Apolipoprotein L1 High-risk Genotypes Research Articles

Surrogate Endpoints in APOL1-Associated Kidney Disease: Evaluation in Three Cohorts.

Surrogate endpoints for the clinical outcome of kidney failure have been accepted by the United States Food and Drug Administration. However, they have not been specifically evaluated in Apolipoprotein L1 (APOL1)-associated kidney disease. This random-effects meta-analysis included African-American participants in the Atherosclerosis Risk in Communities (ARIC) study (N=3071), the Chronic Renal Insufficiency Cohort (CRIC; N=998), and the African American Study of Kidney Disease and Hypertension (AASK; N=609). Surrogate endpoints included three-year 30% and 40% decline in glomerular filtration rate (GFR), doubling of urine protein-to-creatinine ratio (UPCR), and >3 ml/min/1.73 m2 per year decline in GFR. Clinical outcomes included kidney failure requiring kidney replacement therapy, heart failure, cardiovascular disease, and death after three years.Results: 22% in AASK, 18% in CRIC, and 13% in ARIC had the APOL1 high risk genotype. Participants with the APOL1 high-risk genotype had higher risk of all three-year GFR outcomes but not doubling of UPCR, as well as kidney failure after three years. The three-year outcomes were strongly associated with kidney failure, with weaker but statistically significant associations with the development of heart failure, cardiovascular disease, and mortality. There were no differences in associations between short-term and long-term clinical outcomes by APOL1 risk status. Individuals with the APOL1 high risk genotype were more susceptible to three-year GFR-related endpoints and long-term kidney failure than individuals with the APOL1 low-risk genotype. There was no consistent difference in short-term-clinical outcome associations by APOL1 genotype, supporting the use of surrogates in APOL1-associated kidney disease.

Epigenetic associations with kidney disease in individuals of African ancestry with APOL1 high-risk genotypes and Human Immunodeficiency Virus.

Apolipoprotein L1 (APOL1) high-risk variants are major determinants of chronic kidney disease (CKD) in people of African ancestry. Previous studies have identified epigenetic changes in relation to kidney function and CKD, but not in individuals with APOL1 high-risk genotypes. We conducted an epigenome-wide analysis of CKD and estimated glomerular filtration rate (eGFR) in in people of African ancestry and APOL1 high-risk genotypes with HIV. DNA methylation profiles from peripheral blood mononuclear cells of 119 individuals with APOL1 high-risk genotypes (mean age 48 years, 49% female, median CD4 count 515 cells/mm3, 90% HIV-1 RNA <200 copies/mL, 23% with CKD) were obtained by Illumina MethylationEPIC BeadChip. Differential methylation analysis of CKD considered technical and biological covariates. We also assessed associations with eGFR. Replication was pursued in three independent multi-ancestry cohorts with and without HIV. DNA methylation levels at 14 regions were associated with CKD. The strongest signals were located in SCARB1, DNAJC5B and C4orf50. Seven of the 14 signals also associated with eGFR, and most showed evidence for a genetic basis. Four signals (in SCARB1, FRMD4A, CSRNP1 and RAB38) replicated in other cohorts, and 11 previously reported epigenetic signals for kidney function or CKD replicated in our cohort. We found no significant DNA methylation signals in, or near, the APOL1 promoter region. We report several novel as well as previously reported epigenetic associations with CKD and eGFR in individuals with HIV having APOL1 high-risk genotypes. Further investigation of pathways linking DNA methylation to APOL1 nephropathies is warranted.

APOL1 High-Risk Genotype is Not Associated With New or Worsening of Proteinuria or Kidney Function Decline Following COVID-19 Vaccination

