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. Author manuscript; available in PMC: 2019 Apr 1.
Published in final edited form as: Curr Opin Pediatr. 2018 Apr;30(2):252–259. doi: 10.1097/MOP.0000000000000603

Genetic risk of APOL1 and kidney disease in children and young adults of African ancestry

Kimberly J Reidy 1, Rebecca Hjorten 1,2, Rulan S Parekh 3
PMCID: PMC6002812  NIHMSID: NIHMS953683  PMID: 29406442

Structured Abstract

Purpose of review

Understanding the genetic risk of APOL1 in children and young adults is important given the lifetime risk of hypertension and kidney disease among children of African descent. We review recent epidemiologic and biologic findings on the effects of APOL1 and kidney disease.

Recent findings

APOL1 in children and young adults is associated with hypertension, albuminuria, and more rapid decline in kidney function and progression to end stage kidney disease, especially among those with glomerular causes of kidney disease, and those affected by sickle cell disease or HIV. There is conflicting data on the APOL1 association with cardiovascular disease in children and young adults. APOL1 functions as part of the innate immune system. Podocyte expression of APOL1 likely contributes to development of kidney disease. In cell culture and model organisms, APOL1 expression disrupts autophagic and ion flux, leads to defects in mitochondrial respiration and induces cell death.

Summary

APOL1 explains almost 70% of the excess risk of kidney disease in those of African descent, and is common in children with glomerular disease. Evolving understanding of the pathogenesis of APOL1 mediated kidney damage may aid in personalized medicine approaches to APOL1 attributable kidney disease.

Keywords: APOL1, genetics, kidney disease, end stage renal disease, focal segmental glomerulosclerosis, children

Introduction

Until 2008, genetic risk of kidney disease was underestimated in association with complex kidney phenotypes unlike Mendelian forms of kidney disease such as focal segmental glomerulosclerosis (FSGS) and IgA nephropathy. With identification of the chromosome 22q12 locus and the gene, APOL1, genetic risk now accounts for 70% of the excess risk for end stage renal disease (ESRD) and FSGS among African Americans1–3. There are 3 single nucleotide polymorphisms (SNPs) in APOL1, that comprise the G1 (terminal exon with two SNPs: rs73885319 and rs609101) and G2 (six base pair deletion: rs71785313) haplotypes. The development of variants in APOL1 are likely due to changes approximately 60,000 years ago for protection against trypanosomal infection (sleeping sickness) on the African continent. Carriers of 2 risk alleles are at high-risk of progression to ESRD in a recessive pattern. Among African Americans in the US, it is estimated that 12–14% carry 2 high-risk alleles, yet less than 15 out of 100 with high risk alleles are predicted to develop ESRD4. Moreover, APOL1 high-risk variants are virtually nonexistent in other ethnicities5.

Unravelling the epidemiology and biology of APOL1 is complex as the gene exists only in humans and higher order primates, penetrance is not 100%, and interaction with the genes and/or environment is necessary to develop kidney disease. In this review, we will highlight the specific studies focused on the epidemiology in children and young adults impacting lifetime risk, and the recent studies on the biology of APOL1 leading to kidney disease.

Epidemiology of APOL1-related kidney disease (Figure 1)

Figure 1.

Figure 1

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Progressive kidney disease

Initial studies of APOL1 were focused on studying progressive kidney disease with case-control studies of extreme phenotypes, which first identified the association of APOL1 with ESRD in those with nondiabetic kidney disease and FSGS2. Population based studies have subsequently demonstrated an association with progressive disease over years leading to end stage renal disease (ESRD). Middle aged African American adults have a 2 times greater risk of progression to ESRD or composite kidney outcomes compared to low-risk carriers or Whites6,7 Risk was worse in those with proteinuria. Thus, APOL1 is definitely considered a “progressor” gene but its role in inciting new kidney disease is less clear.

