the AASK, CRIC, and FSGS-CT Datasets

Disease Progression in Patients with Two APOL1 Variants and Proteinuric CKD from the AASK, CRIC, and FSGS-CT Datasets

Prevalence of APOL1 Variants in Persons with Proteinuric CKD

Prevalence of APOL1 Variants in Persons with Proteinuric CKD

Osteonecrosis is associated with APOL1 variants in African Americans with systemic lupus erythematosus

Background/purposeAfrican Americans (AA) with systemic lupus erythematosus (SLE) are at higher risk for both kidney disease and Osteonecrosis (ON). Two Apolipoprotein L1 (APOL1) risk variants (RV), G1 and G2, have been associated with chronic kidney disease (CKD), hypertension, and microvascular disease in AAs, which are independent risk factors for ON. Accordingly, we investigated the association between carriers of the APOL1 risk variants and the prevalence of ON in AA SLE patients.MethodsA cohort of 121 adult participants of self-reported AA ancestry and meeting at least four of the American College of Rheumatology (ACR) revised criteria for SLE were recruited from a high volume urban SLE clinical site. PCR/sequencing was used to stratify participants by APOL1 genotype. Medical records, including clinical notes and imaging reports, were retrospectively reviewed for documentation of ON. Association between the number of APOL1 risk variants with time to first ON was tested.ResultsIn our cohort, 18 individuals developed ON; across the APOL1 genotype groups, 2/37 0RV, 11/59 1RV, and 5/15 2RV participants were affected. The mean time to ON was 27 years, 22 years, and 18 years in 0RV, 1RV, and 2RV carriers, respectively. An adjusted Cox regression model showed that carrying the APOL1 risk variants associated with shorter ON free survival with hazard ratios (HR) of 3.1 (95% CI: 1.6–6.2) and 9.6 (95% CI 2.4–37.8) for 1RV and 2RV carriers, respectively. 2RV carriers more often exhibited multiple and bilateral joint sites affected by ON. Disease duration was longer in ON-affected participants at 20.5 years compared to 9.0 years in those unaffected (p < 0.001). In individuals who had received glucocorticoids, median cumulative prednisone equivalent dose was higher in ON-affected participants, though this did not reach statistical significance (18.7 g vs. 9.0 g; p-value = 0.3).ConclusionOur analysis suggests a higher risk of osteonecrosis among African American SLE patients who carry the APOL1 risk variants. In addition, disease duration increased the rate of ON. Given the high frequency of the APOL1 risk variants in African Americans, APOL1 high-risk genotype carriers may represent an ON-vulnerable subgroup within the AA population. Further work is necessary to uncover the mechanism of this association.

Genetic Inhibition of APOL1 Pore-Forming Function Prevents APOL1-Mediated Kidney Disease.

African Americans are at increased risk of CKD in part due to high-risk (HR) variants in the apolipoprotein L1 ( APOL1 ) gene, termed G1/G2. A different APOL1 variant, p.N264K , reduced the risk of CKD and ESKD among carriers of APOL1 HR variants to levels comparable with individuals with APOL1 low-risk variants in an analysis of 121,492 participants of African ancestry from the Million Veteran Program (MVP). Functional genetic studies in cell models showed that APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR mutations. Pharmacologic inhibitors that mimic this mutation blocking APOL1 -mediated pore formation may be able to prevent and/or treat APOL1 -associated kidney disease. African Americans are at increased risk for nondiabetic CKD in part due to HR variants in the APOL1 gene. We tested whether a different APOL1 variant, p.N264K , modified the association between APOL1 HR genotypes (two copies of G1/G2) and CKD in a cross-sectional analysis of 121,492 participants of African ancestry from the MVP. We replicated our findings in the Vanderbilt University Biobank ( n =14,386) and National Institutes of Health All of Us ( n =14,704). Primary outcome was CKD and secondary outcome was ESKD among nondiabetic patients. Primary analysis compared APOL1 HR genotypes with and without p.N264K . Secondary analyses included APOL1 low-risk genotypes and tested for interaction. In MVP, we performed sequential logistic regression models adjusting for demographics, comorbidities, medications, and ten principal components of ancestry. Functional genomic studies expressed APOL1 HR variants with and without APOL1 p.N264K in cell models. In the MVP cohort, 15,604 (12.8%) had two APOL1 HR variants, of which 582 (0.5%) also had APOL1 p.N264K . In MVP, 18,831 (15%) had CKD, 4177 (3%) had ESKD, and 34% had diabetes. MVP APOL1 HR, without p.N264K , was associated with increased odds of CKD (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.60 to 1.85) and ESKD (OR, 3.94; 95% CI, 3.52 to 4.41). In MVP, APOL1 p.N264K mitigated the renal risk of APOL1 HR, in CKD (OR, 0.43; 95% CI, 0.28 to 0.65) and ESKD (OR, 0.19; CI 0.07 to 0.51). In the replication cohorts meta-analysis, APOL1 p.N264K mitigated the renal risk of APOL1 HR in CKD (OR, 0.40; 95% CI, 0.18 to 0.92) and ESKD (OR, 0.19; 95% CI, 0.05 to 0.79). In the mechanistic studies, APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR variants. APOL1 p.N264K is associated with reduced risk of CKD and ESKD among carriers of APOL1 HR to levels comparable with individuals with APOL1 low-risk genotypes.