SARS-CoV-2 infection increases systemic inflammatory cytokines which act as a second-hit driver of Apolipoprotein L1 (APOL1)-mediated collapsing glomerulopathy. SARS-CoV-2 vaccination also increases cytokines. Recent reports of new glomerular disease in individuals with APOL1 high-risk genotype (HRG) following SARS-CoV-2 vaccination raised the concern SARS-CoV-2 vaccination may also act as a second-hit driver of APOL1-mediated glomerulopathy. We screened 1507 adults in the Duke's Measurement to Understand Reclassification of Disease of Cabarrus and Kannapolis (MURDOCK) registry and enrolled 105 eligible participants with available SARS-CoV-2 vaccination data, prevaccination and postvaccination serum creatinine, and urine protein measurements. Paired data were stratified by number of APOL1 risk alleles (RAs) and compared within groups using Wilcoxon signed rank test and across groups by analysis of variance. Among 105 participants, 30 (28.6%) had 2, 39 (37.1%) had 1, and 36 (34.3%) had 0 APOL1 RA. Most of the participants (94%) received at least 2 doses of vaccine. Most (98%) received the BNT162B2 (Pfizer) or mRNA-1273 (Moderna) vaccine. On average, the prevaccine and postvaccine laboratory samples were drawn 648 days apart. There were no detectable differences between pre- and post-serum creatinine or pre- and post-urine albumin creatinine ratio irrespective of the participants' APOL1 genotype. Finally, most participants with APOL1 RA had the most common haplotype (E150, I228, and K255) and lacked the recently described protective N264K haplotype. In this observational study, APOL1 HRG is not associated with new or worsening of proteinuria or decline in kidney function following SARS-CoV-2 vaccination. Validation of this result in larger cohorts would further support the renal safety of SARS-CoV-2 vaccine in individuals with APOL1 HRG.

APOLIPOPROTEIN-L1 RISK GENOTYPES ARE ASSOCIATED WITH CHRONIC KIDNEY DISEASE REGARDLESS OF HYPERTENSION STATUS IN A TRYPANOSOMA BRUCEI GAMBIENSE ENDEMIC AREA

Objective: this study assessed the frequency of Apolipoprotein-L1 high-risk genotypes in an African rural endemic area to Trypanosoma Brucei Gambiense, and evaluated their association with arterial hypertension according to human African trypanosomiasis infection status. Design and method: The study enrolled 94 human African trypanosomiasis-infected and 144 non–infected participants in Masimanimba, the Democratic Republic of the Congo. Apolipoprotein-L1 high-risk genotype was the presence of two variants (G1G1, G2G2, or G1G2), and low-risk genotype the presence of 0 or 1 variant. Albuminuria was an albumin/creatinine ratio greater than or equal to 30 mg/g on freshly voided urine. We evaluated the association between Apolipoprotein-L1 risk genotypes and hypertension in human African trypanosomiasis-infected and non-infected participants. Results: The study population was aged 39.7 ± 17.1 years (females 62.2%). The frequency of high-risk genotypes among hypertensive participants was 14.3% in both human African trypanosomiasis - infected and uninfected individuals. Albuminuria (100% vs. 38.9%; p=0.09) was higher and estimated Glomerular Filtration Rate lower (88.5 vs. 106 ml/min/1.73 m2, p =0.066) in high-risk genotypes than low-risk carrying hypertensive participants. The respective values in non-hypertensive individuals were 100% vs. 37.5% (p=0.002) and 83 vs. 109.5 ml/min/1.73 m2 (p &lt;0.001) for albuminuria and estimated Glomerular Filtration Rate. Conclusions: Apolipoprotein-L1 high-risk genotypes are associated with Chronic Kidney Disease regardless of the hypertension status in Human African Trypanosomiasis endemic area

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 &amp;lt; 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.

#4385 RELEVANCE OF REPEATED ALBUMINURIA AND GLOMERULAR FILTRATION RATE IN A LARGE COHORT OF SICKLE CELL ANEMIA CHILDREN LIVING IN A RESOURCE-LIMITED AREA

