Rates of many types of severe kidney disease are much higher in Black individuals than in other ethnic groups. In 2010, investigators discovered genetic variants in the apoL1 gene that explained a surprisingly large fraction of this major health disparity (1,2). Over the last decade, investigators have established the basic population genetics and epidemiology of APOL1 (3,4). Understanding the biology of APOL1 risk variants has been advancing at the molecular level. Animal models have recapitulated key aspects of disease. The current clinical utility of APOL1 genotyping has been widely debated, although little consensus has emerged among clinicians. With therapeutic approaches for APOL1 kidney disease now being explored by many groups in biotechnology and academia, we consider APOL1 nephropathy from the viewpoint of the clinician both today and how it may change in the near future.
APOL1 Biology: The Basics
The APOL1 gene is one of six members of the APOL gene family on human chromosome 22 (5). Remarkably, APOL1 is absent in all nonprimates, is only known to be present in a few primate species, and has disappeared from the genome of our closest relative, the chimpanzee (5,6). Prior to its discovery as an important kidney disease gene, APOL1 was known as the trypanolytic factor of human serum that protects humans, gorillas, baboons, and some Old World monkey species against common African trypanosomes (7–9). Two disease-causing APOL1 genetic variants arose in humans in sub-Saharan Africa several thousand years ago, and the frequency of theses variants rose quickly in African populations because these variants conferred enhanced protection against the virulent subspecies of trypanosomes that cause acute and chronic African sleeping sickness (1,10). Because these risk variants arose after the Out-of-Africa expansion that populated the rest of the world, the APOL1 kidney risk variants have only been observed in individuals with recent African ancestry (10).
One risk variant called G1 contains two amino acid substitutions (S342G and I384M) near the APOL1 C terminus (1,2) (Figure 1). A second risk variant called G2 is a two-amino acid deletion (del388N389Y) that occurs in the same functional domain of APOL1 as G1 (1). The nonrisk APOL1 allele is referred to as G0, although this includes several sequences with somewhat different functional properties (11). Because a person inherits one copy of the APOL1 gene from each parent, a person possesses zero, one, or two APOL1 risk alleles. Inheriting two risk variants of APOL1 (one on each chromosome) greatly increases risk of kidney disease, whereas inheriting one APOL1 risk allele confers, at most, a small increase in risk or else no increase in risk, depending on the clinical scenario. The fact that the APOL1 risk alleles seem to increase the risk of kidney disease following a mostly recessive mode of inheritance is surprising given that most evidence to date suggests that the G1 and G2 are gain-of-function variants, meaning they have acquired some ability to injure the kidneys rather than losing some essential function. One human has been reported to have no functional APOL1 but appears to have totally normal kidney function, identified because he contracted an infection by a trypanosome species that usually only infects immunocompromised hosts (12,13). APOL1 is an innate immunity gene involved in defense against pathogens that does not yet have a known role in kidney development or basic kidney function (3,14–18). It remains possible that APOL1 is required for kidney health in some environmental conditions. APOL1 circulates at high levels in the blood, whereas experimental data suggest that low levels in tissues may increase dramatically in the setting of inflammation (19–22).
How the APOL1 risk variants G1 and G2 differ in their biologic behavior from G0 is not yet clear. One leading hypothesis is that APOL1 risk variants may create pores in kidney cell membranes in much the same way as APOL1 punches holes in trypanosomal organelles (23–27) (Figure 2). Other investigators pose that risk variant overexpression leads to mitochondrial dysfunction and injury (28–30). However, there is surprisingly little consensus about the specific molecular mechanisms that drive APOL1 kidney disease or even what cell types are injured by APOL1. Highly proteinuric forms of APOL1 kidney disease suggest that the podocyte may be the site of injury, and podocyte-specific APOL1 overexpression in mice does initiate kidney dysfunction, whereas tubular cell APOL1 overexpression does not (31). More indolent forms of APOL1 nephropathy with less proteinuria, such as hypertension-associated CKD, may not be predominantly podocyte driven. Experiments in human cells, transgenic mice, zebrafish, yeast, and flies have all been used to understand APOL1 biologic behavior, with the currently prevailing idea being that the high-risk genotype (two risk alleles) and increased expression may both be required for APOL1 kidney disease to occur (32). The specific triggers capable of increasing APOL1 expression are discussed below.
APOL1 Nephropathy: One Gene, Many Diseases across the APOL1 Spectrum
The APOL1 risk variants cause large increases in susceptibility to multiple different types of kidney disease previously thought to represent distinct entities (Figure 3). Two risk variants confer an odds ratio of approximately 7–10 for hypertension-associated ESKD (H-ESKD), approximately 17 for FSGS, and approximately 29–89 for HIV nephropathy (1,33,34). The fact that the same alleles are an overwhelming risk factor for what are generally considered a vascular disease (H-ESKD), a glomerular disease of the podocyte (FSGS), and a disease with an infectious etiology (HIV-associated nephropathy [HIVAN]) suggests that these diseases are driven by similar, or at least overlapping, mechanisms. For this reason, it may be more useful to think of these diseases as part of an APOL1 nephropathy spectrum rather than as separate disease states in individuals with the high-risk genotype. APOL1 risk variants also have been linked to higher rates of ESKD in patients with lupus nephritis and to a collapsing nephropathy phenotype that complicates diseases such as lupus nephritis and membranous nephropathy (35–37). A collapsing glomerulopathy (also referred to as collapsing FSGS) phenotype in individual with the APOL1 high-risk genotype can, in some rare cases, be driven by therapeutic IFN administration (21,38). High IFN states may be a common link between different types of APOL1 kidney diseases that share collapsing features.
