#NephMadness 2018: Advancing A Defensible System of Practice for Living Donor Risk Assessment

Krista Lentine, MD

Dr. Lentine is Professor of Medicine at Saint Louis University. She is a clinical scientist whose work is grounded in novel integration of registries and electronic health information to address topics in transplant-related epidemiology, outcomes, and economics. Dr. Lentine participates actively in the development of policy and guidance through the OPTN/UNOS, KDIGO, and other professional societies. Follow her @KristaLentine.

Competitors for the Transplantation Region

Pathogenic DSAs vs The Untransplantables

Kidney Donor Risk vs Virally Infected Kidneys

The Transplantation region boasts an all-star lineup of contenders for the most impactful “hot topics” in the care of transplant candidates, recipients, and living donors.

Leading off with innovations in the assessment and management of immunologic risk, the excellent piece on “Pathogenic DSAs” explores how refined combinations of the latest technologies in modern antibody assays, omics techniques, and individualized treatments may mitigate rejection risk without missing opportunities for acceptable offers.

As described in “Transplanting the Un-transplantables,” improvements in ABO incompatible (ABOi) and HLA incompatible (HLAi) living donor kidney transplantation (LKDT) are notable for enabling transplants for patients with limited options due to sensitization, or those with a willing but biologically incompatible potential donor who cannot find a match through Kidney Paired Donation. Although the risks and costs of incompatible LKDT are higher than for biologically compatible transplant, these options can improve survival when long-term dialysis is the only foreseeable treatment option. Importantly, a brand new study estimates that, compared to costs per Quality Adjusted Life year (QALY) of $72K for dialysis, costs per QALY rise from $42K for compatible LDKT, to $60K for ABOi, to $80K (exceeding that of dialysis) for HLAi procedures. Whether new treatments with IgG endopeptidase will be a “game changer” in eliminating DSA and dramatically reducing the risk of HLAi transplantation is an exciting topic that will surely generate more study and discussion in 2018.

Also warranted is intense interest surrounding use of “Virally Infected Kidneys” to expand the donor pool, especially as the development of direct-acting antiviral agents has revolutionized the management of hepatitis C in patients with comorbid kidney disease. However, one key consideration in translating trials to practice will include whether policies are established to ensure reimbursement for these highly effective but expensive medications after transplant-related infection transmissions.

While enthusiastically cheering for continued attention and support of the 3 prior topics, my “top pick” in this region is “Kidney Donor Risk.” LKDT has been practiced for more than 60 years, during which more than 145,000 healthy persons in the United States have donated a kidney to help a family member, a friend, or even a stranger. LKDT is clearly established as the best treatment option for kidney failure, offering patients the best chance for long-term dialysis-free survival at lowest costs to the healthcare system. However, despite the tremendous benefits to recipients and society, the outcomes and optimal care of donors themselves have been relatively under-studied.

Fortunately, things are changing, including recent landmark developments in living donor risk assessment, policy, and guidance. One key advance is recognition of the critical importance of perspectives of comparison for drawing inferences about donor health outcomes. General population comparisons can have value as one context. However, because donors are carefully evaluated and selected, methodologies to assemble control groups of healthy non-donors who would otherwise meet donor selection criteria have been a breakthrough in facilitating estimates of the attributable risks of donation. Incorporation of a requirement to disclose small but significant donation-attributable risks of kidney failure and gestational hypertension in the Organ Procurement and Transplantation Network (OPTN) policy requirements for living donor Informed Consent in 2017 is a model for adapting policy to new evidence to support the optimal care and informed choice of living donors.

The lack of robust donor outcomes data and inconsistent guidance has underscored a growing need to strengthen the rigor, safety, and defensibility of donor selection. As described in the “Kidney Donor Risk” scouting report, 2017 also marked publication of the first KDIGO Clinical Practice Guideline for the Evaluation and Care of Living Kidney Donors. A central goal of the guideline is to advance a framework for evaluating and selecting donor candidates based on long-term risk for adverse outcomes estimated from simultaneous consideration of demographic and health characteristics rather than a single factor in isolation. The guideline development methodology included partnering with the CKD Prognosis Consortium to conduct a de novo meta-analysis of data on nearly 5 million healthy persons from 7 general population cohorts who are similar to kidney donor candidates to develop a tool for projecting 15-year and lifetime risks of ESRD based on predonation GFR and other baseline demographic and health factors. While critically important in establishing a framework, this work is still only a starting point; ongoing efforts are needed to improve the precision and generalizability of estimates of risk before and after donation, including consideration of additional factors such as genetic and familial traits.

Extending the theme of personalized risk prediction, although interest in apolipoprotein-1 gene (APOL1) renal risk variants (RRV) is not new to NephMadness (see 2015 and 2017), the potential relevance of APOL1 genotyping to the evaluation of living donor candidates is increasingly apparent. Beyond implications of the presence of 2 donor RRVs for increased risk of allograft loss in the recipient, APOL1 genotype may also have critical implications for the long-term health of the living donor. A new cohort study of 136 African American living kidney donors reported that those with APOL1 high-risk genotypes had lower pre-donation kidney function and faster rates of decline in post-donation eGFR; 11% (2/19) subsequently developed ESRD after an average 12 years of follow-up.

Some transplant programs (such as ours at Saint Louis University) test African American living kidney donor candidates for APOL1 RRV, but the practice is controversial and variable across transplant centers. While recommending that APOL1 genotyping may be considered in the living donor candidate evaluation, the 2017 KDIGO guideline identified the need to define the role of APOL1 genotyping in the evaluation of donor candidates with recent African ancestry as a key research priority.

Importantly, 2018 will mark the launch of the National Institutes of Health (NIH)-sponsored collaborative APOL1 Long-term Kidney Transplantation Outcomes (APOLLO) Consortium, charged with prospectively assessing the effects of RRV in the APOL1 on outcomes for kidneys from donors with recent African ancestry, and the impact of APOL1 RRVs on the health of living kidney donors. Enrollment for this truly national, comprehensive study is anticipated to begin in late 2018. The critical importance of accurately assessing risk among African American potential donors is highlighted by new data demonstrating growing disparities in access to LKDT among African American transplant candidates.

To strengthen the informed choice of prospective living donors and the safety, protection, and care of all living donors, robust commitment and collaboration across researchers, clinicians, and policy makers are needed to measure and present risks and benefits, and to support donor candidates in informed decision-making. The more we understand risk, and disclose it transparently, the more we can ensure public trust and advance living donation within a defensible system of practice.

One more exciting advance anticipated in 2018 is the impending launch of the “Living Donor Collective” pilot, a scientific registry designed to prospectively follow donors over their lifetimes. 2018 should be declared “Year of the Living Donor,” but there will certainly be more cutting-edge topics on living donation science, practice, and policy to rival for top titles in future NephMadness tournaments!

– Post written by Krista Lentine. Follow her @KristaLentine.

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

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1 Comment on #NephMadness 2018: Advancing A Defensible System of Practice for Living Donor Risk Assessment

  1. Gregory Hess, MD MBA MSc // March 21, 2018 at 12:54 pm // Reply

    Thanks for a great commentary, particularly on the topic of living donors! Really well written, concise and as always very helpful information. Hopefully new data collection and integration will move keep moving ahead to inform further research in these areas, perhaps via the Accelerator Initiative.

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