Abstract Background and Aims Chronic kidney disease (CKD) is associated with significant morbidity and mortality among patients with sickle cell anemia (SCA). Glomerular hyperfiltration (GHF) and albuminuria are known as early manifestations of kidney disease occurring in early childhood and can predict the progression to CKD in these patients. Studies reported the prevalence of these kidney abnormalities in SCA children using a single measure and their association with genetic risk factors, especially the co-inheritance of APOL1 risk variants (RVs). However, data on the prevalence of persistent kidney abnormalities (based on the KDIGO CKD definition) and their association with APOL1 RVs are limited in SCA children, particularly those living in sub-Saharan Africa. This study aimed: (i) to determine the prevalence of persistent kidney abnormalities (albuminuria and/or GHF) in SCA children living in the Democratic Republic of Congo (DRC); and (ii) to assess the association between persistent kidney abnormalities with clinical and genetic risk factors. Method From March 2021 to December 2022, we prospectively enrolled 585 steady state SCA children aged 2 to 18 years (male gender 278/585; 47.5%). The SCA status was confirmed through the molecular sequencing of beta-globin gene. Clinical and biological parameters were obtained. All participants were genotyped for apolipoprotein-L1 (APOL1) G1 (rs73885319, rs60910145) and G2 (rs71785313) variants. APOL1 high-risk genotype (HRG) was defined by the presence of 2 risk variants (G1/G1, G2/G2, and G1/G2), and low-risk genotype (LRG) by the presence of 0 or 1 risk variant. Albuminuria was defined as urinary albumin-to-creatinine ratio (ACR) ≥ 30mg/g. The estimated glomerular filtration rate (eGFRcr) was calculated using the original Schwartz formula and GHF was defined as eGFRcr ≥ 180 ml/min/1.73 m2 for children between 2-10 years of age and &amp;gt; 140 ml/min/1.73 m2 for children more than 10 years of age. All measurements were repeated at least three months later in participants who presented with kidney abnormalities at the first screening. The main outcome parameter was persistent albuminuria or persistent GHF for more than three months. Results At enrollment, 234/585 (40.0%) participants presented with kidney abnormalities, among which 80/585 (13.7%) with albuminuria and 171/585 (29.2%) with hyperfiltration. From participants found with kidney abnormalities at the first screening, 176/234 (75.2%) were available for repeated screening: 56/176 (31.8%) presented with persistent kidney abnormalities and 120/176 (68.2%) had a regression of kidney abnormalities without any treatment. Out of 176 participants who benefited from repeated screening, 57 had baseline albuminuria and 130 had baseline GHF. Persistent albuminuria and persistent GHF were found in 38.6% (22/57) and 28.5% (37/130), respectively. Multivariate logistic regression revealed that APOL1 HRG was significantly associated with persistent albuminuria (OR 3.4, 95CI 1.1-10.7, p = 0.037), while male gender was significantly associated with persistent GHF (OR 2.1, 95CI 1.0-4.2, p = 0.042). Conclusion A significant proportion (almost 70.0%) of SCA children who had kidney abnormalities at the first measure, presented regression of these abnormalities without any reno-protective drugs. This result emphasizes the importance of repeating screening at least three months later to confirm CKD, as recommended by the KDIGO Guidelines. This strategy will reduce the need for unnecessary treatment, which represents a high financial burden in a resource-limited area.

APOL1 genotype in African American patients with kidney neoplasm

Context: African Americans (AA) may carry high risk Apolipoprotein L1 ( APOL1) genetic variants that predispose them to significantly higher incidence of chronic kidney disease (CKD) and renal cell carcinoma (RCC). Objective: To study the role of APOL1 risk alleles in patients of African descent with kidney neoplasms. Design: AA patients with nephrectomy procedure for kidney neoplasms were retrospectively studied for APOL1 genotype. Non-AA patients with kidney neoplasm served as control group. Results: Thirty-six AA patients with kidney neoplasms were included. Sixteen (44%) patients carried no APOL1 risk alleles; 13 (36%) patients carried one APOL1 risk allele and 7 (19%) patients carried two APOL1 risk alleles. Increased risk of end stage kidney disease (ESKD) was observed in patients with two APOL1 risk alleles (OR = 3.45). We also observed a higher papillary carcinoma (pRCC) percentage in patients with two risk alleles. Five (71.4%) of the seven patients with two risk-alleles had pRCC. In patients with zero or one APOL1 risk allele ( n = 29), 8 (28%) had pRCC. However, in AA patients with ESKD ( n = 6), only 2 (33%) had PRCC. Among the non-AA patients ( n = 319), 7 (2.2%) patients presented with ESKD, of which 2 (33%) had pRCC. Conclusions: We observed a cluster phenomenon in APOL1 high-risk genotype, ESKD, and kidney neoplasm. We observed significantly more frequent papillary RCC prevalence in AA patients with high-risk APOL1 genotype.

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.