The effect of APOL1 risk alleles varies across the age spectrum and is markedly influenced by the background rate of kidney disease. For young adults, when rates of nephropathy are typically low, the odds ratios conferred by APOL1 variants are very large, as seen with FSGS. In the original study connecting APOL1 variants to FSGS, the average age of the patients was 22 (1). In late adulthood, the odds ratios for kidney disease conferred by APOL1 are much lower, likely in part because background rates of disease are higher, but also because the most highly susceptible individuals may have already developed APOL1 kidney disease. This is demonstrated by studies where inclusion and exclusion criteria consider only individuals who have reached a certain age without CKD, leading to lower effects of APOL1 risk variants among participants. An example is an analysis from the Atherosclerosis Risk in Communities study that included participants enrolled between ages 45 and 64 (and excluding those with CKD at baseline) where APOL1 risk variants confer an odds ratio for incident CKD of only approximately 1.5 (39). Population-based cohorts that include younger participants, such as the Dallas Heart Study or the CARDIA study, tend to demonstrate larger effect sizes with regard to CKD and/or proteinuria (40,41). Higher odds ratios for APOL1 tend to be observed with well-defined end points such as biopsy-proven FSGS/collapsing nephropathy or ESKD, whereas lower odds ratios are typical with continuous variables such as reduced GFR or increased proteinuria (Figure 1). Much larger studies, such as the Million Veterans Program and “All of Us,” will refine our knowledge of APOL1 kidney disease across the life spectrum.
APOL1 Risk Variants in Children
The effect of APOL1 on kidney disease rates in Black individuals begins in childhood. Although absolute rates are low, the APOL1 risk genotype increases the likelihood of FSGS/nephrotic syndrome. Although the age of diagnosis of APOL1-mediated kidney disease among proteinuric Black children is older than from non-APOL1 causes, the disease may be more aggressive, with lower eGFR at diagnosis and larger yearly eGFR decline (in excess of 10% per year in two different cohorts) (42). Proteinuric kidney disease in children with HIV and the APOL1 high-risk genotype is greatly increased, similar to adults (43). Children and young adults with the high-risk genotype and FSGS seem more likely to progress to ESKD, whereas there is no evidence that response to treatment with standard immunosuppression regimens differs between those with and without the APOL1 risk genotype (44).
The APOL1 risk variants may exert their influence even before childhood. One study found that fetal APOL1 genotype increased risk of preeclampsia during pregnancy, whereas maternal genotype had no apparent effect. A potential role for APOL1 in the placenta is further supported by the observation that among Black children with glomerular disease, there was a more than four-fold increase rate of preterm birth among APOL1 high-risk patients (42), although APOL1 genotype did not confer any significant effect on preterm birth in general among Black children without kidney disease (45).
Global Burden of APOL1 Nephropathy
The vast majority of reports on APOL1 epidemiology are from the United States. Additional studies from Africa make clear that APOL1 kidney disease is also common in other populations with African ancestry and that any nongenetic factors driving disease penetrance must be geographically widespread (46). In Africa, the APOL1 risk alleles are heavily concentrated in West Africa, and they are found at lower frequencies in eastern and southern Africa (15). For example, some groups within Nigeria or Ghana have combined risk variant allele frequencies that may exceed 50% (with high-risk genotypes of 25%), whereas individuals in Ethiopia, Sudan, and Somalia have very low probability of having two APOL1 risk variants. Thus, an individual from Nigeria and an individual from Ethiopia presenting for evaluation in nephrology clinic for kidney dysfunction have markedly different pretest probabilities of having APOL1 kidney disease, which may affect both clinical decision making and public health policy.
Recent studies of Black patients of mixed ancestry on dialysis in Brazil indicate that APOL1 risk alleles are also common in geographically diverse world populations and contribute to kidney disease burden in those populations (47). Because Hispanic individuals often have some degree of African ancestry, they may have the APOL1 high-risk genotype and be at risk for APOL1 nephropathy. The presence of the APOL1 risk variants varies widely between various Hispanic populations, with considerably higher frequency in Caribbean populations than Mexican or Central American populations, in relative proportion to percentage of African ancestry (48,49). A global survey of APOL1 genotype frequency is available at http://APOL1.org (50).
How Common Is APOL1-Associated Kidney Disease?
A high-risk APOL1 genotype is present in about 75% of Black patients with FSGS (1,33). In Black patients with primary FSGS, it is much more likely than not that they have APOL1-associated disease. Similarly, approximately 50% of Black patients with hypertension-attributable ESKD have a high-risk APOL1 genotype (1). In contrast to other kidney disease variants with strong effect sizes, these variants are common. If a nephrologist is asking the clinical question “what is the cause of my patient’s disease,” the answer is informed by APOL1 risk genotype status. This is true in not just African or Black individuals but also individuals from groups with significant recent African ancestry, such as Hispanics. There is evidence that some patients with FSGS who self-identify as White may have APOL1 kidney risk alleles and significant unrecognized recent African ancestry, although how frequently this occurs will require more data (33). We note that a surprising number of FSGS diagnostic testing panels still do not include APOL1 risk variants, likely leading to underdiagnosis.
The lifetime risk of clinically significant kidney disease for individuals with two APOL1 risk alleles remains uncertain. In the pre-HAART era, approximately 50% of individuals with HIV and two risk alleles developed HIVAN. Approximately 4% of high-risk genotype individuals in the general population will develop FSGS compared with approximately 0.25% of Black individuals with the nonrisk genotype (33). Some estimates pose that the lifetime probability of developing ESKD for carriers of the high-risk genotype may be up to 15%, a number that requires refinement (51). Given that CKD and proteinuria markedly increase the risk of mortality from cardiovascular disease prior to ESKD, we suspect that the probability of clinically significant kidney disease in individuals with the APOL1 high-risk genotype may be at least twice as high as the 15% estimate for ESKD.
APOL1 risk variants are unusual in being both common and powerful (10). APOL1 nephropathy is not a Mendelian disease, but the APOL1 genotype is also much more predictive than most genetic variants that contribute to common complex diseases, such as diabetes, hypertension, or CKD in general. This property makes the application of APOL1 genetic testing a challenge without many clear precedents. Below, we depict a range of clinical scenarios and try to consider the benefits and pitfalls of applying APOL1 testing to clinical care. Prior to the development of APOL1-specific therapies, APOL1 testing may help a clinician understand the etiology of a patient’s kidney disease, but in most situations, it is not yet useful for guiding treatment (with the potential exception of transplantation-related decision making). We would emphasize that these examples are on the basis of clinical judgment informed primarily by existing observational datasets and, in general, will require both better data and systematic testing to validate their utility.
