The Evolving Role Of Diagnostic Genomics in Kidney Transplantation Ⅲ

Considerations for Particular Groups APOL1 Risk Alleles 

Variants in this gene are more often identified in populations with African genetic ancestry, with at least 30% of African Americans carrying 1 risk allele.84,85 These risk variants have been linked to the increased rates of CKD and KF found in these populations, with the mechanism by which this occurs is unknown.

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Studies have indicated that African Americans with 2 risk variants (G1/G1, G2/G2, or G1/G2) are at 10.5- fold (95% CI 6.0–18.4) greater risk of having focal segmental glomerular sclerosis–associated KF, 7.3-fold (95% CI 5.6–9.5) greater risk of hypertensive KF, and 7.5-fold greater risk of HIV-associated nephropathy (HIVAN) KF, as compared with patients with 1 risk allele.86 APOL1 risk alleles have subsequently been found to be involved in an increased risk of CKD87 and sickle cell kidney disease.88

The effect of high-risk genotypes in kidney transplant recipients is unclear. One study evaluated 119 African Americans and found that 49% carried high-risk APOL1 alleles, with no differences in graft survival at 5 years after adjusting for kidney type.89 Another study evaluated 2 large prospective cohorts and has revealed a strong correlation between the number of recipient risk alleles and death-censored allograft loss, independent of donor APOL1 genotype and recipient ancestry.90 Furthermore, the recipient APOL1 genotype was associated with clinical and subclinical T-cell–mediated rejection of the graft.90

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Another consideration is when the donor carries a high-risk APOL1 genotype. Data have suggested that patients who received a kidney from these donors have worse graft survival outcomes.91,92 These recipients are more likely to develop focal segmental glomerular sclerosis with earlier allograft failure and subsequent KF in the donor.93 In 1 study, 11% of donors with APOL1 high-risk genotypes developed KF (P ¼ 0.02) and more developed CKD stage 3 or higher (P < 0.01) as compared with low-risk genotype donors.84 The APOLLO study will aim to confirm whether the presence of high-risk APOL1 genotypes in deceased donors is associated with death-censored kidney transplant survival primarily, including the association of high-risk donor genotypes on recipient renal function and proteinuria post-transplant, and donor kidney outcomes.94

At present, there is a debate about whether potential donors with African ancestry should undergo genotyping for APOL1 risk alleles. A recent survey of transplant centers in the United States of America indicated that approximately half offer testing to African American donors,95 with some centers’ clinical decisions based on the outcome of these tests.96 In these situations, testing is mostly being used in live donor situations with donors harboring high-risk alleles being excluded. It is estimated that up to 13% of African American donors would be excluded in transplant survival primarily, including the association of high-risk donor genotypes on recipient renal function and proteinuria post-transplant, and donor kidney outcomes.94

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At present, there is a debate about whether potential donors with African ancestry should undergo genotyping for APOL1 risk alleles. A recent survey of transplant centers in the United States of America indicated that approximately half offer testing to African American donors,95 with some centers’ clinical decisions based on the outcome of these tests.96 In these situations, testing is mostly being used in live donor situations with donors harboring high-risk alleles being excluded. It is estimated that up to 13% of African-American donors would be excluded in Table 3. Disease-specific recommendations for genetic testing

Although awaiting ongoing studies and registries such as the APOLLO to clarify the effect of APOL1 risk alleles on clinical outcomes, the recommendation is to consider APOL1 genotyping in the situation of a live donor with African American ancestry and/or a recipient with African American ancestry. The genetic testing provides additional information that can be used to counsel the donor regarding risk of KF later in life, but also the recipient regarding increased risk of graft failure.

CFHR5

CFHR5 mutations have been identified as a cause of monogenic kidney disease and specific forms of heritable C3 glomerulonephritis. Although rare in the general population, CFHR5-related nephropathy is endemic in Greek Cypriot populations and those of Greek Cypriot heritage. One study has identified 91 cases across 16 families,98 with an autosomal dominant inheritance pattern of a heterozygous exon 2 and 3 duplications identifiable on multiplex ligation-dependent probe amplification but not as easily with other sequencing approaches. Patients are usually presented with microscopic hematuria or synpharyngitic hematuria before the age of 30 years, suggesting some degree of phenocopy with IgA nephropathy. Interestingly, males were more likely than females to progress to CKD and KF (80% vs. 20% respectively)98 though CFHR5 is an autosomal gene. In patients with Greek Cypriot heritage, and unknown cause of KF or a glomerulopathy of unclear cause, it would be important to consider CFHR5 gene mutations resulting in C3GN before transplantation. If a variant in this gene was identified, potential live-related donors could be screened for the same variant, especially given the emerging phenotypic variability in affected individuals.

The Need for Guidelines 

There are no uniform guidelines for genetic testing around kidney transplantation, and given renal genetics is an evolving field, this is an area that requires focus and development in the future. Future studies are needed to evaluate the short- and long-term effects of both primary and secondary genetic findings on medical care, treatment decisions, transplantation eligibility, donor eligibility, and graft survival. Studies such as APOLLO will contribute significantly to this space. Further studies are also needed to investigate ethical issues that may arise from genetic testing around transplantation, including the rate of live donation, delays in time to transplantation, and healthcare utilization. All these factors will affect the suggestions for testing around kidney transplantation and recommendations to do so. Some initial general (Table 2) and condition-specific (Table 3) recommendations are suggested.

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Summary

Although the accumulation of knowledge and clinical experience to date in the area of kidney genetics has evolved in the past decades and is now rapidly accelerating, there remain significant opportunities to realize benefits for patients and their families. Kidney transplantation is one such complementary area of practice, with great promise to both increase access to living-related kidney transplantation safely and to inform multidisciplinary care within affected families. There are some challenges to consider with the ever-evolving field of kidney genetics, including an incomplete understanding of how certain gene variants are related to disease (as is the case with the APOL1 gene variants), inequity in access to a kidney genetics service in some parts of the world, and the cost of tests to the patient when funding is not covered. Furthermore, genetic testing may shed light on the primary kidney disease in recipients and help clarify suitable donors but can delay the time to transplant due to the testing process.

REFERENCES

1. Registry A [43rd Report]. Chapter 

1. Incidence of Renal Replacement Therapy for End Stage Kidney Disease; 2020. Accessed May 11, 2022. http://www.anzdata.org.au 

2. Devuyst O, Knoers NV, Remuzzi G, et al. Rare inherited kidney diseases: challenges, opportunities, and perspectives. Lancet. 2014;383:1844–1859. https://doi.org/10.1016/S0140-6736(14) 60659-0 

3. Jha V, Garcia-Garcia G, Iseki K, et al. l. Lancet. 2013;382:260- 272. https://doi.org/10.1016/S0140-6736(13)60687-X 

4. Wuhl E, van Stralen KJ, Wanner C, et al. Renal replacement therapy for rare diseases affecting the kidney: an analysis of

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