APOL1 promotes endothelial cell activation beyond the glomerulus

Apolipoprotein L1 (APOL1) high-risk genotypes are associated with increased risk of chronic kidney disease (CKD) in people of West African ancestry. Given the importance of endothelial cells (ECs) in CKD, we hypothesized that APOL1 high-risk genotypes may contribute to disease via EC-intrinsic activation and dysfunction. Single cell RNA sequencing (scRNA-seq) analysis of the Kidney Precision Medicine Project dataset revealed APOL1 expression in ECs from various renal vascular compartments. Utilizing two public transcriptomic datasets of kidney tissue from African Americans with CKD and a dataset of APOL1-expressing transgenic mice, we identified an EC activation signature; specifically, increased intercellular adhesion molecule 1 (ICAM-1) expression and enrichment in leukocyte migration pathways. Invitro, APOL1 expression in ECs derived from genetically modified human induced pluripotent stem cells and glomerular ECs triggered changes in ICAM-1 and platelet endothelial cell adhesion molecule 1 (PECAM-1) leading to an increase in monocyte attachment. Overall, our data suggest the involvement of APOL1 as an inducer of EC activation in multiple renal vascular beds with potential effects beyond the glomerular vasculature.

Chronic kidney disease (CKD) and associated risk in rural South Africa: a population-based cohort study.

Background: In Africa, true prevalence of chronic kidney disease (CKD) is unknown, and associated clinical and genetic risk factors remain understudied. This population-based cohort study aimed toinvestigate CKD prevalence and associated risk factors in rural South Africa. Methods: A total 2021 adults aged 20-79 years were recruited between 2017-2018 from the Agincourt Health and Socio-Demographic Surveillance System in Bushbuckridge, Mpumalanga, South Africa. The following were collected: sociodemographic, anthropometric, and clinical data; venous blood samples for creatinine, hepatitis B serology; DNA extraction; spot urine samples for dipstick testing and urine albumin: creatinine ratio (UACR) measurement. Point-of-care screening determined prevalent HIV infection, diabetes, and hypercholesterolemia. DNA was used to test for apolipoprotein L1 ( APOL1) kidney risk variants. Kidney Disease Improving Global Outcomes (KDIGO) criteria were used to diagnose CKD as low eGFR (<60mL/min/1.73m 2) and /or albuminuria (UACR ≥ 3.0mg/mmol) confirmed with follow up screening after at least three months. eGFR was calculated using the CKD-EPI (creatinine) equation 2009 with no ethnicity adjustment. Multivariable logistic regression was used to model CKD risk. Results: The WHO age-adjusted population prevalence of CKD was 6.7% (95% CI 5.4 - 7.9), mostly from persistent albuminuria. In the fully adjusted model, APOL1 high-risk genotypes (OR 2.1; 95% CI 1.3 - 3.4); HIV infection (OR 1.8; 1.1 - 2.8); hypertension (OR 2.8; 95% CI 1.8 - 4.3), and diabetes (OR 4.1; 95% CI 2.0 - 8.4) were risk factors. There was no association with age, sex, level of education, obesity, hypercholesterolemia, or hepatitis B infection. Sensitivity analyses showed that CKD risk factor associations were driven by persistent albuminuria, and not low eGFR. One third of those with CKD did not have any of these risk factors. Conclusions: In rural South Africa, CKD is prevalent, dominated by persistent albuminuria, and associated with APOL1 high-risk genotypes, hypertension, diabetes, and HIV infection.

APOL1 variant-expressing endothelial cells exhibit autophagic dysfunction and mitochondrial stress.

Polymorphisms in the Apolipoprotein L1 (APOL1) gene are common in ancestrally African populations, and associate with kidney injury and cardiovascular disease. These risk variants (RV) provide an advantage in resisting Trypanosoma brucei, the causal agent of African trypanosomiasis, and are largely absent from non-African genomes. Clinical associations between the APOL1 high risk genotype (HRG) and disease are stronger in those with comorbid infectious or immune disease. To understand the interaction between cytokine exposure and APOL1 cytotoxicity, we established human umbilical vein endothelial cell (HUVEC) cultures representing each APOL1 genotype. Untreated HUVECs were compared to IFNɣ-exposed; and APOL1 expression, mitochondrial function, lysosome integrity, and autophagic flux were measured. IFNɣ increased median APOL1 expression across all genotypes 22.1 (8.3 to 29.8) fold (p=0.02). Compared to zero risk variant-carrying HUVECs (0RV), HUVECs carrying 2 risk variant copies (2RV) showed both depressed baseline and maximum mitochondrial oxygen consumption (p<0.01), and impaired mitochondrial networking on MitoTracker assays. These cells also demonstrated a contracted lysosomal compartment, and an accumulation of autophagosomes suggesting a defect in autophagic flux. Upon blocking autophagy with non-selective lysosome inhibitor, hydroxychloroquine, autophagosome accumulation between 0RV HUVECs and untreated 2RV HUVECs was similar, implicating lysosomal dysfunction in the HRG-associated autophagy defect. Compared to 0RV and 2RV HUVECs, HUVECs carrying 1 risk variant copy (1RV) demonstrated intermediate mitochondrial respiration and autophagic flux phenotypes, which were exacerbated with IFNɣ exposure. Taken together, our data reveal that IFNɣ induces APOL1 expression, and that each additional RV associates with mitochondrial dysfunction and autophagy inhibition. IFNɣ amplifies this phenotype even in 1RV HUVECs, representing the first description of APOL1 pathobiology in variant heterozygous cell cultures.

