COVID-19 and APOL1: Understanding Disease Mechanisms through Clinical Observation

• APOL1
• collapsing glomerulopathy
• transplantation
• COVID-19

The coronavirus disease 2019 (COVID-19) pandemic has exerted a terrible toll on people worldwide. In the United States, minorities have suffered disproportionately. AKI is a common manifestation of COVID-19. One striking presentation of COVID-19–related kidney disease that has been reported in Black patients is AKI with high-grade proteinuria, often with collapsing glomerulopathy on kidney biopsy specimens. Several case reports have documented this constellation of findings in the setting of the high-risk APOL1 genotype, the same genetic variants that predispose Black patients to high rates of several other kinds of nondiabetic kidney disease.^1,2 The report by Shetty et al.³ in this month’s JASN confirms this observation, but also presents important differences that force a questioning of some of our basic assumptions about APOL1 genetics and disease mechanisms.

Shetty et al. document six patients with COVID-19 associated with variable degrees of AKI and proteinuria. Each patient demonstrated either collapsing glomerulopathy or other forms of podocyte injury on kidney biopsy specimens. The investigators then genotyped the APOL1 status in three of these patients. The APOL1 risk alleles are known as G1 and G2, whereas G0 signifies the nonrisk APOL1 allele. In general, two risk alleles (one inherited from each parent) are required for the large increase in risk of APOL1 kidney disease, whereas zero or one risk allele is considered low risk.⁴ About 13% of Black individuals in the United States have the high-risk genotype. Two of the three genotyped patients did harbor the high-risk APOL1 genotype, consistent with other reports. The other genotyped patient was unique and potentially highly informative about APOL1 biology. The patient of special interest is a transplant recipient with a germline APOL1 high-risk genotype, but with a low-risk allograft carrying only one risk allele.

Much of our understanding of APOL1 biology comes through learning from clinical observations in humans.⁵ To understand the importance of Shetty et al.’s findings, several previous observations need to be considered. First, we strongly suspect that APOL1 risk variants are toxic gain-of-function mutations on the basis of a single individual with normal kidney function despite two nonfunctional APOL1 alleles.⁶ Second, we believe innate immune responses to viruses can drive APOL1 kidney disease in patients with APOL1 high-risk genotypes on the basis of a case series of collapsing glomerulopathy caused by therapeutic IFNs.⁷ Perhaps most importantly, we attribute APOL1 kidney disease to the kidney-expressed APOL1 rather than the circulating (serum) form of APOL1 on the basis of elegant studies of transplantation in humans.^8,9 Specifically, risk of graft failure is associated with the kidney graft (donor) APOL1 genotype, but not the recipient’s APOL1 genotype, which pins the blame directly on the APOL1 expressed by kidney cells. The transplant patient in the Shetty et al. case report does not conform to this model. In this unusual case, the kidney graft cells have the low-risk genotype, whereas the host cells have the high-risk genotype, so the development of collapsing glomerulopathy in this allograft suggests that either (1) the circulating, host-derived APOL1 is more important than we thought, or (2) a single APOL1 risk allele may actually be sufficient to confer risk in COVID-19 and possibly other extreme challenges to the innate immune system.

The idea that a single risk allele may behave in a “high-risk” fashion in some situations is not entirely unprecedented. In the disease where APOL1 has its most profound effect, HIV nephropathy, a single G1 risk allele may promote intermediate risk between the high- and low-risk genotypes.¹⁰ In a few other settings, a single G1 risk allele also appears to influence kidney phenotypes.⁵ The transplanted kidney in this latest case report also has a single G1 risk allele, perhaps demonstrating more penetrant behavior than usual in the presence of a strong viral stimulus. Although there is not yet evidence to support the contribution of circulating APOL1 in APOL1 nephropathy, the report by Shetty et al. should probably also make us reconsider whether circulating risk variant APOL1 is always just an innocuous bystander.

In addition to insight into APOL1 biology, this case series is informative about the risk factors and natural history of Black patients presenting with COVID-19–related glomerular injury. Four of the six patients had marked reductions in kidney function before COVID-19 infection (eGFR <60 ml/min per 1.73 m²), suggesting the possibility that some of these individuals were already susceptible to APOL1 kidney disease from other triggers. The patients with more compromised kidney function at baseline had greater kidney deterioration after COVID-19, whereas those with better preserved kidney function at baseline had more impressive recoveries. However, even these recoveries were not entirely to pre–COVID-19 levels after ≥6 weeks of follow-up. In light of this data, one wonders whether common forms of APOL1 kidney disease might similarly result from repetitive, less severe, episodic insults to the glomeruli that never fully resolve and that accrue over time.

COVID-19 infection has presented us with another of the protean manifestations of APOL1 kidney disease in the form of AKI with high-grade proteinuria. Important questions about this disease presentation include the relative importance of inflammatory cytokines versus direct podocyte infection by the virus, the utility of immunosuppression or other therapy in preventing glomerular injury, and the long-term sequelae to the kidney. Also worrisome is the possibility of many new cases of CKD in the near future in patients with the APOL1 high-risk genotype who develop less severe COVID-19 infections with subclinical kidney events. Nephrologists will need to be vigilant and consider previous COVID-19 infection as one of the possible risk factors for CKD in populations with African ancestry.

• Copyright © 2021 by the American Society of Nephrology