APOL1 Nephropathy: From Genetics To Clinical Applications

Abstract

The incidence of many types of severe kidney disease is much higher in blacks than in most other racial groups. Much of this disparity can now be attributed to genetic variants in the apoL1 (apoL1) gene, a gene found only in individuals of recent African ancestry. These variants greatly increase the incidence of hypertension-associated ESKD, FSGS, HIV-associated nephropathy, and other forms of non-diabetic nephropathy. We discuss the population genetics of APOL1 risk variants and the clinical spectrum of APOL1 nephropathy. We then consider clinical issues for practicing nephrologists caring for patients who may have APOL1 nephropathy.

Keywords

APOL1 Nephropathy; Genetics; Clinical Applications; Cistanche benefits.

Introduction

The incidence of many types of severe kidney disease is much higher in blacks than in other races. in 2010, researchers identified genetic variants in the apoL1 gene that largely explain this major health disparity. Over the past decade, researchers have established the underlying population genetics and epidemiology of APOL1. The biological understanding of APOL1 risk variants has progressed at the molecular level. Animal models have recapitulated key aspects of the disease. The current clinical application of APOL1 genotyping has been widely controversial, although there is little consensus among clinicians. Many groups in biotechnology and academia are exploring treatments for APOL1 nephropathy, and we consider APOL1 nephropathy from the clinician's perspective, and how it may change in the near future.

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APOL1 Biology: The Basics

The APOL1 gene is one of the six members of the APOL gene family on human chromosome 22. Remarkably, APOL1 is absent in all non-primate species, present in only a few primate species, and has disappeared from the genome of our closest relative, the chimpanzee. Prior to its discovery as an important kidney disease gene, APOL1 was thought to be a trypanosome-solubilizing factor in human serum, protecting humans, gorillas, baboons, and some Old World monkey species from the common African trypanosome. Two pathogenic APOL1 gene variants emerged in humans in sub-Saharan Africa thousands of years ago, and the frequency of these variants is rapidly increasing in African populations because they enhance protection against lethal subspecies of trypanosomes that cause acute and chronic African sleeping sickness. Because these risk variants emerged after the expansion of populations outside of Africa to other parts of the world, APOL1 renal risk variants have only been observed in individuals with recent African ancestry.

A risk variant called G1 contains two amino acid substitutions (S342G and I384M) near the C-terminus of APOL1 (1,2) (Figure 1). The other risk variant called G2 is a two amino acid deletion (del388N389Y) that occurs in the same functional domain of APOL1 as G1. The non-risk APOL1 allele is referred to as G0, although it includes several sequences with slightly different functional properties. Because a person inherits one copy of the APOL1 gene from each parent, a person has zero, one, or two APOL1 risk alleles. Inheriting two APOL1 risk variants (one on each chromosome) greatly increases the risk of kidney disease, whereas inheriting one APOL1 risk allele results in at most a small increase in risk, which would otherwise not increase, depending on the clinical situation. The fact that APOL1 risk alleles appear to increase the risk of renal disease in a recessive mode of inheritance is surprising considering that most evidence to date suggests that G1 and G2 are gain-of-function variants, meaning that they gain some ability to damage the kidney rather than lose some essential function. It has been reported that one individual without functional APOL1 but with seemingly completely normal kidney function was infected with a trypanosome that normally infects only hosts with impaired immune function.APOL1 is an innate immunity gene involved in pathogen defense and its role in kidney development or essential kidney function is not known. Under certain environmental conditions, APOL1 may be required for kidney health. APOL1 circulates at high levels in the blood, however, experimental data suggest that low levels of APOL1 in tissues may be dramatically increased in an inflammatory environment.

Cistanche extract has been used for centuries in traditional Chinese medicine for its potential health benefits, including its effects on kidney inflammation. Inflammation is a natural response of the body's immune system to injury, infection, or stress. However, chronic inflammation can contribute to the development and progression of kidney disease.