Chronic kidney disease (CKD) and associated risk in rural South Africa: a population-based cohort study.

Background: In Africa, true prevalence of chronic kidney disease (CKD) is unknown, and associated clinical and genetic risk factors remain understudied. This population-based cohort study aimed toinvestigate CKD prevalence and associated risk factors in rural South Africa. Methods: A total 2021 adults aged 20-79 years were recruited between 2017-2018 from the Agincourt Health and Socio-Demographic Surveillance System in Bushbuckridge, Mpumalanga, South Africa. The following were collected: sociodemographic, anthropometric, and clinical data; venous blood samples for creatinine, hepatitis B serology; DNA extraction; spot urine samples for dipstick testing and urine albumin: creatinine ratio (UACR) measurement. Point-of-care screening determined prevalent HIV infection, diabetes, and hypercholesterolemia. DNA was used to test for apolipoprotein L1 ( APOL1) kidney risk variants. Kidney Disease Improving Global Outcomes (KDIGO) criteria were used to diagnose CKD as low eGFR (<60mL/min/1.73m 2) and /or albuminuria (UACR ≥ 3.0mg/mmol) confirmed with follow up screening after at least three months. eGFR was calculated using the CKD-EPI (creatinine) equation 2009 with no ethnicity adjustment. Multivariable logistic regression was used to model CKD risk. Results: The WHO age-adjusted population prevalence of CKD was 6.7% (95% CI 5.4 - 7.9), mostly from persistent albuminuria. In the fully adjusted model, APOL1 high-risk genotypes (OR 2.1; 95% CI 1.3 - 3.4); HIV infection (OR 1.8; 1.1 - 2.8); hypertension (OR 2.8; 95% CI 1.8 - 4.3), and diabetes (OR 4.1; 95% CI 2.0 - 8.4) were risk factors. There was no association with age, sex, level of education, obesity, hypercholesterolemia, or hepatitis B infection. Sensitivity analyses showed that CKD risk factor associations were driven by persistent albuminuria, and not low eGFR. One third of those with CKD did not have any of these risk factors. Conclusions: In rural South Africa, CKD is prevalent, dominated by persistent albuminuria, and associated with APOL1 high-risk genotypes, hypertension, diabetes, and HIV infection.

Apolipoprotein L1 High-Risk Genotypes and Albuminuria in Sub-Saharan African Populations.

Recessive inheritance of African-specific APOL1 kidney risk variants is associated with higher risk of nondiabetic kidney disease, progression to kidney failure, and early-onset albuminuria that precedes eGFR decline. The effect of APOL1 risk variants on kidney disease in continental Africans is understudied. Objectives of this study were to determine APOL1 risk allele prevalence and associations between APOL1 genotypes and kidney disease in West, East, and South Africa. This cross-sectional population-based study in four African countries included 10,769 participants largely aged 40-60 years with sociodemographic and health information, anthropometry data, and blood and urine tests for biomarkers of kidney disease. APOL1 risk alleles were imputed from the H3Africa genotyping array, APOL1 risk allele and genotype frequencies were determined, and genetic associations were assessed for kidney disease. Kidney disease was defined as the presence of eGFR <60 ml/min per 1.73 m2, albuminuria, or a composite end point including eGFR <60 ml/min per 1.73 m2 and/or albuminuria. High G1 allele frequencies occurred in South and West Africa (approximately 7%-13%). G2 allele frequencies were highest in South Africa (15%-24%), followed by West Africa (9%-12%). Associations between APOL1 risk variants and albuminuria were significant for recessive (odds ratio, 1.63; 95% confidence interval, 1.25 to 2.12) and additive (odds ratio, 1.39; 95% confidence interval, 1.09 to 1.76) models. Associations were stronger for APOL1 G1/G1 genotypes versus G0/G0 (odds ratio, 3.87; 95% confidence interval, 2.16 to 6.93) compared with either G2/G2 (odds ratio, 1.65; 95% confidence interval, 1.09 to 2.51) or G1/G2 (odds ratio, 1.24; 95% confidence interval, 0.83 to 1.87). No association between APOL1 risk variants and eGFR <60 ml/min per 1.73 m2 was observed. APOL1 G1 and G2 alleles and high-risk genotype frequencies differed between and within West and South Africa and were almost absent from East Africa. APOL1 risk variants were associated with albuminuria but not eGFR <60 ml/min per 1.73 m2. There may be differential effects of homozygous G1 and G2 genotypes on albuminuria that require further investigation. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_05_16_CJN14321121.mp3.