This has significant implications to children and young adults. In studies of young adults followed over decades, rates of ESRD are very low. Thus, APOL1 may be associated with rapid declines to kidney failure only after decades and also require additional exposures to other factors (“second hits”) predisposing to kidney injury. Early kidney disease, however, manifested by albuminuria defined as greater than ACR > 30 mg/g, has a significantly higher incidence rate among high-risk carriers of APOL1 at 15.6 (95% confidence interval [95% CI], 10.6–22.2) per 1000 person years, compared with 7.8 (6.4–9.4) for low-risk carriers and much lower among Whites at 3.9 (3.1–4.8) in a young adult population followed over 25 years8. Decline in kidney function measured by an estimated glomerular filtration rate (eGFR) using cystatin C demonstrated that after adjustment, high-risk carriers of APOL1 had a 0.45% faster yearly decline in eGFR over 9 years compared with whites, and this decline was significantly steeper after development of albuminuria. In children with glomerular disease, APOL1 high-risk carriers had a 2–4 fold faster rate of glomerular filtration rate decline than low risk children9.

Spectrum of kidney diseases

Among African Americans, APOL1 is associated with increased risk of hypertensive disease, lupus, diabetic and HIV-related kidney disease2,10,11. Risk varies depending on selected population with early or advanced kidney disease, and study design and risk ranges from 2 to as high as 89 times greater odds or relative risk of ESRD. Risk is significantly higher in case-control studies of extreme phenotype such as end stage renal disease vs. healthy controls and is significantly attenuated in the longitudinal studies of the general population. Risk is also consistently highest for those with HIV disease, which reflects a possible association of viral infection, innate immunity, and potentially gene-environment interaction. Among African children with perinatal HIV infection, there is a 3.5 increased odds of chronic kidney disease, about 1 case per 100 person years, which is important to consider in long-term risk as these children age12. With the reduction of perinatal HIV transmission globally, the burden may diminish over time. Sickle cell nephropathy may be impacted by APOL1 risk alleles. In two studies (one of over 400 African adolescents and young adults and another of 152 young adults with African ancestry in France with sickle cell disease)13, APOL1 was associated with albuminuria14 and lower eGFR. The spectrum of involvement further highlights the association with progressive kidney disease (Figure 1).

Focal segmental glomerulosclerosis (FSGS)

In children and young adults with African ancestry, the prevalence of APOL1 risk carriers is similar at 67–78% in those with glomerular disease enrolled in the FSGS trial and also prospective cohorts of Chronic Kidney Disease in Children (CKID) or biopsy proven FSGS (Neptune)9,15. Interestingly, age at presentation of FSGS among APOL1 high-risk carriers is older with a mean age of 12 years, as compared to 5 years for low-risk carriers9. Findings from the FSGS trial revealed that there was no difference in treatment response by APOL1 high-risk carrier status, however, this may have been due to limited power with only 94 children in the trial with available DNA and only 27 carried high-risk APOL1 variants. In kidney biopsies of children and adults, coexpression of APOL1 mRNA levels with a group of intrarenal transcripts associated with increased interstitial fibrosis and tubular atrophy in kidney biopsies, support the role of APOL1 in progressive kidney disease phenotypes16.

Gene and environmental interaction with APOL1

Given the incomplete penetrance of APOL1, environmental and genetic interactions may contribute to development of kidney disease. While often underpowered, the majority of studies have demonstrated modest or little association of gene-gene interactions or environmental modifications. HIV remains one of the most important environmental factors. It is not clear if HIV’s impact is related to viral load or the immune response. A circulated protein, suPAR, also shows that among high-risk carriers with elevated suPAR the decline in kidney function is steeper compared to low-risk carriers; although statistically different, this difference in slopes is not clinically significant17. Also, gene-gene interaction with GSTM-1, a gene related to oxidative stress, has demonstrated that carriage of GSTM-1 null allele in the setting of APOL1 high-risk alleles further increased risk from 2 (APOL1 high risk alone) to 3 fold as compared to GSTM-1 active/APOL1 low risk patients) for development of kidney composite outcomes (ESRD and decreased GFR) among 682 African Americans18. This interaction has not yet been tested in children.