Transplantation: From Mechanism to Clinical Utility
Data from transplantation have been instrumental in understanding APOL1 biology. Multiple studies have demonstrated that APOL1 high-risk donor kidneys fail at higher rates than nonrisk kidneys, whereas the recipient APOL1 genotype has not yet been shown to affect graft survival (52–55) (Figure 4). These observations are consistent with the idea that kidney APOL1, rather than circulating APOL1 produced primarily by the liver (56), is the critical factor in driving APOL1 kidney disease. Experimental data from model systems and lack of correlation between circulating APOL1 levels and kidney disease lend further support to the human transplant data that kidney rather than circulating APOL1 is the principal driver of APOL1 nephropathy (19,57).
The clinical implications of these data are less straightforward. A major ongoing multicenter study, APOLLO, is aimed at defining APOL1 transplantation outcomes for both recipients and donors (58). Meanwhile, APOL1 genetic testing in the transplant setting has been initiated by many centers, and clinical recommendations are often on the basis of these test results.
For donors, reports suggest increased rates of kidney failure after donation associated with the high-risk APOL1 genotype compared with low-risk genotype (59). It remains unclear how much of the higher rates of disease among these donors reflects (1) the kidney donation acting as a second hit that triggers APOL1 kidney disease, (2) the loss of kidney reserve revealing preexisting subclinical kidney dysfunction, or (3) baseline higher rates of disease in high-risk genotype donors who often have family history of kidney disease (59,60). Some centers now actively discourage donation from young (<50 years) carriers of the high-risk genotype (61). It is also worth considering that the large benefit of better outcomes for recipients of a living donor kidney versus continuing dialysis (or even versus receiving a deceased donor kidney) may outweigh some level of risk to the donor in some cases. At the very least, it seems necessary that both donor and recipient should be given the option to know if there could be greater than typical risk to the donor.
Although the recipient APOL1 status does not seem to have a major effect on the graft survival, data from larger and prospectively designed trials are awaited to solidify this finding. In the meantime, recipients and transplant teams may have to weigh the APOL1 genotype of the graft in their decision to accept a kidney. Using donor kidney APOL1 genotype can alter the Kidney Donor Risk Index substantially (62). A more comprehensive understanding of the importance of APOL1 genotype across a range of donor and recipient genotypes and causes of the primary kidney disease will become clearer as more data emerge.
Triggers of APOL1 Kidney Disease: Beyond Susceptibility
Not all individuals with the APOL1 high-risk genotype develop kidney disease. Although there are likely to be some genetic modifiers, data to date suggest that environmental influences may play a larger role (63,64). For a small fraction of cases, such as patients with HIVAN or IFN-associated glomerulopathy, we have some understanding of the triggering environmental factor. In most cases of H-ESKD or FSGS, the precipitating events are not known.
Recent reports have linked APOL1 nephropathy to infections with Parvovirus B19 (65) in native kidneys and with cytomegalovirus and BK virus in the transplant setting (66). Provocative, indirect evidence raises the possibility of a complex relationship between JC viruses, APOL1 genotype, and kidney disease, although the precise nature of this interaction is not yet fully understood (67). Acute glomerulopathy has also been observed with hemophagocytic lymphohistiocytosis, a disease driven by aberrant cytokine production (68). Recently, cases of collapsing glomerulopathy have been reported in the setting of acute SARS-CoV-2 coronavirus infection, a transient high-cytokine state (69,70). One common theme in these uncommon examples is a high-IFN state, consistent with the ability of IFNs to upregulate APOL1 in cells such as podocytes (21,22,71). Supporting this idea, APOL1 nephropathy can be induced in mice carrying a human APOL1 transgene encoding the risk variants by administration with IFN (22).
A relationship between viruses and proteinuria has long been observed in the form of nephrotic syndrome onset or relapses that occur in the wake of viral infections, such as upper respiratory illnesses (72). In general, proteinuric kidney disease in Black patients with or without a decline in GFR during or shortly after a viral illness likely warrants consideration of APOL1 status in generating a differential diagnosis.
CKD and ESKD: When Is It APOL1 Nephropathy?
CKD in Black individuals is often attributed to hypertension when no other risk factors are present. Although the association is clear, the direction of causality is not. The discovery that a large fraction of individuals with hypertension-attributable CKD have the high-risk APOL1 genotype has driven a rethinking of this association. It remains uncertain whether hypertension triggers APOL1-related injury to kidney vasculature or whether hypertension results from injury that starts with aberrant APOL1 behavior in the kidney microvasculature (73). Understanding the direction of causality is especially difficult because elevations of BP are detectable immediately, whereas declines in GFR lag far behind kidney dysfunction. The relatively modest effect of hypertension control on development or progression of APOL1 nephropathy suggests that hypertension may be the consequence rather than cause of CKD in individuals with the high-risk APOL1 genotype (74).
Clinicians are often faced with the scenario where a young Black patient presents with kidney disease, hypertension, and no other risk factors. Black patients may be less likely to undergo biopsy than similarly presenting patients of other ancestries because clinicians may make the assumption that the kidney disease is caused by chronic hypertension. Clinicians may forgo biopsy because they believe it will not change management. We believe that APOL1 genotype may alter this decision-making process. Specifically, a negative APOL1 risk genotype merits consideration of further workup that may include kidney biopsy. More routine APOL1 genotyping in the clinic and clinical studies will help clarify best practices.
The Special Case of Diabetic Kidney Disease
Although APOL1 risk variants increase the risk of several kidney diseases in Black individuals, their relationship to diabetic kidney disease (DKD) remains puzzling. Neither population-based nor case-control studies demonstrate significant effects of APOL1 on DKD prevalence (40,75). However, the risk variants appear to speed the rate of progression in individuals with DKD (74).
