Partnering to Address a Critical Issue in Transplantation: APOL1

I want to thank Dr. Win Williams once again for his contribution to last month’s blog which highlighted a constructive approach to addressing an obvious disparity in access to organ transplantation. Continuing in this same vein, I have invited AST Past President Ken Newell to blog about a fantastic conference that the AST hosted on the biology and ethics surrounding APOL1 gene variants and organ donation.

As many of you know, there are APOL1 gene variants, principally within the black population, that confer additional risk of chronic kidney disease. This raises the ethical question of whether to test prospective donors for these variants, and whether the presence of such a deleterious genotype should preclude one from donating. This is a particularly difficult question to resolve when one considers that 1) living donation tends to occur within racially similar groups, and 2) blacks in America have an above average rate of end-stage kidney disease.  The upshot of these realities is that measures to protect the black living donor from excess risk could result in disadvantaging other members of this same group who desperately need a kidney. This issue also raises the ethical question of whether someone is truly free to do what one wants with his or her own body, even if doing so results in the incurrence of additional risk.


Kenneth Newell, MD, PhD, AST Past President

The first time I attended an AST Board meeting, I recall Bob Gaston commenting that the AST should be the "go-to" organization for "all things transplant." Fast forwarding to my year as President-Elect, I began to receive emails from members urging the AST to take a position on how high-risk apolipoprotein L1 (APOL1) variants impact transplantation. I was familiar with the issue, having written yet another unfunded grant on the topic a few years earlier: APOL1 risk variants appear to have arisen in African Americans of sub-Saharan descent, perhaps due to the ability of these variants to protect against African sleeping sickness caused by Trypanosoma brucei rhodesiense. While the presence of one of two APOL1 risk variants confers protection, individuals with two copies are at significantly increased risk of ESRD, FSGS, and HIVAN. 

Recent studies have suggested that the presence of two APOL1 risk variants is also a risk factor for decreased graft survival following deceased donor renal transplantation. In addition, some have voiced concerns about the impact of APOL1 risk variants on the long-term health of affected African American living kidney donors. Beyond my typical inertia, my initial failure to act was driven by the sense that some other group or society would be better suited to address this issue. I then recalled Bob's words and decided that the AST should take on this challenge. I found a sympathetic colleague in Anil Chandraker, currently AST President-Elect, who had a long-standing interest in the topic as well as an expertise that I could not match. Together with an organizing committee composed of Jim Allan, Rich Formica, John Gill, Jesse Schold, and Alex Wiseman, we crafted a meeting agenda to help establish guidelines about when to test for APOL1 risk variants and how to use the results.

Understanding that excluding living or deceased donors might exacerbate existing disparities, we created a program to review these disparities in access to transplantation, and to review the literature associating APOL1 risk variants with ESRD in normal individuals and the impact of APOL1 risk variants on transplant outcomes. We also reviewed our current understanding of the long-term consequences of living kidney donation, and considered how APOL1 risk variants might impact long-term health following living kidney donation. For each topic, we invited key opinion leaders to facilitate the discussion. We also recognized that more was likely to be unknown than known. To this end, key leaders from HRSA, NIAID, NIDDK, NIMHD, AOPO, and UNOS were invited to attend to discuss what research was needed to address this knowledge gap and inform future patients. Thomas Dorney, Senior Healthcare Advisor from the Office of Congressman John Lewis (D-GA), provided the group with a federal healthcare public policy and biomedical research funding update.

In December, this group assembled for a day and a half at the offices of Bryan Cave in Washington, DC. At this point, I must offer the society’s sincere appreciation to John Creel, Maria Lopes, and their colleagues at Novartis Pharmaceuticals who kindly volunteered to provide an educational grant to the AST to offset the meeting expenses.

While the process of crafting recommendations is still ongoing, there was broad agreement that the presence of APOL1 risk variants could not be used in isolation for determining the management of either living kidney donors or kidney transplant recipients. Instead, currently available information should be used to educate patients and considered as part of the joint decision making process between patients and their transplant team. A second very positive consequence of this meeting was the ongoing dialogue between the AST, federal agencies, regulatory organizations, and meeting attendees, focusing on designing and funding research studies so future patients and healthcare providers will not face the same unanswered questions and uncertainties they face today. To me, this is another example of how the AST together with our partners can advance the field and improve the health of our patients.