African American/Black race, apolipoprotein L1 , and serum creatinine among persons with HIV.

Accurate estimation of kidney function is critical among persons with HIV (PWH) to avoid under-dosing of antiretroviral therapies and ensure timely referral for kidney transplantation. Existing estimation equations for kidney function include race, the appropriateness of which has been debated. Given advancements in understanding of race and the necessity of accuracy in kidney function estimation, this study aimed to examine whether race, or genetic factors, improved prediction of serum creatinine among PWH. This cross-sectional study utilized data from the Center for AIDS Research Network of Integrated Clinical Systems cohort (2008-2018). The outcome was baseline serum creatinine. Ordinary least squares regression was used to examine whether inclusion of race or genetic factors [ apolipoprotein-L1 ( APOL1 ) variants and genetic African ancestry] improved serum creatinine prediction. A reduction in root mean squared error (RMSE) greater than 2% was a clinically relevant improvement in predictive ability. There were 4183 PWH included. Among PWH whose serum creatinine was less than 1.7 mg/dl, race was significantly associated with serum creatinine ( β = 0.06, SE = 0.01, P < 0.001) but did not improve predictive ability. African ancestry and APOL1 variants similarly failed to improve predictive ability. Whereas, when serum creatinine was at least 1.7 mg/dl, inclusion of race reduced the RMSE by 2.1%, indicating improvement in predictive ability. APOL1 variants further improved predictive ability by reducing the RMSE by 2.9%. These data suggest that, among PWH, inclusion of race or genetic factors may only be warranted at higher serum creatinine levels. Work eliminating existing healthcare disparities while preserving the utility of estimating equations is needed.

The metabolic effects of APOL1 in humans.

Harboring apolipoprotein L1 (APOL1) variants coded by the G1 or G2 alleles of the APOL1 gene increases the risk for collapsing glomerulopathy, focal segmental glomerulosclerosis, albuminuria, chronic kidney disease, and accelerated kidney function decline towards end-stage kidney disease. However, most subjects carrying APOL1 variants do not develop the kidney phenotype unless a second clinical condition adds to the genotype, indicating that modifying factors modulate the genotype-phenotype correlation. Subjects with an APOL1 high-risk genotype are more likely to develop essential hypertension or obesity, suggesting that carriers of APOL1 risk variants experience more pronounced insulin resistance compared to noncarriers. Likewise, arterionephrosclerosis (the pathological correlate of hypertension-associated nephropathy) and glomerulomegaly take place among carriers of APOL1 risk variants, and these pathological changes are also present in conditions associated with insulin resistance, such as essential hypertension, aging, and diabetes. Insulin resistance may contribute to the clinical features associated with the APOL1 high-risk genotype. Unlike carriers of wild-type APOL1, bearers of APOL1 variants show impaired formation of lipid droplets, which may contribute to inducing insulin resistance. Nascent lipid droplets normally detach from the endoplasmic reticulum into the cytoplasm, although the proteins that enable this process remain to be fully defined. Wild-type APOL1 is located in the lipid droplet, whereas mutated APOL1 remains sited at the endoplasmic reticulum, suggesting that normal APOL1 may participate in lipid droplet biogenesis. The defective formation of lipid droplets is associated with insulin resistance, which in turn may modulate the clinical phenotype present in carriers of APOL1 risk variants.