Studies have shown that Cistanche extract has anti-inflammatory properties that may help reduce kidney inflammation. Cistanche extract contains several bioactive compounds, including Echinacoside and Verbascoside, which have been shown to regulate the production of inflammatory cytokines and enzymes.

One study conducted in rats with kidney inflammation found that treatment with Cistanche extract reduced the levels of inflammatory cytokines and improved kidney function. Another study conducted in human kidney cells found that Cistanche extract suppressed the activation of inflammatory signaling pathways.

While these studies suggest that Cistanche extract may help reduce kidney inflammation, more research is needed to confirm these findings and determine the optimal dosages and duration of treatment. In addition, it is important to note that Cistanche extract should not be used as a substitute for medical treatment or advice.

In conclusion, Cistanche extract has potential anti-inflammatory properties that may help reduce kidney inflammation. However, further research is needed to confirm these findings and determine the optimal use of Cistanche extract in the management of kidney disease.

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It is not clear how the biological behavior of APOL1 risk variants G1 and G2 differs from that of G0. A major hypothesis is that APOL1 risk variants may form pores in the kidney cell membrane in a manner very similar to the way APOL1 perforates the organelles of trypanosomes (Figure 2). Other researchers have suggested that risk variant overexpression leads to mitochondrial dysfunction and damage. Surprisingly, however, there is little consensus on the specific molecular mechanisms that lead to APOL1 nephropathy, or even the cell types that are damaged by APOL1. APOL1 nephropathy in the form of high proteinuria suggests that podocytes may be the site of injury and that mouse podocyte-specific APOL1 overexpression does trigger renal dysfunction, whereas tubular cell APOL1 overexpression does not. APOL1 nephropathy with low proteinuria, such as hypertension-associated CKD, may not be primarily podocyte-driven. Experiments on human cells, transgenic mice, zebrafish, yeast, and flies have all been used to understand the biological behavior of APOL1, and the prevailing view is that both the high-risk genotype (two-risk alleles) and increased expression may be required for the development of APOL1 kidney disease. The specific triggers that can increase APOL1 expression are discussed below.

APOL1 Nephropathy: One Gene, Many Diseases across the APOL1 Spectrum

APOL1 risk variants lead to a substantial increase in susceptibility to many different types of kidney disease previously thought to represent different individuals (Figure 3). The ratio of the two risk variants was approximately 7-10 for hypertension-associated ESKD (H-ESKD), 17 for FSGS, and 29-89 for HIV nephropathy. The fact that the same alleles are commonly considered to be overriding risk factors for vascular disease (H-ESKD), podocyte glomerular disease (FSGS), and infectious etiology diseases (HIV-associated nephropathy [ HIVAN]) as overwhelming risk factors, suggests that these diseases are driven by similar or at least overlapping mechanisms. Therefore, it may be more useful to consider these diseases as part of the APOL1 nephropathy spectrum rather than as independent disease states in individuals with high-risk genotypes. APOL1 risk variants are also associated with a high incidence of ESKD in patients with lupus nephritis and a collapsed nephropathy phenotype that complicates diseases such as lupus nephritis and membranous nephropathy. In some rare cases, collapsed glomerulopathy (also known as collapsed FSGS) in individuals with APOL1 high-risk genotypes can be caused by therapeutic IFN administration. High IFN status may be a common link between different types of APOL1 kidney disease that have collapsed features.