Because few individuals with diabetes, kidney dysfunction, and some degree of proteinuria are biopsied, it is not well defined in most cases when a Black patient has DKD versus diabetes and concurrent APOL1 nephropathy. Both diabetes and APOL1 nephropathy are common entities that are likely to occur together (independently) at a statistically meaningful rate. Understanding when a patient has DKD versus APOL1 nephropathy is needed to understand how APOL1 risk variants change the trajectory of diabetic nephropathy. Further complicating these relationships is the presence of obesity that often coexists with diabetes and can itself facilitate glomerular injury, causing both proteinuria and loss of GFR.
The questions raised here have important implications for both understanding of APOL1 biology and clinical care. Investigators studying basic biology of APOL1 nephropathy and DKD pathogenesis would benefit from knowing whether these disease processes injure the kidney through similar mechanisms. For clinicians, making the distinction between DKD versus diabetes plus APOL1 nephropathy may help weigh the risks and benefits of drugs, such as SGLT2 inhibitors, that are proving highly effective for DKD. Clinical investigators will need to formally test management strategies when diabetes and APOL1 risk genotype are both present. Assumptions that Black individuals with diabetes and kidney dysfunction have DKD should not be reflexive, especially in the absence of other complications such as retinopathy or when occurring with only modest elevations of hemoglobin A1c. APOL1 genotyping may help refine this calculation and help clarify the need for biopsy in selected individuals.
Using APOL1 to Improve Hypertension and CKD Regimens
APOL1 genotyping can help make predictions about the kidney function of populations and, perhaps, in some individuals. Its real usefulness will arise when it routinely helps improve management decisions. Until specific therapies become available, an important goal is to understand whether APOL1 nephropathy responds to any current therapies. One recent study suggests that hypertension in Black individuals may respond differently to angiotensin-converting enzyme inhibitors on the basis of APOL1 genotype, with APOL1 high-risk genotype carriers experiencing greater response in BP than noncarriers (76). To date, there is no definitive evidence that the course of APOL1 nephropathy is ameliorated by any particular regimen in either its FSGS or CKD presentations, although the larger datasets that have the power to identify optimal treatments have not yet been fully tapped. Observational data from these large datasets may guide therapy in the near term and inform prospective, randomized studies. Other studies have linked serum biomarkers to clinical progression in APOL1 high-risk carriers, improving clinical outcome prediction and potentially prioritizing patients for clinical trial selection (77).
Therapeutic Approaches to APOL1 Kidney Disease
Developing therapeutic approaches to APOL1 kidney disease has some major challenges. There is no consensus about the mechanism of APOL1 kidney disease. It is unclear which domains within the APOL1 molecule would be most amenable to targeting. Even the cell types to which therapeutic molecules would need to be delivered in different manifestations of APOL1 kidney disease are not yet known. Moreover, apolipoproteins may pose more challenges with respect to pharmacologic therapy than other types of molecules, such as receptors or kinases.
Despite these knowledge gaps, APOL1 kidney disease does have several features that give cause for optimism. APOL1 nephropathy seems to be a special case of a gain-of-function variant in a gene that can inflict damage on kidneys but is not essential for kidney development or baseline function under most environmental conditions. Inhibiting APOL1 activity may, therefore, not pose the same challenges to kidney disease treatment as blocking proteins with activities vital to kidney function, such as sodium transporters or regulators of kidney blood flow and GFR. Because it is known that at least one individual with no functional APOL1 does not have signs of kidney dysfunction, disabling the protein is less likely to induce kidney disease, possibly eliminating the need for careful modulation of APOL1 levels. APOL1 is a genetically validated target for kidney disease, meaning that nature has already demonstrated in humans that perturbing APOL1 activity directly influences kidney outcomes, as opposed to drug targets identified in animal models or cell-based systems. If studies continue to support the idea that inhibiting rather than restoring activity of APOL1 variants is the goal, one can envision intervening at the protein, RNA, or, even someday, DNA level. Although we understand relatively little about APOL1 biology, therapeutic potential is in many ways more straightforward than for diseases such as diabetic nephropathy, with decades of research data but likely much more complexity with respect to pathophysiology and genetic susceptibility as well as substantial clinical heterogeneity between patients. The expanding tool kit for small molecule discovery, nucleic acid therapies, and gene modification are hopeful signs of progress to come. Our community eagerly awaits the day when nephrologists will be able to help their patients with targeted APOL1 therapy.
D. Friedman and M. Pollak are inventors on patents related to APOL1, own equity in Apolo1bio, and receive research funding from and have consulted for Vertex.
D. Friedman and M. Pollak received US Department of Health and Human Services, National Institutes of Health, National Center on Minority Health and Health Disparities grants 014726 and 007092.
1. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR: Association of trypanolytic ApoL1
variants with kidney
disease in African Americans
. Science 329: 841–845, 2010 20647424
2. Tzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, Tarekegn A, Bekele E, Bradman N, Wasser WG, Behar DM, Skorecki K: Missense mutations in the APOL1
gene are highly associated with end stage kidney
disease risk previously attributed to the MYH9 gene. Hum Genet 128: 345–350, 2010 20635188
3. Friedman DJ, Pollak MR: Apolipoprotein L1
disease in African Americans
. Trends Endocrinol Metab 27: 204–215, 2016 26947522
4. Kruzel-Davila E, Wasser WG, Skorecki K: APOL1
nephropathy: A population genetics
and evolutionary medicine detective story. Semin Nephrol 37: 490–507, 2017 29110756
5. Smith EE, Malik HS: The apolipoprotein L family of programmed cell death and immunity genes rapidly evolved in primates at discrete sites of host-pathogen interactions. Genome Res 19: 850–858, 2009 19299565
6. Friedman DJ: A brief history of APOL1
: A gene evolving. Semin Nephrol 37: 508–513, 2017 29110757
7. Vanhamme L, Paturiaux-Hanocq F, Poelvoorde P, Nolan DP, Lins L, Van Den Abbeele J, Pays A, Tebabi P, Van Xong H, Jacquet A, Moguilevsky N, Dieu M, Kane JP, De Baetselier P, Brasseur R, Pays E: Apolipoprotein L-I is the trypanosome lytic factor of human
serum. Nature 422: 83–87, 2003 12621437
8. Pays E, Vanhollebeke B: Human
innate immunity against African trypanosomes. Curr Opin Immunol 21: 493–498, 2009 19559585
9. Molina-Portela MP, Samanovic M, Raper J: Distinct roles of apolipoprotein components within the trypanosome lytic factor complex revealed in a novel transgenic mouse model. J Exp Med 205: 1721–1728, 2008 18606856
10. Friedman DJ, Pollak MR: Genetics
failure and the evolving story of APOL1
. J Clin Invest 121: 3367–3374, 2011 21881214
11. Lannon H, Shah SS, Dias L, Blackler D, Alper SL, Pollak MR, Friedman DJ: Apolipoprotein L1
) risk variant toxicity depends on the haplotype background. Kidney
Int 96: 1303–1307, 2019 31611067
12. Vanhollebeke B, Truc P, Poelvoorde P, Pays A, Joshi PP, Katti R, Jannin JG, Pays E: Human Trypanosoma evansi
infection linked to a lack of apolipoprotein L-I. N Engl J Med 355: 2752–2756, 2006 17192540
13. Johnstone DB, Shegokar V, Nihalani D, Rathore YS, Mallik L, Ashish, Zare V, Ikizler HO, Powar R, Holzman LB: APOL1
null alleles from a rural village in India do not correlate with glomerulosclerosis
. PLoS One 7: e51546, 2012 23300552
14. Taylor HE, Khatua AK, Popik W: The innate immune factor apolipoprotein L1
restricts HIV-1 infection. J Virol 88: 592–603, 2014 24173214
15. Thomson R, Genovese G, Canon C, Kovacsics D, Higgins MK, Carrington M, Winkler CA, Kopp J, Rotimi C, Adeyemo A, Doumatey A, Ayodo G, Alper SL, Pollak MR, Friedman DJ, Raper J: Evolution of the primate trypanolytic factor APOL1
. Proc Natl Acad Sci U S A 111: E2130–E2139, 2014 24808134
16. Kruzel-Davila E, Wasser WG, Aviram S, Skorecki K: APOL1
nephropathy: From gene to mechanisms of kidney
injury. Nephrol Dial Transplant 31: 349–358, 2016 25561578
17. Thomson R, Samanovic M, Raper J: Activity of trypanosome lytic factor: A novel component of innate immunity. Future Microbiol 4: 789–796, 2009 19722834
18. Samanovic M, Molina-Portela MP, Chessler AD, Burleigh BA, Raper J: Trypanosome lytic factor, an antimicrobial high-density lipoprotein, ameliorates Leishmania infection. PLoS Pathog 5: e1000276, 2009 19165337
19. Bruggeman LA, O’Toole JF, Ross MD, Madhavan SM, Smurzynski M, Wu K, Bosch RJ, Gupta S, Pollak MR, Sedor JR, Kalayjian RC: Plasma apolipoprotein L1
levels do not correlate with CKD. J Am Soc Nephrol 25: 634–644, 2014 24231663
20. Weckerle A, Snipes JA, Cheng D, Gebre AK, Reisz JA, Murea M, Shelness GS, Hawkins GA, Furdui CM, Freedman BI, Parks JS, Ma L: Characterization of circulating APOL1 protein
complexes in African Americans
. J Lipid Res 57: 120–130, 2016 26586272
21. Nichols B, Jog P, Lee JH, Blackler D, Wilmot M, D’Agati V, Markowitz G, Kopp JB, Alper SL, Pollak MR, Friedman DJ: Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1
Int 87: 332–342, 2015 25100047
22. Aghajan M, Booten SL, Althage M, Hart CE, Ericsson A, Maxvall I, Ochaba J, Menschik-Lundin A, Hartleib J, Kuntz S, Gattis D, Ahlström C, Watt AT, Engelhardt JA, Monia BP, Magnone MC, Guo S: Antisense oligonucleotide treatment ameliorates IFN-γ-induced proteinuria in APOL1
-transgenic mice. JCI Insight 4: 126124, 2019 31217349
23. Olabisi OA, Zhang JY, VerPlank L, Zahler N, DiBartolo S 3rd, Heneghan JF, Schlöndorff JS, Suh JH, Yan P, Alper SL, Friedman DJ, Pollak MR: APOL1 kidney
disease risk variants cause cytotoxicity by depleting cellular potassium and inducing stress-activated protein kinases. Proc Natl Acad Sci U S A 113: 830–837, 2016 26699492