Coronavirus disease 2019-associated nephropathy in an African American patient: a case report and review of the literature

BackgroundAcute kidney injury is now recognized as a common complication of coronavirus disease 2019, affecting up to 46% of patients, with acute tubular injury as the most common etiology. Recently, we have seen an increase in cases of collapsing glomerulonephritis in patients with coronavirus disease 2019, also known as coronavirus disease 2019-associated nephropathy. It has been noted to be seen with a higher incidence in African American patients who are carriers of the APOL1 variant allele.Case presentationA 47-year-old African American male with a past medical history of asthma presented to the emergency department with complaints of intermittent chest pain, shortness of breath, and worsening confusion. On admission, he was found to be hemodynamically stable, but labs were significant for elevated creatinine and blood urea nitrogen, signifying acute kidney injury. He was admitted and taken for emergent dialysis. During his hospitalization, he was found to be positive for coronavirus disease 2019. Renal biopsy was done, which showed collapsing glomerulopathy, and the patient continues to require outpatient dialysis after discharge.ConclusionCollapsing glomerulonephritis has emerged as a complication in patients with coronavirus disease 2019. This condition should be particularly suspected in African American patients who present with acute kidney injury, nephrotic-range proteinuria, and who are positive for coronavirus disease 2019. Current treatment options are limited to supportive treatment and renal replacement therapy. More clinical cases and trials are needed to better understand and improve therapeutic outcomes in these patients.

Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants

BackgroundPersons with toxic gain-of-function variants in the gene encoding apolipoprotein L1 (APOL1) are at greater risk for the development of rapidly progressive, proteinuric nephropathy. Despite the known genetic cause, therapies targeting proteinuric kidney disease in persons with two APOL1 variants (G1 or G2) are lacking.MethodsWe used tetracycline-inducible APOL1 human embryonic kidney (HEK293) cells to assess the ability of a small-molecule compound, inaxaplin, to inhibit APOL1 channel function. An APOL1 G2–homologous transgenic mouse model of proteinuric kidney disease was used to assess inaxaplin treatment for proteinuria. We then conducted a single-group, open-label, phase 2a clinical study in which inaxaplin was administered to participants who had two APOL1 variants, biopsy-proven focal segmental glomerulosclerosis, and proteinuria (urinary protein-to-creatinine ratio of ≥0.7 to <10 [with protein and creatinine both measured in grams] and an estimated glomerular filtration rate of ≥27 ml per minute per 1.73 m2 of body-surface area). Participants received inaxaplin daily for 13 weeks (15 mg for 2 weeks and 45 mg for 11 weeks) along with standard care. The primary outcome was the percent change from the baseline urinary protein-to-creatinine ratio at week 13 in participants who had at least 80% adherence to inaxaplin therapy. Safety was also assessed.ResultsIn preclinical studies, inaxaplin selectively inhibited APOL1 channel function in vitro and reduced proteinuria in the mouse model. Sixteen participants were enrolled in the phase 2a study. Among the 13 participants who were treated with inaxaplin and met the adherence threshold, the mean change from the baseline urinary protein-to-creatinine ratio at week 13 was −47.6% (95% confidence interval, −60.0 to −31.3). In an analysis that included all the participants regardless of adherence to inaxaplin therapy, reductions similar to those in the primary analysis were observed in all but 1 participant. Adverse events were mild or moderate in severity; none led to study discontinuation.ConclusionsTargeted inhibition of APOL1 channel function with inaxaplin reduced proteinuria in participants with two APOL1 variants and focal segmental glomerulosclerosis. (Funded by Vertex Pharmaceuticals; VX19-147-101 ClinicalTrials.gov number, NCT04340362.)

Kidney Disease Progression in Membranous Nephropathy among Black Participants with High-Risk APOL1 Genotype.

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. 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. 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 m 2 per year) compared with low-risk APOL1 genotype (-4±0.8 ml/min per 1.73 m 2 per year) or membranous nephropathy participants that did not identify themselves as Black (-2.0±0.4 ml/min per 1.73 m 2 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. 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.