APOL1 associated with cardiovascular disease

Among high-risk carriers of APOL1, incidence of cardiovascular disease is significantly higher compared to low-risk carrier. Cardiovascular events such as coronary disease, stroke, heart failure, peripheral vascular disease, and mortality have been implicated as potentially pleiotropic effects of APOL1. Yet, the findings are inconsistent as the focus has been on various types of cardiovascular disease including atherosclerosis, heart failure, and calcification, which differ in pathogenesis especially in those with underlying kidney disease. In young adults and children, there is risk of hypertension and left ventricular hypertrophy (LVH). In a cross sectional analysis of clinic participants from a single medical system, about 5000 participants had genotyping for APOL1 with replication in an additional 5000 individuals from other centers. Among the 20–39 year old heterozygotes for APOL1, there was a 1.4–1.6 mm Hg higher systolic blood pressure and among homozygotes for APOL1 risk alleles, there was a 2.5–2.9 mm Hg increase in systolic blood pressure. In a prospective cohort of 480 young adults followed over two decades, there was a higher risk of hypertension among African Americans compared to European American children, however, by APOL1 risk status, there was no difference in risk. In the same cohort of young adults, there was also no evidence of subclinical atherosclerosis or left ventricular hypertrophy by APOL1 risk status. In a study of 140 children with underlying chronic kidney disease, there was a borderline association with LVH19 and uncontrolled blood pressure. Dissecting the causal pathway of hypertension and kidney disease among children and young adults is complex. It is not clear if cardiovascular disease is a result of pleiotropic effects of APOL1 or increased cardiovascular events due to underlying kidney disease (Figure 2)20. These associations are further confounded by additional risk factors that accumulate with age such as poor nutrition, obesity and inactivity. Larger studies are need to address genetic screening of children and adolescents and the potential clinical utility in this high-risk African ancestry population.

Figure 2.

Figure 2

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Possible pathways for APOL1 risk alleles leading to the development of hypertension and chronic kidney disease. Reprinted with approval received from Kidney International.20

Implications

In children with hypertensive disease or FSGS, there was a higher proportion of APOL1 risk alleles among those with a family history of ESRD. Highlighting that, irrespective of genetic testing, family history is a potential useful screening test21.

Recent studies have highlighted that recipients of donors with high-risk kidney are at greater risk for graft loss. This is particularly controversial as the absolute risk overtime is low for potential donors, however, the risk to recipients could result in a loss of a kidney 2 times greater risk of kidney allograft failure22. A consortium, APOLLO, funded by the NIDDK will seek to study this question prospectively to study the implications of a kidney transplant with APOL1 high- risk alleles.

There are implications to children and young adults as parents may still want to donate regardless of their own APOL1 risk status. This raises a number of ethical concerns as APOL1 is not routinely screened as risk to the donor and/or the recipient needs to further tested. A study of 3483 young African American adults aged 18–30 years determined the risk scores for transplantation23. It is estimated that the 25 year risk of CKD for an 18 year old with APOL1 high-risk carrier status was significantly increased among women and men with and without baseline clinical characteristics compared to those with low-risk status or White. The absolute risk of CKD was projected to be as high as 6% in women and 11% in men23. Nonetheless, parents may also wish to donate regardless of personal risk as they recognizing that living kidney donation is better for the child. The implications to transplantation are potentially significant since the recipient pool keeps increasing with a diminishing donor pool. Moreover, the competing risk of surviving with end organ kidney disease to reach even wait listing for an organ is a real issue confronting children that may not receive preferential listing after age 18. In pediatric transplantation, the goal is also to provide the best organ for the first transplant as most children with require a second transplant. Until we have further data, it is important to screen all potential donors with a family history before embarking on widespread APOL1 genetic testing.

Potential mechanisms of APOL1 action leading to kidney disease

Recent studies have elucidated mechanisms by which APOL1 functions in both health and disease (Figure 3). APOL1 is among a family of six highly homologous lipoproteins (APOL1-6). APOL1 is the only one that is secreted and exists in a circulating form bound to high density lipoproteins (HDLs). Activation of toll like receptor 3 (TLR3) and cytokines such as interferon gamma and tumor necrosis factor up-regulate APOL1 expression24–27. APOL1 is protective in HIV by blocking HIV-1 transcription and by degradation of HIV-1 Gag via activation of the transcription factor EB (TFEB)28. APOL1 mRNA expression is also increased in skin lesions from patients with self limited (vs. disseminated) leprosy29. These findings are consistent with the concept that the primary function of APOL1 is in innate immunity.

Figure 3. Biologic function of APOL1.

Figure 3

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Left: APOL1 contributes to innate immunity. Secreted APOL1 (depicted in red) circulates in a lipoprotein complex with high density lipoprotein (HDL). The complex is endocytosed by Trypanosoma, whereby APOL1 inserts into membranes and forms pores, leading to lysis of the parasite.