24. Vanwalleghem G, Fontaine F, Lecordier L, Tebabi P, Klewe K, Nolan DP, Yamaryo-Botté Y, Botté C, Kremer A, Burkard GS, Rassow J, Roditi I, Pérez-Morga D, Pays E: Coupling of lysosomal and mitochondrial membrane permeabilization in trypanolysis by APOL1
. Nat Commun 6: 8078, 2015 26307671
25. Heneghan JF, Vandorpe DH, Shmukler BE, Giovinazzo JA, Raper J, Friedman DJ, Pollak MR, Alper SL: BH3 domain-independent apolipoprotein L1
toxicity rescued by BCL2 prosurvival proteins [published correction appears in Am J Physiol Cell Physiol
309: C856, 2015]. Am J Physiol Cell Physiol 309: C332–C347, 2015 26108665
26. Bruno J, Pozzi N, Oliva J, Edwards JC: Apolipoprotein L1
confers pH-switchable ion permeability to phospholipid vesicles. J Biol Chem 292: 18344–18353, 2017 28918394
27. Thomson R, Finkelstein A: Human
trypanolytic factor APOL1
forms pH-gated cation-selective channels in planar lipid bilayers: Relevance to trypanosome lysis. Proc Natl Acad Sci U S A 112: 2894–2899, 2015 25730870
28. Ma L, Chou JW, Snipes JA, Bharadwaj MS, Craddock AL, Cheng D, Weckerle A, Petrovic S, Hicks PJ, Hemal AK, Hawkins GA, Miller LD, Molina AJ, Langefeld CD, Murea M, Parks JS, Freedman BI: APOL1
renal-risk variants induce mitochondrial dysfunction. J Am Soc Nephrol 28: 1093–1105, 2017 27821631
29. Granado D, Müller D, Krausel V, Kruzel-Davila E, Schuberth C, Eschborn M, Wedlich-Söldner R, Skorecki K, Pavenstädt H, Michgehl U, Weide T: Intracellular APOL1
risk variants cause cytotoxicity accompanied by energy depletion. J Am Soc Nephrol 28: 3227–3238, 2017 28696248
30. Shah SS, Lannon H, Dias L, Zhang JY, Alper SL, Pollak MR, Friedman DJ: APOL1 kidney
risk variants induce cell death via
mitochondrial translocation and opening of the mitochondrial permeability transition pore. J Am Soc Nephrol 30: 2355–2368, 2019 31558683
31. Beckerman P, Bi-Karchin J, Park AS, Qiu C, Dummer PD, Soomro I, Boustany-Kari CM, Pullen SS, Miner JH, Hu CA, Rohacs T, Inoue K, Ishibe S, Saleem MA, Palmer MB, Cuervo AM, Kopp JB, Susztak K: Transgenic expression of human APOL1
risk variants in podocytes induces kidney
disease in mice. Nat Med 23: 429–438, 2017 28218918
32. Friedman DJ, Pollak MR: APOL1
disease: From genetics
to biology. Annu Rev Physiol 82: 323–342, 2020 31710572
33. Kopp JB, Nelson GW, Sampath K, Johnson RC, Genovese G, An P, Friedman D, Briggs W, Dart R, Korbet S, Mokrzycki MH, Kimmel PL, Limou S, Ahuja TS, Berns JS, Fryc J, Simon EE, Smith MC, Trachtman H, Michel DM, Schelling JR, Vlahov D, Pollak M, Winkler CA: APOL1
genetic variants in focal segmental glomerulosclerosis
and HIV-associated nephropathy
. J Am Soc Nephrol 22: 2129–2137, 2011 21997394
34. Kasembeli AN, Duarte R, Ramsay M, Mosiane P, Dickens C, Dix-Peek T, Limou S, Sezgin E, Nelson GW, Fogo AB, Goetsch S, Kopp JB, Winkler CA, Naicker S: APOL1
risk variants are strongly associated with HIV-associated nephropathy
in Black South Africans. J Am Soc Nephrol 26: 2882–2890, 2015 25788523
35. Freedman BI, Langefeld CD, Andringa KK, Croker JA, Williams AH, Garner NE, Birmingham DJ, Hebert LA, Hicks PJ, Segal MS, Edberg JC, Brown EE, Alarcón GS, Costenbader KH, Comeau ME, Criswell LA, Harley JB, James JA, Kamen DL, Lim SS, Merrill JT, Sivils KL, Niewold TB, Patel NM, Petri M, Ramsey-Goldman R, Reveille JD, Salmon JE, Tsao BP, Gibson KL, Byers JR, Vinnikova AK, Lea JP, Julian BA, Kimberly RP; Lupus Nephritis–End‐Stage Renal Disease Consortium: End-stage renal disease in African Americans
with lupus nephritis is associated with APOL1
. Arthritis Rheumatol 66: 390–396, 2014 24504811
36. Larsen CP, Beggs ML, Saeed M, Walker PD: Apolipoprotein L1
risk variants associate with systemic lupus erythematosus-associated collapsing glomerulopathy. J Am Soc Nephrol 24: 722–725, 2013 23520206
37. Larsen CP, Beggs ML, Walker PD, Saeed M, Ambruzs JM, Messias NC: Histopathologic effect of APOL1
risk alleles in PLA2R-associated membranous glomerulopathy. Am J Kidney
Dis 64: 161–163, 2014 24731740
38. Markowitz GS, Nasr SH, Stokes MB, D’Agati VD: Treatment with IFN-alpha, -beta, or -gamma is associated with collapsing focal segmental glomerulosclerosis
. Clin J Am Soc Nephrol 5: 607–615, 2010 20203164
39. Foster MC, Coresh J, Fornage M, Astor BC, Grams M, Franceschini N, Boerwinkle E, Parekh RS, Kao WH: APOL1
variants associate with increased risk of CKD among African Americans
. J Am Soc Nephrol 24: 1484–1491, 2013 23766536
40. Friedman DJ, Kozlitina J, Genovese G, Jog P, Pollak MR: Population
-based risk assessment of APOL1
on renal disease. J Am Soc Nephrol 22: 2098–2105, 2011 21997396
41. Peralta CA, Bibbins-Domingo K, Vittinghoff E, Lin F, Fornage M, Kopp JB, Winkler CA: APOL1
genotype and race differences in incident albuminuria and renal function decline. J Am Soc Nephrol 27: 887–893, 2016 26180129
42. Ng DK, Robertson CC, Woroniecki RP, Limou S, Gillies CE, Reidy KJ, Winkler CA, Hingorani S, Gibson KL, Hjorten R, Sethna CB, Kopp JB, Moxey-Mims M, Furth SL, Warady BA, Kretzler M, Sedor JR, Kaskel FJ, Sampson MG: APOL1
