The Ethics of Genetic Testing for Kidney Diseases

Abstract

Growing genomic knowledge has provided immense insight into the aetiology and mechanisms of kidney diseases but raises ethical issues that risk the successful implementation of genomic medicine. We highlight such issues in two contexts: the return of individual genetic results from nephrology research and preimplantation genetic diagnosis for heritable kidney diseases.

The growth of genomic research holds great promise for improving the care of patients and families with heritable kidney diseases. However, this type of research and related practices raise considerable ethical dilemmas for families, clinicians and researchers. Insight into these challenges can be gained from consideration of the issues arising from two areas of genomic nephrology: challenges related to the return of individual genetic results (RoR) from nephrology research to research participants and preimplantation genetic diagnosis (PGD) for heritable kidney diseases.

Return of individual genetic results

The question whether to return individual genetic results from research to research participants, and if so which ones, has stirred much debate. However, the growing consensus is that returning actionable findings to research participants is an integral part of participants’ autonomy and personal choice, and importantly, is an underpinning of genomic medicine. For genomic medicine to be successfully implemented there is a need for patients and research participants to learn about their genetic predispositions and act on these findings to mitigate their risks.

Yet, translational efforts face several challenges. The first relates to the ethical and legal requirements of informed consent, which necessitate that research participants are provided with sufficient information about the risks and benefits associated with genetic testing and RoR to enable them to make ‘informed’ decisions about their involvement in these procedures. However, growing evidence indicates that ‘ideal’ consent rarely exists, especially in the context of genetics and RoR ([1]). In our own genetic study of 724 participants enrolled into a preventive genetic screening study with the option to return 74 actionable results, including some related to kidney disease, we found that patients with low genetic literacy tended to have unrealistic expectations about the benefits of genetic results and had low satisfaction with the pre-testing informed consent process (H.M.R, unpublished work). Ensuring that all research participants are well-informed about genetic testing and findings is necessary for them to implement behavioural changes to reduce their genetic risks.

Whether the requirements of informed consent are unrealistic and need to be replaced (for example, by a deliberative governance approach whereby individuals consent to be governed by procedures and practices created by fellow citizens[1]) or whether improving practices in the informed consent process will suffice to assure that research participants’ consents are indeed informed, can be debated. It is likely, however, that the extent to which research participants understand their genetic results hinges on successful communication with relevant experts. Genetic counsellors are best equipped for this role, and we recommend that genetic counsellors are involved in meetings both before and after genetic testing. However, the imbalance between supply and demand, and the costs associated with the hiring of genetic counsellors limits their deployment in research. Moreover, genetic counsellors’ training in communicating genetic information to certain populations, such as adolescents[2], may be limited. In theory, adult and paediatric nephrologists and other clinicians could assume this role. Yet these professionals may have neither the skills nor the knowledge for such genetics-related communications. Although no study to date has explored genetic literacy among nephrologists, a 2010 study of 133 nephrology fellows found that most expressed a lack of confidence in their genetic competency[3]. For genomic efforts in nephrology to be successful, it will be key to develop educational tools to promote genetic literacy among research participants and to comprehensively assess — and address — the needs of clinicians and researchers involved in RoR from research. Such an effort will improve evaluation of trajectories for both genomic medicine and patients’ health.

Issues of equity, health disparities and minority status are also likely to affect translational genomic efforts in nephrology. Research indicates that members of historically marginalized racial or ethnic communities express lower interest in genetic research and RoR owing to concerns such as limited access to health-care services on follow-up[4], distrust of the clinical and/or research community and lack of minority-status identification with the researchers[5]. Our study of people with disabilities (n = 1,294) further found that disability-based minority status may negatively affect interest in RoR from precision medicine research and that similar rationales of social marginalization have a role in these decisions[6]. Removing such barriers that impede equal access to and benefit from the growing body of genomic knowledge is key, as is the urgent need to address sociocultural challenges. Diversifying the workforce of nephrologists and genetic counsellors, which is overwhelmingly white and abled-bodied, increasing the cultural competency among all professionals in nephrology research (including researchers, clinicians, genetic counsellors and study coordinators) and conducting studies to identify measures that can promote trustworthiness of genomic research are first steps in the right direction.

Preimplantation genetic diagnosis

Increasing knowledge of the genetic underpinnings of kidney diseases combined with advances in assisted reproduction technologies has the potential to markedly affect family planning decisions. PGD bypasses the dilemma posited to prospective parents as to whether to abort a fetus shown by prenatal tests to have a genetically -based kidney disease. Using a previously known genetic diagnosis, PGD allows the selection of embryos that do not have a specific variant of concern before they are transferred to the womb. This approach can be appealing, especially when in vitro fertilization (IVF) is already sought as a consequence of parental infertility.

Given the absence of recommendations regarding PGD for kidney diseases, practices are likely to vary considerably. Recommendations to guide the use of PGD for kidney diseases should — in our view — be developed and should consider the following points: whether PGD should be discussed as an option for all individuals with a family history of kidney disease, whether health-care programmes should cover the costs of PGD given the life-long burden and public health implications of kidney diseases, and the threshold at which a PGD is ‘justified’. Although a survey of 96 patients with autosomal dominant polycystic kidney disease (ADPKD) showed overall support for PGD[7], whether such views extend to other heritable kidney diseases, and how the level of severity, curability and projected onset (childhood versus adult) of a condition might impact these views is unknown.

Beyond these regulatory considerations, several practical issues also need to be addressed. First, the need for a genetic diagnosis for PGD raises questions about the accuracy of genetic testing. Although the rate of genetic diagnosis is high among patients with ADPKD (80–90%), it varies widely for other kidney diseases[8]. Genetic testing might yield inconclusive findings or fail to identify complex genetic variants. The low utilization of genetic testing among patients and families with kidney diseases further compounds this challenge. A 2018 study found that most paediatric nephrologists do not refer patients with kidney hypodysplasia for genetic testing, despite the high diagnostic yield of such tests [9].

How to counsel patients interested in PGD and provide sufficient but not overwhelming information about the risks and benefits of this approach also need to be considered. Whether such information can be provided in a neutral form is unclear. Although genetic counsellors are trained to provide non-directive counselling, PGD is a value-laden practice. Views about the worthiness of life with a kidney disease may unintentionally affect the presentation of information and pressure those with familial forms of kidney diseases to undergo PGD. Of note, a study of clinicians found that views about PGD vary by profession, with geneticists being more supportive, and adult and paediatric nephrologists being less supportive of PGD[10]. Although further research into the reason for these views is merited, this finding may relate to the above-mentioned issue of under-utilization of genetic testing.

Finally, concern exists that PGD will further reinforce socioeconomic and racial and/or ethnic stratifications. PGD is an expensive procedure that is often only limitedly covered by national and private health-care programmes. In the USA, the high costs of one IVF and PGD cycle (which is often insufficient to achieve pregnancy) can reach tens of thousands of dollars. This expense leads to a paradoxical outcome: whereas dialysis treatments — which are among the most burdensome and expensive medical procedures — are generally covered by government-funded health insurance programmes, the costs of PGD are not, making this procedure prohibitive to many. This situation is further concerning given the disproportionately high rates of kidney diseases among racial and ethnic minorities, and concurrently, the high poverty levels among such groups. Ensuring equitable access to PGD would better serve the goals of genomic medicine.

For the hopes of genomic medicine in nephrology to materialize, it will be crucial to develop institutional and national policies to ensure inclusive practices so that genetic opportunities such as RoR from nephrology research and PGD for kidney diseases do not exacerbate social injustices.