A woman donates a kidney to her young son after he is diagnosed with bilateral Wilms tumors and surgeons remove both of his kidneys to eradicate the cancer. The loving gift may extend the child’s life by many decades. However, until recently, little was known about the long-term impact on his mother. Of the more than 21,000 kidney transplantations performed in the United States in 2018, approximately 30%, or about 6400, involved living donors. However, the demand for replacement kidneys is far outpacing the supply: Nearly 500,000 patients with end-stage renal disease currently are on dialysis, and nearly 103,000 individuals are registered on the transplantation waiting list. The chronic organ shortage has required a tricky balance. Living kidney donations produce better outcomes than transplantations from deceased donors, but the goal of saving lives must be weighed against the need to properly inform donors of the risks. “Donors were understudied. There was a perception that they were fine,” says Krista Lentine, MD, PhD, a professor at Saint Louis University School of Medicine and medical director of living kidney donation at the Transplant Center at SSM Health Saint Louis University Hospital in St. Louis, Missouri. Within the past decade, however, multiple studies have challenged that assumption and led to a growing push to determine the true risks of higher blood pressure, cardiovascular disease, end-stage renal disease, pre-eclampsia, and other dangers over time. Living donors are unique because they do not have a disease that is treated by their organ removal and will not directly benefit from it. “So in this context, risk awareness is key,” says Dorry Segev, MD, PhD, professor of surgery and epidemiology at Johns Hopkins University in Baltimore, Maryland. The immediate danger of kidney donation is quite low. Estimates have suggested that donors face odds of 1 in 3000 of dying during the period from hospital admission through surgery recovery. All donors go through screening, and they tend to be healthier than the general population, but the loss of a kidney can come at a cost over the ensuing years and decades. In 2010, Dr. Lentine and her collaborators published what to the best of their knowledge was one of the first studies to conclude that black kidney donors face a significantly higher risk of hypertension, diabetes, and chronic kidney disease compared with their white counterparts.1 A 2014 study by Dr. Segev and colleagues found that kidney donors are at lower risk of end-stage renal disease compared with the general public but at a 6-fold higher risk than similarly screened nondonors.2 Consistent with the findings of the study by Dr. Lentine and colleagues, the study by Dr. Segev and colleagues further demonstrated that black kidney donors have a greater than 3-fold higher risk of end-stage renal disease compared with their white counterparts. Dr. Lentine says the racial disparity may arise from multiple factors. Beyond higher rates of hypertension and diabetes in black adults, some communities have less access to health care and support services. Other studies have suggested that genetic factors can add to the kidney failure risk. For example, 2 variants of the apolipoprotein L1 ( APOL1) gene are especially common in sub-Saharan African populations and individuals of African descent. One copy of either APOL1 variant helps to protect against African sleeping sickness. However, 2 copies dramatically increase the risk of kidney failure. Approximately 13% of African American individuals have the higher-risk genetic profile, putting their estimated lifetime risk of kidney disease at greater than 15% compared with 3.6% for the general population.3 A growing number of transplantation centers are using APOL1 genotyping as part of their evaluation and selection of African American kidney donors. Dr. Lentine says her program advises against donation for anyone with a high-risk genotype, although she concedes that the recommendation is controversial in light of the great need for more African American donors. To better understand the risk in kidney donation from both living and deceased donors, the National Institutes of Health–funded APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) study will begin recruiting patients in 2019. Dr. Lentine, a co-principal investigator for one of the participating consortia, is supplementing the effort with an ancillary collaboration called the Living Donor Extended Time Outcomes (LETO) study. The latter effort, in partnership with the University of California at San Francisco, will enroll individuals who already have donated a kidney in the past, sequence their APOL1 genotype, and assess their long-term risks. What about understanding the attributable risk of donors over time? “I think that for a lot of the science currently on renal health in donors, the questions end on the date of donation,” says Allan Massie, PhD, assistant professor of surgery at Johns Hopkins Medical Institutions. “But for the donor, that’s just the beginning. What does good postdonation health look like? What does poor postdonation health look like?” Finding a good comparison population has been difficult because of the relatively good health of donors who are cleared for the transplantation surgery. “If you ask, ‘What is the risk of kidney donation?’ then that’s to say the risk compared to what?” Dr. Massie says. “How do we know what would happen if you don’t donate?” “There’s an absolute obligation to make sure that donors are as informed as they can be about potential risks. We want them to know what they’re getting into, and it’s imperative that we do this research so that we can give them accurate information.” — Allan Massie, PhD It is important to note that the new collective will feature a built-in comparison population by following all kidney donor candidates, including those who end up not donating for logistical or other reasons. That latter group, Dr. Kasiske says, should provide a useful control group for actual donors, because both groups tend to be considerably healthier than the general population. In addition, the data may help researchers better understand the barriers to donation, especially among minority and underserved communities. Eventually, the collective’s federal registry could provide an invaluable database for researchers investigating wide range of donor-related questions and for efforts to improve their follow-up care. For example, a finding that donors had higher blood pressure than nondonors might alert primary care physicians to the importance of the close monitoring and treatment of hypertension. “So it’s not just knowing the risks for informed consent and the donation decision, but it’s also knowing how to care for people and follow them after donation,” Dr. Kasiske says. To further improve the screening process, in 2016, researchers developed a risk assessment tool that allows transplantation centers and potential donors to create a risk profile based on 10 demographic and health characteristics such as blood pressure and body mass index.4 From the data, the tool computes a 15-year and life-time risk of kidney failure. One important finding was that younger donors face a higher lifetime risk compared with older donors. “It’s completely intuitive just based on the fact that a young person has many more decades of life ahead in which to develop complications and comorbidity and go on to kidney failure,” Dr. Lentine says. Other research has suggested that female kidney donors have an approximately 2-fold increase in the risk of pre-eclampsia during pregnancy. Despite the dangers, multiple experts say determined donors are not easily dissuaded. Nor do many regret the decision afterward. Nevertheless, Dr. Lentine says, researchers have a responsibility to measure the risks, disclose them, and support potential donors in their autonomous decision-making. “You’re not getting that kidney back, so they need to understand what they’re getting into,” she says. Dr. Kasiske and Dr. Massie agree that transplantation centers must balance wanting to donate with understanding the risks. “It’s important to really respect donor autonomy as much as we feel like we can,” Dr. Massie says. “Having said that, there’s an absolute obligation to make sure that donors are as informed as they can be about potential risks. We want them to know what they’re getting into, and it’s imperative that we do this research so that we can give them accurate information.”