The effect of APOL1 risk alleles varies across the age spectrum and is significantly influenced by the background rate of renal disease. For young adults, when the prevalence of kidney disease is typically low, the advantage ratio conferred by APOL1 variants is very large, as seen in FSGS. In the original study linking the APOL1 variant to FSGS, the mean age of the patients was 22 years. In late adulthood, the ratio of APOL1 causing kidney disease was much lower, possibly in part because of the higher background rate of disease, but also because the most susceptible individuals may already have APOL1 kidney disease. This was demonstrated by studies in which inclusion and exclusion criteria considered only those individuals who reached a certain age without CKD, resulting in a lower impact of APOL1 risk variants among participants. An example is the analysis from the Atherosclerosis Risk in Communities Study, which included participants between the ages of 45 and 64 years (excluding those with CKD at baseline), where the ratio of APOL1 risk variants leading to CKD events was only approximately 1.5. Population-based cohort studies that include younger participants, such as the Dallas Heart Study or the CARDIA study, tend to show greater effect sizes for CKD and/or proteinuria. A higher ratio of APOL1 is often observed in clear endpoints (e.g., biopsy-confirmed FSGS/failing kidney disease or ESKD), whereas a lower ratio is typical in continuous variables (e.g., decreased GFR or increased proteinuria) (Figure 1). Larger studies, such as the Million Veterans Project and "All of Us", will refine our knowledge of APOL1 nephropathy across the life spectrum.

APOL1 Risk Variants in Children

Individuals begin in childhood. Although absolute rates are low, APOL1 risk genotypes increase the likelihood of FSGS/nephrotic syndrome. Although apol1-mediated kidney disease in proteinuric black children is diagnosed at an older age than in non-apol1 causes, the disease may be more aggressive, with lower eGFR at diagnosis and greater annual eGFR decline (more than 10% per year in two different cohorts). Similar to adults, proteinuric nephropathy in children carrying HIV and APOL1 high-risk genotypes is greatly increased. Children and young adults with high-risk genotypes and FSGS appear to be more likely to develop ESKD, while there is no evidence that patients with and without APOL1 risk genotypes respond differently to treatment with standard immunosuppressive regimens.

APOL1 risk variants may exert their influence even before childhood. One study found that the fetal APOL1 genotype increased the risk of preeclampsia during pregnancy, while the maternal genotype had no significant effect. In black children with glomerular disease, the rate of preterm birth was more than fourfold increased in patients at high risk for APOL1, further supporting a potential role for APOL1 in the placenta, although APOL1 genotype generally did not have any significant effect on preterm birth in black children without kidney disease.

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Global Burden of APOL1 Nephropathy

The vast majority of reports on the epidemiology of APOL1 have come from the United States. Other studies from Africa have shown that APOL1 nephropathy is common in other populations of African ancestry and that any non-genetic factors contributing to disease ectopics must be geographically widespread. In Africa, APOL1 risk alleles are highly concentrated in West Africa, while they are found less frequently in Eastern and Southern Africa. For example, some populations in Nigeria or Ghana may have a combined risk variant allele frequency of more than 50% (25% for high-risk genotypes), whereas individuals in Ethiopia, Sudan, and Somalia have a very low probability of having two APOL1 risk variants. Thus, an individual from Nigeria and an individual from Ethiopia evaluated in a renal clinic for renal dysfunction have significantly different pretest probabilities of having APOL1 nephropathy, which may influence clinical decision-making and public health policy.

Recent studies of mixed-race black patients on dialysis in Brazil have shown that APOL1 risk alleles are also common in geographically diverse world populations and contribute to the burden of kidney disease in these populations. Because Hispanics typically have some degree of African ancestry, they may have APOL1 high-risk genotypes and be at risk for APOL1 nephropathy. The presence of APOL1 risk variants varies widely across Hispanic populations, with a much higher frequency in Caribbean populations relative to the percentage of African ancestry than in Mexican or Central American populations.

How Common Is APOL1-Associated Kidney Disease?

Approximately 75% of black FSGS patients have a high-risk APOL1 genotype. Among black patients with primary FSGS, they are more likely to have apol1-related disease. Similarly, approximately 50% of black patients with hypertension-attributable ESKD have a high-risk APOL1 genotype. These variants are commonly compared to other renal disease variants with strong effect sizes. If a nephrologist is asking the clinical question "What is the cause of my patient's disease", the answer is determined by APOL1 risk genotype status. This applies not only to Africans or blacks but also to groups with significant African ancestry, such as Hispanics. There is evidence that some FSGS patients who identify themselves as white may have APOL1 renal risk alleles and significant unrecognized recent African ancestry, although more data are needed on how often this occurs. We note that a surprising number of FSGS diagnostic test panels still do not include the APOL1 risk variant, which may lead to underdiagnosis.