Clinical and genetic factors are associated with kidney complications in African children with sickle cell anaemia.

Clinical and genetic factors have been reported as influencing the development of sickle cell nephropathy (SCN). However, such data remain limited in the paediatric population. In this cross-sectional study, we enrolled 361 sickle cell disease children from the Democratic Republic of Congo. Participants were genotyped for the beta (β)-globin gene, apolipoprotein L1 (APOL1) risk variants, and haem oxygenase-1 (HMOX1) GT-dinucleotide repeats. As markers of kidney damage, albuminuria, hyperfiltration and decreased estimated glomerular filtration with creatinine (eGFRcr) were measured. An association of independent clinical and genetic factors with these markers of kidney damage were assessed via regression analysis. Genetic sequencing confirmed sickle cell anaemia in 326 participants. Albuminuria, hyperfiltration and decreased eGFRcr were present in 65 (20%), 52 (16%) and 18 (5·5%) patients, respectively. Regression analysis revealed frequent blood transfusions, indirect bilirubin and male gender as clinical predictors of SCN. APOL1 high-risk genotype (G1/G1, G2/G2 and G1/G2) was significantly associated with albuminuria (P = 0·04) and hyperfiltration (P = 0·001). HMOX1 GT-dinucleotide long repeats were significantly associated with lower eGFRcr. The study revealed a high burden of kidney damage among Congolese children and provided evidence of the possible role of APOL1 and HMOX1 in making children more susceptible to kidney complications.

Novel Human Podocyte Cell Model Carrying G2/G2 APOL1 High-Risk Genotype.

Apolipoprotein L1 (APOL1) high-risk genotypes (HRG), G1 and G2, increase the risk of various non-diabetic kidney diseases in the African population. To date, the precise mechanisms by which APOL1 risk variants induce injury on podocytes and other kidney cells remain unclear. Trying to unravel these mechanisms, most studies have used animal or cell models created by gene editing. We developed and characterised conditionally immortalised human podocyte cell lines derived from urine of a donor carrying APOL1 HRG G2/G2. Following induction of APOL1 expression by polyinosinic-polycytidylic acid (poly(I:C)), we assessed functional features of APOL1-induced podocyte dysfunction. As control, APOL1 wild type (G0/G0) podocyte cell line previously generated from a Caucasian donor was used. Upon exposure to poly(I:C), G2/G2 and G0/G0 podocytes upregulated APOL1 expression resulting in podocytes detachment, decreased cells viability and increased apoptosis rate in a genotype-independent manner. Nevertheless, G2/G2 podocyte cell lines exhibited altered features, including upregulation of CD2AP, alteration of cytoskeleton, reduction of autophagic flux and increased permeability in an in vitro model under continuous perfusion. The human APOL1 G2/G2 podocyte cell model is a useful tool for unravelling the mechanisms of APOL1-induced podocyte injury and the cellular functions of APOL1.

POS-745 SCREENING FOR APOL1 RISK VARIANTS IN POTENTIAL LIVING KIDNEY DONORS OF AFRICAN DESCENT IN RESOURCE-LIMITED COUNTRIES: AN INITIAL EXPERIENCE IN ANTIGUA/BARBUDA AND NIGERIA

The detrimental clinical effects of the apolipoprotein L1 (APOL1) high risk genotype on kidney function are well documented. In living donor kidney transplant (LDKT), specifically, donors with APOL1 high risk genotype are associated with significantly worse donor outcomes and graft survival. This has introduced APOL1 screening into the kidney donation process in high income countries with large populations of African descent, such as the United States, with presence of high-risk genotype constituting an absolute contraindication to donation in most cases.