-associated glomerular disease among African-American children: A collaboration of the Chronic Kidney Disease
in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts. Nephrol Dial Transplant 32: 983–990, 2017 27190333
43. Ekulu PM, Nkoy AB, Betukumesu DK, Aloni MN, Makulo JRR, Sumaili EK, Mafuta EM, Elmonem MA, Arcolino FO, Kitetele FN, Lepira FB, van den Heuvel LP, Levtchenko EN: APOL1
risk genotypes are associated with early kidney
damage in children in Sub-Saharan Africa. Kidney
Int Rep 4: 930–938, 2019 31317115
44. Kopp JB, Winkler CA, Zhao X, Radeva MK, Gassman JJ, D’Agati VD, Nast CC, Wei C, Reiser J, Guay-Woodford LM, Pollak MR, Hildebrandt F, Moxey-Mims M, Gipson DS, Trachtman H, Friedman AL, Kaskel FJ; FSGS-CT Study Consortium: Clinical features and histology of apolipoprotein L1
-associated nephropathy in the FSGS clinical trial. J Am Soc Nephrol 26: 1443–1448, 2015 25573908
45. Robertson CC, Gillies CE, Putler RKB, Ng D, Reidy KJ, Crawford B, Sampson MG: An investigation of APOL1
risk genotypes and preterm birth in African American population
cohorts. Nephrol Dial Transplant 32: 2051–2058, 2017 27638911
46. Ulasi II, Tzur S, Wasser WG, Shemer R, Kruzel E, Feigin E, Ijoma CK, Onodugo OD, Okoye JU, Arodiwe EB, Ifebunandu NA, Chukwuka CJ, Onyedum CC, Ijoma UN, Nna E, Onuigbo M, Rosset S, Skorecki K: High population
frequencies of APOL1
risk variants are associated with increased prevalence of non-diabetic chronic kidney disease
in the Igbo people from south-eastern Nigeria. Nephron Clin Pract 123: 123–128, 2013 23860441
47. Riella C, Siemens TA, Wang M, Campos RP, Moraes TP, Riella LV, Friedman DJ, Riella MC, Pollak MR: APOL1
disease in Brazil. Kidney
Int Rep 4: 923–929, 2019 31317114
48. Udler MS, Nadkarni GN, Belbin G, Lotay V, Wyatt C, Gottesman O, Bottinger EP, Kenny EE, Peter I: Effect of genetic African ancestry on eGFR and kidney
disease. J Am Soc Nephrol 26: 1682–1692, 2015 25349204
49. Kramer HJ, Stilp AM, Laurie CC, Reiner AP, Lash J, Daviglus ML, Rosas SE, Ricardo AC, Tayo BO, Flessner MF, Kerr KF, Peralta C, Durazo-Arvizu R, Conomos M, Thornton T, Rotter J, Taylor KD, Cai J, Eckfeldt J, Chen H, Papanicolau G, Franceschini N: African ancestry-specific alleles and kidney
disease risk in Hispanics/Latinos. J Am Soc Nephrol 28: 915–922, 2017 27650483
50. Nadkarni GN, Gignoux CR, Sorokin EP, Daya M, Rahman R, Barnes KC, Wassel CL, Kenny EE: Worldwide frequencies of APOL1
renal risk variants. N Engl J Med 379: 2571–2572, 2018 30586505
51. Reidy KJ, Hjorten R, Parekh RS: Genetic risk of APOL1
disease in children and young adults of African ancestry. Curr Opin Pediatr 30: 252–259, 2018 29406442
52. Freedman BI, Julian BA, Pastan SO, Israni AK, Schladt D, Gautreaux MD, Hauptfeld V, Bray RA, Gebel HM, Kirk AD, Gaston RS, Rogers J, Farney AC, Orlando G, Stratta RJ, Mohan S, Ma L, Langefeld CD, Hicks PJ, Palmer ND, Adams PL, Palanisamy A, Reeves-Daniel AM, Divers J: Apolipoprotein L1
gene variants in deceased organ donors are associated with renal allograft failure. Am J Transplant 15: 1615–1622, 2015 25809272
53. Freedman BI, Pastan SO, Israni AK, Schladt D, Julian BA, Gautreaux MD, Hauptfeld V, Bray RA, Gebel HM, Kirk AD, Gaston RS, Rogers J, Farney AC, Orlando G, Stratta RJ, Mohan S, Ma L, Langefeld CD, Bowden DW, Hicks PJ, Palmer ND, Palanisamy A, Reeves-Daniel AM, Brown WM, Divers J: APOL1
genotype and kidney
transplantation outcomes from deceased African American donors. Transplantation 100: 194–202, 2016 26566060
54. Reeves-Daniel AM, DePalma JA, Bleyer AJ, Rocco MV, Murea M, Adams PL, Langefeld CD, Bowden DW, Hicks PJ, Stratta RJ, Lin JJ, Kiger DF, Gautreaux MD, Divers J, Freedman BI: The APOL1
gene and allograft survival after kidney
transplantation. Am J Transplant 11: 1025–1030, 2011 21486385
55. Lee BT, Kumar V, Williams TA, Abdi R, Bernhardy A, Dyer C, Conte S, Genovese G, Ross MD, Friedman DJ, Gaston R, Milford E, Pollak MR, Chandraker A: The APOL1
genotype of African American kidney
transplant recipients does not impact 5-year allograft survival. Am J Transplant 12: 1924–1928, 2012 22487534
56. Shukha K, Mueller JL, Chung RT, Curry MP, Friedman DJ, Pollak MR, Berg AH: Most ApoL1
is secreted by the liver. J Am Soc Nephrol 28: 1079–1083, 2017 27932478
57. Kozlitina J, Zhou H, Brown PN, Rohm RJ, Pan Y, Ayanoglu G, Du X, Rimmer E, Reilly DF, Roddy TP, Cully DF, Vogt TF, Blom D, Hoek M: Plasma levels of risk-variant APOL1
do not associate with renal disease in a population
-based cohort. J Am Soc Nephrol 27: 3204–3219, 2016 27005919
58. Freedman BI, Moxey-Mims M: The APOL1
transplantation outcomes network-APOLLO. Clin J Am Soc Nephrol 13: 940–942, 2018 29703792
59. Doshi MD, Ortigosa-Goggins M, Garg AX, Li L, Poggio ED, Winkler CA, Kopp JB: APOL1