The lifetime risk of clinically significant kidney disease in individuals with both APOL1 risk alleles remains uncertain. In the pre-HAART era, approximately 50% of HIV carriers and both risk alleles developed HIVAN. in the general population, approximately 4% of individuals with high-risk genotypes develop FSGS, compared with approximately 0.25% of black individuals with non-high-risk genotypes. Some estimates suggest that the lifetime probability of ESKD in carriers of high-risk genotypes may be as high as 15%, a figure that needs to be improved. Given that CKD and proteinuria significantly increase the risk of death from cardiovascular disease prior to ESKD, we suspect that individuals with APOL1 high-risk genotypes are at least twice as likely to develop clinically significant kidney disease as the 15% estimated for ESKD.

APOL1 risk variants are unusual in being common and robust. APOL1 nephropathy is not a Mendelian disease, but the APOL1 genotype is also more predictive than most genetic variants that cause common complex diseases such as diabetes, hypertension, or chronic kidney disease. This characteristic makes the application of APOL1 genetic testing a challenge without many clear precedents. Below, we describe a series of clinical scenarios and attempt to consider the benefits and drawbacks of applying APOL1 testing to clinical care. Until APOL1-specific therapies are developed, APOL1 testing can help clinicians understand the etiology of a patient's kidney disease, but in most cases, it cannot yet be used to guide treatment (except for potential transplant-related decisions). We would like to emphasize that these examples are based on clinical judgment provided primarily by existing observational data sets and that better data and systematic testing will generally be needed to validate its effectiveness.

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Transplantation: From Mechanism to Clinical Utility

Data from transplantation contribute to the understanding of APOL1 biology. Several studies have shown that APOL1-risk donor kidneys fail at a higher rate than non-risk kidneys, while the recipient APOL1 genotype has not been shown to affect graft survival (Figure 4). These observations are consistent with the notion that renal APOL1, rather than circulating APOL1 produced primarily by the liver, is a key contributor to APOL1 nephropathy. Experimental data from model systems and the lack of correlation between circulating APOL1 levels and renal disease further support the human transplant data that renal, rather than circulating APOL1, is the primary driver of APOL1 nephropathy.

The clinical significance of these data is less straightforward. An ongoing multicenter study, APOLLO, aims to determine the outcomes of APOL1 transplantation in both recipients and donors. In the meantime, many centers have begun to perform APOL1 genetic testing in the transplant setting, and clinical recommendations are often based on the results of these tests.

For donors, reports have shown an increased incidence of post-donation renal failure in high-risk APOL1 genotypes compared to low-risk genotypes. It is unclear to what extent the higher prevalence in these donors reflects the fact that kidney donation is the second attack that triggers APOL1 nephropathy, that loss of renal reserve reveals pre-existing subclinical renal dysfunction, or that donors with high-risk genotypes typically have a higher prevalence of family history of kidney disease at baseline. Some centers are now actively discouraging donation in younger (50-year-old) high-risk genotype carriers. It is also worth considering that the substantial benefit of better outcomes for recipients of living donor kidneys compared with continued dialysis (or even compared with receiving a deceased donor kidney) may in some cases outweigh a certain degree of risk to the donor. At the very least, it seems necessary to give both the donor and the recipient the right to know whether the donor may be at greater risk than would normally be the case.

Although recipient APOL1 status does not appear to have a significant impact on graft survival, data from larger and prospectively designed trials are still pending to solidify this finding. In the meantime, recipients and transplant teams may have to weigh the APOL1 genotype of the graft when deciding to receive a kidney. The use of the donor kidney APOL1 genotype can significantly alter the donor kidney risk index. As more data become available, a more comprehensive understanding of the importance of the APOL1 genotype across a range of donor and recipient genotypes and the causes of primary kidney disease will become clearer.

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David J. Friedman and Martin R. Pollak