Depicted is APOL1 insertion in lysosomes; APOL1 induced mitochondrial dysfunction may also contribute to trypanosomal death. APOL1 genetic variant G2 overcomes T.b. rhodesiense’s serum resistance factor and G1 protects against symptomatic T.b. gambiense infection.

Right: APOL1 (depicted in red) localization in the kidney is debated, with different studies identifying plasma membrane, endoplasmic reticulum (ER), endosomal and mitochondrial localization. Expression of APOL1 G1 and G2 variants in cell and animal models has been shown to: 1) disrupt autophagic flux, 2) induce mitochondrial respiration defects with ATP depletion, 3) induce K efflux and stress response pathways (p38 kinase/stat 3). Expression of the variants are cytotoxic, and cell death variably induced by apoptosis, necrosis and inflammatory cell death (pyroptosis). An inducible transgenic mouse model expressing the APOL1 gene variants in podocytes exhibited cell death by pyroptosis, with increased IL-1beta expression and caspase 1 mediated activation of IL-1 beta.

The most well understood role for APOL1 in innate immunity is as a circulating defense factor against Trypanosoma species T.b. brucei and T. evansi30–35 Trypanosoma are flagellate parasites transmitted by Tsetse flies that cause African sleeping sickness (trypanosomiasis). T.b. rhodesiense express a serum resistance factor that binds APOL1 and prevents the parasite lysis. T.b. gambiense is also resistant to APOL1 mediated cell lysis, but due to different and not fully understood mechanisms. APOL1 has 3 protein domains: a membrane addressing domain, a pore forming domain and serum resistance associated protein binding domain. APOL1 high-risk haplotypes evolved in the binding domain for the serum resistance factor, and in vitro both lyse T.b. rhodesiense2. The presence of at least one copy of G2 variant results in a 5-fold decreased risk of T.b. rhodesiense infection, however, G1 was not protective among infected participants from endemic regions of sleeping sickness31. Instead having one or two G1 variants was protective against symptomatic T.b. gambiense infection, while having either one or two G2 variants was associated with higher risk of symptomatic T.b. gambiense infections31. These findings suggest that G1 and G2 may have differential functions in protection against infection but carriage of any 2 risk alleles (either G1 and/or G2) increases risk of kidney disease.

The current understanding of the trypanolytic function of APOL1 involves endocytosis of APOL1, with insertion of APOL1 into endosome membranes. Once inside the Trypanosome, the low pH alters APOL1 conformation and induces pore formation. The pore forming domain of APOL1 is homologous to pore forming domains of colicin A (a peptide toxin released by E.Coli) and has a BH3 binding domain. APOL1’s BH3 binding domain contributes to alterations in autophagic cell flux and is required to induce cell death26.

Pore formation in lysosomes and mitochondria results in lysosomal swelling, mitochondrial membrane depolarization and fenestration, and ultimately parasite cell death33. The pore forming domain of APOL1 requires an acidic environment for membrane insertion and trypanolytic activity30,36. In addition, the characteristics of APOL1 pores vary with pH36. Modification of the pore forming domain to overcome pH dependence in recombinant APOL1 improved its trypanolytic activity and may lead to new treatments for trypanosomiasis. Despite the importance of pore formation to APOL1’s innate immune function, the precise contribution of pore formation and subsequent ion transport to APOL1 attributable kidney disease is debated37.

Several lines of evidence suggest that the intracellular form of APOL1 leads to increased risk for kidney disease. First, donor kidneys with APOL1 high-risk genotypes had higher risk of graft failure, while recipients (with circulating APOL1 high risk variants) had no increased risk of graft failure22,38–41. Second, circulating APOL1 levels are not associated with kidney disease42. Furthermore, rare humans with loss of APOL1 function (a functional knockout human) do not develop kidney disease43. Thus, there appears to be a change in APOL1 function that results in kidney pathology.

One of the challenges in understanding mechanisms by which APOL1 contributes to kidney disease is that its subcellular localization is not fully understood, with localization reported in plasma membrane44, endoplasmic reticulum45, endosomes46,47, and mitochondria33. Another major challenge is that APOL1 evolved only in primates, and thus all experimental models of APOL1 rely on expression of exogenous APOL1 variants in model organ systems.