genotype and renal function of Black living donors. J Am Soc Nephrol 29: 1309–1316, 2018 29339549
60. Locke JE, Sawinski D, Reed RD, Shelton B, MacLennan PA, Kumar V, Mehta S, Mannon RB, Gaston R, Julian BA, Carr JJ, Terry JG, Kilgore M, Massie AB, Segev DL, Lewis CE: Apolipoprotein L1
and chronic kidney disease
risk in young potential living kidney
donors. Ann Surg 267: 1161–1168, 2018 28187045
61. Mena-Gutierrez AM, Reeves-Daniel AM, Jay CL, Freedman BI: Practical considerations for APOL1
genotyping in the living kidney
donor evaluation. Transplantation 104: 27–32, 2020 31449181
62. Julian BA, Gaston RS, Brown WM, Reeves-Daniel AM, Israni AK, Schladt DP, Pastan SO, Mohan S, Freedman BI, Divers J: Effect of replacing race with apolipoprotein L1
genotype in calculation of kidney
donor risk Index. Am J Transplant 17: 1540–1548, 2017 27862962
63. Zhang JY, Wang M, Tian L, Genovese G, Yan P, Wilson JG, Thadhani R, Mottl AK, Appel GB, Bick AG, Sampson MG, Alper SL, Friedman DJ, Pollak MR: UBD
disease risk. Proc Natl Acad Sci U S A 115: 3446–3451, 2018 29531077
64. Langefeld CD, Comeau ME, Ng MCY, Guan M, Dimitrov L, Mudgal P, Spainhour MH, Julian BA, Edberg JC, Croker JA, Divers J, Hicks PJ, Bowden DW, Chan GC, Ma L, Palmer ND, Kimberly RP, Freedman BI: Genome-wide association studies suggest that APOL1
-environment interactions more likely trigger kidney
disease in African Americans
with nondiabetic nephropathy than strong APOL1
-second gene interactions. Kidney
Int 94: 599–607, 2018 29885931
65. Besse W, Mansour S, Jatwani K, Nast CC, Brewster UC: Collapsing glomerulopathy in a young woman with APOL1
risk alleles following acute parvovirus B19 infection: A case report investigation. BMC Nephrol 17: 125, 2016 27600725
66. Chang JH, Husain SA, Santoriello D, Stokes MB, Miles CD, Foster KW, Li Y, Dale LA, Crew RJ, Cohen DJ, Kiryluk K, Gharavi AG, Mohan S: Donor’s APOL1
risk genotype and “second hits” associated with de novo collapsing glomerulopathy in deceased donor kidney
transplant recipients: A report of 5 cases. Am J Kidney
Dis 73: 134–139, 2019 30054024
67. Divers J, Langefeld CD, Lyles DS, Ma L, Freedman BI: Protective association between JC polyoma viruria and kidney
disease. Curr Opin Nephrol Hypertens 28: 65–69, 2019 30320619
68. Chokshi B, D’Agati V, Bizzocchi L, Johnson B, Mendez B, Jim B: Haemophagocytic lymphohistiocytosis with collapsing lupus podocytopathy as an unusual manifestation of systemic lupus erythematosus with APOL1
double-risk alleles. BMJ Case Rep 12: bcr-2018-227860, 2019 30642866
69. Peleg Y, Kudose S, D’Agati V, Siddall E, Ahmad S, Kisselev S, Gharavi A, Canetta P: Acute kidney
injury due to collapsing glomerulopathy following COVID-19 infection. Kidney
Int Rep 5: 940–945, 2020 32346659
70. Larsen CP, Bourne TD, Wilson JD, Saqqa O, Sharshir MA: Collapsing glomerulopathy in a patient with coronavirus disease 2019 (COVID-19). Kidney
Int Rep 5: 935–939, 2020 32292867
71. Skorecki KL, Lee JH, Langefeld CD, Rosset S, Tzur S, Wasser WG, Shemer R, Hawkins GA, Divers J, Parekh RS, Li M, Sampson MG, Kretzler M, Pollak MR, Shah S, Blackler D, Nichols B, Wilmot M, Alper SL, Freedman BI, Friedman DJ: A null variant in the apolipoprotein L3 gene is associated with non-diabetic nephropathy. Nephrol Dial Transplant 33: 323–330, 2018 28339911
72. Wenderfer SE: Viral-associated glomerulopathies in children. Pediatr Nephrol 30: 1929–1938, 2015 25752759
73. Nadkarni GN, Galarneau G, Ellis SB, Nadukuru R, Zhang J, Scott SA, Schurmann C, Li R, Rasmussen-Torvik LJ, Kho AN, Hayes MG, Pacheco JA, Manolio TA, Chisholm RL, Roden DM, Denny JC, Kenny EE, Bottinger EP: Apolipoprotein L1
variants and blood pressure traits in African Americans
. J Am Coll Cardiol 69: 1564–1574, 2017 28335839
74. Parsa A, Kao WH, Xie D, Astor BC, Li M, Hsu CY, Feldman HI, Parekh RS, Kusek JW, Greene TH, Fink JC, Anderson AH, Choi MJ, Wright JT Jr., Lash JP, Freedman BI, Ojo A, Winkler CA, Raj DS, Kopp JB, He J, Jensvold NG, Tao K, Lipkowitz MS, Appel LJ; AASK Study Investigators; CRIC Study Investigators: APOL1
risk variants, race, and progression of chronic kidney disease
. N Engl J Med 369: 2183–2196, 2013 24206458
75. Freedman BI, Limou S, Ma L, Kopp JB: APOL1
-associated nephropathy: A key contributor to racial disparities in CKD. Am J Kidney
Dis 72[Suppl 1]: S8–S16, 2018 30343724
76. Cunningham PN, Wang Z, Grove ML, Cooper-DeHoff RM, Beitelshees AL, Gong Y, Gums JG, Johnson JA, Turner ST, Boerwinkle E, Chapman AB: Hypertensive APOL1
risk allele carriers demonstrate greater blood pressure reduction with angiotensin receptor blockade compared to low risk carriers. PLoS One 14: e0221957, 2019 31532792
77. Nadkarni GN, Chauhan K, Verghese DA, Parikh CR, Do R, Horowitz CR, Bottinger EP, Coca SG: Plasma biomarkers are associated with renal outcomes in individuals with APOL1
risk variants. Kidney
Int 93: 1409–1416, 2018 29685497