Pathogenesis of coronavirus disease 2019-associated kidney injury.

The current review summarizes the pathologic findings in kidneys from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients who have had autopsies or undergone biopsy, and the pathogenic mechanisms implicated in coronavirus disease 2019 (COVID-19)-associated kidney diseases. Direct infection of the kidney by SARS-CoV-2 is not common, and convincing morphologic evidence of substantive kidney infection by SARS-CoV-2 is lacking. Severe COVID-19-associated acute kidney injury is likely multifactorial and results from the physiologic disturbances and therapies used to treat this illness. COVID-19-associated collapsing glomerulopathy (COVAN) is seen almost exclusively in patients with apolipoprotein L1 high-risk genotypes with no evidence of direct infection of the kidney by SARS-CoV-2. The prevailing evidence does not support substantive or persistent infection of kidneys in COVID-19 and indirect means of tissue injury are favored, although a 'hit and run' model cannot be excluded. COVAN frequently occurs in patients with mild respiratory systems, suggesting that innate and adaptive immune responses to SARS-CoV-2 infection may provide the second hit needed for the development of collapsing glomerulopathy in susceptible individuals.

Podocyte density is reduced in kidney allografts with high-risk APOL1 genotypes at transplantation.

Variants in apolipoprotein L1 (APOL1) gene are associated with nondiabetic kidney diseases in black subjects and reduced kidney transplant graft survival. Living and deceased black kidney donors (n=107) were genotyped for APOL1 variants. To determine whether allografts from high-risk APOL1 donors have reduced podocyte densities contributing to allograft failure, we morphometrically estimated podocyte number, glomerular volume, and podocyte density. We compared allograft loss and eGFR trajectories stratified by APOL1 high-risk and low-risk genotypes. Demographic characteristics were similar in high-risk (n=16) and low-risk (n=91) donors. Podocyte density was significantly lower in high-risk than low-risk donors (108±26 vs 127±40 podocytes/106 um3 , P=.03). Kaplan-Meier graft survival (high-risk 61% vs. low-risk 91%, p-value=0.049) and multivariable Cox models (hazard ratio=2.6; 95% CI, 0.9-7.8) revealed higher graft loss in recipients of APOL1 high-risk allografts over 48months. More rapid eGFR decline was seen in recipients of high-risk APOL1 allografts (P<.001). At 60months, eGFR was 27 vs. 51mL/min/1.73min2 in recipients of APOL1 high-risk vs low-risk kidney allografts, respectively. Kidneys from high-risk APOL1 donors had worse outcomes versus low-risk APOL1 genotypes. Lower podocyte density in kidneys from high-risk APOL1 donors may increase susceptibility to CKD from subsequent stresses in both the recipients and donors.

Apolipoprotein L1 risk genotypes in Ghanaian patients with systemic lupus erythematosus: a prospective cohort study

ObjectiveTwo apolipoprotein L1 (APOL1) risk variants (RV) are enriched in sub-Saharan African populations due to conferred resistance to Trypanosoma brucei. These variants associate with adverse renal outcomes by multiple causes...

Apolipoprotein L1: role in the evaluation of kidney transplant donors.

To summarize the current state of evidence regarding the role of apolipoprotein L1 (APOL1) genotyping in evaluating donors for kidney transplantation. African ancestry is associated with an increased risk of kidney failure following living donation. Moreover, kidney transplants from African ancestry deceased donors have an increased risk of graft failure. Preliminary evidence suggests that APOL1 genotype may mediate at least a portion of this racial variation, with high-risk APOL1 genotypes defined by presence of two renal risk variants (RRVs). A pilot study 136 African ancestry living donors found that those with APOL1 high-risk genotypes had lower baseline kidney function and faster rates of kidney function decline after donation. To date, three retrospective studies identified a two-to-three times greater risk of allograft failure associated with kidneys from donors with high-risk APOL1 genotype. Active research initiatives seek to address unanswered questions, including reproducibility in large national samples, the role of 'second hits' injuries, and impact of recipient genotype, with a goal to build consensus on applications for policy and practice. As evidence evolves, APOL1 genotyping may have applications for organ quality scoring in deceased donor kidney allocation, and for the evaluation and selection of living donor candidates.