Several mouse models have been generated to examine APOL1 function. Inducible transgenic podocyte expression of APOL1 G0, G1, and G2 variants showed that the highest expressing G1 and G2 transgenic mice developed proteinuria and glomerulosclerosis lesions similar to human disease47. Additionally, it was reversible when induction of the APOL1 expression was removed. This is consistent with a concept that stimuli (such as inflammatory signals of interferons) that increase APOL1 expression may lead to manifestation of disease27. Impaired autophagic flux as well as inflammasome activation and cell death by pyroptosis was induced in transgenic APOL1, suggesting that these pathways may mediate podocyte damage in APOL1 related kidney disease.

Other have developed alternative organ systems and cellular culture approaches to investigate APOL1 function. Expression of the APOL1 G1 and G2 alleles in Drosophila disrupted endocytic trafficking and induced hypertrophy and cell death of the “nephrocyte” (Drosophila analogue to the podocyte)48,49. Two independent groups identified mitochondrial dysfunction in cells overexpressing the APOL1 G1 and G2 constructs45,50,51. APOL1 G1 and G2 expression led to impaired mitochondrial respiration, intracellular ATP depletion and activation of stress kinases (JNK/SAPK and p38). The two studies had conflicting data as to whether alterations of K efflux contributed to, or was caused by, mitochondrial dysfunction. Higher expression is consistently associated with cellular toxicity; but the manner of cell death remains under question, with apoptosis, necrosis, impaired autophagy and pyrophagy- all implicated as mechanisms of cellular death with APOL1 expression.

In addition to the APOL1 mouse model described above, a second mouse model was reported by Bruggeman et al. whereby the APOL1 G0 and G2 variants were constitutively (rather than inducibly) expressed under the control of the nephrin promoter52. The constitutive expression resulted in phenotype during fetal development: pregnant mice in this model unexpectedly manifested a preeclampsia like phenotype, with hypertension, proteinuria and seizures. Further investigation demonstrated that APOL1 expression was present in mice placentas and the mice had elevated soluble Flt1 (VEGFR1), a known circulating factor associated with preeclampsia in humans. In contrast to the inducible model, adult mice exhibited only a mild glomerular phenotype, with podocyte effacement with no evidence of glomerulosclerosis.

Interestingly, the APOL1 transgenic mice had smaller litter sizes and increased fetal and perinatal loss. Children with FSGS who are carriers of APOL1 high-risk alleles with FSGS had a 4.6 fold increase in preterm birth compared to low-risk carriers53. A subsequent study of prematurity did not identify an increased prevalence of APOL1 high risk alleles in mothers or infants in 2 studies of premature infants; however, further study of the impact of APOL1 on birth outcomes is ongoing53.

Conclusion

Risk alleles of the gene, APOL1, confer increased risk of hypertension and early markers of kidney dysfunction in young adults, but the lifetime risk for children is less certain. Ongoing work to understand the clinical implications for genetic screening will be important for children and young adults as risk for progressive kidney disease increases with age. Questions remain about which populations are at greatest risk and what are the additional genetic and environmental exposures need to develop kidney disease. Recent advances in biology highlight the relevance of APOL1 to innate immunity. Podocyte over expression of APOL1 results in human-like disease, and these and other models can provide insight into targetable pathways that contribute to APOL1-attributable disease.

Summary.

  • APOL1 gene variants account for the majority of excess risk of kidney disease in people of African descent.

  • APOL1 gene variants are common in children of African descent with glomerular disease and are associated with faster progression of kidney disease.

  • Gene-gene or environmental “second hits” such as HIV contribute to development of APOL1 attributed kidney disease.

  • Understanding the mechanisms by which APOL1 variants result in kidney disease provides an opportunity to develop new therapeutics and personalized medicine approaches in the future.

Acknowledgments

We would like to thank Soulin Haque of Fordham University to her contributions to the manuscript‥

Financial support and sponsorship

KR received support from National Institutes of Health (NIH) NIDDK R03 DK105242 and catalytic seed grant from the NIH CTSA Grant Number 1 UL1 TR001073. R.H. was supported by NIH T32 DK007110. RSP is supported by funding from the Canada Research Chairs program and also NIDDK-NIH U54.

Footnotes

Conflicts of interest

KR is site PI for a Questcor supported clinical trial with no relevance to the contents of this manuscript. The remaining authors have no conflicts of interest.

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