Thank you to those who attended and thoughtfully contributed to this meeting:

Kevin Abbott, MD, MPH, NIDDK
James Alcorn, JD, UNOS
James S. Allan, MD, MBA, AST President, Massachusetts General Hospital
Bill Applegate, AST/Bryan Cave, LLP
James Bowman, MD, HRSA
Anil Chandraker, MD, FRCP, AST President-Elect,  Brigham & Women's Hospital
Shandie Covington, AST
John Creel, Novartis
Thomas Dorney, Sr. Health Policy Advisor, Office of Congressman John Lewis (D-GA)
Elling Eidbo, MBA, AOPO
Michelle Estrella, MD, MHS, Johns Hopkins Hospital
Rich Formica, MD, AST Board, Yale University School of Medicine
Barry Freedman, MD, Wake Forest University School of Medicine
John Gill, MD, MS, AST Board, St. Paul's Hospital, Vancouver BC
Morgan Grams, MD, MHS, Johns Hopkins Hospital
Melissa Greenwald, MD, HRSA
Hassan Ibrahim, MD, MS, University of Minnesota Medical Center
Paul Kimmel, MD, NIDDK
David Klassen, MD, UNOS
Jeffrey Kopp, MD, NIDDK
Maria Lopes, Novartis
Edgar Milford, MD, Harvard Medical School
Kenneth Newell, MD, PhD, AST Immediate Past President, Emory University School of Medicine
Jonah Odim, MD, NIAID
Akinlolu Ojo, MD, MPH, PhD, University of Michigan
Stephen Pastan, MD, Emory University Department of Medicine
Martin Pollak, MD, Beth Israel Deaconess Medical Center
Nishadi Rajapakse, PhD, MHS, NIMHHD
Chris Rorick, MPA, Bryan Cave, LLP
Jesse Schold, PhD, Mstat, MEd, AST Board, Cleveland Clinic Foundation
Emily Wilson, Bryan Cave, LLP
Alex Wiseman, MD, AST Board, University of Colorado - Denver



We need to include this as part of living donor evaluation process for all potential AA living donors. Knowledge of APOL1 will allow physicians to provide appropriate counselling during the evaluation process, and to potentially exclude certain individuals from living kidney donation, whether based on ONLY the knowledge of APOL1 or in addition of other conventional risk factors.

Over the past few years it has become apparent that the presence of two APOL1 risk variants confers an increased risk of renal disease/failure. However, a survey of the directors of AST-certified transplant nephrology fellowship training programs revealed a tremendous variation in if or how APOL1 risk variants were factored into decision making. If one considers APOL1 to be one of a number of risk factors for the development of CKD, it would seem appropriate to discuss this with the prospective donor as one would discuss any identified risk factor. The difficulty in having this conversation is that currently, there is little actual data in living kidney donation to guide recommendations. The challenge to our field is to generate this data with the aims of maximizing patient safety, minimizing existing disparities, and allowing individuals to make truly informed decisions about living kidney donation.

I applaud AST for organizing the conferences as this is an important and timely topic. At this point, it is hard to be dogmatic about how we should use the results until we have more data leading to a better understanding of whether living donation in someone who has the presence of APOL1 risk variants confers a significantly increased risk of worse outcome (either for the donor and/or recipient). And so to that end, I agree with Dorry Segev, who at CEOT this week-end, noted that it will be helpful to obtain the information. I would add that it would be very helpful to have a registry/central repository going forward to maximize what we can learn from the data. As well at this point, given the limits of what we know, but understanding human nature and that the test results could change our decisions about donation and how/what we counsel as well as the potential donor's sense of their own health, it is important to talk to potential recipients about the test, the difficulties regarding interpretation, and whether they truly want to know the information before ordering it as well as after the results are in.

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